Familial Cirrhosis with Autoimmune Features and Raised Immunoglobulin Levels

Vol. 59. No.4 Printed in U.S.A .

GASTitOENTEROLOGY

Copyright @ 1970 by The Williams & Wilkins Co.

FAMILIAL CIRRHOSIS WITH AUTOIMMUNE FEATURES AND RAISED IMMUNOGLOBULIN LEVELS R. A.

JosKE,

M.D. ,

AND

B. H.

LAU RENCE,

M.B.

Departm ent of Medicine , University of Western Australia , Perth, Australia

A kindred is described in which 5 members had chronic liver disease with abnormal immunological findings and eight others had abnormal immunological findings without liver disease. It is suggested that these results are of genetic origin, possibly related to anomalous control of immunoglobulin levels. Although active chronic hepatitis was have an increased incidence of autoimdescribed in 1955, 1 the etiology of this dis- mune disease. Maclachlan and her ease is uncertain, and there is little colleagues7 examined 28 first degree relaknowledge of the role of genetic factors in tives of 9 patients with lupoid hepatitis. it. An extensive literature exists concern- Although none had liver disease, 7 had ing familial cirrhosis, and cirrhosis com- hypergammaglobulinemia, 7 had antinuplicating inborn errors of metabolism such clear factors in serum, 5 had biological as galactosemia and hemochromatosis, 2 ' 3 false-positive reactions for syphilis, and 3 but few reports of familial studies of ac- had histories of polyarthritis. A more detive chronic hepatitis and related types of tailed study was made by Cavell and chronic liver disease with autoimmune Leonhardt8 of 23 paternal and 31 maternal relatives of a girl with lupoid hepatitis. features. King et al. 4 described histological active The maternal relatives showed a significhronic hepatitis in a mother and son, cant increase in age-corrected )'-globulin although the mother was an alcoholic. levels and a possible increase in frequency Some years later Krook 5 included 2 sisters of positive reactions for rheumatoid factor aged 54 and 60 years in a series of 9 pa- compared with both paternal relatives tients with active chronic hepatitis. Rug- and a control group. gieri et al. 6 reported other cases of chronic A more general survey by Elling et al. 9 liver disease in the families of 11 of 27 included sera from 90 siblings of 38 prochildren with juvenile cirrhosis, although bands with cirrhosis of various types inthe immunological aspects of these cases cluding 27 with possible active chronic were not investigated. hepatitis. Five of the siblings had overt There is some evidence that relatives of rheumatoid disease, 20 had serum antinupatients with active chronic hepatitis clear factors, and 15 had positive latex tests. There was no increased frequency of Received November 4, 1969. Accepted March 24, raised )'-globulin levels compared with a 1970. control series of marriage partners. Address requests for reprints to: Dr. R. A. Joske, A genetic factor is established, however, Department of Medicine, University of Western in the syndromes related to chronic hepaAustralia, Victoria Square, Perth, W.A., Australia. titis and occurring with increased freThe authors wish to thank the physicians who quency in the relatives of these patients, referred these patients for study, and Dr. M. Clarke discussed in preceding paragraphs. The and Dr. W. M. C. Keane of St. Vincent's Hospital, literature is large and has been reviewed Melbourne, for copies of the case notes and biopsy of 10 patient 11-6. Immunoglobulin studies were per· by several authors11 including2 Stecher, formed by Miss W. Lynch of the Royal Perth Hospi· Lawrence and Ball, Kunkel/ and Leon13 These diseases are also linked tal. Dr. L. Matz kindly reviewed all of the histologi· hardt. cal specimens. with abnormalities of serum proteins such 546

FAMILIAL CIRRHOSIS

October 1970

as positivity for rheumatoid factor 1 1 and agammaglobulinemia, 14 which have a . bas1s. . 15- 16 genetic Thus, there is some indirect evidence of a genetic factor in some cases of active chronic hepatitis. In. the present paper, a kindred in which hyperglobulinemia and abnormal immunological tests were associated with a high frequency of chronic liver disease is described, and the implications of this association are discussed. Pedigree

547

3, and by biopsy in patients II-3 and 11-5. The report of a biopsy obtained elsewhere was available in patient II-6. Biochemical studies were made by autoanalytic methods and antibody studies by tanned red cell and immunof1uorescent methods. Quantitative estimations of immunoglobulins (lg) were done by a modification of the Mancini radial diffusion method, using commercially prepared plates (Baxter-D.H.A. Laboratories Pty., Ltd.). The normal ranges quoted were determined in this hospital from a study of normal subjects and expressed as the mean ±2 so.

The pedigree of this kinship, family G, is shown in figure 1. The propositus was case II-3. Case Reports The parents (1-1, 1-2) attended the Royal Perth Hospital and records were Case 1-1. This patient died at age 68 in the available for review, as was autopsy mate- Royal Perth Hospital from a carcinoma of the rial for case 1-1. Eight of the 10 siblings in esophagus. His Wassermann reaction was posigeneration II were seen by us on one or tive but no other relevant investigations were more occasions, as well as the children of performed. At autopsy the liver weighed 1174 g and patient 11-3. Patient 11-6 had been admitted to hospital elsewhere and a photostat showed a micronodular cirrhosis. Histologithere was an established cirrhosis with of his record was available, although the cally degeneration and regeneration of hepatocytes patient was not seen personally. and an extensive infiltrate containing many Some of the laboratory findings in this plasma cells (fig. 2) . There was no evidence of kindred are summarized in tables 1 and 2. past or present syphilis. Results cited are those obtained when the Case 1-2. This woman, the wife of patient Ipatient was first seen. All were obtained 1, was born in 1906. She was admitted to the by standard methods. Liver tissue was Royal Perth Hospital late in 1958 with recurobtained at autopsy in patients 1-1 and II- ring upper gastrointestinal hemorrhage due to

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1. Pedigree of family G . The propositus was patient II-3. Squares, males; circles, females . FUll shading, chronic liver disease with abnormal immune features. Half-shading, abnormal immune features or immunoglobulin levels without liver disease. Circled arabic numbers indicate patients seen personally or with histological material available for review. FIG.

548

JOSKE AND LAURENCE

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disease, and showed abnormal immunological results. There was hypergammaglobulinemia, positive lupus erythematosus cell and latex Immunoglobulins mg/ 100 ml Positive tests, and cold agglutinins (40 C) were present Case immune no. reactions to a titer of 1 : 8. The tuberculin reaction was IgM lgA lgG negative to 1: 100 old tuberculin, and lymphocyte transformation in response to phytohemagNormal 800- 1600 95-500 80-300 glutinin was impaired. 17 Liver biopsy showed adult WR" an active established cirrhosis. There was I-1 parenchymal cell damage, and a dense cellular Nil II-1 infiltration with granulocytes and immuno285 540 1500 II-2 II-3' ++ ++ RA-latex LE-cells cytes. Iron and copper stores were normal. + She received prednisone with a good initial 156 LE-cells 1740 880 II-5 response. This continued for 18 months, during RA-latex II-6 which time she required 20 mg daily to main· 212 Nil 2200 990 II-7 tain serum glutamic oxalacetic transaminase 126 Nil 280 II-8 950 (SGOT) levels of approximately 75 Karmen 192 Parietal cell 1600 320 II-9 units. After this time her ascites reaccumuantibody lated and she developed portal-systemic enII-10 450 230 Nil 1600 cephalopathy. 140 140 Nil 840 III-7 WR III-8 This led to her final admission. On this oc165 Nil 140 III-9 1750 casion she was deeply jaundiced with ascites III-10 110 76 Nil 910 and multiple ecchymoses. Investigations included: serum bilirubin , 24 mg per 100 ml; " WR, Wassermann reaction ; LE, lupus erytheserum alkaline phosphatase, 32 King-Armmatosis; RA, rheumatoid arthritis. strong units; SGOT, 171 Karmen units; blood • Case II-3 was studied before quantitative results ammonia, 158 p.g of N per 100 ml; serum albuwere available. +. slight increase; ++. considermin, 2.7 g per 100 ml; -y-globulin, 3.8 g per 100 able increase. ml. Her response to treatment was poor. She a chronic duodenal ulcer. Investigation at this developed hyponatremia and renal insuffitime showed hyperglobulinemia with normal ciency and died 4 weeks after admission. liver function tests but no further investigaAt autopsy the final cause of death was tions were made. She died elsewhere 6 years acute hemorrhagic pancreatitis. The liver later of ischemic heart disease, and the liver weighed 1400 g and showed a micronodular was reported macroscopically normal at au- cirrhosis. Microscopy confirmed the presence topsy. of cirrhosis, with continuing liver cell necrosis Cases Il-l, II-2, and Il-3. These patients and granulocytic infiltration, as well as bile were triplets born in 1926_ Patients Il-l and II- stasis and ductular proliferation (fig. 3). The 2 presented no signs of liver disease, but pa- kidneys showed membranous glomerulonetient Il-l had significant hypergammaglob- phritis of the type seen in active chronic hepaulinemia (1 % level), and patient Il-2 a raised titis. 18 Other findings were unremarkable. Case II-4. A female born in 1927 was not IgA, and a high normal IgM. The third of these triplets (patient Il-3) had seen by us but reported to show no stigmata of chronic liver disease with abnormal immuno- liver disease. logical findings from which she died at age 42. Case II-5. A male born in 1929 developed Case II-3. This patient presented at the age recurring jaundice at the age of 17 years. At 34 of 41 with an insidious onset of weakness, mal- years of age he had hematemeses which led to aise, and anorexia, followed by bruising and laparotomy. The liver was noted to be cirrhotic abdominal swelling. There was no history of and a biopsy was taken. This showed an early previous jaundice or of alcoholism. On exami- cirrhosis, parenchymal cell damage, and an nation she was febrile, with jaundice and an infiltrate of granulocytes and immunocytes. erythematous butterfly rash on her face . The Postoperatively he developed a bleeding tendliver was enlarged to 4 em and the spleen to 2 ency requiring transfusion while his anorexia, em below the costal margins with a moderate vomiting, and weight loss persisted. He was then referred to the University Department of ascites. She was mentally confused. Initial investigations (tables 1 and 2) con- Medicine. Examination at this time showed jaundice, firmed the clinical diagnosis of chronic liver TABLE

1. Summary of immunological findings in family G

FAMILIAL CIRRHOSIS

October 1970 TABLE

Cngc no.

Normal adult 1- 2 11-1 11-2 11-3 11-5 11-6 11-7 Il-8 II-9 II-10 III-7 III-8 III-9 III-10

549

2. Biochemical findings in family G

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SGO'l"

SGPT'

Serum albumin

globulin

K .A . unit.'i

Karmen units

Karm en units

~/IIKiml

~ / IlK!

3-13 2.6 4.5 4.3 26 27 9 16 8 5 5 14 14 11 21

< 40

< 40

28 36 113 90

22 38 110 82

38 130 42 38 34 26 44 38 50

130 40 26 22 16 26 19 22

Serum bilirubin

phosphatase

m~ /1 00 ml

< 1.0 0. 5 0.3 0.6 2.4 3.4 1.1 0.8 0.3 0.3 0.4 0.3 0.1 0.2 0. 2

nlkali nc

3.6-5.4 2.6 4.4 5 .4 3.1 5.1 Dec. 5.0 5.2 5.2 4.8 4 .6 4.5 4.7 5.0

Seru m

ml

2. 4-:3.7 4 .6 3. 6 3.0 5 .3 4.4 Inc. 4.5 2 .7 3.4 4.1 2 .8 3.2 3.2 2.7

y· Wc1lndin

~/J()O

mf

0. 9- l. G 1.9 1.5 :3.2 2.8 Inc. 2.2 1.1 l. :J 1. 8 1.1 1. 2 I. :J 1.0

" SGOT, serum glutamic oxalacetic transaminase; SGPT, serum glu tamic pyruvic transaminase.

FIG .

2. Case I-1. Autopsy specimen showing established cirrhosis of liver. Hematoxylin a nd eosin, X 180.

wasting, spider nevi, and signs of portal-systemic encephalopathy. The liver was irregular in outline with the edge palpable 6 em below the costal margin; there was moderate ascites.

Some results of investigations are shown in tables 1 and 2. In addition the plasma urea was only 6 mg per 100 ml; prothrombin time, 22 sec (control value, 14 sec); and blood ammo-

550

JOSKE AND LAURENCE

nia, 187 11g of N per 100 ml. Lymphocyte transformation with phytohemagglutinin was normal.17 His response to treatment was slow, but after 2 months his improvement was evident and a further liver biopsy was performed at this time. This showed an advanced cirrhosis with continuing hepatocytic damage and cellular infiltration. Neither steroids nor immunosuppressive drugs were used in this case. Since discharge his improvement has been maintained and he has resumed work. Recent liver function tests are normal except for a SGOT of 67 Karmen units. A liver biopsy taken during repair of an incisional hernia showed an established cirrhosis with little evidence of activity, although some mononuclear cells were present in the fibrous tissue septa and the parenchymal cells exhibited nuclear anisocytosis. Case Il-6. A male born in 1930 was not seen by us but clinical notes were made available from other hospitals. He had a heavy alcoholic intake and was separated from his family. He was admitted to another hospital in June 1967 because of vomiting and jaundice associated with a respiratory tract infection and gave a history of recurring episodes of jaundice during the previous 4 years.

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Examination showed occasional spider nevi on his thorax and firm enlargement of his liver to 2 em below the costal margin. The spleen was impalpable. Other findings were unremarkable. Laboratory results are included in tables 1 and 2. A liver biopsy was reported to show an increase in fibrous connective tissue extending from the portal tracts into the lobules. Occasional hepatocytes showed necrosis or were binucleate. There was a portal infiltration of small round cells with occasional polymorphs. No excess fat was present. A diagnosis of portal cirrhosis was made. He was admitted to another hospital in 1969 with essentially similar clinical, laboratory, and histological findings, and again considered to have portal cirrhosis. His present condition is reported to be good and he has resumed his normal work. Case II-7. This man was born in 1932 and considered himself to be in good health. He was seen by us on two occasions and on each had enlargement of the liver to 6 em and the spleen to 2 em below the costal margins. Investigations (tables 1 and 2) showed evidence of active liver cell damage with hypergammaglobulinemia involving IgA and IgG components. Liver biopsy has not been performed,

October 1970

FAMILIAL CIRRHOSIS

but the clinical and laboratory findings, as well as the family history permit a positive diagnosis of chronic liver disease. Cases Il-8, Il-9, and 11-10 were all examined and showed no evidence of liver disease. The only immunological abnormalities were moderate increases in IgG values in cases Il-9 and Il10, with a weakly positive fluorescent reaction against gastric parietal cells in case II-9 (tables 1 and 2). Generation III. Only four members of this generation, the children of case II-3, were seen by us (cases III-7 to III-10). None had stigmata of liver disease, but case III-10, a 3-year-old girl, had a congenital heart lesion, cleft palate, and microcephaly with mental defect. Laboratory studies (tables 1 and 2) showed a positive Wassermann reaction in patient III-8, and raised Ig levels in patients III-7 and III-9, compared with those of normal children of corresponding age group in this city. Other data . Known genetic markers such as eye color and PTC tasting were unrelated to the occurrence of either liver disease or raised immunoglobulin levels. All members of the kindred included in table 1 were Rh(D)+, and ABO grouping showed compatible matings. Blood sugar, serum cholesterol, and iron and iron-binding capacities were normal in all cases tested. Plasma copper oxidase levels and urinary amino acid chromatography were each normal in 2 cirrhotic patients. Thyroglobulin antibodies were not detected in three sera tested, but 2 members (11-3 and II-6) had cold agglutinins present in low titer. Other antibody tests were negative, including antinuclear factor (12 members), WR (11), RA-latex test (10), lupus erythematosus cells (11) , Coombs' test (9) parietal cell antibody (8), and mitochondrial antibody (7 members). Marriage partners of two members of generation II showed no clinical or laboratory abnormalities.

551

sca~tered, and no environmental hepatotoxms were identified. The results must be attributed, therefore, to some familial mechanism, and the evidence presented suggests that it may be genetic, somewhat similar to the families described from Scandinavia.8 • 9 Raised immunoglobulin (Ig) levels were both more frequent and appeared at an earlier age than liver disease in this kindred: the 2 youngest members of generation II and 3 or 4 investigated in generation III had increased Ig values without liver disease. The Ig components affected were IgG and IgA, and results in table 1 show these immunoglobulins to be effective antibody. These results suggest the primary defect to be in immunological function rather than in the liver. Studies of immunoglobulins in patients with liver disease have shown no characteristic patterns in chronic liver diseases of differing etiology, although in a general way IgG and IgM levels are more affected in active hepatitis, IgM levels in primary biliary cirrhosis, and IgA levels in alcoholic (portal) cirrhosis. ~o. ~ 1 There is, however, considerable overlap between diagnostic groups. In this family, the liver disease meets the diagnostic criteria for active chronic hepatitis,"" in terms of duration of the disease, protein changes, immunological findings, and immunocytic infiltration of the liver. Liver diseases due to metabolic causes such as Wilson's disease are excluded by the clinical and laboratory findings. Only 1 member of the family (patient II-6) consumed excessive amounts of alcohol, and it is of the greatDiscussion est interest that in this man the liver disFive members of this family have ease appeared to be similar to that of the chronic liver disease with abnormal im- other members of the family. Whether munological findings and 8 others had vertical transmission of one or other hepaabnormal immunological results only (fig. titis virus was involved is impossible to 1). These figures are statistically signifi- determine. cant, especially as the kinship includes It seems probable, therefore, that this children and young adults in whom the kindred has a genetic anomaly of immuincidence of autoimmune reactions is low noglobulin control resulting in high levels in a normal population. 19 It seems im- of probably all three major classes of probable that they are due to environmen- immunoglobulins. It is nevertheless notetal factors because the marriage partners worthy that the only autoimmune disease examined were normal, the family was in the kindred was chronic liver disease. It

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JOSKE AND LAURENCE

is necessary to postulate, therefore, not only that there was an anomaly of Ig control but that either this was of such a typ~ as to be manifest only as liver disease or to permit liver disease from other causes to become chronic, or that there was a second anomaly of unknown type leading to familial cirrhosis. The first possibility appears more likely on statistical grounds, and because no pa~ient had li_ver disease without abnormal Immunological findings. The genetic mechanism is unknown, but the high incidence of abnormal findings in the kindred suggests a dominant inheritance, possibly at the level of immunoglobulin control. REFERENCES 1. Joske RA, King WE: The "L.E.-cell" phenomenon in active chronic viral hepatitis. Lancet 1: 477-480, 1955 2. Maddrey WG, Iber FL: Familial cirrhosis. A clinical and pathological study. Ann Intern Med 61:667-679, 1964 3. McConnell RB: The Genetics of Gastrointestinal Disorders. Oxford University Press, 1966 4. King WE, Parsons PJ, Perry JW, et a!: Nonsuppurative hepatitis. Lancet 1:864-867, 1948 5. Krook H: Liver cirrhosis in patients with a lupus-erythematosus-like syndrome. Acta Med Scand 169:713-726, 1961 6. Ruggieri BA, Baggenstoss AH, Logan GB: Juvenile cirrhosis. J Dis Child 94:64-76, 1957 7. Maclachlan MJ, Rodnam GP, Cooper WH, eta!: Chronic active ("lupoid") hepatitis. Ann Intern Med 62:425-462, 1965 8. Cavell B, Leonhardt T: Hereditary hypergammaglobulinemia and lupoid hepatitis. Acta Med Scand 177:751-759, 1965 9. Elling P, Ranlov P, Bilds'j'le P: A genetic approach to the pathogenesis of hepatic cirrhosis. Acta Med Scand 179:527-533, 1966

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10. Stecher RM : Hereditary factors in arthritis. Med Clin N Amer 39:499-507 , 1955 11. Lawrence JS, Ball J: Genetic studies on rheuma. toid arthritis. Ann Rheum Dis 17:160-168, 1958 12. Kunkel HG: The rheumatoid factors. Arch ln. tern Med (Chicago) 104:832-836, 1959 13. Leonhardt T: Family studies in systemic lupus erythematosus. Acta Med Scand (Suppl) 416, 1964 14. Fudenberg HH, German JL III, Kunkel HG: The occurrence of rheumatoid factor and other ab. normalities in families of patients with agam. maglobulinemia. Arthritis Rheum 5:565-588, 1962 15. Gitlin D, J a neway CA: Genetic alterations in plasma proteins of man, The Plasma Proteins, vol. 2. Edited by FS Putnam . New York, Academic Press, 1960, p 407-451 16. Cohen S, Milstein C: Structure of antibody molecules. Nature (London) 214:449-452, 540-541, 1967 17. Joske RA, Onesti P, Thompson PL: Lymphocyte transformation studies in patients with liver disease, Proceed in gs of the Third Asian-Pacific Congress of Gastroenterology, vol. 3. Tokyo, Third World Congress of Gastroenterology, 1968, p 38-45 18. Silva H, Hall EW, Hill KR, et a!: Renal involvement in active "juvenile" cirrhosis. J Clin Path 18:157- 163, 1965 19. Whittingham S, Irwin J, Mackay IR, et al: Autoantibodies in healthy subjects. Aust Ann Med 18:130- 134, 1969 20. Feizt T : Immunoglobulins in chronic liver disease. Gut 9:193-198, 1968 21. Gleichmann E, Deicher H : Quantitative immu· noglobulin-bestimmungen im Serum bei entzund· iche Lebererkrankungen. Klin Wschr 46:793802, 1968 22. Mackay IR, Weiden S, Hasker J: Antoimmune hepatitis. Ann NY Acad Sci 124:767-780, 1965