Prevalence of familial disease in primary biliary cirrhosis in Italy

Journal of Hepatology 1997; 26: 737T740 Printed in Denmark AN rights reserved Munksgaard. Copenhagen

Copyright 0 European Association for the Studv of the Liver 1997

Journal of Hepatology ISSN

0168-8278

Correspondence

Prevalence of familial disease in primary biliary cirrhosis in Italy

To the Editor: Sporadic reports of family clusters of primary biliary cirrhosis (PBC) cases have appeared in the literature since 1972. However, the majority of case reports come from Northern countries (Northern Europe and North America); just one case has been reported from Eastern countries (father and daughter from Japan) (l), and two from Mediterranean countries (2,3). This geographical difference in the reports of PBC family clusters may be considered consistent with the higher prevalence of PBC in Northern countries than in Mediterranean and Eastern countries. In fact, epidemiological studies assessing the prevalence of secondary PBC cases in blood relatives of PBC patients have only been carried out in Northern countries. The reported frequency is 5.5% (22 out of 405 patients) in New York (4), and 1.33% (10 of a series of 736 case records) in England (5). These two studies were carried out retrospectively. In particular, in the latter study information was obtained by interview or by informal questionnaire mailed to the patients and affected families, as well as by examining the case records from hospitals. We prospectively examined the families of 156 PBC patients consecutively seen at our Gastroenterology Department, which serves a population of approximately 2 million. Details of family history, including the presence of autoimmune disease and/or signs or symptoms of cholestasis, were obtained from each case; in addition, serological screening for antimitochondrial antibodies (AMA) (by indirect immunofluorescence technique) was carried out in 30 familes (115 blood relatives). In six families (3.8%) we found a definite diagnosis of PBC in a blood relative: four case reports were obtained from the family history, and two more cases were discovered by serological screening for AMA. In another mother-and-daughter pair, the diagnosis was likely: the 21-year-old daughter was found to be AMA+ve (1:160 titre) with normal liver function tests, but refused liver biopsy.

TABLE

In our experience, the prevalence of PBC cases in blood relatives ranges between the 1.33% reported by the King’s College group (5) and the 5.5% reported in New York (4), in spite of the different incidence of the disease in the population. (This indicates that the inherited predisposition is similar.) In our series, we observed three male family members, whereas in the King’s College series all the cases were female. In all six with a definite diagnosis of PBC, the family members had been living apart for many years before the clinical presentation of the disease. This fact is consistent with a genetic, rather than an environmental background for the family clusters. Moreover, a definite association with a particular HLA haplotype has not been confirmed in the literature. Although it has been suggested, a truly maternal inheritance has not been demonstrated. Familial clusters of PBC, confirmed even in a low-to-medium incidence country, support the hypothesis of a genetic predisposition to acquired disease. Annarosa Floreani, Remo Naccarato and Maria Chiaramonte Gastroenterology Department, Institute of Internal Medicine, Vniversity of Padova, Italy. Tel: 0039-49-8212894. Fax: 0039-49-8760820.

References J, Suzuki K, Kumagai M, Nishimimura A, Miyamora H, Kobayashi K. Familial primary biliary cirrhosis. N Engl J Med 1974; 290: 63-9. 2. Chiarantini E, Smorlesi C, Chieca R, Moscarella S, Passaleva A, Berg PA, Gentilini F! Familial immunological disorders and primary biliary cirrhosis. Ital J Gastroenterol 1987; 19: 210-12. 1. Kato

1

The clinical details of the patients Family

Presentation

Date

Age

Biopsy

Follow-up

AutoAb

*l Sister Sister

Itching Itching

1978 1978

45 51

II III

Transplanted 1987 Transplanted 1988 (Died of rejection)

§ANMA 1: 1280 AMA 1: 320

1983 1987

61 58

IV III

Died of liver failure Asymptomatic

LFTs

1987 1988

59 47

III II

4 Sister Sister

Jaundice Altered LFTs

1991 1993

57 58

5 Daughter Mother

Itching Altered

LFTs

1993 1975

6 Sister Brother

Itching Altered

LFTs

7 Mother Daughter

Itching Asymptomatic

Itching Altered

2 Sister Brother 3 1st Cousin, 1st Cousin,

* Case report

male female

Altered Itching

(3). 5 ANMA=antinuclear

LFTs

membrane

1988

AMA AMA

1: 640 1: 320

Mild symptoms Died of liver failure

AMA AMA

1: 320 1: 640

IV II

Evaluated for OLT Mild symptoms

AMA AMA

1: 160 1: 320

49 51

II III

Mild symptoms Mild symptoms

AMA AMA

1: 160 1: 160

1974 1995

48 64

III III

Variceal bleeding Asymptomatic

AMA AMA

1: 320 1: 160

1992 1994

47 21

IV N.D.

Mild symptoms Asymptomatic

AMA AMA

1: 320 1: 160

1994

antibodies.

737

Correspondence 3. Chiaramonte Okolicsanyi

M, Floreani L, Naccarato

ters: a case report. 4. Bach

N, Schaffner

in family

members

A, Venturi R. Primary

Pasini biliary

Ital J Gastroenterol E Prevalence of affected

1982;

of primary patients.

C, Ruffatti cirrhosis

A,

in sis-

14: 169-71. biliary

5. Brind

AM,

Bray

GR Portmann

and

pattern

of familial

Gut

1995: 36: 615-7.

disease

BC, Williams in primary

R. Prevalence

biliary

cirrhosis.

cirrhosis

Gastroenterology

1991; 102: A776.

Lack of epidemiobgical evidence for a link between thyroid auto-immune disease and hepatitis C virus infection

To the Editor. The role of infection with hepatitis C virus (HCV) in inducing thyroid auto-immune disease (TAID) has been suggested by studies showing a high prevalence of anti-HCV antibodies in patients with thyroid autoantibodies (1,2) and a high prevalence of thyroid autoantibodies in patients with chronic hepatitis C before interferon therapy (3). However, the results of these studies have been challenged (46) and there is controversy as to the pathogenic role of HCV in TAID. To clarify this issue, we decided to assess the prevalence of antiHCV antibodies in patients referred to the Departments of Nuclear Medicine and Endocrinology for thyroid investigation and identified as affected by TAID (Graves’ disease or Hashimoto’s thyroiditis and variants of the latter) (7). The criteria for inclusion in our study were: antithyroperoxidase (anti-TPO) antibodies >lOOO HI/ml (upper normal limit: 150 IUiml RIA, Dynotest, Henning Laboratories, Berlin) and/or anti-TSH receptors antibodies >15 IU/ml (upper normal limit: 10 III/l, RIA, TRAK assay, Henning Laboratories, Berlin). The study was: a) retrospective in 140 consecutive patients seen between 1 January and 15 March 1994, meeting the above-mentioned criteria and whose sera were systematically collected and stored at -20°C; and b) prospective in 59 consecutive patients seen between 15 May and 30 June 1994. Among the 140 patients in the retrospective study, 81 were affected by different forms of documented auto-immune thyroiditis, characterized by high titers of anti-TPO autoantibodies (without antiTSH receptors autoantibodies), echographic features of thyroiditis and dysthyroidism (mostly hypothyroidism) or euthyroidism, and 59 had Graves’ disease characterized by hyperthyroidism, diffuse goiter and excess production of anti-TSH receptor auto-antibodies. In the prospective study, 28 of the 59 patients were diagnosed as having auto-immune thyroiditis and 31 as having Graves’ disease. The main features of these 199 patients are shown in Table 1. Serum samples were tested for anti-HCV using a second-generation EIA (Abbott HCV EIA; Abbott Laboratories, North Chicago, IL, USA) and third-generation EIA (Ortho HCV ELISA, Ortho Diagnostic Systems, Raritan, NJ, USA). The serological tests were performed according to the manufacturer’s instructions. Using these serological tests, no serum was found positive for antiHCV among the 199 patients in the retrospective and prospective studies. The role of viruses in the induction of various auto-immune processes including TAID (8) has long been suspected. Chronic HCV infection has been shown to be associated with a high prevalence of several serum autoantibodies (6). Whether HCV is involved in inducing TAID is controversial. Using second-generation EIA to detect anti-HCV antibodies, Quaranta et al. (I) reported a prevalence of

738

6.8% in a series of 147 patients with antithyroid autoantibodies. Positive serum samples were not retested with immunoblot assay, but the nested-PCR was positive in five out of six patients tested. This prevalence was IO-fold that of blood donors, suggesting a role for HCV in inducing antithyroid autoantibodies production. In agreement with these results, Duclos-Vallte et al. (2) found that 12 of 50 patients with Hashimoto’s thyroiditis were positive for anti-HCV antibodies with a second-generation EIA. The positive results on EIA were confirmed by second-generation immunoblot assay in five of them, giving a 10% prevalence of anti-HCV antibodies. In contrast with these results, Pouteau et al. (5) found no case of HCV infection in 30 patients with Hashimoto’s thyroiditis using second-and third-generation EIA. Our results are in agreement with this study and do not suggest a pathogenic role for HCV in TAID. However, it must be emphasized that, in our series, only patients with high levels of thyroid autoantibodies were included because of the strong association between high levels of these autoantibodies and TAID (9). In contrast, low serum levels of thyroid antibodies may be found in other thyroid disease such as multinodular goiter or thyroid cancer. In addition, the presence of low levels of thyroid antibodies which become more frequent with age, has little significance, especially in the elderly, as demonstrated by follow-up studies showing mild fluctuations over time and rare progression to overt clinical hypothyroidism (10). Our results do not exclude a role of HCV in inducing the formation of thyroid autoanti-

TABLE

1

Findings disease

in the 199 patients

No. of patients

Retrospective study Auto-immune 81 thyroiditis Graves’ disease 59 Prospective study Auto-immune thyroiditis Graves’ disease

HypoTh:

28

diagnosed

as having thyroid

Median age (range)

Sex ratio (W/M)

HypoTh

;lj_77)

7912

31

3

42 (8-86)

49/10

0

59

;:-80)

2414

23

1

2813

0

31

31

hypothyroidism;

HyperTh:

hyperthyroidism.

autoimmune

HyperTh