Familial Active Chronic Hepatitis with Hepatocellular Carcinoma

Vol. 62. No.3 Printed in U.S.A.

GASTROENTEROLOGY

Copyright © 1972 by The Williams & Wilkins Co.

FAMILIAL ACTIVE CHRONIC HEPATITIS WITH HEPATOCELLULAR CARCINOMA

Report of a case R. A. JOSKE, M.D., B. H. LAURENCE, M .B. , AND L. R. MATZ , M.B.

Department of Medicine, University of Western Australia, and Department of Pathology, Royal Perth Hospital, Perth , Australia

Another member of a previously described kindred is reported in whom active chronic hepatitis with cirrhosis led to hepatocellular carcinoma with pulmonary metastases. The patient'and his relatives did not show serological evidence of Australia antigen. We have previously reported a kindred (family G) with a high frequency of abnormal immunological findings, and of chronic liver disease meeting the diagnostic criteria of active chronic hepatitis. 1 We have since seen another member of this kindred, a brother of case 1-2 in the initial report, who presented with active chronic hepatitis and died from hepatocellular carcinoma with pulmonary metastases. This case is presented here for two reasons. It is the only report of hepatoma in this type of liver disease, although Denison and his colleagues 2 have described hepatocellular carcinoma in two adult brothers with macronodular cirrhosis and mention three similar sibships described by other workers. This case also establishes the presence of chronic liver disease on both the maternal and paternal sides of the pedigree in our initial report, 1 with possible modification of the postulated mode of inheritance in this family. Clinical and laboratory methods and normal values for this hospital have been included in our earlier paper. 1 Australia Received May 25, 1971. Accepted September 15, 1971. Address requests for reprints to: Dr. R. A. Joske, Department of Medicine, University of Western Australia, Victoria Square, Perth, W.A., Australia. This patient was referred by Mr. A. Gild, Senior Surgeon, Royal Perth Hospital, to whom grateful acknowledgement is made.

antigen was sought for by immunoelectrophoresis with Amido black lOB counterstain. Case Report A male patient was born in Italy in 1910 and migrated to Australia during his childhood. In 1964 he developed symptoms of peptic ulcer and chronic bronchitis. This led to his admission to the Royal Perth Hospital where enlargement of the liver was noted. Relevant investigations, included in table 1, showed only an increased erythrocyte sedimentation rate of 33 mm in 1 hr. He was subsequently well and at work for some years despite fractures of ribs in an accident in 1968. He was readmitted to the hospital in 1969 for investigation of jaundice and right subcostal pain of 5-weeks duration . This pain was accompanied by further dyspepsia related to meals, anorexia, nausea, and flatulence. There was no history of contact with acute hepatitis, blood transfusions, or drug ingestion. His alcohol intake was uncertain, but probably included both brandy and beer daily. Examination showed an obese man with jaundice but with no stigmata of chronic liver disease. The liver was enlarged and firm, the edge being palpable 5 cm below the right costal margin . The spleen was not palpable. The only other abnormal signs were related to his chronic bronchitis. Hematological and other investigations are included in table 1. Radiological studies included a barium meal which showed a prepyloric ulcer. Liver scan ('.BAu) confirmed hepatomegaly with an irregular uptake consistent

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LIVER PHYSIOLOGY AND DISEASE

442 TABLE

1. Selected serum values and other investigations in familial active chronic hepatitis

with hepatocellular carcinoma" 1965

15 .3 Hb a (g per 100 m!) . ... . . . . . . . . .. . . . .... 33 ESR' (mm per hr) . .. . ... . Platelets (per cm 2) . ... Bilirubin (mg per 100 m!) .. 9 .5 SAPe (King-Armstrong units) ... . . . . . . . .. . SGOT" (U) . .. . . . . . . . SGPT' (U) ., ' . Albumin (g per 100 m!) . 'Y-globulin (g per 100 ml) . ... . . .. . . . . . . .. . Urea (mg per 100 m!) . IgG (mg perl 00 m!) .. . . . . . ... . . .. . IgA (mg per 100 m!) .. . .. . . . . IgM (mg per 100 m!) .. ... . - , . .. .

September 1969

August 1969

12.4 95 110,000 22.0 17 157 210 2.8 2.7 22

13.5 102 105,000 3.1 12 92 61 2.9 3.5 28

February 1970

13.5 50 69 , 000 1.5 23 70 47 3.3 2.4 2400 1320 129

June 1970

15.0 65 13 .0 30 150 44 2.3 2.3 31 2000 960 280

July 1970

14.8 164,000 21.5 47 240 60

254

Hb, hemoglobin. ESR, erythrocyte sedimentation rate . e SAP, serum alkaline phosphatase. d SGOT, serum glutamic oxaloacetic trans~minase. , SGPT, serum glutamic pyruvic transaminase. a b

with cirrhosis, as well as splenomegaly. Excretion studies (13 1I-rose bengal) showed reduced clearance and delayed excretion suggestive of impaired liver function. Immunological studies failed to demonstrate lupus erythematosus cells, antinuclear factor, parietal cell, or thyroglobulin antibody. The Wassermann and Paul-Bunnell tests were negative. The rheumatoid arthritis-latex test was positive to a titer of 1: 64, and cold agglutinins (4 C) were present in a low titer of 1: 2. The Mantoux reaction was negative, although chest radiographs showed a primary calcified focus. Bone marrow examination showed erythroid hyperplasia and a moderate reactive plasmacytosis. Liver biopsy demonstrated chronic aggresive hepatitis of moderate severity with hepatic cirrhosis (fig. 1). His course in the hospital was complicated by pneumonia which responded to antibiotic therapy and the development of ascites requiring diuretics. Steroids were withheld in the presence of a proved peptic ulcer. He was discharged after 8 weeks, and laboratory findings at this time are included in table 1. Subsequent visits to the clinic revealed little change in his condition, either clinically or biochemically. Immunoelectrophoretic studies showed increases in IgG and IgA without change in IgM. In June 1970 his jaundice increased and he

developed nausea and vomiting, leading to his final admission. He had at this time multiple spider nevi on his thorax. There had been considerable increase in the size of his liver, the edge being palpable 10 cm below the costal margin. Treatment was begun with azathioprine, but he developed renal failure, the plasma urea rising to 254 mg per 100 ml (table 1). He died with terminal hematemesis 4 weeks after admission.

Necropsy Findings The relevant findings at necropsy included deep jaundice. The peritoneal cavity contained 2.2 liters of straw-colored fluid. The liver weighed 2900 g and the external and cut surfaces were green in color and irregularly nodular. A poorly defined mass of tumor tissue occupied the lower two-thirds of the right lobe and had invaded many veins so that multiple tumor emboli were present in both lobes. Partially necrotic tumor distended and occluded the portal vein. The external biliary drainage system was normal. Miscroscopic examination of the liver showed a well established macronodular cirrhosis. There was considerable terminal necrosis of parenchymal regeneration nodules, but only very slight perilobular in-

March 1972

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443

FIG. 1. Familial active chronic hepatitis. Liver biopsy showing fibrosis, pleomorphism of parenchyma, and inflammation of chronic aggressive hepatitis with cirrhosis (H and E, x 160) .

FIG. 2. Familial active chronic hepatitis. Necropsy specimen showing hepatocellular carcinoma with invasion of vessels (H and E, x 36) .

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LIVER PHYSIOLOGY AND DISEASE

flammation. The tumor was a moderately well differentiated hepatocellular carcinoma with extensive invasion of veins (fig. 2). The spleen weighed 430 g and was congested with moderate perisplenitis. The lungs contained small tumor metastases and there was widespread pulmonary artery tumor embolism. The kidneys showed changes of advanced bile nephrosis, and the terminal hematemesis had been due to multiple superficial gastric and duodenal erosions.

Family Studies and Australia Antigen The patient had been married twice. His second wife, an Australian-born female of 39 years had no stigmata of liver disease, and both she and their two children of 10 and 12 years had normal bilirubin, transaminase, and ')I-globulin levels. Detailed immunological studies were not performed. The kindred were investigated extensively for the presence of Australia antigen since this has been associated with familial hepatoma. 2 Subjects included cases II-I, 11-2, 11-5, 11-7, 11-8, 11-9, and 11-10 of the initial kindred (of whom 6 had immunological abnormalities with associated active chronic hepatitis in 2) 1; and three children of the present patient's first marriage, his second wife, and her two children. In no case was the presence of Australia antigen detected. Discussion This case meets the diagnostic criteria of active chronic hepatitis in the length of history of active liver disease, persisting elevation of transaminase levels, and the increases in IgG and IgA, as well as the histological appearances of chronic aggressive hepatitis with cirrhosis but without fatty change seen in the liver biopsy (fig. 1). The possibility of ethylism as a cause

Vol. 62, No.3

of liver disease is rendered improbable by the family history, clinical and biochemical findings, and these biopsy changes. The presence of hepatic cirrhosis is also consistent with this diagnosis since cirrhosis has been shown by serial studies to develop in active chronic hepatitis (R. A. Joske and D. J. McCully, unpublished observations) as well as being present in most cases of the disease which persist and progress. J The occurrence of hepatoma in this condition is rare, although well documented,4. 5 and it has not previously been described in this type of familial liver disease. This may be due to its relatively short course in most instances. The final point concerns the genetics of this disease. The pedigree, 1 enlarged to include this case, is consistent with the view that the observed abnormalities are inherited as a Mendelian system which manifests as immunological abnormalities in the heterozygote and with liver disease also in the homozygote. This view is unfortunately so straightforward as to be improbable. REFERENCES 1. Joske RA, Laurence BH: Familial cirrhosis with

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3.

4.

5.

autoimmune features and raised immunoglobulin levels. Gastroenterology 59:546- 552, 1970 Denison EK, Peters RL, Reynolds TB: Familial hepatoma with hepatitis-associated antigen. Ann Intern Med 74 :391-394, 1971 Mistilis SP: Natural history of active chronic hepatitis. II. Pathology, pathogenesis and clinicopathological correlation. Australas Ann Med 17:277- 288, 1968 Read AE, Sherlock S, Harrison CV: Active juvenile cirrhosis considered as part of a systemic disease and the effect of corticosteroid therapy. Gut 4:378-393, 1963 Mistilis SP, Skyring AP, Blackburn CRB : Natural history of active chronic hepatitis. I. Clinical features, course, diagnostic criteria, morbidity, mortality and survival. Australas Ann Med 17:214- 223, 1968