MEDICINA - Volumen 62 - Nº 3, 2002
MEDICINA (Buenos Aires) 2002; 62: 241-244

       
     

       
   

Familial association in liver disease

 

FAMILIAL ASSOCIATION IN AUTOIMMUNE LIVER DISEASE

 

Jorge A. Findor, Juan A. SordA, Jorge R. Daruich, Estela F. Manero 

División de Gastroenterología, Hospital de Clínicas José de San Martín, Facultad de Medicina, Universidad de Buenos Aires

Abstract

The occurrence of autoimmune liver disease in members of the same family is hardly a frequent observation in clinical practice. In a group of 204 cases of primary biliary cirrhosis (PBC) (196 women) and 219 of type 1 autoimmune hepatitis (AIH) (183 women), seen from 1985 to 2000, family occurrence of autoimmune liver disease was investigated. Diagnosis of both entities was based on clinical criteria, immunological studies and liver biopsy. Six  families were identified with 2 members each presenting with autoimmune liver disease. In  4 of them  the index case had an AIH. This association was observed between mother and daughter in 3 instances. In the remaining AIH index case the association found was with a PBC in her sister. In the other two families the index cases were PBC. In one of them, PBC and AIH association were observed in sisters. Lastly, in another case, an antimitochondrial (AMA) negative variant of PBC was detected in mother and her daughter. The low frequency of family association observed in this cohort could be due to the fact that only symptomatic cases were included. Concurrent autoimmune manifestations were confirmed in 5 members of 6 families (42%). Our results, given the concurrence of both liver diseases in the same family, suggest a link among diverse entities of the autoimmune lineage. The frequency of AIH family association seems to be more prominent in this series than that of PBC. It is also shown that family association in the case of an AMA-negative variant of PBC is feasible, thus confirming that no substantial differences exist between the latter and AMA-positive PBC.

Key words: primary biliary cirrhosis, autoimmune hepatitis, familial autoimmune liver disease

Resumen

Asociación familiar en la enfermedad hepática autoinmune. El hallazgo de enfermedades hepáticas autoinmunes en miembros de una misma familia constituye una observación poco frecuente en la práctica clínica. Se estudió un grupo de 204 casos con cirrosis biliar primaria (CBP) (196 mujeres) y 219 con hepatitis autoinmune (HA) tipo 1(183 mujeres), asistidos entre los años 1985 y 2000. El diagnóstico de ambas entidades se estableció en base a criterios clínicos, inmunológicos e histológicos. La asociación de enfermedad hepática autoinmune fue hallada en 2 miembros de cada una de las 6 diferentes familias. En 4 de ellas el caso índice presentaba una HA observándose en 3 la misma enfermedad  en las madres y sus respectivas hijas, mientras que en la restante  se comprobó la asociación con una CBP en la hermana. En las otras 2 familias los casos índices tenían una CBP. Una de ellas con la variante anticuerpo antimitocondrial (AMT) negativo presentando la misma variante la madre. En el otro caso, la asociación se observó con una HA en la hermana. La baja asociación observada podría deberse a que solamente se consideraron los casos familiares de enfermedad hepática autoinmune sintomática. El compromiso autoinmune extrahepático se detectó en 5 pacientes de las 6 familias estudiadas (42%). La simultaneidad de la presentación familiar de estas enfermedades con otras manifestaciones extrahepáticas de tipo autoinmune sugieren un mecanismo patogénico común. La asociación familiar en la variante CBP AMT negativo es posible, lo cual confirmaría la ausencia de diferencias  entre esta última y la CBP AMT positiva.

Palabras clave: cirrosis biliar primaria, hepatitis autoinmune, enfermedad hepática familiar autoinmune.

 

Postal address: Dr Jorge Andrés Findor, Charcas 2649, 1425 Buenos Aires, Argentina.

Fax (54-11) 4962-0419        e-mail: jfindor@ciudad.com.ar 

 

Received: 22-II-2001 Accepted: 17-XII-2001

 

 

Autoimmune liver disease rarely affects different members of the same family. In primary biliary cirrhosis (PBC), however, the same disease seems to occur in family members more frequently than it does in autoimmune hepatitis (AIH). The estimated prevalence of family members with PBC ranges from 1.5 up to 14.9%1-3, but evidence of an immunological disorder in asymptomatic relatives of PBC patients is much greater4.

Susceptibility to the disease in relatives of patients with AIH is much less frequent5, although both diseases are thought to be immune-mediated.

Because of lack of publications on familiar occurrence in autoimmune liver diseases in Argentina and very few in the rest of the world, we decided to perform the present analysis of the frequency of this type of diseases in family members of patients with PBC and AIH.

 

Material and Methods

 

From 1985 to 2000, 204 cases of PBC (female 196, male 8) and 219 (female 183, male 36) cases of AIH type 1 were followed in our Liver Unit.

The diagnostic criteria for PBC were: circulating antimito-chondrial antibodies (AMA) by indirect immunofluorescence with titers equal or higher than 1:80, evidence of biochemical or clinical cholestasis and histology compatible with this diagnosis using Scheuer’ s classification. The presence of at least 2 out of these 3 criteria was considered necessary to establish the diagnosis of PBC. Thus, diagnosis of AMA negative PBC was established for the presence of biochemical or clinical cholestasis and compatible  histology of PBC.

Scheuer’ s classification recognizes four histological stages: stage I, florid duct lesion; stage II, ductular proliferation; stage III, scarring and stage IV, cirrhosis6.

Exclusion criteria based on ultrasonography, computed tomography, or cholangiography, were extrahepatic bile duct obstruction and features suggestive of other liver diseases.

For AIH type 1 diagnostic criteria were: the presence of antinuclear antibody (ANA) and/or anti-smooth antibody (ASMA) by indirect immunofluorescence with titers equal or higher than 1:80, elevated aminotransferase levels, hypergammaglo-bulinemia above 2 g%, negativity of viral hepatitis A, B or C markers, exclusion of other causes of liver diseases, good response to immunosuppressive therapy and histology showing a chronic necroinflammatory infiltrate with variable degrees of interface necrosis and fibrosis with or without cirrhosis.

Only those family members of patients with PBC or AIH with overt clinical or biochemical manifestations of any autoimmune liver disease  were evaluated.

In all patients, search for other concurrent autoimmune diseases was carried out.

 

Results

 

In 423 patients with diagnosis of autoimmune liver disease composed by PBC and AIH, only 12 (2.8%) cases of family association of one of these diseases were detec-ted. This association was observed in 6 families and only in females.

En 4 families, the index case was an AIH showing in 3 of them an association with the same disease between mothers and daughters. In the other AIH the association was present with a PBC in her sister. In the other 2 families the index cases were carriers of a PBC. One of them was AMA positive and the other presented as an AMA negative variant. In AMA positive PBC the association was observed with AIH in her sister. In the other, with AMA negative variant of PBC, the daughter showed the same disease. Extrahepatic autoimmune manifestations were confirmed in 5 members of the 6 families (42%). Familial association as  well as concurrent autoimmune manifestation are described in Table 1.

Histologic findings at the moment of diagnosis are shown in Table 2. In the PBC cohort in one case liver biopsy showed slight inflammatory periportal reaction and biliary epithelium damage corresponding  to PBC stage I. In 2 cases biopsy revealed epithelial cell damage in small bile ducts, ductular proliferation and portal tract inflammation with lymphocyte extension into periportal parenchyma and a mild fibrosis. These features were considered to be characteristic  of stage II PBC. Finally, one case showed advanced fibrosis with moderate inflammatory infiltrate and damage of the biliary duct epithelium, corresponding to PBC stage III.

From the 8 AIH patients, 4 showed an active cirrhosis with interface necrosis, lobular involvement and bridging necrosis and in 4 cases severe chronic hepatitis with rosette formation and moderate fibrosis. 

 

Discussion

 

The first case of familial PBC was published in 19736; since then not more

than some 50 cases have been communicated to date. The great variability in prevalence observed in several studies on familial association in patients with PBC or AIH may be due to the diverse screening methodologies employed8. The higher prevalence observed in some studies may be related to a greater awareness of the disease and thus most frequent screening in such populations9. In this study, we were not searching routinely for the presence for immunologic abnormalities or evidence of cholestasis in all relatives of our PBC or AIH patients, thus only those with overt signs or symptoms of the disease were detected. This means that the true familial association in our series was most likely underestimated.

Environmental factors have also been mentioned as possible causes of a significantly higher prevalence of PBC in some geographical areas, but no major familial incidence has been communicated in regions with a high PBC prevalence, probably linked to a single water reservoir1, 9, when compared with the prevalence in the general population.

Variations in the prevalence of this disease have been recorded in several countries, but no link to any ethnic group has been substantiated. Nevertheless, autoimmu-ne liver disease seems to be more frequent in Northern Europe when compared to Southern Europe or Latin America, but there is still an evident lack of thorough epidemiological studies in many areas of the world. Thus, our present observation of 12 patients belonging to 6 families is even more striking.

PBC or AIH may occur in mother and daughter10, 11, father and daughter12, sisters13, 14 and twins15. In our series the association more frequently found was that between mothers and daughters.

In our cohort, one family with a diagnosis of AMA-negative PBC (mother and daughter) was observed. Thus, family association with AMA-negative variant of PBC is also possible, suggesting  that both AMA-positive and AMA-negative PBC represent variations of the same disease. To the best of our knowledge, no other family association in AMA-negative PBC patients is so far available in the literature. AMA negative PBC with high titer of antinuclear and/or smooth muscle antibodies with histology compatible with PBC  is considered by some authors as a separate disease entity designated autoimmune cholangitis16, 17, criteria not accepted by others18. The term overlap syndrome between PBC and AIH should be reserved for the rare patients with features of both diseases, associated either simultaneously (in most cases) or consecutively19, 20.

Curiously enough, in our series, in 2 patients the association of PBC with AIH in another family member was found. Undoubtedly, genetic predisposition exists in both diseases which share a common pathogenic mechanism. Recently, the development of autoimmune hepatitis following liver transplantation for PBC has been published21. This finding represents further evidence of a link between both diseases, as well as does the description of many cases of overlap syndrome between PBC and AIH22 in patients who show characteristic findings of both diseases, emphasizing the broad spectrum of susceptibility to multiple types of autoimmune liver disease.

Nevertheless, the frequency of published cases of AIH family association has been mentioned as being much lower than those of PBC3, a finding not confirmed in the present series in which AIH was found in mother and daughter in three instances and PBC association between mother and daughter in only one instance.

Other  autoimmune diseases such as systemic lupus erythematosus (SLE) also show genetic susceptibility to family association. In one of our families, the index case with a cirrhosis related to AIH, SLE was diagnosed several years before the diagnosis of AIH was established, similarly to another report5, 23, making the interrelation between all such entities with an immunological background even more complex.

One of the best ways to study the genetic background of autoimmune diseases  is to determine the major histocompatibility complex classes I and II. In AIH there is a clear association with class II alleles II DR3 and DR424, 25 and in white hispanics also with HLA class A1126. Further studies should be performed in order to evaluate correctly the true prevalence of these associations. Frequent presentation of AIH and PBC in same family speaks in favor of the close association of both autoimmune diseases.

In conclusion, it may be stated that familial association  in AIH as well as PBC even if infrequent should not be neglected.

 

References

 

  1.   Metcalf JV, Bhopal RS, Gray J, Howel D, James OF. Incidence and prevalence of primary biliary cirrhosis in the City of Newcastle-upon-Tyne. Engl Int J Epidemiol 1997; 26: 830-6.

  2.   Bach N, Schaffner E. Familial primary biliary cirrhosis. J Hepatol 1994; 20: 698-701.

  3.   Brind AM, Bray GP, Portmann BC, Williams R. Prevalence and pattern of familial disease in primary biliary cirrhosis. Gut 1995; 36: 615-7.

  4.   Galbraith RM, Smith M, Mackenzie RM, Lee DE, Doniach D, Williams R. High prevalence of seroimmunologic abnormalities in relatives of patients with active chronic hepatitis or primary biliary cirrhosis. N Engl J Med 1974; 290: 63-9.

  5.   Constans J, Bernard P, Bioulac-Sage P, Barcat D, Conri C. Familial autoimmune hepatitis and C4 deficiency. Rev Med Interne 1998; 19: 731-3.

  6.   Scheuer P, Lefkowitch J. Liver biopsy interpretation. 5th ed. London: Saunders 1994, pp 38-61.

  7.   Howel D, Fischbacher CM, Bhopal R, Gray J, Metcalf J, James O. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology 2000; 31: 1055-60.

  8.   Tsuji K, Watanabe Y, Van De Water J, et al. Familial primary biliary cirrhosis in Hiroshima. J Autoimmun 1999; 13: 171-8.

  9.   Triger DR. Primary biliary cirrhosis: an epidemiological study. Br Med J 1980; 281: 772-5.

10.   Fagan E, Cox S, Williams R. Primary biliary cirrhosis in mother and daughter. Br J Med 1977; 2: 1195.

11.   Jones D, Watt E, Metcalf J, Bassendine M, James O. Familial primary biliary cirrhosis reassessed: a geogra-phically-based population study. J Hepatol 1999; 30:     402-7. 

12.   James SP, Jones EA, Schafer DF, Hoofnagle JH, Varma RR, Strober W. Selective immunoglobulin A deficiency associated with primary biliary cirrhosis in a family with liver disease. Gastroenterology 1986; 90: 283-8.

13.   Ohira H, Shinzawa J, Suzuki T, et al. Two sister cases of autoimmune hepatitis. Fukushima J Med Sci 1998; 44:        113-20.

14.   Williams M, Smith PM, Doniach D. Primary biliary cirrhosis and chronic active hepatitis in two sisters. Br J Med 1976; 2: 566.

15.   Chohan MR. Primary biliary cirrhosis in twin sisters. Gut 1973; 14: 213-4.

16.   Brunner G, Klinge O. A cholangitis with antinuclear antibo-dies (immunocholangitis) resembling chronic destructive non-suppurative cholangitis. Dtsch Med Wochenschr 1987; 112: 1454-8.

17.   Ben-Ari Z, Dhillon AP, Sherlock S. Autoimmune cholangiopathy: Part of the spectrum of autoimmune chronic active hepatitis. Hepatology 1993; 18: 10-5.

18.   Heathcote J. Autoimmune cholangitis. Gut 1997; 40:     440-2.

19.   Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: Clinical features and response to therapy. Hepatology 1998; 28: 296-301.

20.   Colombato L, Alvarez F, Cote J, Huet P.  Autoimmune cholangiopathy: the result of consecutive primary biliary cirrhosis and autoimmune hepatitis? Gastroenterology 1994; 107: 1839-43.

21.   Jones DE, James OF, Portmann B, Burl AD, Williams R, Hudson M. Development of autoimmune hepatitis following liver transplantation for primary biliary cirrhosis. Hepatology 1999; 30: 53-7.

22.   Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Autoimmune cholangitis within the spectrum of autoimmu-ne liver disease. Hepatology 2000; 31: 1231-8.

23.   Krulik M, Zylberait D, Vittecoq D, Audebert A, Debray J. Primary biliary cirrhosis associated with acute disseminated lupus erythematosus. Nouv Presse Med 1980; 9: 31-4.

24.   Donaldson P, Doherty D, Hayllar K, McFarlane 1, Johnson P, Williams R. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology 1991; 13: 701-6.

25.   Donaldson P, Doherty D, Underhill J, Williams R. The molecular genetics of autoimmune liver disease. Hepatology 1994; 20: 225-39.

26.   Pando M, Larriba J, Fernández GC, et al. Pediatric and adult forms of type 1 autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology 1999; 30: 1374-80.

 

TABLE 1.– Familial association and concurrent autoimmune manifestation

 

                                       Index case                                    Family members

Patients       Age at                   Disease             Concurrent autoimmune Patients and              Age at                   Disease             Concurrent autoimmune

                 diagnosis                               manifestation    familiar relation                 diagnosis                                  manifestation

                        

CT                   57                       AIH                ND (mother)                       39                       AIH                           

AF                   51                       AIH             Hashimoto‘s thyroiditis        NB (daughter)      41                       AIH  Hemolytic anemia

                                   Hemolytic  anemia                                                                     Hashimoto‘s thyroiditis

                                                                                                     Glomerulonefritis                        

NM                  59                       AIH                    Sjögren         SM (daughter)                       30                       AIH                           

SL                   72                       AIH                  ML (sister)                       69                       PBC                           

CB                   33                      PBC               MR (mother)                       57                       PBC                           

MC                  44                      PBC                    Sjögren               EC (sister)                       43                        AIH                    Lupus erythematosus

 

 

TABLE 2.– Histologic stage at the time of diagnosis

 

         Index case    Family members

Patients     Histology                   Patients               Histology

                            

CT AIH with cirrhosis             ND            AIH without cirrhosis

AF             AIH with cirrhosis             NB AIH with cirrhosis

NM       AIH without cirrhosis            SM             AIH without cirrhosis

SL        AIH without cirrhosis            ML            PBC stage II

CB         PBC stage I                           MR          PBC stage III

MC        PBC stage II                           EC AIH with cirrhosis