topics in acute and chronic pancreatitis

Topics in Acute and Chronic Pancreatitis

Editors

L. A. Scuro and A. Dagradi

Co-Editors

G. P. Marzoli, P. Pederzoli, G. Cavallini, and C. Banterle

With 95 Figures and 64 Tables

Springer-Verlag Berlin Heidelberg New York 1981

Proceedings of the International Meeting held in Padenghe suI Garda (Italy), 14-15th September, 1979

Professor Dr. L. A. Scuro Istituto Clinica Medica dell'Universita di Padova Sede in Verona, Policlinico di Borgo Roma 1-37100 Verona (Italy)

Professor Dr. A. Dagradi Istituto Clinica Chirurgica dell'Universita di Padova Sede in Verona, Policlinico di Borgo Roma 1-37100 Verona (Italy)

ISBN-13: 978-3-540- I 0439- I

DOl: 10.1007/978-3-642-67879-0

e-ISBN-l3: 978-3-642-67879-0

Library of Congress Cataloging in Publication Data. Main entry under title: Topics in acute and chronic pancreatitis. Proceedings of the international meeting held in Padenghe sui Garda, Italy, Sept. 14-15, 1979. 1. Pancreatitis-Congresses. I. Scuro, L.A. (Ludovico Antonio), 1924- . II. Degradi, Adamo. [DNLM: 1. Pancreatitis. WI 805 T674] RC858.P35T66 616.3'7 81-5618 AACR2

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Preface

The increasing incidence of both chronic pancreatitis and pancreatic cancer was the primary impetus for the organization of this meeting, an additional factor being the widespread existence of pancreatic disease within Italy itself. It is well known that the treatment of chronic and particularly of acute pancreatitis is still a matter of controversy, and it seemed useful to compare our own experience with that of other centers working in the same field. Consequently, in addition to numerous Italian specialists in the field, doctors from the Federal Republic of Germany, Denmark, Great Britain, France, and Austria were invited to attend the meeting. The symposium lasted two days and comprised eight sessions dealing with the anatomy and physiology of the pancreas and the pathophysiology, diagnosis, and treatment of pancreatic diseases. A central feature of the discussion on the surgical treatment of chronic pancreatitis was the debate between those who favor the use of drainage and those who believe resection to be the best treatment. Finally, I would like to thank Dr. Cavallini and Dr. Pederzoli very much for their help in organizing the meeting and also the local authorities for their aid.

Professor Adamo Dagradi Director of the Institute of Clinica Chirurgica, Verona

Opening Address

I am pleased to welcome all partlclpants and particularly the guests from abroad, to this meeting on the clinical evaluation of pancreatitis. A word about this undertaking, which has two main goals: First, to state how far we have advanced in our knowledge of pancreatitis, from both the pathologic and pathophysiologic points of view, and to debate questions of diagnosis and medical or surgical therapy. Second to compare ideas, views, and information; this also applies to the sessions, which hopefully will be profitable. Over the past years interest in pancreatic disease has been increasing, and no doubt the improvement of diagnostic procedures has enhanced diagnosis, chiefly through radiologic and functional studies of the pancreas. Such interest is also justified both by the actual increase in the incidence of pancreatitis and, even more, of pancreatic cancer, which ranks fourth among neoplasms in several countries, and by the severity of clinical findings and complications of acute and chronic pancreatitis. Since in Italy pancreatitis is mainly related to chronic alcohol abuse, which is a problem at least as big as drug addiction, a continuons effort should be made to reduce alcohol consumption to acceptable levels. Also, all alcoholrelated diseases constitute a heavy social burden from the economic point of view. A deep knowledge of alcohol related diseases and health education programs should help in facing this problem. In summing up, this symposium is meant to make some contribution to the advancement of the study of acute and chronic pancreatitis.

Professor Ludovico A. Scuro Director of the Institute of Clinica Medica, Verona

Table of Contents

Radiographic Study of the Anatomy ofthe Pancreas (Ho An-acker) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1

Elements of Surgical Anatomy of the Pancreas (Go Po Mar-zoli, So Vesentini, and Go Mangiante) 0 0 0 0 0 0 0 0 0 0 0 0 11

Physiologic Control of the External Pancreatic Secretion in Man (Ho W orning) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 23

Pancreatic Malfunction - When, How, Why? (Ko Go Wormsley) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 37

Pancreatic Extracts in Chronic Pancreatitis: Which, How, and When? (Go Dobrilla, Mo Felder, and Go de Pretis) 55

Radiological Approach to Acute and Chronic Pancreatitis (Go Fo Pistolesi, C. Fugazzola, C. Procacci, Fo Frasson, and L. Mazzi) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 63

Diagnostic Algorithm for Pancreatic Disease (Go Fontana, Po L. Costa, A. Vandelli, Go Silvani, Po Maiolo, Mo Melan-dri, and C. Camporesi) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 85

Morphogenesis of Acute Pancreatitis (Mo Wanke) 0 0 0 0 0 93

The Role of Total Parenteral Nutrition in the Treatment of Pancreatic Diseases (Ro Dionigi, Uo Prati, C. Tibaldeschi, and L. Dominioni) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 115

Conservative Surgical Treatment of Acute Necrotic-Haem-orrhagic Pancreatitis (Po Pederzoli) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 125

Pancreatic Abscess (Po Pederzoli, To Pilon, Co Bassi, and Go Po Marzoli) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 133

One-Year Follow-Up to Acute Necrotic-Haemorrhagic Pancreatitis (Go Angelini) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 137

Surgical Treatment of Acute Pancreatitis (A. Fritsch) 0 0 0 143

Surgical Treatment of Acute Pancreatitis (Yo Staudacher, Ro Chiesa, and Vo Di Carlo) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 153

VIII Table of Contents

Morphology of Chronic Pancreatitis (Y. Becker) . . . . .. 161

Indications for Surgical Treatment of Chronic Pancreatitis (I. Vantini and C. Cavallini) ................. 173

Intraoperative Cytodiagnosis in Pancreas Disease (E. Bod-ner) ............................ 183

General Remarks to Chapters 19-21 (F. Gschnitzer) 189

The Pancreas-jejunal shunts (G. P. Marzoli) ..... 191

The Use of Resection in the Treatment of Chronic Pancrea-titis (R. Pichimayr and K. D. Rumpf) . . . . . . . . . . .. 205

Chronic Pancreatitis: Surgical Indications, Procedures and Limitations (A. Dagradi) ................... 223

Long Term Results of Pancreaticoduodenalresection (PDR) in Chronic Pancreatitis (G. Serio) .............. 241

The Endocrine Function of the Pancreatic Residue Mter Partial Duodenopancreatectomy (K. D. Rumpf) ...... 245

Follow-up of Chronic Pancreatitis. Methodological Consid-erations. (G. Bianchi Porro, A. Prada and M. Petrillo) 253

Longterm Evolution of Chronic Pancreatitis: The Italian Experience (L. A. Scuro) .................. .

List of Contributors

Prof. H. Anacker, Direktor des Instituts fUr Rontgendiagnostik am Klinikum rechts der Isar der TU Miinchen, Ismaningerstr. 22, D-8000 Miinchen 80

Dr. G. P. Angelini, Istituto Clinica Medica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Dr. J. Antonschmidt, Klinik fUr Abdominal- und Transplantationschirurgie, Karl-Wiechert-Allee 9, D-3000 Hannover 61

Prof. C. Banterle, Primario Divisione Medicina Intema, Ospedale Zonale, I-Besenzano (Brescia)

Dr. C. Bassi, Istituto Clinica Chirurgica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Prof. V. Becker, Direktor des Pathologischen Instituts der Universitat Erlangen-Niimberg, Krankenhausstr. 8-10, D-8520 Erlangen

Prof. E. Bodner, Vorstand der II. Universitatsklinik fUr Chirurgie, Anichstr. 35, A-6020 Innsbruck

Dr. C. Camporesi, Divisione di Medicina Generale, Ospedale G. B. Morgagni, 1-47100 Forli

Dr. G. Cavallini, Istituto Clinica Medica, Universita di Padova, Sede in Verona, Policlinico B. Rom, 1-37100 Verona

Dr. R. Chiesa, Clinica Chirurgica, Universita di Milano, Policlinico, 1-20100 Milano

Dr. P. L. Costa, Divisione di Medicina Generale, Ospedale G. B. Morgagni, 1-47100 Forli

Prof. A. Dagradi, Direttore di Istituto di Clinica Chirurgica Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Dr. Ch. Datan, Klinik fUr Abdominal- und Transplantationschirurgie, Karl-Wiechert-Allee 9, D-3000 Hannover 61

x List of Contributors

Dr. G. de Pretis, Ospedale Generale Regionale di Bolzano, Divisione di Gastroenterologia, Via Sernesi 1, 1-39100 Bolzano

Dr. V. Di Carlo, Clinica Chirurgica, Universita di Milano, Policlinico, 1-20100 Milano

Prof. R. Dionigi, Istituto di Patologia Chirurgica, Policlinico San Matteo, 1-27100 Pavia

Prof. G. Dobrilla, Ospedale Generale Regionale di Bolzano, Divisione di Gastroenterologia, Via Sernesi 1, 1-39100 Bolzano

Dr. L. Oominioni, Istituto di Patologia Chirurgica, Polic1inico San Matteo, 1-27100 Pavia

Dr. M. Felder, Ospedale Generale Regionale di Bolzano, Divisione di Gastroenterologia, Via Sernesi 1, 1-39100 Bolzano

Prof. G. Fontana, Divisione di Medicina Generale, Ospedale G. B. Morgagni, 1-47100 Forli

Dr. F. Frasson, Istituto Radiologia, Universita di Padova, Sede in Verona, Polic1inico B. Roma, 1-37100 Verona

Prof. A. Fritsch, Vorstand der I. Chirurgischen Universitatsklinik, Allgemeines Krankenhaus der Stadt Wien, Aiserstr. 4, A-1090 Wien IX

Dr. C. Fugazzola, Istituto Radiologia, Universita di Padova, Sede in Verona, Polic1inico B. Roma, 1-37100 Verona

Prof. F. Gschnitzer, Vorstand der I. Universitatsklinik fUr Chirurgie, Allgemeines Krankenhaus, A-6020 Innsbruck

Dr. P. Maiolo, Divisione di Medicina Generale, Ospedale G. B. Morgagni, 1-47100 Forli

Dr. G. Mangiante, Istituto di Clinica Chirurgica, Universita di Padova, Sede in Verona, Polic1inico B. Roma, 1-37100 Verona

Dr. L. Mazzi, Istituto Radiologia, Universita di Padova, Sede in Verona, Polic1inico B. Roma, 1-37100 Verona

Prof. G. P. Marzoli, Istituto di Clinica Chirurgica, Universita di Padova, Sede in Verona, Polic1inico B. Roma, 1-37100 Verona

Prof. H.-J. Mitzkat, Arbeitsgruppe Oiabetologie, Medizinische Poliklinik der Medizinischen Hochschule Hannover, 0-3000 Hannover 61

Dr. M. Melandri, Divisione di Medicina Generale, Ospedale G. B. Morgagni, 1-47100 Forli

Dr. P. Pederzoli, Istituto Clinica Chirurgica, Universita di Padova, Sede in Verona Polic1inico B. Roma, 1-37100 Verona

List of Contributors XI

Dr. M. Petrillo, Servizio di Gastroenterologia, Ospedale L. Sacco, Via G. B. Grassi 74,1-20157 Milano

Prof. R. Pichlmayr, Klinik fur Abdominal- und Transplantationschirurgie, Karl-Wiechert-Allee 9, D-3000 Hannover 61

Dr. T. Pilon, Istituto Clinica Chirurgica. Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Prof. G. F. Pistolesi, Direttore Istituto Radiologia, Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Dr. G. Bianchi Porro, Servizio di Gastroenterologia, Ospedale L. Sacco, Via G. B. Grassi 74, 1-20157 Milano

Dr. A. Prada, Servizio di Gastroenterologia, Ospedale L. Sacco, Via G. B. Grassi 74, 1-20157 Milano

Dr. U. Prati, Istituto di Patologia Chirurgica, Policlinico San Matteo, 1-27100 Pavia.

Dr. C. Procacci Istituto Radiologia, Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

PD Dr. K.-D. Rumpf, Klinik fUr Abdominal- und Transplantationschirurgie, Karl-Wiechert-Allee 9, D-30oo Hannover 61

Prof. L. A. Scuro, Direttore Istituto Clinica Medica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Prof. G. Serio, Istituto Clinica Chirurgica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Dr. G. Silvani, Divisione di Medicina Generale, Ospedale G. B. Morgagni, 1-47100 Forli

Prof. V. Staudacher, Direttore Clinica Chirurgica, Universita di Milano, Policlinico, 1-20100 Milano

Dr. C. Tibaldeschi, Istituto di Patologia Chirurgica, Policlinico San Matteo, 1-27100 Pavia

Dr. A. Vandelli, Divisione di Medicina Generale, Ospedale G. B. Morgagni, 1-47100 Forli

Dr. I. Vantini, Clinica Medica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Dr. S. Vesentini, Istituto di Clinica Chirurgica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 1-37100 Verona

Prof. M. Wanke, Chefarzt des Pathologischen Instituts, Stadtkrankenhaus Rendsburg, Akademisches Lehrkrankenhaus der UniversiHit Kiel, Lilienstrasse, D-2370 Rendsburg

XII List of Contributors

Prof. K. G. Wormsley, Department of Therapeutics, University of Dundee, Ninewells Hospital, GB-Dundee DDZ IUB

Prof. H. Woming, Medical Department, Glostrup Hospital, DK-2600 Glostrup

Dr. R. Zick, Klinik flir Abdominal- und Transplantationschirurgie, Karl-Wiechert-Allee 9, D-3000 Hannover 61

Radiographic Study of the Anatomy of the Pancreas

H. Anacker

Institut flir Radiologische Diagnostik, Klinikum rechts der Isar, Technische Universitat Mtinchen, Ismaninger StraBe 22, 8000 Mtinchen 80, Federal Republic of Germany

The radiographic study of the anatomy of the pancreas aims at establishing (a) the topographic relations of the pancreas with regard to neighboring organs and (b) the normal values of the organ, taken as a whole, as well as its individual structures; which are data necessary for the various methods of analysis. The radiographic examinations currently most important in the diagnostics of the pancreas are gastroduodenal radiography, computerized tomography, angiography, and endoscopic retrograde cholangiopancreatography (ERCP). The pancreas is situated dorsally with regard to the stomach. The head of the pancreas is surrounded by the loop of the duodenum, the duodenojejunal flexure caudally touches the caudal edge of the body of the pancreas, and the tail ends at the lower margin of the hilus of the spleen (Fig. 1). To ascertain a process involv-

Fig. 1. Semidiagrammatic anatomic section of the body at the level of the head of the pancreas. The head of the pancreas is in dorsal position with regard to the stomach, and medial with regard to the descending duodenal loop and duodenojejunal flexure

2 H. Anacker

vertebra thickness %

16

11

X XXX X X 39

)()O(

20

X 3 X 11

40 50 60 70 80 90 kg

Fig.2. Extension of the pancreatic loculus (retrogastric space) in 100 persons with healthy pancreas, in relation to body weight, measured in vertebra thicknesses

ing the pancreas it is important during upper gastrointestinal examination to determine the normal size of the retrogastric space by means of lateral radioscopy. In 100 persons tested, the normal size of the pancreatic loculus (retroperitoneal space) corresponds to one diameter (a-p) of the body ofa lumbar vertebra in 39% of the cases, and to one-half diameter in 20% of the subjects (Fig. 2). It is enlarged in the presence of obesity, high stature, following surgery, and in the case of ascites. For these reasons, enlargement of the retrogastric space on its own does not mean with certainty that the organ is enlarged. More important is the circumscribed impression of the posterior wall of the stomach and of the duodenum. However, the image of the posterior gastric wall with enlargement of the retrogastric space can be furnished not only by invasive processes of the pancreas itself, but also by aortic aneurysms and isolated enlargement of caudate lobe of the liver; these may therefore be taken to be an invasive process of the pancreas. In 100 persons, all with healthy pancreas, the normal length of the head of the pancreas along the vertical diameter, indicated by the width of the duodenal loop, was found to be equal to twice the height of the body of a lumbar vertebra in 58% of the cases, and to two and a half times this height in 26% of the cases, with a normal range of oscillation from one (1%) to three (5%) times the height of the body of a lumbar vertebra. Any dilatation of the duodenal loop exceeding these values should be considered pathologic or at least due to an invasive process, especially in association with a circumscribed or universal image of the duodenal wall.

Computerized tomography (CT) reveals the pancreas directly as a complete organ in its size and extent, and with a homogeneous density of + 35 up to + 60 HE. Several individual tomograms are necessary to understand this organ as a whole. In 60% of the cases, if the patient takes as deep a breath as possible, the tail of the pancreas is localized to the same height as the body, and this makes it possible to

Radiographic Study of the Anatomy of the Pancreas 3

Fig.3. Computerized tomogram of the head of the pancreas. To the right of the head of the pancreas, duodenum filled with contrast medium, to the left, superior mesenteric artery and vein, and, in a dorsal position, the inferior vena cava and left adrenal gland. To the left, in a dorsal position, the aorta surrounded by the crura of the diaphragm

reduce the number of tomographic sections. The superior mesenteric artery, limiting the head of the pancreas to the left, · and the descending duodenum full of contrast medium, limiting the head of the pancreas to the right, are important reference points for CT (Fig. 3). The body and the tail of the pancreas appear in the cranial sections. They are found in the ventral-convex position, curved ventrally to the aorta, with respect to the hilus of the spleen (Fig. 4). According to Haaga, the thickness of the head of the pancreas along the a.p. diameter, is one-half to two-thirds the transverse diameter of the relative vertebral body, while the thickness of the body and tail of the pancreas ranges from one-third to two-thirds of the transverse diameter. However, these values afford just a reference for possible pathologic enlargement; greater certainty in ascertaining a pathologic enlargement is given only by further pathologic findings. The values may be considerably lower than those considered "normal" in slim and cachectic patients. An accentuated margin of the external outline is a normal variation. A less dense band between the pancreas and the splenic vein does not correspond to an enlargement of the duct of the pancreas but to normal retropancreatic adipose tissue (Fig. 4). The normal pancreatic duct is invisible in the computerized tomogram. Sometimes it is possible to identify in a computerized tomogram of excellent technical quality a thin line ventrally to the left kidney which corresponds to the anterior renal fascia (Gerota). Knowledge of this is important, since exudate may collect in this site in the case of acute pancreatitis.

4 H. Anacker

Fig. 4. Body and tail of the pancreas in central-convex position in front of the aorta and turned towards the hilus of the spleen. A hypodense band between the tail of the pancreas and splenic vein, corresponds to normal fatty layer and not to a dilatation of the pancreatic duct

vordere und l ihintere ! i Kopfarkade , , :1 , , " " : : i '----'--" 'A"_ .. __ ~

dorsal

Zone II

A. gastrica sin. --.

, , , , , , , , ' '- -----A. p. longi! infer ior __ .1

Fig. 5. Arterial vascularization of the pancreas according to Hentschel


The practice and evaluation of angiography of the pancreas require perfect knowledge of the arterial vascularization of the various sectors of the pancreas (Fig. 5). The head of the pancreas is supplied with blood by both the gastroduodenal artery and the superior mesenteric artery through the anterior and posterior pancreatic arch. The body and tail of the pancreas are supplied by the splenic artery through the pancreatic branches and the dorsal pancreatic artery. Arteriography of the whole pancreas can be effected through the celiac artery, or arteriography may be superselective as representation of the individual sectors of the pancreas. The head of the pancreas is visualized by means of super-selective angiography of the gastroduodenal artery and of the inferior pancreaticoduodenal artery (Fig. 6). The best images of head, body, and tail of the pancreas can generally be obtained with super-selective catheterization of the dorsal pancreatic artery (Fig. 7). The dorsal pancreatic artery originates most frequently from the splenic artery, celiac artery, or hepatic artery, and less frequently from the superior mesenteric artery or directly from the aorta. Visualization of the large arteries surrounding the pancreas should be called an indirect examination of this organ, since its alterations indicate only processes causing enlargement of the pancreas or invading, as in the case of tumors. This means that the tumor is inoperable. Only changes of the intrapancreatic arteries affords the certainty that the process

Fig. 6. Super-selective catheterization of the inferior pancreaticoduodenal artery from the superior mesenteric artery. Clear visualization of all the pancreatic arches and of the gastroduodenal artery

6 H. Anacker

Fig. 7. Super-selective catheterization of the pancreaticodorsal artery from the celiac artery. Good visualization of all the intrapancreatic arteries

occurs within the pancreas. On the one hand, this signifies a secure diagnosis and, on the other, the possibility of early diagnosis of a carcinoma. Visualization of the splenic vein or portal vein is equally important for ascertaining inoperability of a carcinoma. This is achieved as the venous stage of celiacography and mesentericography, to be performed together, or as direct percutaneous splenography.

1 = D. Wirsungianus 2 = D. Santorini 3 = Ramus capitis inf. (sup.) 4 = Ramus corporis sup. (inf.) 5 = Ramus caudae sup. (inf.) 6 = Rami superiores (inf.) 7 = Ductuli 8 = Canaliculi

1 ° = Ductus 2° = Ramus 3° = Ductulus 4° = Canaliculus

Fig. 8. The pancreatic duct system


Knowledge of technical and anatomic realities is indispensable for exact evaluation of a pancreaticogram. The pancreatic duct branches according to the magistral principle (Fig. 8); this means that numerous small secondary canals branch from a main duct, and only some of these are of sufficiently large caliber and continue to branch. Retrograde pancreaticograms do not always reveal the secondary canals, since injection of the contrast medium under pressure is inadvisable in view of the resulting complications. The lumen of the main duct remains almost the same in the head and the body and tapers only in the terminal part of the tail. The course of the main duct and of the secondary ducts is rectilinear, the outlines are smooth (Fig. 9). The lumen of the main duct (Wirsung's duct) is 2-3 mm in 77% of the cases. It enlarges with the passage of the years (Fig. 10) and the outlines of the main and the secondary ducts become irregular. This senile physiologic picture is indistinguishable from the modifications due to mild chronic pancreatitis. Slight stenosis of the lumen is fairly frequently seen at the junctions between the embryonic dorsal and ventral part of the pancreas in the region of the isthmus. It is pathologically significant only in cases of more severe stenosis. Finding ectasia of the duct is still not a pathologic diagnosis like chronic pancreatitis; it should be associated with irregular course and margins of the main duct and the secondary ducts. After catheterization of the major duodenal papilla, contrast-opacification of the duct system occurs only in the head of the pancreas (pancreas divisum) in 4% of the cases (Fig. 11). This result should not be interpreted pathologically, for instance, as obstruction of the duct due to carcinoma.

Fig. 9. A normal endoscopic retrograde pancreaticogram

8 H. Anacker

mm %

6

5

X 4 12

X X XX X 7 )0( X

3 20 X X X X X X XXX 26

XXX 2 31

X

X

20 30 40 50 60 70 76 years

Fig. 10. The width of Wirsung's duct in different age groups (n, 100). The lumen of the main pancreatic duct becomes wider with increasing age

Fig. 11. Pancreas divisum, with sole opacification of the duct system that drains the head of the pancreas


Santorini's duct opens in the minor duodenal papilla in 38% of the cases, an important fact in the case of stenosis or surgery of the major papilla. The anatomic structure of the junction between the common bile duct and Wirsung's duct is of vital importance in the case of papillary stenosis. According to Sterling, both ducts open quite separately in the papilla in 42% of the cases, and almost completely separate in 38%. This means that both the common bile duct and the pancreatic duct can separately become stenotic as the result of a pathologic process. The lumen of the common bile duct is generally about twice as large as that of Wirsung?s duct. However, the diagnosis of papillary stenosis is based not only on the morphologic finding of resulting ectasia of a duct, but also on the observation of delayed emptying of the contrast medium out of one of the two ducts studied by radioscopy.

Summary

The topographic relations of the pancreas with regard to neighboring organs are reported, including the normal states of the whole organ and its individual structures; these data are required for upper gastrointestinal examination, computerized tomography, angiography, and ERCP.

References

Hentschel M (1967) Die Oberbauch-Chirurgie im Lichte neuerer anatomischer Untersuchungen. Forsch Prax Fortbild 18:647

Sterling JA (1954) The common channel for bile and pancreatic ducts. Surg Gynecol Obstet 98:420

Elements of Surgical Anatomy of the Pancreas

G.P. Marzoli, S. Vesentini, and G. Mangiante

Istituto di Clinica Chirurgica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 37100 Verona, Italy

The pancreas is an organ that fairly typically shows the role of the anatomy in the choice of the surgical tactics indeed the operative behavior in pancreatic surgery is mainly dependent on the close relationships of the pancreas to the portal axis and on the presence of the uncinate process. In this work we shall just describe the essentials of the vascular arrangement of the pancreas and the morphology of the uncinate process, in order to better understand the operative steps in radical pancreatic surgery [5, 16]. As is well known, the pancreatic vascular arrangement cannot be illustrated by means of a "normal" diagram, (see Fig. 1) because of an exceedingly high proportion of "anomalous" vessels: we shall therefore illustrate the main variants.

A. hepatica

A.gastro duodenalis----

A supra duodenal is

A pancreatico duodenal is --superior posterior

A pancreatico ___ / duodena lis superior anterior

superior

Truncus coeliacus ,,-- A gastrica sinistra

,f A splenica

\

\ L._ Art. pancreatica dorsalis

- ---- A. mesenterica superior

pa nc rea t ico duodenales inferiores

Fig. 1. The general pancreatic arterial pattern

A. pancreatica magna

The first artery to deal with (also from the tactical point of view) is the arteria gastroduodenalis (AGD), arising in most cases (75%) [20, 25] from the arteria he-

12 G. P. Marzoli, S. Vesentini, and G. Mangiante

patica communis (AHC); the AGD may also arise from the arteria hepatica sinistra (AHS), from the arteria hepatica dextra (AHD) (7%) [20], or from an anomalous hepatic artery arising from the arteria mesenterica superior (AMS) (3,5%) [20]. The AGD is 2 cm long and extends from the back of the duodenopancreatic sulcus; its terminal branch is called the arteria pancreaticoduodenalis superior anterior (APDSA). In its retroduodenal course the AGD has two branches: the arteria pancreaticoduodenalis superior posterior (APDSP) and the arteria supraduodenalis (of Wilkie) (ASD). The AGD generally lies to the left of the choledochus, but it may also be found on the right side. After the identification of the AGD (which may be difficult because of the presence of an AHC that reaches or extends over the superior border of the pancreas), one can section it, opening the way to the mobilization of the anterior aspect of the portal trunk - the first step in the preliminary explorative phase of duodenopancreaticectomy. The section of the AGD opens to the digital exploration the space on the left-anterior portal surface, and this is the easier way because in this space the portal-pancreatic relationships are less close; and also because this side of the vena portae (VP) seldom receives venous affiuents, thus minimizing the risks of portal damage. The APDSA is the terminal branch of the AGD; it is 1.8 mm thick [32] and consistently found (100%) [34]; (93.3%) [3]. The APDSA runs over the head of the pancreas to reach the duodenopancreatic sulcus at the inferior border of the pancreas and then turns medially and backward, descends into the pancreas, and reaches the posterior aspect of the gland, where it joins together with the arteria pancreaticoduodenalis inferior anterior (APDIA) [13, 19, 22, 34]. The APDSA may hinder an eventuallongitunial opening of the main pancreatic duct: it is better sectioned between two sutures, which should include the pancreatic capsule. The APDSP - from the AGD - is constantly found: 100% [13, 24]; 99.3% [34]; 97% [10]; 96% [25]. It always runs over the posterior duodenal aspect and may be hidden by a fibrous band [21]. Its origin is not so consistent as its presence: the APDSP, as well as from the AGD, may also arise from the AHC, (3%) [33], (2.7%) [34]; from an arteria hepatica from the AMS, (10%) [33]; from the arteria dorsalis pancreatis (APD), (0.3%) [34], (2%) [33]. However, the APDSP arises at the left of the choledochus in 42% of the cases, along the left border of the choledochus in 38%, and at its right in 20% of the cases [8]. The APDSP runs in front of the retroduodenal choledochus [8, 20, 21, 30], along the duodenal curvature, and then behind the uncinate process. In this loop there may be three to five branches leading to the choledochus [30]. We would also remember the ASD (of Wilkie): there is much disagreement about its presence [30] and about its source: from the APDSP in 50% of the cases [20] or in 6% [30], from the AGD in 25% [20] or in 60% [30], from the arteria gastrica dextra, from the AHC in various amounts [30]. When present, the ASD is important for its relationships with the choledochus: it forms together with the APDSA and the APDSP a vascular ring around the terminal choledochus. The ASD must be isolated and sectioned in the mobilization of the suprapancreatic portion of the VP. The arterial supply to the head of the pancreas is completed by the arteriae pancreaticoduodenales inferiores anterior and posterior (APDIA and APDIP). The

Elements of Surgical Anatomy of the Pancreas 13

APDIA is present in 100% while the APDIP is present in 99.3% of the cases [34]. Their origin is much more debated. They may arise from a common trunk: 70% [30],46% [34], 57.3% [3], 89% [13],40% [20], or separately. In tum, the common trunk may arise from the first arteria jejunalis (AJ): 28.5% [30], 54% [33], 22% [34],70% [13], or from the AMS. When separated, the APDI may arise, in differently estimated percentages, from the AMS, 1st AJ, ADP, AH from the AMS, 2nd AJ, 3rd AJ [3, 33]. However, they are always short [32] and run behind the AMS, but there may be [61%] an anastomotic vessel, forming a ring around the AMS [20-22], which arises from the 1st AJ. They course within the uncinate process and to section it during pancreaticoduodenectomy one must be careful. When tom, they tend to retract behind the AMS, making the hemostasis difficult. The arterial vascular pattern of the head of the pancreas has a peculiar arrangement in anastomotic arcades, which, after all, realize a communication between the celiac axis and the superior mesenteric trunk [30]. The arcades may be distinguished into anterior and posterior ones. Their development is variable, but they are always present [3, 13, 20, 21, 24, 30]. The usual anatomic description of arterial arcades is not satisfying [20]. There may be different arrangements [20, 21]:

1) Single anterior arcade, whose distal tract lies deep in the pancreas: it originates from the APDIA and ends in the APDI; it has many little branches leading to the duodenum and to the pancreas.

2) Double anterior arcade; the second arcade may join together the APDSA with the arteria gastroepiploica dextra.

3) Triple anterior arcade, which may be described as follows: (a) one branch from the AGD; (b) one branch from the APDSA, which joins togehter with the AMS or the ADP; (c) another branch from the left side of the AGD, which joins togehter with a branch from the ADP.

4) Four arterior arcades, the fourth arcade joining two together with a branch from the ADP.

The posterior arcades may be seen after Kocher manuever: they are covered by the fascia of Toldt. In most cases they originate from the APDSP and join together with the APDI. It may rarely originate from an anomalous arteria hepatica or an ending into the ADP. The number of posterior arcades varies from one to four. "No numerical relation exists between the anterior and the posterior arcades" [20]. French authors also describe a middle intrapancreatic arcade (arcade of Evrard) present in 68% [32] or in 78% of the cases [3]. The presence of this arterial network ensures the blood supply to the head of the pancreas even in the case of section of a main arterial branch (e.g. the AGD). The main arterial vessel, in terms of the blood supply to the remainder of the pancreas, is the arteria pancreatica dorsalis (ADP), first described by Haller in 1742. This important artery is not well know and it is seldom described in current texts [20,21,34]. The ADP is frequently found: 50% of the cases [8], 79% [13], 88% [19], 90% [34], 85% [29]. Its source is variable: from the arteria splenica (AS): 39% [20], 59% [33], 52% [19]; from the celiac trunk: 22% [20], 3% [33], 8% [19]; from the AH: 12% [20]; 14% [33],


A. pancreatica dorsalis

j ! i A. pancreatica magna A pancreatlca Inferior

Arcade of Kirk

Fig.2. The distribution of the arteria pancreatica dorsalis (ADP)

from AGD 2%

14% [19]; and in various amounts from the AGD or from the arteria hepatica dextra (Fig. 2). Despite its variable origin, the ADP has a constant course: under the vena splenica (VS); it gives many little branches to the posterior aspect of the neck and body of the pancreas and then resolves in two main branches: right and left. The right branch from the ADP joins together with one of the posterior arteries of the head and takes the name of arcade of Kirk; the arcade of Kirk is present in 40.7% [13], in 76% [33], in 62% [19, 20], and in 93.3% of cases [34]. The left branch from the ADP runs on the posteroinferior aspect of the body of the pancreas, joins togehter with the arteries of the tail of the pancreas, and takes the name of arteria pancreatica inferior (API) or arteria trasversa pancreatis. The API in its course gives many little branches to the pancreas and after 1-2 cm from its origin it becomes intrapancreatic. The API is very constant: 100% [34], 89% [13] and 54.5% of the cases [19]. The API may rarely originate from the AMS or from the AGD [13, 20, 34]. As for the arterial supply of the body and of the tail of the pancreas other than the API, there is much disagreement. One can roughly draw the following scheme: 1) From two to eight branches from the AS [20, 21]. 2) Arteria caudae pancreatis (ACP), present in 78.7% of the cases [34] and multi

ple in 68% [33]; the ACP may arise from the AS, from the arteria gastroepiploica dextra (AGED) or from arteria gastroepiploica sinixtra (AGES); whatever


the source, the ACP rapidly turns within the gland and joins together with the vessels from the body of the pancreas.

3) Arteria pancreatica magna (APM), present in 64.7% of the cases [34]; it is the largest pancreatic branch of the AS with a diameter of 2-4 mm [20, 21].

All of these arteries realize variable patterns of arterial supply [19). From a surgical point of view it is remarkable that the section of the ADP during pancreatoduodenectomy may result in ischemia of the pancreatic stump, which in tum can explain the postoperative episodes of pancreatitis. As a general conclusion about the arteries of the pancreas we could quote Woodburne and Olsen [34], who write: "The very considerable regularity of the general pattern of the arterial supply to the pancreas is evidenced in the high perrcentage occurrence of the vessels described." On the other hand, Calas [3] states that, maybe, the only uncinate process has a difinite vascular pattern, while in the remainder of the gland one cannot detect any constant arterial pattern. The veins of the head of the pancreas have a very irregular pattern, always different from the arteries [2] (Fig. 3). Grossly, one can describe some main veinous vessels, running on the surface of the head of the pancreas: 1) The vena pancreaticoduodenalis inferior anterior (VPDIA) [8, 9]; it derives

from two to four branches [2] and courses medially, overlapped by the pancreas; the VPDIA may end in the left side of the 1st jejunal vein (after passing behind the vena mesenterica superior (VMS), in the left side of the VMS [13],

Arcata posterior

V. panereat. duodenal is

Arcata intermedia -

Arcata

V. gastriea ---epiploiea dextra .-~ .... -...... ;,

1 V. panereat.

duodenalis inferior anterior

inferior

___ Vena portae

, , , , , V. eoliea

superior dextra superior

V. gastr iea ----- sinistrs

,- V. spleniea

/ ,

--I I

I

- V. panereatieae

, \ \ -_·V, panereatiea inferior

V. mesenteriea in ferio r

Fig.3. The main pancreatic and peri pancreatic venous vessels


in the vena gastroepipleica dextra (VGED) or in the trunk of Henle: 8% [31] and 85.2% of the cases [2].

2) Some authors [13, 24] also describe a vena pancreaticoduodenalis superior anterior (VPDSA) which always joins together with the VGED. The VPDSA drains the anterior and superior part of the head of the pancreas.

3) The vena pancreaticoduodenalis superior posterior (VPDSP) is the biggest vein of the head [2]: it is constantly present [2,13,31], courses togehter with the homologous artery, crosses from behind the choledochus and ends in the posterior aspect of the VP at various levels [13]. The VPDSP is formed from two to four branches [2, 31]; it may end both in the VMS or in the vena gastrica sinistra (Fig. 4).

4) The vena pancreaticoduodenalis inferior (left inferior of Rio Branco) (VPDI) is a fairly constant vessel: 60% of the cases [2,13,31]. It originates from two to four branches [31] on the posterior surface of the head of the pancreas, under the choledochus, courses along the uncinate process and reaches the VMS or the 1st jejunal vein [13]; it can join togehter with the VPDIA [24] or with the VP, the vena mesenterica inferior (VMI) or with the trunk of Henle [2, 31].

V. gastrica dextra I v. gastrica sin istra

V. gastrica dextra presence 82.6% V. gastrica sinistra presence 97,8%

pancreas 75%

t erica superior 22,3%

To the juncture of V, mesenterica superior. V. splenica

58,9%

To V. gastroepiploica dextra

2,7%

To V. pancreaticoduodenalis inferior anterior

3,9%

Fig. 4. The confluence patterns of the left and right gastric veins

Common stem

2,2%

The head of the pancreas has a rich venous network [28] formed by a number of venous arcades: they are always more frequent then the arterial arcades [24]. One can roughly describe three superficial arcades and one intrapancreatic arcade [2, 31]. They are complete in only 75% of the cases [31]. Sow also describes other veins, not quoted in the usual texts, which directly reach the VP and whose frequency is 1%-3% of the cases: one anterior and two posterior veins [31].


The venous drainage of the neck of the pancreas is very inconsistent; the main venous pattern, 32% [2], is constituted by a vena isthmica superior which may end in the VP, in the VS or, rarely, in the vena gastrica sinistra [VGS; 2, 31], and by a vena isthmica inferior which may end in the VMS or in the VMI [2, 31]. The venous drainage of the body and of the tail of the pancreas consists of in two main patterns [2, 31]: 1) Venous branches (three to five) which reach the VS [31]; 2) Little veins (up to ten) which reach the VS along all its course [2, 31]. Douglass

describes only the latter pattern, with 3 to 13 little veins [9]. Also described is a vena pancreatica inferior (VPI), which courses along the inferior border of the body of the pancreas. It may be present in 37% [2] or in 56% of the cases [31]. The VPI may end in the VMI, in the VMS or in the VS [2, 31]. The venous arrangement in the pancreas is more important to surgeons then the parenchymal one. First of all the VP is, of course, the main veinous vessel to deal with in radical pancreatic surgery [17, 23]. The origin of the VP is behind the neck of the pancreas, from VS and the VMS [9] with a 90 degree angle. Very rarely the VP may course anteriorly to the pancreas. The head of the pancreas (see below) is just around the proximal tract of the VP. The VP is 8-10 cm in length [32]; an other estimation is 7 cm [14], while one author [27] states that the "anatomic" length is 7.34 cm (mean) while the "surgical" length is 4.02 cm. The diameter of the VP ranges from 8 to 10 mm [32]; another mean diameter is 2 cm [14]. The VP is always present; its absence is concomitant with other congenital anomalies not compatible with life. Rarely [20, 21] it may be double; even more rarely it may end in the caval system or into the right atrial cavity. The VPs course and its relationships are well known. In 14% of the cases the VP doesn't receive any collateral vein; in 61% of the cases it receives the vena cystica, in 67% the vena gastrica sinistra, in 14% the vena pylorica and in 5% some vessels from the hepatic caudate lobe [27]. The VS runs in tight contact with the superior-posterior border of the pancreas; its diameter in 0.53 cm [27] or 0.94-1.2 cm [14]. Its length is 10 cm [32], 10.5 [27] and 12.2 [14]. In 100% of the cases [27] the VS receives small tributaries from the body and tail of the pancreas; in 44% it receives the VMI and in 27% the VGS [27]. The VMS has a diameter of 1.1 cm [32] or of 0.78 cm [27]. The anatomic length is 6.08 cm while the surgical one is of 3.39 cm [27]. The VMI, rarely pertinent to pancreatic surgery, is 6 mm-2.4 mm [32, 27, respectively]: in diameter and 5.97 cm [27] in length. It may extend into the VMI, the VS, or into the portal confluence in variously estimated amounts [1,9, 14]. Most important from a surgical point of view is the VGS, a very consistent vessel [9]. The VGS may end in: the VS: in 30% [13], 37.7% [2], 24% [14], 32% [32], 16.7% [9], and in 52% of our angiographic cases [18]; the VP: in 40% [13], in 55.8% [2], in 68% [14, 32], in 24.4% [9], and in 20% of the cases [18]; the portal-splenic confluence: in 8% [13], in 6.4% [2], in 58.9% [9] and in 28% of the cases [18]. Then comes the gastrocolic trunk (of Henle), which collects blood from the stomach, from the hepatic flexure of the colon and from the head of the pancreas. It originates from the confluence of the venae colica superior dextra, gastroepiploica


dextra (VGED), pancreaticoduodenalis inferior anterior (VPDIA). There is no general agreement about its frequency or its branches [2, 31], however, surgeons know it very well. The gastrocolic trunk lies within the insertion of the transverse mesocolon to the head of the pancreas; it is coated by a dense connective tissue tightly adhering to the peritoneum: this would explain the possible tearing of the gastrocolic trunk during the mobilization of the head of the pancreas from the portal axis. We think that isolation of the VMS, above and below the confluence of the trunk of Henle, should precede the sectioning of the trunk: this either avoids hemorrhages or allows a prompt control should the trunk be torn. The surgeon should also remember that the gastrocolic trunk may end not only in the right-lateral surface but also in the right-anterior surface of the VMS, so that the digital exploration from below of the anterior aspect of the portal vein may first necessitate of the section of the trunk of Henle. Near and before the end of the trunk, on the right side of the VMS, there may be (75% of the cases) the confluence of a vena pancreaticoduodenalis (inferior); the sectioning of this vein - whose diameter may be large - is usually easy after the section of the overlying pancreas. The ligature must be close to the VMS for a better mobilization of the remainder of the pancreas (Fig. 5). At the same level, but on the left side of the VMS, there may be the confluence of the VPI. The usual texts of techniques in surgery often point out the absence of venous tributaries to the anterior surface of the retropancreatic VP and the ease with which

V. panereatieo duodenalis inferior anterior to

V. mesenteriea superior 8,8% calas 66% sow

superior

1,8% ealas

V. paner. duodenalis inferior anterior with

V. gastroepiploiea dextra to

V. mesenterica superior 4,7% ealas

V. paner. duodenal is inferior

26% sow

anterior V. coHea

\

\ i I

"Trunk of Henle" 85,2% ealas

8% sow

superior dextra

Fig.5. The confluence of the Vena pancreaticoduodenalis inferior anterior (VPDIA)


one can separate it from the pancreas. This is not always true: the VGS may (50% of the cases) join togehter with the VP at its left-anterior surface, just above the splenic confluence. Moreover, in about 75% of the cases, the right-anterior surface of the VP receives the confluence of the vena pylorica, which must be divided during duodenopancreaticectomy, and this may be a difficult step. Finally, one must remember the thin inferior and more often superior venae isthmicae whose confluence is on the left side of the VP; their section is not difficult. The mobilization of the posterior surface of the VP must also be very careful because of the presence, in about 90% of the cases [15], of small vessels - the retroportal veins - which from the uncinate process reach the VP (Fig. 6).

V. pancreatica inferior 24%

V. istmica inferior

v. retroportales 90 % (Hess)

Fig. 6. The retroportal veins

------ -------- High confluence (61,7%)

of - --------- -------- V. pancreatico duodenal is

posterior superior Presence: 98%

------ V. pancreat ico duodenalis inferior

The last vein to be cut in the course of duodenopancreatectomy is the VPDSP, which - crossing from behind the choledochus - (vascular ring) reaches the right lateral or the posterior aspect of the VP. The VPDSP sometimes receives the confluence of a venous vessel which runs on the anterior aspect of the coledochus, thus reinforcing the vascular ring. The venous drainage of the body and of the tail of the pancreas has no role in the usual pancreatic surgery, while it assumes great importance in the performance of the distal splenorenal shunt of Warren. This discussion about the surgical anatomy of the pancreas would not be complete without the description of what the French authors call the retrovenous segment (RS) [4] (Fig. 7). The parenchymatous cephalic layer which extends behind


Fig. 7. The extension of the retrovenous segment (RS)

the mesenteric-portal axis is what we call the RS: the uncinate process forms its caudal portion. The RS reaches the AMS by means of a fibrous tissue called the retroportal plate [4, 26]: it is not only the main element of fixity of the pancreas but also represents a very important anatomic structure which contains arterial and venous vessels (e.g., the AHC or the right hepatic when they arise from the AMS, the APDIP, the VPI), the nerves of the pancreas and the lymphatic vessels and nodes inserted between the parenchymal lymphatic network and the mesenteric and paraortic lymphatic vessels [6, 7, 12]. The impossibility of completely eradicating this retroportal plate is in our mind the main restriction to a successful radical surgical excision of the carcinomas of the pancreas. The parenchymatous components of the RS are divided - on the basis the arrangement of the excretory system (i.e., by means of injection studies) - into three portions: the inferior one, or uncinate process; the middle one, or retromesenteric segment; and the superior one, or retroportal segment [4]. The uncinate process reaches the AMS in 30% of the cases and passes behind it in 18% of the cases; its secretory system reaches (75% of the cases) by means ofa big duct, the duct of Santorini [4].


The retromesenteric segment, usually not very large, can also reach (30% of the cases) the AMS [4]. The retroportal segment, when present, is the smallest and never extends over the VP. The presence within the RS of destinct excretory channels represent a difficult question: the not complete excision of RS in course of duodenopancreaticectomy (as suggested by some surgical handbooks) can of course create focal conditions favoring acute pancreatitis.

References

1. Barry P, Repolt A, Autissier JM (1968) Le confluent portale. Notes statistiques sur son mode de constitution. CR Assoc Anat 141:510-515

2. Calas, F, Bouchet Y, Martin R, Couppie G (1956) Les veines du pancreas. CR Assoc Anat 89:366-372

3. Calas F, Martin R, Bouchet Y, Polliak D (1956) Les arteres de la tete du pancreas. CR Assoc Anat 89:362-365

4. Calas F, Bouchet Y, Martin R, Couppie G (1957) Le segment retroveineuse de la tete du pancreas. CR Assoc Anat 98:211-219

5. Charpentier J, Letoublen C, Durand A (1978) Anatomical bases of cephalic pancreaticoduodenectomy. Anat Clin 1:189-197

6. Couinaud C (1970) Le meso-pancreatico-duodeno-ombilical. J Chir (Paris) 100/4:249-266

7. Debeyre J (1933) Nerfs du pancreas. CR Assoc Anat 32:251-263 8. Do Rio Branco P (1912) Essai sur l' anatomie et la medecine operatoire du tronc coelia

cus et de ses branches de l' artere hepatique en particulier. Medical dissertation, Paris 9. Douglass BE, Baggenstoss AH, Hollinshead WH (1950) The anatomy of the portal vein

and its tributaries. Surg Gynecol Obstet 91:562-576 10. Edwards LF (1941) The retroduodenal artery. Anat Rec 81:351-355 11. Deleted in production 12. Evans BP, Ochsner A (1954) The gross anatomy of the linphatics of the human pan

creas. Surgery 36:177-191 13. Falconer CWA, Griffiths E (1950) The anatomy of the blood vessels in the region ofthe

pancreas. Br J Surg 37:334-344 14. Gilfillan RS (1950) Anatomic study of the portal vein and its main branches. Arch Surg

3:449-461 15. Hess W (1961) Die Erkrankungen der Gallenwege und des Pankreas, 1st edn. Thieme,

Stuttgart 16. Hollinshead WH (1971) Anatomy for surgeons, 2nd ed., vol II/8. Harper & Row, New

York 17. Maillard IN, LeBeaur A, Hay JM, Desgignes G, Rodany M (1975) La resections de la

veine porte. Bases anatomiques, resultats c1iniques. Chirurgie 101:871-876 18. Marzoli GP, Vesentini S, Frasson F, Fugazzola C, Mangiante G (1979) Die distale sple

no-renale termino-Iaterale Anastomose nach Warren. Langenbecks Arch Chir 348:93-103

19. Melliere D (1968) Variations des arteres hepatiques et du carrefour pancreatique. J Chir (Paris) 95:5-42

20. Michels NA (1951) The hepatic, cystic and retroduodenal arteries and their relations to the biliary ducts. Ann Surg 133:503-524

21. Michels NA (1955) The blood supply and anatomy of the upper abdominal organs:with a descriptive atlas. Lippincott, Philadelphia

22. Nebesar RA, Kornblith PL, Pollard JJ, Michels NA (1969) Celiac and superior mesenteric arteries (a correlation of angiograms and dissections). Little & Brown, Boston

23. Peri G, Zanoli PG, Trivellini G (1969) Variazioni ed anomalie del tronco portale. Arch Ital Chir 95:442-452


24. Petren T (1929) Die Arterien und Venen des Duodenums und des Pancreas-Kopfes beim Menschen. Anat Entwicklungsgesch 90:234-277

25. Pierson JM (1943) The arterial blood supply of the pancreas. Surg Gynecol Obstet 77:426-432

26. Prioton JB, Laux R (1960) La lame retroportale du pancreas cephalique. Incidences de sa topographie en chirurgie pancreatique et portale. CR Assoc Anat 108:667-673

27. Purcell HK, Connor JJ, Alexander WF, Scully NM (1951) Observations of the mayor radicles of the extrahepatic portal systems. Arch Surg 5:670-677

28. Reichardt W, Lunderquist A, Tylen U (1978) Selective flebography in carcinoma of the pancreas. Acta Radiol [Diagn] (Stockh) 19:305-315

29. Romodanowskaja Z (1926) Die Arterien der Bauchspeicheldrtise. Z Anat Entwicklungsgesch 79:506-514

30. Shapiro AL, Robillard GL (1946) Morphology and variations of the duodenal vasculature. Arch Surg 52:571-602

31. Sow ML, Dintimille H, Padonou N, Sylla S, Argeson C (1975) La vascularisation veineuse du pancreas. Bull Assoc Anat (Nancy) 164:255-264

32. Testut L (1893) Traite d' anatomie humaine. Doin, Paris 33. Vandamme JP, Van der Schueren G, Bonte J (1968) Vascularisation du pancreas: pro

position de nomenclature P.N.A. et angioarchitecture des ilots. CR Assoc Anat 139:1184-1192

34. Woodbume RT, Olsen LL (1951) The arteries of the pancreas. Anat Rec 3:255-270

Physiologic Control of the External Pancreatic Secretion in Man

H. Worning

Medical Department F. Glostrup Hospital, 2600 Glostrup, Denmark

Introduction

The exocrine pancreatic secretion has been studied for many years. Most of the studies have been performed on different species of animals, using more or less invasive procedures. These studies have brought to light the existence of species differences concerning the regulation of the pancreatic secretion. Thus, a simple conclusion by analogy from animals to man is not sufficient to describe the physiology of the human pancreatic secretion. In recent years, an increasing number of studies in the intact human organism have been performed. This review will mainly deal with such studies, a few experiments from animals are included either for comparison or because no data from man are available.

Total Pancreatic Secretion

It is generally accepted that the human pancreas increases the secretion of fluid, bicarbonate, and enzymes in connection with intake of food. This is a reasonable assumption, but substantial studies demonstrating this event in intact humans are few. The pancreatic flow, calculated as the degree of dilution of the gastric contents entering the duodenum, has been studied (Miller et al. 1978), and the trypsin secretion following ingestion of a meal has been estimated in a limited number of studies (Ekelund and Johansson 1975, 1976; MacGregor et al. 1976, 1977; Malagelada et al. 1979). Moreover, few studies of the enzyme secretion following infusion of food into the stomach exist (Brunner et al. 1974; Miller et al. 1978, 1979). The observed values for total trypsin secretion are demonstrated in Table 1. These values vary to a considerable degree, justifying some scepticism regarding the applied method. No data for the pancreatic bicarbonate secretion during digestion of a meal are available. The duration of the increased secretion following ingestion of a meal depends on size and composition of the meal (Brunner et al. 1974; Ekelund and Johansson 1975, 1976; Malagelada et al. 1979). In most studies, a rapid increase in secretion up to a maximum within the first 20-30 min is seen followed by a gradual decrease to fasting values in about 2.5-3 h (Brunner et al. 1974; Ekelund and Johansson 1975, 1976; MacGregor et al. 1976, 1977; Miller et al. 1978, 1979; Mala-

24 H. Worning

Table 1. Total trypsin secretion following ingestion of or gastric infusion of a meal in normal subjects, m ± SEM

Author

Ekelund and Johansson (1976) MacGregor et al. (1976) MacGregor et al. (1977) Miller et al. (1979)

a 1 mg trypsin = 0.0385 KU

Amounta

26± 3 KU/3 h 53± 5KU/2.5h 39±11 KU/2.5 h

108±14 KU/3 h

gelada et al. 1979). Thus, the regulation of the pancreatic secretion includes a phase with stimulation followed by a period either with decreasing stimulation or with combined stimulation and inhibition of the pancreatic secretion. In the following, different ways of stimulation and inhibition will be discussed, first the nervous influence, then the chemical messengers, and lastly the possible interaction between nervous and hormonal influence.

Nervous Stimulation:

Studies in different species of animals have clearly shown the influence of vagal stimulation on the pancreatic secretion (see Wormsley 1979). This effect is probably mainly responsible for the cephalic phase in the postprandial pancreatic secretion. However, the direct influence of vagal stimulation in the intact human organism is not defined (Wormsley 1979). The effect is probably mainly mediated via the nervous-hormonal interaction, as mentioned below.

Hormonal Stimulation

It is accepted that the main stimulus for the pancreatic secretion is mediated via chemical messengers specifically responsible for the so-called gastric and intestinal phase in the pancreatic secretion. A number of chemical messengers have been found. The question about their physiologic relevance is still a matter of dispute. Before going through the different isolated messengers (hormones), a few general points concerning the method and the definition of when an isolated peptide is proven to be physiologically active will be made. According to Grossman (1979) the chemical messages are transmitted by one of three ways: 1) The neurocrine transmission which spans a very short distance of the synaptic

cleft. 2) Endocrine transmission which occurs by way of the blood (the hormonal

transmission). 3) Paracrine transmission which occurs by diffusion of the chemical messenger

through the intracellular space between receptor and target cells.

Physiologic Control of the External Pancreatic Secretion in Man 25

For the exocrine pancreatic secretion a neurocrine example is acetylcholine, an endocrine is secretin, and a candidate for paracrine message is vasoactive intestinal polypeptide (VIP). The present knowledge about the chemical regulation of the pancreatic secretion is mostly limited to the endocrine transmission. A number of isolated polypeptides are, at least in pharmacologic doses, active as stimulants or as inhibitors of the exocrine pancreatic secretion. One of the problems is to find out which of these are of physiologic importance. The general problem about when a candidate becomes a hormone is a matter of discussion. According to Grossman (1978) "a hormone is a peptide with a physiological role," whereas Mutt (1978) uses the following definition: "if plasma-concentration of a peptide increases during a meal, then that peptide is a hormone." As can be seen in the following, these two defmitions are not necessarily in accordance with each other. The definition given by Grossman is accepted for the following discussion.

Secretin

Although secretin has been known as a potent stimulator for the pancreatic secretion of fluid and bicarbonate for 77 years, its actual role in the physiologic regulation in the intact human has been questioned until recently (Wormsley 1973, 1979). The release of secretin following perfusion of the human duodenum with hydrochloric acid or bile has been demonstrated in a number of publications (Osnes et al. 1978; Schaffalitzky de Muckadell and Fahrenkrug 1978 a, b, c; Hacki et al. 1978; Hanssen 1978). The question of the physiologic role of secretin has been concentrated around the absence of an increase in plasma concentration following a meal. However, an increasing number of observations are now available demonstrating a small but significant increase in plasma concentration of secretin after ingestion of a meal (Chey et al. 1977, 1978; Hacki et al. 1978; Schaffalitzky and Fahrenkrug 1978a, b, c). The basis for this observation is the steadily increasing accuracy and sensitivity of the secretin assay. The observed concentrations of secretin in plasma, fasting, and following a meal are depicted in Table 2. The increase after a meal is significant but rather small. Boden et al. (1978), however, were unable to demonstrate any increase in secretin

Table 2. Concentrations of secretin (pmol/litre, m ± SEM or range) in plasma in the fasting state and following ingestion of a meal"

Author

Chey et al. Chey et al. Hacki et al. Osnes et al. Schaffalitzky de Muckadell and Fahrenkrug Schaffalitzky de Muckadell and Fahrenkrug

" 1 pg/ml = 3 pmol/l

(1977) (1978) (1978) (1978) (1978a) (1978 c)

Fasting

1.10±0.12 1.47 2.5 ±0.34 1.5 ±0.3 1.5 -6.2 0.5 -2.0

Postprandial

1.75±0.42

5.1 ±0.67

3.0 -6.8 0.3 -3.0

26 H. Worning

concentrations in portal blood after a meal. The study was performed on patients with advanced liver disease. The fasting secretin concentration was much higher (58 ± 22 pg/ml equivalent to 19 ± 7 pmol/litre) than those given in Table 2, indicating a different sensitivity and specificity of the assay. The observed increases in secretin concentrations are very small and equivalent to extremely small dosages of exogenous secretin (Schaffalitzky de Muckadell and Fahrenkrug 1978a; Schaffalitzky de Muckadell et al. 1978, 1979a, b). However, the pancreatic sensitivity to secretin is much higher than hitherto believed (Schaffalitzky de Muckadell et al. 1978, 1979 a, b). Referring to these papers it is reasonable to conclude 1) That secretin is liberated in small amounts as a result of short-lived pH spikes

below pH 4 in the proximal duodenum after a meal (Schaffalitzky de Muckadell et al. 1979b).

2) That the released amounts of secretin are equivalent to 125-250 fmol' kg -\ = 0.0013-0.0027 clin. units' kg -\ exogenous secretin given as a bolus (Schaff alitzky de Muckadell et al. 1979a)

3) That these amounts of secretin induce a pancreatic bicarbonate secretion be-tween 283-524 J.Lmol in 15 min (Schaffalitzky de Muckadell et al. 1979a).

These amounts of bicarbonate secretion are far below the expected values. However, they are of physiologic significance for two reasons. First, because the pH spikes induce a secretin-mediated bicarbonate secretion amounting to about 50% of the amount of acid necessary to induce the pH spike; and second, because the secretin effect on the pancreas under combined stimulation, is potentiated by other stimulants, nervous and/or hormonal (Henriksen et al. 1976; Singh and Webster 1978; Wormsley 1979). Thus, secretin is a chemical messenger with a physiologic role, a hormone engaged in the neutralization inside the duodenum.

Vasoactive Intestinal Polypeptide (VIP)

VIP acts as a secretinlike partial agonist of human exocrine pancreatic secretion (Domschke et al. 1977b, 1978 a, b). It is located in nerves which are intimately associated with small blood vessels and smooth muscles of the gastrointestinal tract (Fahrenkrug et al. 1978). VIP is detectable in human blood in the fasting state (Domschke et al. 1978a, b; Mitchell and Bloom 1978). The observed concentrations are shown in Table 3. The concentration does not increase after ingestion of a meal in man (Fahrenkrug et al. 1978; Mitchell and Bloom 1978). This is in contrast to observations in dogs (Ebeid et al. 1978), where the concentration of VIP increases from 45 to 70 pg/ml following ingestion of a meal.

Table 3. Concentrations (pmol/litre) of VIP in human plasma, fasting state

Author Mean SEM Median

Domschke et aI. (1978a) 3 2 Domschke et al. (1978b) Mitchell and Bloom (1978) 2.1 1.7

Range

1-19 0.5-21


In pharmacologic doses, VIP exerts a small but consistent stimulating effect on the pancreatic secretion of fluid and bicarbonate in man (Domschke et al. 1977 b) and in pigs (Lindkrer Jensen et al. 1978). The amounts of exogenous VIP necessary to induce pancreatic secretion in humans result in plasma concentrations of VIP much higher than those observed under normal conditions (Domschke et al. 1977b, 1978 a, b). The calculated minimal concentration of VIP in human blood able to induce pancreatic secretion is about 50 pmol/litre (Domschke et al. 1977b, 1978a, b). For comparison it is worth mentioning that the minimal concentration of VIP in the perfusate, able to induce a secretion from the isolated pig pancreas, is 30 pmol/litre (Lindkrer Jensen et al. 1978). The conclusion to be drawn is that VIP does not function as a hormone in the pancreatic regulation in man. However, it may have a paracrine influence and if so it may be responsible for the atropine-resistant effect of vagus on the bicarbonate secretion from the pancreas (Fahrenkrug et al. 1978).

Cholecystokinin (CCK)

CCK is a well-known potent stimulant for the pancreatic secretion of enzymes. However, the physiologic role of CCK in the pancreatic secretion after a meal is still a matter of dispute. One of the main problems is concentrated around the estimation of CCK concentrations in blood. The results are contradictory mainly on account of the different molecular forms of CCK (Rehfeld 1978) and problems with the specificity of the radioimmunoassay of CCK (Rehfeld 1978). The release of CCK has been argued on the basis of bioassays showing a marked pancreatic enzyme secretion following ingestion of a meal (Brunner et al. 1974) or following jejunal perfusion with amino acids (Go et al. 1970a, b, Ertan et al. 1971). The induced enzyme secretions were equivalent to the secretion induced by infusion of exogenous CCK in dosages between 2 and 4 Ivy Dog Units =

IDU·kg- 1 ·h- 1 (Go et al. 1970a, b; Ertan et al. 1971; Brunner et al. 1974). The same value was calculated by Malagelada et al. (1979). The value is much higher than that calculated by the same technique in dogs (Henriksen and Worning 1969), where the calculated amount of liberated CCK after a meal was about 0.4 IDU/kg. Go (1978), Harvey (1978), and Rayford et al. (1978) all postulate an increase in plasma concentrations of CCK following a meal. The published concentrations vary highly. Rayford et al. (1978) observed a postprandial concentration of CCK of 290 pg/ml while Harvey (1978) found values about 1100 pg/ml. Harvey (1978) observed nearly identical curves for CCK concentration in venous blood after a meal and during intravenous infusion of exogenous CCK, 2 ID U . kg - 1 • h - 1. This value fits with those calculated in the above-mentioned studies, but exceeds by far the amount of other hormones liberated from the proximal intestine in the postprandial phase. A recent observation in dogs (del Mazo et al. 1979) casts doubt on the role of CCK in the protein secretion during intestinal perfusion with amino acids. They observed a marked stimulation of the pancreatic protein secretion but they were unable to fmd any increase in CCK concentration in plasma. Consequently, CCK may be engaged in the postprandial stimulation of the pancreatic enzyme secretion. The actual role of CCK is still uncertain awaiting more

28 H. Worning

sensitive and specific assays for CCK. However, CCK is still our best candidate as regulator of the enzyme secretion in man.

Gastrin

The concentration of gastrin following a meal increases to a maximum about 20 min after the meal and decreases to fasting values in about 1-2 h (Dockray 1978; Greenberg et al. 1979 a, b; Malagelada et al. 1979). The human pancreas is nearly insensitive to pentagastrin (Petersen et al. 1971) whereas normal human gastrin possesses a moderate stimulatory effect on the pancreatic enzyme secretion (Valenzuela et al. 1976). The dosage of gastrin necessary to induce pancreatic secretion is much higher than those liberated under normal physiologic conditions (Wormsley 1979). Thus it is not reasonable to believe that gastrin has any physiologic role in the regulation of the pancreatic secretion. This conclusion is further substantiated by the observation, that patients with achlorhydria (and markedly increased concentrations of gastrin in serum) do not have any signs of increased pancreatic secretion under normal physiologic conditions or under exogenous stimulation with secretin and/or CCK.

Glucagon

The effect of glucagon on human pancreatic secretion is unclear. Some studies show a stimulatory effect on volume and bicarbonate secretion (Clain et al. 1978), others describe the inhibitory effect on secretion of volume, bicarbonate, and enzymes (Schapiro und Ludewig 1978) while still other postulate no effect of glucagon on the pancreatic secretion (Buchanan et al. 1978). Concentrations of glucagon in human plasma increases following a meal, valid for gut-type glucagon (12-42 pmol/litre) and pancreatic-type glucagon (18-45 pmol/litre) as well (Bloom and Polak 1978; Fallucca et al. 1978; Holst 1978). The dosages of glucagon used in the above-mentioned studies on the effect of exogenous glucagon on the pancreatic secretion by far exceed the physiologically released amounts. Thus, it is reasonable to believe that glucagon is without a physiologic role in the regulation of the exocrine pancreatic secretion. The function of gut-type glucagon still remain to be established (Moody et al. 1978).

Bombesin

Bombesin is distributed in nerve ends in the whole gastrointestinal tract except for the pancreas (Bloom et al. 1979; Polak et al. 1978). Bombesin exerts a stimulatory effect on the pancreatic secretion of enzymes in man (Polak et al. 1978) as well as on mouse pancreas in vitro (Petersen 1978). No data concerning the bombesin concentration in human blood are available. It is not known whether the concentration is influenced by intake of food.


It is postulated that the physiologic effect of bombesin may be dependent on its effect on liberation of different gastrointestinal hormones (Fallucca et al. 1978; Lezoche et al. 1979 a, b). The physiologic relevance of these observations is still not determined.

Pancreatic Polypeptide (PP)

It is a well-documented fact that concentrations of PP in plasma in man increase following ingestion of a meal (Adrian et al. 1977, 1978a, b, 1979a; Floyd et al. 1978; Greenberg et al. 1979b; Schwartz et al. 1978 a, b). The observed concentrations before and after a meal are shown in Table 4. Both Adrian et al. (1977) and Schwartz et al. (1978 b) point to the existence of an early high PP concentration followed by a long lasting plateau at a somewhat lower level. Floyd et al. (1978) observed a steady increase in the fasting PP concentration with increasing age (mean concentration at 25 years 54 pg/ml, at 65 years 130 pg/ml). Moreover, the increase in plasma concentration after a meal was dependent on the size and composition of the meal. Concentrations of PP in blood increase after sham feeding (Schwartz et al. 1978b, 1979), indicating a vagal release, at least valid for the initial peak in PP concentration after a meal (Adrian et al. 1977; Schwartz et al. 1978b). PP exerts an inhibitory effect on the exocrine pancreatic secretion in the fasting state (Greenberg et al. 1979a) and on the stimulated pancreas (Adrian et al. 1978c, 1979b). The same effect has been observed in dogs (Taylor et al. 1979). In dogs, the effect is probably of physiologic relevance, as the inhibitory effect is obtainable with plasma concentrations of PP within the physiologic range. In man, however, the physiologic relevance of the inhibition is very doubtful. Infusion in man of bovine PP in doses between 60 and 320 pmol· kg -1 • h -1 induces plasma concentrations between 450 and 950 pmol/litre (Adrian et al. 1978 b, c, 1979b; Greenberg et al. 1979a), values well above the normal physiologic range (Table 4). The lowest rate of infusion was without any influence on the pancreatic secretion (Adrian et al. 1978c). The lowest plasma concentration with inhibitory effect on the secretin induced secretion was about 700 pmol/litre (Adrian et al. 1979b), being an unphysiologically high concentration (see Table 4). Thus, it is

Table 4. Concentrations of PP (pmol/litre, m ± SEM or range) in human plasma in the fasting state and following a meal

Author Fasting Postprandial

Adrian et al. (1977) 30 340 ..... 180 (1978a) 30 160 (1978 b) 20±5 (1979a) 28±5 167±25

Greenberg et a1. (1979b) 51±23 176±32 Schwartz et a1. (1978 a) 11 (9.5-12.5) Schwartz et a1. (1978b) 25 250

30 H. Worning

reasonable to conclude that PP is without a physiologic role in the regulation of the external pancreatic secretion.

Somatostatin

Somatostatin is detectable in the proximal part of the gastrointestinal tract including the pancreas (McIntosh et al. 1978). It has a widespread inhibitory effect on the release and the effect of gastrin, secretin, and CCK (Domschke et al. 1977 a; Hanssen et al. 1977; Konturek 1978; Konturek et al. 1978 a; Raptis et al. 1978). The concentration of somatostatin in human blood is not known, no data about the release of somatostatin after intake of food in man are available, some data showing increased concentration in caval blood after a meal in dogs have been published (Schusdziarra et al. 1978, 1979). The amounts of somatostatin necessary to induce the above-mentioned inhibitory effect are rather high. Until now the effect might be characterized as a pharmacologic effect and the conclusion to be drawn is that there is no substantial support for a physiologic role of somatostatin in the regulation of the exocrine pancreatic function in man.

Enkephalin

Enkephalin is detectable in the human gastrointestinal tract from antrum to colon and probably in the pancreas too (Polak et al. 1978). Animal experiments demonstrate an inhibitory effect of enkephalin on the secretin and meal-induced pancreatic secretion of bicarbonate and enzymes (Konturek et al. 1978 b, 1979). No data concerning concentration in blood or effect of exogenous enkephalin exist. The physiologic role of enkephalin in human pancreatic secretion is undeftned.

Gastric Inhibitory Polypeptide (GIP)

G IP concentrations in peripheral blood in man increase following duodenal acidiftcation (Ebert et al. 1979) and following ingestion of a meal (Cataland 1978; Ebert and Creutzfeldt 1978; Ebert et al. 1979; Greenberg et al. 1979 b). GIP stimulates the secretion of insulin and glucagon from the pancreas (Brown et al. 1978) and is the best candidate for the so-called incretin-effect. However, GIP is without any known effect on the exocrine pancreatic secretion, consequently it is without any physiologic role in the regulation of the exocrine pancreatic secretion in man.

Motilin

Concentrations of motilin in human plasma increase after injection of acid (Christoftdes et al. 1978; Mitznegg et al. 1978) or bile (Domschke et al. 1979) into


the duodenum, and after oral ingestion of food (Christofides et al. 1978, 1979 a, b). Exogenous motilin in a slightly unphysiologic dose (Christo fides et al. 1979b) was without effect on concentrations of PP, GIP, glucagon, or VIP in plasma. Motilin is without any known effect on the exocrine pancreatic secretion. It is reasonable to conclude that motilin has no physiologic role for pancreatic function in man.

Neurotensin, Substance-P

Neurotensin is detectable in the human gut. The pharmacologic effect includes production of hyperglycemia, release of glucagon, and inhibition of insulin release. Its physiologic role is undefined both for the endocrine and exocrine pancreatic regulation (Buchan et al. 1978). Substance-P is detectable in human plasma in concentrations between 41 and 298 pg/ml (Powell et al. 1978). Substance-P has a stimulatory effect on the exocrine pancreatic secretion in dogs but nothing is known about the effect in man, the physiologic role has not been determined.

A summary of the effect of the different chemical messengers on the exocrine pancreas and the influence of food on concentrations in blood is given in Table 5.

Table 5. Gastrointestinal hormones: effects in man on the exocrine pancreas and effect of a meal on concentrations in peripheral blood

Substance Effect on exocrine Concentration in plasma pancreatic secretion after a normal meal

Secretin Stimulation Increases VIP Stimulation Unchanged CCK Stimulation Increases? Gastrin Stimulation Increases Glucagon Stimulation? Increases Bombesin Stimulation Unknown PP Inhibition Inkreases Somatostatin Inhibition Unknown Enkephalin Inhibition Unknown GIP None Increases Motilin None Increases N eurotensin Unknown Unknown Substance-P Unknown Unknown

Interaction Between Hormones and Between Nerves and Hormones

The hormones can interact either on the target organ or in the release. The best known example of interaction on the target organ is the potentiating effect of secretin and CCK, valid for secretion of bicarbonate and enzymes (Singh and Webster 1978; Wormsley 1979). Interactions of other hormones even given in combination with two or even more hormones are studied to a very limited ex-

32 H. Worning

tent; no defmite conclusions can be drawn. The hormonal effect on the release of other hormones has been mentioned above, the most pronounced effect is for somatostatin. The physiologic relevance of these effects are still not known. The interaction between nerves and hormones is in fact complicated (Grossman 1979). The interaction could be mediated by a nervous release of hormones, by nervous modulation of the release, and by nervous modulation of the response to hormones. According to the release, it is well-documented that vagus are able to release gastrin, PP, and probably VIP and pancreatic-type glucagon. The nervous modulation of hormone release is insufficiently studied. There are reasons to believe that vagus modulate the release of secretin from the duodenum (Henriksen et al. 1976), but the physiologic role of this interaction is not known. Finally, the nervous modulation of the response to hormones is probably of physiologic relevance for the effect of secretin and CCK on the exocrine pancreas (Grossman 1979; Wormsley 1979). The role of the hormonal and nervous/hormonal interactions for the regulation of the pancreatic secretion after a meal remains to be determined.

Conclusion

The pancreatic secretion following a meal in man depends on a stimulation by the vagal nerve but probably mainly on a hormonal (endocrine) stimulation of the pancreas. Uptil now only one peptide has satisfied Grossman's definition of a hormone, namely secretin. CCK is a very good candidate but more substantial observations about the plasma concentration are needed. It is unclear if other hormones are engaged in the regulation and still more is not known about to what extent the hormonal interaction and the nervous hormonal interaction have a physiologic role. No substantial support for the existence of inhibitors for the pancreatic secretion exists. The half-life for exogenous hormones are shown in Table 6. It is evident that these short half-lives result in a decreased pancreatic secretion as soon as the release ofthe hormones decreases. Consequently, it is reasonable to accept the decrease in pancreatic secretion 2-3 h after a meal, simply as a result of the absence stimulation to the pancreas.

Table 6. Half-lives for exogenous hormones in man range or m ± SEM

Substance

Secretin CCK VIP PP Motilin GIP

Half-life (min)

2.6 - 6.2 204 - 3.0 1.0 - 1.2 704±0o4 4.5±004 21

(Schaffalitzky de Muckadell et al. 1978) (Go 1978) (Domschke et al. 1978a) (Adrian et al. 1978c) (Christo fides et al. 1979b) (Cataland 1978)


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falitzky de Muckadell OB, Stadil F (1978a) J Clin Invest 61:781 Schwartz TW, Stenquist B, Olbe L (1979) Scand J Gastroenterol14:313 Schwartz TW, Stenquist B, Olbe L (1978b) In: Bloom SR (ed) Gut hormones. Churchill

Livingstone, London, p 261 Singh M, Webster PD (1978) Gastroenterology 74:294 Taylor IL, Solomon TE, Walsh JH, Grossman MI (1979) Gastroenterology 76:524 Valenzuela JE, Walsh JH, Isenberg 11 (1976) Gastroenterology 71:409 Wormsley KG (1973) Gut 14:743 Wormsley KG (1979) In: Duthie HL, Wormsley KG (ed) Scientific basis ofgastroenterolo

gy. Churchill Livingston, London, p 199

Pancreatic Malfunction - When, How, Why?

K. G. Wormsley

Department of Therapeutics, University of Dundee, Ninewells Hospital, Dundee DDZ IUB, United Kingdom

Pancreatic Malfunction - When?

This question can be interpreted in two ways - by asking "under what circumstances, or in association with what other disease processes, does pancreatic disease occur" and "what determines the precise period in time at which the pancreatic dysfunction occurs". The second question can be answered quite simply by "we do not know". It is quite extraordinary that when my patients have an alcoholic debauch on Friday evening (the local tradition) - they come into hospital on Sunday with a recurrence of acute pancreatitis. We have no idea why 36-48 h usually elapse between the alcoholic insult to the pancreas and the pancreatic cellular necrosis, but I suspect, from the duration of the lag period, that the mechanism involves induction of a protein-synthetic process. On the other hand, acute pancreatitis has been precipitated by an infusion of calcium as soon as 4 h after conclusion of the infusion, so that hypercalcaemia can cause pancreatic cellular necrosis more acutely. However, in hypercalcaemic diseases we do not know and cannot prophesy when a patient is going to develop an attack of acute pancreatitis. We know much more about the circumstances of, or predispositions to, pancreatic disease. Let us take acute pancreatitis first. There are difficulties in interpreting the information about the incidence of acute pancreatitis because we can only definitely establish the diagnosis of pancreatic disease by carrying out a laparotomy or autopsy - and we do not do either of these investigations in most of our patients. The remaining diagnostic criteria beg the question. For example, if a patient has abdominal pain and has a high circulating level of amylase, we make a diagnosis of acute pancreatitis. Probably correctly, if the value of the amylase is very high and the patient does not develop symptoms which show the presence of some other disease. But what about slight attacks of pain? Or slight increases of amylase? How many individuals suffer from painless pancreatitis, we just do not know. So all the figures for acute pancreatitis are incomplete and based on highly selected clinical information. The newer diagnostic techniques don't help us, because all are based on the primary diagnosis of acute pancreatitis, which, in tum, is based on the clinical combination of abdominal pain and high blood amylase. A number of clinical conditions appear to be associated with acute pancreatitis more than one might expect on the basis of chance.

38 K. G. Wormsley

In Britain (as, for example, in Sweden and Israel) acute pancreatitis occurs most frequently in association with disease of the biliary tract. There may be obvious calculi, particularly within the bile duct. Alternatively, the calculi may be very small and only visible on analysis of the bile. In yet other patients, no calculi may be visible at all in the biliary system, but examination of the stool shows that there have been biliary calculi, which have passed into the intestine. For example, in one study 85% of patients with gallstone associated pancreatitis had gallstones in their stools. The reason for the development of acute pancreatitis in patients with diseased biliary systems is not known, although there has been lots of speculation about bile refluxing up the pancreatic duct and causing pancreatic damage. The importance of recognising disease of the biliary system is that the acute pancreatitis associated with biliary tract disease usually occurs in patients older than 60 years and tends to be very severe, with many complications and high mortality. Recurrences, and therefore occurrences, car be prevented by elective surgery so that gallstone-associated pancreatitis can be completely cured by operation. So when I encounter a patient with symptomatic gallstones, I arrange for surgical treatment of that patient. Overall, alcoholism is the most common condition associated with acute pancreatitis. A high incidence is found particularly in the United States with parts of Europe and South Africa also quite high. Even in Scotland, where biliary disease is the commonest associated disease, the incidence of alcohol associated pancreatitis is increasing rapidly and now apparently differs from that associated with biliary disease because the alcoholic type tends to be recurrent. The first attack may be very severe, with complications and death. Subsequent attacks are mild and have a low mortality although the recurrent attacks do result in progressive destruction of the pancreas and ultimately in exocrine insufficiency. No satisfactory information is available about the nature of the toxic effects of alcohol resulting in pancreatitis. Apart from these two conditions which are probably aetiologically related to the acute pancreatitis a number of other clinical situations and diseases seem to predispose to the development of acute pancreatitis. For example, acute pancreatitis may follow abdominal surgery particularly involving the biliary tract, pancreas or stomach. In these patients pain may be absent post-operatively and the pancreatitis may present as shock, ileus and so on. Post-operative pancreatitis occurs within 1-2 days of the operation and may therefore be very misleading and overlooked. Acute pancreatitis also develops after pancreatic trauma, or invasive clinical tests such as ERCP and translumbar aortography. Recently, a number of cases of acute pancreatitis have also been reported after transplantation of, for example, the kidneys. It has been reported that the incidence of acute pancreatitis after transplantation is about 2% with a mortality of 50%-60%. The mortality is so high, it is thought, because of the immunosuppression with which these patients are treated and because the patients are hypercalcaemic and hyperlididaemic, and some suffer from infections with organisms such as cytomegalovirus. In a smaller number of patients, acute pancreatitis is associated with metabolic disorders. The one which has been recognised longest is the association with hypercalcaemia. Both acute pancreatitis and chronic pancreatitis have been observed in association with hyperparathyroidism, but acute pancreatitis has also been described during the course of hypercalcaemia caused by hypervitaminosis

Pancreatic Malfunction - When, How, Why? 39

D and metastatic bone disease. Acute pancreatitis has even been reported in patients with hypercalcaemia caused by calcium infusions. More important, numerically, is the association between acute pancreatitis and hyperlipidaemia. The hyperlipidaemia may be hereditary, and a number of reports have noted the occurrence of repeated attacks of acute pancreatitis in patients with Fredericksen's types I, IV and V hyperlipidaemia. More commonly, there is a complex interrelationship between alcoholism, alcohol-induced hyperlipidaemia (especially where the latter is acute and the result of an alcoholic binge) and acute attacks of pancreatitis. Perhaps even more important is the recently recognised association between oral contraceptives, hyperlipidaemia and acute pancreatitis. The hyperlididaemia, which may be very severe, seems to be related to the oestrogen content of the pill. When intake of the contraceptive pills is stopped, the hypertriglyceridaemia disappears and the attacks of pancreatitis cease. In addition to the acute pancreatitis associated with the intake of contraceptive drugs, it has long been recognised that acute pancreatitis occurs in patients with other diseases, who are therefore also taking drugs. A connection between attacks of acute pancreatitis and a whole range of drugs has therefore been proposed. The matter has been investigated systematically recently, since the drug histories of patients with acute pancreatitis were compared with those of age-matched controls. The only really significant difference between the two groups was a considerable excess of patients having diuretics in the group of individuals with acute pancreatitis (the diuretics being cyclopenthiazide and frusemide.). Individual reports have attributed the development of acute pancreatitis to a number of other drugs, without much reason other than the evidence of preceding drug intake. Thus, a number of reports have stated that acute pancreatitis has been associated with intake of azathioprine, for immunosuppression after transplantation and in disease such as Crohn's disease. In one such patient, reintroduction of azathioprine resulted in a recurrence of acute pancreatitis so that this matter does seem fairly well established. In a few elderly patients with diabetes who have been treated with phenformin, the development of abdominal pain following an attack of lactic acidosis was shown to be due to acute pancreatitis. Acute pancreatitis has also been observed in individuals suffering from paracetamol overdosage and it has been claimed that acute pancreatitis occurs sometimes in patients being treated with high dose steroids. Clearly, the potential importance of drug-induced acute pancreatitis is such that much more study must be devoted to this problem. Acute pancreatitis has been observed during the course of a number of infections. The association between acute pancreatitis and mumps is well known, but recent reports have shown from the examination of serum of patients with acute pancreatitis there is evidence of infection with Micoplasma pneumoniae in up to a third of the cases. Enteroviruses, such as coxsackie viruses of group B and ECHO viruses have also been reported in association with acute pancreatitis. A connection has also been proposed between viral hepatitis and acute pancreatitis. Acute pancreatitis has also been described in association with anatomical abnormalities of the pancreatic ducts or the duodenum, particularly if the latter is partly obstructed. For example, after gastric operations with afferent loop obstruction. Acute pancreatitis has been observed in patients suffering from hypothermia

40 K. G. Wormsley

and in patients voluntarily or forcibly overfed after prolonged fasting (prolonged fasting incidentally causes functional hypoplasia of the pancreas). Acute pancreatitis occurs in conditions resulting in vascular occlusion and has been reported, for example, in nearly 20% of patients with malignant hypertension. Occasionally acute pancreatitis is observed in children and is then found to be familia1. Many of the conditions which give rise to acute pancreatitis are also associated with a progressive pancreatic disease which we know as chronic pancreatitis. In particular, chronic pancreatitis occurs in alcoholics but chronic pancreatitis has also been described in patients with hypercalcaemia and hyperlipidaemia. It seems that if the pancreatic insult operates for sufficiently long, or is repeated sufficiently often, or if there is ductal obstruction, then the pancreatic repair from acute pancreatitis becomes defective and chronic pancreatitis results. We know less about the conditions under which chronic pancreatitis occurs. All studies of the epidemiology of chronic pancreatitis have emphasised the relationship to chronic alcoholism. Recently, quite a lot has also been written about the interaction of alcoholism and general nutrition in the development of chronic pancreatitis. For example, the development of chronic calcifying pancreatitis has been attributed to an interaction between alcoholism and intake of a high protein and high fat diet. Alternatively, chronic calcifying pancreatitis has been noted to develop in countries in which there is a lot of malnutrition, in the form of protein deficiency. In the latter countries, the chronic pancreatitis develops quite early in life with a mean age of onset under 15 years. In the UK and Western countries it is interesting that the apparent mean age of onset of chronic pancreatitis is about 35 years while the mean age of onset of acute pancreatitis is about 2 decades older. These values have been interpreted as showing that in Europe and the United States there is probably a population of alcoholics who develop chronic pancreatitis in middle age, while another group, of non-alcoholic chronic pancreatitis, has a low incidence of acute pancreatitis which is fairly uniform throughout life. Severe pancreatic dysfunction, of the type seen in chronic pancreatitis, occasionally occurs in families and may then be associated with other clinical features, such as aminoaciduria or bone marrow dysplasia etc. In the United States cancer of the pancreas is the fourth commonest cause of cancer death after lung, large intestine and breast with nearly 25000 new cases per annum. The incidence has increased threefold during the past 30 years or so. The disease is more common in males than females and in persons over 45 years old. A very high incidence has been reported in the Maoris of New Zealand but there is also an increased incidence in the Negroes ofthe United States and Polynesians in Hawaii. An increased incidence of pancreatic cancer has also been recorded in professional chemists in the United States and this increase has been attributed to some environmental carcinogens. Cancer of the pancreas is about twice as common in smokers than in non-smokers. There is also a significant correlation between the intake of fat in a population and the national incidence of the disease. Pancreatic cancer is twice as common in patients with diabetes mellitus as in the general population. Significant correlation has also been recorded between the national incidence of inflammatory pancreatic disease and the incidence of pancreatic cancer. We have a little information about circumstances under which the pancreas goes malignant, derived from experimental studies. Thus, we have found recently that


repeated injection of cholecystokinin for 6 months may result in pancreatic malignancy. Similar changes occur when rats are fed raw soya flour. We do not yet know whether these fmdings have human implications.

Pancreatic Malfunction - How?

This question, too, can be asked in two ways. Thus "how does malfunction occur?". What are the mechanisms by which the pancreatic cells die acutely and then why do they not, sometimes, regrow? We cannot answer either part of this question defmitively. Since Chiari, it has been held that acute pancreatitis represents "autodigestion" of the pancreas. I have never heard anyone suggest that the acute cell death in acute hepatitis is caused by "autodigestion" and since the processes seem rather similar, I think that we must keep an open mind about the cause of the acute cell death in acute pancreatitis. As for the development of chronic pancreatitis, the only suggestion about why acute cell death is not followed by regeneration has been the finding that experimental pancreatic ductal occlusion prevents regrowth of pancreatic cells. There are clear clinical implications in this finding. We also know that repeated administration of large amounts of pancreatic stimulants such as caerulein can result in failure of pancreatic acinar cells to regrow after necrosis, while some dietary deficiencies (such as copper) can also result in pancreatic acinar cell atrophy. The relevance of these fmdings to human disease is not yet clear. As for determining why pancreatic cells undergo malignant change, the only hint we have from experimental studies is that a persistent stimulus to hyperplasia, especially when combined with an environmental carcinogen, can result in a high incidence of pancreatic cancer in experimental animals. We can also reinterpret the question "how does the pancreas malfunction?" by asking "how do we know that the pancreas is not functioning normally?". Both acute and chronic inflammatory disease of the pancreas have quite profound effects on the function of other systems of the body. I am going to deal with the systemic manifestations of acute pancreatitis first, and then with those of chronic pancreatitis and I will deal with these manifestations system by system. I will deal with involvement of the gastrointestinal system in acute pancreatitis first. The most serious gastrointestinal complications of acute pancreatitis are, of course, those affecting the pancreas itself and peripancreatic tissues which are involved in the necrosis and which become infected easily because of the quite severe tissue damage. Ileus, of the paralytic type, occurs when there is general peritoneal involvement in the pancreatitic process. Alternatively, localised paralytic ileus may affect short segments of jejunum or colon, adjacent to the inflamed pancreatic tissue, and give rise to radiological "sentinel" signs. That means that there is just one dilated loop of the bowel visible. Intestinal obstruction may also be mechanical, on the basis of localised colonic or, less commonly, small intestinal or duodenal stenosis. These stenoses are thought to arise from direct involvement in the pancreatic inflammatory process or from ischaemia caused by occlusion of the appropriate ar-

42 K. G. Wormsley

terial supply. More acutely, intestinal obstruction of the mechanical type may result from small intestinal infarction following mesenteric arterial or venous occlusion. An important cause of morbidity and mortality during attacks of acute pancreatitis is bleeding from the alimentary tract. Severe haemorrhage is reported to occur in up to 12% of patients with acute pancreatitis and to be fatal in up to 50% of these. The most severe haemorrhage is caused by erosion of major blood vessels such as splanchnic or colonic arteries by the pancreatic inflammatory process and occurs during the 2nd or 3rd week of the illness. In other instances, bleeding may result from vascular occlusions, e. g. of the splenic or portal vein (which may result in secondary development of varices), or acute haemorrhage may occur on the basis of acute erosive ulceration of the stomach and duodenum or sometimes may reflect a generalised haemorrhagic diathesis. Acute pancreatitis may also result in the development of perforation or intestinal fistulae. For example, perforation of the colon has been reported on a number of occasions. In other instances, there is no free perforation into the peritoneal cavity but fistulation occurs which reflects rupture of a pseudocyst into the stomach or colon. More dangerous enteric fistulae include duodeno-colonic communications, or entero-cutaneous fistulae. Perhaps the most common manifestation of fistula formation, however, is the development of serosal effusions. Acute pancreatitis, like chronic pancreatitis, may result in massive ascites, or pleural or pericardial effusions, which are recognised because of serosal fluid contains large amounts of pancreatic enzymes.

Hepatobiliary System

The manifestations of acute and chronic pancreatitis may involve dysfunction of the hepatobiliary system. Jaundice is quite common in acute pancreatitis and has been reported to occur in up to 20%-40% of patients during or after an acute attack. In many patients, the jaundice reflects the underlying calculous disease of the biliary tract which has presumably caused the pancreatitis. Stones in the bile duct are therefore the commonest cause of jaundice in acute pancreatitis. However, other reasons for bile duct obstructions are obvious, since the bile duct passes through the head of the pancreas in more than 90% of individuals. Inflammatory and pseudocystic masses may obstruct the bile duct, or there may be actual stenosis of the lower end of the bile duct as a late result of the fibrotic changes following the acute inflammatory process. A different clinical problem may be presented by the patients in whom obstructive jaundice develops in the absence of gallstones, since it is imperative to exclude small carcinomas of the papilla or head of the pancreas in these instances. Not only bile duct obstruction, but hepatocellular disease is common in patients with acute pancreatitis. Some type of cellular disease of the liver has been reported in up to 70% of patients with acute pancreatitis. One of the commonest changes is acute fatty liver, which occurs in about two-thirds of the patients with alcoholic pancreatitis and about one-quarter of patients with acute pancreatitis attributable to other causes. The fatty infiltration may be an acute process, ac-


companied by rapid enlargement of the liver. Biochemical features of cholestasis or hepatocellular damage are common. Severe degrees of acute fatty change may result in hepatocellular failure and death. In addition to fatty liver, liver cell necrosis also occurs particularly in patients who have developed shock. Liver cell necrosis also occurs in patients who have necrotic lesions of other parts of the alimentary tract such as small intestinal or splenic infarction or in those with septicaemia. A few patients who develop acute alcoholic pancreatitis do, of course, suffer from alcoholic cirrhosis of the liver, which may decompensate during an attack of acute pancreatitis.

Metabolic Complications

One of the most important complications of acute pancreatitis is the accompanying hypocalcaemia. Hypocalcaemia is found in 10%-30% of patients with acute pancreatitis and is important because low serum calcium values mean that the attack of pancreatitis is severe and that prognosis is bad. There has been a lot of argument about the causes of the hypocalcaemia. Originally, the hypocalcaemia was considered to be caused by the binding of calcium to the fatty acids in areas of fat necrosis. More recently, the changes in serum calcium levels have been attributed to the alterations in levels of some circulating hormones which occur in acute pancreatitis. For example, it was noted that in acute pancreatitis, the blood levels of glucagon were often raised. Glucagon stimulates the release of calcitonin (which is, of course, a calcium-lowering hormone) and it has indeed been shown that blood levels of calcitonin are also increased during attacks of acute pancreatitis. However, it has also been reported that the level of these hormones, which lower blood calcium concentrations, do not correlate with the hypocalcaemia which is found during attacks and papers have even reported that glucagon and calcitonin are not abnormal at all in acute pancreatitis. So that the role of glucagon and calcitonin and the development of the hypocalcaemia of acute pancreatitis is not at all certain. Perhaps more important, there has been a lot of argument about the role of parathyroid hormone and the development of hypocalcaemia. Some of the patients have had undetectable levels of parathyroid hormone, and this has been interpreted as being caused by parathyroid exhaustion. In other patients parathyroid hormone levels are normal, or even raised. These patients have been considered to suffer from a relative lack of parathyroid hormone (i.e. the blood level of parathyroid hormone has not been as high as it should be relative to the low calcium levels.). Alternatively, it has been suggested that there may be resistance to the action of the parathyroid hormone. Acute pancreatitis with significantly raised levels of parathyroid hormone, of course, must raise the suspicion that the acute pancreatitis is the consequence of the hypercalcaemia rather than that the calcium changes are the consequence of the acute pancreatitis. Just one last word about calcium levels. It has been reported that in many patients with hypocalcaemia the low calcium levels mainly reflect hypoalbuminaemia and do not indicate real hypocalcaemia at all. That can easily be worked out by correcting for true calcium levels, of course.

44 K. G. Wormsley

Another complication of both acute and chronic pancreatitis, is disturbance of carbohydrate metabolism because pancreatic disease affects the function of the pancreatic islets. For example, in some patients with acute pancreatitis the serum glucagon levels may be raised, despite high blood sugar levels, indicating impaired a-cell function. In more severe haemorrhagic pancreatitis, blood glucagon levels may be very low, comparable with a-cell destruction. Similarly, in chronic pancreatitis, glucagon release in response, for example, to intravenous infusion of aminoacids such as arginine may be quite abnormally low, suggesting the a-cells of the islets are not functioning properly. This hase some clinical significance because on occasion patients with chronic pancreatitis present with attacks of hypoglycaemia, rather than the usual diabetes which we recognise in this disease. In additions, patients with chronic pancreatitis are often extremely sensitive to insulin and may develop hypoglycaemic unresponsiveness because of the abnormalities of glucagon release. Abnormalities in the secretion of insulin are more important than the abnormalities of glucagon secretion. In many patients with acute pancreatitis, blood levels of insulin are raised, almost to the levels expected from the blood levels of glucose. There is, however, usually a relative deficiency in the secretion of insulin, which may become absolute if the ~-cell destruction is severe and lead to transient or permanent diabetes mellitus, sometimes with acute keto-acidosis. While transient diabetes is quite common in acute pancreatitis, permanent diabetes as a result of acute pancreatitis is rare and occurs in only about 2% of the cases. The state of function of the ~-cells of the islets in chronic pancreatitis varies enormously and ranges from quite normal to totally impaired. That is, there may be no diabetes mellitus, there may be mild adult onset type diabetes which is treatable with hypoglycaemic drugs or there may be insulin-requiring diabetes which requires normal amounts of insulin, may be very resistant to insulin or may be very brittle in type presumably because of coincident glucagon deficiency. A third metabolic complication of acute pancreatitis is hyperlipidaemia. There is a lot of confusion about this topic, because it is still not clear whether the abnormalities in the circulating lipoproteins are primary and precede and perhaps even cause the acute pancreatitis, and rarely chronic pancreatitis, or whether the hyperlipaemia is the consequence of the acute pancreatitis or whether both pancreatitis and hyperlipaemia are manifestations of some underlying disease process. We can be certain that in some patients with acute pancreatitis, abnormalities of circulating lipoproteins precede the attacks of acute pancreatitis and the blood abnormalities persist when the patients have recovered from the pancreatitis. The hyperlipoproteinaemia is usually of types 1 or types 5 with high levels of circulating chylomicrons and may be hereditary, or the consequence of taking contraceptive pills. In other patients, there is associated diabetes, which, of course, may also be responsible for the hyperlipaemia. Alternatively, both the hyperlipoproteinaemia and the acute pancreatitis may be the result of alcoholism. It has been estimated that only about 2% of patients with acute pancreatitis develop transient hyperlipaemia during the course of the attack. In some of these patients an inhibitor of plasma lipoprotein lipase has been described. Other reports have suggested that the lipoprotein lipase levels may be abnormally low or that the complexes between lipoprotein lipase and triglyceride are unusually resistant


to the action of lipoprotein lipase. Alternatively, deficiency of insulin may result in a type 1 hyperlipoproteinaemia. Whatever the nature of the defect of fat metabolism in acute pancreatitis, it is necessary to make quite sure that the changes, if they are persistent, are not the cause of the pancreatic disease because very often the hyperlipoproteinaemia is treatable and needs to be treated for reasons other than the acute pancreatitis.

H aematological Complications

While anaemia, attributable to haemorrhage from the alimentary tract, thrombocytopenia and pancytopenia have been recorded in patients with acute papcreatitis, abnormalities involving the cellular elements of the blood are not particularly important in this disease. On the other hand, disorders of the coagulation of blood may playa very important part in the clinical picture of all the pancreatic diseases. In acute pancreatitis both impaired coagulability of the blood and excessive coagulability have been described. The impaired coagulability may result in or aggravate bleeding from the alimentary tract and into the skin, as well as into the necrotic pancreas itself. While factors such as thrombocytopenia and, perhaps more important decreased circulating clotting factors such as factors II, VII, IX and especially fibrinogen are responsible for the impaired coagulability, these deficiencies themselves may represent, and be secondary to, a state of disseminated intravascular coagulation, resulting also in disseminated fibrin thrombi, which are responsible for some of the clinical manifestations of severe attacks of acute pancreatitis, particularly the pulmonary complications which result in hypoxaemia, and the renal impairment with azotaemia, as well as the hepatocellular disruption which I have already described. Rather different, patients with acute pancreatitis, chronic pancreatitis and pancreatic cancer, may suffer from an increased tendency to thrombose major arteries and veins. The thrombotic tendency manifests by an increased incidence of deep vein thrombosis of the legs, or occlusion of major arteries like the cerebral circulation. Occasionally there may be frank thrombophlebitis migrans which may also affect the arteries, and, in patients with pancreatic cancer especially, the thrombotic tendency may result in the production of a verrucous endocarditis which can loose off emboli which also produce, for example, occlusion of cerebral arteries and other major- blood vessels. The mechanisms of both the disseminated intravascular coagulation and the tendency to thrombose blood vessels has been considered to reflect liberation of proteolytic enzymes like trypsin and elastase into the circulation but we really do not know the cause yet. What I would say is that both these disorders of coagulation of blood can have really very important implications for the life of the patients.

Renal Complications

The renal complications of acute pancreatitis are common and important and range from reversible renal tubular defects which account, for example, for the

46 K. G. Wormsley

increased amylase to creatinine clearance ratio in patients with this disease to severe renal failure, which is lethal in more than half the affected patients. Several lesions may be responsible for the acute renal failure. Hypovolaemic shock may produce prerenal uraemia, or renal tubular necrosis. Acute renal failure may result from renal artery thrombosis as a result of the pancreatitic process of from renal cortical necrosis when the small arteries are thrombosed. Quite commonly, the renal glomeruli are shown to be site of fibrin thrombi, reflecting the tendency to develop diffuse intravascular coagulation in acute pancreatitis.

Neurological Complications

During attacks of acute pancreatitis, patients may become confused, anxious and acutely delirious, with hallucinations, as well as being apparently ataxic and dysarthric. Examination revealed hyperreflexia and sometimes extensor plantar responses. Such neurological involvement often occurs in attacks of acute pancreatitis which end fatally, so that is has been possible to show that there are foci or diffuse areas of demyelination throughout the central nervous system, which have been attributed to the action of circulating lipase. The encephalopathy usually occurs between the 2nd and 5th day of acute attacks of pancreatitis. This type of organic delirium must be differentiated from delirium tremens, which may accompany an attack of acute pancreatitis in an alcoholic patient.

Cardiovascular Complications

The most important cardiovascular complication of acute pancreatitis is circulatory failure in the form of shock, some degree of which occurs in up to 60% ofpatients. There is reduction in circulating plasma volume, with vasoconstriction and fluid sequestration. These changes have been attributed to diffuse vascular injury, perhaps caused by circulating proteases and kinins from the damaged pancreatic cells. In some patients, circulatory collapse is more simply attributable to overt haemorrhage from the gastrointestinal tract. Surprisingly, transient hypertension has been reported in patients with acute pancreatitis in up to a third of the effected individuals during an acute attack. Such attacks seem to have a bad prognostic significance, since ,the patients with hypertension subsequently developed serious complications ranging from shock, renal failure, hypocalcaemia to pancreatic ascites and death. Acute pancreatitis can confusingly mimic cardiac infarction. ECG changes resembling myocardial infarction quite frequently develop and may be associated with an arrhythmia such as atrial fibrillation. The association of upper abdominal pain, transient hypertension and ECG abnormalities in patients with acute pancreatitis must be kept in mind for differentiating from myocardial ischaemia or infarction. Thrombosis of major or minor arteries and veins has been described in all forms of pancreatic disease and may, of course, give rise to protean clinical manifestations. The thrombotic tendency has been attributed to the effects of circulating proteases on the coagulation factors of the blood.


Pulmonary Complications

Pleuro-pulmonary complications occur in 10%-55% of patients with acute pancreatitis. By far the most serious is acute respiratory failure, which results in progressively severe hypoxaemia, a condition which is potentially lethal within 24 h. About 5% of patients with acute pancreatitis develop clinical respiratory distress characterised by an increase in the pulmonary extravascular water and abnormal gas distribution patterns. It has been suggested that circulating pancreatic enzymes and kinins act on the pulmonary capillaries to produce loss of integrity of the alveolo-capillary membrane resulting in fluid loss and pulmonary oedema. The specific "pancreatic" pulmonary changes may be aggravated by fat emboli (from the associated fat necrosis) and especially the fibrin thrombi resulting from the disordered intravascular coagulation. In addition to the pulmonary oedema, areas of atelectasis, pneumonitis and pulmonary infarction occur. In fatal cases of acute pancreatitis, the lungs are stated to be oedematous, with subpleural haemorrhage, and areas of atelectasis and interstitial pneumonitis. Local pulmonary changes are aggravated by the subdiaphragmatic, inflammatory and infective conditions and the ileus which often accompanies acute pancreatitis. The clinical features are those of respiratory decompensation with anxiety and tachypnoea, with progressive arterial hypoxia. Dyspnoea and confusion become more severe and radiological investigation shows bilateral diffuse pulmonary infiltrates. In patients with alcoholic pancreatitis, the differential diagnosis includes delirium tremens and aspiration of gastric contents. Treatment involves intermittent or continuous positive end pressure ventilation with a tidal volume of about 10-15 ml/kg. The haemoglobin should be above 130 g/litre and serum albumin > 30 g/litre. About one-third of patients who die do so of pulmonary failure and it seems probable that respiratory insufficiency contributes to death in another third.

Cutaneous Changes

The external manifestations of acute pancreatitis are uncommon and reflect other underlying pathophysiological processes. For example, icterus indicates bile duct obstruction or hepatocellular disease and ecchymoses often indicate a generalised disorder with defective blood coagulation, although the bleeding may have been confined to the necrotic pancreas, whence the blood has tracked into the left flank (Grey-Turner's sign) or to the periumbilical skin (Cullen'S sign). Perhaps the only specific cutaneous feature of acute pancreatitis and other forms of pancreatic disease like cancer, is the necrosis of the subcutaneous fat which occurs sometimes. Clinically, the fat necrosis presents as fluctuant lumps, which may resemble erythema nodosum, although ulceration through the skin with discharge of the necrotic contents also occur sometimes. The differential diagnosis is from other forms of panniculitis, such as Weber-Christian disease, or cutaneous vasculitis.

48 K. G. Wormsley

The cutaneous fat necrosis may be accompanied by fat necrosis of the synovial membranes of the large joints, resulting in severe arthralgias and arthropathies or necrosis of the fat of the bone marrow, with resulting necrosis of the long bones. It has been suggested that the fat necrosis results from the action of circulating lipase, released from the necrotic pancreatic tissue.

Prognostic Factors

The implications of some of the systemic manifestations of acute pancreatitis are well shown by an analysis of the factors which have been shown to affect the prognosis of an acute attack. As you can see, evidence of pulmonary involvement in the form of polypnoea and progressive arterial hypoxaemia, cardiovascular involvement in the form of shock, producing fluid sequestration, gastrointestinal complications causing haemorrhage, hepatic involvement with raised serum enzymes, renal failure as shown by increased blood urea or creatinine, or metabolic complications giving rise to hypocalcaemia and diabetes all have bad prognostic implications. That is, these systemic manifestations of acute pancreatitis are the cause of death. In the case of chronic pancreatitis and pancreatic cancer the systemic manifestations really are of no more than incidental interest.

Cause of Death

To sum up, one facet of the importance of the different systemic manifestations of acute pancreatitis is the effect on the life of the patient. About half the fatalities occur in the 1st week after the onset of the attack, usually the first attack. Many of these patients suffer from intractable circulatory collapse, with respiratory and or renal failure. Other causes of death include septicaemia and gastrointestinal haemorrhage particularly from erosion of major blood vessels. A number of patients with alcoholic pancreatitis die in a delirious hyperactive state with mental confusion suggesting delirium tremens. So in acute pancreatitis the systemic manifestations are very often lethal and very important.

Chronic Pancreatitis

The principal systemic complications of chronic pancreatitis are the consequence of the progressive destruction of the pancreatic exocrine and endocrine function. The result is severe disturbance of all the processes involved in the assimilation of food. It is easiest to consider pancreatic exocrine insufficiency as a disturbance of the food assimilation of the body system. We see the body as a system demarcated from the environment, with a subcompartment ofthe environment - the lumen of the small intestine - within the body. A disease creating dysfunction, of one of the processes involved in the transferring food from the environment into the body, produces disturbances of all the other processes. In the case of chronic pancreatitis the process that is disturbed is that of digestion of food.


If we start with the ingestion of food as our first process of assimilation we note that this process is abnormal in patients with chronic pancreatitis. Some patients eat very little because they have severe pain, and are drug addicts, and that has made them anorexic. The majority eat a lot, more than normal, and therefore fill their alimentary tract with greater than normal amounts of food. In the stomach we encounter abnormalities of two important processes involved in the assimilation of food. Firstly, gastric secretion is often abnormally increased in patients with chronic pancreatitis, although other patients, perhaps suffering from alcoholic gastritis, secrete normal or less than normal amounts of gastric juice. The second abnormality of gastric function involves the process of transferring food from the stomach into the small intestine, that is gastric emptying. In patients with chronic pancreatitis gastric emptying is often abnormally rapid. The net result of these abnormal processes is that abnormally large amounts of food and acid are delivered into the upper small intestine excessively rapidly. In the duodenum, the abnormally large amounts of food encounter abnormally small amounts of pancreatic digestive enzymes, and the abnormally large amounts of acid meet abnormally small amounts of bicarbonate. This latter results in acid intraluminal contents which further reduce, by denaturation, the abnormally small amounts of enzymes secreted by the diseased pancreas. The maldigestion which according to secretory tests may not be very severe, is therefore rendered sufficiently complete to result in steatorrhoea, and so on. It is interesting that here we have a vicious circle, where defect in one process -maldigestion - produces defects in all the other processes involved in the assimilation of food. When there is malassimilation of food, appetite increases, because both local alimentary and blood-borne hormonal factors stimulate the appetite centres of the hypothalamus. Gastric secretion is abnormally high both because normal inhibition of gastric secretion is impaired, the normal inhibition being caused especially by the breakdown products of fat in the upper small intestine (and, of course, there are only small amounts of these breakdown products of fat available in chronic pancreatitis) and also because gastric secretion is actually stimulated by undigested food in the small intestine. Similarly, gastric emptying is abnormally rapid because gastric emptying is usually braked by the breakdown products of food in the proximal duodenum. As a result of all these interacting abnormal processes, there is very severe maldigestion of food. There is also, however, some malabsorption. The malabsorption may be specific. For example, half the patients with chronic pancreatitis have malabsorption of vitamin B12 because some factor related to pancreatic proteases is necessary for the normal absorption of the vitamin. There is also actual malabsorption of fat. Thus, there is interference with a normal transfer of fatty acids from the micelles in the intestinal lumen into the absorptive cells of the small intestine. The abnormality appears to be caused by lack of phospholipase in the pancreatic juice of patients with chronic pancreatitis. As a result lecithin in the luminal contents of the intestine is not converted to lysolecithin and lecithin has been found to inhibit the transfer of fatty acids.

Summing up. The pancreatic exocrine deficiency which characterises chronic pancreatitis results in maldigestion which, in turn, affects other processes involved in the digestion and absorption of food, so that severe malassimilation results. The

50 K. G. Wormsley

effects of the malassimilation are aggravated by the abnormalities of disposal of food products once they have been absorbed, because of the often severe abnormalities of endocrine function of the pancreas, especially of the secretion of insulin and glucagon. The symptoms of pancreatic cancer depend in part on the site within the pancreas since, for example, this location determines the site of the pain and the incidence of jaundice. Pain occurs as a presenting feature in 50%-80% of patients and at some time during the disease in up to 90%. The pain is dull, aching epigastric and going through to the back, worse at night and sometimes aggravated by food intake. Jaundice is present as first symptom in 10%-30% of patients but occurs at some time during the disease process in up to 90% of patients. Pain preceded jaundice by an average of 13 weeks in one study. In other patients jaundice is painless originally but only 20% remain painless throughout the course of their disease. Spontaneous fluctuations in the severity of the jaundice occur in 10% of the patients. Jaundice is accompanied by severely disabling pruritus in many of these individuals. Loss of weight is the commonest symptom and usually precedes the other symptoms. Weight loss affects 70%-90% of patients at the time of diagnosis. The cause of the weight loss, which is progressive, is probably a combination of maldigestion and anorexia. Other symptoms include flatulence, weakness, fatigue, diarrhoea or constipation. The commonest physical signs are jaundice, hepatomegaly and abdominal tenderness. Hepatomegaly occurs in 20%-60% of the patients in different series, and abdominal tenderness in up to half. Less usual features include thrombophlebitis migrans and thrombotic features like non-bacterial verrucous endocarditis, which may embolise. Panniculitis can also occur. In patients with cancer of the tail of the pancreas, a few patients develop abdominal masses before a diagnosis is made. Diabetes mellitus may occur abruptly or if diabetes has been present for a long time it may become difficult to manage. There is almost no 5 year survival in this disease and the 1 year survival rate is only 8%.

Pancreatic Malfunction - Why?

We do not know why pancreatic malfunction occurs - but we can state that pancreatic malfunction is observed when the pancreas does not secrete sufficient enzymes to digest food satisfactorily or does not secrete sufficient hormones to maintain glucose etc., homeostasis. Four main clinical pictures make us suspect that pancreatic disease is present. That is, we have to think of pancreatic disease when a patient complains of upper abdominal pain; or has steatorrhoea; or if an elderly patient suddenly develops severe diabetes mellitus; or if a patient becomes jaundiced. We have available a large battery of tests now, which are perhaps best used thus:

Abdominal pain. If we suspect that the pain is attributable to an attack of acute pancreatitis, or to relapse of chronic pancreatitis, there are often changes in blood


levels of pancreatic enzymes. Most hospitals measure amylase (in blood or urine) but amylase can originate in other tissues, so that unless blood levels are very high, or the isoamylase is shown to be pancreatic, we cannot make a definitive diagnosis. Perhaps measurement of the pancreatic proteases by immunoassay techniques will improve the discriminant power of blood enzyme determinations. Blood levels of enzymes do not help in diagnosing pancreatic cancer. If serum enzyme levels indicate acute pancreatic necrosis, or if we suspect that the pain is caused by pancreatic cancer, we next carry out morphological tests. Ultrasonography, or CT scanning, shows us the size and shape of the pancreas, and whether the pancreas is clearly separated from surrounding tissues or infiltrates surrounding structures. The pancreas involved in acute inflammation is often large, oedematous and merges into its surroundings - as, of course, do sufficiently large pancreatic cancers. Functional studies are also quite usefu1. During the acute phase of pancreatitis, radioselenium uptake may be absent, while secretory tests are necessary after recovery from an acute episode of pain to determine whether exocrine and endocrine function has been reestablished. We must not, of course, forget to investigate for associated conditions, such as disease of the biliary system and metabolic disorders which may be responsible for the pancreatic disease. Patients who present with steatorrhoea require, in the first place, secretory studies to demonstrate pancreatic hypofunction. In a recent prospective study, a test of pancreatic secretory capacity with stimulation of the pancreas by cholecystokin and ultrasonography were equally sensitive in detecting the presence of pancreatic disease. Similarly, the findings of secretory studies and ERCP were well corre-lated. " We can therefore use a test of pancreatic secretory capacity to detect pancreatic hypofunction and, consequently, the presence of pancreatic disease. Similarly, we can use morphological measures of the size of the pancreas -like ultrasonography and a CT scan, to show us whether the pancreas is enlarged or not and whether it is deformed or not and whether it merges into the surrounding tissues - but neither of these investigations differentiate between cancer of the pancreas and chronic pancreatitis. The differential value of ERCP is somewhat greater, since ductal appearances may be diagnostic of pancreatic cancer, although the appearances are usually non-specific. Appearances which are characteristic of cancer include partial or complete stenosis of the duct, necrotic tumour cavities and parenchymal filling defects. The only means we have at present of definitively establinshing the diagnosis of pancreatic cancer is cytologica1. Neoplastic cells have been successfully demonstrated in aspirated pure pancreatic juice and in duodenal contents after tests of pancreatic function and also in the brushings during endoscopic cannulation of the pancreatic duct. Alternatively, biopsy material can be obtained during endoscopy by pushing a needle through the wall of the duodenum into the head of the pancreas; by laporoscopy or laparotomy or also percutaneously and these biopsies can then by examined for malignant cells. Patients with obstructive jaundice require screening of the same type as patients with steatorrhoea. Pancreatic hypofunction, established by secretory tests, shows that the pancreatic duct is occluded by whatever disease is causing the bile duct

52 K. G. Wormsley

obstruction - or, if pancreatic exocrine function is normal, the obstruction involves the bile duct alone. The secretory studies must be followed my morphological tests, especially ERCP, and by cytological studies to provide confirmation of malignancy. Angiography has been used in the diagnosis of the cause of obstructivejaundice (and steatorrhoea, etc) but is really useful only for the staging of the pancreatic cancer. Patients who suffer from diabetes mellitus may have quite markedly impaired pancreatic exocrine function as a result of the diabetes. However, the pancreatic hypofunction is not sufficiently severe to cause steatorrhoea. If diabetes is secondary to inflammatory or malignant pancreatic disease, the morphological tests (such as ultrasonography or CT scanning) usually show an abnormal pancreas. Cytological studies are then required to establish the presence of malignancy.

Acknowledgements

The author gratefully acknowledges receipt of a research grant from the Scottish Hospital Endowments Research Trust.

References

Arvanitakis C et al. (1978) Diagnostic tests of exocrine pancreatic function and disease. Gastroenterology 74:932

Cameron IL (1978) Chronic pancreatic ascites and pancreatic pleural effusions. Gastroenterology 74:134

Cotton PB (1977) Progress Report. ERCP. Gut 18:316 Cushieri A et al. (1978) Value oflaparoscopy in the diagnosis and management ofpancreat

ic carcinoma. Gut 19:672 Day IL et al. (1972) The role of pancreatic glucagon in the pathogenesis of acute pancreati

tis. Clin Sci 43:597 Di Magno EP et al. (1977) A prospective comparison of current diagnostic tests for pan-

creatic cancer. N Engl I Med 297:737 Dreiling DA et al. (1975) Pregnancy and pancreatitis. Am J Gastroenterol 64:23 Dreiling DA et al. (1977) Steroids revisited. Am I Gastroenterol 67:21 Evander A et al. (1978) Percutaneous cytodiagnosis of carcinoma of the pancreas and bile

duct. Ann Surg 188:90 Ferrucci IT (1976) Radiology of the pancreas. Radiol Clin N Am 14:543 Fitzgerald PI et al. (1978) The value of diagnostic aids in detecting pancreatic cancer. Can

cer 41:868 Freund H et al. (1976) Gallstone pancreatitis. Arch Surg 111:1106 Frier BM et al. (1976) Exocrine pancreatic function in juvenile onset diabetes mellitus. Gut

17:685 Goldman ML et al. (1977) Preoperative diagnosis of pancreatic carcinoma by percutaneous

aspiration biopsy. Am I Digest Dis 22:1076 Haaga IR et al. (1975) Computed tomographic scanning of the pancreas. Radiol Clin N Am

15:367 Hatfield ARW et al. (1976) Assessment of endoscopic retrograde cholangiopancreatogra

phy and pure pancreatic juice cytology in patients with pancreatic disease. Gut 17:14 Hayes MF et al. (1974) Adult respiratory distress syndrome in association with acute pan

creatitis. Am J Surg 127:314 Heitsch RC et al. (1976) Delineation of critical factors in the treatment of pancreatic trau

ma. Surgery 80:523


Jacobs ML et al. (1977) Acute pancreatitis: Analysis of factors influencing survival. Ann Surg 185:43

Kelly TR (1976) Gallstone pancreatitis: Pathophysiology. Surgery 80:488 Kruse A et al. (1978) Endoscopic retrograde cholangiopancreatography in pancreatic can

cer and chronic pancreatitis. Scand J Gastroenterol13:513 Levitt MD et al. (1978) Is the Cam/Ccr ratio of value for the diagnosis of pancreatitis? Gas-

troenterology 75:118 Morgan RGH et al. (1977) Cancer of the pancreas. Gut 18:580 Mungall IPF et al. (1975) Pancreatitis and the pill. Postgrad Med J 51:855 Ranson JHC et al. (1974) Prognostic signs and the role of operative management in acute

pancreatitis. Surg Gynecol Obstet 139:69 Reuben A et al. (1978) Operative pancreatic biopsy. Ann R Coll Surg Eng160:53 Riccardi VM et al. (1975) Hereditary pancreatitis. Arch Intern Med 135:822 Robertson GM et al. (1976) Inadequate parathyroid response in acute pancreatitis. N Engl

J Med 294:512 Rosen RD (1976) Pancreatitis and hyperparathyroidism. Postgrad Med J 52:95 Salmon PR (1978) Re-evaluation of endoscopic retrograde cholangiopancreatography as a

diagnostic method. Clin Gastroenterol 7:651 Sarles H et al. (1978) Cholestasis and lesions of the biliary tract in chronic pancreatitis. Gut

19:851 Sarles H et al. (1979) A multicenter inquiry into the etiology of pancreatic diseases. Diges

tion 19:110 Sheedy PF et al. (1977) Computed tomography of the pancreas. Radiol Clin N Am

15:349 Stanley JC et al. (1976) Major arterial haemorrhage: A complication of pancreatic pseudo

cysts and chronic pancreatitis. Arch Surg 111:435 Storck G et al. (1976) A study of autopsies upon 116 patients with acute pancreatitis. Surg

Gynecol Obstet 143:241 Toft PM et al. (1978) Acute pancreatitis following renal allotransplantation. Am J Digest

Dis 23:541 Trapnell JE et al. (1975) Patterns ofincideace in acute pancreatitis. Br Med J 11:179 Tsuchiya R et al. (1977) Endoscopic aspiration biopsy of the pancreas. Gastroenterology

73:1050 Vicary FR (1977) Ultrasound and gastroenterology. Gut 18:386 White TI et al. (1976) Operative and endoscopic pancreatography in the diagnosis of pan

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Surgery 80:518 Wormsley KG (1976) Pathophysiology of the pancreas. In Handbuch der inneren Medizin,

Vol 3: Digestive organs; Part 6: Pankreas; Fore11 MM (ed). Springer, Berlin Heidelberg New York, p 195

Pancreatic Extracts in Chronic Pancreatitis: Which, How and When?

G. Dobrilla, M. Felder, and G. de Pretis

Ospedale Generale Regionale di Boizano, Divisione di Gastroenterologia, Via Sernesi 1, 39100 Boizano, Italy

Introduction

The primary function of the exocrine pancreas is the secretion of amylolytic, lipolytic, and proteolytic enzymes into the duodenum in response to the alimentary stimulus. The almost instinctive tendency to administer pancreatic enzymes to patients with pancreatic disease and secondary functional insufficiency is therefore not surprising, so that enzymatic activity in the small intestine can remain sufficient to prevent and/or to treat maldigestion of foods. However, although an oral enzyme replacement of this kind has for quite a long time been available, many reviews [1-4] have pointed out the lack of a rational therapy based on sound physiologic measurements. This explains the existence of numerous pharmacologic preparations, different dosages used, frequent variability of their administration, and the difference in clinical results obtained. Even authoritative textbooks, both of pharmacology and gastroenterology [5, 6], do not prove to be entirely pertinent, thus confirming how slow they are to assimilate data deriving from new scientific developments or from the controlled clinical trials [7]. It is in the light of this recent information that in the following paragraphs we shall discuss which enzymatic preparations are suitable for use, and how and when to administer them.

Which?

The digestive enzymes employed in clinical practice are usually total extracts of bovine or porcine pancreas or sometimes, alone or in combination with these, some proteolytic enzymes of vegetal origin [8]. It has also been maintained that enzymes of bacterial origin may prove to be therapeutically suitable [9]. When the problem of choice is practically considered, i.e., which are the marketed preparations to be used, one is faced with the fact that little is known about the degree of enzyme activity of the commercial extracts and that only limited information is available as far as the activities of the replacement enzymes ingested by the patients are concerned. In fact, it is difficult to perform either a precise evaluation or a comparison of the in vitro digestive capacity of the enzymatic preparations, as reported by the manufacturers, due to the great variations in the enzyme assay procedures and units used. After a relatively recent introduction of a standard method of assay [10] an acceptable comparison of the enzymatic activities of the

56 G. Dobrilla, M. Felder, and G. de Pretis

commercial pancreatic extracts has become possible. Adopting such a method, a wide range of enzymatic activities has been shown in commercial pancreatic extracts [11], which confirms some older reports [12, 13] and is itself confirmed by a more recent paper [14]. Although there is more than one factor which can influence the final therapeutic result of the pancreatic extracts, as will be discussed below, an adequate enzymatic activity in vitro of these preparations seems a basic condition for an effective treatment, because correlation between activity in vitro and clinical potency in vivo has been documented [15]. Therefore, in order to answer the first of our questions "which?" we must remember that some preparations may be preferable to others for clinical purposes, especially in terms of the lipase content, the activity of which is insufficient in the majority of commercial supplements. Figure 1 gives a example of the extremely wide range of lipase activity present in some marketed pancreatic extracts.

ActiVity! ~ U' ec

4000 -

3600 -

3200 -

2800 -

2400 -

2000 -

1 Hozyme 2 Ku ·Zyme HP

3 Festa l. 4 Cotazym

5 Viokase

t - tablets : 1,5,13,15,16 c - capsules: 2,4, 11, 12

ec = enteric coated tab: 3, 6,7,8,9,10, 14

6 Gastroenterase, 7 Ro-Bile, 8 Entozyme

9 Enzopan, 10 Phazyme, 11 Ku ·Zyme

1600 -

1200 -

800 -

400 -

< 100 12 Digolase I 13 Arco· Lase, 14 Convert in, 15 Kanu lase, 16 Z

' 1 U = 1 mol of substrate split per minute

Fig. 1. Lipase activity in some commercial pancreatic extracts. Data drawn with approximation from Graham (1977 [15])

How?

How must pancreatic extracts be administered? The simplest answer to such a question is: in such a way that the enzmatic activity recovered in the duodenum be as great as possible. The problem derives from the fact that pancreatic enzymes are quickly and irreversibly inactivated by gastric juice which, consequently, is the most important cause of the failure of replacement therapy. The gastric inactivation, reaching 78% for trypsin and 92% for lipase 1 h after oral administration [16], is much more pronounced than the already substantial inactivation previously reported, resulting in, respectively, 30% and 50% [17]. A number of at-

Pancreatic Extracts in Chronic Pancreatitis: Which, How and When? 57

tempts have been made to obviate the inactivation by acid and pepsin during the gastric transit of the pancreatic enzymes.

Antacids

Since antacids buffer gastric HCI and may inactivate pepsin even irreversibly, their use in association with pancreatic extracts would seem theoretically justified. And in fact the longer the intragastric pH remains above 4 and the higher the average intraduodenal pH is, the greater the reduction of steatorrhea obtainable with the pancreatic extracts proves to be. However, the use of antacids in clinical practice, only as a protection of pancreatic supplements, raises a twofold query. First, the amount of antacids which must be administered in order to reduce the gastric acidity persistently and so significantly as to inhibit HCI-pepsin activity is very elevated, almost 250 ml when employing a strong preparation of Al and Mg hydroxide [18, 19J. Second, the replacement therapy, when necessary, has to be continued for many years, which brings with it, adding the antacids, a risk which should not be overlooked of annoying (abnormality of bowel movement) [20J or even serious (milk alcali syndrome) [21J untoward side-effects. Besides, such a heavy, frequent, and protracted consumption would certainly increase the incidence of drop-outs. Something will be said later of the probably profitable use of antacids in connection with H2-antagonists.

Anticholinergics

Anticholinergics would also seem appropriate from a theoretical point of view, because of their gastric secretory inhibition, which may also allow the protection of the pancreatic extracts by a more reduced amount of antacids. However, anticholinergics suppress food stimulated hydrochloric acid secretion by only 30% and with a larger dose side-effects are such that the treatment can not be continued [22J.

Hz-Receptor Antagonists

The rationale for the use of the Hrblockers in pancreatic insufficiency has been well defined [23], and it is shown in Table 1. The clinical results (Table 2) confirm the soundness of the theoretical presupposition. In agreement with this, it has been found that the addition of cimetidine to pancreatic extracts normalizes the urinary excretion of PABA after oral administration of N-benzoyl-L-tyrosyl-paminobenzoic acid (PABA test) (Fig. 2). Antacids, which alone are not a satis factory ancillary measure of replacement therapy with pancreatic extracts become effective if associated with Hrreceptor-antagonists, since they buffer the gastric acidity which still remains after the H2-blockers-induced inhibition [31J.


Table 1. Rationale for treatment with cimetidine in pancreatic insufficiency

Effects Results

Marked depression in meal-induced gast- __ . . . ric secretory response ReductIOn of the mtragastnc

_____ destruction of pancreatic enzymes Decrease of intragastric acidity

Great decrease of delivery of gastric acid ------> Reduction of the intraduodenal in duodenum destruction of pancreatic enzymes

Reduction of gastric secretory volume ------> Increase of the intraduodenal concentration of pancreatic enzymes

Table 2. Effect of cimetidine on pancreatic steatorrhea in some trials'

No. patients Fecal fat g/24 h peb pe+Cc

6 [16,24] 6 [25] 8 [26] 5 [27]

10 [28] 6 [29]

8 [30]

27 12 30 13 25 49

fecal weight

11 5,5

12 9

16 28

257 198

• Mean values: 400-900 mg/day with meals b pe, pancreatic extracts C C, cimetidine

% of PABA urinary re<:overy

o 25

without treatment

pancreatic extracts'

pancretic extracts + cimetidineb

i 50

lower normal limit

a Pancrex V forte . 8 tab lets with test meal

75

b Tagamet . 3 x 200 mg tablets 2 h before PABA-test

No. patients with steatorrhea pe pe+C

6 6 8 4

100

2 2 3 3

Fig. 2. PABA-test in a patient affected by chronic relapsing pancreatitis with and without replacement therapy


Pancreatic Extracts in Special Physical Form

Patients receiving pancreatic supplements in the form of a powder have the advantage of an optimal mixing with food but the disadvantage of an easier inactivation of the pancreatic enzymes during gastric transit. Moreover, the unpleasant taste of the extracts does not encourage the patients to regularly follow the replacement therapy [3]. The use of tablets coated by a pH-sensitive acid-resistant stratum or capsules which can only dissolve in pH neutral or alcaline seems another appropriate attempt from a theoretical point of view. However, in some therapeutic trials enteric coated preparations had totally ineffective [15, 32] or only occasionally effective results [24]. This failure is probably due to a premature release into the stomach of the pancreatic enzymes from the capsules and/or to only a partial disintegration of the capsules in the small intestine. A comparison among antacids, enteric-coated pancreatic enzymes, and cimetidine on therapeutic response to oral enzymes in severe pancreatic insufficiency has shown that [24, 31] (a) cimetidine and pancreatin, each given orally, produce significantly higher postprandial duodenal recoveries and concentrations of trypsin and lipase than pancreatin alone; (b) neither enteric coated enzymes nor neutralizing antacids were on average more effective than pancreatin alone in decreasing steatorrhea or improving duodenal enzyme delivery; (c) steatorrhea is inversely related to duodenal lipase recovery; (d) addition of antacids to Hrantagonists and pancreatic extracts results in a further increase of enzymatic concentration in the intestine due to a more prolonged stability of duodenal pH at an approximately neutral value. Unlike steatorrhea, azotorrhea may also normalize in most patients in simpler treatment groups, e. g., pancreatic enzymes alone or associated with antacids and enteric coated preparations [16, 33]. This is probably because lipase either is more readily destroyed than proteolytic pancreatic enzymes or needs additional factors such as colipase and bile acid for a full enzymatic activity [34, 35]. Very recent reports [36, 37] show that the enteric coating, if applied to a highly concentrated pancreatic extract in a granulated form, renders the duodenal concentration of enzymes suitable for correct pancreatic maldigestion.

When?

The question of "when to administer pancreatic extracts?" implies a double query, and that is: [1] when does one administer them to patients in the course of the day, and [2] when is there a real need to use them in patients with chronic pancreatitis? As for the first question, there are data from more than 20 years ago [38] favoring the greater clinical effectiveness of hourly administration of pancreatin, which would be all the more appropriate in the case of particularly severe steatorrhea. Nevertheless, more recent studies [16, 39] do not show any significant difference between enzyme activity in duodenal aspirate and fecal nitrogen and fat of hourly (2 pancreatin tablets/h)and prandial (8 pancreatin tablets with each meal) dosage schedules.


As for the second question, the answer is already implicit in the notion that defective digestion of food occurs in chronic pancreatitis only when pancreatic function, i. e., pancreatic enzyme output, is reduced by 90% or more [40]. It is, therefore, only when the pancreatic secretion capacity is so severly reduced, resulting in steatorrhea (i. e., more than 7 g of fecal fat/24 h) and azotorrhea (i. e., more than 2.5 g/24 h), that the pancreatic extracts become absolutely necessary and clinically useful, even if they rarely abolish steatorrhea [16]. They can also probably be useful in patients with partial gastrectomy (Billroth II) with very low enzyme concentrations in the efferent loop [36]. In fact, an improvement of the dyspeptic symptoms is not infrequently observed with pancreatic extracts, even when the pancreatic function damage is less than 90%, but that is attributed to a favorable placebo effect [41], an effect which should certainly not be overlooked, and that not only in the field of gastroenterology [42]. Of course, it will be the clinical response (i. e., the reversion to normal of the abnormal fecal excretion of fat and nitrogen), which eventually determines the therapeutic behavior: a therapy, even if conceptually well planned, must be modified if the reversion to normal of the maldigestion of food results are disappointing. In fact, a protracted administration of high dosage of pancreatic extracts and/or cimetidine and/or antacids seems rather questionable either if the caloric gain results are ridiculously low or if the caloric loss due to the malassimilation is not accompanied by significant clinical consequences. The notable social cost of such treatment is a further substantial aspect which should not be underestimated. In conclusion, clinical practice teaches that the long-term replacement treatment with pancreatic extracts and ancillary therapeutic agents is fully justified but only in a limited number of chronic pancreatitis patients with pancreatic insufficiency or pancreatectomy, obvious underweight, and gross steatorrhea. In others, it could be questionable whether the tedium and expense of this substitutive therapy can be warranted, in view of the abnormal but not significantly troublesome fecal fat excretion, in order to improve absorption and nutrition. In any case, in these cases it is the policy of some gastroenterologists [43] not to treat the patients. We think in regard to this that there cannot be fixed rules of any general validity and that it is more expedient to exercise individual choice patient by patient considering all the psychological, medical, and economic factors in play. However, once it has been decided to go ahead with the treatment it is mandatory to ensure that the patient consumes the strongest and least expensive pancreatic extract in a suitable from and that the enzymes be adequately protected against the gastric acid inactivation. In patients with chronic pancreatitis without significant functional insufficiency the replacement therapy is assigned the value of an "active placebo." The substitutive therapy with pancreatic extracts can still occasionally be considered in patients with or without pancreatitis, who have undergone surgical modification of the biliary and digestive tracts with consequent asynchronized mixing of bile, pancreatic juice, and food.

References

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to. Ruysen R (1969) Assay method of the F. I. P. Commission on pharmaceutical enzymes. In: Ruysen R. (ed) Symposium on pharmaceutical enzymes and their assay. Universitaire Pers, Ghent, p 99

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18. Peterson WL, Sturdevant RAL, Frankl HD, Richardson CT, Isenberg JI, Elashoff JD, Sones JQ, Gross RA, McCallum RW, Fordtran JS (1977) Healing of duodenal ulcer with an antacid regimen. N Engl J Med 297:341-345

19. Ippoliti AF, Sturdevant RAL, Isenberg JI, Binder M, Camacho R, Cano R, Cooney C, Kline MM, Koretz RL, Meyer JH, Samloff 1M, Schwabe AD, Strom EA, Valenzuela JE, Wintroub RH (1978) Cimetidine versus intersive antacid therapy for duodenal ulcer. A multicenter trial. Gastroenterology 74:393-395

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23. Regan PT, Malagelada JR, Di Magno EP, Go VLW (1978) Rationale for the use ofcimetidine in pancreatic insufficiency. Mayo Clin Proc 53:79-83

24. Regan PT, Malagelada JR, Di Magno EP, Glanzman SL, Go VLW (1977) Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 297:854-858

25. Bianchi Porro G, Dolcini R, Grossi E, Petrillo M, Prada A (1977) Cimetidine in treatment of pancreatic insufficiency. Lancet 2:878-879

26. Dobrilla G, Bonoldi MC, Chilovi F (1980). Effects of cimetidine on pancreatic function and disease. In: Torsoli A, Lucchelli PE, Brimblecombe RW (ed) Further experience


with H2-receptor antagonists in peptic ulcer disease and progress in histamin research. Excerpta Medica, Amsterdam, pp 140-152

27. Ahuja AS, Mann NM (1978) Cimetidine in cystic fibrosis. Arch Dis Child 53:766 28. Cox KL, Isenberg IN, Osher AB, Dooley RR (1978) The effect of cimetidine on pan

creatic replacement therapy in the maldigestion of cystic fibrosis. Cystic fibrosis club (Abstr). Pediatr Res 12:433A

29. Hubbard YS, Dunn GD, Lester LA, Sant'Agnese PA (1979) Effectiveness ofcimetidine in patients with cystic fibrosis. Clin Res 72:552A

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31. Saunders JHB, Drummond S, Wormsley KG (1977) Inhibition of gastric secretion in the treatment of pancreatic insufficiency. Br Med J 1:418-419

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33. Regan PT, Malagelada JR, Di Magno EP, Go YLW (1978) Cimetidine as an adjunct to oral enzymes in the treatment of malabsorption due to pancreatic insufficiency. Gastroenterology 74:468

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Radiological Approach to Acute and Chronic Pancreatitis

G.F. Pistolesi, C. Fugazzola, C. Procacci, F. Frasson, and L. Mazzi

Istituto di Radiologia, Universita di Padova, Sede in Verona Policlinico B. Roma, 37100 Verona, Italy

Introduction

Many radiologic methods are available at the present moment for studying diseases of the pancreas [1-29]. Hence, the problem for the radiologist now is not -as it was in the recent past - to get information, often uncertain and late, from the few available procedures, so much as to choose the technique or group of techniques which is most accurate for studying each single pancreatic disease. Indiscriminate use of too many diagnostic techniques should be avoided, if only for economic motives. An unexpected and significant technologic advance creates the problem of choosing the most accurate method in all radiologic fields. Experience teaches that, for a certain period of time, old techniques - although less accurate or even dangerous - continue to be utilized, sometimes in addition to the more recent and accurate techniques. This superfluous technical complexity derives both from the difficulty of modifying well established protocols, which continue to be routinely employed, and from the rather slow circulation of the most recent knowledge. Selection among the various methods depends on three criteria: the diagnostic efficacy, the risk for the patient, and the cost of the examination. This report presents the radiologic policy employed in the University Hospital of Verona, in the light of present experience in chronic and acute inflammatory diseases of the pancreas and their complications.

Methods and Materials

A series of 102 patients with acute or chronic pancreatitis, examined between October 1976 and July 1979, is considered here: the series consists of 48 cases of chronic pancreatitis without pseudocyst (CP); 35 cases of pseudocyst (PsC); 19 cases of acute necrotic-hemorrhagic pancreatitis (ANHP). All cases were surgically controlled. In these patients the following examinations were performed: plain film of the abdomen (PF), 59 cases; upper GI tract examination (UGI), 58 cases; intravenous cholangiography (IVC), 57 cases; ultrasound (US), 41 cases; computed tomography (CT), 102 cases; angiography (A), 28 cases; endoscopic retrograde pancreatography (ERCP), 28 cases.

64 G.F. Pistolesi, C. Fugazzola, C. Procacci, F. Frasson, and L. Mazzi

The results obtained with each technique were evaluated on four diagnostic levels: (a) specific diagnosis (definite diagnosis of the nature of the lesion); (b) nonspecific nonspecific diagnosis (identification of the lesion, without definite diagnosis of its nature), in order to simplify analysis of the results, errors of over diagnosis and under diagnosis, which were anyway uncommon in this series, are included here; (c) pancreatic involvement diagnosis (sum of specific diagnosis and nonspecific diagnosis), this level demonstrates the overall potential of each technique to recognize a pancreatic lesion; (d) false negativity (this includes both true false negatives and technical failures, which may occur in US, CT, and ERCP). The distinction between the two diagnostic levels, specific and nonspecific, is very important, because failure to make such a distinction may invalidate any comparative evaluation among different radiologic methods. In fact, it is impossible to assess the accuracy of two methods if the data concerning pancreatic involvement diagnosis (which include both the data of specific and nonspecific diagnosis) provided by one method are compared with the data concerning specific diagnosis of the other; o\>viously specific diagnosis - clinically more important - is achieved less frequently.

Correlation Between Pathologic Abnormalities and Radiologic Methods in Diseases of the Pancreas

In pancreatic diseases the following fundamental pathologic abnormalities may be considered: [1] abnormalities of duct system; [2] abnormalities of pancreatic parenchyma; [3] abnormalities of pancreatic morphology. Although these abnormalities are frequently associated together, nevertheless in each individual disease one is more marked than the others. Obviously the most accurate radiologic technique (or group of techniques) in each single pancreatic disease is that which is most sensitive to the prominent pathologic abnormality. Therefore it is useful to consider briefly the potential of each radiologic technique for identifying the three fundamental pathologic abnormalities.

Radiologic Techniques Suitable for Identifying Pancreatic Duct System Abnormalities

At the moment, ERCP is the most accurate technique for demonstrating any abnormalities - intrinsic or extrinsic - of the duct of Wirsung and its collateral branches (Fig. 1 a). However, CT (limited to fast scanners) is able to identify dilatation of the duct ofWirsung, although its spatial resolution is considerably lower than that permitted by ERCP (Fig. 2).

Radiologic Techniques Suitable for Identifying Pancreatic Parenchymal Abnormalities

All pancreatic diseases cause parenchymal abnormalities. Although histologic fmdings are very different in each single disease, the ability of the various radio-


Fig. 1 a-c. Endoscopic pancreatography. a Chronic pancreatitis: beaded dilatation of the duct system, b Pseudocyst: direct opacification of the cyst located in the tail, c Carcinoma: irregular narrowing of the distal tract of the Wirsung and common bile ducts, caused by the tumor located in the head

65


Fig. 2. Computed tomography (fast scan with scanning time of 4 s). Chronic pancreatitis: Dilatation of the duct of Wirsung, in particular in the head. Some calcifications can be seen in the body and tail

logic techniques to distinguish exactly the various abnormalities of the pancreatic parenchyma are very limited, so that the precise definition of such abnormalities can only be obtained in certain circumstances.

Acute Inflammation of the Pancreas. The following parenchymal abnormalities are characteristic of acute pancreatitis (AP): edema (in acute edematous pancreatitis: AEP); necrosis (in ANHP); suppuration (in ASP). At present, only CT and US can identify these abnormalities directly: CT shows a decreased and/or nonhomogeneous density of pancreatic parenchyma as well as extrapancreatic collections (Fig. 4), while US shows a markedly reduced reflectivity in the pancreatic area. PF very rarely directly shows ASP by demonstrating gaseous bubbles; more frequently PF can supply indirect information ("sentinel loop"; colon "cut-off'), which only presumes the presence of AP (Fig. 3 a).

Chronic Inflammation of the Pancreas. The pathologic abnormalities in CP which can be demonstrated with radiologic techniques are of two types: Fibrosis of the parenchyma with loss of its normal soft consistency. At present, only US is able to specifically identify pancreatic fibrosis, showing an increase in reflectivity in the pancreatic area (Fig. 5a). The attenuation values ofCT in fibrosis do not allow differential diagnosis either with normal or tumoral tissue (Fig. 6a). The other radiologic techniques (lYC, UGI, A) can only supply indirect information, as a consequence of secondary involvement - caused by pancreatic fibrosis -of the structures visualized by these techniques. The importance and precocity of this information vary according to whether the structures are close to the pancreas (stomach and duodenum) or even contained in it (intrapancreatic vessels; common bile duct). In fact IYC may precociously show narrowing of the intrapancreatic common bile duct (Fig. 7 a), while A may show variations in course and/or in caliber and above all the notable rarefaction of pancreatic vessels (Fig.

Radiological Approach to Acute and Chronic Pancreatitis 67

Fig. 3 a-c. Plain Film. a Acute necrotic-hemorrhagic pancreatitis: colon "cut-off' sign, b Chronic pancreatitis: calcifications distributed throughout the pancreas, c Cystadenoma: huge calcified mass in the head

9a, b). UGI supplies more delayed information, as a consequence of the involvement of the stomach and duodenum (indentation and rigidity of the gastroduodenal walls: Fig. 8 a).


Fig. 4 a-d. Computed tomography. Acute necrotic-hemorrhagic pancreatitis, a b Scan taken through the pancreas: pancreas enlarged with unsharp borders and nonhomogeneous density, c Scan taken at a higher level: subdiaphragmatic liquid collection, localized between the diaphragm and the spleen, d Scan taken through the mid portion of the kidneys: extra pancreatic collections in the left paracolic recess and in the mesenteric and mesocolic roots can be seen

Parenchymal calcifications and intraductal calculi are the next stage in the development of the inflammatory process in CPo Therefore radiologic techniques, if they can identify such calcifications, provide specific diagnosis of CP; PF (Fig. 4 b), CT (Fig. 2), and US are able to recognize pancreatic calcifications, while ERCP can demonstrate intraductal calculi.

Pseudocyst Development. The liquid content allows direct identification of PsC both by US, which shows echo-free masses with strong far-wall echoes (Fig. 5 b), and CT, which shows water density masses with sharp borders (Fig. 6 b). Specific diagnosis of PsC can also be provided by ERCP, when contrast medium directly opacifies the cyst (Fig. 1 b).


Fig. 5 a-c. Ultrasound. a Chronic pancreatitis; transverse scan: enlargement of the head with a markedly increased reflectivity, b Pseudocyst; transverse scan: huge echo-free mass in the head and body with strong far-wall echoes, c Carcinoma; sagittal scan: enlargement of the head with few scattered echoes

69

The other radiologic techniques can only supply indirect information, as a consequence of a mass impression. For PsC, as well as for fibrosis in CP, the importance and precocity of indirect information are proportional to how close the structures examined with the various techniques are to the mass: ERCP (displacement or obstruction of the duct of Wirsung); A (displacement of the intrapancreatic arterial branches: Fig. 9c); IVC (displacement of intra pancreatic common bile duct, when PsC is located in the head of the pancreas: Fig. 7b); UGI (indentation on the gastroduodenal walls by the PsC: Fig. 8 b).

Tumoral Processes. The ability of radiologic techniques to recognize parenchymal abnormalities induced by neoplasms depend on the histologic type of the tumor.

Tumor of exocrine pancreas. In theory, specific diagnosis of exocrine tumor can be achieved only when specific parenchymal abnormalities are directly recognized: this is possible at present only by US, which may show a decrease in reflectivity in the tumoral area (Fig. 5 c), and by A, which may show serpiginous encasement and/or obstruction of arterial branches and - more rarely - tumor vessels (Fig. 10).


Fig. 6 a-c. Computed tomography. a Chronic pancreatitis: overall enlargement of the pancreas; nevertheless its density is the same as in tumor or in normal pancreas, b Pseudocyst: round water-density mass in the tail with a diameter of about 3 cm, c Carcinoma: solid mass in the body and tail, with infiltration of the retropancreatic adipose layer (superior mesenteric artery cannot be recognized)

In practice, however, any technique, when it shows signs of infiltration by the pancreatic lesion, may be considered specific: CT, when it shows infiltration of the retropancreatic space (Fig. 6c) (this finding, which is observed in unresectable lesions, is of fundamental importance for the surgical approach); ERCP, when it shows infiltration of the duct of Wirsung and of the common bile duct (Fig. 1 c); transhepatic cholangiography, when it shows infiltration and/or obstruction of the common bile duct (Fig. 7 c) (this may occur with tumors of the head of the pancreas); UGI, when duodenal and gastric walls are infiltrated (Fig. 8c). Obviously, the frequency with which each technique can provide specific diagnosis must be considered: UGI in particular, in most cases, only gives nonspecific information (identation on the gastroduodenal walls by the tumor).


Fig. 7 a, b. Intravenous cholangiography. c Trans-hepatic cholangiography. a Chronic pancreatitis: narrowing of the intra pancreatic common bile duct, b Pseudocyst: sharp impression on the intra pancreatic common bile duct by the mass located in the head, c Carcinoma: infiltration and obstruction of the common bile duct by the mass located in the head


Fig. 8 a-c. Upper GI tract examination. a Chronic pancreatitis: impression on the duodenalloop with mucosal fold effacement, b Pseudocyst: smooth indentation on the medial wall of the duodenal loop by the mass located in the head, c Carcinoma: infiltration of the wall in the distal duodenum by the mass located in the head and body

Tumor of endocrine pancreas. The ability of radiologic techniques to identify endocrine tumors are completely different. In fact, only A can provide specific diagnosis when it demonstrates the characteristic tumor stain (Fig. 11); all the other techniques are either completely silent or only supply nonspecific information.


Fig. 9 a-d. Angiography. a Chronic pancreatitis: selective gastroduodenal artery injection; abnormalities in course and caliber of the pancreatic arcades and of their branches, b Chronic pancreatitis: selective superior mesenteric artery injection; notable rarefaction of the arterial branches in the head, c, d Pseudocyst of the head: selective hepatic artery injection c shows displacement of the hepatic and gastroduodenal arteries; the pancreaticoduodenal branches are stretched with abnormalities in course and caliber. Superior mesenteric artery injection d shows a small aneurysm at the origin of the inferior pancreaticoduodenal artery


Fig. 10 a, b. Angiography. Pancreatic carcinoma of the head and body. Selective celiac injection a shows infiltration of the celiac, splenic, left gastric, and hepatic arteries. Selective superior mesenteric artery injection b shows infiltration of the common trunk, of the pancreatic arcades and of the gastroduodenal artery. Slight hypervascularity can be recognized in the head


Radiologic Techniques Suitable for Identifying Pancreatic Morphological Abnormalities

75

Pancreatic morphological abnormalities are modifications - partial or general -of the organ size. In the majority of cases of pancreatic diseases there is an increase in the size of the pancreas; cases in which size is unchanged are much less frequent; cases in which size is reduced are extremely rare.

Fig. 11. Angiography insulinoma. Selective celiac injection: round, well. Insulinoma vascularized tumor in the body

Reduction in panreatic size may only be identified by US and CT.

Increase in pancreatic size may obviously be identified earlier and more specifically with techniques which are able to demonstrate the pancreas directly (US and CT: Figs. 5, 6). The techniques which provide indirect information are able to recognize greater changes in size: A (impression, displacement and infiltration of extrapancreatic arteries and veins; Figs. 9, 10); IVC (impression and infiltration of extrapancreatic and intrapancreatic common bile duct, when the head of the pancreas increases in size: Fig. 7b); UGI (indentation, displacement and infiltration of the gastroduodenal walls: Fig. 8). Finally PF allows direct identification of masses only when very large or calcified (Fig. 4c).


Radiologic Policy in Chronic Pancreatitis

It has been said in sect. 1 that the most topical problem for the radiologist is the choice among the many techniques available to day for investigating pancreatic diseases. In the remainder of this paper the personal radiologic policy in chronic and acute inflammatory processes of the pancreas and in their possible complications is presented: such protocols are justified in the light of comparative results achieved with the different radiologic techniques in the same series of patients. Obviously not all the 102 patients of this series underwent all the radiologic examinations analyzed in this report: the number of patients submitted to each examination is shown in the first column of Tables 1-3. As regards CP (48 cases, Table 1), which of the noninvasive and cheaper techniques was the most accurate was first established, with reference to the levels of specific and nonspecific diagnosis.

Table 1. Chronic pancreatitis (48 cases)

Radiologic No. Specific Nonspecific Pancreatic False examination of cases diagnosis diagnosis involvement negativity

diagnosis

PF 48 48% 48% 52% UGI 31 65% 65% 35% IVC 35 57% 57% 43% US 17 47% 24% 71% 29% CT 48 64% 30% 94% 6% ERCP 28 80% 80% 20% A 18 28% 72% 100%

As is clearly shown in Table 1, of the three conventional noninvasive techniques (PF, UGI, IVC) analyzed, the only one able to provide specific diagnosis of CP was PF, with demonstration of pancreatic calcifications: this fmding was observed in 48% of cases (23/48 CP). On the contrary UGI and IVC, which did not show any characteristic sign of CP, could only supply nonspecific diagnosis, respectively in 65% of cases (20/31 CP) and in 57% of cases (20/35 CP). Therefore, in chronic pancreatitis, the use ofUGI and of IVC is not advisable, except - obviously - when there are precise clinical symptoms, in order to search for intrinsic lesions of the stomach and duodenum or of the common bile duct, which may be associated with CPo In fact, thanks to clinical symptoms, laboratory data and PF, specific diagnosis was reached in 75% of cases (36/48 CP). The diagnostic problem of the remaining 25% of cases (12/48 CP), in which a specific diagnosis was not achieved with clinical symptoms, laboratory data, and PF, was then considered.


Analysis of the results obtained with the other radiologic techniques (Table 1) excludes not only the conventional techniques already mentioned (UGI and IVC)able to reach only nonspecific diagnosis - but also the more recent noninvasive techniques. In fact, both US and CT provided specific diagnosis of CP with a lower rate (respectively in 47% and 64% of cases) than that of clinical and laboratory data associated with PF. As regards US, specific diagnosis of CP is based on the finding of enlargement - focal or global - of the pancreas, in addition to an increase in reflectivity (caused by fibrosis and calcifications). In this series specific diagnosis of CP was achieved in 47% of cases (8/17 CP). When US shows focal enlargement of the pancreas, without the typical changes in echopattern mentioned above, the diagnostic level is only nonspecific (24% of cases: 4/17 CP). It should be emphasized that technical failure played an important part in the amount offalse negativity of this series (29% of cases: 5/17 CP), because of blockage of sound waves by gas within the bowel. As regards CT, specific diagnosis of CP is based on the finding of general enlargement of the pancreas; if enlargement is focal, calcifications are essential to specific diagnosis. In this series, specific diagnosis of CP was achieved in 64% of cases (31/48 CP). When CT shows focal enlargement without calcifications, the diagnostic level is only nonspecific (30% of cases: 14/48 CP); in fact this pattern cannot be differentiated from that of pancreatic tumor. False negativity (6% of cases: 3/48 CP) was due both to pictures considered normal and to technical artifacts,

. which prevented visualization of pancreatic area. The contribution of A to specific diagnosis of CP was disappointing (28% of cases: 5/18 CP): there is only one angiographic sign which is specific of CP ("beaded" encasement); all the other angiographic signs (variations in course and/or caliber and rarefaction of intrapancreatic vessels), since they may be found also in other pancreatic diseases, are to be considered nonspecific (72% of cases: 13/18 CP). Therefore this technique cannot be used either to solve the diagnostic problems of cases of CP, in which a specific diagnosis is not reached by clinical and laboratory data associated with PF. Angiography may be utilized only as a preoperative aid for a surgical approach; in particular it is useful for providing a precise vascular map. Therefore, as regards the problem of the cases of CP not specifically diagnosed by the above mentioned clinical-radiologic methods, ERCP, which is the most reliable technique, should be used. In fact ERCP (Table 1) provided specific diagnosis in 80% of cases of this series (22/28 CP); the enlarged duct system, smooth or beaded, is the unequivocally specific sign of CP; sometimes ERCP may also show the presence of intraductal calculi. The false negativity (20% of cases: 6/28 CP) is only partly due to the finding of a normal duct system, while in most cases there were technical failures (unsuccessful cannulation of the duct). In conclusion, in CP, the radiologic techniques which, in our opinion, can be utilized, are PF, which first must be performed in all the cases in which CP is clinically suspected, and ERCP, which may be performed only when neither clinical and laboratory data nor PF findings confirm the diagnostic suspicion. The routine use of all the other radiologic techniques - old or recent, invasive or noninvasive - is not justified; these techniques, in our opinion, should be employed only in some cases, in which there are precise and detailed clinical problems.


Radiologic Policy in Pseudocyst

The development of pancreatic PsC - although sometimes due to an acute inflammatory process - in most cases is a complication of CPo The clinical suspicion of the presence of a PsC complicating CP is based on persistent abdominal pain, poor general condition associated with high values of urinary amylase. Table 2 shows the results (concerning specific and nonspecific diagnosis) achieved in the radiologic study of the 35 cases of PsC of this series. Neither PF nor ERCP are considered here: in fact PF was never used, because, as has already been said, this technique is able to identify only large masses and in practice cannot be usually employed; as regards ERCP, although this technique can provide specific diagnosis (when contrast medium directly opacifies the cyst) or nonspecific diagnosis (extrinsic impression on the duct by the cyst), it is not our policy to use it. Operative pancreatography (sometimes associated with direct needle puncture of the cyst) is preferred, as it provides more detailed information concerning the duct system.

Table 2. Pseudocyst (35 cases)

Radiologic No. Specific Nonspecific Pancreatic False examination of cases diagnosis Diagnosis involvement negativity

diagnosis

UGI 27 45% 37% 82% 18% IYC 22 9% 59% 68% 32% US 17 70% 6% 76% 24% CT 35 88% 6% 94% 6% A 10 50% 50% 100%

As regards noninvasive techniques, it is clear that IYC is not advisable: in fact this technique reached specific diagnosis of PsC only in 9% of cases (2/22 PsC), showing a wide-angle impression on intrapancreatic common bile duct by PsC located in the head. Nonspecific information provided by IVC in this series (narrowing of intrapancreatic common bile duct) was frequent (59% of cases: 13/22 PsC): this finding is probably due to coexisting CPo On the contrary, the contribution of UGI to specific diagnosis of PsC (displacement and above all smooth indentation of the gastroduodenal walls) was satisfactory (45% of cases: 12/27 PsC); obviously this result is influenced by the size of the PsC, because if the cysts are small UGI can provide only nonspecific information (flattening of the gastroduodenal walls) caused by coexisting CPo In this series of PsC, nonspecific findings were observed with UGI in 37% of cases (10/27 PsC). Therefore, these results justify the use of UGI in the radiologic study of PsC, when other noninvasive techniques - more accurate concerning the specific diagnosis level - are not available.


In fact, both US and CT showed a higher rate of specific diagnosis of PsC than UGI (Table 2). As regards US, specific diagnosis is based on the finding of an echo-free mass, with possible strong far-wall echoes: in this series specific diagnosis of PsC was achieved in 70% of cases (12/17 PsC). The low rate of nonspecific diagnosis (6% of cases: 1/17 PsC) depends on the high sensitivity of this technique in recognizing the liquid content of the cyst. However, in our experience, US was usually able to identify pseudocysts 3 cm or more in diameter; in fact, in 12% of cases (2/17 PsC with a diameter less than 3 cm) US did not identify the cysts, showing a normal pancreas (true false negativity). Finally in 12% of cases (2/17 PsC) the examination was uninterpretable because of technical failure. As regards CT, specific diagnosis of PsC is based on the finding of a water density mass with sharp borders: in this series specific diagnosis of PsC was achieved in 88% of cases (31/35 PsC). Also CT is characterized by a low rate of nonspecific diagnosis (6% of cases: 2/35 PsC), which depends on the considerable sensitivity of this technique for identifying liquid content masses. CT was able to recognize pseudocysts of a diameter a little smaller (about 2 cm) than US. However, CT in 6% of cases (2/35 PsC) did not identify the cysts with a small diameter, providing only nonspecific diagnosis (under diagnosis of CP). Finally in 6% of cases (2/35 PsC) there was true false negativity; in fact CT did not identify the cysts with a small diameter, showing a normal pancreas.

Angiography is not advisable for diagnosis, because, in this series, it provided specific diagnosis of PsC only in 50% of cases (5/10 PsC), based on the findings of impression and displacement of the extra and intra pancreatic vessels. In the remaining 50% of cases (5/10 PsC) A provided only nonspecific information: in particular there were angiographic under diagnoses, since A showed abnormalities usually observed in CPo For the PsC, as well as for CP, as has been said in Sect. 4, A should be utilized only for preoperative evaluation; in particular it provides a precise vascular map (identification of anatomic variants of arteries and veins) and may show extrapancreatic vessel involvement (arterial encasement; arterial aneurysm: Fig. 9d; venous thrombosis).

In conclusion, in PsC, the choice of the most accurate radiologic technique depends on the techniques available in each radiologic departement. When both US and CT are available, CT should be preferred - on the basis of the comparative results obtained in this series (Table 2); however, if one considers the present organization of almost all the radiologic departments of Western Europe - innundated with requests for CT examinations - and the much higher cost of CT, US may be proposed in this pancreatic disease. In fact, although the rate of US specific diagnosis (70%) is certainly less satisfactory than that of CT (88%), nevertheless the fairly high rate of US false negativity (24%) depends, in about half the cases, on technical failure (blockage of sound waves by bowel gas), which may very probably be obviated by future technical improvement: this will make US more accurate in achieving specific diagnosis level.

But if the radiologic department does not have US or CT, the choice must fall on UGI, which reaches the level of specific diagnosis in a fairly high percentage of cases (45%), if the pseudocysts are moderate or large in size and if the procedure is carried out with some technical refinements (double contrast, hypotonia induced by anticholinergic drugs).


Radiologic Policy in Acute Pancreatitis

In pancreatic emergencies two clinical problems - one consequent on the other -are to be solved: the former, which is fundamental, is to recognize the possible evolution of AP towards necrotic-hemorrhagic or suppurative types. Both these types require immediate surgical treatment, while acute edematous pancreatitis only needs medical treatment. The latter clinical problem, which arises when the necrotic-hemorrhagic or suppurative evolution of AP has been identified, is to establish the number, the site, and the extent of extrapancreatic liquid collections, in order to permit the surgeon to apply the drainage tubes properly so as to perform a continuous perfusion by enzymatic inhibitors and antibiotics. The following considerations are based on 19 cases of ANHP, all surgically controlled. The radiologic examinations carried out were only PF, US, and CT (Table 3), because of the particularly serious conditions of the patients.

Table 3. Acute necrotic-hemorrhagic pancreatitis (19 cases)

Radiologic No. Specific Nonspecific Pancreatic False examination of cases diagnosis diagnosis involvement negativity

diagnosis

PF 11 72% 72% 28% US 7 29% 29% 71% CT 19 100% 100%

Identification of Necrotic-Hemorrhagic Evolution of Acute Pancreatitis

In our experience, neither PF nor US were able to provide this fundamental clinical information (Table 3). In fact PF showed only nonspecific findings (72% of cases: 8/11 ANHP): signs of peri ton ism in most cases (7/8 ANHP) and only occasionally signs which suggested acute pancreatic involvement (1/8 ANHP: colon "cut-off': Fig. 3 a); therefore PF never allowed specific diagnosis of ANHP. As regards US, in our experience, although based on a small number of patients (7/19 ANHP), the use of this technique in pancreatic emergencies is not advisable: in fact in about 70% of cases (5/7 ANHP) the examination was unsatisfactory because of bowel gas and in the remaining 30% of cases (2/7 ANHP) US only showed a general pancreatic enlargement with decrease in reflectivity, without therefore being able to establish necrotic-hemorrhagic evolution. The results of CT were extremely encouraging (Table 3). In fact in 100% of cases (19/19 ANHP) CT provided specific diagnosis, based on the finding of pancreatic enlargement - general or focal- associated with extrapancreatic liquid collections (Fig. 4). The differential diagnosis between AEP and ANHP is very difficult, before the appearance of extrapancreatic collections. In fact, in both situations the pancreas is enlarged; the attenuation values may be of some help in differential diagnosis, since density is usually noticeably reduced, with a homogeneous appearance in AEP, while density is nonhomogeneous in ANHP.


Map of Extrapancreatic Collections and Postoperative Follow-Up in Acute Necrotic-Hemorrhagic Pancreatitis

81

Surgery is only successful if the drainage tubes are properly located at the site of pancreas and extrapancreatic collections. All the collections must be drained and drainages must be located at the cranial and caudal extremes, in order to allow continuous perfusion by enzymatic inhibitors and antibiotics. This procedure is essential to obtain good results in surgical treatment of ANHP. On the other hand, without CT aid, the exact identification of the number and extent of extrapancreatic collections is not easy, even during surgical operation: in fact, the surgical team at the University Hospital of Verona found very different results, concerning survival, in similar series of patients operated on before and after CT employment, as is said in another report (P. Pederzoli: Early surgical and conservative therapy in the treatment of the necro-hemorrhagic acute pancreatitis). In almost all cases (17/19 ANHP) considered here, extrapancreatic collections (Fig. 12) were found with the following appearance frequency: left paracolic recess (11/17 ANHP); mesocolic and mesenteric roots (13/17 ANHP); left subdiaphragmatic recess (6/17 ANHP); right paracolic recess (4/17 ANHP). In 12/ 17 ANHP two or more extrapancreatic collections were found in the same patient. CT was very useful for monitoring patients after surgery: in fact the gradual reduction of pancreatic volume (which returned within normal limits between 2 and 4 months) and the more delayed decrease of extrapancreatic collections

Fig. 12. Acute necrotic-hemorrhagic pancreatitis. Main pathways of diffusion of extra-pancreatic collections: 1 left paracolic recess; 2 mesenteric root; 3 mesocolic root; 4 left subdiaphragmatic recess; 5 right paracolic recess


(which disappeared entirely in about 4 months) could be observed by CT. The CT visualization of unchanged or increased collections indicates the need for immediate further surgical procedures. In conclusion, in the radiologic diagnosis of AP, in our experiences CT is the only technique to be employed.

References

Anacker H (1975) Retrograde pancreatography in inflammatory diseases of the pancreas. In: Anacker H (ed) Efficiency and limits of radiologic examination of the pancreas. Thieme, Stuttgart, pp 194-202

2 Bilbao MK, Rosch J, Frische LH, Dotter CT (1968) Hypotonic duodenography in the diagnosis of pancreatic disease. Semin Roentgenol 3:280-287

3 Brascho OJ, Reynolds RN, Zanca P (1962) The radiographic "colon cut-off sign" in acute pancreatitis. Radiology 79:763-768

4 Clouse ME, Costello P, Legg MA, Soeldner SJ, Cady B (1977) Subselective angiography in localizing insulinomas of the pancreas. AJR 128:741-746

5 Doust BD, Pearce JD (1976) Gray-scale ultrasonic properties of the normal and inflamed pancreas. Radiology 120:653-657

6 Duncan JG, Imrie CW, Blumgart LH (1976) Ultrasound in the management of acute pancreatitis. Br J Radiol 49:858-862

7 Eaton SB, Benedict KT, Ferrucci JT, Fleischli OJ (1970) Hypotonic duodenography. Radiol Clin North Am 102:267-274

8 Ferrucci JT, Benedict KT (1971) Anticholinergic-aided study of the gastrointestinal tract. Radiol Clin North Am 9:23-39

9 Ferrucci JT, Wittenberg J, Black EB, Kirkpatrick RH, Hall DA (1979) Computed body tomography in chronic pancreatitis. Radiology 130:175-182

10 Freeny PC, Ball TJ (1978) Evaluation of endoscopic retrograde cholangiopancreatography and angiography in the diagnosis of pancreatic carcinoma. AJR 130:683-691

11 Frommhold W, Frommhold H (1975) Value and limitations of intravenous cholangiography in the diagnosis of pancreatic diseases. In: Anacker H (ed) Efficiency and limits of radiologic examination of the pancreas. Thieme, Stuttgart, pp 101-108

12 Goldstein HM, Neiman HL, Bookstein 11 (1974) Angiographic evaluation ofpancreatic disease. Radiology 121:275-282

13 Haaga JR, Alfidi RJ, Havrilla TR, Tubbs R, Gonzalez L, Meaney TF, Corsi MA (1977) Definitive role of CT scanning of the pancreas. Radiology 124:723-730

14 Haertel M, Tillmann U, Fuchs WA (1979) Die akute Pankreatitis in Computertomogramm. ROEFO 130:525-530

15 Hauser H, Battikha JG, Wettstein P (1980) Computed tomography of the dilated pancreatic main duct. J Comput Assist Tomogr 4:53-58

16 Lawson TL (1978) Sensitivity of pancreatic ultrasonography in the detection of pancreatic disease. Radiology 128:733-736

17 Lee JKT, Stanley RJ, Melson GL, Sagel SS (1979) Pancreatic imaging by ultrasound and computed tomography. A general review. Radiol Clin North Am 16:105-117

18 Levene G, Scheff S (1957) Intravenous cholangiography as an aid in diagnosis of carcinoma of the head of the pancreas. Radiology 68:714-717

19 Levin DC, Eisenberg H, Wilson R (1977) Arteriography in the evaluation of pancreatic pseudocysts. AJR 129:243-248

20 Mackie CR, Lu CT, Noble HG, Cooper MJ, Collins P, Block GE, Moossa AR (1979) Prospective evaluation of angiography in the diagnosis and management of patients suspected of having pancreatic cancer. Ann Surg 189:11-17

21 Moss AA, Federle M, Shapiro HA, Ohto M, Goldberg H, Korobkin M, Clemett A (1980) The combined use of computed tomography and endoscopic retrograde cholangiopancreatography in the assessment of suspected pancreatic neoplasm: a blind clinical evaluation. Radiology 134:159-163


22 Okuda K, Tanikawa K, Emura T, Kuratomi S, Jinnouchi S, Urabe K, Sumikoshi T, Kanda Y, Fukuyama Y, Musha H, Mori H, Shimokawa Y, Yakushiji F, Matsuura Y (1974) Nonsurgical, percutaneous transhepatic cholangiography. Diagnostic significance in medical problems of the liver. Am J Dig Dis 19:21-36

23 Pereiras R, White P, Dusol M, Irvin G, Hutson D, Lieberman B, SchiffER (1976) Percutaneous transhepatic cholangiography utilizing the Chiba University needle. Radiology 121:219-221

24 Pistolesi GF, Gortenuti G, Marzoli GP (1975) A comparative study of the roentgenologic evaluation of pancreatic disease. In: Anacker H (ed) Efficiency and limits of radiologic examination of the pancreas. Thieme, Stuttgart, pp 84-91

25 Pistolesi GF, Frasson F, Fugazzola C, Taddei G, Caresano A (1977) Angiographic diagnosis of endocrine tumors of the pancreas. Radiol Clin (Basel) 46:401-421

26 Pistolesi GF, Marzoli GP, Quarta Colosso P, Pederzoli P, Procacci C (1978) Computed tomography in surgical pancreatic emergencies. J Comput Assist Tomogr 2:165-169

27 Reuter SR (1975) Superselective pancreatic angiography. In: Anacker H (ed) Efficiency and limits of radiologic examination of the pancreas. Thieme, Stuttgart, pp 149-158

28 Ring EJ, Eaton SB, Ferrucci JT, Short WF (1973) The differential diagnosis of pancreatic calcifications. AJR 117:446-452

29 Stein GN, KaIser MH, Sarian NN, Finkelstein A (1959) An evaluation of the roentgen changes in acute pancreatitis: correlations with clinical findings. Gastroenterology 36:354-361

Diagnostic Algorithm for Pancreatic Disease

G. Fontana, P.L. Costa, A. Vandelli, G. Silvani, P. Maiolo, M. Melandri, and C. Camporesi

Divisione di Medicina Generale, Ospedale G. B. Morgagni, 47100 Forli, Italy

During the past 10 years new diagnostic techniques for pancreatic disease have been developed, such as angiography, endoscopic retrograde pancreatography (ERCP), ultrasonography (US), and computed tomography (CT). By means of these diagnostic tests there have been major developments in pancreatic imaging and a big improvement in diagnostic strategy for pancreatic disease. Although studies of the accuracy of individual tests have been reported, many were retrospective and only some of these compared the efficacy of different tests in the same cases. These studies have ascertained the sensitivity, specificity, and predictive value (high proportion of diseased patients with positive results and a high proportion of disease-free patients with negative results) of these new techniques. The diagnostic accuracies for the diagnosis of pancreatic disease of US and CT do not seem to differ (Di Magno et al. 1977; Sheedy et al. 1977; Sample and Sarti 1979), while ERCP had greater clinical impact than US or CT (Cotton et al. 1978). Imaging methods are not mutually exclusive and results are often complementary. For instance US and CT are both capable of directly and noninvasively imaging the pancreas, while angiography and ERCP are invasive and may be associated with side-effects. At present the aim should be to find a logical sequence in each clinical context, minimizing cost and discomfort. The clinical problem of a diagnosis of pancreatic disease is that of a patient with typical clinical features or that of a patient with physical, laboratory, or radiologic findings atypical or not indicative for a particular form of pancreatic disease. As a matter of fact some pancreatic diseases are characterized by a typical clinical syndrome, such as chronic relapsing pancreatitis and usually acute pancreatitis. Conversely, other pancreatic diseases (cancer, painless pancreatitis, chronic pancreatitis in the early stages, cysts, endocrine tumors) in a majority of cases may be occasionally heralded by seemingly bizarre and unexpected symptoms. It follows that, when a classic galaxy of symptoms and signs brings to mind the diagnosis, a sensitive if not highly specific diagnostic test is sufficient. In fact, if ultrasound studies are positive for chronic pancreatitis with good clinical correlation, the diagnostic work-up is considered completed. Less frequently clinical evaluation of a patient with persistent upper abdominal or mid back pain resolves into a decision as to whether or not the pancreas is the offending organ and if so whether the pathologic process in the pancreas is chronic pancreatitis or a malignant tumor.

86 G. Fontana et al.

At present, US and CT have achieved only modest success in establishing the precise etiology of an abnormality. Usually a more invasive procedure such as ERCP with cytology (CYT) or pancreatic function test (PFT) with CYT has been required to establish a more specific diagnosis. The choice of the major screening method for pancreatic lesion and the study of sequence and clinical impact of different techniques must be assessed in the clinical context and related to the characteristics of each investigation. The most useful test must have a low failure rate, a low rate of false-positive diagnoses in normal subjects, a low rate of false-normal reports in those with disease, a low cost, a rapid and noninvasive approach, and be easily repeated. In our opinion US fulfills these criteria remarkably well and certainly is noninvasive and can be performed without major discomfort. We and others (Di Magno et al. 1977; Cotton et al. 1978; Freeny and Ball 1978; Di Magno 1979; Lees et al. 1979; Gorelick and Spiro 1979; Mackie et al. 1979) recommend, for reason oflower cost and absence of ionizing radiation, that US be the initial imaging procedure (Fig. 1).

z o C3 ii: (I) :J (I)

....I « ~ z :::i (.)

I ? pancreatic problem I STOp_normal ...... _------US ~ abnormal

pk ~L J I ~~" I /0051

STOP_normal_---r----i~ERCP normal_CYT _abnormal-'GOAL

~ normal

SUSPICION

Fig. 1. Algorithm for the diagnosis of pancreatic disease

When clinical suspicion of pancreatic disease is low, a normal US report is often sufficient. CT and especially ERCP, PFT, and angiography are reserved for the patients in whom US does not provide precise data or where the result is negative but the clinical configuration is highly suggestive of pancreatic disease (Di Magno et al. 1977; Cotton et al. 1978; Lees et al. 1979; Di Magno 1979). If a pancreatic lesion is found by US, then in most cases ERCP is necessary to confirm the diagnosis and to make the etiology more precise (Cotton et al. 1978; Lees et al. 1979). CT and angiography are reserved for a few problem patients, often those with mass lesions who have undergone surgery (Lees et al. 1979). In a patient with symptoms of acute pancreatitis, in addition to clinical evaluation and laboratory examination, we first perform US (Fig. 2). Evidence of enlarged pancreas (demonstrated in about 90% of cases) and of biliary tract disease (gallstones) is the most

Diagnostic Algorithm for Pancreatic Disease 87

helpful evidence of all (Weill et al. 1975). The serum enzyme levels usually return to normal before echographic resolution (Doust and Pearce 1976). Ileus, so frequent in acute pancreatitis, or obesity may limit the contribution of US by making satisfactory examination of the pancreas difficult. In these cases we may turn to CT. Both US and CT have been effective in following the course of acute pancreatitis demonstrating complications (pseudocyst, ascites, abscess). These findings are more specifically identified with CT, which is the ideal diagnostic procedure, especially for surgical treatment planning in cases of pancreatic abscess: by means of a CT map, the surgeon can apply the drainage tubes at the cranial and caudal extremes of the abscess in order to assure a continuous abscess sac perfusion (Pistolesi et al. 1978).

I ONSET

ileus gallstones enlargement edema necrosis

ABD~AL.F~~~': I OUTCOME

pseudocyst abscess ascites

~~~ I COMPLICATIONS AND SEQUELAE I ""'j'" 'p'"'' ""'1"" ","OW,'''

us-- CT ANG

a Frequent technical failures.

b Ideal for surgical treatment planning.

Fig. 2. Acute pancreatitis

necrosis

CT/~G(?) fistulas, choledochal and main pancreatic

duct strictu res

~ ERCP

After the acute phase, US is the most useful technique for the diagnosis of pancreatic pseudocysts and for their follow-up; ERCP is the most useful for evaluation of fistulas, choledochal, and main pancreatic duct strictures or obstructions; angiography is the most useful for detection of splenic or portal narrowing or occlusion. In chronic pancreatitis (Fig. 3) the diagnostic importance of the discovery of pancreatic calcifications on a plain film of the abdomen is self-evident and pathognomonic of the disease. In a young patient, a heavy drinker with painful attacks lasting 2-3 days or longer which recur at irregular intervals of months or years, an US examination showing a pancreatic enlargement (Fontana et al. 1976) or an impaired PFT (Gullo et al. 1976) is strongly suggestive. ERCP is necessary for the diagnosis in the few patients in whom this combination does not provide precise


data (US not showing an enlarged pancreas and equivocal PFT). However, our policy is to perform ERCP in virtually all patients in order to outline the ductal system. To avoid infectious complications, we don't perform ERCP in those patients in whom US showed a pancreatic cyst. In conclusion US is performed first: in most cases this technique in followed by ERCP to complete the documentation and give information about the Wirsung duct and choledochus and in view of surgical treatment. ERCP can also provide a tissue diagnosis through endoscopic cytology and then help to make a definitive diagnosis in the few cases with an overlapped suspicion of malignancy. In chronic pancreatitis angiography can be reserved for the documentation of splenic or portal occlusion.

Tests to detect disease:

PLAIN FILM OF THE ABDOMEN

Clinical picture strongly suggestive US

I-______ DOUBTFUL DIAGNOSIS

or t PH ERCP

'--_.DEFINITIV~ DIAGNOSIS ... ~-----_____ -,I

To complete the documentation and for surgical treatment planning: To outline ductal system • ERCP Cysts • US Narrowing or obstruction of the common bile duct ____ 1. V. cholangiography, ERCP Splenic and portal narrowing .. ANG Duodenal stenosis • Hypotonic duodenography Suspicion of malignancy .. CYT, ANG To assess surgical treatment strategy • E RCP

Fig. 3. Chronic pancreatitis

A common clinical problem is that of the patient with abdominal pain who is suspected of having a pancreatic cancer, but in whom results of routine laboratory tests and barium examinations of the intestinal tract are normal. At this point there have been several attempts to develop algorithms for guidance (Ostrow 1975; Bass and Shaff 1976; Di Magno et al. 1977; Freeny and Ball 1978; Cotton et al. 1978; Di Magno 1979; Mackie et al. 1979; Weingarten et al. 1979) usually including US or CT or both and ERCP, PFT, and angiography. The increasing interest in the diagnosis of pancreatic disease and the proliferation of new diagnostic tests, particularly imaging techniques, is related to the rapidly increasing incidence of pancreatic cancer (Krain 1971; 10chimsen et al. 1977; Silverberg 1977) and its mortality which remains unchanged. Therefore the diagnosis of pancreatic cancer has became a major clinical problem; the hope is that early diagnosis, before metastasis, will increase survival. Actually the low survival rate means that incidence and mortality are almost identical (Weingarten et al. 1979). To increase the survival rate of patients with pancreatic cancer, it whould be necessary to detect and appropriately treat patients who have small lesions be-


fore metastasis, but the early diagnosis of pancreatic cancer despite rather sophisticated diagnostic techniques is very unusual (McCormack et al. 1977). The major reason for this is the fact that, by the time the patient is symptomatic and seeks medical attention and the diagnosis is made, the tumor is already inoperable. The current trend in the management of pancreatic cancer is to achieve a diagnosis with a minimum of tests and to avoid laparotomy. Following initial clinical evaluation (history, physical examination, screening, blood studies), US is performed (Fig. 4). If a pancreatic lesion is found by US and liver metastasis is seen on either US or radionuclide liver scan, the diagnostic work-up is completed; histologic diagnosis can be achieved by means of liver biopsy in conjunction with peritoneoscopy to avoid laparotomy. If US is positive and there are no evident liver metastases, also excluded by liver scan, and if US is negative or indeterminate, an ERCP, possibly with aspiration cytology, is used to confirm the pancreatic carcinoma. Pancreatic function testing is sensitive and specific if associated with cytologic examination (Endo et al. 1974; Di Magno et al. 1977; Mackie et al. 1979). We feel that few patients with a high clinical suspicion of pancreatic disease should undergo angiography if ERCP is normal, equivocal, or technically unsatisfactory. CT scanning and angiography can be used to assess the operability. Pancreatic angiography is the only method which can reliably determine the unresectability of a pancreatic carcinoma; this involves the indentification of major extrapancreatic vascular involvement, invasion of contiguous organs or hepatic metastases (Tylen and Amesjo 1973; Goldstein et al. 1974).

~j~ abnormal with abnormal without normal or liver metastasis liver metastasis equivocal

S1~LIVJSCAN I

no liver metastasis

EJCP .. ----------~ ~bn1rm~

normal to assess technical failure

I the operability I high clinical I suspicion t

I .. ANG ...... _----------.....J Fig. 4. Pancreatic cancer


Since many patients with pancreatic carcinoma present with jaundice, an algorithm based on US and including percutaneous transhepatic cholangiography, if biliary ducts are dilated, can be used. For the latter, US may prove the greatest help in guiding biopsy needles to pancreatic masses. Because of the demonstrated safety and accuracy of percutaneous fme-needle pancreatic biopsy (Hancke et al. 1975; Smith et al. 1975) this procedure is being more widely adopted. Pancreatic biopsy may not affect survival but in special circumstances may eliminate the need for further diagnostic procedure such as ERCP or angiography. Some large pancreatic masses are obviously unresectable or US and CT may demonstrate metastatic tumor; in such cases, direct confirmation of the diagnosis by fine-needle biopsy is a logical departure from the algorithm. This is only a provisional algorithm: in fact some of these techniques (especially CT) are not always available because of their cost and diagnostic accuracy depends, as in ERCP, US, and ANG, on individual skills. However, a different availability of equipment and of experience may change this diagnostic approach. Moreover, a rigid diagnostic scheme is impossible to apply: in the fmal analysis the physician, in the light of his clinical experience, evaluates in each case the clinical impact of various methods of imaging and then dictates the diagnostic procedure. If more accurate tests for pancreatic cancer are developed, different diagnostic approaches may be appropriate; however much the sensitivity of tests improves, its benefits may be limited by the late onset of symptoms. Despite the speed and accuracy of this or other algorithms, only in 10% of cases of pancreatic carcinoma is the tumor resectable, due to the advanced stage of the disease at the time of clinical presentation or to delay in referral of the patient for diagnostic evaluation.

References

Bass EM, Shaff MI (1976) An accelerated diagnostic approach to surgical jaundice. S Afr Med J 50:2041-2043

Cotton PB, Denyer ME, Kreel L, Husband J. Meire HB, Lees W (1978) Comparative clinical impact of endoscopic pancreatography, grey-scale ultrasonography, and computer tomography (EMI scanning) in pancreatic disease: preliminary report. Gut 19:679-684.

Di Magno EP (1979) Pancreatic cancer: a continuing diagnostic dilemma (Editorial) Ann Intern Med 90:847-848

Di Magno EP, Malagelada J-R, Taylor WF, Go VLW (1977) A prospective comparison of current diagnostic tests for pancreatic cancer. N Engl J Med 297:737-742

Doust BD, Pearce SD (1976) Gray scale ultrasonic properties of the normal and inflammed pancreas. Radiology 120:653-657

Endo Y, Morri T, Tamura H, Okuda S (1974) Cytodiagnosis of pancreatic malignant tumors under direct visualization using a duodenal fiberscope. Gastroenterology 67:944-951

Fontana G, Bolondi L, Conti M, Plicchi G, Gullo L, Caletti GC, Labo G (1976) An evaluation of echography in the diagnosis of pancreatic disease. Gut 17:228-234

Freeny PC, Ball TJ (1978) Rapid diagnosis of pancreatic carcinoma. An algorithmic approach. Radiology 127:627-633

Goldstein HM, Neiman HL, Bookstein JJ (1974) Angiographic evaluation of pancreatic disease. A further appraisal. Radiology 112:275-282

Gorelick FS, Spiro HM (1979) The gastroenterologist's view of the indication and efficacy of ultrasound examination. In: Taylor KJW (ed) Clinics in diagnostic ultrasound, vol 1,


Diagnostic ultrasound in gastrointestinal disease. Churchill Livingstone, New York Edinburgh London, pp 1-21

Gullo L, Costa PL, Fontana G, Labo G (1976) Investigation of exocrine pancreatic function by continuous infusion of caerulein and secretin in normal subjects and in chronic pancreatitis. Digestion 14:97-107

Hancke S, Holm HH, Kock F (1975) Ultrasonically guided percutaneous fine needle biopsy of the pancreas. Surg Gynecol Obstet 140:361-364

Jochimsen PR, Pearlman NW, Lawton RL (1977) Course and treatment results of young patients with carcinoma of the pancreas. Surg Gynecol Obstet 144:32-34

Krain LS (1971) The rising incidence of cancer of the pancreas-further epidemiologic studies. J Chronic Dis 23:685-690

Lees WR, Vallon AG, Denyer ME, Vahl SP, Cotton PB (1979) Prospective study of ultrasonography in chronic pancreatic disease. Br Med J 1:162-164

Mackie CR, Dhorajiwala J, Blakstone MO, Bowie J, Moossa AR (1979) Value of new diagnostic aids in relation to the disease process in pancreatic cancer. Lancet 2:385-389

McCormack LR, Seat SG, Strum WB (1977) Pancreatic carcinoma: survival following detection by ultrasonic scanning. JAMA 238-240

Ostrow JD (1975) Jaundice in older children and adults, algorithms for diagnosis. JAMA 234:522-526

Pistolesi GF, Marzoli GP, Quarta Colosso P, Pederzoli P, Procacci C (1978) Computed tomography in surgical pancreatic emergencies. J Comput Assist Tomogr 1:290-299

Sample WF, Sarti DA (1979) Diagnosis of pancreatic disease by ultrasound and computed tomography. In: Taylor KJW (ed) Clinics in diagnostic ultrasound, vol 1, Diagnostic ultrasound in gastrointestinal disease. Churchill Livingstone, New York Edinburgh London, pp 85-101

Sheedy PF II, Stephens DH, Hattery RR, McCarty RL, Williamson BJr (1977) Computed tomography of the pancreas. Radiol Clin North Am 25:349-366

Silverberg E (1977) Cancer statistic. CA 27:26-41 Smith EH, Bartrum RJ, Chang YC, D'Orsi CJ, Lokich J, Abbruzzese A, Dantono J (1975)

Percutaneous aspiration biopsy of the pancreas under ultrasonic guidance. N Engl J Med 292:825-828

Tylen U, Arnesjo B (1973) Resectability and prognosis of carcinoma of the pancreas evaluated by angiography. Scand J Gastroenterol 8:691-697

Weill F, Bourgoin A, Aucant D, Eisenscher A, Gallinet D (1975) Pancreatite chronique, cancer du pancreas: differentiation par ultrasons. Nouv Presse Med 4:567-570

Weingarten L, Gelb AM, Fischer MG (1979) Dilemma of pancreatic ductal carcinoma. Am J Gastroenterol 71:473-476

Morphogenesis of Acute Pancreatitis

M. Wanke

Pathologisches Institut, Stadtkrankenhaus Rendsburg, Akademisches Lehrkrankenhaus der Universitat Kiel, Lilienstrasse, 2370 Rendsburg, Federal Republik of Germany

Introduction

Patho- and morphogenesis of acute pancreatitis remained a domain of speculative theories for quite a long time. This is principally due to the problematic diagnosis and therapy of this disease in vivo in connection with the postmortem autolysis of the excretory parenchyma occurring so rapidly. The knowledge gained in the last 15 years in biochemistry and pathophysiology of pancreatic enzymes in connection with a clear differentiation of the morphological phenomena of the different forms of acute pancreatitis, and their morpho- and pathogenesis, does now allow a synthesis. For the morphogenetic disposition it is fruitful to recall the morphological essentials of the aspects of this disease: hemorrhage, fatty tissue, and parenchymal necrosis. These components are the characteristic representation of the three forms of pancreatitis: the biliary, lipolytic, and proteolytic variants (Wanke 1966). With a view of the findings made by Heidenhain as early as 1875 that the proteolytic enzymes were present as zymogenes, Chiari (1883) postulated a preceding impairment of the metabolism of the acinar epithelial cells that allowed the pancreatic juice to develop it's autodigestive effect at the wrong place. The close structural and functional correlation between vessel tissue and parenchyma due to the enzyme status causes a typical lesion in shape and feature. The morphogenesis of the (chemical) inflammation is determined by blood-tissue, blood-pancreatic juice, and lymph-pancreatic juice barriers. Regardless of the cause, course, and primary aggression of the noxa on the unit of parenchymal and mesenchymal tissue, an early disturbance causes an edema and an enzymatic parapedesis, so that the organ specific interchangeability of metabolism is stopped. This initial edema, Zoepffel edema, is a common morphological substrate of all kinds of acute autodigestive pancreatitis. The special pathogenesis is characterized by dyscholia, edema, circulatory disturbances, necrobiosis, and autodigestion. In our opinion, the main difference between acute and chronic pancreatitis is the time expiration and volume of parapedesis (compare contribution from V. Becker). The etiology determines the morphological picture, forms, and pace of the parenchyma destruction (Wanke et al. 1966). The noxa invade either the organelles of the cell respiration (hypoxic type) or of the cell metabolism (metabolic type). The many sided clinical and morphological picture of acute pancreatitis is based upon the following phases, which can be differently stressed: dyscholia, edema,

94 M. Wanke

circulatory disturbance, necrobiosis, and autodigestion. The phases are dependent upon the inhibitor capacity or the enzyme pool, in loco, or the dominant, in the beginning, existing circulatory disturbance. If we overlook the opinion of Opie and Halsted (1901) on the acute biliary reflux pancreatitis, one can realize from the primary autodigestive pancreatitis course, the phases mentioned above, which are of clinical, therapeutic, and prognostic importance.

First Phase, Dyscholia

The dyscholia contains the following disturbances of the secretion process: juice production in the acinar epithelium, juice excretion and transportation in the duct system (see Fig. 1). Regionally one differentiates between acinar and ductal dyscholia (Becker 1957; Seifert 1966); biochemically the dualism complies with proteo- and hydrodyscholia. The ductal dyscholia refers to a dilute secretion, 'juice shower" from Becker in the duct system, and is based upon changes in the electrolyte and water regulation of the metabolism as you find it in accompanying pancreatitis by uremia, burns, diarrhea, and dumping syndrome (see in Forell 1976). The emphasis is on the gastrointestinal diseases with pronounced water and electrolyte losses.

Fig. 1. Acute exacerbated LPP with hemorrhages; SN 218/79, aged 68, male

Proteodyschylia is due to a disturbance in the enzyme production; the cause is damage to the intracellular protein metabolism as you find it in athionin pancreatitis, kwashiorkor, alcoholism, liver diseases - in other words in the metabolic pancreatitis forms (Wanke 1970 a, b).

Morphogenesis of Acute Pancreatitis 95

The morphological feature of the acinar dyscholia is: hydropic vacuolic degeneration as a sign of the acinar cell's acute oxygen insufficiency (see below, shock), loss of basal basophilia, acidophilic degeneration, dyscholic atrophy (Doerr et al. 1965).

Second Phase, Edema

The first most important morphological changes in the early phase of acute pancreatitis is the edema. In 1922, it was described by Zoepffel as a glassy edema and is always a cause of dyscholia. The physiologic secretion process of the gland is already marked by increased parapedesis through it's inclination to edema production. Here we see the Achilles heel of the pancreas and key to the understanding of acute pancreatitis. Every extra burden of the secretion process is also adapted to produce through the chronic inveterated edema, a gradual organ alteration. Here are two edemas that have to be differentiated in their biologic aggression: the vascular and the acinar edema. The vascular edema by cardial and portal congestion, in time, turns into a interacinar fibrosis; it is a very common finding (Table 1). Toxically caused impregnation increases in the capillary and lymphatic systems produce extravasation with additional leucocyte-lymphocyte inmtrations. If dyscholic degenerative acinar epithelial changes also occur, mixed forms result. Kinins playa big role in the primary genesis of the vascular edema (Amundsen 1967; Creutzfeldt 1969). Discharged enzymes from mast cells and parenchymal acinar enzymes influence quantitatively the genesis ofthe interstitial edema (Arnesjo 1968; Creutzfeldt and Schmidt 1970; Wanke 1966). Vascular components, in connection with biliary pancreatitis will be dealt with in detail later. From a general pathological view, the pancreas edema can be interpreted as a serous inflammation in RossIe's opinion. Compensated, it represents an unimportant finding, decompensated it is a component of a necrosis. Acinar edema: in accordance, the Zoepffel edema represents the most important component of the acute pancreatitis. The bland variants are: acute pancreas edema, acute transitional pancreatitis, interstitial pancreatitis. The phenomenon of the enzyme derailment is biochemically, clinically, always present; The local morphological changes do not surpass the discrete dyscholic lesions. From this experience, clinical and patholigical statistics are not comparable concerning the frequency of the acute pancreatitis, in that no objective diagnosis

Table 1. Frequency of chronic interstitial pancreatic lesions in 110 unselected autopsies in patients aged more than 25 years

Interstitial fibrosis Fatty necrosis Scars Periductal fibrosis

38 cases 34 cases 32 cases 9 cases

(34.5%) (31.0%) (29.1%)

(8.2%)

96 M.Wanke

" at Laparotomy" can follow (White 1966); even the new method of computer tomography (CT) did not change this. The acute pancreatic edema is often seen in connection with acute episodes of bile duct diseases, when a short bile reflux of the duct system in the head of the pancreas follows; an anatomic prerequisite is an accessory juice duct that runs into the retro- and intrapancreatic flowing common bile duct - up to 85%. An increase in the intrapancreatic secretion duct with juice retention and reflux in the interstitial space is seen as the precipitating factor in the acute pancreatitis. Secretion against an obstacle occurs by: Pancreas lithiasis Papillary folding of the duct epithelium Squamous epithelial metaplasia of the duct epithelium Scar stenoses of the pancreas duct Concrements Papillitis stenosans Vateriana Juxtapapillary duodenal diverticular Parasite invasion Papillary cancer In reference to drainage malfunctions due to increased viscosity see Becker's report (Sarles et al. 1978). The extent of the lymph drainage determines whether a biochemical pancreatitis can morphologically become a pancreatitis. Thereby, the organ's own lymph system acts as an overflow and security valve, just in case a high secretion pressure, high secretion volume, or an obstruction is present. On the one hand, the edema can join the acute pancreatitis, or on the other hand, it can stand as an intersection of the biliary (see below) and the lipolytic-proteolytic variation. It causes the lipolytic-proteolytic late phase of the biliary and subacute exacerbation of the lipolytic form. Depending upon the inhibitor capacity in loco and the function capacity of the lymph system, the acute pancreatitis can finish in the following phases: Dyscirculation with vascular edema and DIC Pancreatic edema Dyscholic necrosis Acinar cell and group necrosis or It can accumulate in the massive autodigestion.

Third Phase, Circulation Disturbance

An analysis of the possible causes of circulatory disturbances leads us to the following morphological considerations: In addition to the already mentioned components, edema and secretion against an obstruction, a decreased artery flow rate, an obstructed venous backflow, as well as an increased capillary permeability are potential factors in the precipitation of an acute pancreatitis. This circulatory disturbance can become nervous vagal, hematogenic, ductal, or cellular effective; cellular in so far as in shock or by maximal secretion stimulation a work hypoxia can lead to a acinic epithelial and fat cell necrosis. The functional-nervous com-


ponents are, according to the present experimental experiences, clinically irrelevant. On the other hand, hematogenic offered vasoactive substances like epinephrine or arterenol cause, depending on the dose, circulatory disturbances in the pancreas vessels (SchOnbach 1969; Wanke 1970 a, b). Flowing transitions to digestion physiology exist on the subject of the circulatory dependent pathophysiology of secretion. During digestion as well as a few minutes after histamine neostigmine (Prostigmin), secretin or pancreozymin release, the oxygen consumption and circulation rate of the pancreas increases many times over in relation to the resting stage (Ritter 1971). If the arterial circulation can not adapt to this increase, for'example, arteriosclerosis (compare age distribution of acute pancreatitis), a work hypoxia and cell necrosis result (Wanke 1965). Functional-physical disturbances: the arterial hyperemia accompanies every acute inflammation, on the other side, the venous hyperemia is seen by all obstruction situations (heart defects, pulmonary-portal hypertonia: lung diseases, liver cirrhosis). The chronic obstruction causes a cyanosed induration of the pancreas with an increase of support and fat tissue as well as atrophia of the excretory parenchyma.

Shock Hypoxia

During the course of shock the pancreas occupies a special position since it can either produce shock or be secondarily involved in shock (Table 2). One has to differentiate between pancreatitis as a consequence of shock and postpancreatitis shock (Wanke 1965, 1968, 1969; Seifert 1970).Circulatory disorders are essentially significant in both modes. Since 1965 we have kept emphasizing

Table 2. Findings in patients, older than one year, suffering from shock"

Type of shock No. of cases Positive findings Clinical Pathologic- Pan- Lung Liver Kid- Sto-

anatomic creas ney mach Male Female

Hypovolemicb 52 14 38 47 32 26 38 41 37 Cardiogenic: 268 102 166 173 128 104 91 82 83 Myocardial infarction 190 56 134 128 89 92 65 61 62 Myocarditis 10 7 3 6 3 3 5 3 3 Lung embolism 68 39 29 39 36 9 21 18 18 Septic 68 34 34 51 15 33 24 23 21 Postpancreatitis 13 5 8 13 13 11 11 10 7

Percentage 100 59.7 40.3 70.8 46.9 49.4 40.9 38.9 36.9

" Study based on 750 continuous autopsies (on 302 females and 448 males) performed at the Institute of Pathology, Academic Teaching Hospital, Rendsburg, 1973-74

b Deaths due to acute hemorrhage after accidents are not included

98 M. Wanke

the central significance of local acidosis in the pancreas and it's responsibility for the onset of acute pancreatitis, an experience which is based on clinicopathologic and experimental investigations (Becker and Wilde 1963); this is confirmed by an unexpected frequency of lipolytic-proteolytic pancreas necrosis in shock noticeable on first sight (Table 1). Pancreatic edema and subsequent neutralization of the initially substrate-bound and localized acidosis stand at the beginning of shockinduced pancreatitis as necrosis and acute exacerbation of lipolytic-proteolytic pancreatitis (LPP) since the pancreatic enzymes which are essential for autodigestion develop their optimal activity during the acid pH phase while their optimal effectiveness is found in the alkaline pH level (Nagel et aL 1965) (see below). Short lasting hypoxic phases become thus dangerous; one has to take into account a spontaneous activation from trypsinogen to trypsin with a chain reaction. The LPP goes hand in hand with an autodigestive acinar epithelial necrosis and an inital fat necrosis, whose genesis is attributed to an acidosis (Figs. 1 and 2). A comparison between the pancreas changes due to shock and those due to a metabolic pancreatitis produces fundamental differences in the lapse of time (Doerr et aL 1965; Donath et aL 1970; Schmitz-Moormann and Keilos 1971; Wanke 1968): vascular-hypoxic noxae first cause disintegration of mitochondrial structure and then later the rest of the cell organelles are destroyed; metabolic noxae primarily damage the cell organelles connected with protein synthesis and secondarily the mitochondria. While the absolute hypoxia causes a cessation of the secretion, the partial ischemia induces an extrusion of zymogenous granula, vacuolic degeneration, nuclear edema, and monocellular necrosis - thus the equivalent of an acinar dyscholia. The arteriosclerosis of the pancreas vessels cause, on the one hand, extensive organ fibrosis and reduction of the excretion parenchyma, on the other hand, significant relationships exist pertaining to the acute pancreatitis (Table 3). The relatively rare occurrence of pancreatitis during infancy (frequency 1:4 compared to adults, Wanke 1971 a, b, 1972 a, b) can be attributed to the fact that the pre phase is not yet morphologically realized. The morphological substrate of the prephase:

Table 3. Distribution of 157 cases of acute pancreatitis 90 male: 67 female out of 14501 autopsies, Heidelberg/ Rendsburg 1963-1979

O-tO years 11-20 years 21-30 years 31-40 years 41-50 years 51-60 years 61-70 years + 70 years

Male

1 1 4

14 9

22 24 15

Female

1 3 2

11 25 25

Morphogenesis of Acute Pancreatitis

Periductal fibrosis Lymph blockade - intramural/cisterna chyli Saliva blockade Vessel sclerosis F at tissue proliferation

99

If the prephase is humorally realized we find it in infancy in the sense of a "cortisone pancreatitis" (Wanke and Griss 1969; Wanke and Horeyseck 1970). The intrapancreatic fatty tissue as an intraorganic substrate for the already actively present pancreas lipase is of increasing importance. Beyond the age of 50 we found a marked interstitial proliferation of fatty tissue in the pancreas (Walters 1966: 60%, Wanke 1972 a, b: 63%). Considering the changes in body weight ofpatients who died due to acute pancreatitis these relations are significant: sum 157 cases 67 women : 90 men

+ 47 37 NC 7 17

13 36

only 15,3% out of 157 cases had normal weight according to the Geigy tables while the rest showed intrapancreatic proliferation of fatty tissue in cachexia or increased fatty tissue interposition corresponding with adipositas interna, 53,5% of our cases! The frequency of the lipolytic-proteolytic foci which were clinically untraceable in the beginning runs parallel to the aging process (Table 4): general arteriosclerosis, sclerosis of the pancreatic arteries (Wanke 1965), intrapancreatic proliferation of fatty tissue in adipositas interna, and a metabolic situation corresponding with diabetes. In an analysis of the frequency of diabetes mellitus and diabetic metabolism in 401 cases of lethal shock, 66% of the cases were seen to have "cardiogenic shock" following myocardial infarction (Table 5). On the other hand the coincidence of diabetic coma and acute pancreatitis is a known phenomenon (DUrr 1969; Hayduk et al. 1968; Wanke and Sebening 1969). According to DUrr (1969) the diabetic coma stands at the beginning while pancreatitis is an

Table 4. Relationship between fatty tissue interposition, fatty tissue necrosis, and perifocal acinolysis (Wanke 1972a)

Fatty tissue Fatty tissue Acinolysis Age No. of interposition necrosis autopsies No. of cases No. of cases No. of cases

5 (2.4%) 8a (3.8%) 6 (2.8%) 1- 5 years 211 8 (8.6%) 5 (5.4%) 4 (4.7%) 6-10 years 93 7 (14.0%) 6 (12.0%) 6 (12.0%) 11-15 years 50

20 (5.6%) 19 (5.4%) 16 (4.5%) 1-15 years 354 11 (11.8%) 5 (5.4%) 5 (5.4%) 16-20 years 93 24 (15.5%) 12 (7.9%) 12 (7.9%) 21-25 years 152 35 (14.3%) 17 (6.9%) 17 (6.9%) 16-25 years 245 69 (62.7%) 38 (34.6%) 34 (31.0%) >25 years 110

11 58 years

a Peri pancreatic only

100 M.Wanke

Table 5. Frequency of diabetes mellitus and/or an altered carbohydrate metabolism"

Type of shock

A. Hypovolemic B. Cardiogenic

Myocardial infarction Myocarditis Lung embolism

C. Septic D. Postpancreatitis

No. of cases

52 268 190

10 68 68 13

Diabetes mellitus and/or altered carbohydrate metabolism

26 (50.0%) 171 (63.8%) 126 (66.3%)

6 (60.0%) 39 (57.4%) 23 (33.8%) 7 (53.9%)

a 401 lethal shock patients, all older than 1 year, out of750 continuous autopsies performed at the Institute of Pathology, Academic Teaching Hospital, Rendsburg, 1973-74

"after-effect" in this special constellation. Bossak and 10elson (1965) point out that shock is the crucial point in the diabetic coma. According to our own experience there is a morphological manifestation of latent diabetes in cardiogenic shock; generalized and local acidosis cause the pancreas to develop LPP (compare before: topic shock!).

Fourth Phase Necrosis

The necrosis is defined as an intravital dying of cells with nuclei and cell band under pathological conditions. The nuclear atrophy, the karyolysis, is proof of an increased proteolytic activity and is pH-dependent; by nuclear atrophy and chromatolysis the protein components are split off the nucleoprotein through proteases, while polynucleotidases take care of the nuclein themselves. Therefore, it is legitimate to describe this, for the specific organ destruction of the pancreas with inflammation, as autodigestion. The common morphological substrate of the chronic and acute pancreatitis is, apart from the biliary reflux pancreatitis and the calcified form, a phenomenon of the acinar and occasionally also the ductal dyscholia. The cause of this dyscholia is metabolic or hypoxic. Destruction ofthe oxygen apparatus of the acinar epithelium is the consequence. Gradual differences in the intensity of the destruction reach from single cells to group cell necrosis. Next to the clearance reaction with interstitial inflammation, creeping organ reorganization, and fibrosis, lipolytic-proteolytic foci develop. The number of them depends upon the extent of the interstitial fat tissue (compare with the above!). Therewith, pictures of chronic pancreatitis develop and 85% of our cases pave the way for the prephase of the acute LLP, according to my own experiments. The low frequency of acute pancreatitis in childhood is as mentioned above thought to be caused by a lack of development of the prephase. Several facts underline the importance of pancreatic lipase in the production of nonbiliary pancreatitis according to Wanke (1972 a, b):


1) An obvious relationship between obesity and intensity of LPP 2) Intrapancreatic fat tissue acts as primary substrate for lipase 3) Acinar epithelial necroses are first seen in the vicinity of fat necrosis 4) Intraductal instillation of lipase induces LPP only in obese animals 5) The steroid pancreatitis in man and in animals is a LPP 6) There is a significant correlation between the adrenal cortical function, obesity

and pancreatic enzyme activity 7) In bilateral adrenalectomized animals the intraductal instillation of olive oil

does not produce any changes 8) Hormone-producing tumors of the adrenal cortex may be associated with

LPP The pathogenesis and morphogenesis of LPP in generalized acidosis (shock!) is associated with loosening of cellular membranous structures that provide the site of attack for lipase on the lipid components of the membranes. Then the stored fat of the intra- and peripancreatic fat cells become the substrate for lipolysis.

Fifth Phase Autodigestion

According ly, the morphological substrate of the acinar dyscholia by acute pancreatitis is distinctly marked and determinative. An autodigestive lipolytic and proteolytic necrosis develops out of the dyscholic necrobiosis. Depending on the composition of triglycerides, different fatty acids are released. The local acidosis activates proteolytic proenzymes, resulting in perifocal acinolysis and a triggering of the chain reaction known as acute lipolytic-proteolytic pancreatitis. In addition, circulation disturbances like hemorrhagic edema and hemorrhages result. Due to the edema, the structure of the lobular unity ruptures. The intramural lymph system decompensates the flood of detritus, necrotic acinar epithelial components, as well as juice and vascular edema. The acute exacerbation has taken place. It is triggered 1) Hematogenically, through direct damage to the acinar epithelium with inva

sion in the organelles of the structure and function circulation by the metabolic form, as well as in the organelles of the cell respiration by shock and hypoxia.

2) Lymphogenically, from adjoining areas or metastatically. 3) Mesenchymally, through liberation of the mast cell's own enzymes as well as

indirect hematogenic as metastatic-septic excretion inflammation. 4) Ductogenically, through bile or chyme reflux as well as bacteriogenic ascend-

ing and parasitally. In the organ repairing with parenchymal atrophy every chronic pancreatitis conceals, up to a certain degree, morphologically the danger of an acute exacerbation. The enzyme-empty, burned out pancreas is no longer capable of functioning; it provides a model of adrenalectomy, protein malnutrition, too little protein in the nutrition (Wanke 1970 a, b). The etiologic spectrum of lipolytic-proteolytic and biliary pancreatitis, considering the hematogenic, lymphogenic, mesenchymal and ductogenic stream of noxae, is morphologically organized into the following:

102 M. Wanke

a) Metabolic: toxic, alimentary, hormonal. b) Hypoxic: due to shock, organ-vascular, traumatic, allergic-hyperergic, neu

rovascular-functional. c) biliary: classical OPIE pancreatitis, chyme reflux.

Fig.2. Acute exacerbated LPP with extensive fat cell necrosis in the periphery and centrally following proteolytic necrosis; SN 34/67, aged 84, female. Stain HE

The phase sequence of the acute pancreatitis becomes by the autodigestive forms especially clear (Fig. 3), that develop from the discussed phases of acinar dyscholia with edema. The pathological accomplishment of the acinus' own enzyme sets the morphological picture. The lipase influence has already been discussed in detail; since it already exists in the active form, it takes on a special position in the pancreatic enzymes. Through the dispersion capability of bile (detergent effect) a surface increase of the substrate is achieved, increasing the attack surface of the lipase, which is equal to an increased reaction - compare biliary form. Phospholipase A is found in the acinar epithelium as a zymogen (Figarella et al. 1969); the conversion of prephospholipase A in the active enzyme needs trypsin as a prerequisite. The cytotoxic aggression of the reaction products of the phospholipase A - lysolecithin and lysocephalin - is based upon it's installment in the cell membrane (Deenen 1965). The advanced parenchymal destruction during acute pancreatitis is due to the phospholipase A (Creutzfeldt and Schmidt 1970). Since human bile is rich in lecithin, the morphological effect after bile reflux (see below) is accordingly interpreted. So, it is in vitro possible, within minutes of mixing bile and pancreas secretion, to register the lysolecithin effect (Schmidt and Creutzfeldt 1969). The unconjugated bile acids also show the same effect (Wanke 1967).


A· MORPHOLOGIC B· HUMORAL

al perlductal fibrosIS a) enzymatic adaptation

bl blockade of lymphatic 1. alimentary

circulation 2. hormonal

1. Intramural b) stimulation of enzyme secretion PREPHASE- 2. cisternal 1. alimentary r-PREPHASE

INDUCTORS

c) stasis of pancreatic juice

d) vascular sclerosis e) substitutive or exuberant

proliferation of adipose tissue

2. hormonal

3. nervous

4. tox,<

t-= PRIMARY CHRONIC

LIPOLYTIC PANCREATITIS ~

CIRCULATORY ALTERATIONS

Iby biliary reflux)

METABOLIC ACIDOSIS SUBSTRATE·BOUND ACIDOSIS

BILE PANCREATITIS

Liberation of mesenchymal proteo

lytic and lipolytic "lysosomal" enzy-

mes ! EDEt-1A

ACI~OSIS

after reflux of chyme

triglyceride splitting

by lipase

INDUCTORS

substrate·bound

autodigestIOn after

activation of aCinary

enzymes

ACUTE PHASE activation of aCinar proteolytic and

lipolytiC enzymes

ENZYMATIC DERAILMENT

hepatIC' b,l,ary·card,ac· renal

tissue necrOSIS

POST PHASE

• TRYPSIN

chymotrYPslns, carboxypeptidase A

elastases, phospholipase A

+ PROTEOLYTIC PANCREATITIS

1 Circulatory alterations

clotting defects

liberation of vasoactive polypeptides

indirect stimulations of prateo· and

hydrochyll by H·substances

Fig. 3. Phases and forms of acute pancreatitis

ENZYMATIC DERAILMENT

hepat IC' billa ry· ca rd lac·rena I

tissue necroSIS

POST PHASE

104 M. Wanke

Pro teases

For the pathogenesis of an acute pancreatitis, it is important that trypsin, in a neutral milieu (edema phase), quickly changes into an inert protein again. This "autodigestion" is delayed by calcium ions. In it's energy metabolism compensated balanced cells can't devolve to "trypsis" - malonate experiments from Becker and Wilde (1963). Prerequisite for the trypsis is a choking of the cell respiration with protein denaturation. Accordingly, one sees by the in statu nascendi engaged autodigestive pancreatitis first a fat cell necrosis by general hypoxia in shock (see above), then a local acidosis due to a triglyceride fissure, an hypoxic vacuolization perifocal acinar epithelium and the phases of dyscholia up to autodigestive necrosis. The majority of examiners agree upon the morphological effect of trypsin up to the development of the hemorrhagic edema. In this phase large surface bleeding and the enzyme rich edema partially cause an extensive structure rupture. In the neighborhood of the edema areas, the acinar epithelium is vacuolated, so that the enzyme activation quickly spreads to further parenchyma areas. A proteolytic digestion according to Todd (Fig. 4) (Bleyl et al. 1966, 1967) can be made histochemically objective through fresh autodigestive necrosis. The conversion dyscholia - necrobiosis - necrosis happens so fast that typical zones of the cell destruction, as they are registered as kokarden phenomenon around fat tissue, are only partially recognizable (Fig. 5). The autodigestion depends upon edema and substrate. The elastase plays an important role in the vascular components of the proteolytic pancreatitis. Necrosis of the elastic fibers of intramural vessels, thrombosis, and surface bleeding result (Doerr et al. 1965; Geokas et al. 1968). The proelastase is always activated by trypsin.

Fig. 4. Early autodigestive pancreatic necrosis demonstrated by the method of fibrinolysis autographs. Stain HE


Fig. 5. Early acinar necrosis encircling necrotic fat cell with typical perifocal karyolysis and karyorhexis - kokard phenomenon. Early stage of LPP. Stain HE

The carboxypeptidase A and B complete the protein degeneration initiated by trypsin, chymotrypsin, and elastase (see Table 6). The common feature of the proteolytic enzymes that take part in the autodigestive tissue destruction is that they spread their effect from the periphery to the lobuli, after activation in a sour milieu during the phase-increased parapedesis by neutralization of the edema through additional vascular edema.

Biliary Pancreatitis

The group of ductogenic induced acute pancreatitis prevented attempts to bring etiology, pathogenesis, and morphological substrate in congruity, and therefore led to general misunderstandings of the concept. Next to the spectrum of pathophysiological and pathological facts in the papilla of Vater and ductal area (Wanke 1968), it is the mass of pre, additional, and accompanying diseases that are judged so differently in their pathogenic importance (see Table 7 for an example using cholecystopancreatitis). The bile chyme reflux is the most important pathogenetic factor in connection with the obstruction hypersecretion theory (McCutcheon 1968). During the chyme reflux the effect of three components: bile, substrate, and activated enzymes accumulates. The possible reasons for bile occlusion are: Edema of papilla of Vater (e.g. alcoholics) Papillitis stenosans and sphincter sclerosis Stones of the Wirsung duct and/or of the papilla Parasites Papilla carcinoma.

106 M. Wanke

Table 6. Summary of the lipolytic and proteolytic enzymes that take part in autodigestion and their cellular substrate

Enzyme Substrate Effect

Lipase Triglyceride Fat tissue necrosis, intracellular- local acidosis after triglyceride fis-extracellular sure,

intraacinar lipolysis, loosening of the cell membrane

. Phospholipase A Cell membrane Lysophosphatide building, phosphatide membrane destruction,

dyshoria Trypsin Activation from Coagulation necrosis,

trypsinogen dyshoria chymotrypsinogen prephospholipase A + B kallikreinogen denaturated protein frame

Chymotrypsin, Denaturated protein frame Coagulation necrosis, carboxypeptidases dyshoria Elastase Protein frame Coagulation necrosis proteolytic component Elastolytic component Elastic and colla- Elastocollagenolysis,

genic fibers dyshoria Kallikrein Kinin Dyshoria

The increased appearance of acute pancreatitis after interfering with the duct system, especially in the vicinity of the papilla, is more than coincidental and occurs in 10%-30% of the exogenic-post-traumatic forms (Wanke 1971 a, b; White 1966). The heterogenic spectrum of the postoperative pancreatitis is mentioned above. The frequency of pancreatitis by cholecystopathy varies in the literature between 25% and 91%; in 14960 autopsies Link (1965) saw in 0.87% an acute pancreatitis; in 85% it was determined as the cause of death, and was in 68.5% combined with a biliary disease. While on the subject, one has to refer to the problem of the diagnosis of an acute pancreatitis, which in our observation material from 157 cases (Heidelberg/Rendsburg 1963/1979) only 43% were diagnosed in vivo. A reflux of duodenal contents in the pancreas duct should be possible according to McCutcheon (1968) under the following conditions: a) Normal intraduodenal pressure and relaxation of the sphincter of Oddi - evi

dent in patients with biliary stones. b) Increased intraduodenal pressure with a normal papilla of Vater - demonstra

ble by the blind loop syndrome and experimentally. c) Relatively low intraduodenal pressure values and an abnormal papilla where

the mucosa folds of the orifice are insufficient or defective.


Table 7. Pathogenically important factors of "cholecystopancreatitis". Hypercholesterinemia or hyperlipemia as common underlying factors

Gallbladder

Cholesteatosis t

Cholecystitis t

Cholelithiasis

Choledocholithiasis Obstruction of the Papilla of Vater Biliarypancreatic reflux

"cholecystopathy" Operation

Postoperative pancreatitis 1) Direct surgical trauma

Bile pancreatitis

Pancreas

Fatty tissue interposition

t Enzymatic adaptation

t Fatty tissue necrosis with Perifocal acinolysis

Primary chronic lipolytic pancreatitis

Postoperative pancreatitis

a) Excision of a gastroduodenal ulcer with penetration into the pancreas b) Extensive mobilization and devascularization of the pancreas head - BII resection c) Lesion of the papilla of Vater, ligation of the main pancreatic duct d) Lesion of the pancreatic tail- gastrectomy/splenectomy

2) Circulatory disturbances and shock during nercosis 3) Postoperative

a) Afferent loop syndrome with duodenopancreatic reflux b) Mobilization of a ductal gallstone c) Metabolic - coma diabeticum/uremicum d) Concomitant pancreatitis (Doerr 1964) e) Exacerbation of a chronic relapsing pancreatitis f) Drug pancreatitis, e. g., steroid therapy

The "pure form" of biliary reflux pancreatitis is rare, 1%-5% of cases, and is known by trapped papilla stones and common channel as Opie-syndrome. Generally, the ductogenic mixed forms occur in our own material 15%, in comparison to 85% with a metabolic feature. The morphogenesis of a single case depends on its acuteness upon the chyme mixture. The morphological picture of the biliary reflux pancreatitis is determined by the concentration of unconjugated bile salts (Wanke 1967). The intraductal instillation of 1 %-5% sodium taurocholate solution into a dog pancreas, for example, has

108 M. Wanke

Fig. 6. Acute hemorrhagic necrotizing bile pancreatitis. Subtotal necrosis of ductal epithelial cells, intramural hemorrhages and periductal coagulation necrosis with acinolysis. Stain HE

the same effect as the detergent Triton X-100. Immediately after instillation of the noxa, coagulation necrosis of the duct epithelium and of acinar complexes -which is the primary goal of the infusate - result (Fig. 6). The intramural vessels of the pancreatic ducts are hyperemic. Vascular edema and hemorrhages cause mechanical ruptures of the acini and lobuli. The hypoxic acinar epithelium undergoes vacuolate degeneration. These hypoxic vacuoles lie near the nucleus and depress the nuclear membrane. The acinar epithelium is destroyed; initially no autodigestion occurs. The extent of the chemical destruction is correlated with the concentration, amount, and contact time of the noxa and it tends to lead in less than 60 min to the full picture of a hemorrhagic pancreatitis by secretion against a blockage - experimental duct ligature after noxa instillation - and of a decompensated lymph circulation. Vascular and juice edema are intensified through the inserted lymph blockade; the result is an increased intrapancreatic enzyme concentration. During the hypoxic phase of the biliary pancreatitis, the activation of the pancreas enzymes occurs; then the membrane damaged acinar epithelium as well as the intra- and peri pancreatic fat cells devolve on the lipo-and proteolysis. The lobuli primarily not affected by the reflux, are included in the secondary autodigestive necrosis. The time factor is, for the judgment of the morphology of biliary pancreatitis, definitely important. The hemorrhagic components can complicate every pancreatitis form in it's late phase, and is especially characteristic of the biliary form and is already dominant in the initial phase. In addition to the direct vessel damage due to bile, a histamine type increased vessel permeability also occurs (Nagy et al. 1971; Wanke 1969). Generally the vessel factor has biliary, lipolytic, proteolytic-elastolytic causes; pathogenetically it is many sided.


Chyme Reflux

If the intracellular accumulated fat becomes - by the metabolic and hypoxic induced acinar dyscholia - the primary substrate of the active lipase, and therewith the focus of the lipolytic-proteolytic pancreatitis, the substrate reaches ductogenically and intrapancreatically after chyme reflux the lipase. It develops strictly substrate-tied autodigestive parenchymal necrosis. The acinar epithelium affected by reflux shows the dyscholic phase up to autodigestive necrosis. The following factors are pathogenetically important for the course and the type of reflux pancreatitis: 1) Composition of the Reflux

a Duodenum contents, higher/lower fat contents; fine/coarse emulsified b Contents of active proteolytic and lipolytic enzymes c Ratio between conjugated: unconjugated bile acids d Bile plus duodenum contents with active proteolytic and lipolytic en

zymes

2) Quantity of the reflux

3) Time of contact

Table 8. The most important complications of acute pancreatitis'

Complications

Fatty tissue necroses peri-intra pancreatic, retroperitoneal subpleural subepicardial Necrotizing nephrosis Acutely damaged liver parenchyma with jaundice and hemorrhagic diathesis Pleural effusion Ascites Thrombosis/embolism Hemorrhagic-erosive gastritis Peritonitis Ulcer Myocardial infarction Pericardial effusion Thrombosis of the portal vein Vascular erosion aorta, pancreaticoduodenalis artery, lienalis artery/vein Adrenal necrosis Rupture of the spleen

No. of cases

151 10 9

53 26

151

109 94

73 70 61 42 34 28 27 24 10 10

8 3

a Complications in acute pancreatitis cases (90 males, 67 females) out of 14501 autopsies performed at Heidelberg/Rendsburg between 1963 and 1979

110

4) Reason for reflux a Papillary stones b Papillary spasm

M. Wanke

c Parasites in the pancreatic duct system d Afferent loop syndrome after B II stomach resection.

The following processes protect against the precipitation of an acute pancreatitis (Becker 1973; Wanke 1978):

1) Continuing and unrestrained juice flow 2) Sufficient mucus secretion of the duct epithelium 3) Parallel secretion from enzymes and their inhibitors 4) Regulated permeability of the acinar epithelium

"choked parapedesis" 5) Inactivation of the interstitial (by parapedesis) secreted juice 6) Inactivation of proteolytic intracellular enzymes 7) Missing substrate for lipolytic intrapancreatic enzymes 8) Unstrained lymph discharge 9) Sufficient secretion synchronous with organ blood-flow.

Table 8 is a review of the most important complications of acute pancreatitis that have an important influence on the high mortality of the disease complex in ques-

Table 9. Correlation of leading diseases and cause of death in acute and acute relapsing pancreatitis'

Leading diseases

1. Arteriosclerosis 2. Obesity 3. Pulmonary heart disease 4. Liver and biliary

tract disease cholecystitis/ cholelithiasis cirrhosis hepatitis

5. Diabetes mellitus 6. Postoperative

gastrectomy, splenectomy, cholecystectomy

7. Gastroduodenal ulcer 8. Alcoholism 9. Renal failure

to. cancer 11. Endocarditis 12. Burn 13. Morbus Cushing 14. Hyperparathyreodism 15. E-605 poisoning

39 23 4

93 84 74

66

45 34

33 24 17 16 4 2 2 2 2

Cause of death

1. Cardiac failure 82 postpancratitic shock 65 cardiogenic shock 17

2. Infections 30 pertonitis 23 (septic-postpancreatitic shock) pneumonia 7

3. Liver/renal failure 22 4. Hemorrhage 12

(oligohemic-postpancreatitic-shock)

5. Pulmonary embolism 11

a 90 males and 67 females out of 14501 autopsies performed at Heidelberg/Rendsburg 1963/1979


tion, which, due to the enzyme derailment - lymphogenic and hematogenic - especially in connection with an accompanying cavernous effusion, should get more attention. The correlation of leading diseases and cause of death in acute and acute relapsing pancreatitis is shown in Table 9. The stated findings are the sum of many years of experimental investigations as well as partially the analysis of especially impressive autopsies during a 17-year observation period; it is an attempt to demonstrate, from the particular individual observations with the knowledge of experimental facts, a clinically relevant morphogenesis of the acute and acute relapsing pancreatitis.

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Wanke M (1969) Morphologische Befunde bei der experimentellen akuten Pankreatitis. Gastro-Enterologie (Antwerpen) 12:132-146

Wanke M (1970a) Patho- und Morphogenese akuter Pankreatitiden nebst Bemerkungen zur Klinikopathologie. Med Welt (NF) 21:1226-1237

Wanke M (1970b) Experimental acute pancreatitis. In: Grundmann E, Kirsten WH (eds) Current topics in pathology, vol 52. Springer, Berlin Heidelberg New York, pp 64-142

Wanke M (1971 a) Die lipolytische Pankreatitis im Kindesalter. Verh Dtsch Ges Pathol 55:502-505

Wanke M (1971 b) Postoperative Pankreatitis. In: Chiari H, Wanke M (eds) Oesophagus. Magen. Springer, Berlin Heidelberg New York (Spezielle pathologische Anatomie, vol 11/1, p 842

Wanke M (1972 a) Significance oflipolytic pancreatitis in childhood in the development of acute relapsing pancreatitis. Beitr PathoI146:272-284

Wanke M (1972 b) Postpancreatitic-shock - clinical pathology and the influence of treatment. Clin Excerpts 34: 1025-1034

Wanke M (1974) The morphological shock substrate. Clin Excerpts 39:1269-1278 Wanke M (1976) Akute Pankreaserkrankungen. In: Forell MM (Hrsg) Pankreas. Springer,

Berlin Heidelberg New York (Handbuch der inneren Medizin, 5. neubearb. Aufl, Bd I1I/ 6, S 519-615)

Wanke M (1978) Pathogenese und morphologisches Bild der akuten Pankreatitis. In: Sarles H, Singer M (Hrsg) Akute und chronische Pankreaserkrankungen. Witzstrock, BadenBaden Koln New York, S 28-56

Wanke M, Griss P (1969) Metastasierendes Nebennierenrindencarcinom mit Cushing-Syndrom und lipolytischer Pankreatitis. Morgagni 2:267-278

Wanke M, Horeyseck G (1970) Beziehungen zwischen Nebennierenrinde und lipolytischer Pankreatitis. Demonstriert am Modell der "Cortisonpankreatitis". Z Gastroenterol 8:86-95

Wanke M, Nagel W (1968) Degranulierung des exkretorischen Pankreas und autodigestive Pankreatitis. Verh Dtsch Ges Pathol 52:311-316

Wanke M, Nagel W, Linder MM, Sebening H (1968) Ober die Stellung der Phospholipase A im Ablauf der akuten Pankreatitis. Z Gastroenterol 6:434-442

Wanke M, Nagel W, Willig F (1966) Formen der experimentellen Pankreatitis patho-anatomisch gesehen. Frankf Z Pathol 75:207-227


Wanke M, Schumann G (1974) Patho-anatomisches Bild des Schocks und seiner verschiedenen Formen. Chirurg 45:97-102

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White TT (1966) Pancreatitis. Arnold, London

The Role of Total Parental Nutrition in the Treatment of Pancreatic Diseases

R. Dionigi, U. Prati, C. Tibaldeschi and L. Dominioni

Istituto di Patologia Chirurgica, Policlinico San Matteo, 27100 Pavia, Italy

Total parenteral nutrition (TPN), as proposed in 1968 in clinical practice by Dudrick et al. [8], is considered one of the most useful modalities of support and/or treatment of several medical and surgical diseases. It has been stated that TPN should be started when oral alimentation is impossible, ill-advised, debatable, or hazardous. The patients who could profit from TPN can be subdivided in three groups: [1] patients with lesions of the continuity and/or function of the gastrointestinal tract; [2] patients with increased caloric or protein requirements (burns, sepsis, multiple trauma); [3] patients with different types oflesions which compromise their nutritional status. In some of these patients nutritional support can also be achieved with partial parenteral nutrition (PPN) or enteral nutrition (EN). In the Institute of Patologia Chirurgica of the University of Pavia, TPN was administered in 389 patients (August 1970-July 1979) - in 355 as nutritional support and in 34 (9.5%) as primary therapy. Indications for TPN are summarized in Table 1, where it is shown that 23 patients received TPN for pancreatic diseases.

Table 1. Series of patients treated with TPN at the Istituto di Patologia Chirurgica, University of Pavia (August 1970 to July 1979)

Diagnosis

GI tumors Antineoplastic chemotherapy Severe malnutrition (non-neoplastic) Liver insufficiency ( + encephalopathy) Enteric fistula Pancreatic diseases Peritonitis Generalized sepsis and severe trauma Wound dehiscence Ulcerative colitis Anorexia nervosa

Total number of patients treated: 389

Indication

Adjuvant TPN

182 42 32 31 6

20 18 12 7 4 1

355

Curative TPN

7 4

18 3

2

34

Mean duration (days)

12 5 (x 3)

14 6

18 21 9

13 11 38 27

16

116 R. Dionigi, U. Prati, C. Tibaldeschi, and L. Dominioni

In 20 cases TPN served as nutritional support for pancreatic cancer (12 patients) and acute pancreatitis (eight patients), whereas in three cases TPN has been the primary treatment for patients with external pancreatic fistulas. The purpose of this paper is to review the few reports which appeared in the literature about the use of TPN in pancreatic diseases and to present some of the cases treated in our institution. The pancreatic lesions which can be treated with TPN are: acute pancreatitis, severe malnutrition secondary to chronic pancreatitis, pancreatic fistulas, pre- and postoperative treatment of pancreatic resection, and nutritional support during chemo and/or radiotherapy for advanced cancer of the pancreas.

Acute Pancreatitis

The therapy of acute pancreatitis is mainly symptomatic and empiric, since the cause of this lesion has not been completely established. In recent years several new drugs have been used in association with the ones traditionally believed to be essential in the treatment of the disease. The following drugs are the most used: glucagon [19], aprotinine [26], atropine [20], antibiotics [20], and steroids [9]. It is almost impossible to establish the effectiveness of these drugs in the treatment of acute pancreatitis, since diagnostic procedures and classification criteria often vary between centers. Moreover, it is difficult to perform prospective randomized clinical trials on these patients, because a precise diagnosis of the type ofpancreatitis (edematous, hemorrhagic, necro-hemorrhagic) cannot be made at admission, but only during the course of treatment. Recently many authors [1, 3,4, 11, 12, 14, 16, 18,21] have recognized that an efficient nutritional support should be associated to other therapies during acute pancreatitis. Several methods are used for nutritional support of these patients. Enteral nutrition has been used through nasogastric tube, gastrostomy, or jejunostomy: nevertheless intravenous feeding is still the most common method. In fact the gastrointestinal tract should not be utilized, because during acute pancreatitis episodes ileus is present, and one of the aims of the therapy is to establish a functional rest of the intestine and of the exocrine activity of the pancreas. It has been noted that one of the most beneficial effects of TPN, if 25% glucose and 4.25% amino acid solutions are used, is the reduction of gastrointestinal and pancreatic secretions. Hamilton [17] and Towne [25] have shown that TPN allows a reduction of duodenal, pancreatic, and biliary secretions, whereas it does not interfere with gastric acid and pepsin production. According to the same authors, glucose is the substance responsible for the reduction of pancreatic secretions. Their studies confirm the results of Nakajima and Magee [22], who noted that intravenous administration of glucagon and glucose inhibits pancreatic secretions, whereas amino acids are responsible for the reduction of biliary secretions. During acute pancreatitis TPN is also used because of concomitant malnutrition. Moreover it has been observed that the decreased intake of some amino acids (methionine) can be the cause of the pancreatic inflammation and can worsen the degree of inflammation [10, 13, 23].

The Role of Total Parental Nutrition 117

The authors who propose EN during pancreatitis believe that hyperosmolar glucose solutions should be avoided in these patients, because they are very often septic and present severe metabolic alterations and possible cardiovascular instability. At the present time TPN is often carried out in association with symptomatic therapy during acute pancreatitis. The positive and negative results obtained by the authors who use TPN can be summarized as follows: [1] correction of nutritional deficits results in reduction of mortality (from 22% to 14%) according to Feller [11]; [2] in severe necrohemorrhagic pancreatitis, TPN allows the delay of surgery to improve the general condition of the patient and to achieve a better demarcation of the necrotic tissue [29]; [3] TPN sometimes improves the condition of patients with severe dysfunctions of the gastrointestinal tract secondary to acute pancreatitis complications [14]; [4] in the early phase of TPN treatment of acute pancreatitis an increased incidence of septic complications due to endocaval catheter has been observed [14]; [5] morbidity due to technical and/or metabolic complications is superior to that observed during TPN treatment of other lesions, but it can be reduced with a careful monitoring of the patient.

Personal Observations

In the last 3 years eight patients with severe hemorrhagic pancreatitis have been treated with TPN in association with traditional therapy. The diagnosis of acute hemorrhagic pancreatitis has been done collecting the following data: history, physical examination, blood glucose, BUN, WBC, RCT, ESR, SGOT, blood and urine amylase, amylase clearance and creatinine clearance ratio (Ac/Cc) [28], abdominal plain X-rays, and percutaneous intra-abdominal drainage [24]. In these eight patients diagnosis has been always confirmed during the surgical procedure. Therapy consisted of: surgical procedure (sequestrectomy, biliary bypass, multiple drainage), nasogastric suction, TPN (25% glucose and 4.25% amino acids, Freamine), electrolyte and vitamins according to formulas and infusion modalities previously described [5, 6], glucagon (1 mg/day continuous infusion for 4 days), aprotinin (800,000 units/day), support therapy, and antibiotics if infection was clinically evident. TPN started at the end of surgery; the induction phase with 10%-20% glucose solution lasted for 4 days and the mean duration has been 12 days (min 9-max 15). None of the patients died and no major metabolic complications due to TPN occurred. The central venous catheter has been removed in two patients because of sepsis. The overall effectiveness of TPN treatment has been evaluated comparing the values of Ac/Cc at diagnosis and at the end ofTPN. The mean Ac/Cc at diagnosis was 7.6, whereas at the end of TPN treatment the ratio was 2.6 (values less than 3 are considered to be normal). The mean date of discharge from the hospital was the 16th day (min 14-max 21). Two of these patients were readmitted after a few months due to pseudocyst formation. A retrospective study on patients in the same conditions and not treated with TPN is neither possible nor acceptable; however, we believe that TPN plays a major role in the therapy of pancreatitis, because the incidence of early complications decreases, the metabolic conditions


of the patients are more stable, and the healing processes are accelerated, as confirmed by the early discharge of these patients. In our experience metabolic and hydroelectrolyte abnormalities are the most important problems. Hypocalcemia is particularly frequent in these patients; it can be worsened by hemodilution, and if it is not corrected in a short time it may create major problems. Glucose intolerance is the other disorder which needs to be controlled, since pancreatic endocrine insufficiency is always present on admission and is worsened in stress situations secondary to operation. Thus when TPN begins immediately after surgical procedures, the induction phase has to be prolonged and a meticulous monitoring for the first 3-4 postoperative days assured. In this series of eight patients intensive monitoring was sufficient to avoid severe metabolic complications.

External Pancreatic Fistulas

External pancreatic fistulas are the most severe complications after pancreatic surgery. Zinner [27] observed that they occur in 18% of pancreas operations; 24% have been observed after duodenopancreatectomy, 21% after operations for pancreatic injuries, 16% after excision for biopsy, and 10% after caudal resection. They can be classified as low output fistulas if the drainage of pancreatic juice is

100

90

80

<ft. w 70 a: :::J 60 U)

0 ...J U 50

40

30

20

10

Fig. 1

100

90

80 <ft. U) 70 z Q

60 I-<l: ~ 50 ...J 0-

~ 40 0 u

30

20

10

LOW OUTPUT HIGH OUTPUT « 200 ml/day) (> 200 ml/day)

FISTU LAS

Fig. 2

-

LOW OUTPUT HIGH OUTPUT « 200ml/day) (> 200ml/day)

FISTULAS

Fig. 1. Incidence of spontaneous closure in patients with pancreatic fistulas (Zinner et aI, 1974)

Fig.2. Incidence of complications in patients with pancreatic fistulas (Zinner et aI, 1974)


less than 200 ml/day, or high output fistulas (more than 200 ml/day). The complication risk (death, sepsis, metabolic disorders, pseudocyst) is significantly greater in high output fistulas, the spontaneous closure of which is more difficult and slow (Figs. 1,2). The basic principles in the treatment of pancreatic and other gastrointestinal fistulas are maintenance of the patency of the drainage, prevention of severe skin irritation, and control and correction of hydroelectrolyte modifications. Total parenteral nutrition is fundamental in the therapy of pancreatic fistulas. It allows optimal nutrition in a situation in which malnutrition is frequent. Moreover TPN allows absolute bowel rest and reduction of pancreatic secretions. In order to understand the major contributions ofTPN in this area, reference should be made to the results shown in a recent review on external pancreatic fistulas by Zinner [27] (Table 2). This author studied the clinical outcome of 35 patients with pancreatic fistulas treated with conventional methods before TPN was used in clinical practice. Out of the 35 patients, 17 presented severe complications, such as localized and generalized sepsis, which were particularly frequent. Seventeen of the patients had low output fistula and 18 high output fistula. The mean duration of drainage was 76 days for low output fistulas and 92 days for high output fistulas. In the group of patients with high output fistulas, four deaths occurred.

Table 2. Complications of pancreatic fistulas treated without TPN (Zinner et aI, 1974)

Patients studied Patients with severe complications Total number of complications - Localized infections - Generalized sepsis - Abscess formation - Electrolyte imbalance - Pseudocyst formation

35 17 25 11 3 6 4 1

Only a few data are available in the literature dealing with patients affected by external pancreatic fistulas and treated with TPN in association with other treatments. Thirteen cases have been described in the literature [3, 2, 15, 7], and we have recently observed three cases (Table 3); the spontaneous closure of the fistula was obtained in 13 cases (81%); the mean duration ofTPN was 23.6 days. Even if it is not methodologically correct, for the evaluation of TPN we compared the results obtained by Zinner with the ones obtained by other authors using TPN with a similar approach. Spontaneous closure has been observed in 68% of patients in the group treated without TPN, whereas in the TPN-treated group it has been recorded in 81 % of the cases. In the group of patients treated without TPN four deaths due to septic complications have been observed, whereas none of the patients treated with TPN died. The mean duration for closure of the fistulas in


Table 3. Treatment of external pancreatic fistulas with TPN

Author Patients Spontaneous Mean duration closure ofTPN (days)

Dudrick 1970 5 5 33 Di Costanzo 1975 2 1 19 De Salvo 1979 3 3 20 Grundfest 1979 3 1 20 Dionigi 1979 3 1 26

Total 16 13 (81%) 23.6

the 35 patients without TPN has been 84 days, whereas in the 16 treated patients the closure time has been 24 days. Septic complication rate in the two groups has been 49% and 25% respectively.

Personal Observations

The two most significant cases observed in our institution are described below:

Case 1. V. A., 53-year-old male, who 1 year previously had undergone emergency gastric resection for bleeding duodenal ulcer. Recently the patient was admitted to our department for severe anemia secondary to melena. Routine X-rays, angiographies, and endoscopic examinations did not show bleeding points in the gastrointestinal tract. The patient underwent explorative laparotomy and during surgery multiple small angiomas on the head of the pancreas were found. Several of these angiomas were strictly connected with the duodenal stump and the residual part of the stomach. All the visible angiomas were meticulously ligated and the pancreatic area was drained with a tube. The postoperative course was normal until the 5th postoperative day, when the patient suddenly complained of severe pain in the mesogastric area, hyperthermia (38.5°), and ileus. Serum and urinary amylases, which were normal until that point, increased (1000 and 3000 Somogyi units/100 ml). Conventional therapy for pancreatitis was started and on the following day the pain attenuated but serohematic fluid appeared in the drainage tube. 70 ml/day of fluid drained for 18 days, then an increase of its volume was recorded (200 ml/day). Amylase concentration in the drainage fluid varied between 17000 and 19000 US/100 ml, whereas serum and urinary amylases returned to normal from the beginning of the drainage (Fig. 3). The increased external drainage suggested that TPN should be started in association with nasogastric suction and glucagon administration. Fistulography performed on the 25th day showed several cavities communicating with the main ducts of the head of the pancreas. During TPN alternating phases of increase and decrease of drainage output were observed. On the 28th day the fistula output decreased to 60 ml/day with an amylase concentration of 9000 US/


I--------T.P.N.-------f

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~ 200 E s: 0 ...J 100 LL

3000 10 20 30 40 50 60

E ,~ *' " \ vi 2000 I \ , \ :::I , \ w / \ ~ rn , \ , \ I « \ , \' ...J 1000 o..---_C/ "t1 >- ,.0..... ...Q.. :2 « , ..... ..,. ........,.

~ """"[)o....... ... .. ~" urine " serum

10 20 30 40 50 60 days

Fig. 3. Flow chart indicating serum and urine amylase levels, and volume of pancreatic fistula output in a 53-year-old male with postoperative pancreatic fistula

100 ml. The output remained constant up to the 55th day, when it suddenly stopped and the drainage tube was removed; TPN was discontinued on the 60th day. Case 2. M. A., 17-year-old male. The patient was admitted to a Community Hospital after a severe abdominal injury sustained during a football game. Acute post-traumatic pancreatitis was diagnosed and after a short period of supportive medical treatment the patient underwent explorative laparotomy and drainage of the pancreatic region. The patient improved, but after removal of the drainage tubes two external (left and right) pancreatic fistulas were present; the patient was then transferred to our institution. On admission the left fistula drained 300 ml/ day, whereas the right one presented only minimal secretion (Fig. 4). The nutritional status of the patient was severely compromised (18 kg weight loss, albumin serum concentration: 2.5 g/1oo ml). Serum and urinary amylase concentrations were normal. TPN was started and in a few days the left fistula closed, whereas the right fistula output increased to 800 ml/day, with an amylase concentration in the drainage fluid of about 15000 US/loo ml. The flow progressively decreased from the 9th to the 11th day from the beginning ofTPN, when spontaneous closure was recorded; TPN was continued until the 17th day.


E

*' 800

uS 600 ::i w

5 400 >~ « 200

800

..c: "'" ~ 600 E :!: 0 ..J 400 u.

200

1----- APROTININ -----I II------T.P.N.-----~

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5 10 15

F 1\

~/\ i ~ I '. , I I tj I , I

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left Qright \

5 10 15

.... ..... urine

serum

days

20

20

Fig. 4. Flow chart indicating serum and urine amylase levels, and volume of pancreatic fistula output in a 17-year-old male with post-traumatic double pancreatic fistula

Conclusion

Total parenteral nutrition is very effective in the treatment of several pancreatic diseases. It is fundamental for nutritional support during acute pancreatitis because it allows complete bowel rest with a reduction in the pancreatic secretions. TPN can also be curative in some cases of pancreatic fistulas, because it facilitates spontaneous closure and reduces the incidence of major complications.

References

1. Blackburn GL, Williams LF, Bistrian BR, Stone MS, Phillips E, Hirsch E, Clowes GHA, Gregg J (1976) New approaches to the management of severe acute pancreatitis. Am J Surg 131:114-124

2. De Salvo L, Adami GF, Iachino C, Parodi AG, Vita M (1979) Il ruolo dell'alimentazione parenterale totale nella terapia delle fistole pancreatiche esterne postoperatorie. Minerva Dietol GastroenteroI25:71-76


3. Di Costanzo J, Fouilloux C, Dugne P, Gautier A (1975) Nutrition parenterale et affections pancreatiques. In: Romieu C, Solassol C, Joyeux H, Astruc B (eds) Proceed Internatl Symp Parenteral Nutrition. Universite de Montpellier Publ, Montpellier, p 419-424

4. Dionigi R, Guaglio R, Bonera A, Cerri M, Rondanelli R, Campani M (1979) Clinicalpharmacological aspects, application and effectiveness of total parenteral nutrition in surgical patients. Int J Clin Pharmacol Biopharm 17:107-118

5. Dionigi R, Zonta A, Ballabio A, Dominioni L, Gnes F (1975) Immunological observations on surgical patients undergoing parenteral nutrition through central veins and internal arteriovenous fistulas. Surg Italy 5:58-73

6. Dionigi R, Zonta A, Tibaldeschi C, Nazari S (1973) L'ipernutrizione parenterale nei pazienti chirurgici gravi. Min Chir 19:1-32

7. Dudrick SJ, Wilmore DW, Steiger E, Mackie JA, Fitts WT (1970) Spontaneous closure of traumatic pancreatoduodenal fistulas with total intravenous nutrition. J Trauma to:542-553

8. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE (1968) Long term total parenteral nutrition with growth, development and positive nitrogen balance. Surgery 64:134-142

9. Eskwith IS, Cacace VA, Sallary A (1955) Acute hemorrhagic pancreatitis: treatment with cortisone. N Engl J Med 252:494

to. Farber E, Popper H (19,50) Production of acute pancreatitis with ethionine and its prevention with metionine. Proc Soc Exp BioI 7:838

11. Feller JH, Brown RA, MacLaren Toussaint GP, Thompson AG (1974) Changing methods in the treatment of severe pancreatitis. Am J Surg 127:196-201

12. Fourtanier G, Mason J, Vaysse Ch (1975) L'hyperalimentation parenterale dans Ie traitment des pancreatites aigues. Rev Med Toulouse 11:17-28

13. Friedman SM, Friedman CL (1940) The effect oflow protein diet on the structure of the pancreas. Can Med Assoc J 55:15-21

14. Goodgame JT, Fischer JE (1977) Parenteral nutrition in the treatment of acute pancreatitis: effect on complications and mortality. Ann Surg 186:651-658

15. Grundfest S, Steiger E, Selinkoff P, Fletcher J (1979) A study of the effect ofintravenous fat emulsion in patients with pancreatic fistulae. J Parent Enteral Nutrition 3:26

16. Gouzi JL, Fourtanier G, Mason J, Escat J, Barret A, Gouzi M (1974). In: Romieu C, Solassol C, Joyeux H, Astruc B (eds) Alimentation parenterale et pancreatites aigues. Proceed. Internal Symp Parenteral Nutrition. Universite de Montpellier Publ, Montpellier, p 413--418

17. Hamilton RF, Davis WC, Stephenson DV (1971) Effects of parenteral hyperalimentation on upper gastrointestinal secretions. Arch Surg 102:348-353

18. Hartig W, Albert H, Czarnetzhky HD (1977) Parenterale ernahrung bei postoperativer pancreatitis. Dtsch Z Verdau Stoffwechselkr 37:7-16

19. Kinght MJ, Condon JR, Smith R (1971) Possible use of glucagon in the treatment of pancreatitis. Br Med J 11:440--442

20. McHardy G, Craighead CC, Balart L, McHardy R (1964) Current medical therapy of pancreatitis. Med Clin North Am 48:389

21. Migliori G, Michelangeli F, Inglesakis JA (1974). In: Romieu C, Solassol C, Joyeux H, Astruc B (eds) Alimentation parenterale equilibree. Utilization des emulsions lipidiques dans la reanimation des pancreatites aigues. Proceed Internal Symp Parenteral Nutrition. Universite de Montpellier Publ, Montpellier, p 403-412

22. Nakajima S, Magee DF (1970) Inhibition of exocrine pancreatic secretion by glucagon and D-glucose given intravenously. Can J Physiol Pharmacol 48:299

23. Shaper AG (1960) Chronic pancreatic disease and protein malnutrition. Lancet 1:1223-1224

24. Staudacher V, Chiesa R, De Rai P, Di Carlo V, Staudacher C (1978) La terapia in ambiente chirurgico delle pancreatiti acute. Urgentis Chirurgie 1:9-24

25. Towne JB, Hamilton RF, Stephenson DV (1973) Mechanism of hyperalimentation in the suppression of upper gastrointestinal secretions. Am J Surg 126:714--716

26. Trapnell JE, Rigby CC, Talbot CH, Duncan EHL (1974) Controlled trial oftrasylol in the treatment of acute pancreatitis. Br J Surg 61:177-182


27. Zinner MJ, Baker RR, Cameron JL (1974) Pancreatic cutaneous fistulas. Surg Gynecol Obstet 138:710-712

28. Warshaw AC, Fuller AF (1975) Specificity of increased renal clearance of amylase in diagnosis of acute pancreatitis. N Engl J Med 292:325-328

29. White TT, Heimbach DM (1976) Sequestrectomy and hyperalimentation in the treatment of hemorrhagic pancreatitis. Am J Surg 132:270-275

Conservative Surgical Treatment of Acute N ecrotic-Haemorrhagic Pancreatitis

P. Pederzoli

Istituto Clinica Chirurgica, Universita di Padova Sede in Verona, Policlinico B. Roma, 37100 Verona, Italy

Three paths have been followed in the attempt to propose the ideal treatment for acute necrotic-hemorrhagic pancreatitis (ANHP):

Conservative surgical treatment, Medical treatment, Radical surgical treatment.

As regards conservative surgical treatment, Moynihan proposed incision of the pancreatic capsule associated with cholecystostomy back in 1925. Other conservative techniques have been proposed since then, such as peritoneal dialysis (Wall 1965; Rasmussen 1967; Waterman et al. 1968; Bolooki and Gliedman 1968; Rosato et al. 1973) as well as the triple gastric-cholecystic-jejunal fistulas with multiple intraperitoneal drains (Lawson et al. 1970). It appears difficult to assess the results obtained with these treatments; only the case lists relative to groups of patients treated according to Lawson's method offer encouraging figures, especially in the experience of Grana and Wise (1976), who report a 23% mortality in a group of patients operated on within the first 48. Medical treatment, which aims at maintaining and restoring the normal blood volume and the electrolyte balance, suppressing the pancreatic secretions, attenuation of the pain, and prevention of infective complications, has not given satisfactory results in necrotic-hemorrhagic forms accompanied by extensive local necrosis and massive systemic involvement (Trapnell et al. 1974). Finally, more radical treatment has been effected since 1967, particularly through the influence of French authors (Hollender et al. 1970, 1971; Edelmann and Boutelier 1974; Rives and Lardennois 1974; Alexandre et al. 1977, Rettori 1979), with recourse to "methodical" pancreatectomy (left splenopancreatectomy and total pancreatectomy). The mortality results from this group of authors are around 40%, with notable remote dysmetabolic sequelae, especially in the case of total pancreatectomy. Sequestrectomy, also proposed recently in association with other therapeutic measures (White and Heinbach 1976), is to be classified as radical surgery, but on a theoretical basis different from that of massive exeresis. Analysis of the results obtained with some of the procedures described, especially the radical ones, external drainage of the bile, and those exclusively regarding medical treatment, are discouraging and show that no completely satisfactory measure exists in those cases where the disease occurs in the anatomical-clinical form of pancreatic necrosis. Confused knowledge as to the etiologic and pathogenetic factors, as well as

126 P. Pederzoli

the difficulty in interpreting the physiopathologic mechanisms that unforeseeably lead to the picture of hemorrhagic necrosis are at the basis of this therapeutic uncertainty. The same polymorphism of the lesion both at the glandular level, with the different degree of involvement ofthe parenchyma (superficial-focal, massive necrosis), and as regards extension beyond the pancreatic cavity into the retroperitoneal cells, has convinced several authors of the need to propose new therapeutic measures that differ not only from the technical standpoint, but also from that of the outcome. All this justifies both the large number of radical and/or conservative surgery proposals and the empirical background of the proposed surgical treatments. This is why surgical treatment (which is generally used) should be based mainly on "reasonable" suppositions, i. e., dictated by evaluation of results obtained by other authors and by elements acquired through personal experience. This makes it difficult to understand what are the scientific basis of the arguments held by supporters of medical treatment as an alternative to surgery, and vice versa. In practice, a rigid attitude of nonintervention leaves the doubt that patients cured at the end were perhaps suffering mainly from edematous forms, while a strict attitude of intervention at all costs leaves the doubt that some patients could have been cured by medical treatment alone. The fact that nearly all surgeons agree on a compromise position that leads, in the first place, to attempted medical treatment and then, on the basis of the results of this, to a decision for surgery or not, means that the disease can give rise to weighty diagnostic, clinical, and prognostic doubts. For this reason, current management of the disease in our clinic is based on:

1) The conviction that the process frequently tends to extend to the entire gland, causing not only lesions at this site but also general damage (systemic) due to reabsorption and passage into the blood stream of enzymes and toxic substances (reabsorption which takes place mainly through the peritoneum and the lymphatic system).

2) The observation that the activated liquid which diffuses following ductal and capsular rupture causes necrosis of the retroperitoneal cells along the interstitial spaces and mesenteries, according to well defined routes revealed by CT (retrocavity of the epiploon, root of the mesenterium, right and left parietocolic cavities, and left subdiaphragmatic cavity).

3) The fact that I V administration of any drug has only poor therapeutic efficacy as a result of the early phenomena of disseminated vascular coagulation in the tributary vessels of the area affected by the necrotic-hemorrhagic process.

4) The frequent finding in our caselist of infections (30%) of the necrotic areas, whether of the pancreas of the retroperitoneal tissue.

5) Finally, the possible discrepancy between the macroscopic findings relative to lesions observed during the operation, and the picture of the specimen taken during surgery and its histologic examination, which may reveal mainly capsular and interstitial necrotic damage at the surface of the gland, the deeper parenchyma being spared.

We have observed this last rmding in five out of eight patients subjected to left pancreatectomy.

Conservative Surgical Treatment 127

On the basis of the above considerations, we have attempted to focus therapeutic procedure on the following points:

1) Early diagnosis (clinical and laboratory elements, US, CT);

2) Early treatment in the attempt to block progressive damage at the glandular and retroperitoneal level;

3) Attempt to impede reabsorption of enzymes and toxic substances in order to limit systemic damage;

4) Prevent complications (purulent effusions, fistulas, pseudocysts). In fact, the behavior to follow when faced with a patient with suspected ANHP is first of all aimed at a differential diagnosis between edematous and necrotic-hemorrhagic form. This is possible not only on the basis of clinical and laboratory parameters (hyperamylasemia, hyperglycemia, fall of Ht and Hb, leucocytosis, hypocalcemia, increase in transaminases, metalbuminemia, hyperbilirubinemia) but also through the help of radiologic, semeiotics elements supplied by CT. In particular, we refer to leakage of activated substances into the retroperitoneal space and to pancreatic contrast roentgenography. Once the diagnosis of ANHP has been made, the patient is generally subjected to intensive medical treatment for the first 24. If no rapid and favourable evolution of the clinical and laboratory picture is seen, the patient undergoes surgery, the operation varying according to the topical localization of the lesion. The following treatment is effected if the necrotic-hemorrhagic process involves the tail and/or the body of the pancreas (Fig. 1):

x Fig. 1. Type of operation performed in patients with acute necrotic-hemorrhagic pancreatitis mainly localized at the body-tail of the pancreas

128 P. Pederzoli

1) Left splenopancreatectomy with controlled suction according to Rives; 2) External gastric and cholecystic fistulas; 3) Guided drainage; 4) Guided perfusion; 5) Total parenteral nutrition (only when 36-48 h from surgery have elapsed).

We propose with this program to: 1) Remove the portion of the gland affected by the necrotic process;

2) Create a further route for discharge of the pancreatic secretion, through controlled suction under vacuum;

3) Guarantee, through the double fistula, against possible stimuli on the gland and ensure an outlet for the biliary route;

4) By guided drainage we mean apposition of drainage tubes placed in correspondence to the slice of pancreas ("section surface") on the anterior and posterior walls of the gland and in the most sloping part of any previously open "flows;"

5) Two other drainage tubes are positioned in Douglas's pouch;

6) "Perfusion" means local-regional, retro-, and endoperitoneal lavage, which permits the evacuation of necrotic fragments, enzymes, and toxins, which flow therein. It is defined as "guided," since it selectively brings into contact with the gland and retroperitoneal structures affected, drugs such as aprotinin, and also antibiotics, in the attempt to block evolution of the disease and bacterial infection.

If the necrotic-hemorrhagic process involves the head of the gland or is general or multi/ocal (see Fig. 2): 1) External gastric and cholecystic fistulas;

2) TPN (only when 46-48 h from surgery have elapsed);

3) Sequestrectomy is effected, especially in patients from other areas who come under our observation, generally after the 3rd day, and if areas of clearly apparent necrosis easily removable by "digitoplasty" are present;

4) In any case, an incision is practiced in the pancreatic capsule so as to obtain the biggest possible surface of parenchyma available for contact with pharmacologic substances brought to the site by means of the perfusion;

5) The pancreas is mobilized in order to allow placing of drainage tubes on the anterior and posterior walls of the gland and at the most sloping points of the retroperitoneal flows. Lavage drainage tubes are also positioned in the peritoneal cavity;

6) "Guided" perfusion is effected with isotonic dialysis solution for a total volume of 5 liters every 24 h, and continuously for the first 5 days. The concentration of enzymes in the evacuated liquid progressively falls during this period. Successively, the lavages are effected four times daily, with physiologic saline, until the solution flowing out is free from necrotic fragments and poor in pancreatic enzymes.


Fig. 2. Type of operation performed in patients with acute hemorrhagic pancreatitis involving the pancreas as a whole

The lavage solutions are "medicated" with: (a) antibiotics (Tobramycin and Cephalosporin); (b) aprotinin 1,000,000 KID/liter. We believe that topical use of drugs may permit an "optimum" therapeutic action in view of the already mentioned phenomena of necrosis and microthrombosis at the level of the portion affected by the necrotic-hemorrhagic process.

Case List

The case list relates to the October 1976 to December 1979 period and refers to 51 patients with ANHP, all of whom underwent surgery. Associated biliary pathology was found in 21 patients, 16 patients were very heavy drinkers and this condition was associated, or not, with excessive food consumption. No apparent cause was found in six more cases and one patient had a perforated diverticulum of the third portion of the duodenum. Seven patients complained of acute postoperative pancreatitis; four of them underwent an operation on the papilla and the other three gastric resection. Eleven of the 51 patients presented necroses mainly involving the body-tail of the pancreas, 28 multifocal or general lesions, and 12 cephalic pancreatitis. Left sple-

130 P. Pederzoli

nopancreatectomy and guided perfusion were effected in 9 patients, while 42 were treated conservatively according to the method previously described. Ten deaths occurred: two in the series treated with left splenopancreatectomy and seven in the other group. We feel it important to bring out the ratio between survivors and deaths in relation to the time when the symptomatology appeared and the moment of surgical treatment. In fact, it was found that the mortality was 6.6% (one death) in the group of 15 patients operated on during the first 48 h, while the mortality rose to 20% (four deaths), in the group of 20 patients treated between 48 and 96 h. The mortality for the 16 patients who underwent surgery only after 96 h was 37.5 % (six deaths) (Fig. 3). It appears from our results that survival is affected by the time between onset and surgical treatment.

p 20

18

16

14

12

10

8

6

4

2

--

~

0-48 o survivors o died

Comment

37,5%

20%

48-96 96- 144 h Fig, 3. Relationship between the mortality of patients with acute necrotic-hemorrhagic pancreatitis and the time of start of the treatment

In the light of personal experience, both experimental and clinical, it is felt that partially conservative surgical treatment is reasonable if effected within 24-48 hrs of the acute event recognized as necrotic-hemorrhagic. In fact, it only exceptionally presents immediately with clinical pictures of clear indication for surgery (fulminating ANHP), while in the majority of cases the process affects a limited sector of the gland and then expands from this to all or a large part of the glandular tissue. In view of the progressiveness of the process, we consider that its evolution can be limited only by appropriate and, above all, early surgery. Although delaying of surgery probably makes it easier to detect the affected areas and remove them, it would nevertheless lead to longer reabsorption of toxic substances capable of causing systemic damage that is probably partly responsible for the high mortality.


Perplexity may be expressed, we feel, with regard to a wait and see attitude about surgery, which, moreover, is burdened by an extremely heavy quota of failures. In fact, a group of patients dies or else is in such conditions as to allow no effective surgical measure to be undertaken, within the 4th to 5th day after the acute event. Furthermore, some of the remaining patients would survive independently of surgery, the latter being capable only of preventing possible complications: sepsis and pseudocysts. Moreover, even if it cannot be clearly proved that drugs brought directly into the pancreatic area are effective or more effective than when administered by other routes, the very fact that they are brought into direct "contact" forms an attempt to permit their higher concentration in this site and to facilitate their claimed therapeutic action. Furthermore, in a recent personal study (unpublished data) on a series of dogs with experimental acute necrotic-hemorrhagic pancreatitis, the group of animals treated with peritoneal dialysis supplemented by aprotinin had a better survival rate than that treated with peritoneal dialysis only. The lavage liquid should exert not merely an exclusive action of vehicle for the drugs and drainage of the enzymes, toxic substances, and catabolites, but also a real mechanical action with regard to the necrotic parts of the gland which are thus removed through the drainage tubes, leaving the underlying healthy parenchyma in position. Since the present clinical investigation has been designed as a pilot study, no conclusions should be drawn as to the effectiveness in the treatment of acute pancreatitis. Nevertheless, we feel it of interest to stress the fact that the mortality due to ANHP has fallen in our ward from 60% to 19% after introduction of this treatment. In actual fact, we do not know if this treatment affects the early alterations and mechanisms of the disease, but it is quite probable that it has been able to effectively influence the latter's natural course. In fact, no suppurative processes were seen in these patients as long as treatment was started as early as possible. In other words, all those septic and systemic complications which are the chief causes of death from ANHP do not occur.

References

Alexandre JH, Camilleri JP, Assan MT, Guerrieri MT, Bonand A (1977) Indications et n~sultats de la pancreatectomie totale dans Ie traitement des pancreatites aigiies necrosantes. Chirurgie 103:858-861

Banks PA (1979) Pancreatitis. Plenum Medical Book Company Ed, New York and London

Berchtold R (1977) Zu Fragen der Operationsindikation und Taktik bei der schweren akuten Pankreatitis. Ther Umsch 34:886-392

Bolooki H, Gliedman ML (1968) Peritoneal dialysis in treatment of acute pancreatitis. Surgery 64:466-472

Edelmann G, Boutelier PH (1974) Le traitement des pancreatites aigiies necrosantes par l'ablation chirurgicale precoce des portions necrosees. Chirurgie 100/21:155-167

Frey HP, Meyer W, Miller G, Maurer W (1978) Subtotale distale Pankreatektomie in der Behandlung akuter nekrotisierender Pankreatitiden. Helv Chir Acta 45:693-698

Grana W, Wise L (1976) Role of emergency laparotomy in acute pancreatitis. Am. Surg. 128:134-139

132 P. Pederzoli

Hofmann R, Berthold S (1979) Akute haemorragische Pankreatitis, ausgedehnte abdominale Drainage und perirenale Drainage links. Helv Chir Acta 46:593-597

Hollender LF, Gillet M, Sava G (1970) La pancreatectomie d'urgence dans les pancreatities aigiies: a propos de 13 observations. Ann Chir 24:647-660

Hollender LF, Gillet M, Kohler JJ (1971) Die dringliche Pankreatektomie bei der akuten Pankreatitis. Langenbecks Arch Klin Chir 328:314-327

Hubbard TB, Eilber FR, Oldroid JJ (1972) The retroperitoneal extension of necrotizing pancreatitis. Surg Gynecol Obstet 134:927-930

Imrie CW, Benjamin IS, Ferguson JC, McKay AJ, Mackanzie J, O'Neill J, Blumgart LH (1978) A single-centre double blind trial of Trasylol therapy in primary acute pancreatitis. Br J Surg 65:337-341

Kiimmerle F, Neher M, Schonborn H, Mangold G (1976) Intervento precoce nella pancreatite emorragico-necrotizzante acuta. Minerva Chir 31:765-771

Lawson DW, Dagget WN, Civetta JM (1970) Surgical treatment of acute necrotizing pancreatitis. Ann Surg 172:605-615

Leger L, Chiche B, Louvel A (1977) La necrose dans les pancreatites aigues. Confrontations operatoires et anatomo-pathologiques. 7 observations. Nouv Presse Med 6/5:337-340

Leger L, Chiche B, Ghouti A, Louvel A (1978) Pancreatites aigue. Necrose capsulaire superficielle et atteinte parenchimateuse. 115/2:65-70

Mercadier M (1977) Sur une serie de 100 cas de pancreatite aigue graves operes precocement. Chirurgie 113:835-845

Ohlsson K (1975) Treatment of acute pancreatitis with peritoneal lavage and trypsin inhibitors. In: Gastrointestinal emergencies. Pergamon, p 347

Pederzoli P (1978) L'urgenza chirurgica nella P.A.N.E. e nelle sue complicanze. Atti VII congresso S.I.C.U.P.S. 15-38

Pederzoli P, Maffezzoli GF, Ischia S (1978) La dialisi peritoneale nel trattamento della pancreatite acuta necro emorragica indotta nel cane: note preliminari. Acta AnaesthesioJ Ital 29:727-731

Ranson JHC, Ritking KM, Roses DF, Fink K, Spencer FC (1974) Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 139:69-81

Ranson JHC, Spencer FC (1978) The role of peritoneal lavage in severe acute pancreatitis. Ann Surg 178:565-575

Rasmussen BL (1967) Hypothermic peritoneal dialysis in the treatment of acute experimental hemolytic pancreatitis. Am J Surg 115:716-717

Rettori R (1979) Indications et resultats du traitement chirurgical dans les pancreatites aigues avec necrose. Lyon Chir 75/6:383-387

Rives J, Lardennois B (1974) La therapeutique d'assechement dans Ie traitement des pancreatites aigues necrotico-hemorragiques (aspiration gastroduodenale, pancreatectomie gauche d'assechement et drainage externe controle). J Chir (Paris) 107/3:249-274

Rosato EF, Mullis WF, Rosato FE (1973) Peritoneal lavage therapy in hemorragic pancreatitis. Surgery 74:106-115

Staudacher JE, Martinotti A (1976) Possibilita terapeutiche d'urgenza nelle pancreatiti acute. Minerva Chir 31:515-522

Trapnell JE, Rigby CC, Talbot CH, Duncan EHL (1974) A controlled trial of Trasylol in the treatment of acute pancreatitis. Br J Surg 61:177-182

Warshaw AL, Imbembo AL, Civetta JM, Dagget WM (1974) Surgical intervention in acute necrotizing pancreatitis. Am J Surg 127:484-491

White TT, Heinbach DH (1976) Sequestrectomy and hyperalimentation in the treatment of acute hemorrhagic pancreatitis. Am J Surg 132:270-277

Vankemmel M (1975) L'eputation peri-pancreatique par "dialyse retropertoneale" complement de la chirurgie lesionelle des pancreatites aigues necrosantes. Med Chir Dig 4: 113-119

Vankemmel M (1979) Pancreatite aigue necrosante et irrigation-lavage post-operatorie. Helv Chir Acta 46:583-591

Pancreatic Abscess

P. Pederzoli, T. Pilon, C. Bassi, and G.P. Marzoli

Istituto Clinica Chirurgica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 371()() Verona, Italy

Pancreatic abscesses consequent to acute necrotic-hemorrhagic pancreatitis (ANHP) are reported increasingly frequently. This is probably due to the fact that the present medical and reanimation treatment of ANHP leads to longer survival times, which more easily result in complications of the disease, such as abscesses, fistulas, and pseudocysts [10]. Called "pancreatic abscesses," in actual fact they are purulent collections which involve the affected pancreatic area, i.e., the retroperitoneal tissue necrotized by the action of the activated juice oozing out following rupture (breaks) in the pancreatic capsule. These are formations which involve the retroperitoneum in an unusual way, without having a pyogenic wall like true abscesses [6, 11]. The mortality of patients suffering from these suppurative formations reaches 100% in the case of those not surgically treated, and has also been reported to be very high - 30%-40% [1-5] - in patients subjected to drainage. The following are the elements leading to the diagnostic suspicion of pancreatic abscess: recent attack of acute pancreatis and, at a variable period of days, onset of diffuse pain with abdominal distension, tenderness, nausea and vomiting, epigastic pain, serum amylase elevation, and, above all, septic fever with leucocytosis. The investigations used before utilization of ultrasonography and CT (computed axial tomography) were plain film of the abdomen which revealed in 5% of the patients the presence of gas bubbles in the retroperitoneal space (or soap bubbles or enclosed air in the lesser sac) and study of the gastrointestinal tract using contrast medium, which in 40% of the cases revealed compression (or dislocation) on the stomach, duodenum, or colon. These can often provide elements for a diagnosis of retroperitoneal collections. However, these investigations do not reveal the margins of the retroperitoneum, a point which is important for the correct placing of drainage tubes and consequent perfusion treatment. In fact, while the pseudocyst (even when suppurative and also considering its variable spatial development) has borders represented by its walls, the abscess collection after acute pancreatitis travels along badly defined routes which preferentially involve the right and left paracolic sulci, the left subdiaphragmatic area, and the root of the mesenterium and mesocolon [9]. These are the routes along which the activated pancreatic juice travels, after flowing from the glandular area affected by the necrotic-hemorrhagic process, and which is the cause of necrosis of the retroperitoneal tissue; these routes are revealed on CT and, as already mentioned, help in the diagnosis of ANHP. Infection of these necrotic areas leads to the formation of effusions arranged in

134 P. Pederzoli, T. Pilon, C. Bassi, and G . P. Marzoli

"fox den" form, consisting of pouches, separated by septa or developed in various directions. So that it may happen that one part of an abscess is drained surgically, leaving out a more declive area or a part not communicating with the drained sac. F or this reason relapse of drained abscesses occurs in 30% of the patients and represents the most frequent cause of failure in surgical treatment of these patients [3, 4, 8, 9] . On the basis of our experience, use of CT has been found to be useful in the study of suppurative retroperitoneal formations, since it has made it possible not only to reach diagnoses, but also to work out an ideal plan of surgical treatment [9] (Fig. 1).

17.6%

100%

Fig.1. Percentage anatomic distribution of retroperitoneal suppurative effusions in our series

In actual fact, CT does not permit the distinction between a serous or a purulent collection to be made; differentiation in this sense is possible only with the aid of the above-mentioned clinical and laboratory methods. This investigation informs us exactly of the site and extent of these collections in the craniocaudal direction. For surgical purposes, it is essential to define their axial extent; in fact, on in possession of these indications we have been able to: (1) choose the ideal access (route of surgical attack) (extraperitoneal and peritoneal route); (2) remove the necrotic and/or purulent material; (3) break any septa within the margins of the collections, paying great attention to adjacent vascular formations; (4) apply drains to the cranial and caudal poles (upper or lower) of said collections; and (5)

Pancreatic Abscess 135

start continuous perfusion treatment with normal saline solutions and antibiotics chosen on the basis of bacterial sensitivity tests. The purpose of this perfusion treatment is to hinder further formation of septa, and to effect continuous cleansing of the cavity, sterilizing it with the antibiotics.

Case List

Suppurative forms operated on in the surgical department, University of Verona, from 1970 to 1979 total 32, of which 15 occur in the "pre- CT epoch", with a death rate of 40% and 17 patients studied by means of CT and SUbjected to surgery on the basis of the information supplied by it, with a mortality of 5.9% (Fig. 2).

Fig. 2. Distribution of mortality in two groups of patients; the operation of group II was performed on the basis of CT findings

p 18

16

14

12

10

8

6

4

2 -40%

D died

D survivors

5,9%

II

Pain was present in 20% of the cases observed, nausea and vomiting in 53%, while all had a temperature exceeding 38 DC , a white cell count of more than 15,0001 mm3, and signs of hepatic damage. The following bacteria, in order of frequency, were isolated on the basis of cultural examination of the evacuated liquid: Escherichia coli, Aerobacter, enterococcus, Proteus, Pseudomonas, and Klebsiella, often associated with anaerobes of the Bacteriodes genus. A polymicrobial infection was found in 80% of the patients. 16 of the 17 patients studied by means of CT came from other hospitals 7-19 days after the onset of the symptoms. The mean hospitalization period was 25 days for the group operated on with the guide of CT, while it was 39 days for survivors of the other group. One patient of the group studied with CT had to undergo surgery a second time to drain a collec-

136 P. Pederzoli, T. Pilon, C. Bassi, and G. P. Marzoli

tion evacuated incorrectly, while such a situation occurred seven times in the other group. Furthermore, the patients underwent CT controls at various intervals after surgery.

Conclusions - Comment

Polymicrobial infection of the pancreas affected by a necrotic-haemorrhagic process and of the colliquative retroperitoneal areas is a quite frequent and serious event that necessitates early diagnosis and early surgery. In the light of our personal experience, it appears that it can be stated that CT has an useful utilization in these situations. It has permitted the solving of four serious problems connected with the evolution of ANHP abscesses, in particular: (1) early diagnosis; (2) exact spatial extent of the collections; (3) guide to correct positioning of the drains; (4) control of the evolution of the collections in the right time.

References

1. Carner SY, Tan EGC, Warren KW, Braasch JW (1975) Pancreatic abscess. A critical analysis of 113 cases. Am J Surg 129:426-431

2. Clinical conferences at the Johns Hopkins Hospital (1978) Pancreatic pseudocyst. Johns Hopkins Med J 134/3:109-113

3. Dencker H, Liedberg G, Tibblins G (1972) Surgical aspects of pancreatic abscess. Acta Chir Scand 138:545-551

4. Hubbard TB, Eilbert FR, Oldroid J (1972) The retroperitoneal extension of necrotizing pancreatitis. Surg Gynecol Obstet 134:927-930

5. Jones CE, Polk HC, Fulton RL (1974) Pancreatic abscess. Am J Surg 130:44-47 6. Kodesch R, Dupon HL (1973) Infectious complications of acute pancreatitis. Surg Gy

necol Obstet 136:763-768 7. Miller TA, Lindenauer SM, Frey CF, Stanley JK, Arbor A (1974) Pancreatic abscess.

Arch Surg 108:545-551 8 Owens BJ, Hamit HF, (1977) Pancreatic abscess and pseudocyst. Arch Surg 112:42-

45 9. Pistolesi GF, Marzoli GP, Quarta Colosso P, Pederzoli P, Procacci C (1978) Computed

tomography in surgical pancreatic emergencies. J Comput Assist Tomogr 2/2:165-169 10. Ranson JHC, Spencer FC (1977) Prevention, diagnosis and treatment of pancreatic ab

scess. Nurjngy 82:99-106 11. Warshaw AL (1972) Pancreatic abscess. N Engl J Med 287:1234-1236

One Year Follow-Up to Acute NecroticHaemorrhagic Pancreatitis

G. Angelini

Istituto Clinica Medica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 37100 Verona, Italy

Until now little information has been available about the evolution of necrotichemorrhagic pancreatitis after its clinical recovery. This is a consequence both of the relatively low incidence of the disease and the mortality, which has been very high until recent years (Lawson et al. 1970; Banks 1971; Geokas et al. 1974; White and Heimbach 1976). Moreover, the available data are an inadequate basis for a reliable evaluation due to the different types of treatment - medical or surgical based on drainage or resection procedures - used by various centers (Jordan and Spjut 1972; Norton and Eiseman 1974; Warshaw et al. 1974; White and Heimbach 1976). It therefore seemed worthwhile conducting a long term follow-up (it is still being carried out) on patients who can be compared on a treatment basis. The treatment has been surgical and consisted of a twofold drainage (gastrostomy and cholecystostomy) plus guided perfusion of the peritoneal cavity and retroperitoneal spaces. The aim of the study is to verify the long term outcome of the illness and to investigate the influence of various etiologic factors on this outcome in the 41 patients who have survived the episode of acute necrotic-hemorrhagic pancreatitis. The estimated duration of the study is about 3 years. So far 15 patients have completed the 1st year follow-up - 14 men and 1 woman, with an average age of 46 and ages ranging from 27 to 71. The follow-up consists of regular clinical controls and laboratory tests, including determination of fecal fat and glucose oral tolerance test if the patient does not suffer from clinical diabetes mellitus. It further includes a Secretin-Caerulein test for functional evaluation. Secretin (GIH) 0.5 CU/Kg plus Caerulein (Farmitalia) 75 ng· kg· h were given by continuous I V infusion for 2 hours, as previously reported by us (Cavallini et al. 1978). Duodenal juice was collected in 30-min samples and lipase (Sarles et al. 1963), chymotrypsin (Figarella et al. 1965), and bicarbonate (titrimetric method) concentration and output were determined. For the evaluation the period from 60 to 90 min was considered because secretion usually remains steady at that time. Computed body tomography and endoscopic retrograde pancreatography were carried out for a morphological assessment. The clinical control and laboratory investigation are performed every 6 months while functional and radiologic tests are carried out on a 1 year basis. With regard to the etiology of the disease, three patients were affected by bile stones and had previously suffered from another episode of acute pancreatitis. In another patient a perforated duodenal diverticulum, which has been considered the cause of pancreatitis, was observed. The most common potential etiologic factor has so far been alcohol consumption, which was higher than 160 g/day in three cases, be-

138 G. Angelini

tween 80 and 160 gjday in seven cases, and lower than 40 gjday in only five cases. It is worthwhile pointing out that after recovery from illness there was a marked decrease of average alcoholic intake: eight patients entirely gave up drinking, five cut down to no more than 40 g, and only two continued drinking between 80 and 160 gjday. With regard to clinical features, only two patients complained about occasional abdominal pains, usually turning into cholic with a mainly postprandial onset. One of the two patients keeps on drinking heavily while the second sticks to a strict diet. Ten patients regained their original weight prior to the occurrence of necrotic-hemorrhagic pancreatitis and even increased it, whereas five patients averaged 5-6 kg under the previous level. This weight, however, tends to be stable and there is no tendency to further decrease. Mild steatorrhea (about 10-15 gjday) was found only in one patient. Finally diabetes, which was present in three cases before pancreatitis was now found in five. In one of these cases only the oral glucose tolerance test was found to be altered. As far as the instrument check-up is concerned, computed body tomography showed a normal pancreas for shape, size, and density in four cases, a sectional volumetric increase of the gland in four cases, an overall increase in six cases, and, finally, very slight calcifications in one case. The latter being so difficult to detect that plain roentgenogram of the abdomen couldn't trace them. Retrograde pancreatography results are on the whole consistent with this general picture, showing normality of the pancreatic ductal system in four patients, abrupt termination of flow of the contrast material at the body-tail passage in one case, pancreatic duct abnormalities in four cases (mild strictures and dilatations) and irreg-

Table 1. Short term follow-up (about 1 year) of necrotic-hemorrhagic pancreatitis in 15 pa-tients (Secretin-Caerulein test)

Patient Volume HCO Chymotrypsin Evaluation ml/30 min mmol3/liter IU/ml

P.G. 108 68 72 ++ P.P. 82 66 62 + C.E. 126 55 53 ++ N.B. 126 93 92 +++ B.L. 158 98 84 +++ A.A. 32 58 58 + P.O. 118 92 90 +++ L.A. C.M. 83 62 71 ++ D.S. B.N. 106 88 101 +++ B.G. 41 56 39 + G.A. 115 91 85 +++ T.G. Z.G.

+ Marked deficiency ++ Mild deficiency +++ Normal function

One Year Follow-Up to Acute Necrotic-Haemorrhagic Pancreatitis 139

ularities of the accessory ducts in two patients. Finally in four cases this examination was unsuccessful: in two of these cases cannulation of only the bile duct was achieved, while for the other two, who had previously undergone a Billroth II gastric resection, the papilla cannulation didn't succeed. The Secretin-Caerulein test (Table 1) was normal in five cases, compatible with slight insufficiency in three cases and with conspicuous insufficiency in three other cases. It was not carried out on the two cases which had undergone gastric resection and, finally, a correct tube positioning did not succeed in two other patients. The results of these instrument checks were then compared with the clinical condition of each patient. A relevant discrepancy appeared between the actual well

Table 2. Short term follow-up (about 1 year) of necrotic hemorrhagic pancreatitis in 15 patients; comparison using historical, morphological, and functional data

Duodenal di enicu-lum

+

Yc

Dia- Bile Icohol be Ie Slone

+ x x

+ x x x

x x

+ x x

x x

+ x x

+

+ x

x x

x

x x

x x

x

x

x

x < 40g/da x 0 160g/day

x x x > 160g/day

Palient T ER P S-C

P.G .

P.P.

.E.

.B.

B.L.

A.A.

P.O.

L.A. ormal biliary -tree

C.M. Bile duct steno i

D.S. - -

B.

B.G.

T.G. - -

Z.G . -

o Allered o rmal

140 G. Angelini

being of almost all the patients and the large number of pathologic results supplied by computed tomography, endoscopic pancreatography and Secretin-Caerulein test. In fact, while 13 out of the 15 patients felt all right and have resumed their normal working activity, only one was found to have a morphologically and functionally normal pancreas. Even disregarding the tomography data, which is of primary importance in acute phase diagnosis but which at this stage supplies the least significant data, 7 patients out of 11 have an altered excretory tree and 6 out of 11 have reduced pancreatic exocrine secretion. The second aim of this study is to determine the outcome of our patients in relation to the etiopathogenesis of necrotic-hemorrhagic pancreatitis. Therefore we compared morphological and functional results with the possible etiologic factors such as bile stones and excessive alcoholic intake, observed in our patients (Table 2). Patients with high alcohol intake show constant anatomic and functional alterations but similar results were also found in patients whose alcoholic consumption was more moderate. As far as the evolution of the disease is concerned the role of bile stones cannot be determined since two of the tree patients affected by cholelithiasis are also heavy drinkers. The data mentioned so far are not yet sufficient to forecast the outcome of necrotic-hemorrhagic pancreatitis reliably, as the follow-up period is still short and the patients who have undergone clinical examination are too few to pursue reliable statistical comparison between the different etiologic groups. Our experience has, however, pointed out some fairly interesting features; first, there are patients who are feeling well in spite of anatomic or functional pancreas alterations; second, it has not been possible to determine any clear relation between the presence of pancreatic alterations, the patient's conditions, and the etiopathologic factors. The crucial point, however, is to assess whether damage to the ductal system and secretory impairment can be regarded simply as the stabilized outcome following the necrotic-hemorrhagic pancreatitis without indicating progression of the disease or whether on the contrary they are the markers of chronic pancreatitis. It will be only possible to reply to this question by increasing the number of patients and, particularly, by extending the period of the follow-up with repeated controls, namely pancreatography and the Secretin-Caerulein test.

References

Banks PA (1971) Acute pancreatitis. Gastroenterology 61:382-397 Cavallini G, Vantini I, Angelini G, Mirachian R, Vaona B, Bovo P, Gelpi F, Ederle A, Do

brilla G, Scuro LA (1978) The role of caerulein in tests of exocrine pancreatic function. Scand J Gastroenterol13:3-15

Figarella C, Taulier J, Sarles H (1965) Dosage de la chymotrypsine et de la trypsine dans Ie suc duodenal. Bull Soc Chim BioI 47:679-683

Geokas MC, Rinderknecht H, Walberg CB, Weisman R (1974) Methemalbumin in the diagnosis of acute hemorrhagic pancreatitis. Ann Intern Med 81:483-486

Jordan GL Jr, Spjut HJ (1972) Hemorrhagic pancreatitis. Arch Surg 104:489-493 Lawson DW, Dagget WM, Civetta JM, Corry RJ, Bartlett MK (1970) Surgical treatment of

acute necrotizing pancreatitis. Ann Surg 172:605-617

One Year Follow-Up to Acute Necrotic-Haemorrhagic Pancreatitis 141

Norton L, Eiseman B (1974) Near total pancreatectomy for hemorrhagic pancreatitis. Am J Surg 127:191-195

Sarles H, Taulier J, Figarella C (1963) Dosage de la lipase dans Ie suc duodenal. Rev Fr Clin BioI 8:706

Warshaw AL, Imbembo AL, Civetta JM (1974) Surgical intervention in acute necroziting pancreatitis. Am J Surg 127:484-491

White TT, Heimbach DM (1976) Sequestrectomy and hyperalimentation in the treatment of hemorrhagic pancreatitis. Am J Surg 132:270-275

Surgical Treatment of Acute Pancreatitis

A. Fritsch

I. Chirurgische Universitatsklinik, Allgemeines Krankenhaus der Stadt Wien, Alserstrasse 4, 1090 Wien IX, Austria

The surgical treatment of acute pancreatitis is still a subject of controversy. In particular it is the early organ resection, which is primarily advocated by many French surgeons [1, 3, 10, 19, 22] as an alternative to the less aggressive procedures of conserving the organ, which causes the controversy [2, 4,5,17,18,23]. In referring to the serious possibilities of errors arising from surgical treatment, Warren and McDonald [20] talk about the "too early" and the "too late" with a view to the timing of the operation and of "too much" with respect to the type of intervention. In the light of our present knowledge we also ought to give the same attention to the "too little." Apart from the timing and the type of intervention the selection of the patients is of special importance. The indication for a diagnostic laparotomy in an unclarified abdominal situation characterized by the term "acute abdomen" is not disputed, and in most cases will be established within the first hours of the disease. In case of doubt the decision should be made in favor of the operation because the diagnostic laparotomy, which, in the case of acute pancreatitis limits itself to the clarification of the present changes and avoids direct manipulations on the organ, does not have a detrimental influence on the development of the disease [5, 12, 23]. The indication for an early operation in the early stage of the disease, between the 2nd and the 4th day of the onset of the disease, is, however, handled in a very different manner and/or is rejected. The decision to operate is most easily justified when after attempting conservative treatment there is no improvement or when even with the therapy a progressive deterioration of the condition of the patient is noticed [13, 10, 16, 19], or when vital organ functions (kidney, lung) become insufficient [6]. The basic approach to only operate on the assumption of a necrotizing pancreatitis is disputed [1, 10, 11, 16, 19]. Local complications such as an abscess, sequester, erosion, hemorrhages, intestinal fistulas, or sepsis with or without insufficiency of vital organ functions will make a delayed operation necessary towards the end of the second stage of the disease or after the 2nd week of the disease [2, 5, 10, 15, 17, 18, 19, 21, 23]. The early operation in the early stage of the disease is handled very differently with regard to the tactical and technical method. The most radical method consists of the organ resection and/or "ectomies" respecting the anatomic structures [1, 2, 10, 16, 19, 22]. This aggressive surgical treatment concept dates back to the first total pancreatectomies due to acute hemorrhagic necrotizing pancreatitis by Watts [22] in 1963. It was further extended and especially advocated by Hollen-

144 A. Fritsch

der [10, 11] and other French surgeons [1, 3, 19]. By this method the elimination of the diseased focus should interrupt the effects of the disease on the whole organism, prevent dangerous organ lesions in lung and kidney, and obviate late local complications. The difficulties of this method consist of the determination of the correct timing of the operation and in the intrasurgical assessment of the organ. For technical surgical reasons the intervention should if possible be undertaken before the 3rd day, i. e., at a moment when wrong judgments of the extent of the disease are possible, thus making erroneous, e. g., superfluous, resections likely. To avoid these Hollender [10, 11] advocated the intrasurgical clarification by multiple biopsies and the examination of freeze sections. Numerous authors, however, [1,3,16,19] who originally were in favor of resection rejected this method as being too difficult and risky. With this procedure the mortality after operation is alarmingly high as can be seen from Table 1. The results in total or subtotal necrosis are discouraging and require 85% removal or the total removal of the organ (Table 2).

Table 1. Operation mortality of the early operation in resections or ectomies respecting the anatomic structure

Author

Jordan (1972) Guivargh et a1. (1972) Edelmann and Boutelier (1974) Alexandre (1976) Hollender (1977) Klimmerle (1979) Rettori (1979)

Segmental "left resection" 35%-40%

No. of cases

21 20

148 32 35 44

229

Partial or total duodenopancreatectomy > 60%

Mortality

57% 50% 42,5% 47% 37% 61% 41,5%

Table 2. Operation mortality after early operation with total necrosis of the pancreas

Author No. of cases No. of deaths

Edelmann and Boutelier (1974) 28 27 Ranson et a1. (1974) 5 5 Alexandre (1976) 9 2 Fritsch (1978) 5 4 Klimmerle (1979) 27 21 Rettori (1979) 70 66

144 125 (86%)

This negative experience has led to the organ resection, which is increasingly limited to cases of segmental attack in which a "left resection" is possible. The operation mortality is between 35% and 49%.

Surgical Treatment of Acute Pancreatitis 145

The alternative to the organ resection in the framework of a early operation is the limitation of the intervention to a simple drainage of the peritoneal cavity, possibly combined with an ablation of the necrosis if the latter is well delimited. In addition some authors undertake a triple-ostomy operation. The operation mortality of this method is considerably lower than in the organ resections (see Table 3).

Table 3. Operation mortality after early operation under restriction of the intervention

Author Method No. of cases No. of deaths

Fritsch (1978) 1) 19 5 (26%) Lawson et al. (1970) 2) 15 4 (26%) Warshaw et al. (1974) 3) 38 8 (21%)

1) Drainage and probably necrosectomy 2) As 1) and additional gastro-, jejuno-, and cholecystostomy

The triple-ostomy operation reported by Kiekens et al. [14] was especially made known by Lawson et al. [17]. The gastrostomy permits a long term decompression of the stomach without using a nasogastric catheter. In this way it is certainly possible to prevent an ulcer caused by the catheter and to avoid unfavorable effects on the respiratory tract. The jejunostomy is made to secure alimentation. White and Heimbach [23] who use these procedures have, with two exceptions, always managed parenteral alimentation by a central venous catheter in addition to the enteral alimentation. In 4 out of 20 cases. They have also seen considerable complications such as obstructive ileus, volvulus, and the formation of an abscess around the jejunostoma. Some patients only tolerated 1500 ml daily and one patient had refractory diarrhea after any intake of food. Based only on these observations the question ought to be raised, whether in this situation a jejunostomy is meaningful because it cannot replace the parenteral alimentation and may in itself become the cause of dangerous complications. The mandatory cholecystostomy or choledochus-T drainage of the efferent biliary ducts under normal conditions has already been questioned by Fock and Kyosola [4], and White and Heimbach [23] too only undertook it in case of need. Without an existing mechanical obstruction of the discharge, the installation of an external gall drainage must appear as an unnecessary intervention, which will not bring any advantages but rather disadvantages to the patient due to local complications. Ranson et al. [18] criticized the triple-ostomy operations in general by pointing out the accumulation of septic complications and the lengthening of the hospital stay. We believe that next to the already mentioned objections the different "ostomies" impair the intervention in many cases when a reoperation becomes necessary and therefore harm the patient rather than benefit him. Gliedmann et al. [8] recommended the installation of a peritoneal dialysis to remove toxic and vasoactive substances from the peritoneal cavity. From this they expected a favorable effect on the general condition of the patient. So far this method has been advocated by some other authors who, however, could not supply convincing data about the assumed effect. Up to the present we have not

146 A. Fritsch

been able to find an indication for such a procedure. In the case of kidney insufficiency we perform a hemodialysis. Looking soberly at the mortality figures of the available alternative measures of an early operation the question must be raised what makes the advocates of the active surgical "resecting" treatment concept still justify its further application since it not only causes a higher mortality than the organ-preserving methods but also maintains the possibility of an unnecessary reduction of the parenchyma. I would also like to express my doubts about the basic control of the biliary ducts, and if need be of the pancreas, in all cases of acute pancreatitis and known cholelithiasis within the first 12 h of the onset of the disease, as recommended by Hollender [10]. Apart from the arguments against a premature pancreas resection, there are also doubts about the intervention in the biliary duct itself. At the time of an acute pancreatitis the initial situation for the control of an affection of the biliary duct is at any rate more unfavorable than in a bland stage. This is true both for the total risk and for the local conditions in the efferent biliary ducts. Due to the great danger of complications in this special situation transduodenal papilla interventions and biliodigestive anastomoses, for example, cannot be justified and ought to be replaced by a palliative external biliary duct drainage. The fmal control would be left to a further intervention. I do not believe that such a procedure can be of advantage to the patient. The delayed operation is a well founded and necessary intervention for the management of local complications. As a rule it is undertaken toward the end of or after the 2nd week of the disease [1, 2, 7, 23]. At that time a good demarcation of the necroses can be expected without the presence of secondary consequences such as arrosion hemorrhages or intestinal fistulas [2, 5,6, 18,21,23]. The indications for the intervention are sufficiently known. But it should be pointed out that in case of doubt a decision shall be taken in favor of the operation, because "too early" will at most result in another operation, whereas waiting too long will under certain circumstances favor the creation of irreparable situations [2, 5, 6, 16]. Apart from the possibilities of errors in the choice of timing of the operation, Warren and McDonald [20] have pointed to the "too much" mainly in connexion with the performance of the intervention. By this "too much" we understand the effort to possibly force the final control with a single intervention. This error can certainly be prevented by strictly avoiding organ resections and by only bluntly removing the necroses with the finger fraction method and suction [6, 16]. However, we believe that "too little" is just as disadvantageous for the patient. If the intervention is to be purposeful it must be as clear and radical as possible, i. e., denudation of all possible roads of expansion. The readiness for repeated interventions in the given situation seems to us of special importance for the fmal successful control of the local alterations [2, 6, 7, 23]. Thus, in theyr last communication concerning 30 cases of acute hemorrhagic pancreatitis, White and Heimbach [23] reported that they performed on average 2.5 operations per patient and observed a total mortality of 20%. These figures prove very impressively that for the surgical control of acute hemorrhagic necrotizing pancreatitis in most cases several interventions are necessary (Table 4). Our present therapeutic concept of acute pancreatitis includes the basic primary

conservative treatment involving all the possibilities of intensive care. But in this context it must be quite clear that the intensive therapy in the special situation -


Table 4. Mortality after delayed operation limited to necrosectomy and avoiding oriented resections of organs

Author Patients Operation in No. Mortality each patient

White and Heimbach (1976) 30 20% 2,5 B6hmig and Roka (1977) 21 35% 1,2 Ranson et al. (1974) 19 26% Schima (1977) 51 33% Fritsch (1978) 65 33% 1,6 Klimmerle (1979) 102 31%

be it the respirator case, the dialysis patient, or when both organs are failing -only represents a symptomatic measure. This therapy may indeed temporarily replace a vital organ function but it cannot control the disease focus. The control can only take place by surgical means or the inevitable end is only postponed. Apart from diagnostic laparotomies, surgical measures are if possible avoided in the early stage of the disease, and in no cases are organ resections to be performed prematurely. On the contrary, the indication for a delayed operation in the secondary stage of the disease is handled in a relatively generous manner. Failure of vital organ functions (anuria, respiratory insufficiency) does not present a counter-indication but an indication for intervention.

Patients and Results

From January 1, 1977 to August 31, 1979 we operated on 51 patients with acute pancreatitis. There were 41 males and 10 females with the mean age of 50,1 years. Thirty six patients were transferred from other hospitals for intensive care to our clinic because there was a progressive deterioration of the overall situation with a dangerous restriction of vital organ functions. Of these patients 12 had already been under surgery. Fifteen patients were directly admitted to our clinic and treated there. During the reporting period no patient was excluded from an operation considered necessary on account of his "too bad" general condition. No patient who was only treated by conservative methods died. The 51 patients underwent 88 operations (Table 5). The indication to operate in the 88 interventions is shown in Table 6. In three patients we had to perform a diagnostic laparotomy within the first 24 h because there was an acute abdomen which could not further be clarified. The judgment of the pancreas was undertaken by direct inspection and palpation from the omental sac. No intervention was made on the organ itself, and the operation was concluded by a drainage of the peritoneal cavity. One patient with a total necrosis of the pancreas died on the 4th postoperative day, the two other patients had to undergo a reoperation and sequestrotomy. Between the 2nd and the 3rd day of the disease we decided to perform an early operation on two patients because they did not respond to the conservative meas-

148

Table 5. Fifty-one patients with acute pancreatitis

Time (days)

1st 2nd-3rd 10th-14th ;;.15th

No. of operations

3 2

15 52 5

Type of intervention

Diagnostic laparotomy, drainage Drainage (necrosectomy) Sequesterotomy, necrosectomy, drainage Sequesterotomy, necrosectomy, drainage Local hemostasis Drainage of abscess

A. Fritsch

8 3 Vagotomy, circumsuturing (1), pyloropl. (2)

gastroenteroanastomosis (1)

Table 6. Indications for surgery for the patients mentioned in Table 5

Indication

No clear diagnosis Failure of the conservative initial treatment Palpable resistance Sepsis Peritonitis Intra-abdominal hemorrhage Gastrointestinal hemorrhage Duodenal stenosis Deterioration of the kidney function Deterioration of the lung function

No. of patients

3 2

37 25

4 5 2 1 6 3

ures and because the total situation progressively deteriorated in spite of exhausting all the possibilities of the conservative treatment. Apart from limited and unimportant ablations of necrotic lesions the intervention was restricted to the exploration and drainage of the omental sac. One patient with a total necrosis died due to a situation of refractory shock, the second patient secondarily underwent a reoperation and sequestrotomy. The delayed operation in the secondary stage of the disease was performed in 49 patients after the 10th day of the onset of the disease. The aim of the intervention consisted of a possibly radical removal of all distinguishable and attainable necrotic foci by the finger fraction method and aspiration, while strictly avoiding specific organ resections. This could only be done satisfactorily when the preferred roads of expansion around the pancreas, alongside the ascending and descending colon in the radix mesenterii of the small intestine, in the renal capsules, and in the subphrenic area were clearly denuded. Since it is necessary to leave the drains in position for a long time, which causes the danger of erosion hemorrhage or an erosion of the hollow organs (stomach, intestines), we have recently only used soft Penrose drains for the final drainage. Taking into consideration the 12 patients with preliminary operations in other clinics, 32 ofthe 51 patients had to be operated on several times. This means that these 32 patients underwent 47 reoperations (Table 7). In 14 patients after previous diagnostic laparotomy, the sequesterotomy during the first operation was


Table 7. Number of operations per patient

No. of No. of No. of Preliminary operation operations patients operations in other hospitals

performed

1 29 29 10 2 11 22 2 3 7 21 -4 4 16 -

51 88

the first surgical therapeutic intervention. In 26 cases the reoperation was the consequence of an insufficient elimination of the necrosis during the first intervention; in five cases the reoperation was caused by a local intra-abdominal hemorrhage, in two cases by gastrointestinal hemorrhage and in one case by duodenal stenosis Eighteen of 51 patients (35%) died. Two patients with a total necrosis died during a refractory progressive shock after a diagnostic laparotomy and/or an early operation. Of nine patients with a local disease process controlled in the region of the pancreas, two died of a fresh myocardial infarction, one of an abscess-forming pneumonia, five of a diffuse peritonitis, and one bled to death from an ulcer in the esophagus caused by the catheter. Seven patients died of sepsis, in no case of which was the local process of the disease under control. When relating the operation mortality to the manifest organ insufficiency it can be shown that 13 of 26 patients suffering from an insufficiency of the lung, the kidney, or both systems died whereas only 5 of 25 patients without organ insufficiency died (see Table 8).

Table 8. Operation mortality in relation to the renal and respiratory insufficiency

Organ insufficiency

None Lung (artificial respiration) Kidney (dialysis) Lung and kidney

No. of patients

25 7 4

15

No. of deaths

5 (20%)

~} (50%) 10

The material presented here represents a selection of the particularly serious cases because two-thirds of the patients were transferred from other hospitals for intensive care. The treatment results correctly reflect the efficiency of our present therapeutic efforts, since all the patients admitted as in-patients were taken into consideration during the indicated period. A comparison of these results with those obtained in earlier periods show that the operation mortality per se does in no way permit conclusions as to the overall therapeutic situation (Table 9). In the first period between 1957 and 1971, 31 of70 patients operated on for acute pancreatitis died, corresponding to a mortality rate of 44%. During that time we

150 A. Fritsch

Table 9. Operation mortality in three consecutive periods with differing indications and operation tactics

Period No. patients Deaths Surgical procedure

1957-1971 70 31 (44%) Restricted indication, limited interven-tion, few reoperations

1972-1976 65 17 (26%) Consistent control, generous indication for reoperation

1977-Aug/1979 51 18 (35%) Widening the indication for operation, also to the patient under intensive care

were rather cautious as to the indication and the extent of the operation. The decision to reoperate was made very rarely. In many cases the autopsy showed that the intervention in itself was not adequate to the alterations, because the operation was not radical enough or too irresolute. The consequence of this inconsistent tactical operation procedure was the relatively high operation mortality of 44%. However, these 44% do in no way correspond to the total mortality of the hemorrhagic necrotizing pancreatitis, because during this period patients under refractory shock or with marked organ insufficiency were no longer operated on. These cases appear as deaths in the exclusively conservative treatment group, in which 22 of 79 patients or 27% died. In retrospect we must note that according to our present attitude there would have been for these 12 patients a clear indication to operate with a corresponding pathologic organ substrate. Only the attempt of an operative cardiac control would have resulted in chances of survival. The second period is characterized by a reduction of the operation mortality to 26%. We attribute these improved results to the strict observance of our now already clearly defined tactical surgical concept, which envisages the consistent control of the local situation, if need be several times. The experience and the results in this context encouraged us to extend the indication to operate also to the so-called desolate cases with organ insufficiency so that during the last period no patient was excluded from the necessary operation. As expected, the operation mortality rose under these circumstances. But since here mortality after an operation and total mortality are identical and nevertheless 50% of the patients with an organ insufficiency survived, we believe that these results justify us in retaining our present therapeutic ideas.

References

1. Alexandre JH, Germain M, de Hochpied F, Chambon HG, Trevoux-Paul J, Poilleux F (1974) Chirurgie 100:893

2. B6hmig HJ, Roka R (1977) KongreBbericht der Osterreichischen Gesellschaft flir Chir-urgie, 18th meeting, Graz, Dorrong, S 679

3. Edelmann G, Boutelier P (1974) Chirurgie 100:155 4. Fock G, Kyosola K (1975) Ann Chir Gynaecol Fenn 64:88 5. Fritsch A (1978) Langenbecks Arch Klin Chir 347:559 6. Fritsch A (1979) KongreBbericht der Osterreichischen Gesellschaft flir Chirurgie ,20th

meeting, Innsbruck, Grafelfing, Demeter, S 319


7. Fritsch A, Mach K (1973) Brun's Beitr Klin Chir 220:413 8. Gliedmann ML, Bolooki H, Rosen RG (1970) Curr Probl Surg 9. Guivarg'h HM, Beaufils F, Neury N, Marquand J, Mouchet A (1972) Chir (Paris)

103:479 10. Hollender LF (1977) Fortschr Med 95:1029 11. Hollender LF, Starlinger M, Meyer C (1972) Aktuel Chir 12:43 12. Howard JM, Jordan GL (1960) Surgical diseases of the pancreas. Lippincott, Philadel-

phia 13. Jordan GL, Strug BS, Crowder WE (1977) Am J Surg 133:46 14. Kiekens R, Kinnaert P, Govaerts JP (1967) Acta Chir Belg 66:45 15. Kiimmerle F (1979) Lyon Chir 75:392 16. Kiimmerle F, Neher M, SchOnborn H, Mangold G (1975) Dtsch Med Wochenschr

100:2241 17. Lawson DW, Daggett WM, Civetta JM, Corry RJ, Bartlett MK (1970) Ann Surg

172:605 18. Ranson JHC, Ritkind KM, Rosis DF, Fink K, Spencer FC (1974) Surg Gynecol Obstet

139:69 19. Rettori R (1979) Lyon Chir 75:383 20. Warren KW, McDonald WM (1964) Annu Rev Med 15:335 21. Warshaw AL, Imbembo AL, Civetta JM, Daggett WM (1974) Am J Surg 127:484 22. Watts GT (1963) Lancet 2:384 23. White TT, Heimbach DM (1976) Am J Surg 132:270

Surgical Treatment of Acute Pancreatitis

V. Staudacher, R. Chiesa, and V. Di Carlo

Clinica Chirurgica, Universita di Milano, Policlinico, 20 tOO Milano, Italy

Introduction

The therapeutic program for acute pancreatItIs has undergone substantial changes in the past few years. However, despite improvements in preoperative diagnostic procedures, no general agreement has been reached on this problem, and in particular the choice of a conservative of operative regimen and the timing and extent of surgery are still controversial.

Indications for and Timing of Surgical Management

Acute pancreatitis presents a broad clinical spectrum ranging from cases with mild symptoms to cases which progress rapidly to multisystem failure and death despite current modes of therapy. While the former, the majority (90%) of the cases, almost never require surgical treatment, for the latter it is mandatory and relatively urgent. Between these two extremes there are intermediate forms of varying degrees of severity for which the therapeutic approach has not yet been established. Several methods have been proposed to evaluate such cases with the aim of identifying promptly those patients at high risk who can be expected to respond poorly to conservative measures and who might benefit from surgical therapy. In 1974 Ranson et al. [8] made a statistical analysis of 43 early objective findings which revealed that 11 had significant prognostic value. Each sign correlated with subsequent overall morbidity and mortality, and the risk of death or major morbidity was related to the number of positive early signs present. Clinical and laboratory examinations were analyzed by Jacobs et al. [4] to determine their prognostic value; among patients in this series with three or more clinical characteristics associated with poor prognosis, nonoperative treatment yielded a survival rate of 29%, compared with the 64% survival rate for a group of patients treated operatively with multiple drainage. Recently Warshaw and Kang-Hyun [10] suggested that measurements of serum ribonuclease in acute pancreatitis may provide a reliable indication of pancreatic necrosis. Therefore, RNase determination should be of value for early identification and monitoring of patients at high risk for late complications, and in helping

154 v. Staudacher, R. Chiesa, and V. Di Carlo

to select those patients who will benefit from early surgical debridement before secondary infections occur. The criteria we use to evaluate patients with acute pancreatitis are wider in that they include not only the prognostic signs identified by Ranson but also the data obtained from peritoneal paracentesis and by monitoring hemodynamic parameters [2]. The characteristics of the peritoneal liquid (hemorrhagic, purulent or biliary) obtained from diagnostic paracentesis performed according to Staudacher's technique [9] provide us with direct information on the extent and nature of the underlying pathologic process. Additional prognostic information is obtained from the time course evaluation of hemodynamic parameters. During the initial phase of the disease a reduction in vascular tone represents the basic abnormality seen in all our patients, while a depression in ventricular function was observed in more than 40% of them. With the progression of pancreatitis a clear deterioration of the hemodynamic parameters occurred: all patients developed a hyperdynamic state with mild to severe insufficient oxygen extraction. To predict the probability of survival for these patients a survival index was calculated. Our study [2] shows that the 5th day after hospital admission is the best time to identify those patients at high risk for rapid deterioration. For these cases, early identification of circulatory dysfunction related to poor prognosis will facilitate clinical decisions concerning therapeutic procedures and timing of surgery. In this connection, we consider patients with major physiologic impairment among the few for whom early surgery is advisable. During the observation period, peritoneal dialysis together with general supportive care seems to be the best way of attenuating the systemic effects of pancreatitis [7]. The above general criteria are not applied to patients with post-traumatic pancreatitis for whom immediate surgery is mandatory, even though the diagnosis may be suspect, nor are they applied to patients with pancreatitis associated with septic cholangitis, who also require emergency surgery. Lastly, it should be remembered that late indications for surgery include localized septic complications (pancreatic abscesses) and pseudocysts which increase rapidly in size. In such cases surgery must be preceded by careful investigations of the lesions with CT and echotomography.

Surgical Procedures

Several surgical procedures have been recommended in the treatment of pancreatitis, but none of these can be said to have been fully tested. Three basic therapeutic choices are available for the surgeon. The first is to attempt a major pancreatic resection such as left-to-side subtotal pancreatectomy, cephaloduodenopancreatectomy, or total pancreatectomy. The second is to provide adequate drainage and proceed with peritoneal dialysis. The third approach is to perform a gastrostomy (to aspirate acid and decrease ileus), a jejunostomy (for the purpose of feeding), a decompressing cholecystostomy (if there is evidence of biliary tract obstruction or impending obstruction) and drainage of peritoneal cavity and retroperitoneal spaces. Another therapeutic possibility has been


proposed by French authors [5, 6] which consists of sequestrectomy and necrosectomy. There is no standard optimal procedure for pancreatitis, but a choice must be made in each individual case on the basis of anatomic-pathologic data found at laparotomy. Therefore, it is seen that exploration of the retroperitoneal cavity and extent of the lesion are fundamental for making the correct therapeutic decision. The particular anatomic site of the pancreas and the extreme variability of the lesions make it difficult to evaluate the extent and location of the necroses. The biggest pathologic problems from the surgeon's point of view are: 1) Pancreatic edema with focal necroses, localized or diffuse, evolving into pseu

docysts, which often regress spontaneously if noncommunicating with the Wirsung duct or which expand progressively if they communicate with the Wirsung duct (Fig. 1). In these cases therapy is conservative (indirect surgery).

Fig. 1. Acute pancreatitis: schematic drawing showing parenchymal necroses of various depths. The most serious ones are those penetrating into the Wirsung duct as they spread pancreatic secretion within the pancreas and to peri pancreatic tissues. Penetrating necroses are those which may need resective surgery. Nonpenetrating intraparenchymal necroses usually give rise to pseudocysts

2) Edematous pancreatitis with diffuse necrotic peripancreatitis. These cases are the most difficult for the surgeon to evaluate. In fact it is well known that if the necrosis is peripheral and interstitial, spontaneous regression is frequent. Distinguishing between these lesions and deep glandular necroses has, therefore, significant prognostic and therapeutic importance, and to do so it is necessary first to decapsulate the pancreas and then to perform a superficial necrosectomy in order to expose healthy glandular tissue. If this can be done, the surgery is in this case of the conservative type.

156 V. Staudacher, R. Chiesa, and V. Di Carlo

3) Acute necrotic-hemorrhagic pancreatitis diffused throughout the parenchyma with necroses which extend up to the large excretory ducts. For this type of lesion, as for post-traumatic pancreatitis, surgery must be radical, i. e., resection. As well as evaluating the pancreatic lesions, abdominal exploration must be extended to the surrounding viscerae and in particular to the biliary tree.

Conservative Therapy

This is indicated for lesions of types (a) and (b) above. The systematic application of triple drainage in these cases is no longer acceptable for the following reasons: 1) The administration of cimetidine to these patients has significantly reduced in

dications for gastrostomy. 2) Cholecystostomy is performed only when biliary hypertension is documented

or when there is associated biliary pathology. 3) Feeding jejunostomy is still, in our opinion, a valid procedure to be carried out

systematically on all patients. The administration of an elemental diet via this route is today one of the most rational supportive treatments for acute pancreatitis [1].

As far as necrosectomy is concerned, carried out manually or by sump, this is useful not so much as therapy in itself but in particular to ascertain if the necroses are deep or superficial. Sequestrectomy or removal of circumscribed and deep necroses is dangerous because on the one hand it impedes the formation of pseudocysts (a benign event) and on the other it facilitates the formation of pancreatic fistulas. On the contrary, the practice of associating peritoneal dialysis with aprotinine with jejunostomy and eventual retroperitoneal sump drainage seems useful.

Radical Surgery

This is sometimes reduced to simple regularization of a spontaneous pancreatectomy. The indications for this type of surgery are type (c) lesions (see above) and post-traumatic pancreatitis. According to the site of greater intensity of the necrotizing process, the pancreatectomy should be subtotal, from left to right, up to the level of the pancreaticoduodenal artery (Fig. 2) associated with splenectomy, or total. In exceptional cases there are indications for cephaloduodenopancreatectomy. This type of surgery raises the problem of how to treat the residual pancreatic stump. We ourselves insert the pancreatic stump in a submucosal pouch on the posterior wall of the stomach, and the Wirsung duct is made to communicate with the gastric cavity and protected with a thin polyethylene tube (Fig. 3). We are presently experimenting with the possibility of arresting exocrine pancreatic secretion from the residual stump by occluding the pancreatic duct system by injection of a fast-solidifying amino acid solution [3].


Fig. 2. Acute pancreatitis: technique of left-to-side pancreatectomy. The resection should be subtotal up to the level of the pancreaticoduodenal artery

POlYT.TUBE

Fig. 3. Acute pancreatitis: technique of left-to-side pancreatectomy. Residual pancreatic stump is inserted into a submucosal pouch on the posterior wall of the stomach. The Wirsung duct is protected by a thin polyethylene tube

158 V. Staudacher, R. Chiesa, and V. Di Carlo

Results of Surgical Treatment

During the period 1970-1979, 301 patients with acute pancreatitis were admitted to the Department of General Surgery and the Department of Emergency Surgery of Milan University, of whom 105 (34.9%) underwent surgery (Table 1). Extensive surgery was performed on 31 patients, with 32.2% mortality. Causes of death were: septic shock (4 cases), hemorrhagic complications (2 cases), renal failure (2 cases), recurrent pancreatitis at the residual stump (1 case), and duodenal fistula (1 case). We carried out conservative surgery (biliary surgery, retroperitoneal drainage, jejunostomy) on 72 patients with 30.5% mortality. Death was mainly due to the evolution of the disease with superimposed sepsis.

Table 1. Surgical treatment

Extensive Subtotalleft-to-side pancreatectomy Duodenopancreatectom y Total duodenopancreatectomy

Total

Limited Retroperitoneal drainage Biliary surgery + retroperitoneal drainage Biliary drainage + retroperitoneal Drainage + jejunostomy

Total Mortality

Conclusions

Total

No. of cases Death

26 7 3 0 4 3

31 10 (32.2)

23 7 20 4

29 11

72 22 (30.5)

105 32 30.4%

Since there still exist difficulties in correlating the clinical picture of acute pancreatitis with the anatomic-pathologic situation, especially considering the evolution of the disease, diagnosis and treatment must be performed in highly specialized departments (intensive care surgical units). Checking the evolution of the clinical picture by means of evaluating the criteria proposed by Ranson [7, 8], together with exploratory paracentesis and peritoneal dialysis as well as monitoring hemodynamic parameters, makes it possible in our experience to establish more accurately the indications for and timing of surgery. At laparotomy, the location and extent of the necrosis constitute the basis on which the decision to carry out radical or limited surgery is made. Resection is mandatory when the necroses are extensive and communicate with the Wirsung


duct. Delayed surgery may become necessary when abscesses or pseudocysts develop in acute pancreatitis. Finally, more attention should be paid to the supportive care given to patients with acute pancreatitis since the complications arising from insufficient fluid replacement, shock, and renal failure may be avoided by taking appropriate intensive therapeutic measures. In addition, associated diseases, such as penetrating ulcer, acute cholecystitis, and cholangitis, which provoke and perpetuate pancreatitis, may be life threatening and should be cured promptly.

References

1. Cristallo M, Staudacher C, Andreoni B, Sallusti M, Di Carlo Y, Chiesa R (1978) L'associazione della nutrizione parenterale ed enterale nel paziente chirurgico acuto. Urg Chir Comment 1:137-143

2. Di Carlo Y, Nespoli A, Chiesa R, Staudacher C, Cristallo M, Bevilacqua G, Staudacher Y, (to be published) Hemodynamic and metabolic impairment in acute pancreatitis. World J Surg

3. Gebhardt C, Stolte M (1978) Pankreasgang-Okklusion durch Injektion einer schnellhartenden Aminosaurenlosung. Langenbecks Arch Chir 346:149-166

4. Jacobs ML, Dagget WM, Civetta JM, Yesu MA, Lawson DW, Warshaw AL, Nardi GL, Bartlett MK (1977) Acute pancreatitis. Analysis of factors influencing survival. Ann Surg 185:43-51

5. Lataste J, Serpault P (1977) Le traitement chirurgical des pancreatites aigues hemorragiques. J Chir (Paris) 113:447-456

6. Leger L, Chiche B, Ghouti A, Louvel A (1978) Pancreatites aigiies. Necrose capsulaire superficielle et atteinte parenchymateuse. 115 observations, 11 exerese. J Chir (Paris) 115:65-70

7. Ranson JH, Spencer FC (1978) The role of peritoneal lavage in severe acute pancreatitis. Ann Surg 187:565-575

8. Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC (1974) Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 139:69-81

9. Staudacher Y, Chiesa R, DeRai P, Di Carlo Y, Staudacher C (1978) La terapia in ambiente chirurgico della pancreatiti acute. Urg Chir Comment 1:9-24

to. Warshaw AL, Kang-Hyun L (1979) Serum ribonuclease elevations and pancreatic necrosis in acute pancreatitis. Surgery 86:227-234

Morphology of Chronic Pancreatitis

V. Becker

Pathologisches Institut Universitat Erlangen-Niirnberg, KrankenhausstraBe 8-10, 8520 Erlangen, Federal Republic of Germany

In its essence, chronic pancreatitis is identical to acute pancreatitis. In chronic pancreatitis, the autodigestive destruction of the organ is the decisive feature of the pathogenic process. And yet, in common with the clinical symptomatology, the anatomic picture is also quite different from that seen in the acute form of the disease (Becker 1973). Acute pancreatitis is characterized by the precipitate occurrence of necrosis of large sections of the pancreas. Chronic pancreatitis, in contrast, leads to the gradual destruction of the parenchyma in a number of episodes of painful attacks. A very broad, almost tumorous, formation of scar tissue remains. The formation of the scar tissue maintains the disease process; it must be held responsible for at least some of the subsequent acute phases. The formation of scar tissue also gives rise to the frequently observed complications, such as diabetes and steatorrhea as signs of pancreatic insufficiency. It is certain that, after prior acute pancreatitis, the anatomic picture of chronic pancreatitis can be highly typical. Usually, however, chronic pancreatitis does not begin with acute autodigestion, but with an initially undefined sensation of pain in the upper abdomen. During the course of time, this sensation becomes more marked and is also experienced more frequently. With each painful attack, a portion of the gland is destroyed (Fig. 1). Chronic pancreatitis represents the autodigestion of the pancreas in episodes that are widely separated both regionally and temporally. The anatomic characteristic is the progressive destruction of parenchyma and the progressive and predominating formation of scar tissue. The formation of the scar tissue is so luxuriant that, despite the considerable reduction in the functioning mass, the gland as a whole appears larger. This circumstance is important, in particular for diagnosis with ultrasound. This scar formation also represents the basis for the assumption of an immunologically determined autoperpetuation (Richter 1979). Owing to the protracted course of the disease, the anatomic phenomenon of the disease manifests considerable variety. First of all, we have the pseudocyst. It always represents an indication of destruction of tissue by an acute pancreatitis. As a result of the fact that, thanks to shock therapy, more patients are now surviving acute pancreatitis, a more or less extensive pseudocyst is now being seen more frequently. We have found pseudocysts in 35% of surgical preparations of chronic pancreatitis. When it is particularly large, when it is pushing outward, the pseudocyst gives rise to clinical symptoms corresponding to those producd by a space-

162 v. Becker

Fig.1. Chronic pancreatitis with acinar atrophy, dense fibrosis and slightly dilated small ducts. x 60

consuming tumor. It may, under certain circumstances, simulate a rapidly growing tumor. The majority of pseudocysts are, however, small and lack any symptomatology of their own, since the symptoms they produce are not distinguishable from the overall clinical picture of chronic pancreatitis. The pseudocyst in the pancreas does not represent any acute danger, but is does pose a potent and potential threat. There are two reasons for this:

1) The pseudocyst is often filled with cell detritus, which cannot be organized. The wall of the cyst is rigid and scarred and lacks any capillary system capable of giving rise to granulation. The cell detritus can become infected with bacteria, either from the blood or from adjoing areas (hematogenically), or per continuitatem. The cell detritus is an excellent substrate for bacteria and can become the starting point for a suppurative pancreatitis.

2) The second danger is the compression of the efferent system. Not infrequently, this finding can be established by (ERCP) (endoscopic retrograde pancreatography). When the pancreatic duct is displaced by a pseudocyst in the neighborhood, the pseudocyst can be detected by virtue of its space-consuming effects. There is then no connection of the ductal system with the pseudocyst.

Pseudocysts are a sign of a previous bout of acute pancreatitis (Fig. 2). They maintain the chronic pathologic process by a compression effect on the efferent duct. We distinguish between chronic pancreatitis with and without the formation of stones. Stones and calcifications were first described in alcoholic pancreatic diseases (Sarles et al. 1961, 1970) (Fig. 3). They do not, however, prove that the pan-


Fig. 2. Chronic pancreatitis; pseudocyst, duodenal mucosa (left), deviation of the duct of Wirsung (above)

163

Fig. 3. Chronic calcifying pancreatitis. Longitudinal section of the gland

164 V. Becker

creatitis has been caused by alcohol abuse. In our material, we have observed calcifications in about one-third of all patients with pancreatitis (32%), but have also found no deposits of calcium salts in half of all cases of alcoholic pancreatitis (Phillip 1976). The stones can be seen, both in the plain film of the upper abdomen and, even better, in the X-ray film of the surgical preparation. Sometimes, the main ducts, the pancreatic duct, and Santorini's duct contain a tremendous number of stones. Even the small ducts may be blocked by stones and calcific incrustations. Calcification is not a sign of chronic pancreatitis, but merely a secondary finding, which may be explained by the richness of the pancreatic juice in calcium ions. As seen histologically, initially a fibrosis may develop, then a remodeling of the acini, accompanied by a progressive destruction of parenchyma; all that remains are the islets and a luxuriant proliferation of the small ducts and canaliculi. Finally, a cicatricial field results. Since, now, the parenchyma has been "burnt out" and no tryptic necrosis can develop, we speak of the metatryptic stage (Fig. 4).

Fig.4. Chronic pancreatitis: metatryptic stage; exocrine parenchyma totally replaced by fi brous tissue, only few preserved islets of Langerhans

Summarizing what has been said so far: what has happened by the time the metatryptic stage has developed? A digestive gland weighing some 100 grams, responsible for the production of the pancreatic juice and for the endocrine functions associated with insulin and glucagon, has been gradually destroyed over a period of 10-20 years by a protracted, insidious, autodigestive process. The gland has now completely disappeared, being replaced by a coarse, larger mass of scar tissue. For no other organ is a comparable process known!

Morphology of Chronic Pancreatitis 165

How has it been possible for this to come about? The honest answer is that we do not know the exact cause of these processes. We know that alcohol abuse plays a decisive role; but how alcohol can lead to such a total destruction of the organ is by no means clear. Furthermore, there are a number of other unexplained points: Only 4% of patients who develop an alcoholic liver cirrhosis and who die from esophageal variceal bleeding, are found to have chronic pancreatitis. Some alcoholics experience quite a different form of damage to the pancreas, namely, the Entlaubung (literally, shedding) of the pancreatic ducts, which, while not an inflammation, does represent a degenerative destruction of the gland. We know of a number of factors that favor the development ofa chronic pancreatitis, the risk factors. In the first instance we might mention the obstruction of the flow of pancreatic juice out of the gland. If the pancreatic duct has been obstructed by a gallstone, in a large majority of cases, the outflow is maintained via Santorini's duct (Fig. 5).

Fig. 5. Chronic pancreatitis combined with cholecystolithiasis and cholangiolithiasis; imprisoned stone in the papilla of Vater

The occlusion of both ducts does not lead to chronic pancreatitis, but rather, (according to Banting and Best) to a destruction of the exocrine gland, the islet system being preserved. This fact has been repeatedly confirmed experimentally and, today, is put to therapeutic use. In particular the constriction of the duct, but not its complete occlusion, represents a predisposing factor. From the material of our examination facility, we have been able to discover a number of special cases of chronic pancreatitis resulting from different degrees of constriction of the ductal system.

166 v. Becker

It has long been known that a duodenal diverticulum favors the development of chronic pancreatitis, not regularly, but certainly to an increased degree. The duodenal diverticulum is common in the region of the papilla; in nonselected autopsy material, we found it in 20% of all adults, but only when "unfolding fixation." In the vicinity of the papilla, the duodenal diverticulum is harmless. If, however, the wall of the diverticulum becomes rigid as a result of an inflammation followed by scarring, it may constrict the pancreatic duct. The diverticulum alone is not dangerous; on the other hand, in the presence of diverticulitis and, in particular, peridiverticulitis, the papilla may be compressed and constricted (Fig. 6).

Fig. 6. Giant diverticulum close to the papilla of Vater causing deviation both of the duct ofWirsung (at the bottom of the diverticulum) and the common bile duct. Dorsal view, longitudinal section

The situation is similar in the case of pseudocysts in the head of the pancreas -here too displacement and constriction of the duct are possible. Surprisingly, in our examination material of chronic pancreatitis, we have found true cysts of the duodenal wall in 35% of the cases (Fig. 7). When these develop further, they constrict the duct of the exocrine pancreas, As a result, a duodenal stenosis occasionally occurs. Duodenal wall cysts may be either solitary or multiple. The largest we have seen to date, which had constricted the lumen of the duodenum, had a diameter of 10 em! In this case, the duodenal stenosis had been the indication for the operation on the pancreas. In such cases, we speak of duodenal wall cyst pancreatitis (Stolte 1976). A further special form presents when the information spreads throughout the groove between the duodenum and the pancreas, where it gives rise to a substantial, cicatricial plate. Occasionally, we are dealing here with previous acute pan-


Fig. 7. Duodenal wall cyst pancreatitis. Longitudinal section of the papilla of Vater: duct of Wirsung completely filled with calculi. common bile duct upwards displaced. Constriction of the common bile duct by two duodenal cysts protruding in the duodenal lumen

Fig. 8. So-called groove pancreatitis: widespread scars replacing both the pancreatic ducts and the duodenal mucosa within the groove between the duodenum and the pancreatic head

167

168 v. Becker

creatitic processes predominantly involving the periphery. Both the bile duct and the pancreatic duct are constricted. We employ the term "groove pancreatitis," since the disease begins in the groove between the bowel and the gland. Among 90 cases of chronic pancreatitis, we found the groove pancreatitic form in 10% (Fig. 8). The symptomatology occurs early on and in a manner very similar to that seen in different forms of pancreatitis. The chronic inflammation progresses segmentally to the head, the destruction of the parenchyma in the remaining pancreas occurring - when Santorini's duct is lacking - at a much later date (Fig. 9).

Fig. 9. Model of the groove pancreatitis; fibrous tissue constricting the pancreatic ducts and replacing the parenchyma of the pancreatic head (black)

At this point, we shall leave the so-called special forms. At the same time, however, I should like to point out that the degree and intensity of the condition, the dilatation, and the deformation of the ducts, the impairment of the islet system, the reaction of the ductal epithelium all vary from one patient to another, so that if we speak truly we must say that only "special cases" are observed. Constriction - not obstruction - is a factor that a favors the development of chronic pancreatitis. This does not seem to fit in with the fact that the clinical characteristic of chronic pancreatitis, for example, in the ERCP image, is dilatation of the duct. This situation is not so easy to explain. The wall of the pancreatic duct is rigid, firm, substantial, and inelastic. The possibility of dilatation due to the secretion pressure or the X-ray contrast medium, may be virtually left out of consideration. And yet, the duct as a whole is dilated when a constriction presents in the region of the papilla. This may be explained by the tension exerted by the cicatricial tissue to the outside, accompanied by a disappearance of the parenchyma, in particular subsequent to a pancreatitis with a more peripheral spread. It is not easy to explain the complicated dynamics of peripheral scarring (Becker and Stolte 1979). Nevertheless, the wide, deformed, or kinked duct is an established diagnostic feature of chronic pancreatitis. Here at Erlangen, we have developed a technique for handling the anatomic preparations that is similar to the clinical representation of the duct (Stolte and


Schaffner 1978). When they arrive, the surgical preparations are in an unfixed state. We fill the ducts under pressure using an X-ray contrast medium to which a fixative has been added. In this way, we are able to compare the anatomic pancreatogram with the ERCP representation obtained prior to surgery. We can also carry out a selective histologic investigation of the question as to why a duct is dilated, or kinked, and what has given rise to its constriction. On the occasion of the German Surgical Congress held in 1976, we asked those surgeons who carry out surgery of the pancreas to send us their surgical preparations. In this way, we hope to obtain uniform material for anatomic investigations. So far, more than 500 surgical preparations have been investigated in our examination facility, uniformly, using the method described above. Here I should like to point to a future therapeutic aspect. We have seen that the outflow obstruction represents a decisive risk factor, i. e., that the secretion is dammed back and forced out into the surrounding tissue, where it destroys the parenchyma. The results of pathophysiologic examinations led to the conclusion that it would be better to close off the duct completely and, in this way, cause the gland to atrophy within a period of a few months. This apparently logical conception is occasionally realized here in Germany (Hoffmann et al. 1977). My colleague Stolte, working together with Gebhardt, in Erlangen, has applied a new method, initially in the dog and then also in human subjects (Gebhardt and Stolte 1978). They fill the duct with a mixture of amino acids which solidify within a matter of minutes. The duct is completely filled, as in a cast, and totally occluded. The decisive point is that the mass fills the entire duct and the occlusion of the duct extends right into the acini, so that the pancreatic juice is "blocked off' right at the source (Fig. 10). No further pancreatic juice is then produced.

Fig. 10. Principle of the therapeutically induced atrophy of the pancreatic parenchyma caused by filling the ducts with a quickly solidifying substance; that mixture (black) reaches into the acinar lumen and blocks off secretion right at the source

170 V. Becker

After a number of weeks, the duct becomes patent again, since the amino acid mixture is broken down and absorbed by reparative processes. The acini have been destroyed, the islets are preserved, and the complicating diabetes prevented. The ducts are patent and of medium sized caliber. We consider this to be a promising method of treating chronic pancreatitis without the need for extensive surgical intervention. The method is based on pathophysiologic and morphological experience and knowledge and, to date 1979, has been successfully employed by Gall and Gebhardt in about 50 cases. Finally, I should like to mention a topical point of interest in pancreas pathology as a whole. Can a carcinoma of the pancreas develop on the ground of chronic pancreatitis or from a chronic pancreatitis? This question cannot be answered with a simple "yes" or "no." There is, however, evidence that would make it seem possible that such a transition does actually occur. Such evidence is to be found in unequivocal observations of case histories - but these are solitary cases. On the other hand, the age distribution curve for chronic pancreatitis, revealing predominance of the disease in the 4th decade, is quite different and reveals a shift of 20 years as compared with the age distribution curve for carcinoma. We have examined our carcinoma case material for the presence of signs of a previous chronic pancreatitis and, in doing so have taken into account not merely the case history, but also other anatomic parameters. In the case of chronic pancreatitis, hyperplasia of Brunner's glands occurs after a period of at least 6 years. This does not occur with carcinoma (Stolte and Schwabe 1977). In the presence of the reduction in the mass of parenchyma of the pancreas, the vessels adapt themselves to a reduced requirement, by the development of an adaptive intimal fibrosis, so that the blood flow is very much diminished. This adaptation of the intima develops very slowly and presupposes a long persisting loss of parenchyma (Kaiser und Hommel 1975). From the point of view of the time factor, the destruction of the gland by means of a carcinoma is not able to give rise to such an adaptation of the intima. In approximately 17% of our cases of carcinoma, we gained the impression that the carcinoma had been preceded by chronic pancreatitis. In common with Cubilla and Fitzgerald (1976) we examined our cases of chronic pancreatitis for the presence of epithelial dysplasia. It is astonishing what great variety of epithelial remodeling can be observed in the ductal system in chronic pancreatitis. There are papillary projections - cell atypias, squamous epithelial metaplasias with dysplasia - in other words an epithelial disharmony, from which, as we may safely assume, a carcinoma might easily develop. With respect to the tissue, the chronic inflammation maintains a constant cellular tissue disharmony which is a source of constant compulsion for regeneration. But an unequivocal assertion as to the degree of prognostic certainty with which a case of chronic pancreatitis develops into a carcinoma, or as to the percentage of cases that do so, is not possible at the present time. Chronic pancreatitis is a disease with a protracted course. The surgical indication for a more or less extensive resection still remains the constantly recurring pain caused by the destruction even of small sections of the gland. The pain is also maintained by the compression of nerves in the scar tissue, or even in the celiac trunk.


While chronic pancreatitis is not life threatening, it is a protracted condition which, on account of the constant attacks of pain, decreases the quality of life and which may even cause its victim to become dependent on drugs, or occasionally induce diabetes mellitus. The question as to whether a pancreatic carcinoma develops on the basis of a chronic pancreatitis has not yet been decided, nor is it capable of being decided at the present time. Chronic pancreatitis consists in a continuing process of self-destruction which is favored by a constriction - less so by a total obstruction - of the duct. Perhaps, here, too, autoimmunologic processes are involved when an autodigestive process has been initiated (Richter 1979). Chronic pancreatitis can now be seen - perhaps on account of the increased consumption of alcohol- at a level of incidence such as, a mere 15 years ago, was observed only by Sarles (1961, 1972, 1973). The increase in chronic pancreatitis over the last 15 years now poses, in particular in young people, a social, an epidemiologic, and above all a medical problem which concerns us all - including the pathologic anatomist. All medical men must work together to clarify and solve this problem.

References

1. Becker V (1973) Bauchspeicheldruse. Inselapparat ausgenommen. (Springer Berlin Heidelberg New York (Spezielle pathologische Anatomie, vol 6)

2. Cubilla AL, Fitzgerald PJ (1976) Morphological lesions associated with humar primary invasive nonendocrine pancreas cancer. Cancer Res 36:2690-2698

3. Gall FP, Gebhardt C (1979) Ein neues Konzept in der Chirurgie der chronischen Pankreatitis. Dtsch Med Wochenschr 28

4. Gebhardt C, Stolte M (1978) Pankreasgang-Okklusion durch Injektion einer schnellhlirtenden AminosiiurelOsung. Experimentelle Studien. Langenbecks Arch Chir 346:149-166

5. Hoffmann E, Usmiani J, Gebhardt C (1977) Die Ausschaltung der exocrinen Funktion des Pankreas als Behandlungskonzept der chronischen Pankreatitis. Dtsch Med Wochenschr 102:392

6. Kaiser G, Hommel G (1975) Morphometrisch-statistische Analyse der Pankreasarterien bei chronischer Pankreatitis. Virchows Arch [Pathol AnatJ 365:103-118

7. Phillip J (1976) Chronische Pankreatitis. Med Welt 27:287-291 8. Richter K (1979) Immunpankreatitis. Habilitationsschrift, University of Erlangen

Ntirnberg 9. Sarles H (1972) Pathogenie et distribution geographique des pancreatites chroniques.

Arch Fr Mal App Dig 61:512-514 10. Sarles H (1973) An international survey on nutrition and pancreatitis. Digestion 9:389-

403 11. Sarles H, Mercadier M (1960) Les pancreatites chroniques de l'adulte. Expansion

Scient entifique Francaise Paris 12. Sarles H, Sahel J (1976) Pathology of chronic calcifying pancreatitis. Am J Gastroente

roI66:117-139 13. Sarles H, Singer M (1978) Akute und chronische Pankreatitis. Witzstrock, Baden-Ba

den KOln New York. (Das gastroenterologische Kompendium, vol 4) 14. Stolte M (1976) Cysten in der Duodenalwandung und chronische Pankreatitis Verh

Dtsch Ges Pathol 60:320 15. Stolte M, Schaffner 0 (1978) Entfaltungsfixation und rontgenologische Pankreas

Gang-Darstellung als Pfadfinder fUr die pathologisch-anatomische Diagnostik. Verh Dtsch Ges Pathol 62:400

16. Stolte M, Schwabe H (1977) Chronische Pankreatitis und Hyperplasie der Brunner'schen Drusen. in: Creutzfeldt W, Classen M (eds) Ergebnisse der Gastroenterologie

Indications for Surgical Treatment of Chronic Pancreatitis

I. Vantini and G. Cavallini

Clinica Medica 3", Universita di Padova, Sede in Verona, Policlinico B. Roma, 37100 Verona, Italy

Any treatment implies a choice which should be based on the principles of decision making. Its overall aim is to get the maximum benefit with the minimum disadvantage, or at least a reasonable risk. In order to do so one must stick to a realistic aim, know the efficacy of the treatment, its side effects, if any, and what might result from either administration or non administration. All this makes up the evaluation of benefits and disadvantages and is based upon the severity of the disease. Accordingly, in a rational therapeutic approach, a suitable monitoring of the clinical and laboratory parameters useful for an estimate of the outcome of the treatment is almost compulsory. This policy requires a great deal of data, collected and estimated on a scientific basis, to be available, so that the key criteria of the treatment are as rational and effective as possible. This introduction to the surgical treatment of chronic pancreatitis will focus on some aspects of the disease which might help with the choice of a suitable treatment. First of all, it should be emphasized that the results of a treatment depend on the etiology and the natural history of the disease, to some extent at least. Even if in westem/westemlike regions chronic pancreatitis shows relatively homogeneous characteristics, a few differences are detectable; namely in the food habits and therefore in the frequence of alcoholism, in the sex and age distributions, and in the cultural and socioeconomic status of the patients. Therefore, the therapeutic approach and the management and the results obtained in an area might not be regarded as "safe" for another area. Besides, the lack of randomized, controlled trials doesn't allow one to objectively evaluate the results of the treatments. Retrospective evaluation of the results of medical and surgical therapy doesn't allow a correct comparison between the two treatments since the two groups are most probably different because the patients are preselected. Therefore, if we can foresee, to some extent, what outcome might be in patients chosen for either treatment, the analysis of the results obtained cannot supply us with objective, safe criteria to be used in making a choice of treatment. As a matter of fact we are not in a position to evaluate "how much" is due to the treatment and "how much" to the natural history of the disease, even if impairment of the exocrine pancreatic function and alcohol withdrawal appear to be factors favorable or adjunctive to pain relief (Amman et al. 1979). However, even if abstinence is followed by an improvement of the pain and it seems reasonable to prescribe a diet excluding the alimentary "risk factors," the data available were mostly empirically collected and therefore they shouldn't be accepted without reserve.

174 I. Vantini and G. Cavallini

In spite of these difficulties, the bulk of pathologic and clinical data allows the definition of general criteria for therapeutic approach. The first step consists in the diagnosis of the disease and the knowledge of its etiology. It is necessary to prove the clinical and pathologic chronicity and to detect the etiologic factors. Since chronic alcoholic calcifying pancreatitis is quite common in Southern Europe (Sarles et al. 1979) as well as in Italy (Gullo et al. 1977; Vantini et al. 1978), diagnosis is not so difficult to attain. In fact, about two-thirds of cases can be diagnosed by only using clinical, laboratory data and a well performed plain X-ray of the abdomen. It is not so easy, especially in the absence of a biliary disease, to make a differential diagnosis between acute pancreatitis and relapsing pancreatitis. Therefore, an accurate "anatomic," functional investigation or, in individual cases, a follow-up of the patient is required. Besides, in our regions, where alcohol consumption is heavy, chronic pancreatitis seldom occurs in teetotallers. Since there is no threshold toxicity of alcohol on the human pancreas (Durbec and Sarles 1978), only in very few cases can alcoholic etiology be ruled out. In patients with chronic pancreatitis the frequency of gallstones is no higher than in the general population (Gullo et al. 1977; Vantini 1979). With one exception from our patients, chronic pancreatitis was never attributable to a stenosis of the Oddi's sphincter or to a stone in the common biliary duct. Since gallstones might induce an acute relapse, it seems reasonable to surgically treat this risk factor. Actually, we have never been able to state a relationship between painful relapses and a biliary tract disease.

It is difficult to foresee the risk of relapses. In fact, while in some patients pancreatitis becomes painless after several years, in about one-third of our cases there was a steady impairement of the pain, but in most cases relapses were not foreseeable at all. As the main purpose of surgery in chronic pancreatitis is the relief of pain, the therapeutic choice is essentially a clinical problem and therefore a thorough knowledge of clinical data is needed. Where there is a lack of complications which make surgical treatment necessary (i. e. a large cyst or a hyperparathyroidism) it is advisable to state whether "medical" treatment of the pain has failed. In other words, one should know if: (1) the patient has really given up drinking; (2) alcohol withdrawal is followed by an improvement of the pain; (3) relapses are to be related to alcohol and/or food abuses. Moreover, it should be investigated: (1) whether the patient is aware of his disease and its causes (i. e., chronic alcoholism); (2) to what extent the disease affects his life and his working activity; (3) whether he is really willing to give up drinking and to have the pain removed by surgery. Although alcohol withdrawal appears to be a favorable adjunctive factor (Amman et al. 1979) and a positive relationship seems to exist between alcohol withdrawal and pain relief in surgically treated patients (unpublished personal data), the risk of complications and drug addiction, as well as the worsening conditions of life, compel us to surgically treat even those patients who most probably won't give up drinking. On the other hand, alcohol withdrawal appears to be capable of avoiding surgical treatment in only 35%-50% of the patients, since it is duct obstruction which probably accounts for the pain persistence or relapses. On the other hand, alcohol increases the risk of liver cirrhosis.

Indications for Surgical Treatment of Chronic Pancreatitis 175

Although indications for surgical treatment of chronic pancreatitis haven't changed much over the years (Table 1), what has changed are the modalities and the quality of the selection of the patients thanks to new procedures by which anatomic evaluation of the disease is attained (i.e., ERCP, US, CT, etc.). Such procedures allow us to get accurate information about the chronicity of the disease, its extension and degree, and to know what the situation is with adjacent organs such as biliary tract, digestive tract, blood vessels, and the retroperitoneal structures.

Table 1. Main indications for operation

Intractable pain Incapacitating painful relapses Pseudocyst or cyst (and its complications) Obstructive jaundice Duodenal stenosis with gastric stasis Biliary stones Stenosis of the papilla of Vater Hemorrhage from esophageal varices (thrombosis and/or compression on the splenic vein) Internal fistula Possibility of carcinoma (doubtful diagnosis)

Table 2 shows the main indications for surgical treatment observed in patients with chronic calcifying pancreatitis. It is generally agreed that cysts are one of the main indications for surgery. While cysts following acute pancreatitis often spontaneously shrink and disappear in a few weeks (at least in 50% of the cases), chronic pancreatitis cysts very varely do so (Sankaran and Walt 1975). However, since a successful result of surgery seems to be related to the formation of a cyst wall, the operation should be delayed, if possible, by 5-7 weeks. During such periods one should follow the evolution of the cyst by means of, for example, US and resort to early operation only in the case of either a progressive enlargement of the cyst or other complications. While the mortality rate of untimely operation is usually very high (Carilli and Faris 1967), after a 6-week delay it is lower and

Table 2. Main indications for surgical treatment observed in 154 patients with chronic relapsing pancreatitis

Cause

Intractable pain or incapacitating relapses Pseudocyst or cyst (± pain) Obstructive jaundice Gallstones Doubtful diagnosis (possible cancer) Pancreatic ascites

No. of cases

88 45 14 13 4 3

%

57.14 29.22 9.09 8.44 2.59 1.90


monitored US controls may be able to show the disappearance of the smaller cysts (Bradley and Clements 1975). Anyway, a great deal of attention should be paid to an early diagnosis of complications which are considered the main causes of an unfavorable outcome of pancreatic cysts and make surgery nondeferrable, i. e. persistence of pain, abscess development, cyst hemorrhage, intestinal obstruction, compression of the common bile duct with jaundice, compression of portal vein or splenic vein thrombosis, hemorrhage into the peritoneal cavity or into the gut, leakage from the cyst with chronic pancreatic ascites formation.

Pancreatic ascites is a rare complication of chronic pancreatitis and in over 50% of the cases it occurs in alcoholic patients and/or in the presence of a small cyst (Hotz et al. 1977). However, sometimes a free leakage of pancreatic juice into the peritoneal cavity takes place because of disruption of the pancreatic ducts, above all in chronic alcoholics (Donowitz et al. 1974; Cameron 1978). This may happen both in the absence of any symptom and after an acute relapse, probably because of free leakage from necrotized areas into the peritoneal cavity and/or into the retroperitoneal space (Pacifico et al. 1971). Once other causes and types of ascites have been excluded, all efforts should be aimed at detecting the origin of the ascites, chiefly a cyst (US, CT) and the site of the leakage (ERCP) (Davis and Graham 1975, Rawlings et al. 1977; Levine et al. 1977). This procedure is invaluable in the selection of surgically treatable patients, shortens the period of collection of "pathologic" data, and helps with surgical strategy (Sottomayor et al. 1978; Sankaran and Sugawa 1979), as we ourselves have recently observed in two cases of pancreatic ascites with free leakage into the peritoneum. Where the existence of a cyst and an increasing peritoneal accumulation of fluid are not observed and a carcinoma of the pancreas has been ruled out, one may try a conservative treatment by inhibition of pancreatic secretion, administration of diuretics, and total parenteral nutrition for 2-4 weeks. Even if this treatment has succeeded in 40%-60% of the cases, its mortality rate reaches as high as 20%-30% (Hotz et al. 1977; Cameron 1978). Therefore, as soon as the signs of failure are detectable (i. e., loss of weight, peritoneal fluid accumulation requiring several ascites draining, sepsis), immediate surgery is needed in order to correct the anatomic cause ofthe ascites. However, a 2-3 weeks TPN period could be attemted in order to improve the general condition of the patient and reduce the surgical risk. Radiation therapy has occasionally been successfully employed before surgery (Gambill et al. 1960; Kavin et al. 1971), but it should be taken into consideration only for individual patients with a very high surgical risk.

Obstructive jaundice is considered another classical indication for surgery in chronic pancreatitis. In the natural history of the disease about one-third of the patients show jaundice (Sarles et al. 1965, 1976). However, in most cases it means slight to moderate hyperbilirubinemia in the presence of a painful relapse. Jaundice lasts 7-10 days and is not associated with shudder and/or fever. Actually, persistent obstructive jaundice seldom occurs, therefore it is a correct indication for operation only in a small percentage of cases. On the other hand, edema of the head of pancreas together with a transient stenosis of the intrapancreatic common bile duct or an alcohol-induced acute or chronic liver damage should account for moderate jaundice occurrences.


The presence of an acute or chronic alcohol-induced hepatic damage has been assessed in about one-third of our patients, but its frequency is even higher (60%) when such liver damages are systematically searched for (Dutta et al. 1978). In most patients lesions are made up by fatty liver or alcoholic hepatitis, while liver cirrhosis is considered to be unusual (Sarles et al. 1965; Strum and Spiro 1971) (about 5% in our series). However, Dutta et al. (1978) found a figure as high as 33% of confirmed liver fibrosis and/or cirrhosis in patients with chronic alcoholic pancreatitis. Although chronic cholestasis, even if moderate, may increase the risk of biliary cirrhosis (Leger et al. 1972; Warshaw et al. 1976), in our series of313 patients this complication has never been observed, in accordance with other findings (Sarles and Sahel 1978). Besides, in nonoperated patients, acute cholangitis seems to be exceptional, even in the presence of an evident stenosis of the common bile duct. Acute cholangitis has been observed only in three of our patients (all had previously undergone choledochojejunostomy), one of which died of sepsis. In any case, where cholestatic jaundice is not accounted for by a painful relapse or an acute liver damage, one should reach full differential diagnosis of jaundice by means of the most suitable techniques and investigative tests. Another indication for surgery is a doubtful diagnosis, chiefly pancreatic cancer. Except for an ampullary neoplasm, which can easily be diagnosed by endoscopy (Cotton et al. 1978) and surgically treated with an acceptable survival rate, pancreatic cancer is one of the hardest dilemmas in gastroenterology and a diagnostic challenge. Unfortunately there is little clear-cut information about the relationship between cancer and chronic pancreatitis, and it is quite difficult to tell whether cancer is actually subsequent to chronic pancreatitis. However, a few individual cases of chronic pancreatitis (even surgically treated) have been reported in which cancer of the pancreas had "developed." In our experience, out of 322 patients diagnosed as chronic pancreatitis, 9 were in fact affected by cancer. The study of clinical history and the postmortems suggested in only two cases that cancer might be subsequent to pancreatitis. Experimental investigations in animals, studies on duct epithelial pathologic changes in chronic pancreatitis, and analysis of risk factors (Morgan and Wormsley 1977) might enable us to link the two diseases to a certain extent, but there is no proof that chronic pancreatitis increases the risk of cancer development. However, since nobody can possibly quantify such a risk, it is difficult to have a general policy and all efforts should aim at improving diagnostic tools. As a matter of fact, the main problem lies in early detection of resectable cancer, which is faced by an almost invincible obstacle since symptoms and signs are quite often vague and/or late (Limburg and Roos 1979). Unfortunately diagnosis is confirmed too late, particularly if it is associated with chronic pancreatic lesions. Cancer associated antigens detection have not supplied satisfactory results and studies on inhibition of leucocyte adhesivity gave interesting, but partial, improvement (Taguchi 1978). The latest investigation methods, such as the trypsin/ creatinine ratio (Lake-Bakaar et al. 1979) and the assay of trypsin and lactoferrin on the pure pancreatic juice collected by ERCP (Fedail et al. 1978), might be able to improve differential diagnosis between chronic pancreatitis and cancer of the pancreas. Cytology of pure pancreatic juice is described as being capable of up to 90% correct diagnosis (Osnes et al. 1975, 1979), particularly when associated with


brushing endoscopic techniques. However, its diagnostic capacity is less efficient when cancer is in the distal portions of the gland. US is widely used in cancer diagnosis, because of its capacity to both detect the disease (Berger et al. 1979; Johnson and Mack 1978) and sometimes to spot it when it is still resectable. US is found to be more accurate than CT (Barkin et al. 1977; Braganza et al. 1978; Mackie et al. 1979). In fact, CT cannot easily make out the density of cancer tissue and that of normal pancreatic parenchyma (Holm et al. 1977; Wittemberg and Ferrucci 1978). CT is suitable for detecting capsular and extracapsular spreading with involvement of regionallymphnodes. Unfortunately these are signs of a nonresectable cancer. Moreover, US and CT are liable for false positive results in the presence of chronic pancreatitis (Fitzgerald et al. 1978; Berger et al. 1979).

ERCP is another test widely used in cancer diagnosis. The presence of stop, roughness, and encasement of pancreatic ducts are the main signs of cancer (Cotton 1977; Kruse et al. 1978). Its accuracy is agreed to be satisfactory (82%-89% correct diagnosis) (Hotz et al. 1977; Osnes et al. 1979; Mackie et al. 1979) provided the endoscopist is experienced, the duct system is involved, to some extent at least, but decreases where cancer lies in the tail of the pancreas. Moreover, in our hands at least, it has never been possible to detect cancer by means of ERCP alone when it was "implanted" on chronic pancreatitis. When US, CT, and ERCP techniques were not available, angiography was regarded as the main tool to be used in pancreatic cancer diagnosis. Although it can also detect small sized lesions (Suzuki et al. 1972), angiography is responsible for a significant number of false positive and negative results (Gortenuti et al. 1978; Fitzgerald et al. 1978; Mackie et al. 1979), but it is useful in detecting a nonresectable cancer where extrapancreatic vessels appear to be involved. It is generally agreed that the 75Se-scintiscan no longer has any diagnostic value; in fact, it takes the lowest rank in the scale of diagnostic techniques of pancreatic cancer (Mackie et al. 1979), even if some authors claim a certain usefulness for this procedure (Barkin et al. 1977). On the other hand, the high percentage of false positive and false negative results have suggested also dismissing scintiscan technique in the diagnosis of chronic pancreatitis (Tori et al. 1975). However, some technical devices (longitudinal multiplane emission tomography LMET) would seem to allow diagnosis of resectable cancer in individual cases (Hall et al. 1977). A neoplastic tissue pathologically confirmed should represent the most reliable criteria in the diagnosis of pancreatic cancer and in the differential diagnosis between cancer and chronic pancreatitis. For this reason, several efforts have been made to preoperatively detect cancer by thin needly biopsy of the pancreas and cytologic examination of the aspirate (Oscarson et al. 1972; Tylen et al. 1976; Hancke et al. 1975) which allow correct diagnosis in 72%-87% of the cases. However, since this technique implies that cancer lesions are spotted by US and angiography, Bodner (1979) and Dekker and Lloyd (1979) suggest an explorative laparotomy and multiple thin needle biopsies ofthe pancreas and extemporaneous cytologic evaluation of the centrifugate to be executed. In their hands, this method was successful in over 90% of the cases without any risk and is considered the most reliable in differentiating cancer from chronic pancreatitis.


Therefore, preoperative diagnosis of pancreatic cancer lies in the association of different investigation methods such US, ERCP, CT, and angiography which allow us to know different and complementary pathologic aspects of the disease and its resectability. A reasonable approach would be represented by US followed by ERCP (DiMagno 1977; Go and Sheedy 1978). Unfortunately, results of surgery in pancreatic cancer are still discouraging, but some improvement in the mortality rate has been reported by Bergstrand et al. (1978) and by Moossa et al. (1979) by a more aggressive diagnostic and surgical approach. In the management of chronic pancreatitis and, to some extent at least, in choosing therapy, a few associated diseases should be searched for and taken into account. Table 3 shows the frequency of associated diseases (and complications) in our series of 313 patients with chronic pancreatitis. The increased frequency of peptic ulcer observed in our patients, independently from digestive insufficiency, could interfere with the evaluation of the origin of the pain. Besides, above all in alcoholics with liver damage and impaired general conditions, an increase in pulmonary tuberculosis has been observed. The frequency of gallstones was not higher than that of the popUlation as a whole, but an increase in extra pancreatic tumors (and pancreatic?) has also been found. Digestive, infectious and metabolic associated diseases should therefore be taken into account in the management of the patients and treated, if possible, before making a therapeutic choice, as far as pancreatitis is concerned.

Table 3. Associated diseases or complications observed in 313 patients with chronic pancreatitis

Duodenal ulcer Gastric ulcer Biliary stones Liver cirrhosis Obstructive jaundice Acute cholangitis Pseudocyst or cyst Pancreatic ascites Diabetes Arteriosclerosis Pulmonary tuberculosis Pancreatic cancer Extrapancreatic tumors

No. of cases

58 5

30 18 17

3 48

3 90 14 17

2 4

%

18.53 1.59 9.58 5.75 5.43 0.95

15.33 0.95

28.75 2.87 5.43 0.68 1.27

The therapeutic approach is based on both clinical data and adequate knowledge of the anatomy of the affected pancreas and of other organs which might be involved in the disease through a rational radiologic and endoscopic investigation. ERCP is a compulsory guide as far as surgical strategy is concerned. In addition, ERCP might also sometimes be helpful with the decision between a surgical or a medical treatment. In fact, when there are no compulsory indications for surgery and the analysis of the behavior of the pain doesn't allow one to detect a definite


indication for operation, the absence of a widened Wirsung duct found by ERCP (13% of the patients in our series) may suggest delaying the operation. In individual cases monitored with ERCP, the Wirsung duct progressively widened in about 2 years. The choice of the right time for surgery may not be so easy since there aren't any safe data available which help by stating strict criteria. On the other hand, Amman et al. (1979) find that pancreatic insufficiency is associated with significant pain relief. Therefore, in some cases at least, a reasonable attitude might consist in following the clinical evolution of the disease keeping in mind that any worsening of life conditions should be avoided. Summing up, the therapeutic choice in chronic pancreatitis is essentially based on clinical criteria and data, which are sometimes attainable only with a careful long-term observation of the patient. The quality of such choice is improved by radiologic and endoscopic studies, which are undoubtedly useful in the surgical strategy.

References

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Berger LA, Rhodes JM, Agnew JE, Harrocks RA, Chudleigh PM, Elias E, Summerfield JA (1979) Screening for pancreatic disease: a comparison of grey-scale ultrasonography and isotope scanning. Lancet 1 :633-635

Bergstrand 0, Ahlberg J, Ewerth S, Hellers G, Holmstrom B (1978) A retrospective study of carcinoma of the pancreas with special reference to the result of surgical treatment. Acta Chir Scand 482:26-28

Bodner E (1979) Diagnostica citologica intraoperatoria. Primo Congresso Intemazionale Interdisciplinare su "Bilancio Clinico delle Pancreopatie". Padenghe suI Garda, Italy, September 14-15th

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Cameron JL (1978) Chronic pancreatic ascites and pancreatic pleural effusions. Gastroenterology 74:134-140

Carilli J, Faris TD (1967) Pancreatic pseudocysts: delayed versus immediate treatment. Surgery 61:541-543

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Durbec JP, Sarles H (1978) Multicenter survey of the etiology of pancreatic diseases. Relationship between the relative risk of developing chronic pancreatitis and alcohol, protein and lipid consumption. Digestion 18:337-350

Dutta SK, Mobrahan S, Iber FL (1978) Associated liver disease in alcoholic pancreatitis. Am J Dig Dis 23:618-622

Fedail SS, Salmon PR, Harvey RF, Brown PB, Read AE (1978) Radioimmunoassay of trypsin in pure pancreatic juice. Gut 19:A445

Fitzgerald PJ, Fortner JG, Watson RC, Schwartz MK, Sherlock P, Benua RS, Cubilla AL, Schottenfeld D, Miller D, Winawer SJ, Lightdale CJ, Leidner SD, Nisselbaum JS, Menendez-Botet CJ, Poleski MH (1978) The value of diagnostic aids in detecting pancreas cancer. Cancer 41:868-879

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Go VLW, Sheedy PF (1978) Ultrasonography, computed tomography, endoscopic retrograde cholangiography and angiography in the diagnosis of pancreatic cancer. Med Clin North Am 62:129-140

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Hall TJ, Cooper M, Hughes KG, Levin B, Skinner DB, Moossa AR (1977) Pancreatic cancer screening. Analysis of the problem and the role of radionuclide imaging. Am J Surg 134:544-548

Hancke S, Holm HH, Koch F (1975) Ultrasonically guided percutaneous fine needle biopsy of the pancreas. Surg Gynecol Obstet 140:361-364

Holm HH, Smith EH, Bartrum RJ (1977) The relationship of computed tomography and ultrasonography in the diagnosis of abdominal disease. J Clin Ultrasound 5:230-237

Hotz J, Goebell H, Herfarth C, Probst M (1977) Massive pancreatic ascites with carcinoma. Report of three cases. Digestion 15:200-216

Johnson ML, Mack LA (1978) Ultrasonic evaluation of the pancreas. Gastrointest Radiol 3:257-266

Kavin H, Sobel JD, Dembs AJ (1971) Pancreatic ascites treated by irradiation of pancreas. Br Med J 2:503-504

Kruse A, Thommesen P, Frederiksen P (1978) Endoscopic retrograde cholangiopancreatography in pancreatic cancer and chronic pancreatitis. Differences in morphologic changes in the pancreatic duct and the bile duct. Scand J Gastroenterol 13:513-517

Lake-Bakaar G, McKavanagh S, Summerfield JA (1979) Urinary immunoreactive trypsin excretion: a non-invasive screening test for pancreatic cancer. Lancet 2:878-880

Leger L, Lemaigre G, Roscan E, Lenriot JP (1972) Les lesions hepatiques des pancreatites chroniques: 50 observations. Nouv Presse Med 1:2159-2163

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Sarles H, Sahel J (1978) Cholestasis and lesions of the biliary tract in chronic pancreatitis. Gut 19:851-857

Sarles H, Sarles JC, Camatte R, Muratore R, Gaini M, Guien C, Pastor J, LeRoy F (1965) Observations on 205 confirmed cases of acute pancreatitis, recurrent pancreatitis and chronic pancreatitis. Gut 6:545-559

Sarles H, Payan H, Tasso F, Sahel J (1976) Chronic pancreatitis, relapsing pancreatitis, calcifications of pancreas. Part I. Pathology. In: Bockus HL (ed) Gastroenterology. Saunders, Philadelphia, p 1040

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Sottomayor M, Nom Chong R, Dawson M (1978) Use ofERCP in the diagnosis of internal pancreatic fistula. Gut 19:244-246

Strum WB, Spiro HM (1971) Chronic pancreatitis. Ann Intern Med 74:264-277 Suzuki T, Kawabe K, Imamura M, Hanjo I (1972) Survival of patients with cancer of the

pancreas in relation to findings on arteriography. Ann Surg 176:37-41 Taguchi K (1978) Immunologic detection of primary carcinoma of the pancreas. Can J

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test par la secn':tine-pancn':ozymine dans l'exploration fonctionnelle du pancreas exocrine. J Radiol Electrol Med Nucl 56:521-523

Tylen U, Arnesjo B, Lindberg LG, Lunderquist A, Akerman M (1976) Percutaneous biopsy of carcinoma of the pancreas guided by angiography. Surg Gynecol Obstet 142:737-739

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Intraoperative Cytodiagnosis in Pancreas Disease

E. Bodner

II. Universitatsklinik fUr Chirurgie, Anichstrasse 35, 6020 Innsbruck, Austria

The purpose of a biopsy is the microscopic clarification of tumorous alterations, which cannot be assessed clinically nor macroscopically, for adequate therapeutic treatment. In particular, the purpose is to ascertain the diagnosis of real tumors thus leading to the indication for radical surgery. A biopsy procedure can fulfill this purpose only if it enables an exact determination, made quickly enough, without further considerable strain or the possibility of serious complications. The time available for intraoperative use in the sense of a rapid diagnostic procedure is about 20 min. Applying these criteria to cases of pancreatic tumors we have to base our considerations on the fact that with a certain size of alteration it is not the histogenetic nature but only the technical resectability that is decisive in the choice of the operative procedure. According to general opinion, every big tumor formation indicates by itself resection independent of whether chronic pancreatitis or a real neoplasm is the cause of the tumor. Furthermore an experienced surgeon is in such cases almost always able to make a correct diagnosis intraoperatively based on the exact history, the clinical picture, the initial fmdings, and on the particular nature of morphological alterations. A clarification based on a biopsy is therefore not necessary. However, in cases of discrete tumor formation or in cases of mere hardening of a certain area of the pancreas, as can occasionally be found as accidental result at laparatomy, the correct clinical evaluation can be extremely difficult or even impossible. The various very valuable methods of modem preoperative pancreatic diagnosis can only register in such cases the localization but not the nature of the alteration. The more such early stages, due to these examination procedures, are allocated to surgeons for operative clarification (we have to aim at that objective for better prognosis of pancreatic carcinomas) the more important it will be to have suitable biopsy methods at hand. We think that the indication for resection of the pancreas is limited by the size of the alteration in as far as with small tumors not the quantity but only the quality of the pathologic process is decisive. An inflamed hardening of the head of the pancreas cannotjustify its resection because of the still high short- and long-term lethality of duodenopancreatectomy. The smaller the size of the pancreatic tumor formation the more the choice of the correct operational procedure depends of the safe diagnosis. Although many renowned authors argue against carrying out pancreas biopsies despite these points, this must not be considered a curtailment of the practicality of microscopic tumor diagnosis; this attitude is mainly due to the negative experi-

184 E. Bodner

ences which have often occurred with conventional pancreas biopsies (wedge excision but also the Silverman biopsy). Because of the low rate of accuracy, a high rate of complications, and the uncertainty of the frozen microscopic evaluation these procedures have found only few supporters.

Methods

We started the development of the cytodiagnostic procedure of the fine needle biopsy taken from the pancreas 8 years ago. Experiments had to be collected concerning the extraction of the tissue as well as the cytodiagnosis as such. The question was to what extent representative tissue material from the pancreas can be obtained by means of the fine needle biopsy. Puncture technique with the risks of complications had to be tried out. The pathologist developed suitable preparation and dyeing methods for the biopsy material. By comparing with histologic controls the diagnostic value of pancreatic cytology was tested.

Technique of Fine Needle Biopsy

We use a holding device as shown in Fig. 1 and a syringe topped with a needle as used for puncture of the veins, size 2. This instrument has the advantage that it can be held with only one hand so that the second hand can fix the previously mobilized altered section of the pancreas in order to localize the tumor area. From any direction, if necessary even through neighboring organs such as the duodenum, the tumor is punctured and substantially aspired. After waiting for a pressure balance the instrument is drawn back in order to put the aspired material on to an object slide and to spread it there. The slide is put into a vessel contain-

Fig. 1. Instrument for fine needle biopsy

Intraoperative Cytodiagnosis in Pancreas Disease 185

ing ether alcohol for fIxation. We carry out in any case between four and eight biopsies. All the slides - which in the meantime have been fIxed - are taken to the pathologic department and are dyed immediately by means of a time saving modifIed Papanicolaou procedure. Thus within 15 min the cytologic fmdings can be reported via telephone.

Microscopic Assessment

Microscopic assessment is carried out (because often larger cellular formations are aspired) both according to cytologic and histologic criteria. Most of the tumorous growths of the pancreas have proved to be clearly determinable and the fmdings are therefore of high diagnostic value. In cases of chronic pancreatitis mainly ductular epithelia and inflammed cells are to be found. However, in cases of severe fIbrosis sometimes only cell-detritus or blood can be obtained, which prevents a defmite diagnosis. The evidence of foreign-body-giant-cells indicates with great likelihood the primary inflammatory genesis of the tumor. Atypical cells are of decisive diagnostic importance in proving a malignant growth. Difficulties in the assessment can arise in cases of highly differentiated carcinomas and in cases of carcinomas of island cell type. Our experience so far shows that mesenchymal tumors such as sarcoma metastases of the pancreas can also easily be registered cytologically.

Material and Results

Out of a total of 181 patients to whom fIne needle biopsy was applied up to the end of Apri11979 we have excluded 29 from the assessment because the correctness of the cytologic report could not to be verifIed. In 152 cases the diagnosis was mainly proved histologically by procedures shown in Table 1.

Table 1. Intraoperative fine needle biopsy of pancreatic lesions

Cases total Diagnosis not proven Diagnosis proven

Histologically by Total duodenopancreatectomy Whipple operation Hemiduodenocephalopancreatectomy Subtotal left resection (95%) Left resection Test excision from tumor Test excision from metastasis Autopsy

Clinically by Metastasis of liver Course (more than 3 years)

3 46

2 3

17 20 32 7

4 18

181 29

152

186 E. Bodner


Cases total 181 Diagnosis proven 152 100.0% Cytologic result

Correct positive 92 60.5% Suspect 11 7.2% False positive Correct negative 32 21.2% False negative 9 5.9% Cannot be judged 8 5.3%

Total correct cytologic results 135 88.8%

The results of the total material are analyzed in Tables 2-4: 135 times, that is 88.8% of all cases the cytologic assessment was in agreement with the fmal diagnosis. We have not so far obtained a false positive result. Five of eight cases which did not contain suitable cells for differentiation had chronically inflamed tumors.


Not Diagnosis proven Cases Pos. Susp. Neg. judg.

Carcinoma of pancreas or periampullary regiona 84 71 6 4 3 Highly differentiated 7 2 3 2 Islet cell type 4 2 1 1

Carcinoma of papilla 6 4 2 Intrapancreatic metastasis (Ca, Sa) 5 5 Neurofibrosarcoma (duodenum) 2 2 Retropancreatic tumors (NN, Meta) 7 6 1 Chronic pancreatitis 37 32 5

Cases total 152 92 11 41 8

a Histologic carcinoma type: polymorphous, indifferent, anaplastic, scirrhous, adeno-. cystadeno-. mucous

Table 3, in which the results are divided according to the different tumor types, shows the lower rate of diagnostic accuracy in cases of highly differentiated pancreatic carcinomas, for example, in the island cell type and naturally also in cases of tumors of the papilla - as a result of a wrongly localized puncture. Furthermore we found out that cytodiagnosis also enables a differentiation of unusual pancreatic tumors such as metastases of an oat cell bronchus carcinoma in which the cytologic assessment referred to a tiny cell malignant tumor that was not of the type of the primary pancreatic carcinoma. Metastasis of a malignant fibroma of os ischium in the pancreas as well as a neurofibrosarcoma of the duodenum are examples that show that mesenchymal tumors can be diagnosed.

Intraoperative Cytodiagnosis in Pancreas Disease 187

Discussion

The accuracy of modem diagnostic procedures for the pancreas is demonstrated almost always in only incurable cases. Therefore we have deliberately separated all resectable malignancies in our patient series. Also in such cases the diagnostic accuracy of the fme needle biopsy is very high as can be seen in Table 4: in 40 out of 44 patients atypical cells were to be found. Several times we were able to find extremely small carcinomas, which would not have been detected by means of a conventional biopsy without risk of damage because of its localization.

Table 4. Intraoperative fine needle biopsy with resectable pancreatic malignancies

Cases total

Cytodiagnostic result Correct positive Suspect Incorrect negative

44

36 4 4

In order to get test results of this method based on a large number of patients we have - as can be seen in Table 1 - also puncturated clinically defmite malignancies. The pathologist was not informed of the diagnosis obtained operatively beforehand. In 34 patients, however, the alteration of the pancreas was not classified intraoperatively either in spite of the extensive experience of the surgeon. In this group 19 proven correct diagnoses stand opposite 5 wrong negative results (Table 5).

Table 5. Intraoperative fine needle biopsy with clinically unc1assificable pancreatic lesions

Diagnosis not proven

Diagnosis proven

Cases total

Cytologic result

Positive Negative Correct positive Correct negative False positive False negative Cannot be judged

Cases

2 8 6

13

5

34

We are aware that in cases of pancreatic carcinoma only the positive report, which means that the evidence of atypical cells is a diagnostic proof. Negative results do not exclude a carcinoma. The cytologic negative report may in many cases strengthen the clinical impression. Only in one case of an incorrect negative

188 E. Bodner

result we have lost valuable time for the patient. On the other hand since the introduction of the fme needle biopsy no duodenopancreatectomies have been carried out because of a presumed pancreatic carcinoma, in which the histologic examination afterwards had shown only inflamed alterations which would not have justified a resection according to their size. Such cases can be found in our earlier material. The intraoperative cytologic diagnosis of tumors of the pancreas by means of fme needle biopsy doubtless plays a less important role in cases of chronic pancreatitis than with carcinomas. As the procedure proved to be without any complications at all - in altogether 110 patients, whose altered section of the gland was not resected after several punctures but left in situ, neither pancreatic fistulas nor serious postpuncture bleeding or acute pancreatitis occurred - we consider the fine needle biopsy in the sense of the definition made at the beginning a quite adequate and the safest biopsy procedure presently available for intraoperative differentiation of pancreatic tumors. All conventional methods are inferior at least because of their risk of complications. Because of the harmless execution of any number of punctures the pancreas can also be examined section by section, which is rather important with regards to a possible formation of carcinoma stemming from chronic pancreatitis. Thus in diagnostically doubtful cases this procedure can indicate the correct treatment.

General Remarks to Chapters 19-21

F. Gschnitzer

I. Universitatsklinik fUr Chirurgie, Allgemeines Krankenhaus, 6020 Innsbruck, Austria

Today chronic pancreatitis, and its various progressive forms, is more commonly observed than in the past. This is due to an increase of this disease and is not a result of improved diagnosis. Improvement of diagnosis is only related to better morphological differentiation by sonography, computed tomography, and endoscopic retrograde pancreatography but not by refinement of laboratory methods. Because of these refinements in morphological diagnosis, essentially brought about by the pre- or intraoperative exploration of the pancreatic duct, new surgical methods have been developed in the last two decades which have expanded the surgical and therapeutic capacity to treat this disease. We will be informed in this meeting by various experts in this field about their findings obtained with different surgical procedures. Surgical treatment pursues two essential goals: (1) restoration of the drainage of pancreatic secretion into the intestine from the obstructed gland area reached by removing calculi, and performance of a pancreaticojejunostomy or drainage of pseudocysts into the small intestine; (2) the other procedure is based on the principle of resection of the afflicted area: left resection, right resection, 95% resection, and finally total pancreatectomy as the most radical procedure. This radical method stops further progression of the illness, but requires a permanent substition of ex- and incretoric gland function, which is stressful and dangerous for the patient. Because of this and because of the considerable operational lethality, indications for total pancreatectomy are extremely limited. Certainly one should in certain cases use radical and derivative combined operational methods. Here, one must stress that the oldest operational technique, which in the past years was not taken seriously, the pseudocystojejunostomy, has proven when correctly used to have an astonishing effect. Especially experienced and internationally known surgeons of these principally different operational methods will now hold the introductory reviews: Prof. Marzoli will report on the secretion drainage operations, Prof. Pichlmayr will speak about findings from organ resections. Prof. Dagradi will review the indications, tactical procedures, and the limitations of the surgical methods of chronic pancreatitis and this will be followed by several reports of experiences in Italian and German clinics. We can expect that these reports will be followed by lively discussion. It is not possible in such a short time to present an overall description of all surgical possibilities. So we can keenly await the time when experiences with duct occlusion, as a possible therapy, will be reported. This method has passed the clinical trial and

190 F. Gschnitzer

can be used alone or in combination with resective methods in chronic pancreatitis as well as in pancreas transplantation. This is a wide scope of indication for the future. We will also hear of experience in operations on the nervous system. Operational methods for the treatment of choledochus stenosis should not be discussed in this session. Its indications, as well as the drainage of the gall duct in cases with calculi are not open for discussion. During this session, we should be able to get a clear picture of the present position of surgical treatment of chronic pancreatitis and hear about its future trends. We can expect that the direction toward organ preservation, as seen in the last few years, will be continued.

The Pancreas-Jejunal Shunts

G.P. Marzoli

Istituto di Clinica Chirurgica, U niversita di Padova, Sede in Verona, Policlinico B. Roma, 37100 Verona, Italy

The main aim of the surgical therapy of chronic (relapsing) pancreatitis (CRP) is to relieve pain. Since the pancreas is extensively affected by progressive fibrosis [3,4, 28, 32] also involving the biliary system [19], complete anatomic and functional recovery is not possible [3, 17, 35]. There is indeed little clinical [9, 25] or experimental evidence in favor of an improvement of CRP after internal drainage procedures, as proven by ERCP findings after drainage surgery. The progressive fibrosis makes it difficult to carry out ERCP [1, 18], which shows progressive changes of the pancreatic duct system [18, 29]. Nevertheless, even without improvement, there are reasons [3, 20] for stating that the wide drainage of the pancreatic duct, relieving obstruction, may lessen the fibrotic evolution of CRP. This is suggested by the reduction or by the disappearance of calcifications or by the reduction of the diameter of the duct of Wirsung, when seen on ERCP [1, 29]. The preservation of endocrine parenchyma, the hope of delaying the fibrotic evolution of CRP, and the clinical observation [25] that pain resolves after spontaneous formation of an external fistula, all these considerations lead to the rationale for surgical internal drainage as the chief procedure in the treatment of CRP. Cattel (1947), Zollinger (1954), and DuVal (1954) first recommended the internal drainage of the duct of Wirsung for the control of pain in CRP. The DuVal procedure implies the mobilization of the spleen and of the tail of the pancreas, the splenectomy, the excision of the tail of the pancreas (3-4 cm), and the end-to-end anastomosis of the pancreatic stump to the stomach or to a Roux-en-Y loop of jejunum. Puestow and Gillesby [26] obtained a better control of pain by means of a wide opening of the duct of Wirsung (after splenectomy and excision of the tail of the pancreas) throughout the length of the duct until all strictures have been overcome; the Wirsung duct is then anastomosed to a Roux-en-Y loop of jejunum. Partington and Rochelle [22] describe an amelioration of the Puestow procedure: They do not perform the splenectomy and the excision of the tail of the pancreas and only incide as far as possible the pancreatic duct, thus reducing the biologic weight of the procedure (Fig. 1). The choice between the DuVal, Puestow, and the Partington-Rochelle procedure may be also conditioned by peculiar localizations of the disease, e. g., a caudal pseudocyst may indicate the excision of the tail of the pancreas.

192

Partingt on Rochelle

Puestow-Gi llesby

Fig.1. Diagram showing the different pancreaticojejunai procedures

G. P. Marzoli

Our experience avails of both procedures: they, however, do not seem comparable in terms of mortality, morbidity, and therapeutic value. The reasons are the lesser drainage attitude [35] and the different biologic weight of the DuVal procedure, which endangers endocrine function and implies a major intervention such as splenectomy. For these reasons we shall describe our experience and our results only for the Partington-Rochelle procedure. At the surgical clinic of the University of Padua, in Verona, starting from 1969, we operated upon 230 patients for CRP. There were 162 cases involving internal drainage procedures, 98 of which were Partington-Rochelle procedures. The male/female ratio was 9/1; the m/f ratio in others reports is as low as 1/1 [32]; this is possibly due to different social behavior. Only 5 patients were abstemious; the mean alcoholic consumption in the other patients was 110 g/day. The mean age was 43 years, and the interval from the beginning of symptoms was 3 years (mean).

The Pancreas-Jejunal Shunts 193

Thirty three per cent of the patients had had previous surgery: 17% biliary, 11 % gastric, and 5% pancreatic surgery. The literature also refers to high percentages of previous surgery: White and Slavotinek [35] in 48% of their cases (40% of which on the biliary system), Sato et al. [29] in as much as 81%, Prinz et al. [24] in 30% (half of which on the biliary system). In 43% of the cases it has been possible to demonstrate pancreatic calcifications; this frequency is similar to the quoted frequencies: Lawrence 42%, DuVal and Enquist [8] 57%, White and Slavotinek [35] 44%, Puestow and Gillesby [26] 50%, Prinz et al. [24] 51%, Traverso et al. [32] 39%, Way et al. [34] 42%. Leger et al. [20, 21] refers to a very high incidence of pancreatic calcifications, 68%. The calcifications in CRP, evaluated as an index of the fibrosis [31], have an important prognostic value. Many authors [3, 7, 20, 24, 32, 33] point out that the better results of drainage procedures are seen in presence of calcifications, and Jordan states that good results are achieved in a calcified pancreas three times more frequently then in noncalcified ones.

Fig. 2. Operative pancreatography. To be noted: the dilatation of the main and of the secundary ducts, the prepapillary stenosis and the intraductal calcifications

The main prancreatic duct in our cases was alway enlarged (Fig. 2), the diameter being larger than 8 mm in all the patients. In 80% of the cases we found a "lakechain" appearance, with dilatation of the canaliculi. In 46% of the cases we found

194 G. P. Marzoli

a stenosis of the preampullar portion of the main duct and in 18% of the cases there was difficult drainage. The operative radiographic exploration of the duct ofWirsung is mandatory [16]; in our experience this in feasible in nearly all the cases by means of direct injection of the contrast into the duct. In other series [17] there is a reported quote of 60% failures: the operative pancreatography is then obtained by means of a caudal cannulation of the duct. In our opinion the ERCP has mainly diagnostic value and cannot be used as a guideline for surgical tactics. The operative demonstration of pancreatic duct distension is the main indication for an internal drainage procedure [22, 24, 26, 37]. We agree with the "Wirsung's rule" [21], which denies the usefulness of the sideto-side internal drainage procedures when the diameter of the pancreatic duct does not exceed 8 mm, because of the time limited benfits of the derivation in such circumstances. The distension of the pancreatic duct, which in turn signifies the advanced fibrotic evolution of CRP, is a sign of reliance upon the future anastomosis [22] and is of prognostic value since the wider the duct, the better the results of the drainage procedures [20, 34]. The pancreatic pseudocysts - which express the troubled evolution of CRP [15, 23]- were found in 48% of our cases. Similar figures are quoted elsewhere [20, 28, 34], while other authors found smaller figures: Prinz et al. [24]21%, Sato et al. [29] 22%, White and Slavotinek [35] 28%, Traverso et al. [32] 32%. In 70% of our cases [30] it has been possible to find - on operative pancreatography - a direct communication between the pseudocyst and the main duct. In the majority of the cases the pseudocysts did not get beyond the pancreatic outline. In the Sarles' series two-thirds of the pseudocysts are within the pancreas; similar figures were found by other authors [20, 37]. In recent years, the many published cases of spontaneous regression or resolution of pancreatic pseudocysts have added confusion to the problem of the surgical tactics in CRP in the presence of even a single pseudocyst [5, 10, 23]. It is a difficult clinical problem to assess the "age" of a pseudocyst [9], nevertheless this is important because after 6 weeks from onset there is no longer spontaneous resolution of the pseudocyst [5, 12]. Thus "chronic" pseudocysts deserves surgical management insofar as up to 70% of them complicate within 13 weeks from the diagnosis [5]. The complication rate increases with the increase (over 5 cm) of the diameter of the pseudocyst [37]. Hemorrhage complicates the pancreatic pseudocysts in 15% of the cases [12] and this danger is greater in the presence of pseudaneurysms, with an overall mortality of 60% [9]. Dagradi rightly points out that one cannot omit the drainage of pseudocysts together with the drainage of the main duct [6, 15, 35]. Indeed there are better results when surgical drainage also extends to the pseudocysts [34]. In 50% of our cases the pancreatic fibrotic process also involved, to various extents, the bile duct (Fig. 3). The literature presents similar figures [2, 28], but there are authors [7, 29, 32] who refer to figures varying from 10% to 20%. From these data it is evident that a careful operative exploration of the biliary system is mandatory. In 33% of our cases it has been necessary to perform a biliary drainage (simple sphicterotomy or choledocostomy). A duodenal ulcer was found in 11% of our patients; similar figures are reported elsewhere [34].


Fig. 3. Common bile duct dilatation. Calcifying CRP compresses the distal choldedochus

195

In 8% of our cases we found the splenoportal axis involved by the pancreatitic process. These forms of regional portal hypertension are rarely symptomatic (only three of our cases required a splenectomy) and are more often seen in the presence of calcifications [27].

Surgical Procedure

The laparatomic access must be wide, and we adopt a bilateral subcostal incision (after West). This incision and the use of a Rochard retractor give an optimal exposure of the pancreas. The next step is the pancreatography which is nearly always feasible by means of direct injection. It is to be remembered that the main duct runs into the depth, alongside the posterior surface, of the pancreas [22]; it is then necessary to overcome the fibrotic resistance of the gland. It is recommended that the needle is inserted into the duct of Wirsung, or into an enlarged secondary duct when one can observe the overflow of drops of a clear fluid. Once the ductal pattern is found, which requires an internal side-to-side drainage, the duct of Wirsung is opened longitudinally - cutting the overlying parenchyma with the electric bistoury - as far as the knee of the duct of Wirsung, which is, from the functional point of view, the Achilles' heel of the pancreatic ductal system [4, 32] (Fig. 4). Such an incision often requires the ligature section of the ar-

196 G. P. Marzoli

Fig.4. a) The incision of the main duct takes place in the site of contrast injection; b) incision of the main duct is the widest possible, as far as the Wirsung duct's knee; c) anastomosis completed


teria gastroduodenalis or of the arteria pancreaticoduodenalis superior anterior, which may cross the duct. The incision of the duct of Wirsung must comprise of little pseudocysts communicating with the main duct: they are often cephalic, sometimes belong to the Santorini's system (Fig. 5). The great pseudocysts which

Fig. 5. The incision of the duct ofWirsung is extended to a little intraparenchymal pseudocyst to allow a complete drainage

extend out of the pancreas, both communicating and not with the main duct, must be drained together with the duct of Wirsung and by means of the same jejunal loop (Fig. 6). The cleansing of the internal surface of the pseudocyst must be gentle: otherwise a hemorrhage may result [15]. The intraluminal band of the pseudocysts must also be sectioned with care: they may contain large pancreatic vessels. The jejunal loop to be anastomosed must be chosen with care, in order to avoid any kinking around the mesentery. The free end of the isolated loop must be anchored to the caudal aspect of the opened duct, as indicated by Partington. Thus, one ensures the better drainage of the jejunal loop. The anastomosis is performed by a single row of non absorbable interrupted sutures; the sutures are seromuscular on the jejunum and bite the capsule and the parenchyma on the pancreatic side. The jejunal mucosal lining and the ductal epithelium are not placed in direct contact. Other authors, e. g., Warren, on the other hand, argue for a two-row suture with an inner row joining together the epithelial surfaces of the duct and of the jejunum. We recommend the ablation of every calcification in the proximal and distal end of the main duct not included in the anastomosis. Of course, the end-to-side jejunal-jejunal anastomosis must be constructed with care, to avoid any tension, compression, or kinking of the mesentery.

198 G. P. Marzoli

Fig. 6. Drainage of a large extrapancreatic pseudocyst together with the Wirsung duct's drainage

Results

In our series we registered only one operative death. Other authors [1, 17, 25] had no operative deaths. Jordan, from a review of some United States series, refers to an operative mortality of 2%; more elevated figures were obtained by Leger et al. [20, 21] (4%) and by Prinz et al. [24] (5%). The overall number of complications in our series was six; in four of these six cases we ought to perform an emergency reintervention. Similar figures are quoted in the series of Proctor et al. [25] (8%) and of Jordan et al. [17] (10%). The postoperative hemorrhages were two: in one patient the hemorrhage arose in the pancreas along the incision line, in the other patient it arose from a pseudocyst, they are perhaps due to tryptic activation by jejunal enterokinases [36] . In the published series, a hemorrhage complicates pancreatic drainage procedures in various amounts, as much as in 8% of the cases [19, 24]. In our series we had three postoperative fistulas: they may be due, as hemorrhages may, to tryptic relapses acting on the pancreatic anastomotic surface. The fistulas often complicate pancreatic internal drainages: 10% of the cases of Jordan et al. [17], 18% and 20% of the cases of sa to et al. [29] and of White and Slavotinek [35]. In one case we had a kinking of the Roux-en-Y loop; in the published results this complication is not rare, White and Slavotinek [35] observed it in 6% of the cases. Late reinterventions were, in our series, 19. In the published series the late reinterventions range from 8% [24] to 40% [20]. The reinterventions on the biliary sys-


Fig.7a-c. Progressive biliary involvement in CRP. a) Preoperative cholangiography; b) the same case 2 years after an internal drainage procedure: the common bile duct is slightly enlarged; c) the same as in A and in B 4 years after the operation: the common bile duct is very enlarged

199

200 G. P. Marzoli

tern were 8: it is an elevated figure explained by the late extension of CRP to the biliary system (Fig. 7); similar or more elevated figures were published: e. g., 20% in the Lamy series. In five of our cases a stenosis of the pancreaticojejunum anastomosis required a reintervention. Anastomotic stenoses are also frequently encountered: as much as in 20% of the cases [20]. It has up to the present date not been understood how much these anastomotic stenoses influence the postoperative clinical fmdings. Some authors think that the anastomotic stenosis does not influence postoperative clinical fmding [17, 18, 24]; on the other hand, someone points out that as much as 50% of reinterventions are due to an anastomotic stenosis [20]. The postoperative ERCP is important in assessing anastomotic patency, but it should be remembered that on ERCP the anastomosis always seems narrower than it really is because the contrast medium outlines only a part of the anastomosis. Patency and wideness of the anastomosis are best assessed by the velocity of defluxion of contrast medium on ERCP, which gives a functional evaluation (Fig. 8). In three of our patients a recidive pseudocyst required a reintervention; in other series this complication amounts to as much as 5% of the cases [36]. In one patient a reintervention was required for mechanical intestinal obstruction, 2 years after the internal drainage procedure. Another patient developed a pancreatic cancer, which was perhaps misdiagnosed during the first operation. The problem of pancreatic cancer in CRP and of its diagnosis is widely debated [35]. Our and other series figures demonstrate that:

1) The fibrotic pancreatitic process may extend to the biliary system even late after an internal drainage procedure.

2) It is important to operate upon a widely enlarged pancreatic duct and to perform wide anastomoses.

Elsewhere in this book (Scuro), the results of the late clinical controls of our cases will be given in detail. Approximately half of our patients were first observed preoperatively by colleagues from the medical clinic, and then were monitered postoperatively at an interval from the intervention ranging 2-9 years (mean 5.3 years). Complete control of pain was obtained in 55% of the cases; a good to moderate control of pain was achieved in 37% of the patients while in 6% pain was unmodified and in 2% it worsened. That means that satisfying results were obtained in 92% of the cases. A review of the published cases shows figures similar to ours. Adloff and Ollier [1] achieve good results in 90% of his cases, Way et al. [34] in 80% at 5 years, Jordan et al. [17] in 80%, Sato et al. [29] in 67% at 5 years, White and Slavotinek [35] in 27 out of31 patients after 9.6 years (mean), Prinz et al. [24] in 83%, Proctor et al. [25] in 96%; Jordan et al. [17], in a collective review of cases published in the United States, refers to good results in 70% of the cases. The better results were achieved in calcifying CRP: Way obtained good results in 93% of calcifying CRP as compared to 76% of noncalcifying CRP and Leger, at 5 years, in 75% versus 48%. On this basis, it would seem that the results of operative treatment of CRP depends on the pathology of the pancreas rather than on the modality of surgical procedure [25, 32]. Most authors point out that the passing of time affects results. [13, 17, 29, 34], thus reflecting the natural history ofCRP and of its fibrotic evolution [1, 3, 20].


Fig. 8. a) Operative cholangio pancreatography: the radiographic appearance indicates the need of a Partington-Rochelle procedure and of a biliary drainage procedure. b) Postoperative ERCP: reduction of the pressure in of the pancreatic ducts; good defluxion of the contrast medium in the jejunal loop

202 G. P. Marzoli

A conclusive balance of the Puestow-Rochelle internal drainage procedures, in our and in most authors' experience may be summarized as follows. The side-toside pancreaticojejunostomies demand defmite indications (pain, enlarged main duct, and calcifications) and defmite technique contrivance. They have a low mortality rate and satisfying results. Their somewhat high morbidity and complication rate may be ascribed to the natural evolution of CRP rather than to surgical therapeutic ineffectiveness. Indeed these internal drainage procedures achieve in the vast majority of the patients the goal of a pain-free life.

References

1. Adloff M, OIlier J-CL (1978) Les pancreatico-jejunostomies latero-Iaterales dans Ie traitement des pancreatites chroniques. Chirurgie 104:214-220

2. Adson MA (1979) Discussion. Ann Surg 189:669 3. Ammann RW, Largiader F, Akovbianz A (1979) Pain relief by surgery in chronic pan

creatitis? Relationship between pain relief, pancreatic dysfunction, and alcohol withdrawal. Scand J GastroenteroI14:209-215

4. Becker V (1973) Bauchspeicheldruse. Berlin Heidelberg New York (Spezielle pathologische Anatomie, vol. 6)

5. Bradley EL, Clements JL, Gonzalez AC (1979) The natural history of pancreatic pseudocysts: A unified concept of management. Am J Surg 137:135-141

6. Dagradi A, Serio G (1976) Considerazioni su 92 casi operati per pancreatite cronica: problemi di tattica chirurgica e risultati a distanza. Chir Triveneta 16:94-119

7. Doubilet H (1958) The physiological basis for the surgical management of acute and chronic pancreatitis. Surg Clin North Am 38:505

8. DuVal MK, Enquist IF (1961) The surgical treatment of chronic pancreatitis by pancreaticojejunostomy: an 8-years reappraisal. Surgery 50:965-969

9. Frey CF (1978) Pancreatic pseudocyst-operative strategy. Ann Surg 188:652-662 10. Gebhardt J, Mundhenk K, Klinggriiff G, Slotty M (1978) Sonographische Langzeit

kontrolle von Pankreaspseudozysten. Dtsch Med Wochenschr 103:1941-1942 11 Gillesby WJ, Pueston CB (1962) Pancreaticojejunostomy for chronic relapsing pancrea

titis: an evaluation. Surgery 50:859-862 12. Grace RR, Jordan PH (1976) Unresolved problems of pancreatic pseudocysts. Ann

Surg 184:16-21 13. Grodsinsky C, Schumann BM, Block MA (1977) Absence of pancreatic duct dilation in

chronic pancreatitis. Arch Surg 112:444-449 14. Grosdidier J, Boissel P, Paquis H (1972) Avenir lontan des anastomoses pancreato-di

gestives dans la chirurgie de la pancreatite cronique primitive. 9th Congress Soc. Int. Gastro-enterol, Paris

15. Heerden JA van, ReMine WH (1975) Pseudocysts of the pancreas; Review of71 cases. Arch Surg 110:500-505

16. Hermann RE, AI-Jurf AS, Hoerr SO (1974) Pancreatitis. Surgical management. Arch Surg 109:298-303

17. Jordan GL, Strug BS, Crowder WE (1977) Current status ofpancreatojejunostomy in the management of chronic pancreatitis. Am J Surg 133:46-51

18. Kugelberg CH, Wehlin L, Amesjo B, Tylen U (1976) Endoscopic pancreatography in evaluating results of pancreatico-jejunostomy. Gut 17:267-272

19. Lamy J, Sarles JC, Dubau R (1972) Resultats it 5 ans du traitement chirurgical des pancreatites chroniques. 9th Congress Soc. Int. Gastro-enterol., Paris

20 Leger L, Lenriot JP, Lemaigre G (1974) Five to twenty years followup after surgery for chronic pancreatitis in 148 patients. Ann Surg 180:185-191

21. Leger L, Claret Y, Louvel A (1978) Le canal de Wirsung dans les pancreatites chroniques chirurgicales; etude radiologique et anatomique. Nouv Presse Med 7:3115-3118


22. Partington PF, Rochelle REL (1960) Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg 152:1037-1043

23. Pollak EW, Michas CA, Wolfman EF (1978) Pancreatic pseudocyst. Management in fifty-four patients. Am J Surg 135:199-201

24. Prinz RA, Kaufman BH, Folk FA, Greenlee HB (1978) Pancreaticojejunostomy for chronic pancreatitis. Two-to 21-years follow-up. Arch Surg 113:520-525

25. Proctor HJ, Mendes OC, Thomas CG, Herbst CA (1979) Surgery for chronic pancreatitis. Drainage versus resection. Ann Surg 189:664-671

26. Puestow CB, Gillesby WJ (1958) Retrograde surgical drainage of pancreas for chronic relapsing pancreatitis. Arch Surg 76:898-907

27. Rignault D, Mine J, Moine D (1968) Splenoportographic changes in chronic pancreatitis. Surgery 63:571-575

28. Sarles H, Sahel J (1976) Die chronische Pancreatitis. In: Schwiegk H (ed) Handbuch der inneren Medizin, vol 3/6. Springer Berlin Heidelberg New York

29. Sato T, Saitoh Y, Noto N, Matsuno K (1975) Appraisal of operative treatment for chronic pancreatitis with special reference to side to side pancreaticojejunostomy. Am J Surg 129:621-628

30. Serio G, Marzoli GP, Petronio R, Pederzoli P, Tenchini P, Romanelli GV (1978) Problemi di tattica chirurgica ne' trattamento delle pseudocisti pancreatiche e delle relative complicanze. Chir Ital 30: 1-41

31. Stobbe KC, ReMine WH, Baggenstoss AH (1970) Pancreatic lithiasis. Surg Gynecol Obstet 131:1090-1099

32. Traverso LW, Tompkins RK, Urrea PT, Longmire WP (1979) Surgical treatment of chronic pancreatitis. Twenty-two years' experience. Ann Surg 190:312-319

33. Way LW, Gadacz T, Goldman L (1974) Surgical treatment of chronic pancreatitis Am J Surg 127:202-209

34. Warren KW (1979) Discussion. Ann Surg 189:670 35. White TT, Slavotinek AH (1979) Results of treatment of chronic pancreatitis. Ann Surg

189:217-224 36. Winship D, Butt J, HenstorfH, Ivey K, Smith IN, Trenbeath M, Turner F, Wilhelm K

(1977) Pancreatitis: Pancreatic pseudocysts and their complications. Gastroenterology 73:593-603

37. Zeppa R (1979) Discussion. Ann Surg 189:669

The Use of Resection in the Treatment of Chronic Pancreatitis

R. Pichlmayr and K.D. Rumpf

Klinik flir Abdominal- und Transplantationschirurgie, Karl-Wiechert-Allee 9, 3000 Hannover 61, Federal Republic of Germany

Until the end of the 19th century the pancreas was considered to be a surgically inapproachable organ [42]. For a very long time inflammatory pancreatic disease was thought to be a complication of cholelithiasis (reflux theory). Therefore the goal of operative intervention in benign pancreatic disease was always the removal of gallstones from the common duct. Works expressing an increased surgical interest in pancreatic disease were those by Billroth in 1894, Halsted in 1899, and Desjardins, Cotte, Kausch, and Kehr from 1909 until 1913, as described by Kiister [32] and Melchior [41]. They were almost exclusively concerned with the therapy of malignant processes through resections of the pancreatic tail and head as well as total pancreatectomy. In 1935 A. O. Whipple took the existing techniques for the removal of the pancreatic head with the middle part of the duodenum, developed them further, and

FIRST OPERATION

SECOND OPERATION END STACE

Fig. 1. Whipple's operation, original method (partial duodenopancreatectomy)

206 R. Pichlmayr and K. D. Rumpf

in a grand manner transferred his experimental experiences with animals to clinical therapy for the first time. Whipple's original procedure removed stepwise the entire duodenum and the pancreatic head [66] (Fig. 1). This procedure, initially developed only for the removal of malignant tumors of the pancreatic head region, was later increasingly used also for treatment of inflammatory pancreatic disease. A logical operative procedure with the goal of removing the inflammatory locus from the pancreas was not handed down from the years before 1935. One may assume that until this time mostly or entirely palliative procedures were undertaken for the removal of complications of a pancreatitis, such as bypass operation. The technical procedure, and especially the restoration of continuity after partial duodenopancreatectomy, was later improved through diverse modifications: 62 variations have been published [30], and the principle of choledochus reimplantation into a jejunal sling and construction of a pancreaticojejunostomy has prevailed until today.

Pathogenesis - Surgical Therapy

The distinguishing attribute of forms of chronic pancreatitis (i. e., recurrent chronic pancreatitis and primary chronic pancreatitis) is a progression of inflammatory attacks by which each one leads to irreversible damage of pancreatic tissue (Marseille Nomenclature, 49). The morphological changes do not heal, as with forms of acute pancreatitis, and the functional loss is continually increased. In Western Europe the cause of this illness is mainly alcohol abuse [52, 67]. Of our own patients, 78% admitted chronic alcohol abuse of more than 40 g/day and 51% of more than 80 g/day. Other causes such as mechanical flow obstruction in the prepapillary region, hyperparathyroidism, mucoviscidosis, and others are very seldom [52]. Chronic pancreatitis is primarily treated conservatively [2, 53]. However, even after removal of the causal factors such as alcohol abuse, treatment does not always succeed in bringing about healing. The course of the disease is progressive and leads sooner or later to an exocrine and endocrine insufficiency parallel to an increasing destruction of pancreatic parenchyma [2, 4]. A specific curative and causal therapy based on conservative methods does not exist [51]. Occasionally it has been suggested that spontaneous healing can be precipitated through a "burning out of the gland" [1, 2]. This conception assumes that after about 5-7 years a complete atrophy of the exocrine acinar part and a defect healing simultaneously occur [4]. This goal appears desirable in two patient groups: 1) In those with persistent alcohol abuse; and 2) In the seldom instances of a so-called "silent", i. e., painless, primary chronic

pancreatitis. Beyond that it is hardly recommendable to wait for a spontaneous quietening of the illness through the conservative measures alone because of the great pain caused by the recurring inflammatory attacks. A psychological, social, and physical decay of the patient is to be feared.

The Use of Resection in the Treatment of Chronic Pancreatitis 207

The average age of patients affected by the illness lies between 35 and 45 years and men are affected more often than women.

Idications for Operative Therapy

Similar to the diagnosis of the illness itself [2], as a rule the indication for surgery is presented only after its history of several years. It is reputed to be certain that the appearance of further inflammatory attacks cannot be prevented by conservative measures alone [1, 4,51]. Thereby the persistent alcohol abuse acquires a distinct significance. The acute inflammatory attack within the scope of chronic recurring pancreatitis is connected with considerable pain. When the intensity, duration, and frequency of these complaints pass beyond a certain limit, the introduction of surgical therapy can result. The threshold of tolerance is mostly established according to the individual characteristics of the patient himself and to the experience of the examining internist. In the following pages an attempt will be made to demarcate the sphere of indication for surgery. The presence of only one of the following four symptom complexes as a rule leads to an operation. 1) Most frequently it is strong continuing pain that leads to surgical intervention.

The main localization point is in the epigastric region, with radiation of the pain into the left flank [30]. This may make hospital admittance necessary long before the operation itself, because of continuous inanition or the occurrence of a toxic-septic general symptomatology. In a pancreatic attack the intensity of pain is considerable and as a rule the length of an attack is a few days to many weeks. According to Visick, the subjective complaints can be depicted better objectively when we assess their influence on the occupation of the patient [61]. Lighter, that is, tolerable pain of Visick's categories I-II is particularly frequent in the initial stage of chronic pancreatitis; it seldom makes therapy necessary. Only when the symptomatology must be classified as stage III of IV (i. e., strong complaints that essentially influence life and occupation), does surgery become a necessity in cases of frequent occurence. From our own patients on whom surgery was performed 91 % of those with chronic recurring pancreatitis belonged to stages III and IV. As a rule, the subjectively perceived complaints - not so much the exocrine pancreatic insufficiency - lead to considerable malnutrition as a result of dysphagia. This is explained by the fact that a direct connection exists between ingestion and the occurrence of pain [25]. A consequence of a longer-lasting illness is that the patient is almost underweight and often has a cachexia. Stronger states of pain are considered to be an indication for surgery, especially when they have occurred repeatedly through the years and have led to a state of malnutrition.

2) The urgency to operate increases when the recurring attacks develop a symptomatology of acute pancreatitis. Demonstrable elevations of enzymes in serum and urine, hints of a toxic-septic general symptomatology, or hints of damage to neighboring organs all constitute an increased danger to the patient. In all of these instances, an acute, self-perpetuating, increasing destruction of the pan-


creatic parenchyma is to be reckoned with. In acute attacks it can be demonstrated that multiple, bounded, tryptic necrosis develops, which goes far beyond the stage of salivary edema and leads directly to cell destruction [4]. An increased number of inflammatory attacks within the scope of chronic pancreatitis should therefore be considered an indication for an operation between attacks. The primary consideration here is the prevention of progressive parenchymal destruction.

3) Macroscopically, recurring inflammatory attacks lead to discrete inflammatory nodules, which often have an increased petrous consistency. Mostly it is the head of the pancreas that is affected [18, 48], so that through compression it can lead to an injury of the neighboring organs. In these cases the indication to operate is derived from the loss of function of these organs: a) Even a partical choledochus obstruction requires operative correction when a cholestasis exists. Mostly a longer, only partial stenosis of the intrapancreatic choledochous duct is present as the cause of the enzyme constellation of bile obstruction type. This can lead to the development of an icterus. Spontaneous remissions are frequent. b) More serious is the portal vein/mesenteric vein compression by an inflammatory nodule in the pancreatic head. This leads, often unnoticed over a longer period, to considerable portal hypertension with strong collateral development. These bypass circulations can make resection of the pancreatic head a dangerous procedure. It is therefore desirable to anticipate the collateralization through operative correction. In practice this occurs almost only in connection with other complications, because development of portal hypertension can pass unnoticed for a long time. On the other hand, a pronounced collateralization can be a decisive factor in the choice of operative procedure, because a high endangerment of the patient does not allow an approach employing resection. Splenomegaly with hypersplenism as a result of obstruction of the splenic vein is a rare consequence. c) Stenosis of the duodenum is also within the scope of chronic inflammatory pancreatitis of the pancreatic head region. It requires an early operative correction because the often already existing malnutrition can rapidly deteriorate as a result of postpyloric stenosis.

4) Drainage obstruction of the pancreatic secretions, itself resulting from a stenosis in the pancreatic duct system, is an essential condition for the genesis of a pancreatitis [4, 11, 52]. Becker could prove that the resulting increase in pressure leads, by way of a salivary edema, to a pericanicular fibrosis, whereby the islets of Langerhans are not yet damaged [4]. In the further course of chronic pancreatitis, loci of tryptic necrosis unavoidably develop, which also results in a limited destruction of endocrine active tissue [11]. The healthy pancreas has a high endocrine functional reserve [12, 69]. Nevertheless, one may assume that under these pathophysiologic conditions an endocrine insufficiency must develop after increased pancreatic attacks. Diabetes mellitus is one of the most serious co~plications of chronic pancreatitis. However, an exact and real correlation between the severity of the glucose metabolic disturbance and the magnitude of the chronic pancreatitis cannot be established [44]. It therefore appears necessary continually to control a predia-


betic metabolism within the scope of chronic pancreatitis. An increased progressivity can make the decision to operate an urgent matter. This is recongnizable in the decrease of the glucose assimilation coefficient shown by the glucose tolerance test or in a reduction of the amount of C-peptide in the 24-h urine. Excretory insufficiency alone does not constitute an indication to operate. This can always be adequately treated with drugs and if necessary with additional diet. A resecting or nonresecting operation does not improve this situation [2, 10, 51]. Even in the seldom cases of a primary chronic pancreatitis, one must say no to an indication for operation, the reason being that the endocrine function of the pancreas is not yet restricted. This rare form of chronic pancreatitis is practically painless [49]. It leads, however, to a continually increasing loss of function, so that, especially here, the monitoring of the glucose metabolism is extraordinarily important.

Choice of Method

In view of the different causes and symptoms of chronic pancreatitis there cannot be a standard operative procedure. The choice in each individual case must be based on the symptoms present and the state of the duct system. Three groups of different operative methods are available:

Operations External to the Pancreas

Biliodigestive anastomosis, common duct reVlSlons, gastroenterostomies, and pain-reducing operations on the vegetative nervous system belong to the group of relieving or functional reconstruction operations on nonpancreatic organs. These operations have in general been abandoned because of their unsatisfactory results as shown by follow-up studies [18, 26, 36, 54]. Common bile duct restoration (with cholecystectomy) is adequate as an operative procedure when a causal connection between gallstone affliction and recurring pancreatitis is certain. In opposition to earlier assumptions [32, 55, 62], this connection with its regional differences [50] can be counted as certain in hardly more than 15%-23% of the cases [2, 25, 27, 37]. The construction of a biliodigestive anastomosis without proof of gallstones is j ustified when chronic pancreatitis of the pancreatic head region has indeed led to a manifest cholestasis but a burdening pain symptomatic is lacking. This situation can materialize within the scope of chronic pancreatitis as a seperate form that was especially elaborated on by Bartholomew and Comfort [4] as a painless form of primary chronic pancreatitis. It is probably more frequent than we assume [1]. A further area of indication for biliodigestive anastomosis is icterus in risk patients, in whom resection must be avoided because of the general operative dangers. The operative technique that proved to be successful is choledochojejunostomy with a long, Y -shaped jejunum loop according to Roux.


Gastroenterostomies are used as the sole therapy of the less painful chronic pancreatitis when inflammation of the pancreatic head as a result of compression of the duodenum has led to a postpyloric stenosis.

Methods for Drainage of Pancreatic Secretions

Anastomotic techniques for pancreatic duct relief belong to the category of nonresection operations. A stenosis in the proximal part of the main efferent duct as a result of compression or obturation results in a considerable increase in pressure in the afferent duct system, and frequently there is a uniform dilation of the duct. A relief in pressure in these cases is also accomplished through a widely placed pancreaticojejunostomy after the techniques of Du Val, Mercatier, Puestow I and II, and Cattel [53, 57, 67]. Follow-up studies on duct anastomosis operations point especially to three disadvantages: 1) The late mortality is considerable. After 8 years 80% of the so-treated pancrea

titis patients have died [67]. Continuing alcohol abuse appears to have a considerable influence in this respect.

2) The desired painlessness is not attained in many cases or it is not permanent [42, 45, 51, 64]. Stock [57] points out that in 35%-56% of cases one must assume poor late results. Reoperations are frequently necessary. It is suspected that the in situ remaining inflamed pancreatic head prevents the well-being of the patients.

3) Obviously the rate of overlooked pancreatic carcinomas is high: according to White, almost 20% [67]. The problem of uncertainty of intraoperative clarification as to the histologic nature of a pancreatic head tumor through biopsy, fine needle cytology, etc. has in general not yet been satisfactorily solved. This question is important when a nonresecting method is chosen. Therefore in the individual case indication for secretion-diverting operations is strictly dependent on the individual findings and not so much on the individual attitude of the surgeon.

Occasionally smaller, mostly multiple pseudocysts occur within the scope of chronic pancreatitis. They are hardly larger than 3 cm in diameter and originate from bounded ectasia of the duct in cases of constant elevation of pressure. In ERCP, this is the "chain oflakes." Contrary to the principles of treatment oflarge solitary pseudocysts, the proof of these smaller hollow bodies justifies no deviation from the therapeutic concept of chronic pancreatitis.

Resection Procedures

In the treatment of recurring chronic pancreatitis, resection is being increasingly chosen for the following reasons: a) The inflammation always leads to loci of parenchymal necrosis whose most

frequent area of manifestation is the pancreatic head. b) The pressure in the region of the pancreatic head is not sufficiently and per

manently relieved by way of a distal duct anastomosis.


c) Resection of the pancreatic head leads, among other things, to the decompression of the portal vein.

d) A certain and permanent drainage of the secretions can be brought about by resection of the inflammatory locus. In this way continuing atrophy of the islets of Langerhans can be stopped.

e) Differential diagnostic difficulties exist between inflammation and pancreatic carcinoma.

a) It must be regarded as an attribute of chronic pancreatitis that it always occurs in a bounded, limited form, which means that the pathologic and anatomic changes are local. Remaining healthy parenchyma is always found next to the tryptic and lipolytic necrotic loci [4, 35]. One must differentiate between the actual inflammatory loci and a secondary, more pericanicular localized fibrosis which frequently occurs distally from the main inflammatory locus. A causal connection exists between this and chronic elevation of pressure in the pancreatic duct system. Autolytic necrotic loci are not to be found here, in contrast to their existence in the primary and central inflammatory region [4]. The main site of manifestation of the illness is the pancreatic head [11, 48]. It is here that the greatest changes, even macroscopic, are to be found the duct system and the parenchyma, such as multiple obstructions, ectasia, pseudocysts, and necrosis. They represent a constant danger for the patient. The hard, inflammatorily altered pancreatic head must be considered in connection with an always existing extrapancreatic edema as cause and origin of the often unbearable pain. The inflammatory loci in the region of the nerves and the intraglandular ganglions also point to this connection, which Mallet-Guy found especially in the late stages of chronic pancreatitis [36].

b) A caudally situated duct anastomosis can relieve only the distal portion of the duct system and thereby parts of the parenchyma. The desired relief of pain is herewith only partially achieved, that is to say, it is only temporary [26, 42, 45, 51, 64]. a) and b) contain the essential arguments for a partial duodenopancreatectomy acc. to Whipple. c) Simultaneously with resection of the pancreatic head, relief of the often constricted portal vein is obtained and therewith relief of the flow region of the superior mesenteric vein. This appears to be important, because the portal hypertension within the scope of chronic pancreatitis is an especially difficult therapeutic problem. Relief of the choledochous duct is indeed achieved by way of a pancreatic head resection; however, this can also be brought about through a choledochojejunostomy. In general chronic pancreatitis leads to the occurrence of a multitude of simultaneously existing symptoms, such as severe pain, digestion insufficiency, diabetes mellitus, cholestasis, stenosis of the portal vein, and compression of the duodenum. Stenosis of the portal vein seldom occurs alone. Further, often not yet burdening symptoms can frequently be revealed only by means of a precise diagnostic clarification. In the end, it is the total picture that determines the decision for or against resection. d) The most important function of the pancreas is the endocrine hormonal regulation of the glucose metabolism. The goal of every pancreatic therapy is to retain


this function. In general a correlation between the severity of the diabetes and the topographic extent of the inflammatory changes cannot be established [44]. On the other hand, it is certain that the longer the inflammatory process of the pancreas is demonstrable, the greater is the extent of parenchymal loss [4]. Our own experiences with the late results of pancreatic head resection show that the procedure could abolish the danger of continuing damage to the endocrine tissue. The resection procedure also leads naturally to a reduction of the total number of the islets of Langerhans. As a result of this, in our own patients (Table 1) an additional 9% of diabetes cases appeared after pancreatic head resection. However, control of the patients over the next 2-5 years showed without exception an endocrine stabilization, that is, further diabetic cases did not develop. From this one may deduce that pancreatic head resection creates a more permanent drainage of the secretion. With the end of the stasis in the duct system one of the conditions for the genesis of a tryptic autolytic inflammatory locus no longer exists [4].

Table 1. Development of manifest diabetes mellitus in patients with chronic pancreatitis before and after resection of the head of the pancreas

Diabetes before operation

More than 1 year after part. duodenopancreatectomy

Increase in diabetes by part. duodenopancreatectomy

Oral agents: Insulin dependent: Oral agents: Insulin dependent:

Oral agents: Insulin dependent:

8 (17%) 7 (14%) 9 (20%)

10 (21%)

+3% +6%

The extent to which continuing alcohol consumption directly damages the rest of the pancreas and hence becomes a diabetogenic noxa must be considered, in a toxicologic sense, as not yet clarified. The relevant diagnostic possibilies are limited in view of the few cases. Partial duodenal pancreatectomy usually causes a change in the patient's drinking habits. However, even in the seldom cases of continuing alcohol abuse, we could not diagnose an acute pancreatitis of the pancreatic residue with laboratory methods. With the construction of an unrestricted drainage an important condition for the occurrence of further inflammatory attacks could be eliminated. Continuing potential toxic damaging through alcohol then no longer leads to the corresponding pathohistologic changes. e) Differentiation of an inflammatory pancreatic nodule from a pancreatic carcinoma is usually impossible preoperatively using the conventional diagnostic methods. Carcinoma also has a preference for the pancreatic head [15, 31]. Even though density measurements in computer tomogram, sonography, or cytologic fmdings of transcutaneous fine needle biopsy from the pancreas might yield negative results, one still cannot rule out a pancreatic carcinoma. Especially in older people the general symptoms such as short history, unspecific upper abdominal pain, loss of weight, etc. attain an important significance. If the histologic nature


of a pancreatic head nodule cannot be adequately clarified intraoperatively, the decision to resect is sensible. Increased genesis of carcinoma as a result of chronic pancreatitis has not yet been proven [5, 6, 34]. Our own observations as well as those by Grotzinger [23], who observed preceeding chronic pancreatitis in one-third of cases of pancreatic carcinoma, suggest a possible connection. Becker [5] found four cases of chronic pancreatitis from which pancreatic carcinomas had developed. A connection in the sense of precancerosis cannot be determined even from a larger number of cases [39]. In the individual case, and especially in chronic pancreatitis of an older patient, an etiologic connection cannot, however, be excluded [2, 5, 34], so that this should be considered as a further argument for resection therapy in chronic pancreatitis.

On the Technique of Resection Procedures

General Rules. The normal human pancreas has a soft consistency, which can only become increasingly solid under the influence of reoccurring inflammatory attacks or through a permanent elevation the pressure in the duct system. According to the consistency, diverse treatment as regards the placing of parenchymal sutures is necessary. The 4/0 mono file fiber has proven itself to be a good gliding suture material. As yet it is only available in nonresorptive material. In contrast, one may use braided, resorptive fiber material without hesitation on a chronically inflamed, solid, firm pancreas. The cutting of the parenchyma is carried out with an electric or a sharp scalpel. Bleeding areas are carefully stitched with thin, mono file sutures. Hemostasis by way of electrocoagulation is seldom successful because of the ample fat tissue on the pancreas and can easily lead to late bleeding. Special consideration must always be given to the construction of unrestricted drainage conditions for the pancreatic secretions.

Left Resections on the Pancreas. An earlier, especially from French authors [36, 37, 42] frequently documented pancreatitis which occurs predominantly in the caudal region is very seldom seen, at least in our patients (Table 2). In these cases resection of the inflammatory loci would be suitable to a wide left resection, which corresponds to the medical findings. In general, resection of the pancreatic tail can also be carried out without splenectomy. However, it is then technically more difficult. If one decides to do a simultaneous splenectomy then one must consider the intact blood supply that flows to the middle part of the pancreas as one ligates the splenic vessels. The pancreatic body is cut transversely like the mouth of a fish, so that better adaptation of the resection surfaces is achieved. The pancreatic duct must always be located and distally selectively be ligated. However, one must first obtain information about the drainage conditions to the duodenum. This can be done by way of probing the main duct in the direction of the papilla and/or through an intraoperative X-ray. If the proof of free drainage in the direction of the papilla or a certain distal duct obstruction is not reliable enough, then it is suggested that the


Table 2

Partial duodenopan- Left resections createctomy

n Lethality n Lethality

Chronic rec. pancreatitis 62 8.1% 20 0.0% Pancreatic carcinoma 24a 13.0%a 5 40.0% Papilla carcinoma 21 10.5% - -

Infringing tumors 29 13.8% 58 8.6%

Total 136 10.3%b 83 8.4%

a Included in this total are seven total duodenopancreatectomies without lethality b Excluding infringing tumors

cut surfaces be covered according to the method of the Duvall duct anastomosis with a disconnected jejunum loop. The extension of a left resection up to the right portal vein border as a so-called 95% subtotal resection after Child [16] has only a limited indication, that is, the seldom cases of total pancreatic tail destruction with an attack on the bordering parts of the body. The following are arguments against the liberal use of this technique: Becker [6] could show that the pancreatic changes in most cases extend as far as the duodenum wall, which hints mostly at inflammatory degenerative, often cystic changes. Using the Child resection one must always assume that regressively changed pancreatic tissue remains. Furthermore, as a result of this operation diabetes mellitus almost always develops [38, 51]. This and the large number of complications caused Leger and his associates to warn against the increased use of this technique [34]. Nevertheless, the lethality of this operation is, at the quoted figures of 0%-4.3%, distinctly lower than that of pancreatic head resection [6, 18, 38].

Partial Duodenopancreatectomy. In chronic pancreatitis, operability, that is, the ability to resect the pancreatic head, depends above all on the preparative possibilities of the portal vein and the superior mesenteric vein. These should be initially exposed from the bottom edge of the pancreas and the anterior surface of the portal vein should be carefully exposed in a cranial direction. The same procedure is employed from the cranial side, at first without ligation of the gastroduodenal artery. In this way a complete undertunneling of the pancreatic body can be accomplished. If difficulties arise in the subsequent proceedings, especially by the cutting of the pancreatic body and the detachment of the head from the right lateral side of the portal vein, a narrow parenchymal hedge may be left on the portal vein. For the most part the portal vein can be totally exposed and thus decompressed. It is especially important to pay attention that one avoids damaging the portal vein when the middle part of the duodenum is pulled to the right and away from


it, because some small veins usually exist there, leading from the duodenum to the superior mesenteric vein. A suture-caused constriction of the lumen should not be allowed to result from an injury of the portal vein. If necessary, the vein must be enlarged with a Saphena patch or spanned with a double anastomosed Saphena [181. In cases of considerable fibrosis of the organ, injury to the superior mesenteric artery is especially likely to occur during the last step of the operation, that is, during dissection of the uncinate process. Reanastomosis or reinsertion is then necessary. Special attention should be given to the arterial blood vessel supply of the liver because the right hepatic artery frequently originates from the superior mesenteric artery and crosses underneath the pancreatic head to the right. The occurrence of peptic jejunal ulcer is prevented through a high antrum resection of the stomach or, more recently, through a truncular vagotomy [8, 17, 22, 241. Selective vagotomy can become difficult because of peri pancreatic adhesions, the danger of splenic injury, and the prolongation of the already long operation. After the removal of the pancreatic head it is vital to control the duct system toward the tail, which means to probe it and/or depict it in an X-ray. Only when it is free from additional stenoses the completion of a pancreaticojejunostomy anastomosis can follow. On the other hand, if examination of the pancreatic tail duct system reveals obliteration by way of concrement, stenosis, or other means, then an extensive operative revision is necessary. In these cases it appears sensible to split the pancreatic duct lengthwise (Fig. 2), that is, over the obstruction, which allows encrusted concrements to be removed also from the supplying ducts of the second order. If necessary, an additional resection of the distal pancreatic tail can be carried out. As a rule, when the pancreatic duct is split lengthwise, anastomosis of the anterior side of the pancreas occurs effortlessly with a corresponding long antimesenterial

Fig. 2. Dividing the pancreatic duct in the pancreatic tail; performed in addition to a partial duodenopancreatectomy to eliminate pancreatic duct stones as completely as possible


incised jejunal loop. As a result of this procedure the danger of recurring complaints through the occurrence of pancreatic tail inflammatory should be largely excluded. In our procedure principally two jejunal loops are employed for reanastomosis, one for the stomach and the other for the pancreas/choledochus (Figs. 3,4). This has the following advantages: First, in this way bile reflux into the stomach is

Fig. 3. Resecting lines of the standard pancreatic head resection technique

Fig. 4. Scheme of the reanastomotising techniques following partial duodenopancreatectomy; Clinic for Abdominal and Transplantation Surgery, Medical School, Hannover


largely avoided; a protective effect against carcinoma is attributed to this measure, especially in younger patients [9]. Second, there cannot be a reflux of stomach contents into the bile duct in cases of nonclosure of the papilla. Third, in the event of occurrence of a pancreatic anastomosis insufficiency, deterioration of the situation is avoided. The distance between the pancreas and the choledochal anastomosis must be so chosen that neither tensions nor loops cause an elevation in pressure and thereby an accumulation of secretions. The choledochal anastomosis is best placed on the posterior wall of the jejunal loop in the corresponding physiologic position. As a rule the pancreatic anastomosis can be constructed reliably and without difficulties as a result of the induration in cases of chronic pancreatitis. A mucosa adaptation suture from the pancreatic duct and the jejunum as well as internal anastomosis splints appear to be unnecessary and could even be dangerous as a result of a potential grasping suture effect. There are contradictory opinions as to this effect [8, 24, 56]. An end-to-side anastomosis technique on the pancreas has the advantage of safer, undisturbed circulatory conditions, including the avoidance of hematomas. However, in the case of an end-to-end anastomosis an injury of the mesenteric vessels is not always avoidable through the anastomotic sutures. Since 1967 techniques have been developed in Erlangen [20] and Lyon [13] which cause a complete obliteration of the pancreatic duct system through the introduction of a fast-hardening substance. By way of atrophic damage of all glandular elements there is a cessation of every exocrine secretion without injury to the islets of Langerhans [20, 17]. Clinically the advantage consists of an additional protection of the anastomosis, because the potential autolytic components are totally eliminated. Anastomotic insufficiencies on the pancreas after partial duodenopancreatectomy were no longer observed in over 60 of the so-treated cases [17]. Tumors of the peripapillary region are to be considered as the main indication for this procedure. The duct occlusion technique leads to valuable protection of the anastomosis on the unchanged, soft pancreatic tail. This technique appears to be unnecessary in cases of chronic pancreatitis, because to put a pancreatic anastomosis on the reactive, inflammatory, hardened pancreatic remains is as a rule safer, i. e., involves less risk. Furthermore, total elimination of the remaining digestive function intensifies the already existing pancreatic exocrine insufficiency.

Total Pancreatectomy. Total duodenopancreatectomy, involving the removal of the whole pancreas, does not appear to be indicated in chronic pancreatitis, or at least only very rarely. It is in the nature of chronic pancreatitis that it mainly occurs in bounded loci. One can always reckon with the fact that larger areas of tissue are primarily not included in the inflammatory process and therefore can be preserved. The hard consistency of these areas can simulate parenchymal destruction. The glucose metabolism has proved itself a reliable parameter for quantitative judgment of the functional loss of parenchyma [48]. Recently it has been possible to detect even the smallest amount of insulin synthesis by the existence of an insulin-dependent diabetes through the quantitative analysis of the C-peptide in 24-h urine [70].


Besides the frequent existence of remaining insulin production, pancreatic glucagon has a special significance [10, 60, 65]. Diabetics without a pancreas are especially endangered due to increased instability of blood sugar regulation and the tendency to hypoglycemia [56, 59]. The cessation of a counter-regulation mechanism through glucagon is considered to be the cause. This, among other factors, has induced Najarian and Sutherland to retransplant pancreatectomized patients with their own pancreas [58].

Results

Of our own patients between 1970 and 1. 1. 1980, 82 underwent resection treatment because of reoccurring chronic pancreatitis. Of these 82, 20 were left resections, four of which were subtotal (Table 2). Pancreatic duct anastomoses were placed in only nine cases. Without exception duct anastomoses were performed on the basis of special indications by which resection does not appear advisable. These are: mesenteric vein thrombosis, multiple preoperations, and already operated left resections. The hospital lethality is 8.1% using partial duodenopancreatectomy. After an analysis of the cause of death one can compute a specific lethality of 3.3% because three out of five patients died from causes other than technical-operative ones. Our own patients were questioned and reexamined for assessment of the longterm results of pancreatic head resection in chronic pancreatitis (Table 2); in 90% ofthe cases pancreatic head resection was found to have led to total or almost total freedom from complaints (Fig. 5). Pancreatitis of the pancreatic residue was not demonstrable in any case, even through the evaluation of interim hospital stays. The conditions of pain occasionally described by patients after a Whipple operation in cases are probably to be attributed to complaints of intestinal adhesions.

complaints Visick preoperative postoperative

none 0) 13 53

small ® 17 37

medium ® 72

severe @84

100% 80 70 60 50 40 30 20 10 0 10 20 30 40 50 60 70%

number of patients in % of n =48

Fig. 5. Grading of the patients' complaints before and after resection of the head of the pancreas because of chronic pancreatitis, according to Visick, modified by Goligher


The symptomatology of ascending cholangitis was sometimes demonstrable. A partially scarred stenosis of the biliodigestive anastomosis has been discussed as a cause of this late complication. In the individual case they can be diagnosed by way of a hepatobiliary sequence scintigram. As a result of the operation 9% + of those operated developed a clinically manifested diabetes mellitus, which beforehand was subclinical (Table 1); 6% + became dependent on insulin. These findings correspond to the earlier findings of Mangold (38), who observed a 9% increase of diabetics after partial duodenopancreatectomy. Gall (18) reported a 20% increase of diabetes. However, he refers to an abnormally high amount of persisting alcohol abuse. In our own patients, 80% of those who were duodenopancreatectomized had an exocrine insufficiency (Fig. 6). When untreated this leads as a rule to steatorrhoea, loss of weight, and mainly to chronic malnutrition. Enzyme substitution is therefore necessary in the majority of cases after pancreatic head resection because of chronic pancreatitis. Powder or granules are recommended as the application from since the hypoacidity of the gastric juices (stomach resection) and the quick passage does not allow for the release of the working components of capsules or tablets, or release occurs too late.

lipid utilisation after partial duodenopancreatectomy

because of chronic pancreatitis n = 38

71 %

pathological

«90%)

Fig. 6. Lipid utilization (oral-fecal lipid balance) in patients with chronic pancreatitis 1 year after resection of the head of the pancreas

In one-fourth of the patients a sufficient digestion is not to be reached solely through enzyme substitution (47). Here a dietetic therapy combination is necessary. Enrichment of the normal (long-chained) nutrition fat through MCT fats has proved itself to be effective. In general this mild form of diet is perceived by the patients as nonburdening, so that it does not detract from the overall good results of pancreatic head resection in chronic pancreatitis.

Summary

The use of resection in chronically occurring pancreatitis appears to be justified on the basis of certain limited indications. It leads most reliably to a vast improve-


ment of the complaints and probably to permanent freedom from recurrences. The retention of pancreatic tissue seems to be important for endocrine reasons. Where technical difficulties exist, the appropriate alternative operations are indicated, such as a duct anastomosis operation by dilation of the distal part of the pancreas or the combination of papillotomy with the extended splitting of the duct also proximally. In cases of calcifying pancreatitis indication for operative therapy must be identified as early as possible, so that the endocrine situation does not deteriorate. By way of a graduated choice of operations between resecting and nonresecting techniques one can keep lethality low. The long-term results of resection treatment are predominantly good, with the exception of those patients who continue in their alcohol abuse.

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20. Gebhardt C, Stolte M (1978) Pankreasgangokklusion durch Injektion einer schnellhartenden Aminosaurelosung. Langenbecks Arch Chir 346:149-166

21. Goebell H, Hotz J (1976) Kalzium, Pankreassekretion und Pankreatitis. Leber Magen Darm 6:4, 211-216

22. Grant CS, Van Heerden JA (1973) Anastomotic ulceration following subtotal and total pancreatectomy. Ann Surg 190:1-5

23. Grotzinger KH (1979) Atio-Pathogenese der Pankreatitis. Langenbecks Arch Chir 334:323-331

24. Guillemin G, Berard Ph, Bigay D et al. (1979) 103 duodeno-pancn:atectomies cephaliques pour pancreatite chronique. Chirurgie 105:147-153

25. Hess W (1969) Die chronische Pankreatitis. H. Huber, Bern 26. Hollender LF, Meyer Ch, Marrie A et al. (1979) Etude "comparative" des resections et

des operations de derivation dans Ie traitement de la pancreatite chronique. J Chir 116:6,7,401-406

27. Hotz J, Goebell A (1975) Diagnostik der Pankreasinsuffizienz. Klinikarzt 4:11, 443-450

28. Hotz J, Goberna R, Clodi PH (1973) Reserve capacity of the exocrine pancreas. Digestion 9:212

29. Howard JM, Ehrlich EW (1961) The clinical study of alcoholic pancreatitis. Surg Gynecol Obstet 113:167

30. Kern E (1974) Pankreaschirurgie. In Chirurgie der Gegenwart, Bd II. 31. Kummerle F (1977) Die kurative Behandlung des Pankreascarcinoms. Therapiewoche

27:5010-5016 32. Kuster E (1915) Die Geschichte der neueren deutschen Chirurgie. Enke, Stuttgart 33. Lawrence WW, Gadacz Th, Goldmann L (1974) Surgical treatment of chronic pan

kreatitis. Am J Surg 127:202-309 34. Leger L, Lenriot JP, Lemaigre G (1974) 25 year follow-up after surgery for chronic

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37. Mallet-Guy P, Michoulier J (1973) Les pancreatites chroniques recidivantes parenchymateuses primitives. Helv Chir Acta 30:268-271

38. Mangold G, Neher M, Oswald B, Wagner G (1977) Ergebnisse der Resektionsbehandlung der chronischen Pankreatitis. Dtsch Med Wochenschr 102:229-234

39. Marks IN (1968) The natural history of calcific pancreatitis in the western cape. Trans ColI Phycns S Afr 12:54

40. Martina A (1907) Uber chronische interstitielle Pankreatitis. Dtsch Z Chir 87:499 41. Melchior E (1917) Die Chirurgie des Duodenum. In Kuttner H (Hrsg) Neue deutsche

Chirurgie, XXV. Enke, Stuttgart 42. Mercatier M, Chicot IT (1974) La derivation dans les pancreatites chroniques. Ann

Chir 28:473 43. Najarian JS, Sutherland DER, Matas AJ, Goetz FC (1979) Human islet autotransplan

tation following pancreatectomy. Transplant Proc 11:1, 336-340 44. Peters N, Dick AP, Hales C (1966) Exocrine and endocrine pancreatic function in dia

betes mellitus and chronic pancreatitis. J Br Soc Gastroenterolog 7:277-281 45. Priestley JT, Re Mine WH (1965) Chronic relapsing pancreatitis treatment by surgical

drainage of pancreas. Ann Surg 161:838-844 46. Ruckert K, Kummerle F (1978) Totale Duodenopankreatektomie als Regeloperation

beim Pankreascarcinom. Chirurg 49:162-166 47. Rumpf KD, Pichlmayr R (1980) Die Verdauungsleistung des Restpankreas nach par

tieller Duodenopankreatektomie. In: Haring R (Hrsg) Die Chirurgie der akuten und chronischen Pankreatitis. TM-Verlag, Bad Oeynhausen 261-268

48. Rumpf KD, Neter A, Atuahene K (1977) Ergebnisse der chirurgischen Therapie chronischer Pankreatitisformen. Zentralbl Chir 102:869-876

49. Sarles H (1963) Pankreatitis. Symposion Marseille. Karger, Basel


50. Sarles H (1973) An international survey in nutrition and pancreatitis. Digestion 9:389 51. Sarles JC, Sarles H (1976) Konservative und chirurgische Therapie der chronischen

Pankreatitis. Leber Magen Darm 6:5, 294-299 52. Sarles H, Tiescornia U, Sahel J (1976) Atiologie und Pathogenese der chronischen Pan

kreatitis. Leber Magen Darm 6:4, 206-209 53. Schwemmle K (1974) Operationsindikation und Operationstaktik bei der chirurgischen

Therapie der chronischen Pankreatitis. Chirurg 45:10, 465-470 54. Schwemmle K (1976) Chirurgische Gesichtspunkte bei der Therapie der chronischen

Pankreatitis. Dscht Arztebl 32:20, 65-71 55. Schwemmle K, Botticher R, MUller E (1974) Die chirurgische Therapie der chroni

schen Pankreatitis. MUnchn Med Wochenschr 116:44, 19,23-28 56. Spratt JS (1976) Improving trends with pancreatoduodenectomy. Am J Surg 131:239-

245 57. Stock W, Rosenberger J, Sander H, Pichlmaier H (1977) Ergebnisse nach organerhal

tenden und resezierenden Operationen wegen chronischer Pankreatitis. Med Welt 28:39, 1539-1542

58. Sutherland DER, Najarian JS (1979) Transplantation of the pancreas. Transplant Proc 11:1,1158-1162

59. Trede M (1976) Die tot ale Pankreatektomie. Langenbecks Arch Chir 340:227-230 60. Valverde I (1978) Formen des zirkulierenden Glucagons beim Menschen. MUnchn

Med Wochenschr 120:12, 407-409 61. Visick WD, Golligher JC et al. (1972) Five to eight year results of truncul vagotomy

and pyloroplasty for duodenal ulcer. Br Med J 1:7 62. Vossschulte K, Wagner E (1968) Chirurgische MaBnahmen bei chronischer Pankreati

tis. Chirurg 39:7, 307-312 63. Vossschulte K, ScheId H (1977) Resektionsverfahren oder Splanchnektomie bei chro

nischer Pankreatitis. MUnchn Med Wochenschr 119:13, 25-28 64. Warren KW, Mountain JC (1971) Comprehensive Management of chronic relapsing

pancreatitis. Surg Clin N Anm 51:693-710 65. Werner PL, Palmer JP (1978) Immunoreactive glucagon responses to oral glucose in

pancreatektomized man. Diabetes 27:10, 1005-1012 66. Whipple AO, Parsons WB, Mullins CR (1935) Treatment of carcinoma of the ampulla

of Vater. Ann Surg 102:4,763-779 67. White TT, Keith RG (1973) Longterm follow-up study of fifteen patients with pancrea

ticojejunostomy. Surg Gynecol Obstet 136:3, 353-358 68. Willig F, Schmidt FH, Trede M et al. (1977) Chronische Pankreatitis, Nachbehandlung

und Oberwachung total-pankreatektomierter Patienten. Verh. Dtsch. Ges. Inn. Med. 84: 1053-7

69. Yasugi H, Mizumoto R, Sakuri H, Honjo I (1976) Changes in carbohydrate metabolism and endocrine function of the pancreas after major pancreatic resection. Am J Surg 132:1570-1576

70. Zick R, Schatter E, Schurek HJ, Mitzkat H-J (1979) C-Peptid-Kinetik bei StOrungen der Nierenfunktion. In: Die Bedeutung der C-Peptid-Bestimmung flir die Diagnostik. Schnetztor, Konstanz

Chronic Pancreatitis: Surgical Indications, Procedures and Limitations

A. Dagradi

Istituto di Clinica Chirurgica, Universita di Padova, Sede in Verona, Policlinico B. Roma, 37100 Verona, Italy

Preliminary to any surgical approach to chronic pancreatitis (CP) is its nosographic delimitation. According to Sarles, CP is a condition of progressive anatomic damage, continuing its evolution even when the cause is eliminated [28]. Therefore, the term autonomous pancreatitis is justified. Clinically there are signs of progressive exocrine-endocrine functional failure, associated in most cases with a relapsing or continuous pain. As for etiology, this disease is generally linked with alcohol consumption, sometimes it is hereditary, some other times it is caused by malnutrition or hyperparathyroidism [4, 15, 28]. Exceptionally, it is induced by a mechanical condition, i. e., because of a difficult discharge from the duct system, or a gallstone stuck in the papilla, or papillitis, or the aftermath of an acute pancreatitis. Therefore for CP a mostly male population of patients is expected (at least in our country), aged 35-40 when first showing symptoms. The link with chronic biliary papillary diseases is theoretically possible, but it is worth stressing that the pancreatic consequences of biliary disease usually remain sporadic and of an acute nature (recurrent acute pancreatitis) [4, 7, 27]. They disappear, completely and permanently, once the cause is removed. The possibility of passing from this pancreatic elementary profile to an autonomous chronic form only exists theoretically, and a great deal of caution must be exercised in this respect. The same can be said for the aftermath of a necrotic-hemorrhagic acute pancreati tis.

Leaving aside the nosographic approach, the term CP is improperly used to include several forms which require quite different surgical procedures, with results for "recovery" that do not apply to CPo

Progressive and autonomous CP allows only symptomatic and palliative surgery directly on the pancreas. The reports that in the past filled the literature without taking into account what has been said above should be reconsidered.

In CP, pancreatic calcifications are frequent but not always present (50% of our cases). They express the age of the disease and therefore have a greater chance of coinciding with serious functional damages, but this is not the rule.

Calcifications do not represent in themselves a surgical indication, even if this indication becomes more probable in their presence. Thus the term "calcification" carelessly applied to CP is unacceptable as it excludes half the cases, and the term "calcifying" is preferable. Theoretically, it can be stated that CP is a diseases that interests the physician because of its natural evolution and because its main effects (exocrine failure, diabetes, pain) can only be controlled pharmacologically

224 A. Dagradi

for its duration. It must be said that such a natural history only occurs in about half the patients. Thus two considerations emerge: 1) That the study and the control of the disease must be mainly carried out in

gastroenterologic medical centers. 2) That surgical indications, though very frequent, must be assessed individually

in relation with the impossibility of medical therapy controlling each situation.

Table 1. When to operate on chronic pancreatitis

Pain resistant to medical therapy

Complications: Pseudocyst, stenosis of choledochus-duodenum, digestive hemorrhages, pancreatic ascites

Suspected tumor

Surgical indications for CP are summarized in Table 1. Personal experience allows the following deductions: pain resistant to medical therapy represents about 50% of surgical indications. It is usually dependent on duct stenosis and therefore on hypertension within the excretory system (Fig. 1). The evaluation of pain for surgery is largely subjective and has social and biologic reasons. Pain makes the patient an invalid and doomed to undernourishment - and to the concomitant damage. Waiting for the pain to diminish or disappear, as a consequence to the gradual destruction of the parenchyma, is unfair since this is possible for only a small number of cases and does not consider the serious complications which may arise from waiting for the conclusion [10, 13, 30, 32, 33]. During CP, pseudocysts and their complications require surgery in about 25% of patients selected for surgery [1, 8, 12]. In about 10% of pancreatic patients who have undergone surgery, the surgical indication is specifically linked with ingravescentjaundice due to stenosis of the common bile duct. It must be stated that retropancreatic choledochus surprisingly escapes the pressure caused by CP, in contrast to what happens in cases of cephalopancreatic carcinoma. Moreover, when there is dilation and kinking (Fig. 2) of the bile duct itself, even in the absence of jaundice, a drainage operation is advisable in order to avoid further surgery. It is exceptional for CP to cause duodenal stenosis (Fig. 3) to such a clinical and anatomic extent as to require surgery (1% of cases).

Digestive hemorrhages so severe as to require urgent surgery occur in up to 6% of cases. First of all, there are portal hypertension hemorrhages caused by compression of splenic vein or portal trunk. They are generally cured by simple splenectomy, and we have never been compelled to carry out portocaval shunts. Then there are erosion hemorrhages of an intra- or parapancreatic arterial vessel which occur inside a pseudocyst or directly inside the dilated duct system (Figs. 4, 5, 6). They are, therefore, Wirsung hemorrhages, usually occurring through hematemesis. They are detected through duodenoscopy, but angiography is necessary to identi-

Chronic Pancreatitis: Surgical Indications, Procedures and Limitations 225

Fig. 1. Operative pancreatography and cholangiography in a patient with chronic pancreatitis

226 A. Dagradi

Fig. 2. Preoperative and operative cholangiography in a patient with chronic pancreatitis

fy exactly the responsible artery. In these cases, a partial pancreatectomy is preferred, including the source of hemorrhage or, alternatively, artery ligature above and below it. A simple hemostatic suture in the pseudocyst wall layer is risky, even with an internal pancreatic drainage. The hemorrhage very easily reappears after a short time [8]. In 1 %-2% of cases, surgery is linked with pancreatic ascites which follow free leakage of juice into the peritoneum from the dilated duct system or pseudocysts (Fig. 7). It is known that this juice causes a chemical peritonitis whose clinical


Fig. 3a, b. Duodenal stenosis in a patient with chronic pancreatitis: a, c operative pancreaticocholangiography; b X-ray of upper gastrointestinal tract

signs quickly disappear because of the plentiful peritoneal seepage. The result is a clinical picture which is confusing and resembles hepatic ascites [3, 17, 31]. Clinical diagnosis is determined according to high serum amylase, high ascitic fluid amylase, and high protein content in the ascitic fluid.

The suspicion of carcinoma is usually due to: 1) Neoplastic transformation of CP and this is the situation in Table 1. Canalicu

lar histologic lesions (hyperplasia-metaplasia) during CP can explain the possible transformation into carcinoma, but this could also be by chance. Neoplastic transformation is found in about 3% of cases (2.5% in my papers).

2) Primitive carcinoma causing canalicular stasis, with a clinical picture similar to that of CP and a consequent diagnostic doubt, is difficult to solve. This situation is very frequent and doubts can still remain after surgical exploration. It must be added that the evolution of carcinoma in the pancreatic head is not always so quick as commonly affirmed and that, in my experience, pancreatic carcinoma can have such a long history that it causes not only canalicular stasis but lesions as well, which are more characteristic of CP (pseudocysts) [2].

228 A. Dagradi

==============~====~~==~~~~======== __ a

Fig. 4a, b. Upper intestinal bleeding (hemorrhage into the Wirsung) in chronic pancreatitis: a celiac angiography showing pseudoaneurismatic lesion in pancreatic artery; b as before, operative pancreatography showing cephalic pseudocyst

Nevertheless, the situations outlined in [1] and [2] have in common the problem of carcinoma diagnosis, upon which depends the rationale for pancreatectomy. With the exclusion of rather small tumors with possible metastasis, diagnostic difficulty specifically concerns the small nodes. Presurgical tests (CT, US, angiography) have obviously been meaningless in these cases. Pancreatography can in many cases contribute to the suspicion of carcinoma, but it does not solve the problem (Fig. 8). Even surgical biopsy can be deceiving because of the tendency of surgeons to keep to either superficial depths in the sampling of the inflammatory layer surrounding the tumor or lymph nodes only affected by a misleading reactive hyperplasia.


b

Fig. Sa, b. Hemorrhage into the Wirsung in chronic pancreatitis: a celiac angiography showing pseudoaneurismatic lesion in a gastric artery; b as before, operative pancreatography (pseudocyst of pancreas)

I think that at present the cytologic test of the material picked up from the center of the node by aspirating needly is the most suitable procedure. The principles of surgical strategy and its goals are shown in Tables 2 and 3. Excluding cases with canal pancreatic calcifications which favor diagnosis, the detection of CP can be difficult, above all in case of recurrent acute pancreatitis [34]. As for anamnesis we must consider that alcohol origin becomes more probable as a cause in our region when over 80-100 g of ethanol is consumed per day, though individual sensitivity is extremely variable, whereas the existence of bilia-

230 A. Dagradi

Fig. 6. Celiac angiography showing pseudoaneurismatic lesion of the splenic artery

a

b

Fig.7. Operative pancreatography showing fluid leakage from a pancreatic duct (a) or pseudocyst (b)


Fig. 8. Intraoperative pancreatography showing exstensive head stenosis in chronic pancreatitis (left) and in carcinoma of head of the gland (right)

Table 2. The principles of surgical strategy

Detection of the existence of CP

Result of pancreatic lesions: anatomic (specifically of ducts and pseudocyst) and functional, and of nearby organs (biliary ducts, duodenum, portal system, etc.)

Exclusion of a concomitant cancer

Table 3. The goals of surgical strategy

Elimination of cavitary and duct stasis and control of its complications (arterial erosions, peritoneal leakage of pancreatic juice, etc.) Elimination of extrapancreatic, secondary or associated lesions (biliary, duodenal, portal stasis) Resection of malignancies Preservation of residual exocrine-endocrine functions

ry pathology, either simultaneously or following, strongly backs the idea of recurrent acute pancreatitis. Out of 168 patients of Howard and Ehrlich, with whom this association was present, only one, nonalcoholic case, showed calcifications which could justify the diagnosis to be recurrent CPo Although there are researchers in the United States and in Europe who link 15%-20% of CPs with an original

232 A. Dagradi

disease of the biliary tree, it is necessary to underline the point that biliary disease and alcoholism are often associated, with a more convincing dependence of pancreopathy from the latter factor. The concomitance of biliary stones can be quite a chance (10%-15% biliary stones in the Caucasian population; 7% asymptomatic biliary stones in the Verona area). We must also admit that the precise definition of pancreatitis, whether chronic or recurrent acute, is only possible later, on the basis of results from surgical removal of gallstones. In alcoholic-induced cases this measure does not solve pancreatitis. Another problem is the defmition of CP in comparison with the so-called idiopathic pancreatitis which repeats the clinical model of CP, but occurs in older patients and is less frequently distinguished by pancreatic duct calcifications [14, 22]. From the surgical point of view, the distinction could represent a simple semantic question, since painless idiopathic pancreatitis does not require surgery, if it is painful then it requires the same surgery normally needed for CPo The assessment of pancreatic lesions is carried out both in the anatomicomorphological and functional points of view. At the same time, an assessment of secondary lesions in nearby organs must be done, i. e., of the biliary ducts, the duodenum, and the portal system. A series of radiologic tests are available, such as CT, US, angiography, barium study radiography, IV cholangio&raphy, and the pancreatography. Endoscopic retrograde pancreatography (ERCP) is worth mentioning as it is our opinion that CP surgery should be organized around it, the same as cholangiography for biliary duct surgery. In case backward ERCP pictures are not sufficient it is necessary to repeat intraoperative examination in order to obtain a better and more complete picture of the duct system and of its links with psuedocysts. Angiography is of secondary importance, often not being diagnostically effective speaking, however, it is able to detect congenital vascular abnormalities, which can be useful in cases of radical surgery. Moreover, it can be compulsory in case of hemorrhagic complications as it detects the source of hemorrhage. A functional survey has the purpose of measuring the exocrine and endocrine damage. Finally, I want to underline the point that surgical exploration can provide new and important fmdings to preoperative study. It must, therefore, be carried out thoroughly with a wide exposition both of pancreatic head (Kocher maneuver), body, and tail by thorough palpation. As for the exclusion of possible concomitant malignancies, I reaffirm what I have previously said about positive or negative false results of radiologic tests and about the advantages deriving from the cytologic study of material taken through fme needle aspiration. Surgical strategy chiefly aims at the elimination of pancreatic stasis within the duct system and the pseudocysts [23]. Stasis is in fact the main cause of pain. As in a single case there are several stenotic tracts with lacunar dilatations in between, and sometimes even pseudocystic cavities communicating or not with the duct system, it is necessary to remove all diaphragms building up free passage among stagnant lacunae. In the presence of pancreatic ascites, leakage of pancreatic juice must be treated by resection.


Secondary extrapancreatic lesions are treated with additonal operations (hepaticocholedochoduodenojejunal anastomosis, gastroenteroanastomosis, etc.) if the basic operation is represented by pancreaticojejunum drainage, and they are automatically cured by resection such as duodenocephalopancreatectomy or total pancreatectomy. The presence or suspicion of carcinoma implies segmental excision or total pancreatectomy. A very important goal of surgical strategy is the maintenance of residual exocrine-endocrine function. Though natural progress of CP causes functional impairment, all patients react adversely to drastic surgical suppression of these functions. This stresses the importance of pancreaticojejunal operations or of partial excision compared with total or subtotal pancreatectomy. The overall therapeutic needs and the several kinds of suggested operations for the treatment of CP show that the search for an ideal operation has no rational justification. The main principle in surgical strategy is to choose surgery for individual cases keeping in account the above-mentioned aims (Table 3).

Table 4. Indications of pancreaticojejunum anastomosis

Dilated ducts (linked pseudocyst) Maintenance of exocrine-endocrine function If needed: Tail resection Biliary/digestive anastomosis

Table 5. Indications for duodenocephalopancreatectomy

Concentration of duct lesions in the head particularly if associated with choledochoduodenum stenosis Suspected carcinoma Maintenance of exocrine-endocrine function

Table 6. Indications for the resection of body and tail

Concentration of body-tail duct lesions (stenotic segments, "chain of lacunae", pseudocyst) Important jeopardizing of insular function

In Tables 4, 5, and 6 we have tried to point out indications for each of the operations. It is worth adding that formulations of precise rules are only useful as a general indication every choice being subjective and thus dependent on the selfconfidence of the surgeon in respect of the different kinds of operation. In addition, different operations can nevertheless reach the same goals. However, it must

234 A. Dagradi

be clear that the monotonous adoption in advance of only one operation is theoretically and practically wrong. Duodenocephalopancreatectomy is theoretically the most suitable for achieving all aims [21, 25, 33]. It eliminates duct stasis as it removes, together with the pancreatic head, the most affected segmental duct; it removes possible extrapancreatic lesions such as biliary and duodenal stasis; it removes compression on the portal vein and carries away possible neoplasms, which are most frequently localized in the pancreatic head. At the same time, this operation preserves the exocrine and endocrine functions of pancreatic body and tail. Nevertheless, it is worth saying that the surgical risk of this operation is relatively high. The gastric body and duodenum are systematically demolished thus increasing the risk both of malnutrition and the absorption of alcohol (it increases the risk of liver cirrhosis); in addition, by annulling duodenobiliary-pancreatic "synergism" it quickens, perhaps, the evolution of the disease. Last but not least, we must not forget, for a population of young patients, the risk of a late carcinoma in the gastric stump. In the series of Leger, follow-ups in 5-10 years have shown unsatisfactory results for this operation because of deficient metabolic conditions, liver cirrhosis, etc. Each operation implied in general surgical strategy deserves specific considerations. As for pancreaticojejunal anastomosis, we usually open the Wirsung at the isthmus (in the track of the needle used for pancreatography) then enlarge the opening to all the duct system, both toward the head, as far as beyond the loop, in order to obtain an outlet from the Santorini duct and toward the tail. This large pancreatic passage is then anastomosed with a long jejunal Y-shaped loop. The very large opening in the Wirsung is not only meant to obtain a large anastomotic mouth, as it is the Wirsung width that determines the amount of the discharge, but also to demolish all septa along the duct system, since they jeopardize the results of short pancreostomies and make them with time pointless. Small intraparenchymal cavities and pseudocysts are widely opened and included in the anastomosis in order to allow the discharge of all the lacunar system. In short, we carry out Partington and Rochelle's technique, only modified by the very large width of pancreaticojejunum drainage [16, 24, 25, 29]. The basic operation can imply an additional resection of the tail if lesions are concentrated there (i. e., small pseudocysts, series of lacunae limited to the tail, etc) [9]. If needed an internal biliary anastomosis is added, usually a choledochus-duodenum anastomosis. As for duodenocephalopancreatectomy we follow the well-known Child's scheme (1943), with only one variation, the opening of Wirsung body-tail starting from dissection in order to remove possible septa in the remaining pancreas and to avoid their formation in the future as a consequence of the evolution of CP [14, 18,19,20]. A jejunum loop is placed by the transmesocolic route and its terminal end is opened on the antimesenteric margin in order to enable connection with the remaining pancreas, whose duct system has been widely shown. The thickness of pancreatic tissue, damaged by CP, improves the holding of suture stitches. Internal biliary anastomosis consists of liver-jejunum anastomosis, which offers better functionality, above all in CP where the biliary duct is not or only slightly dilated.


Gastric resection is wide, in order to avoid the risk of ulcers of anastomosis. We never fit any tubular drainage inside pancreatic or biliary ducts, as we are convinced that it is the flow of secretions that mould anastomosis and that tubular drainage even causes irritation, and thus can be dangerous. From the technical point of view it is proper to point out that duodenocephalopancreatectomy carried out for CP is more difficult than when performed for carcinoma localized in the head, because of strong adhesions which can tie the organ to the portomesenteric axis. Actually, unexpected surgical accidents, such as portal lacerations, have happened to us in this surgery more frequently than in carcinoma surgery, though they have always been repaired. As I have already said, impediments for this operation are all physiopathologic and mainly concern long term results.

b

Fig. 9a. b. Segmental chronic pancreatitis: a operative pancreatography showing injury of body and tail; b operative specimen

In our experience, body and tail segmentary CP are very rare (Fig. 9). They require the resection of these pancreatic segments. A stenosis in the isthmus to determine a clear prevalence of body and tail lesions which imply a suitable resection of these segments. In any case, body and tail resection is followed by a large

236 A. Dagradi

opening in the Wirsung head and subsequent jejunum drainage of the head canal system [9]. Total pancreatoduodenectomy and Child's 95% pancreatectomy are performed according to the rule, from left to right with splenectomy. These are suitable operations in anatomomorphological conditions particularly with suspected carcinoma transformation in the body or tail, and in patients with serious and very serious diabetes with difficult compensation [5, 26]. The impediments for these two operations do not concern the surgical risk, but the complete and fmal functional mutilation. Even in situations of very serious diabetes, the glycoregulation mechanism due to glucagon is never totally destroyed. Thus, from this point of view, the above operations cannot be considered lightly. These operated patients do have real control difficulties and strict and methodic checking in specialized medical centers is compulsory. As for the less dramatic 95% pancreatectomy, it is not to be neglected even though it has frequent complications such as fistulas in the remaining pancreas and abscess formation (Frey).

Table 7. Autonomous chronic pancreatitis (ACP)

Etiologic or associated factors:

Alcohol Undefined Biliary

Table 8. Chronic pancreatitis operations (Verona Surgical Clinic, 1969-1979)

Pancreaticojejunumstomies Duodenocephalopancreatectomy Left pancreatectomy Subtotal 95% pancreatectomy Total pancreatectomy Operations on sympathetic system

Operated patients

76% 19%

5%

162 (71%) 38 (16%) 12 ( 5.4%)

~}( 5.6%)

4 ( 2%)

229

Tables 7 and 8 show our experience in the decade 1969-1979. They refer to 229 patients (Table 8), nearly all hospitalized and studied in several gastroenterology medical centers, mainly in the local medical clinic. They represent, at present, 58% of CP patients hospitalized in these centers. It is interesting to note that in previous years, the percentage of patients undergoing surgery was up to 75% and that the present decrease is actually in relation with the detection of CP in early stages, and judged "not yet surgically mature." Alcohol origin clearly prevails (76%), which could also include a quota of etiologically not well-defmed forms (19%). In the latter there is often a previous biliary anamnesis whose relationship with pancreopathy is still very disputable. Biliary


stones are at present associated with pancreatitis in 5%-9% of cases, probably by chance. Only in one case did it determine jaundice. In 5.6% of cases, at the time of operation, it was associated with liver cirrhosis. Jaundice was present in 9 cases (3.8%), justified by CP itself, with the exception of one case with biliary stones. Altogether, 162 drainage operations have been performed (71% of cases), Table 9, 42 in association with small tail resections.

Table 9

Operated patients under control: Follow-ups (2 to 9 years): Results: Good Partial Insufficient

109 67

59 (88%) 4 ( 6%) 4 ( 6%)

The results in this group of patients are shown, in detail, in Marzoli's report. Duodenocephalopancreatectomy was performed in 38 cases. The results of this group are shown in Serio's report. Here, I only state that mortality was 3%, with very good short and average term results (follow-ups from 2 to 10 years: definitive pain disappearance in 94% of cases, ponderal (weight) increase and restarting of work activity in 84% of cases) though steatorrhea increased (in patients who carried on drinking alcohol) and there were persistent CalP metabolism alterations able to cause osteoporosis and osteomalacia sensitive to the administration of vitamin D. Tail-body pancreatic resection was carried out 12 times (5.5% of cases) with very good results. In 13 cases (5.6%) subtotal or total pancreatectomies were performed, with disappointing results overall in terms of the difficulty in controlling postsurgical diabetes. Five patients died from hypoglycemic coma which suddenly appeared in a period from 3 to 5 years after the operation. Splanchnicectomy was only reserved for four patients with the precise purpose of controlling pain in conditions highly dangerous for pancreas-jejunum derivation. In our hospital, we have improved, in the last few months, the technique of novocaine or alcoholic infiltration of the splanchnics and of celiac plexus [6]. Our perplexity with the methodic adoption of this procedure in patients with pain concerns their exposure to complications such as: pseudocysts, digestive hemorrhages, and ascites. Finally, in following the surgical strategy dealt with in this paper, we have achieved the following results: satisfactory 88% (59 patients), unsatisfactory 12% (8 patients). For satisfactory results we mean both the complete or partial disappearance of clinical symptoms, specifically pain. In short, the complete or partial restoration of a socially active life for the patient.

238 A. Dagradi

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cites. Am Surg 170: 668 4. Carey CL (1973) The pancreas. Mosby, Saint Louis 5. Child CG, Frey CF, Fry WJ (1969) A reappraisal of removal of95% of the distal por

tion of the pancreas. Surg Gynecol Obstet 129: 49-56 6. Copping J, Willix R, Kraft R (1969) Palliative chemical splanchnicectomy. Arch Surg

98:418-420 7. Dagradi A, Serio G (1976) Considerazioni su 92 casi operati per pancreatite cronica:

problemi di tattica chirurgica e risultati a distanza. Chir Triveneta 16:94--119 8. Dalton WE, Lee HM, Williams GM, Hume DM (1970) Pancreatic pseudocyst causing

hemobilia and massive gastrointestinal hemorrhage. Am J Surg 120: 106 9. Duval MK, Enquist IF (1961) The surgical treatment of chronic pancreatitis by pan

creaticojejunostomy: an 8-years reappraisal. Surgery 50: 965-969 10. Frey CF (1969) The operative treatment of pancreatitis: Arch Surg 98:406-417 11. Goldsmith HS, Ghosh BC, Huvos AG (1971) Ligation vs. implantation of the pancreat

ic duct after pancreatico duodenectomy. Surg Gynecol Obstet 132: 87-92 12. Grace RR, Jordan PH (1976) Unresolved problems of pancreatic pseudocyst. Ann Surg

184:16-21 13. Griffin JM, Starkloff GB (1971) Surgery of chronic pancreatitis. Am J Surg 122: 18-

21 14. Grodsinsky C, Schumann BM, Block MA (1977) Absence of pancreatic duct dilation in

chronic pancreatitis. Arch Surg 112:444--449 15. Guillemin G, Culleret J, Michel A, Berard P, Feroldi J (1971) Chronic relapsing pan

creatitis. Am J Surg 122: 802 16. Jordan GL, Strug BS, Crowder WE (1977) Current status of pancreatojejunostomy in

the management of chronic pancreatitis. Am J Surg 133:46-51 17. Kavin H, Sobel JD, Dembo AJ (1971) Pancreatic ascites treated by irradiation of pan

creas. Br Med J 1: 503 18. Lamy J, Sarles JC, Dubau R (1972) Resultats Ii 5 ans du traitement chirurgical des pan

creatites chroniques. 9th Congress Soc. Int. Gastro-enterol., Paris 19. Leger L, Lenriot JP, Lemaigre G (1974) Five to twenty follow up after surgery for

chronic pancreatitis in 148 patients. Ann Surg 180: 185-191 20. Levrat M, Descos L, Moulinier B, Pasquier G (1970) Evolution au long cours des pan

creatites chroniques. II. Etude de l'evolution de la pancreatite chronique chez les malades operes. Arch Fr Mal App Dig 59:305-314

21. Mercadier M, Melliere D (1967) Indications et resultats de la duodeno-pancreatectomie cephalique. Presse Med 75: 1683-1687

22. Nakamura K, Sarles H, Payan H (1972) Three-dimensional reconstruction of the pancreas in chronic pancreatitis. Gastroenterology 62: 942-949

23. Nardi GL, Lyon DC, Sheiner HJ, Bartlett MK (1969) Solitary occult retention cyst of the pancreas. N Engl J Med 280: 11-15

24. Prinz RA, Kaufman BH, Folk FA, Greenlee HB (1978) Pancreaticojejunostomy for chronic pancreatitis. Two-to 21-year followup. Arch Surg 113: 520

25. Proctor HJ, Mendes OC, Thomas CG, Herbst CA (1979) Surgery for chronic pancreatitis. Drainage versus resection. Ann Surg 189:664--671

26. ReMine WH, Priestley JT, Judd ES, King IN (1970) Total pancreatectomy. Ann Surg 172: 595-604

27. Sarles HM (1965) Pancreatitis. Symposium Marseilles 1963. Karger, Basel 28. Sarles HM (1971) Alcoholism and pancreatitis. Alcoholic pancreatitis in man (review).

Scand J Gastroenterol 6: 193-198 29. Sato T, Saitoh Y, Noto N, Matsuno K (1975) Appraisal of operative treatment for

chronic pancreatitis with special reference to side pancreaticojejunostomy. Am J Surg 129:621-628


30. Sato T, Saitoh Y, Noto N, Suda Y (1970) Evaluation of surgical treatment of chronic pancreatitis. Tohoku J Exp Med 101: 351-362

31. Schindler SC, Schaefer JW, Hull D, Griffen WO (1970) Chronic pancreatic ascites. Gastroenterology 59: 453

32. Strum WB, Spiro HM (1971) Chronic pancreatitis. Ann Intern Med 74: 264-277 33. Warren KW, Mountain JC (1971) Comprehensive management of chronic relapsing

pancreatitis. Surg Clin North Am 51:693 34. Warshaw AL (1972) Pancreatic abscesses. N Engl J Med 287: 1234

Long Term Results of Pancreaticoduodenalresection (PDR) in Chronic Pancreatitis

G. Serio

Istituto Clinica Chirurgica, Universita Padova, Sede in Verona, Policlinico B. Roma, 37100 Verona, Italy

At present the indications for operation in cases of chronic pancreatitis and the criteria for selecting the correct technique among the various available are sufficiently coded. However, as far as pancreaticoduodenal resection (PDR) is concerned a number of limits and problems persist, which are yet to be solved, that are interfering with a more systematic and rational application of the procedure: (a) whether this operation is advisable in cases of chronic pancreatitis as an alternative to other surgical palliative procedures (such as pancreaticojejunostomy); (b) the still remarkable intraoperative mortality rate which, according to some case reports still ranges between 8% and 10% of the patients operated on; and, finally, (c) the predictable biologic long term repercussions from an extensively radical operation, liable to cause significant deficiencies in the functions of other organs, as well as severe alterations in the intestinal dynamics. With a view to giving a contribution to the solution of these problems, a clinical and functional investigation was made on a group of patients selected from a total of 38 cases of PDR which were performed during the last 9 years at the surgical clinic of Verona. The group comprised of 18 patients, all of whom had been operated on not less than 2 years earlier; of the remaining 20 patients, 19 were excluded for various reasons (12 because they had been operated upon in the course of the last 2 years, 2 had died from cirrhosis 4-5 years after the operation, and 5 because they could not be traced or refused to cooperate); the last one had died in the postoperative stage (postoperative mortality 3%). The criteria, on which the operation was found to be indicated, may be summarized as follows: (a) Pancreatography results showing multiple or extensive stenosis in relatively long tracts of the head Wirsung, particularly when associated with a higher concentration of calcifications in the head of the gland. These are conditions for which no alternative technique could be found, since the problem related to sclerocalcified areas of the head - which are excluded from the duct drainage and cause pain - would remain unsolved. (b) The doubt would remain whether it was a carcinoma, despite the various diagnostic techniques available pre- and intraoperatively. (c) A lesser indication is given by pseudocysts, either single or multiple, particularly those which do not communicate with the main pancreas duct. (d) The stenosis of choledochus and/or duodenum would call for the resection of the head of the gland, only when associated with at least one of the above conditions. The 18 patients selected were subjected to the following clinical and functional investigations: anamnestic scrutiny, weight control, X-rays (rachis and hands), as-

242 G. Serio

sessment of the total fecal lipids, glycemia and glycosuria over 24 h, total and fractionated proteinemia, calcemia and calciuria over 24 h, tubular reabsorption of Ca and P, alkaline phosphatasemia, plasmic 25-hydroxicholecalciferol, and biopsy of the bone tissue. From the anamnesis it is worth mentioning that out of 17 patients who claimed to have painful symptoms before the operation only one had occasional pain relapses, and that out of 17 patients fit for work before the operation 14 had resumed their former activities after the operation.

The weight control showed that 15 patients out of 18 had increases in weight up to 40% over their weights when discharged from the hospital, which was equal to 15-18 kg. The three patients whose weight remained unchanged or had decreased at the anamnestic scrutiny were found to have incorrect dietary habits, "potus," insufficient enzyme-digestive correction, or associated hepatic conditions.

The functions of digestion were checked through the assessment of the total fecal lipids after the enzymatic therapy was discontinued. A lipidic excretion of more than 7 g/24 h occurred in 13 patients out of 18 (72%). In a few subjects the assessment was repeated after a standard enzymatic therapy (4-16 g/day of B.P. pancreatin) which caused a manifest decrease of the lipid dispersion (Fig. 1). The behavior of glycoregulation, which was ascertained through glycemia, and glycosuria over 24 h, showed a manifest diabetes in three cases, one more than those reported before the operation. The protein and hemoglobin values were found to be within the standard limits. Two-thirds of the patients were found to have a calcium hypotrophy of the skeleton, inconsistent with the mean age of these patients. This observation has suggested the hypothesis of either a deficiency in calcium absorption secondary to

g/24h

100 0

en Cl 80 a:: 0 ::::i ....I 60 <I: u 0 w <I: 40 0 u.

0 20 0

0 0 0 0

°A ° A ° 7- oA ° 0 0 OA A A

2 3 4 5 6 7 8 9 years

o without enzymes A with enzymes

Fig.1. Total fecal lipids in 18 patients who had undergone PDR for at least 2 to 9 years. The survey covered the whole group after the enzymodigestive therapy was discontinued, and also 6 cases while the therapy was in course

Long Term Results in Chronic Pancreatitis 243

Ca-s p-s Ca-u p-u MG/DL MG/DL MG/24h IMG124h

10,5 4,5 • 250 1300

8,5 2,5 100 'i o. 900 • .o~ •• • 0 o •

0 .0 .0 ••••• .0 • •

TR Ca TR P • 25-0H D3 ALP % % •• ng/ml U/L

••• 0

99 90 •• 0.

6 90 • o • • • 94 84 2 30

• • 0

• • bone decalcification o normal bone calcification

Fig.2. Alterations in P and Ca metabolism in patients who underwent pancreaticoduodenectomy_ The following were the values considered: serum and urine calcium and phosphorus, calcium and phosphate tubular reabsorption (TR Ca/P), 25-idroxicolicalciferol (25-OHD3), serum alkaline phosphatase (ALP) in relation to the Xray examination for bone decalcificatio

the steatorrhea, or a deficiency in the absorption of vitamin 0_ The latter hypothesis would be corroborated by some biochemical observations (Fig_ 2): (a) a frequent shifting towards the lower standard limits of plasmic Ca and P; (b) steady decrease of urine Ca; (c) increase of tubular reabsorption of Ca and P (the increase of Ca reabsorption, in particular, would also suggest the interference by a secondary hyperparathyroidism); (d) decrease of 25-hydroxi-cholicalciferol values in four out of eight patients studied_ The biopsy of bone tissues showed - in those who were affected - a mixed picture of osteoporosis and osteomalacia_

Conclusions

1) The first impression which is drawn from a evaluation of these results is that in all cases where PDR is indicated it seems to be able to solve - with reasonable operative risk (postoperative mortality is 3%) - one of the most important pathophysiologic and pathologic problems which lie at the basis of chronic pancreatitis, i. eo, hampered pancreatic, biliary, and digestive discharge, pseudocysts, and sclerocalcification of the pancreas head, portomesenteric compression_ As a consequence, the main clinical problem, i_ eo, pain, is favorably influenced_

2) We think that the low postoperative mortality (which proved to be definitely lower than the 10% we reported after the same operation for periampullary neoplasms) might be due to the lower mean age of the patients, as well as to

244 G. Serio

the surgeon being less influenced in his choice of PDR, and the possibility of making a selection from the patients to be operated on (i. e., excluding those in poor general conditions and those who could not be sustained through total intravenous alimentation, as well as jaundiced patients, alcoholies, drug addicts, and those suffering from portal hypertension).

3) The life standard turned out to be more than satisfactory, following these short and medium distance controls: defmitive regression of pain was reported in 94% of cases, and increase in body weight and resumption of work activities in 84% of cases.

4) Once again the importance of periodic controls of the alimentary habits is confirmed, the complete abstention from alcohol, the periodic adjustment of the enzymatic therapy - essential to control steatorrhea, which would otherwise affect more than 70% of the patients operated. The risk of diabetes in the postoperative stage appeared to be worrying in a lesser degree (only one patient in our case reports).

5) Finally, this report has called attention to the remarkable frequency (more than two-thirds of the patients operated on) of persistent alterations in Ca and P metabolism, which might cause osteoporosis or osteoporomalacia, and on the need for prevention or treatment of such ailments by adjusting steatorrhea and administering vitamin D. Despite some reservations due to the rather short time elapsed after the operation (2-9 years), the ample possibility emerges from this clinical and functional survey for the biologic recovery of patients who underwent PDR; particularly when they are adequately supported in those functions which were most severely affected by the surgical treatment.

References

1. Fish JC, Smith IB, Williams RD (1969) Digestive function after radical pancreaticoduodenectomy. Am J Surg 117:117-123

2. Hivet M, Roullet-Audy J-C, Poilleux J (1976) Bilan de 56 duodenopancreatectomies cephaliques pour pancreatite chronique. Ann Chir 30:371-376

3. Mori K, Misumi A, Sugiyama M, Sakamoto Y, Ishii J, Kaneko T, Akagi M (1979) Postoperative evaluation of the exocrine function of the pancreas after pancreaticoduodenectomy. Surg Gynecol Obstet 148:16-18

The Endocrine Function of the Pancreatic Residue After Partial Duodenopancreatectomy

K.-D. Rumpf, J. Antonschmidt, Ch. Datan, H.-J. Mitzkat, and R. Zick

Klinik fUr Abdominal- und Transplantationschirurgie, Karl-Wiechert-Alle 9, 3000 Hannover 61, Federal Republic of Germany

Inflammatory diseases of the pancreas are increasingly being treated by resection. The center of the main inflammatory process in chronic pancreatitis is usually localized in the head of the pancreas [8]. For its elimination, it is necessary to perform a partial or a total duodenopancreatectomy (in German-speaking countries: Whipple's operation). Using this surgical treatment, the total number of the islets of Langerhans is necessarily reduced, which influences the glucose metabolism in that way that it causes a relative insulin deficiency, which in the worst cases manifests itself as diabetes mellitus. A total pancreatectomy completely removes the most important sources of insulin production. Consequently, this operation is always accompanied by hormone substitution therapy, which in most cases is more difficult than the therapy administered to patients with an existing pancreatic residue [5, 6, 11]. The danger of a progressive fibrotic transformation of the parenchyma is very high if the indication to resect comes too late or is dismissed by the surgeon. Such a transformation occurs especially in the pancreatic body and tail regions in the late stage [1]. Ultimately the continuing destruction of tissue leads to a total loss of endocrine function. Therefore, the decision to perform a resection of the pancreatic head in benign' cases, should be influenced by knowledge of the specific endocrine condition of the pancreas. It is especially important to consider this factor, so that one may avoid an insulin-dependent diabetes. The decreased production of exocrine pancreatic enzymes is not quite so important, because a correct oral substitution therapy can be achieved without problems [7]. Therefore, the following investigations will also try to answer questions such as whether a diabetes can be avoided by preservation of the pancreatic tail by duodenopancreatectomy or whether the pancreas should be preserved for endocrine metabolic reasons.

Patients and Methods

In our clinical tests we conducted follow-up studies of 48 patients with chronic pancreatitis who had undergone duodenopancreatectomy (Tab. 1). In 32 of them

246 K.-D. Rumpf

(i.e., 74.5% of those who were still alive) we made the examinations under clinical conditions. The operation had been performed at least 1 year previously. The following tests were performed: a) The daily profile of the blood sugar; b) An intravenous glucose tolerance test; c) The C-peptide determination in the serum after stimulation; d) The daily output of C-peptide without stimulation.

Table 1. Number of patients with partial duodenopancreatectomy, 1970-January 1980, Clinic for Abdominal and Transplantation Surgery, Medical School, Hannover

Patients with partial duodenopancreatectomy

Date: 1. 1. 80 Letality Follow-up

n % n %

Pancreas carcinomas 24 13 Ampullary carcinomas 21 to,5 Chronic relapsing 62 8 48 96 pancreatitis

Total 107*

* Excl. infringing tumors (n = 29)

We compared the thus obtained picture of the actual functional condition of the islets of Langerhans with the functional situation before the operation. It had to be assumed that the chronic inflammatory process had led to various changes in the whole organ prior to the operation. From the comparison of the metabolism before and after surgery, it was possible to draw conclusions about the influence of the resection itself on glucose regulation. The question that seemed very important was whether a progressive inflammatory process in the rest of the pancreas worsens the endocrine situation, resulting in the manifestation of diabetes mellitus after a longer period. At first we tried to discover unknown diabetic situations by determining daily values ofthe blood sugar from all the patients. Simultaneously, we checked the metabolic glucose situation of the already known diabetics. The remainder of the nonmanifest diabetic persons were subjected to a glucose tolerance test with O,6g glucose/kg body weight. The C-peptide measurements were made by radioimmunoassay according to the methods of Heding [3]; human C-peptide from the company Novo was used as the standard. The insulin excretion from the B cells was stimulated by 1 mg glucagon IV.

Results

Of the 48 patients with pancreatitis, 15 (31%) already had a manifest diabetes mellitus before the operation, and 7 of them (14.5%) also had to take insulin (Tab.

The Endocrine Function of the After Partial Duodenopancreatectomy 247

2). Immediately after the operation we registered four more cases of manifest diabetes, three of which were insulin-dependent. This resulted in a 12% increase in diabetic patients, including a 9% increase in the insulin-dependent ones.

Table 2. Diabetes before and after partial duodenopancreatectomy because of chronic pancreatitis

Diabetes before operation Oral agents: 8 (17%) Insulindependent: 7 (14%)

More than 1 year after Oral agents: 9 (24%) Duodenopancreatectomy Insulindependent: 10 (21%)

Increase in diabetes by Oral agents: +3% duodenopancreatectomy Insulindependent: +6%

Their glucose disorder began immediately after the operation, which permitted us to correlate the diabetes caused by the lack of pancreatic tissue. In our own patients, we did not fmd any glucose metabolic disorders that manifested themselves after a longer period. These fmdings were strengthened by the daily glucose prome of nondiabetics in the follow-ups. Our results showed that no occult diabetes could be detected. It was note worthy that the insulin-dependent diabetics often complained about hypoglycemic signs, such as hunger, outbreaks of perspiration, tachycardia, etc. and especially at night and/or following hard physical work. It was especially difficult, in all of the diabetics, to influence the glucose situation by an additional diet. This special treatment, i. e., to limit the intake of carbohydrates and the total number of calories, in most cases had to be abandoned because a rapid loss of weight occurred, which on the other hand resulted in an elevation of insulin dosage. A iv. glucose tolerance test could be performed on 29 duodeno-pancreatectomized patients (Fig. 1). Only four of them had a normal glucose tolerance with a K-value of more than 1.2. In 21 of the patients (72%), the K-value was determined to be less than 1.0, which is certainly within the pathologic range. In four of thepatients, a questionable glucose tolerance with K-values between 1 and 1.2 was found. A direct correlation exists between C-peptide (i. e., the peptide removed from proinsulin to make insulin) and insulin in the serum of healthy indviduals, even after stimulation of the B cells by glucagon, as shown by Thiel et al. and Zick et al. [9, 12]. The direct proportionality offers the possibility of using the C-peptide instead of insulin as a parameter when statements are made regarding the remaining capacity of the B cells in the islets of Langerhans. This also allows us to investigate insulin-dependent diabetics and patients with an insulin-antibody syndrome. Figure 2 shows the content of C-peptide in the serum as basic secretion as well as the sum of C-peptide concentrations 6, 10, 15, and 20 min after stimulation with glucagon. The analysis of the different groups of patients, separated on the basis of glucose tolerance results, shows almost identical basic values in each group:

248 K.-D. Rumpf

patients after partial duodeno-pancreatectomy

n = 48

I I I

Iv - glucose- manifest tolerance -test diabetes

n = 29 n = 17

I I

healthy doubtfully subclin.

(KG >1.2) pathological diabetes

14% (KG = 1,0-1,2) (KG <1,0)

14% 72 % 20%

, --

80%

Fig.t. Glucose tolerance tests of nondiabetic patients, who underwent a partial duodenopancreatectomy; KG = glucose assimilation coefficient

C - peptide in the serum [pg/mll

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

I (KG> 1.2) (KG 1.0- (KG <1.0) manifest 1.2) dlabeles

normal afler partial duodenopancraataclomy

+11%

Fig. 2. C-peptide excretion from the pancreatic residue of patients who were duodenopancreatectomized because of chronic relapsing pancreatitis: CPR concentrations before and afer stimulation with glucagon; X = I CPR after 6, to, 15, and 20 min


0.5-0.6 pg/ml. The stimulation of insulin excretion in diabetics did not produce any effect, i. e., there was no additional elevation of C-peptide excretion. In patients with a reduced glucose tolerance (K < 1.0), the liberated quantities of Cpeptide were only about one-third of those in patients who had a normal glucose tolerance (i. e., 0.3 pg/ml instead of 0.96 pg/ml). After excluding renal failure in 27 patients, we measured the daily output of Cpeptide in the urine by way of radioimmunoassay (Fig. 3). This showed that manifest and subclinical diabetics have a highly diminished daily output of C-peptide (13,9 and 7,5 nmol/24 h) respectively, when compared with those who have a normal glucose metabolism (28,5 nmol/24 h).

C - peptide [nmoI/24hurine]

30

25

20

15

10

5

patients with nonnal glucose

tolerance

- i"- T' patients with subclinical diabetes

(KG < 1.0)

patients with - '-- manifest

diabetes

n =17

+ normal I aft.er partial duodenopancreatectomy

Fig. 3. C-peptide in urine (based on measurements in 24 hour urine) of normal patients and of those with subclinical and manifest diabetes following a partial duodenopancreatectomy; n = 43

Discussion

Partial duodenopancreatectomy involves two immediate technical dangers for the patient: insufficiency of the biliary and of the pancreatic anastomosis. The pancreatic anastomosis is especially important, because of the tryptic and autolytic components of the resulting inflammation, which has a high morbiditiy and often necessitates total pancreatectomy. If one tries to avoid this danger by electively performing a total pancreatectomy, one produces a severe diabetes as a result of the lack of pancreatic tissue. In these cases, insulin substitution is necessary, which, of course, involves a lot of difficult problems. On the other hand, it is possible to live without a pancreas, as shown by Kummerle and Trede [4, 10], who made their investigations with a large number of patients. These diabetics are nevertheless very apt to develop hypoglycemic

250 K.-D. Rumpf

states, which are frequently the cause of death. The reason for this severe complication seems to be a limited tolerance in the insulin therapy of diabetic patients, which is caused by a lack of glucagon production [2, 6]. If part of the pancreatic tissue is retained, the question arises as to whether an insulin-dependent diabetes can be avoided and some production of glucagon preserved. As already stated, from our own clinical experience, 31% of the patients already had a manifest diabetes before operation. Immediately following surgical intervention, four additional diabetic cases occurred, of which three were insulin dependent. These were obviously caused by the operation itself. These results match with earlier investigations of Mangold [5], who observed a 9% increase in diabetic patients after resecting the head of the pancreas in chronic pancreatitis. As we could see in our observations, it is highly improbable that the transformation of adenoid cells to an undifferentiated fibrotic tissue will continue in the pancreatic tail and finally lead to a diabetic situation if the proximal pancreas has been removed a long time previously. Of course, this assumes that the duct system of the remaining pancreas has good drainage of pancreatic juice and that no stasis occurs. This seems quite important for cases of pancreolithiasis, because the distal duct system could contain a lot of occluding stones which would result in stasis and progression of the inflammatory process. All new and postoperative diabetic cases developed immediately following the operation. This agrees with the findings, that diabetes mellitus of short duration could not be found in those patients whose surgical treatment was performed some years ago. In the therapy of diabetes caused by the lack of pancreatic tissue, it is very important to consider that the human body is dependent on carbohydrates as the main source of energy as a result of the extraordinarily developed malassimilation. When the pancreas is totaly removed, the resulting increased need for exogenous insulin can lead to an increase in hypoglycemic situations, especially at times of reduced food intake and as a result of a lack of glucagon. The high proportion of subclinical diabetes (72% of the duodenopancreatectomized patients show a reduced glucose tolerance) can probably be explained by the fact that the former high endocrine functional reserve of the pancreas was considerably reduced as a result of the operation. However, this is still sufficient to maintain a normal homeostatis of the blood sugar, provided that the quantities of glucose, which are to be metabolized, remain in the physiologic range. On the other hand, an axcessive amount of glucose can no longer be successfully compensated. We have found that the intracellular reserves of proinsulin were reduced to about half of the original amount after resection of the pancreatic head (Fig. 2). The clinical importance of these results is not very severe for the patients. In approximately three-quarters of all those operated, the only consequence is to avoid extraordinary large glucose intake. It is neither necessary to employ special therapy nor a diet.

Summary

The follow-up results of endocrine pancreatic function in 48 patients with chronic relapsing pancreatitis were investigated more than 1 year after resection of the


pancreatic head. It was shown that in 9% of all cases the operation led to an additional manifestation of a diabetes mellitus, whereby 4% were insulin dependent. In threequarters of all nondiabetics the subclinical diabetic situation (Ko < 1.0) was expressed by a pathologic decrease in the iv. glucose tolerance test. These fmdings were supported by a considerable decrease in the C-peptide values in the serum and the urine, which are explained by the reduction of the pancreatic endocrine capacity, following resection of the pancreatic head or by the inflammatory process itself. A remarkably large number of all diabetic changes are caused by calcifying pancreatitis, whereby multiple concremental obstructions were found inside the pancreatic duct system.

References

1. Becker V (1973) Bauchspeicheldrtise. In: Doerr, Seifert, Uehlinger (Hrsg.) Spezielle pathologische Anatomie. Bd VI. Springer, Berlin Heidelberg New York

2. Dammann HG, Besterman HS, Bloom SR, Schreiber HW (1979) Gastrointestinale Hormone und totale Duodenopankreatektomie. Z Gastroenterol 567

3. Heding LG, Rasmussen SM (1975) Human C-peptide in normal and diabetic subjects. Diabetologia 11:201

4. Kiimmerle F, Beck K, Tenner R (1969) Leben ohne Pankreas. Dtsch Med Wochenschr 94:691

5. Mangold G, Kiimmerle F (1979) Resektionstherapie bei chronischer Pankreatitis. In: Haring R (Hrsg.) Die Chirurgie der akuten und chronischen Pankreatitis. TM-Verlag, Bad Oeynhausen

6. Mielke F, Beger HG, Schirop TH (1975) Digestive und inkretorische Funktionen nach partieller Duodenopankreatektomie Dtsch Med Wochenschr 100:171

7. Rumpf KD, Antonschmidt J, Datan CH, Zick R, Mitzkat HJ (1980) Die B-Cell-Restfunktion des Pankreas nach partieller Duodenopankreatektomie. Langenb Arch Chir 351:285

8. RumpfKD, Neter A, Atuahene K (1977) Ergebnisse der chirurgischen Therapie chronischer Pankreatitisformen. Zentralbl Chir 102:869

9. Thiel M, Krause U, Mangold G, Wolff E, Beyer J (1979) Untersuchungen zur Sekretion des Enteroglucagon bei Patienten nach totaler Duodenopankreatektomie. Med Klin 74:14, 51

10. Trede M (1976) Die totale Pankreatektomie. Langenbecks Arch Chir 340:227 11. Willig F, Schmidt FH, Trede M (1976) Nachbehandlung und Uberwachung total-pan

kreatektomierter Patienten. Med Klin 71:999 12. Zick R, Schladder D, Schurek HJ, Mitzkat HJ (1979) C-Peptid-Kinetik bei Storungen

der Nierenfunktion. In: Die Bedeutung der C-Peptid-Bestimmung flir die Diagnostik. Schnetztor-Verlag, Konstanz, S. 149

Follow-up of Chronic Pancreatitis. Methodological Considerations

G. Bianchi Porro, A. Prada, and M. Petrillo

Servizio di Gastroenterologie, Ospedale L. Sacco, Via G. B. Grassi 74, 20157 Milano (Italy)

Introduction

Chronic pancreatitis is a disease generally arising under the age of 40. Its etiology in Italy, as well as in Europe and the United States in general, is mainly linked to the abuse of alcohol [1]; it continues for many years with progressive destruction of the pancreatic parenchyma and the appearance of complications. Two forms of chronic pancreatitis are recognized clinically [2] - relapsing, and non-relapsing or painless - which differ chiefly in their speed of development and incidence of complications. Apart from the pain, treatment of chronic pancreatitis consists of treatment of the complications, and a fundamental aspect is to follow up these patients in order to (1) facilitate abstention from alcohol; (2) promptly identify and treat complications or the onset of other pathology, possibly masked by the symptoms of chronic pancreatitis; and (3) assess the possibility of surgical treatment. The complications of chronic pancreatitis can be divided into four groups: alterations of the pancreatic gland (calcification, pseudocysts, abscesses, cancer); alterations of the exocrine function (steatorrhoea, creatorrhoea) and/or of the endocrine function (diabetes mellitus); damage to adj acent organs (stenosis of the bile duct with or without lithiasis, portal or splenic thrombosis with splenomegalia or portal hypertension, perineural inflammation of the sympathetic chains, pancreatic ascites); and associated pathology (cirrhosis of the liver, gastro-intestinal haemorrhage, duodenal ulcer, biliary lithiasis). The incidence of such complications varies considerably in the various series of cases. Table 1 presents data for two series of cases at the Mayo Clinic.

Table 1. Complications in two series of cases of chronic pancreatitis at Mayo Clinic (%)

Author Cases Pseudo- Pan- Dia- Pan- Pan- Upper Asci-repor- cyst creatic betes creatic creatic gastro- tes ted calcifi- mellitus steat- abs- intestinal

cation orrhoea cess bleeding

Gross (3) 125 6 22 11 8 0.8 0.8 0.8 Gambill and Mason (4) 96 15 9 8 6 3 0 3

254 G. Bianchi Porro, A. Prada, and M. Petrillo

In view of the progressive nature of the disease, the incidence obviously increases considerably as time passes, and particularly, as already stated, in the forms of chronic relapsing pancreatitis. Table 2 shows the relative percentage of the main complications at the time of observation and after a follow-up period of 16-20 years [5]. Our centre's most recent experience (the last 4 years) is summarized in Table 3.

Table 2. Complications in 56 patients with chronic relapsing pancreatitis. (By EE Gambill, 1973, modified) [5]

At time of original reports At time of 16- to 20-years' follow-up

Patients Patients

Complications Number I Percent Number I Percent

Diabetes mellitus 11 20 30 54 Steatorrhoea 11 20 24 43 Pancreatic calcification 17 30 22 39 Pseudocyst 6 11 10 18 Upper gastro-intestinal

haemorrhage 6 11 9 16 Ascites 4 7 6 11 Pancreatic, peri-

pancreatic abscess 2 4 7 13 Intra-abdominal venous

thrombosis 1 2 5 9

Table 3. Follow-up in 25 patients with positive initial diagnosis of chronic relapsing or painless pancreatitis at the Gastrointestinal Unit, Ospedale L. Sacco, Milano

Complication Initial observation 2nd year 4th year No. of patients No. of patients No. of patients

Pain 23 22 21 Weight loss 21 18 16 Jaundice 6 1 1

Calcifications 5 5 6 Diabetes mellitus 4 7 8 Steatorrhoea 4 8 10

Upper gastro-intestinal haemorrhage 1 1

Gastric/duodenal ulcer 2 1 1 Cirrhosis 2 1 1

Follow-up of Chronic Pancreatitis. Methodological Considerations 255

Methodology

In view of the complex possible evolution of chronic pancreatitis, the follow-up must therefore be made at different levels, i. e. clinical, biochemical, functional and morphological. Frequent clinical check-up is valuable above all in keeping the patient "on the hook" and hence in promoting abstention from alcohol, as well as in evaluating the trend of pain, which is the chief symptom found in 90% of cases. Such evaluation is useful not only for adjusting therapy, but also allows observation of any changes in duration, irradiation and rhythm, since these changes can give grounds for suspecting the rise of complications. Other important parameters are bowel characteristics, the state of nutrition and, of course, the objective conditions. Checking the biohumoral data is useful for confirming clinical suspicions, revealing alterations that are not yet apparent or monitoring already-established complications. Amylasaemia may be moderately high even in the absence of clinical exacerbations, provided that destruction of the parenchyma is not already widespread. Isoamylase determination often reveals a reduction in the pancreatic fraction. The haemochrome is altered whenever there is a blood loss or if the protein balance is negative, in which case macrocytosis appears. Leukocytosis arises in poussees or a result of secondary infection of a pseudocyst, which sometimes not observed at first. Proteinaemia decreases through antalgic malnutrition or through creatorrhoea, but only in the very advanced stages. Postprandial glycaemja or the glucose tolerance test reveals glucose impairment earlier than basal glycaemia does. The prothrombin time and calcaemia tests (in the absence of liver disease or parathyroid or bone pathology) should reveal any insufficient fatsoluble vitamin absorption as a result of steatorrhoea, but this condition is very rare (as is also vitamin BI2 and vitamin E deficiency) [6]. Bilirubinaemia and the alkaline phosphatase assay, as well as other indexes of cholestasis, are carried out to check bile duct patency in view of the possible compression that the pancreas may exert on the bile duct or the presence of bile duct fibrosis which may be associated with chronic pancreatitis. It is now possible (by radio-immunoassay) to assay plasma trypsin, low levels of which are linked to pancreatic failure. Our experience in follow-up is still limited, but is certainly positive [7]. Checking of the exocrine function is generally done through quantitative determination of faecal fat. However, steatorrhoea appears only when the reduction in lipase output reaches 90%. A periodical check of patients with chronic pancreatitis is nevertheless necessary in order to identify its appearance, especially as there is often no diarrhoea, or to monitor the effectiveness of treatment when steatorrhoea is already present. Creatorrhoea, due to proteolytic enzyme deficiency, arises even later than steatorrhoea and is not a useful parameter. The PABA test has increased hopes of allowing evaluation of the functional state of the pancreas, but because it is unfortunately affected by a number of factors

256 G. Bianchi Porro, A. Prada, and M. Petrillo

(transit time, intestinal absorption, renal function), it is of no great clinical use. In a recent trial we observed up to 50% of false positives [8]. The test of direct pancreas stimulation with secretin with or without cerulein, a fundamental aspect of the diagnosis of chronic pancreatitis, is too complex an examination to play any part in follow-up of patients with no complications. Morphological investigation using ultrasound or computerized axial tomography, and especially with endoscopic retrograde pancreatography, enables changes affecting the ducts to be observed, but can be applied only after exacerbations, when complications are suspected or in preparation for surgery [9]. A possible follow-up scheme is summarized in Table 4.

Table 4. Chronic pancreatitis - follow-up schedule

Clinical check-up:

Biochemical check-up:

Functional check-up: Morphological check-up:

Conclusions

Alcohol, pain, bowel, nutrition, objective conditions: at least every 3 months. Serum amylase, blood count, serum protein, electrophoretic pattern, glucose tolerance test, prothrombin time, alkaline phosphatase, bilirubinaemia, calcaemia, serum trypsin: at least every 6 months. Faecal fat determination: every 12 months; Echotomography and retrograde pancreatography: for clinical suspicion of complications or for surgery preparation.

One of the most difficult problems in assessing the prognosis of chronic pancreatitis lies in the absence of homogeneity of the reported series of cases as regards the clinical form of the disease, duration, treatment, presence or absence of complications, as well as tests made. In general, however, except where some acute complications are concerned, the death of patients with chronic pancreatitis is not due to this disease. Even in the case of relapsing chronic pancreatitis, the form most seriously affected by complications, if patients survive the 1st years, they generally die from other causes. Table 5 shows the cause of death of 33 patients with chronic relapsing pancreatitis, with a follow-up of 16-20 years. The outlook is much more serious for those who continue taking alcohol, with a 56% death rate at 19 years [11] following the onset of the disease. Follow-up of patients with chronic pancreatitis thus is meant to (1) ascertain the appearance of complications and allow them to be treated without delay; (2) identify the appearance of any other pathology, which may be misinterpreted owing to the preponderance of the pancreatic symptoms; and (3) assess the effectiveness of medical treatment and possibly enabling a decision in favour of surgical treatment to be made [12]. In addition, the use of a worksheet makes the data more homogeneous and allows a comparison of data from both the epidemiological and the therapeutic standpoint.

Follow-up of Chronic Pancreatitis. Methodological Considerations 257

Table 5. Causes of death in 33 patients with chronic relapsing pancreatitis followed for 16-20 years (By EE Gambill, 1973 a, modified) [10]

Causes of death

Vascular (Seven cerebral, two cardiac) Diabetes mellitus Pancreatitis (two with abscess) Respiratory Carcinoma (non-pancreatic) Duodenal haemorrhage from calcium spicule in pancreas Miscellaneous

References

No. of patients

9 5 4 3 3 1 8

1. Sarles H, Sahel J (1976) Pathology of chronic calcifying pancreatitis. Am J Gastroentero166:117-139

2. Symposium on the etiology and pathological anatomy.of chronic pancreatitis: Marseille, 1963, Am J Dig Dis 9:371-376 (1964)

3. Gross JB (1958) Some recent developments pertaining to pancreatitis. Ann Intern Med 49:796-819

4. Gambill EE, Mason HL (1963) One-hour value for urinary amylase in 96 patients with pancreatitis: comparative diagnostic value of tests of urinary and serum amylase. JAMA 186:24-28

5. Gambill EE Complications of pancreatitis. In: Gambill E E: "Pancreatitis". CV Mosby Company, Saint Louis, 1963, pgg. 213-229

6. Taubin HL, Spiro HM (1973) Nutritional aspects of chronic pancreatitis. Am J Clin Nutr 26:367-373

7. Andriulli A, Vantini I, Grossi E, Felder M, Masoero G, Bianchi Porro G, Cavallini G, Dobrilla G (1979) Relationship between serum immunoreactive trypsin (IT) levels and exocrine pancreatic function in chronic pancreatitis. Danish Medical Bullettin 26: suppl 1,28

8. Dobrilla G, Bonoldi MC, Chilovi F, Rizza F, Cavallini G, Piubello W, Bianchi Porro G, Petrillo M, Andriulli A, Masoero G (1980) Inadequacy of Bz-Ty-PABA as diagnostic test in chronic relapsing pancreatitis. A study in 100 patients. Italian Journal of Gastroenterology, 1980, in press

9. Kawanishi H, Sell JE, Pollard HM (1975) Combined endoscopic pancreatic juice collection and retrograde pancreatography in the diagnosis of pancreatic cancer and chronic pancreatitis. Gastrointest Endosc 22:82-85

10. Gambill EE (1973a) Prognosis of pancreatitis. In: E E Gambill "Pancreatitis", CV Mosby Company, Saint Louis, pgg 260-281

11. Strum WB, Spiro HM (1971) Chronic pancreatitis. Ann Intern Med, 74:264-277 12. Frey WJ, Child CG III (1965) Ninety-five per cent distal pancreatectomy for chronic

pancreatitis. Ann Surg 162:543-548

Longterm Evolution of Chronic Pancreatitis: The Italian Experience

L.A. Scuro

Clinica Medica 3", Universita di Padova, Sede in Verona, Policlinico B. Roma, 37100 Verona, Italy

Present data about the long term evolution of chronic pancreatitis are mainly based on empirical observations and retrospective analysis. The choice of different types of surgical treatment makes it difficult to objectively evaluate to what extent a treatment is more or less effective than another one. On the other hand, several authors often claim to have attained excellent results by quite different surgical procedures. However, this reflects the pathophysiologic uncertainties on which the surgical treatment of chronic pancreatitis is based. Actually, while there are several factors which may influence the outcome of the treatment (be it surgical or medical), it is difficult to assess the role which each of them may play in the evolution of the disease and of its symptoms. First of all, one should evaluate how much is due to treatment and how much to the natural history of the disease. In other words, results which are believed to be satisfactory, particularly as far as pain relief is concerned, might be linked with an impairment of the pancreas, not only with surgery (Amman et al. 1979). Moreover, although in western/westernlike regions the characteristics of chronic pancreatitis - namely food and drinking habits, sex distribution - are known and relatively homogeneous, a few differences are detectable in some areas within those regions (Durbec and Sarles 1978; Sarles et al. 1979). Such differences could influence the clinical findings of the disease; therefore, one should be careful in comparing results obtained in different areas from different populations. Finally, one shouldn't underestimate the way that results obtained with a treatment depend on the method of selecting patient. Moreover, patients themselves cannot be compared since those to be surgically or medically treated are preselected according to specific criteria. Therefore, it seems advisable to both search for the causes which account for the type of clinical evolution of the disease and also to describe the evolution of the disease in several series of treated patients. The search for clear clinical, anatomic, and functional criteria and their prospective application on homogeneous series of patients should be encouraged in order to define the real efficacy of treatments and to allow a better management of the disease.

260 L. A. Scuro

Results and Discussion

Between 1970 and 1979, 195 patients with chronic pancreatitis (189 relapsing and 6 painless) were followed over an average of 5.3 years. They mainly came from North-East Italy. Radiologic pancreatic calcification was detectable in 107 cases, while a daily alcohol intake (more than 100 g) was reported by 156 patients. Only 13 of them were teetotallers. Whereas 112 patients were selected for surgery, mainly because of invalidating pain, 83 were assigned to conservative treatment. With two exceptions, all surgically treated patients showed pathologic changes of chronic calcifying pancreatitis, even in the absence of radiologic calcification. An increase in food intake (carbohydrates, proteins, and fats) could be retraced in the clinical history of these patients, in accordance with previous observations (Vantini et al. 1977). The mean age of the clinical onset of the disease was 38.4±7.9 years. As a whole, this series has shown clinical, epidemiologic and pathologic characteristics quite similar to those found in Southern Europe (Sarles et al. 1979) and consistent with previous findings in North-Eastern Italy (Vantini et al. 1978). All the patients were periodically (every 2 years at least) checked by a medical team. In the 112 surgically treated patients, different types of operation were performed (Table 1) on the basis of clinical indications, mainly consisting in pain no longer treatable with "medical" therapy. Moreover the surgical indication was improved by means of a thorough "anatomic" investigation of the pancreas and adjacent organs (US, ERCP, CT, angiography, IV cholangiography, etc). Most patients underwent drainage operation; four patients were submitted to total pancreatectomy for strongly suspected cancer (three cases) and for unforseeable surgical problems (one case). Internal drainage of a cyst was performed in nine cases and some patients only underwent sphincteroplasty. This last procedure, adopted in early days, was abandoned later. Duodenopancreatectomy was made in the presence of a non widened Wirsung duct and/or of a large cyst at the head of the pancreas. Further operations were performed in nine patients because of relapses or surgical complications. During the follow-up 16 patients (8.2%) died, 12 had been surgically treated (Table 2).

Table 1. Different types of surgical operation performed in 112 patients with chronic relapsing pancreatitis

Operation

Pancreaticojejunostomy Duodenopancreatictomy Distal pancreatectomy (tailor body-tail with

jejunal anastomosis) Total pancreatectomy Sphincteroplasty Other

No. of cases

74 9

7 4 9 9

Longterm Evolution of Chromic Pancreatitis: The Italian Experience 261

Table 2. Cause of death observed in 195 patients with chronic pancreatitis

Cause

Complications after operation Liver cirrhosis Cancer of the pancreas Diabetic coma Hypoglycemic coma Severe malnutrition Acute cholangitis Massive bleeding from peptic ulcer Acute hemorrhage into a cyst Myocardial infarction Lymphoma Drug addiction

No. of cases

3 2 2 1 1 1 1 1 1 1 1 1

Table 3 shows the experience of pain in both surgically and medically treated patients. In about 50% of the cases complete lasting pain relief was observed, while in a few cases partial success was recorded (decrease in the frequency and severity of relapses). No improvement was observed in a group of surgically treated patients and in about 20% of the patients selected for medical therapy.

Table 3. Pain experienced in 179 patients with chronic relapsing pancreatitis submitted to surgery or to conservative treatment

Pain

Complete and lasting relief Partial relief" Impaired

Operated (No. 100)

51 (51%) 42 (42%) 7 (7%)

• As reduction of frequency and severity of painful relapses

Nonoperated (No. 79)

32 (40.5%) 30 (37.9%) 17 (21.5%)

While the results of sphincteroplasty weren't satisfactory, no painful relapse was observed after duodenopancreatectomy. In the latter group of patients, however, steatorrhea always occurred at different times after the operation. In addition, many endoscopic checks had to be performed because of pain induced by lesions of the gastric remnant (gastritis, ulcer). During the follow-up, 40% of nonsurgically treated patients didn't complain of the continuation of painful relapses, while an improvement of symptoms was observed in about one-third of the cases. Moreover, in about one-third of nonoperated patients, whose follow-up lasted at least 7 years, pancreatitis appeared to have become painless. However, in about one-fifth of the patients all medical efforts failed, which was an indication for surgery. Out of 157 patients whose alcohol intake was heavy before the clinical onset of the disease, 93 stopped drinking while 48 only reduced by 50% the quantity of daily consumption. Sixteen patients stuck to heavy drinking.

262 L. A. Scuro

%

80

60

40 o 20

.... I ,.....~---,.: -:.;.;.

... . A B c

Fig. 1. Drinking habits in operated patients with chronic relapsing pancreatitis in respect to pain experienced (A, complete and lasting relief; B, partial relief; C, impairment). Elll ofpatients who stopped drinking; 0 of patients who stuck to drinking

Figure 1 shows the percentage of surgically treated patients who have stopped drinking in relation to the pain experienced. Since the percentage of patients who have stopped all alcohol consumption progressively increases as clinical evolution of symptoms improves, it seems that alcohol withdrawal is an adjunctive factor in pain relief, as Amman et al. (1979) found. However, in the nonsurgically treated group (Fig. 2) such a relation doesn't appear to be clearly detectable; it is not easy to supply a convincing explanation for this unexpected finding. On the other hand, in our experience at least, some of the patients who haven't experienced painful relapses for a length of time drink or go back to drinking a moderate quantity of alcohol (usually wine at meals). (However, in an increased percentage of patients who even occasionally suffer from painful relapses, there is a trend to ward alcohol abstinence.) Since the cause-effect relationship between alcohol and pain has not been grasped, in our series of nonoperated patients at least, most probably factors other than alcohol interferred with the pain experienced. In both groups we weren't able to detect a clear relationship between pain and steatorrhea as an index of impairment of the pancreas. However, in most nonsurgically treated patients who haven't experienced painful relapses for at least 7 years, steatorrhea and diabetes were detectable. What is interesting is that no more than 50% of them had stopped drinking altogether. Therefore, even if complete, lasting alcohol withdrawal must always be prescribed and all efforts should be made to achieve this, such steps don't guarantee a favorable outcome of symptoms. On the other hand, one should keep in mind that pain relief might be connected with functional impairment of the pancreas, which might be useful in the management of this disease. During the follow-up, diabetes was observed in 63 patients. Except for the four patients who underwent total pancreatectomy and five patients who were submit-


%

80

60

40

,.....--.. ?J •••• It

· ... . 20 · ... . · ... . · ... . · ... . · ... . · ... .

A B

-

~

.... It •• It . ...

c Fig. 2. Drinking habits in nonoperated patients with chronic relapsing pancreatitis in respect to pain experienced (A, complete and lasting pain relief; B, partial relief; C, impairment). 0 of patients who stuck to drinking

ted for resection of the tail of the pancreas, in whom diabetes occurred immediately after the operation and within one year from it respectively, in the remaining cases surgery doesn't seem to have contributed to the onset of diabetes. In fact, leaving aside the the above mentioned patients, the frequency of diabetes in surgically treated patients (31%) is not significantly higher than in nonoperated cases (27.8%). Besides, in both groups diabetes occurred on an average of 6.7 and 6.3 years from the clinical onset of the disease, respectively. These data, as a whole, suggest that the best results with pain relief without an impairment of the pancreatic function can be obtained through derivative operations, mainly longitudinal pancreaticojejunostomy, in accordance with previous clinical findings (Jordan et al. 1977; Prinz et al. 1978; Reber 1978; Amman et al. 1979; White and Slavotinek 1979). However pancreatoduodenectomy was shown to be effective in pain relief (in accordance with the results of Mangold et al. 1977) but at a cost of early digestive insufficiency, which was only partially treatable with enzymes, cimetidine, and antacids (Regan at al. 1977). Moreover, the occurrence of disturbances related to the presence of a gastric remnant should be kept in mind. Total pancreatectomy, performed in only four cases, caused difficult problems in treating exocrine pancreatic insufficiency and in the management of diabetes at home. Therefore, this procedure should be dismissed or adopted only when there is a reasonable suspicion of carcinoma. On the other hand, total pancreatectomy for the final stage of chronic pancreatitis or as a further operation after other surgical procedures results in a high mortality (Braasch et al. 1978). The 80%-95% pancreatectomy, which at first was favorably accepted (Frey and Child 1965), seems to involve considerable problems of pancreatic insufficiency and diabetes

264 L. A. Scuro

(Frey et aI., 1976). Hopefully, in such cases, the efficacy of alternative treatments such as alcoholization of the celiac plexus or injection of an alpha-cyano-acrylate glue into the Wirsung duct (Little et al. 1979) should be assessed by clinical trials. As a matter of fact, the best results were obtained in patients treated with a derivative operation, in accordance with previous findings (Prinz et ai. 1978; Reber 1978). However, ReMine (1973) reported results as favorable with resection of the tailor of the body-tail. As far as pain is concerned, pancreatic pathologic changes have been considered to be factors influencing its evolution. In fact, the presence of pancreatic calcification and the widening of the Wirsung duct, as well as alcohol withdrawal, have been considered (Jordan et al. 1977; Proctor et al. 1979) factors which may guarantee a more favorable evolution, whatever the operation may have been (Traverso et al. 1979). On the other hand, the most favorable results have been obtained in patients with alcoholic pancreatitis, pancreatic calcification, and widened Wirsung duct who gave up drinking (79% had complete and lasting pain relief in this particular subgroup).

Conclusions

In patients who were not selected for surgery, the collected data do not allow, in our series, one to clearly state the factors which influenced the outcome of the disease. Even if about 50% of the patients withdrew from alcohol and in most cases a significant decrease in daily alcohol intake was reported, no evident relation between pain and drinking habits was detected. This was wholly unexpected since the clinical impression and medical lore have always suggested that alcohol withdrawal is almost a "cure" in itself in nonoperated patients with chronic relapsing pancreatitis. However, as no data about alcoholemia were available, we cannot draw a line between drinking and nondrinking patients. On the other hand, the presence of exocrine and endocrine insufficiency seemed to be related to a favorable evolution of the pain, but only in those patients who had a longer followup. As far as surgical treatment is concerned, our experience suggests choosing derivative operations, where anatomic conditions allow one to. The chances of a "rational" surgical therapy lie in a choice which is mainly based on an accurate clinical and anatomic evaluation of the disease. Besides, in evaluating benefits and disadvantages of surgery as in a prognostic assessement, one should take into account the natural evolution of the disease and factors which can influence its outcome. Prospective clinical trials may enable us to attain a safe evaluation of risk/benefits in the management of chronic pancreatitis.

References

Amman RW, Largiarder F, Akovbiantz A (1979) Pain relief by surgery in chronic pancreatitis? Relationship between pain relief, pancreatic dysfunction, and alcohol withdrawal. Scand J Gastroenterol 14:209-215


Braasch JW, Vito L, Nugent FW (1978) Total pancreatectomy for end-stage chronic pancreatitis. Ann Surg 188:317-322

Durbec JP, Sarles H (1978) Multicenter survey of the etiology of pancreatic diseases. Relationship between the relative risk of developing chronic pancreatitis and alcohol, protein and lipid consumption. Digestion 18:337-350

Frey WJ, Child CG (1965) Ninety-five per cent distal pancreatectomy for chronic pancreatitis. Ann Surg 162:543-548

Frey CF, Child CG, Fry W (1976) Pancreatectomy for chronic pancreatitis. Ann Surg 184:403-408

Jordan GL, Strug BS, Crowder WE (1977) Current status of pancreatojejunostomy in the management of chronic pancreatitis. Am J Surg 133:46-51

Little JM, Stephen M, Hogg J (1979) Duct obstruction with an acrylate glue for treatment of chronic alcoholic pancreatitis. Lancet 2:557-558

Mangold G, Neher M, Oswald B, Wagner G (1977) Ergebnisse der Resektionsbehandlung der chronischen Pankreatitis. Dtsch Med Wochenschr 102:229-234

Prinz RA, Kaufman BH, Folk FA, Greenle HB (1978) Pancreaticojejunostomy for chronic pancreatitis. Arch Surg 113:520-525

Proctor HJ, Mendes OC, Thomas CG, Herbst CA (1979) Surgery for chronic pancreatitis. Drainage versus resection. Ann Surg 189:664-671

Reber HA (1978) Chronic pancreatitis. In: Sleisenger MH, Fordtran JS (eds) Gastrointestinal disease, 2nd edn. Saunders, Philadelphia London Toronto, p 1439

Regan PT, Malagelada JR, Di Magno EP, Glanzman SL, Go VLW (1977) Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. Engl J Med 297:854-858

ReMine WH (1973) Surgical treatment. In: Gambill EE (ed) Pancreatitis. Mosby, SaintLouis, p 235

Sarles H, Cros RC, Bidart JM and the International Group for the Study of Pancreatic disease (1979) A multicentre inquiry into the etiology of pancreatic diseases. Digestion 19:110-125

Traverso LW, Tompkins RK, Urrea PT, Longmire WP (1979) Surgical treatment of chronic pancreatitis. Twenty-two years' experience. Ann Surg 190:312-319

Vantini I, Cavallini G, Angelini G, Piubello W, Bovo P, Benini L, Ederle A, Dobrilla G, Vallaperta P (1977) Nutritional aspects of chronic pancreatitis in Verona, Italy. Rend G astroenterol 9: 13-17

Vantini I, Piubello W, Cavallini G, Ederle A, Benini L, Scuro LA (1978) Chronic pancreatitis in North-East Italy: a clinical and pathological study. Acta Hepatogastroenterol (Stutt.) 25:130-135

White TT, Slavotinek AH (1979) Results of surgical treatment of chronic pancreatitis. Report of 142 cases. Ann Surg 189:217-224

H. D. Becker, W. F. Caspary

Postgastrectomy and Postvagotomy Syndromes 1980. 84 figures, mainly in 2 colors, 55 tables. XII, 188 pages ISBN 3-540-09445-8

1. L. Chassin

Operative Strategy in General Surgery An Expositive Atlas

Volume 1 Il\ustrated by C. Henselmann 1980. 528 figures, 10 tables. XXIII, 558 pages ISBN 3-540-90452-2

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Manual of Renal Transplantation With contributions by numerous experts 1979. 55 figures, 22 tables. XV, 190 pages ISBN 3-540-90337-2

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Ultrasonography of the Abdomen With a contribution by R Bard 1976.215 figures. XVI, 127 pages ISBN 3-540-90166-3

G. P. Marzoli, S. Vesentini

Warren's Operation With cooperation ofF. Frasson, G.Fugazzola, G.Mangiante, RMaso In preparation

M.AMeyers

Dynamic Radiology of the Abdomen Normal and Pathologic Anatomy

With a contribution in Ultrasonography by E.Kazam 1976.638 figures including 14 color plates. LVI, 351 pages ISBN 3-540-90178-7

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Renal Calculus Foreword by D. Innes Williams 1979.55 figures, 27 tables. XIV, 370 pages ISBN 3-540-09080-0

Springer-Verlag Berlin Heidelberg New York

Comprehensive Manuals of Surgical Specialties Editor: R H. Egdahl

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Manual of Urologic Surgery Illustrated by I. Takamoto 1979.532 color illustrations. XVIII, 284 pages ISBN 3-540-90423-9

Al.Edis, L. A Ayala, RH.Egdahl

Manual of Endocrine Surgery 1975.266 figures, mostly in color, 242 color plates. XIII, 274 pages ISBN 3-540-07064-8

B. 1. Harlan, A Starr, F. M. Harwin

Manual of Cardiac Surgery Volume 1 1980.193 figures (183 in full color), 8 tables. XV, 204 pages ISBN 3-540-90393-3

RE.Hermann

Manual of Surgery of the Gallbladder, Bile Ducts, and Exocrine Pancreas With contributions by A M. Cooperman, C. B. Esse\stynjr., E. Steiger, R T. Holzbach 1979. 197 color figures (123 black and white figures), 16 tables. XIV, 306 pages ISBN 3-540-90351-8

w. S. McDougal, C. L. Slade, B. A Pruittjr.

Manual of Burns Medical Illustrators: M. Williams, C. H. Boyter, D. P. Russell 1978.214 color figures, 4 tables. X, 165 pages ISBN 3-540-90319-4

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Manual of Gynecologic Surgery With contributions by KE.Krantz, W. 1. Cameron, 1. W. Daly, 1. A Fayez, E. W. Franklin Illustrator: D. McKeown 1979.204 figures, 192 in color, 12 tables. XV, 256 pages ISBN 3-540-90372-0

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Manual of Lower Gastrointestinal Surgery 1980.215 figures (138 figures in color), 7 tables. XVI, 276 pages ISBN 3-540-90205-8

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Manual of Vascular Surgery Volume 1 1980.557 figures, 471 in full color. XII, 264 pages ISBN 3-540-90408-5

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topics in acute and chronic pancreatitis

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