nodular, associated with · oesophageal varices. the liver was small and showed a nodular,...

J. clin. Path, 1974, 27, 963-966

Nodular, non-cirrhotic liver associated withportal hypertension in a patient with rheumatoidarthritisM. HARRIS, R. M. RASH, AND I. W. DYMOCK

From the Department of Pathology, University of Manchester, and the Departments of Geriatric Medicineand Medicine, University Hospital ofSouth Manchester

SYNOPSIS A patient with rheumatoid arthritis developed portal hypertension and died from bleedingoesophageal varices. The liver was small and showed a nodular, non-cirrhotic pattern similar tothat described by Blendis et al (1970 and 1974) in association with Felty's syndrome. This appearsto be the first report of a patient with this liver lesion associated with rheumatoid arthritis in theabsence of Felty's syndrome. The liver lesions described here are compared with partial nodulartransformation and nodular regenerative hyperplasia; in spite of some differences it is not proventhat these are distinct entities and further study is required to settle this question.

In a recent study of the liver changes in Felty'ssyndrome, abnormalities ranging from lymphocyticinfiltration to macronodular cirrhosis were described(Blendis, Ansell, Lloyd Jones, Hamilton, andWilliams, 1970). Included in the eight cases wherehistology was available was one (case 5) in whichthere was nodularity without fibrosis causing portalhypertension. This abnormality had not beenpreviously described but since then a more detailedaccount of this patient plus four additional patients,all of whom had Felty's syndrome, has been pub-lished (Blendis, Parkinson, Shilkin, and Williams,1974); three of these five patients had portal hyper-tension.

In this paper we report a further patient withrheumatoid arthritis whose liver showed a similarnodularity and who also had portal hypertension.This appears to be the first recorded example of thisassociation where the patient did not also haveFelty's syndrome.

Case Report

The patient was a woman aged 79 years who hadbeen diagnosed as having rheumatoid arthritis 40years previously but who had been free from arthriticsymptoms for several years.On 8 March, 1973 she was admitted to hospital

with swelling of the abdomen which had first beenReceived for publication 10 September 1974.

noticed one year previously. On examination thepositive findings were of massive ascites, ankle andsacral oedema, and gangrene of two finger tips.There was inactive rheumatoid arthritis of the handsand wrists; skin nodules were absent. At no timewas the liver palpable and there was no lymph nodeenlargement.The ascites was tapped to relieve abdominal dis-

comfort, and 3 litres of clear, pale yellow fluidremoved. On 11 March 1973 coffee ground vomitingoccurred and on 5 April an EEG was reported asbeing abnormal and compatible with a metabolicencephalopathy.The ascites recurred despite diuretic therapy and

was tapped on several further occasions. Foetorhepaticus was noted on 18 May and althoughtherapy for liver failure was given there was steadydeterioration, death occurring on 1 June followingseveral episodes of melaena. The clinical diagnosiswas hepatic cirrhosis with portal hypertension andbleeding from oesophageal varices.

INVESTIGATIONSHaemoglobin: 9-5 g/dl (red cells hypochromic);white cell counts: 7-2 x 109 and 8-9 x 109 per 1;platelets: 155 x 109 and 126 x 109 per 1; ESR: 10mm in first hour.Serum bilirubin: 14 ,umol/l rising to 34 ,umol/l;

alkaline phosphatase: 440 KA units per I falling to190; LDH and SGOT normal.

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Plasma NH3 (on 19 March): 168 ,u mol/l (normal13-34); serum albumin 26 g/l, serum globulin 32 g/l.Prothrombin activity 45%; factor V 70°%, factor

VII 90%, factor X 70%.LE cells (x 3) negative; antinuclear factor

positive; smooth muscle antibodies negative; mito-chrondial antibodies: negative.SCAT negative; F II latex test positive (titre > 1

in 640).Hepatitis B antigen negative. Liver scan com-

patible with cirrhosis and portal hypertension.Needle biopsy of liver (taken after death) no diag-nostic features.

Necropsy

The finger joints showed rheumatoid deformitiesand a section through a metacarpo-phalangeal jointshowed replacement of the articular cartilage byfibrous pannus and minimal chronic inflammatorycell infiltration.The liver was very small, weighing 592 g. The

Fig 1 The cut surface ofthe liver afterfixation showingvariably sized, ill defined nodules.

M. Harris, R. M. Rash, and I. W. Dymock

capsule was slightly thickened and opaque, theouter surface of the liver having an ill definednodular pattern. On the cut surface this ill definednodularity was also apparent, the nodules measuringup to 1-3 cm diameter and lacking any definitefibrous boundaries; they were most obvious besidelarge portal septa but were also present throughoutthe parenchyma (fig 1). The gallbladder, bile ducts,pancreas, and portal and hepatic veins were normal.

Evidence of portal hypertension was present,there being ascites (600 ml of serous fluid), slightcongestive splenomegaly (spleen weight 191 g), andvarices with mucosal ulceration in the lower oeso-phagus. The stomach, small intestine, and colonwere filled with altered blood.

In the cardiovascular system there were changeswhich may have been associated with the rheumatoidprocess. These were organizing fibrinous pericarditis;two small non-bacterial vegetations on the tricuspidvalve; obliterative endarteritis of the digital arteriesassociated with gangrene of the finger tips (as des-cribed in rheumatoid disease by Bywaters, 1957).No other abnormalities were noted in the cardio-

vascular system or elsewhere.

Histology of the Liver (Figs 2 and 3)

Many sections were examined using haematoxylinand eosin, Masson's trichrome, van Gieson andreticulin stains, and all showed a basically similarpattern. The nodularity was finer than the macro-scopic appearances had suggested and was due tochanges in the texture and arrangement of the livercell plates. Within the nodules the liver cells wererelatively large with pale staining cytoplasm andwere arranged in broad, closely packed trabeculaeseparated by narrow sinusoids. At the periphery ofthe nodules the liver cells appeared atrophic, andtheir cytoplasm was more eosinophilic; they werearranged in narrow trabeculae separated by relativelywide sinusoids, sometimes appearing to pass cir-cumferentially around the nodules. In some areassmall portal tracts occupied the centres of thenodules producing the pattern of reversed lobula-tion but this was not present in all regions. Someportal tracts showed fibrosis; this was variable indegree and although in places it was marked andtended to accentuate the nodulaiity, in general thelobular architecture was readily discernible andconnective tissue stains did not demonstrate fine orcoarse fibrous septa at the petiphery of the paren-chymal nodules. There was thus no evidence of atrue cirrhosis. Some portal tracts showed moderatelymphocytic infiltration. Scattered areas of recentparenchymal cell necrosis were present which werethought to be attributable to terminal shock.

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Nodular, non-cirrhotic liver associated with portal hypertension in apatient with rheumatoid arthritis

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Fig 2 Several nodules ofcompactly arrangedpalestaining liver cells are bounded by darker stainedtrabeculae separated by dilated sinusoids. Masson'strichrome (MT) x 55.

Discussion

The histological features found in this patient's liverresemble those observed in the five patients des-cribed by Blendis et al (1974), although the size ofthe liver appears to be different. Blendis et al (1974)stated that the livers in all of their cases wereclinically enlarged (necropsy weights were notquoted) whereas in the present case the liver weightwas greatly reduced. Clinically, the main differencesare the inactivity of the rheumatoid process and theabsence of Felty's syndrome in the present patient.The latter is of particular interest because in all fivepreviously reported cases there was an associationwith Felty's syndrome, and, although Blendis et alstated that a causal relationship was not proven, itwas considered that the conditions were 'trulyrelated' because no examples of the liver lesion

Fig 3 The edge ofa nodule showing pale staining cellswithin the nodule (right) and circumferentially arrangedtrabeculae at its periphery (left). Note the absence ofafibrous septumfrom the edge ofthe nodule. MT x 150.

could be found in necropsy series of 51 cases ofrheumatoid arthritis, 21 cases with other connectivetissue disorders, 14 cases with splenomegaly fromblood dyscrasia or lymphoma, nor in 100 consecutivenecropsies at one hospital. The case reported heresuggests that the association may be with therheumatoid process rather than exclusively withFelty's syndrome, although on the evidence of thesix examples so far described it appears to be morecommon in Felty's syndrome.However, the extreme rarity of the association

raises the further question as to whether the liverchanges really do constitute part of the spectrum ofrheumatoid disease (with or without Felty's syn-drome), or whether the liver lesions are a rareindependent entity fortuitously associated withrheumatoid disease in the patients so far described.In this connexion, it is relevant to examine des-

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criptions of other conditions of the liver in whichthere is nodularity without cirrhosis to try todetermine if other cases havingsimilarliverpathologyoccur independently of rheumatoid disease. Twoconditions appear to merit consideration, namely,nodular regenerative hyperplasia (Steiner, 1959) andpartial nodular transformation (Sherlock, Feldman,Moran, and Scheuer, 1966).

In nodular regenerative hyperplasia the histo-logical changes in the liver appear to be similar tothose under consideration here, although in the fourcases reported in Steiner's paper where weights weregiven they ranged from 1300 to 1720 g, a sharpcontrast with the very small liver in the presentinstance. Steiner considered the lesions to representa regenerative phenomenon associated with paren-chymal damage from various causes; the commonestbeing passive hyperaemia. No reason for chronichepatic congestion was present either in the patientdescribed here (the tricuspid valve vegetation wastrivial and the cusps themselves normal) nor,apparently, in the cases reported by Blendis et al.Steiner does not mention rheumatoid arthritis in hispaper nor does he describe the occurrence of portalhypertension in his patients.On the other hand, portal hypertension was present

in all four cases of partial nodular transformationdescribed by Sherlock et al. However, none of thesepatients had rheumatoid disease and the liverpathology differed from the cases under considera-tion here in that the nodules were not uniformlydistributed throughout the liver, tending to be foundmainly around hilar tissue. The weights of the liversin three of Sherlock's cases were 1200, 1200, and1400 g.Thus, there appear to be some grounds for

regarding these three described varieties of nodular,non-cirrhotic liver disease as distinct entities butthe evidence is far from conclusive and the questionmust remain open until further examples of thesetypes of liver disease are described and their associa-tion with rheumatoid disease (with or without

M. Harris, R. M. Rash, and L W. Dymock

Felty's syndrome) and portal hypertension clarifiedstatistically. However, Blendis et al (1974) appearto accept that the liver lesion in their patients is bestclassified as nodular regenerative hyperplasia.

It is noteworthy that a precise anatomical diag-nosis of the liver condition may be impossible toestablish even when a needle biopsy is performed.The liver biopsy in our patient was unhelpful andthis was also so in two of the three cases of Blendiset al (1974) where needle biopsy was performed.Furthermore Scheuer (1973) comments that needlebiopsy is unlikely to demonstrate the diagnosticfeatures of partial nodular transformation. Thereason for this is probably that large areas of livertissue are necessary to appreciate the alteringpattern of the parenchymal cells which defines thenodules, and such a sample is only likely to beobtained at open wedge biopsy or necropsy.The mechanism whereby the nodules form in any

of these conditions is far from clear, although thepossibility that disordered regeneration as postulatedby Steiner in nodular regenerative hyperplasia mightplay a part in all three conditions cannot be ruledout.

We are indebted to Dr P. J. Scheuer for his commentson the liver sections and to Dr E. Freeman foraccess to the clinical records. The photomicrographswere taken by Mr G. Humberstone.

References

Blendis, L. M., Ansell, I. D., Lloyd Jones, K., Hamilton, E., andWilliams, R. (1970). Liver in Felty's syndrome. Brit. med. J.,1,131-135.

Blendis, L. M., Parkinson, M. C., Shilkin, K. B., and Williams, R.(1974). Nodular regenerative hyperplasia of the liver in Felty'ssyndrome. Quart. J. Med., n.s., 43, 25-32.

Bywaters, E. G. L. (1957). Peripheral vascular obstruction in rheuma-toid arthritis and its relationship to other vascular lesions.Ann. rheum. Dis., 16, 84-103.

Scheuer, P. J. (1973). Liver Biopsy Interpretation, 2nd ed., p. 87.Bailliere, London.

Sherlock, S., Feldman, C. A., Moran, B., and Scheuer, P. J. (1966).Partial nodular transformation of the liver with portal hyper-tension. Amer. J. Med., 40, 195-203.

Steiner, P. E. (1959). Nodular regenerative hyperplasia of the liver.Amer. J. Path., 35, 943-953.



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nodular, associated with · oesophageal varices. the liver was small and showed a nodular,...

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