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1972

The development of a symptom analysis flow sheetfor the Navajo Community Health Medic ProgramRobert Francis GoodmanYale University

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YALE UNIVERSITY LIBRARY

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Digitized by the Internet Archive in 2017 with funding from

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https://archive.org/details/relationofportalOOgony

THE RELATION OF PORTAL VENOUS BLOOD FLOW

TO

EXPERIMENTAL PORTAL HYPERTENSION

by

Robert J. Gonyea \H

B,A. Univ. Minnesota 1955

A thesis submitted to the Faculty

of the Yale University School of Medicine

in candidacy for the Degree of Doctor of Medicine

Department of Surgery Yale University School of Medicine

1959

5

ACKNOWLEDGMENTS

Dr® William W. L. Glenn, Department of Surgery,

■who suggested and directed this study.

Dr. Milton Hales, Department of Pathology, and

Dr. William Tisdale, Department of Medicine, for their

generous advice and criticism.

Mr. Armand Negri, Department of Surgery, who taught

the author the value and care of the experimental

animal

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TABLE OF CONTENTS

Page

Introduction 1

The Pathogenesis of Portal Hypertension 3

Methods 21

Results 2h

Table I 2£

Table II 26

Discussion 27

Summary 30

Bibliography 31

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INTRODUCTION

The predominant clinical complication of hypertension of

the portal venous system in man is hemorrhage from esophago-gastric

varices. Current surgical management of this life-threatening prob¬

lem is predicated upon the proposition that the clinical and patho¬

logic manifestations of portal hypertension are a direct consequence

of elevated portal venous pressuresThe fundamental pathologic

lesion which has received the greatest attention and which is of most

significance in the majority of instances is a mechanical block some¬

where within the portal vascular bed. It is presumed that this factor

of obstruction results in an increased vascular resistance and a

consequent rise in portal pressure with the development of a colla¬

teral circulation to effectively by-pass the site of obstruction,

Vascular pressure is, however, a function of volume flow

as well as resistance, so that, theoretically, alterations in flow

might also lead to changes in portal pressure. The importance of

this mechanism would become of practical significance if instances of

portal hypertension in the absence of evident obstructive factors

could be demonstrated and if abnormally increased blood flows were

found within the portal vascular inflow in such instances.

Understanding of the fundamental etiologic and pathogenetic

factors in the development of portal hypertension has been handi¬

capped by the inability to reproduce the disease in the experimental

animal. It is the purpose of this paper to review the traditional

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concepts of the pathogenesis of portal hypertension, emphasizing

certain discrepancies which demand a reappraisal of these concepts*

A new method -will be described for the experimental study of this

disease with particular reference to the problem of increased portal

venous flow as an etiologic factor in the development of increased

portal pressure*

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THE PATHOGENESIS OF PORTAL HYPERTENSION

It has been customary to consider portal hypertension as

being directly related to intrahepatic or extrahepatic portal venous

obstruction, and this has served as a convenient form of classifies-

tion. The intrahepatic lesions include the various forms of cir¬

rhosis, hemochromatosis, schistosomiasis and hepatic syphilis. There

have been numerous studies attempting to correlate the pathological

findings, particularly in the cirrhotic liver, with the concomitant

existence of portal hypertension. The preparation of corrosion casts

of cirrhotic livers injected with gelatin, for example, has demon-

strated a marked diminution to the total vascular bed. Johnston'

directly measured the circumference of comparable portal venules and

their accompanying hepatic arterioles in normal and cirrhotic livers

and observed a significant narrowing of the venules of the latter.

In addition to the factor of vascular obstruction in cirrhosis Herrick0

7 and later Dock indirectly demonstrated that there were free communi¬

cations between the hepatic artery and the portal vein; these authors

suggested that these arterio-venous communications may be a signifi¬

cant factor in the elevated portal pressures. Injection studies have

also demonstrated the presence of arterio-venous shunts as well as

8 communications between the portal and hepatic veins within the liver.

Direct observation of arterio-venous anastomoses in the normal rat

liver by a technique of direct illumination has revealed that about

75 percent of the hepatic circulation is ordinarily inactive.' It is

suggested by these observations, therefore, that the elevated portal

pressures in cirrhosis are the result of an increased vascular rests-

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tance subsequent to a diminished vascular bed as well as increased

flow through hepatic arterial-portal venous anastomoses. The rela¬

tive contribution of these two factors in the genesis of portal

hypertension is unknown,

Extrahepatic portal venous obstruction is commonly asso¬

ciated with portal hypertension. Chronic thrombosis of the portal

or splenic vein may be caused by neonatal omphalitis^"0, pylephlebitis,

11 trauma, thrombocytosis, or neoplastic invasion or pressure. Steno¬

sis of the portal or splenic vein may be the result of congenital

malformation, 9 9 post-operative adhesions, or tumor compression.

Cavemomatous transformation of the portal vein is occasionally the

only pathological finding in a case of portal hypertension; it has

been postulated that this lesion may represent a recanalized portal

vein thrombosis, an hemangioma of the portal vein or a congenital

1E> malformation. All of these lesions may become clinically manifest

following hemorrhage from esophageal varices, progressive splenomegaly

or mild ascites. They are more commonly observed in children*^ and

young adults, and characteristically these patients have livers which

are functionally and histologically normal. Thrombosis or endophle-

bitis of the hepatic veins, prolonged and severe congestive heart

failure or chronic constrictive pericarditis may also give rise to

lesser degrees of elevated portal toisions and splenomegaly.

Although the majority of patients with portal hypertension

will be found to have either an intrahepatic or extrahepatic portal

venous obstruction, there remains an irreducible minimum of patients

in whom no obstructive element can be demonstrated either at autopsy.

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operation or by radiologic visualization of the portal system. Among

55 cases of "Banti’s Syndrome" observed by Rousselot, no obstructive

17 factor could be found in 22, In a report of 15 cases of assumed

extrahepatic portal hypertension with normal liver function and strue-

ture this same author was unable to demonstrate the presence of the j Q

extrahepatic lesion in seven. With the advent of splenoportography,

hoirever, by means of which the entire portal system could be adequately

visualized a more sensitive method of determining the presence or ab¬

sence of vascular obstruction became available.

In Rousselot’s papers frequent reference is made to the con¬

cept of "Banti5 s Disease" and "Banti!s Syndrome". In a discussion of

the pathogenesis of portal hypertension it is pertinent to introduce

a discussion of these eponymic entities, even though the theories of

Banti have served more to obscure our understanding of the disease than

to clarify it.

In 1883 Banti described a disease -which he felt was a new and

19 20 distinct clinical syndrome. ' * Essentially, Banti postulated that

some cases of portal hypertension were caused primarily by a spleno-

genous toxin -which was a direct cause of the splenic and hepatic patho¬

logy observed in his cases. He outlined three phases of this process.

The first phase consisted of gradually increasing splenomegaly with

anemia and leukopenia] this phase was said to last three to five years

or as long as twelve years. The second phase, lasting 12 to 18 months,

was characterized by diminishing urine volume with urobilinuria along

with painless enlargement of the liver without jaundice or ascites. The

final phase was manifested by a shrinking liver, ascites, hepatic in¬

sufficiency, jaundice, splenomegaly, gastrointestinal hemorrhage and

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death. Banti felt that this sequence of events was initiated and per¬

petuated by a toxin produced by the spleen. Splenomegaly was a promi¬

nent feature of the disease, the spleen seldom weighing less than 1000

grams and often as much as 3000 grams. He described a lesion in the

spleen which he felt to be a specific sign of the disease. This lesion

consisted of a thickening of the splenic reticulum about the terminal

penicillar arterioles with extension into the malpighian corpuscles

and their eventual replacement along with periarterial hemorrhage and

fibrosis, producing a lesion tiiich was termed "fibroaderde1* or sidero¬

tic nodule. The subsequent changes in the liver were thoseof cirrhosis

with an associated portal and splenic endophlebitis, The essential

feature of this concept was that the changes in the spleen preceded

those in the liver, and that the changes in the latter were directly

caused by the pathology in the former.

It was quickly demonstrated, however, that many of Banti*s

cases were caused by other well-known causes of hepatic cirrhosis and

splenomegaly. Numerous pathologists were quick to point out that the

"fibroadenic" was a non-specific lesion which represented a response

of the splenic reticulum to increased portal tension and chronic splenic

congestion. ^ The terms "Banti1 s Syndrome" or "Splenic Anemia" per¬

sisted, however, and were applied to those instances of portal hyper¬

tension in which splenomegaly with secondary hypersplenism were pro¬

minent features of the clinical course, representing a vastly dif¬

ferent concept from that which Banti had described. Rousselot,^-

27 Larrabee, and Thompson - emphasized that all the changes in the

spleens of "Banti*s Syndrome" were the result of an obstruction in

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the portal circulation with a resultant "congestive splenomegaly".

The bulk of evidence accumulated since the publication of

Banti’s papers towards the turn of the century seemed to adequately

refute the idea that the disease Banti described was a clinical or pO

pathologic entity. In 19i|0, however, Ravenna^ emphasized that the

theory of congestive splenomegaly secondary to portal venous obstruct

tion failed to explain those cases of portal hypertension in which no

obstructive factor could be demonstrated. He reiterated the concept

that in such cases a splenic lesion might be involved, but rather

than the elaboration of a splenic toxin, he postulated an increased

flow of blood through the spleen as of primary etiologic significance.

Without producing any experimental or pathologic observations Ravenna

suggested that the small splenic arterioles were the site of early

lesions which allowed blood to enter the spleen in increased amounts,

leading to splenic congestion and increased intrasplenic pressure.

Splenic fibrosis and hyperplasia were felt to be directly related to

the persistent splenic engorgement, while the hypertension led to dila¬

tation of the splenic and portal veins with their eventual thrombosis®

He further related the final development of hepatic cirrhosis (BantiJe

third phase) to the increased blood flow aid primary portal hyper-

29 tension. In a subsequent paper Ravenna presented clinical evidence

to demonstrate that chronic passive hyperemia of the spleen does not

in itself invariably lead to significant splenomegaly. He pointed out

that the Banti spleen weighs more than 1000 grams, and that conges-

tion alone does not produce splenic enlargement approaching that size.

With the chronic passive congestion of the spleen in chronic cardiac

failure, in fact, there is frequently a reduction in size of the spleen

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(cyanotic atrophy). Experimentally, splenic congestion by partial

portal vein obstruction in rabbits was not followed by splenic en-

30 largemer.t within six months. Partial constriction of the splenic

vein of the dog with ligation of the splenic collateral vessels pro™

duced little increase in splenic size after six months to two years

There is little direct evidence to substantiate Ravenna’s

theory. Complete denervation of the spleen of the dog leads to an

31 initial increase in volume of the organ but with subsequent shrinkage.

32 Henschen and Howald observed a two-fold increase in the splenic

weights of two dogs within six and ore-half months following denerva¬

tion of the spleen. Histologically, the sinuses were congested, but

no proliferative or fibnotic changes were described. Pathological

confirmation of the arterial lesions Ravenna suggested has not been

obtained. Perhaps of greater significance than the hypothesis which

Ravenna proposed, however, was the fact that he recognized that portal

hypertension could occur in the absence of obstruction and that in

such cases increases in portal flow might be important.

Since Ravenna’s papers published reports emphasizing portal

hypertension without portal obstruction have been few. Pemberton

33 and Kiemarr* in 191$ also observed that the hypothesis of mechanical

obstruction in the development of splenomegaly failed to explain

portal hypertension in the absence of cirrhosis or extrahepatic portal

block. These authors felt that in such cases the splenic enlargement

was primary and due to an increased blood flow to the spleen as a re¬

sponse to infection, pulp hyperplasia or a primary derangement of the

^ I' mechanism controlling the activity of the splenic vasculature. Foster"

in 195k referred to Ravenna’s papers and suggested that the terra

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HB anti’s Syndrome" be reserved for those cases with intra- or extras

hepatic obstruction and mth splenomegaly, varices, anemia and leu¬

kopenia. Hallenbeck and Schocket^*5 reported 55 patients treated by

porta-caval shunts. Three of these had no roentgen evidence of hepatic

or extrahepatie obstruction, and liver function tests were normal.

Liver biopsies revealed only "increased fibrous tissue and venous

spaces in the periportal tissues". No explanations of pathogenesis

were attempted in these instances. In the most complete study to

date Tisdale, Klatskin and Glenn"5 are reporting four cases of non-

obstructive portal hypertension manifested by massive heraatemesis

from esophageal varices with normal liver function and structure*

Splenoportograms demonstrated no obstructions in the portal vascular

bed, and all had elevated portal venous pressures determined at lapa¬

rotomy. There was splenomegaly in two cases, and liver biopsies in

two patients revealed only minimal periportal fibrosis. Biopsies were

normal in the remaining two patients. Repeat biopsies two and four

years after porta-caval shunts demonstrated no progression of the

hepatic lesions. The authors discuss the factor of increased blood

flow as an etiologic factor to account for the increased portal ten¬

sions and suggest the possible existence of arterio-venous anastomoses

to account for increased flows. It is also suggested that a functional

increase in the intrahepatie or portal venous tone could lead to in¬

creased vascular resistance and pressure.

Clinical examples of increased portal flows secondary to

arterio-venous fistulas are uncommon. Occasionally, not invariably,

these have been associated with the development of portal hypertension,

esophageal varices, and occasionally ascites in the absence of intra-

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hepatic disease. Although the cause of the fistulas may be traumatic*

they appear to be more commonly a developmental malformation. Two q>Q

cases of hepatic artery-portal vein fistulas have been reported."”*"”

Both became manifest by massive hematemesis* and both had normal livers

39 at autopsy. Cassel et al have reviewed the cases of arteriovenous

fistulas of the splenic vessels with portal hypertension* hematemesis

or ascites. In the case which they reported the lesion was demonstrated

by aortography and was presumed to be the result of a bullet wound to

the left lower thorax eleven years previously. Their patient had

ascites with an enlarged but histologically normal liver. The BSP re¬

tention was 3l$ before operation* falling to 6% after splenectomy. In

the six previously reported cases reviewed in this report two were

associated with ascites and four had gastrointestinal bleeding. In

two cases portal venous pressures of 35 and. ii3 cm. of water were re-

iiO corded. In the well-studied case of Sigwart^ an arterio-venous

aneurysm was located three centimeters from the hilus of the spleen*

and the portal vein pressure measured h3 cm. The patient had had re¬

peated episodes of hematemesis for nine years. After ligation of the

aneurysm the oriental vein pressure fell to 15 cm.* and after splenec¬

tomy the esophageal varices disappeared. Of particular interest is

the observation that there were no changes in the liver after nine

years of portal hypertension.

Owen and Coffey^" reviewed 198 cases of splenic artery-

aneurysm and found positive evidence of portal hypertension in 20 per¬

cent without any other cause for the increased portal pressures. No

apparent fistulous connection with the splenic vein existed in these

cases. The authors compare a 1 percent incidence of splenic artery

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aneurysm in cases of portal hypertension -with a 0,037 percent incidence

in the general population.

Recently, direct evidence for the existence of arterio-venous

shunting in cases of "Banti’s Disease" has been suggested by Womack and

Peters.^ In several of their cases at operation palpable thrills were

detected in branches of the portal vein or in the hemiazygous vein.

Oxygen saturations as high as 92 percent were found in the hemiazygous

vein, suggesting arterio-venous shunting into the azygous and peri¬

esophageal venous system. In the same report an experimental study in

dogs attempting to demonstrate the activity of arterio-venous shunts

within the portal system was presented. They observed that the oxygen

saturation of the portal venous blood fell to 69 percent of control

following partial occlusion and to 73 percent of control after complete

occlusion of the portal vein for five to fifteen minutes. At the same

time the oxygen saturation in the inferior vena cava fell to h9 percent

and 37 percent respectively of the control values. Upon release of

the occlusion the oxygen saturation returned to normal or near normal

levels. Occlusion of the hepatic artery alone caused no change in

oxygen saturation within either vessels. If both the portal vein and

the hepatic artery were occluded for two to fifteen minutes, thereby

rendering the liver anoxic, and then the portal vein was again occluded

five to ten minutes the oxygen saturation in the portal vein fell to

U6 percent of control, whereas the inferior vena cava oxygen satura¬

tion remained at control levels. The authors concluded from these

experiments that the preservation of the oxygen saturation of the por¬

tal venous blood after occlusion of the portal vein was due to the

activity of arterio-venous shunts. They suggest further that these

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shunts are under the control of a humoral agent -which is sensitive to

hepatic anoxia. Anatomic evidence for the existence of such shunts

in the gastro-intestinal tract has been presented by Barclay and

Bentley4”5 who observed a shunting mechanism in the stomach submucosa

of cadaver and operative specimens by a microarteriographic technique.

Whether these shunts are present and active throughout the intestinal

tract remains to be demonstrated.

Perhaps of significance in view of Womack's suggestions that

there may be direct shunting of arterial blood into the azygous and

esophageal venous systems are the accumulating reports of symptomatic

esophageal varices occurring in the absence of portal hypertension.

by Palmer and Brick found thirteen such cases among 35>0 patients with

esophageal varices demonstrated by esophagoscopy. Nine of the thirteen

had had upper gastro-intestinal bleeding, and all had normal livers

microscopically and functionally. Even in the presence of cirrhosis

with hemorrhage from bleeding varices Dye^ reported four patients who

had normal portal pressures, suggesting either that portal hypertension

is not necessary for the existence of bleeding varices or that there

may be considerable fluctuation of portal pressures. The supposition

that esophageal varices and hemorrhage are the sole result of elevated

L.9 portal pressures has been questioned by Taylor who observed an aggre¬

gate pressure of 160 cm. water, three times the highest portal pres¬

sures observed at laparotomy, in the distal esophagus during a reversed

Valsalva maneuver. Baronofsky^® has suggested that the acid-peptic

factor may be of greater importance in the actual bleeding of varices.

In a skeptical critique of surgically created venous shunts in the

therapy of bleeding varices Nachlas has summarized the data against

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the supposition that portal hypertension is solely responsible for

variceal hemorrhage. He points out that esophageal varices have been

found in the absence of portal hypertension, that not all patients

with varices bleed from them, that the occurrence of bleeding does

not correlate with the degree of portal pressure, that varices may

persist and bleed again following lowering of the portal pressure by

operation, and that varices which have disappeared following venous

shunting may return even though the portal pressure remains low. Evi¬

dence therefore exists that portal hypertension per se is not the sole

factor in the pathogenesis of esophago-gastric varices nor for the

hemorrhage which may result from them. It is conceivable that the

discrepancies observed may be the result of variations in volume flow

52 through the submucosal esophageal veins or localized venous stasis

without significantly elevated venous pressures.

Understanding of the pathogenesis of portal hypertension has

been handicapped by the inability to reproduce the syndrome in the

experimental animal as it exists in man. Most studies have utilized

the dog as the experimental animal, although the rat, cat and monkey

have also been studied.

A number of approaches have been utilized by different in-

53 vestigators, and these have been reviewed by Wiles and Taylor* .

Essentially, three different methods have been tried: The effect of

experimentally induced hepatic cirrhosis, the effect of obstructing

the vascular outflow or inflow of the liver, and the effect of the

introduction of blood at arterial pressures directly into the portal

system by a variety of surgically produced arterio-venous fistulas.

Opinion differs upon what constitutes normal portal venous

pressures in the dog. In the carefully controlled experiments of

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Hoffbauer, Bellman and Grindlajr the average portal venous pressure

of the unanesthetized dog was 6.1* cm. of water with a range of three

to seven centimeters. Using pentobarbital anesthesia Douglass, et

al^ report normal portal pressures of 10-15 cm. of water, whereas

TaylorJ accepts any pressure below 30 cm. as normal for the dog.

Hepatic cirrhosis can be produced in the dog by the repeated

53 injection of fine suspensions of silica. Taylor followed five dogs

with silica cirrhosis for one to three years, and their portal pres¬

sures remained between 20 and 30 cm. of water. Volwiler, Grindlay and

Bollman-^ produced a silica fibrosis in ten dogs over a period of six¬

teen to twenty-five months and observed portal pressures of 15.5 to

28.0 cm. of water® These animals developed large collateral vessels

involving the retroperitoneal, paraesophageal, abdominal wall, azygous,

diaphragmatic and hemorrhoidal veins. Two animals developed enlarged

submucosal esophageal veins but no true varices. The production of

cirrhosis by the administration of carbon tetrachloride produced por-

55 tal pressures of eight to fifteen centimeters of water. p

Detailed studies have been made of the pressure changes in

the portal vein and inferior vena cava of the unanesthetized dog follow¬

ing the partial or complete occlusion of the vascular inflow and out¬

flow of the liver, the inferior vena cava and the azygous vein both

58 59 singly and in various combinations.'' iJ Acute occlusion of the in¬

ferior vena cava or the portal vein is fatal to the dog, unlike man or

the monkey who tolerate these procedures without difficulty. With

acute occlusion of the portal vein of the dog there is an immediate

fall in arterial pressure with a rise in portal pressure to 30-35 cm®

of water. Complete occlusion of either the portal vein or inferior

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vena cava may be achieved, however, if the procedure is staged. In

none of these experiments has the portal venous pressure exceeded

27 centimeters of water and in none have esophageal varices been pro¬

duced. The inability to produce significantly elevated portal pres¬

sures by these methods seems to be related to the rapid development

of an extensive collateral circulation around the site of the block.

Perfusion studies of the portal circulation of the dog following portal

vein constriction have demonstrated the main collaterals to be the

periesophageal, hepatoduodenal, retroduodenal, splenorenal, omental

60 and retrocolic veins. The coronary-esophageal shunt may account

for as much as 50 percent of the total shunt flow, and the periesopha¬

geal veins become markedly dilated, although the intramural esophageal

veins remain normal.

Obstruction of the venous outflow of the liver does not re¬

sult in portal hypertension, but it does represent the most effective

means to produce experimental ascites. Numerous observers have stressed

the inconstancy of the presence of ascites in relation to the presence

6I-6I4. or degree of portal hypertension. Experimentally, however, ascites

can be consistently produced by any procedure which will effectively

obstruct the hepatic venous outflow with resultant hepatic engorgement

and elevated hepatic venous pressures. Practically, this has been

fx* ££

achieved in dogs by constriction of the thoracic inferior vena cava,

67 68 hepatic vein ligation, right heart pericardial constriction, experi-

69 mental tricuspid insufficiency, and by anastomosis of the thoracic

70 inferior vena cava to the right pulmonary artery. The effect is a

transient one, since the ascites will disappear with eventual collateral

by-pass of the obstruction and relief of the hepatic venous engorgement.

68 Holman and Parsons demonstrated that the ascites would reoccur with

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subsequent constriction of the superior vena cava. The source of

the ascitic fluid is felt to be a transudate from the hepatic capsular

lymphatics.^* The hepatic pathology produced by chronic thora¬

cic inferior vena cava constriction has been studied by Zimmerman and

Hillman^ who observed pericentral congestion, necrosis and fibrosis

■with subcapsular sinusoidal dilatation. Eventually, pseudolobule

formation with bands of connective tissue between hepatic veins was

observed,

Hypoproteinemia and salt and water retention are also impor-

tant factors in the pathogenesis of ascites.'4 McKee, Schilling, et

al studied the ameliorating effect of a high protein diet upon the

ascites following constriction of the thoracic inferior vena cava.

With the rise in serum protein, however, there was a concurrent rise

in ascitic protein, demonstrating the free exchange of protein between

the plasma and ascitic fluid. Studies of the effect of sodium chloride

ingestion upon experimental ascites reveal a reduction in ascites for¬

mation with a low sodium diet and a prompt increase in fluid reten¬

tion with increase in the sodium consumption.1^ Salt and water re¬

tention have been related to an increased aldosterone secretion in

these experimental preparations. It is emphasized, however, that

this adrenal response is secondary to the extravasation of fluids and

electrolytes and that the elevated hepatic venous pressure is the

primary event leading to the accumulation of fluid in the peritoneal

cavity.

The post-mortem perfusion of cirrhotic livers from patients

with or without ascites has emphasized the degree of hepatic venous ob»

9 struction in the development of ascites. In cirrhosis with irreversi-

.

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ble ascites there is an absolute and compensatory increase in the

portal venous and hepatic arterial vasculature with an absolute de-

crease in the hepatic venous bed. Where there was clinically absent

or reversible ascites the liver showed a symmetrical deficit in all

the intrahepatic vascular systems, especially the hepatic and portal

venous beds. It was felt that the cause of irreversible ascites with

cirrhosis was due to an obliterative fibrosis of the hepatic veins,

whereas with reversible ascites the hepatic venous obstruction was

believed to be due to diffuse intrahepatic cellular edema secondary

to both protein and electrolyte imbalance. This concept of the im¬

portance of hepatic venous obstruction of the pathogenesis of ascites

las been utilized by McDermott0^ in the surgical treatment of ascites

by combining both portal and hepatic venous decompression by means of

a "double shunt ”»

This explanation, however, does not explain the uncommon

cases of extrahepatie portal obstruction which are associated with

ascites. Eaggenstoss and Wallaeger'0 reported fifteen cases of

chronic portal vein thrombosis without associated liver disease. In

five of these ascites was present. It seems that in these cases,

the ref 02B, portal hypertension per se must be an important factor in

the genesis of ascites. In experimental animals constriction or liga¬

tion of the portal vein alone does not produce ascites. If this pro-

cedure is combined with ligation of the abdominal vena cava and the

induction of hypoproteineraia by plasmapheresis a transient low-protein

ascitic transudate is produced. '' It is possible that the pathogenesis

of ascites differs in these instances and that they are not comparable®

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Attempts to produce portal hypertension in the dog by the production

of various arterio-venous fistulae within theportal system have usually-

been incidental to study of the functional alterations following the

arterialization of the liver. Significant and sustained elevations of

the portal venous pressure have been obtained by these methods* how¬

ever* and opportunity has been afforded to observe the effect of in¬

creased pressure and flow per se upon the hepatic vasculature and

functions.

79 80 One of the earliest of these studies was that of Schilling 9

who implanted the hepatic artery into the portal vein of the dog.

Eighteen months later portal pressures and liver biopsies were normal.

In animals followed up to five years no portal hypertension or spleno¬

megaly were observed. The liver* however* showed progressive fatty

infiltration* sinusoidal dilatation and periportal fibrosis. Aneurysmal

dilatations were present at the site of the anastomoses.

8l 02 Cohn and Parsons J were the first to describe the tech¬

nique of total arterialization of the liver. Their technique consisted

of an end-to-side portacaval anastomosis with insertion of a venous

autograft between the aorta and the proximal portal vein. Portal pres¬

sures two weeks after this procedure were three to four times the con¬

trol values* averaging 31 cm. Vascular changes resembling an acute

necrotizing vasculitis were described in the portal venous radicles.

Numerous vessels showed internal fibrosis and medial hypertrophy. Se¬

vere jaundice was also noticed in a few animals postoperatively.

The vascular lesions observed by Cohn resembled those de-

8h scribed by Ferguson and Varco in the pulmonary circulation. These

83

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authors anastomosed the subclavian or brachiocephalic artery of the

dog to the pulmonary artery and observed irreversible medial hyper¬

trophy and intimal proliferation, often progressing to obliteration,

in the pulmonary arterioles two or more weeks following operation.

They felt that increased vascular pressure was of greater significance

than increased flow in producing the vascular lesions. Changes in the

larger portal vessels have also been studied in patients with portal

hypertension?"*9^ These have shown intimal thickening and medial hyper¬

trophy, presumably caused by the increased venous pressures. In the

few well-studied cases reported similar changes in the intrahepatic

portal venules have not been observed in patients with increased por-

tal tensions but without liver disease or vascular obstruction. ! Qj

On the other hand, Fisher et al studied 85 dogs prepared

in a manner similar to those of Cohn and observed up to 106 days post¬

op era tively, In the long-term survivors the livers were grossly and

microscopically normal % no vasculitis or hypertrophied venous radicles

were observed. Additional observations on these animals demonstrated a

two-fold increase in hepatic blood flow, a one and one-half fold in¬

crease in cardiac output, a two-fold increase in hepatic glucose pro¬

duction and an unchanged splanchnic oxygen consumption. All of these

parameters tended to return towards normal thirty days or more after

operation, associated with progressive narrowing and eventual throm¬

bosis in the main portal vein near the site of the anastomosis. In

several animals cytoplasmic acidophilic inclusions were described

88 within hepatic parenchumal cells. Histochemically, these were un¬

saturated, non-lipid, protein complexes resembling similar inclusions

observed following partial hepatectomy. Additional effects observed

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in dogs with totally arterialized livers included an enhanced hepatic

89 regenerative capacity and a reduction in fatty acid content follow-

90 ing an Eck fistula.

91 Servello and Pelionio arterialized the liver by performing

a latero-la tero anastomosis of the aorta to the splenic vein. No

change in the liver was observed after "several months".

Whereas some have utilized arterio-venous shunts as a method

92 to produce experimental portal hypertension, others have suggested

the same technique as a therapeutic method for the treatment of portal

hypertension. Five patients with cirrhosis have been treated by this

method, and four are known to have died." Follow-up data on the fifth

93 patient is unavailable; there was little change, however, in the

wedged hepatic venous pressure one month following end-to-side porta¬

caval shunt with anastomosis of the right gastro-epiploic artery to

the proximal portal vein.

In order to further elucidate the long-term effect of an in¬

creased blood flow per se upon the function and structure of the liver

and of the portal venous system of the dog a new experimental method

has been developed. It is proposed to increase the blood flow to the

liver by the creation of a reversed Eck fistula together with an aortic-

caval fistula. By ligating tbs inferior vena cava below the fistula

arterial blood has been directed into the portal vein by way of the

reversed portacaval shunt. Continued studies over a period of months

will be directed at determining changes in flow and portal pressures

along with observations of hepatic structure and function.

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METHODS

Adult mongrel dogs were used in this study. Hepatic blood

flows were determined before and after the creation of the vascular

9ii shunts by the bromsulfalein clearance method of Bradley.'

The animals were anesthetized with Nembutal, 30 mg/kg. The

left and right external jugular and the left femoral vein were exposed.

The left external jugular vein was cannula ted with a polyethylene

catheter connected by a 3-way stopcock to a heparin-saline infusion

for the sampling of peripheral venous blood. Under fluoroscopic con¬

trol the right or left hepatic vein was then catheterized with a No. 8

cardiac catheter via the right external jugular vein and connected to

a 3-way stopcock and saline-heparin infusion. The hepatic catheter

was wedged and then withdrawn about one centimeter so that a free flow

of hepatic venous blood was obtained. The left femoral vein was then

catheterized, and a priming dose of BSP, It mg/hg. was given intra¬

venously. Immediately following the priming dose the catheter was

95 connected to a mercury displacement constant infusion pump, calibrated

to deliver a l£0 mg.$ solution of BSP at a rate of about 1 ce/min., so

as to deliver about l.S> mg./cc/min,, and the time was recorded. Thirty

minutes were allowed for stabilization of the peripheral blood BSP

levels. Then six simultaneous 5 cc. blood samples were withdrawn at ten

minute intervals into heparinized and siliconized syringes from the

hepatic and left external jugular veins and placed in labeled silicon¬

ized centrifuge tubes. Five cc. specimens were withdrawn and discarded

immediately before the samples in order to eliminate the catheter dead

space, and the samples were withdrawn over a one minute interval in

order to reduce hemolysis to a minimum. Following the last samples the

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BSP infusion was stopped, the time recorded, the catheter removed and

the incision closed.

Following determination of the microhematocrits of the six

peripheral blood samples all the samples were centrifuged for 20 min,

at 20 RPM, and the plasma was separated from the cells. Badly hemolyzed

specimens were discarded. The plasma samples were then analyzed for

their BSP content using a Coleman Spectrophotometer at an absorption of

580 mu. Duplicate samples were prepared of 0.5 cc. plasma and 2.0 cc,

normal saline. Following the adjustment of each sample to 100% trans¬

mission two drops of 1.0 N NaOH were added, the sample mixed to develop

the color and the percent transmission determined. If the transmission

ware less than 30 percent additional dilution was required. The concen¬

tration of the infusate was determined similarly. From the percent

transmission the concentration of BSP was determined from a standardized

graph, prepared from the transmission properties of varied dilutions of

known BSP concentrations (courtesy of Dr. Milton Hales, Department of

Pathology).

The Estimated Hepatic Blood Flow (EHBF) was then calculated

9k using the formula proposed by Bradley.

EHBF = R XI 03Q1(P-Hj l=R&b

Where R s total BSP removal rate

rate of BSP infusion, mg/min.

P - concentration of BSP in peripheral blood, mg»%

H - concentration of BSP in hepatic venous blood, mg.$

Hct - microhematocrit

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If the peripheral BSP concentration is not constant in successive sam¬

ples, a correction must be made for the BSP removal rate (R):

R = I 1 (APxV)

Inhere R - total BSP removal rate, mgm/min,

I - rate of BSP infusion, rag/min.

AP s rate of change of peripheral BSP concentra¬ tion, mg/mX/mln.

V - plasma volume

. ‘ 96 - 10*2% of the body weight

Samples in which PpSP varied more than 0»Q005> mg/ml/min. were discarded.

A reversed portacaval shunt was subsequently performed, ex¬

posing the portal vein and inferior vena cava by a right thoraco-abdominal

incision through the bed of the ninth rib. A liver biopsy was taken, and

pre-shunt pressures were recorded in the portal vein and inferior vena

cava with a water manometer, corrected to the level of the portal vein.

A side-to-side two centimeter anastomosis was performed between the portal

vein and inferior vena cava, doubly ligating the vena cava above the

anastomosis. The left adrenal vein and the three left lumbar veins were

identified, ligated and divided. Post-shunt pressures were recorded,

and the incisions closed.

After allowing a suitable time for recovery a second operation

was performed in yiich the aorta and inferior vena cava were exposed

through a lower midline abdominal incision. A one centimeter arterio¬

venous fistula was constructed just above the inferior mesenteric ar¬

tery, and the vena cava was ligated below the anastomosis. Pressures

were recorded in the vena cava and mesenteric vein before and after con¬

struction of the fistula. Pos toper at ively the dogs were digitalized.

After recovery liver blood flows were again determined as previously

described

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RESULTS

Data are presented for one animal in which a reversed Eck

fistula and an aortie-caval fistula have been constructed* Following

the second operation a loud bruit has remained audible over the animal’s

lumbar spine. Liver blood flows, portal venous and inferior vena cava

pressures were recorded before and after construction of the vascular

shunts* These data are summarized in Table I and II.

It will be observed that the mean estimated hepatic blood

flow, as determined by the BSP extraction method, increased from liQ.l

cc/kg/min. to 97.0 cc/kg/min., an increase of 2.U times. There was an

8.5> cm, rise in portal venous pressure following the reversed Eck fis»

tula, and the inferior vena cava pressure was 19.6 cm. following com¬

pletion of both shunts.

A liver biopsy taken at the time of the first operation

demonstrated a normal liver structure.

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-25-

TABLE I

COMPARISON OF ESTIMATED HEPATIC BLOOD FLOW (EHBF)

Dog #5 - Wt. 26.5 kg®

A. Pre-Shunt

Sample #

PBSP mg 4

HBSP mg.#

P-H mg.#

R mg/min. Hot.

AP mg/ml/min. cc/kg/rain«

1 1.195 0.795 0.1-00 I,ii2 50 0 26.8 2 1.285 1.035 0.250 1.30 k9 0.00009 38.6 3 1.690 1435 0.255 1.17 53 0.0002 36.9 h 1.760 1.505 0.255 1.33 52 0.00007 Ui.x < 1.880 1.720 0.160 1.26 52 0.0001 57.2

Mean - 1|0.1 t 11.0

B. Post-Shunt

(1U Days PO)

Sample FBSP HBSP P-H R " "IF" ” EBBF # mg.# mg.# mg/rain. Hot. mg/ml/raln. c c/kg/min.

1 O.It95 0.1-20 O.C75 1.50 2lt 0 100 2 0.150 O.3I1G 0.110 1®59 2h o.00005 72.1 3 0*1465 o.la5 0.050 1«1*7 23 0.00002 315 It 0.1*70 0.365 0.305 1.1(9 2 It 0.00001 70.8

Mean ■ 97.0 t 3ko7

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TABLE II

COMPARISON OF EHBF, PORTAL VEIN AND

INFERIOR VENA CAVA PRESSURES

Pre-Shunt:

Post-Portacaval Shunt:

Post-Aortic-Caval Shunt:

PiV PIVC 1HBF Cm«H20 Crn.HpO ec/kg/min.

10.8 8,5 Uo.i

18.3 17.3

2i;*S*- 28.1 97.0

* Uncorrected pressure in mesenteric vein

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DISCUSSION

The experimental approaches to the study of the pathogenesis

of portal hypertension have been extensively reviewed in the first part

of this paper. It was emphasized therein that a considerable body of

evidence exists which implicates increased portal venous blood flow as

a responsible factor in rare cases of portal hypertension. The method

which has been described represents an attempt to Investigate the ef¬

fects ©f persistently elevated hepatic flows in the dog over a period

of perhaps several years. It is proposed to study these animals with

intermittent liver biopsies, liver function tests, hepatic blood flows,

wedged hepatic venous pressures and esophagoscopy. Although the de¬

tails of the method are unique it is fully recognized that others, nota¬

bly Schilling,®0 Cohn®^ and Fisher,®^ have utilized similar techniques

to obtain comparably increased hepatic blood flows In the course of

investigating certain other aspects of hepatic physiology* Any unique¬

ness which this method may possess may lie solely in that it is being

directed at a study of the relations, if any, of increased hepatic flows

to experimental portal hypertension in the dog over a lengthy period of

follow-up study. It may well be that the failure of all attempts to

produce portal hypertension experimentally may simply represent a species

variation. The facility whereby the dog develops a collateral circula¬

tion following portal bed obstruction Is conspicuous in the absence of

the utilization of the esophageal submucosal vessels, representing per¬

haps an anatomical or functional variation from the human organism.

Child"*- has already shown that the macaque responds to acute portal vein

occlusion in a manner similar to man, and it would be of interest to

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-28-

evaluate the effects of increased portal flows in this species.

The hepatic blood flows measured in this experiment utilized

the BromsuLfaledn extraction method which was first introduced by

Bradley.9** The method is an application of the Fick principle* and

its validity has been generally accepted. Bradley extensively discussed

the assumptions whichUfe made in order to utilize this method. Para¬

mount among these is that the liver is the only significant site for

BSP removal* so that the BSP concentration in a peripheral vein or

artery is the same as that in the portal vein. In the experiment de¬

scribed in this paper it must be further assumed that following the

production of the vascular shunts no BSP reaches the liver before it

reaches the right atrium, since the concentration of BSP is higher in

the inferior vena cava than in the external jugular vein where the blood

is sampled. The high venous pressure proximal to the ligated vena cava

makes this assumption a reasonable one.

97 Sapirstein and Reininger have emphasized the catheter in¬

duced error in hepatic venous sampling, demonstrating increasing vena

cava reflux as the catheter is withdrawn from its wedged position® They

pointed out also that local resistance changes produced by deeply placed

catheters are of importance in determining the portal inflow to the

98 catheterized area* Pratt, et al demonstrated that changes in the rate

of dye infusion produced proportional changes In the BSP extraction

rate up to a maximum limit» An important limitation of the method was

emphasized by Russ, et and became evident in this study. With in¬

creasing hepatic blood flows the extraction rate of BSP falls, so that

the concentration of BSP leaving the. liver approaches that entering the

liver. With the high flows produced by the vascular shunts Fggp

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-29-

Hggp occasionally fell -within the error of the analysis itself,

necessitating elimination of the sample.

DeteriTiination of the estimated hepatic blood flows in four

normal dogs in this laboratory has given an average value of I4.2.O

cc/kg/min. (U0.1-U5o6), in essential agreement with other observers

using the BSP and other methods.The wide variations that may be

observed in the hepatic blood flow in a given animal at different

101 times have been noted by Casselman and Rappaport. They observed

variations from one sampling period to another in the same animal

ranging from H5 percent less to 57 percent more than the preceding

values. In a given series of measurements the flows varied from 805

to 76 percent greater than the minimum value. Werner and Horvath*^

observed similar wide spontaneous variations and emphasized that a

single observation represents only the blood flow under the conditions

during that period of observation. Such wide variations were not as

notable in the present series. Other investigators"^9using me¬

thods other than the BSP method have observed similar wide variations

in the hepatic blood flow. These observations lend greater signifi-

9 cance to the direct hepatic illumination studies of Wakim and Mann

and their conclusion that much of the hepatic circulation may be in¬

active at any given moment.

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-30-

SUMMARY

(1) The clinical, pathologic and experimental factors in the patho¬

genesis of portal hypertension are reviewed#

(2) Particular attention is drawn to the occasional existence of

portal hypertension in the absence of any demonstrable portal

vascular obstruction. The possible significance of increased

portal venous blood flow as an etiologic factor in the elevated

portal pressures of such cases is discussed.

(3) A method is described for the production of increased portal blood

flow in the dog in an attempt to study the long-term effects of

elevated flows upon the hepatic structure and function and portal

vasculature. In one animal reported the hepatic blood flow, de¬

termined by the Bromsulfalein extraction method, was increased

2times following construction of a reversed Bek fistula and

an aortic-caval fistula*

(it) Experience with the determination of the estimated hepatic blood

flow by the Bromsulfalein extraction method is reported, and the

limitations of the technique are discussed#

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-31-

BIBLIOGRAPHY

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...

,. , . .... .... s* .0 OIci 'S :.£tJFbJTrC

y bis s x u1 ’■■■ 'd[o«orfolrfq

..... ....

flRoaogond's'-i ba : :xx.LL/t ... '

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I ‘ . . :'X£: ■« . . * jrcoael e, .vx^as'incor*” $ti& lo chroqqi/a berfo ti/i

• 1 nftc .tq « ■ • .

-32-

15. Klemperer, P.: Cavernomatous transformation of the portal vein. Arch, Path., 6:353> 1928.

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-33-

33. Pemberton* J, and Kieman* P.s Surgery of the Spleen. Surg. Cl.

N.A., August* 19h$} p. 188.

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U8. Dye*W.S: Observations on the inconstancy of portal hypertension in hepatic cirrhosis. Surgical ^orum* Philadelphia* Saunders * 1952*

~

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laesvox'is^is jiou/Jb domhstoorf ■ ft ' : , ■

. . . • » * 0 lo cKoqe'i z

.

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.

... . . ■: .

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. '

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.

U9. Taylor, F.W. • Portal tension and its dependence on external pressure. Ann. Surg., Iij0:652, 195^4*

£0. Baronofsky, I.D.: Portal hypertension, with special reference to the acid-peptic factor in the causation of hemorrhage and ex¬ tensive gastric resection in its treatment. Surgery, 25:135* 19U9.

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11$: 169* 1958.

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Gastroenterology, 16:19U* 1950.

56. Douglass* T.C., Mehn, W.H., Lounsbury, B.F., Swigert, L.L. and Tanturi C.A.: Attempts at the experimental production of portal hyper¬ tension. Arch. Surg., 62:785, 195l»

57. Volw iler, Grindlay, J.L. and Bollman, J.L.: Chronic portal vein obstruction in dogs from silica cirrhosis. Gastroenterology, 2I4:

i|05* 1953.

58. Hoffbauer, F.W.: Factors influencing pressure in the portal vein. Transactions of the Seventh Conference on Liver Injury. Josiah Mary Foundation, I9I48.

59. Vol wiler, W., Grindlay, J.L. and Bollman, J.L.: The relation of portal vein pressure to the formation of ascites: An experimental study. Gastroenterology, iL^liO, 1950.

60. Farrar, T., Eollman, J.L., Gray, H.E. and Grindlay, J.H.: Spontaneous and induced canine venous collateral circulation after chronic extra hepatic occlusion of the portal vein. Surgical Forum, Philadelphia, Saunders, 195U.

61. Eisenmenger, W.J. and Nickel, W.F.. Relationships of portal hyper¬ tension to ascites in Laennec’s cirrhosis. Am. J. Med., 20:879* 1956. “

62. McDermott, W.V.: The treatment of cirrhotic ascites by combined hepatic and portal decompression. N, Eng. J. Med., 259:897, 1958.

63. Cross, F.S., Raffucci, F.L., Toon, R.W. and Wangensteen, O.H.: Effect of complete hepatic vein ligation on portal pressures and as¬ cites formation in dogs with porta-caval shunts. Proc. Soc. Eheper. Biol. & Med., 82:505, 1953.

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