- Email: [email protected]
Autoimmunity and the female liver
Hepatology Research 28 (2004) 171–176
Review
Autoimmunity and the female liver Ian G. McFarlane∗ , Michael A. Heneghan Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK Received 14 October 2003; accepted 12 December 2003
Abstract In common with several other autoimmune diseases, there is a marked female preponderance in both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Whether this is due to gender differences relating specifically to the liver or more generally to the female constitution is unknown. The clinical expression of these disorders provides few clues to explain their predilection for females. Sexual dimorphism in the metabolic functions of the liver is well recognised, and several studies have suggested that donor-recipient gender matching/mismatching has a major impact on the outcome of orthotopic liver transplantation (OLT) but, overall, the available evidence does not support the concept that the female liver is inherently more susceptible to immune mediated damage. Since the majority of patients present peri-menopausally and endocrinopathy is frequently associated with these conditions, it seems more likely that hormonal factors may be involved. Review of the available information about hormonal effects on the immune system and how they might impact on what is known about the pathogenetic mechanisms, and interact with genetic factors, in the two conditions unfortunately provides no definitive explanation for the predilection of these disorders for females. However, this is clearly a potentially fruitful area for further research. © 2004 Elsevier B.V. All rights reserved. Keywords: Autoimmune hepatitis; Primary biliary cirrhosis; Sexual dimorphism
Three chronic diseases of the liver are thought to be autoimmune mediated: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) [1]. Although patients have been described with overlapping features of AIH and PBC or PSC [2], in most cases each condition is associated with distinct serological profiles, hepatic morphological changes, course of disease and response to therapy. AIH is a disease characterised by inflammation and destruction of the hepatic parenchyma which shows a striking response to immunosuppressive therapy, while PBC and PSC are primarily diseases of the biliary tract [3]. In PBC, damage is confined to the small intralobular bile ducts whereas, in PSC, the extrahepatic and/or intrahepatic ducts may be affected. Part of the evidence for an autoimmune diathesis derives from the association of these disorders with a high frequency of hypergammaglobulinemia and the presence in serum of a variety of autoantibodies—some of which, such as antimitochondrial antibodies (AMA) in PBC, are relatively disease-specific but most others, such as anti-nuclear antibodies, are non-specific markers. Addition∗ Corresponding author. Tel.: +44-207-346-3253; fax: +44-207-346-3167. E-mail address: [email protected] (I.G. McFarlane).
1386-6346/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.hepres.2003.12.002
ally, between 40 and 70% of patients with these conditions have at least one concomitant extrahepatic immunological disorder, most frequently Sjögren’s syndrome, thyroiditis, rheumatoid arthritis, diabetes or ulcerative colitis [1]. Although familial AIH, PBC, or PSC is rare, there appears to be an underlying genetic susceptibility to each condition as evidenced by well established associations with various HLA haplotypes or allotypes, several of which are also associated with other autoimmune disorders [4]. These include the A1-B8-DR3 haplotype and DR3 and DR4 allotypes in AIH; DR8 in PBC; B8, DR3 and DR2 in PSC. Also in common with many other autoimmune diseases [5], there is a marked female preponderance in AIH (4:1, F:M) and especially in PBC (9:1). In PSC, however, males predominate. The present discussion will therefore focus on AIH and PBC as paradigms of autoimmune liver disease in females. Perhaps because of the rarity of AIH and PBC, especially in males, there is a relative paucity of information about gender differences in the clinical expression of these conditions. The most recent comprehensive study of a large cohort of well-defined patients failed to find many significant differences between males and females with AIH [6]. The few differences which were identified appeared to be related mainly to genetic (HLA) factors rather than
172
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176
to gender per se and, as might be expected, females had a higher frequency of concurrent immunological disorders at presentation than males. But, importantly, there were no significant differences in other clinical or laboratory features, including severity of disease, response to treatment, or long-term outcome. In PBC, an early study from our Institute described the presenting features and clinical course of 39 men and 191 women seen between 1970 and 1984 [7]. Of note, pruritus was significantly less common in men than in women, both at diagnosis and throughout the period of follow up. The difference in incidence of pruritus was most evident when the male group were compared with a group of pre-menopausal women, an observation consistent with the involvement of sex steroid metabolism in the origin of pruritus. Autoimmune associated conditions, such as sicca syndrome were more common in women. Although survival was similar among men and women, hepatocellular carcinoma developed with greater frequency amongst men [7]. In a more recent study of patients with PBC, overall survival was found to be similar in males and females, although liver-related deaths were reportedly significantly higher in females [8]. However, the latter observation conflicts with a subsequent report that progression of fibrosis is significantly slower in females with PBC [9]. Other studies have shown that there are no significant gender differences in titers or sub-specificities of AMA in patients with PBC [10]. Overall, therefore, the clinical expression of these diseases provides few clues to explain their female preponderance. This begs the question of whether there is something different about the female liver that makes it more susceptible to immune-mediated damage, or whether the predilection of these diseases for females is related more to the female constitution in general? In other words, is it the female liver or is it the female herself? Studies in humans and animals have established that there is undoubtedly marked sexual dimorphism in the metabolic functions of the liver. To cite only a few examples, the female organ reportedly regenerates faster after partial hepatectomy and has a lower apoptotic index [11], but is more susceptible to oxidative stress [12] than the male liver. There are female-specific cytochrome P450 isoenzymes that appear to be under hormonal control and may be involved in different metabolic pathways, especially in the disposal of drugs and other xenobiotics [13,14]. Females have a higher liver cytosolic estrogen:androgen receptor ratio than males but a lower frequency of variant estrogen receptors (which may have implications for malignancy) [15]. But the data are complex, sometimes confusing, occasionally conflicting, and difficult to interpret in the present context. Can more useful information be gleaned from studies of what may be described as a unique human experimental situation, namely liver transplantation? Several investigations of the effects of donor:recipient gender matching and mismatching on the outcome of orthotopic liver transplantation (OLT) have been undertaken in large series of patients. Two studies in the USA found that male:female grafts had the
most, and female:male grafts the least, favourable outcomes in terms of both patient and graft survival in adults [16,17], although this was not confirmed by a comparable study in the UK [18]. In children undergoing OLT, two similar studies found no significant differences in outcome between the four possible combinations of donor:recipient gender matching or mismatching [19,20] but a third report agreed with the American studies in adults that female:male grafts had the worst outcome [21]. Although these data are somewhat conflicting, on balance they suggest that perhaps the female liver may be more susceptible to immune-mediated damage. If so, do PBC and AIH recur after OLT more frequently in patients receiving grafts from female donors than those with other donor:recipient gender combinations ? The issue of PBC recurrence is still somewhat controversial but most studies support the concept of AIH recurrence [22]. Unfortunately, very few reports of such studies have included the genders of the donors, and the numbers of patients documented with possible recurrence of either disease is still too small for meaningful analysis. There have, however, been several recent reports of AIH developing in patients who were transplanted for other conditions [23–29]. This has been termed “de novo” AIH, defined as an AIH-like syndrome developing in patients receiving grafts for non-AIH disorders [22]. Some investigators prefer the terms “graft dysfunction mimicking autoimmune hepatitis” or “post-transplantation immune hepatitis”. Nonetheless, the syndrome does appear to have all of the features of AIH [3], including elevated serum IgG concentrations, high titers of autoantibodies and the morphological changes of interface hepatitis with a lymphoplasmacytic infiltration without the characteristic changes associated with rejection, and it responds to conventional AIH therapy with corticosteroids and azathioprine. Again, unfortunately, most of the reports of this syndrome do not include the genders of the donors. But two of the largest series, one in adults [24] and the other in children [23], were undertaken in our Institute and it has been possible to obtain the information. It transpires that, far from there being a high incidence of gender mismatching, most of the patients developing de novo AIH in these studies had actually received gender-matched grafts (Table 1). Furthermore, only two of the fourteen reported cases had female:male grafts, most of the patients were male, and there was no correlation between rapidity of development of de novo AIH and either the primary disease or the genders of the donors or recipients. From the above, it would appear that there is little evidence to support the concept that there is something different about the female liver that makes it more susceptible to the development of AIH or PBC. So, is the predilection of these disorders for females related more to the female constitution in general? The large majority of patients with AIH and PBC presenting to general gastroenterology and hepatology clinics around the world are peri- or post-menopausal females [3,30], and the age distribution at presentation of the more severe cases of AIH seen in tertiary referral centres shows a
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176 Table 1 “De novo autoimmune hepatitis” following orthotopic liver transplantation (OLT) Primary disease
Gender Donor
Recipient
Years to AIH onset post-OLT
Adultsa Alcoholic liver disease Primary sclerosing cholangitis Cryptogenic cirrhosis Primary sclerosing cholangitis Primary biliary cirrhosis Chronic hepatitis C Drug-induced liver disease
Male Male Male Female Female Male Female
Male Male Male Female Female Female Male
1.8 7.2 0.3 5.0 4.3 1.1 3.4
Childrenb Alpha-1-antitrypsin deficiency Alagille’s syndrome Biliary atresia Biliary atresia Biliary atresia Biliary atresia Drug-induced liver disease
Male Male Male Male Female Female Male
Male Male Male Male Female Male Female
3.8 0.8 2.0 0.5 3.4 1.5 1.6
OLT: orthotopic liver transplantation. a Heneghan et al. [24]. b Kerkar et al. [23].
second (smaller) peak around puberty [31]. Additionally, endocrinopathy is frequently associated with both conditions. These observations strongly suggest that hormonal factors may be important. It is known that the immune system is under some form of hormonal influence, but the interactions between the neuroendocrine and immune systems are complex and are still poorly understood. Background genetic susceptibility, modulated by environmental agents and neuroendocrine factors may all contribute to the outcome of an immune response [5]. Before discussing the possible influence of hormonal factors in the development of AIH and PBC, it is necessary first to consider the mechanisms involved in the development of a potentially tissue-damaging autoimmune reaction. Initiation of such a reaction requires the presentation of an autopeptide Low estrogen Prolactin
TH 1
TH 0
173
by a professional antigen presenting cell to an uncommitted helper T cell (TH 0) in the context of a major histocompatibility complex (MHC) class II molecule. The resulting activation of the TH 0 cell leads to its differentiation into one of two functional phenotypes, TH 1 or TH 2, and triggers a whole cascade of immune responses. Which phenotype results from the activation of TH 0 depends on the nature of the autopeptide, the affinity of binding between the T-cell receptor and the MHC/peptide complex, and the cytokines in the microenvironment [32]. Interleukin-12 (IL-12) promotes differentiation of TH 0 into TH 1, while IL-4 favours differentiation into TH 2 cells. TH 1 cells produce IL-2 and interferon-gamma (IFN-␥) which promote cell-mediated cytotoxicity through activation of macrophages and cytotoxic T-lymphocytes, while TH 2 cells release IL-4, IL-5 and IL-10 which promote co-operation with B cells to produce antibodies. Thus autoreactive tissue injury may arise via either the TH 1 pathway (leading to cell-mediated cytotoxic reactions) or the TH 2 pathway (resulting in antibody-mediated cell damage). These processes are under some form of immunoregulatory control which normally maintains self-tolerance by “switching off” the autoimmune response—although whether this involves discrete subsets of “suppressor” T lymphocytes is still somewhat controversial. The cytokines produced by each type of activated T cell are counteractive. Thus, TH 1 cytokines suppress production of TH 2 cytokines and vice versa, resulting in one pathway usually predominating over the other [33]. Which pathway predominates is profoundly influenced by the effects of sex hormones on cytokine production (Fig. 1). Estrogens have a biphasic effect, with low concentrations favouring production of TH 1 cytokines and high concentrations promoting secretion of TH 2 cytokines [34]. High prolactin concentrations favour a TH 1 response while progesterone and testosterone tend to promote TH 2 cytokine production [5]. Evidence of this can be most strikingly seen in the changes in disease activity that occur during pregnancy in different autoimmune disorders. In multiple sclerosis and rheumatoid arthritis, TNF-alpha IL-2 IFN-gamma
Cell-mediated cytotoxicity
Cross-inhibition Progesterone Testosterone High estrogen
TH 2
IL-4 IL-5 IL-6 IL-10
Antibodymediated cytotoxicity
Fig. 1. Hormonal influences on the immune system: Activation of an uncommitted helper T lymphocyte (TH 0) leads to its differentiation into one of two functional phenotypes, TH 1 or TH 2, and triggers a cascade of immune responses. In an autoimmune disease, this may lead to either cell-mediated cytotoxic (TH 1) or antibody-mediated (TH 2) tissue damage. The different cytokines produced by each phenotype are counteractive, with TH 1 cytokines suppressing production of TH 2 cytokines and vice versa. Thus, one pathway usually predominates over the other. Which pathway predominates depends on a number of factors (see text) but is also strongly influenced by the relative concentrations of various hormones (adapted from Whitacre et al. [53], with kind permission of the authors and publishers. Copyright 1999 AAAS).
174
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176
which are thought to be primarily TH 1-mediated, disease activity often decreases during pregnancy—particularly during the third trimester when estrogen and progesterone concentrations are at their highest [5]. This is in keeping with a sex hormone induced shift towards increased TH 2 cytokine production, with consequent suppression of the TH 1 pathway. When the levels of these hormones fall during the post-partum period there is often a flare of disease activity, which may be explained by a shift back towards a TH 1 response. In contrast, in systemic lupus erythematosus, which is thought to be a TH 2-mediated condition, disease activity either remains unchanged or worsens during pregnancy [5]. Whether the above can shed light on the predilection of AIH and PBC for females is uncertain, in part because the pathogenetic mechanisms underlying the development of these two conditions are poorly understood. In PBC, its unique association with AMA notwithstanding, there is some evidence to suggest that biliary epithelial cell damage is mediated by direct T-cell cytotoxicity (at least in the early stages of the disease), i.e. via the TH 1 pathway [30,35,36]. In AIH, the picture is less clear. Studies in some animal models and other artificial systems have suggested that AIH is TH 1-mediated but this has not been supported by studies in patients, which have failed to implicate direct T-cell cytotoxicity as the prime mechanism of hepatocellular injury [37]. On the contrary, most such studies in patients have indicated that antibody-dependent cellular cytotoxic (ADCC) reactions appear to be important in liver cell damage in AIH, suggesting that it is predominantly a TH 2-mediated condition [37]. The defects in immunoregulation that lead to loss of self-tolerance in PBC have not been defined but, in AIH, there is evidence to indicate that there are at least two defects in this regulatory mechanism which might account for persistence of the autoimmune response. These genetic defects cannot, however, explain the female preponderance of AIH because they are not X-linked (they are inherited in an autosomal recessive mode) [37]. Can anything be learned from evidence relating to hormonal changes in these conditions, as in the other autoimmune disorders discussed above? No comprehensive studies of hormonal profiles in either AIH or PBC appear to have been reported, but prolactin does not seem to be a factor in AIH. We have recently measured plasma prolactin concentrations in 30 female patients before treatment and all had completely normal prolactin levels (McFarlane, unpublished observations). There is, however, a substantial amount of information about changes in disease activity in AIH during pregnancy. There are well documented case reports of treated patients showing marked improvement during pregnancy and requiring lower doses of immunosuppressive drugs to sustain remission, and of untreated patients having spontaneous remissions during pregnancy but experiencing exacerbations of disease post-partum [38,39]. This scenario would suggest that the TH 1 pathway predominates in AIH. But there are equally well documented reports of treated patients in remission who suffer relapses of their disease
during pregnancy and even of previously asymptomatic patients presenting for the first time during the second or third trimesters of pregnancy when estrogen levels are highest [40], which suggests that the TH 2 pathway predominates. Pregnancy in women with pre-existing PBC is rare but, as in AIH, the available evidence on changes in disease activity during pregnancy is conflicting. Early observations indicated a worsening of the liver disease during pregnancy [41] but this has not been supported by later reports that there is no significant change in liver function during or after pregnancy in PBC [42,43]. If hormonal factors are involved in the development of these disorders, it might be expected that their influence may be less in pre-pubertal children. PBC has not been reported in children, but both AIH and PSC occur in the paediatric age groups. It transpires, however, that the female preponderance in children with AIH and the male preponderance in children with PSC is the same as in adults with these diseases [44]. Interestingly, females also predominate in autoimmune sclerosing cholangitis (a paediatric disorder with features of both AIH and PSC) but to a lesser degree (55:45, F:M) than in AIH [44]. It will be apparent from the above discussion that there is no concrete information which provides an explanation for the predilection of AIH and PBC for females. In part, this is because of a lack of knowledge of the precise pathogenetic mechanisms in these conditions, which is compounded by a number of confounding factors. One of the latter is the recognition that in both disorders (and, indeed, also in PSC) there is a prolonged presymptomatic phase before the diseases become clinically manifest [45,46]. The development of an autoimmune disorder is thought to require a triggering event to initiate the condition in a genetically susceptible individual. Environmental agents, including infections with viruses or bacteria, or exposure to drugs and other chemicals, have been implicated as initiating factors. The hepatitis A and Epstein–Barr viruses have been reported to trigger AIH in genetically susceptible subjects [47,48]. Molecular mimicry between self antigens and antigens expressed on microorganisms is a popular hypothesis which has been proposed to account for the breakdown of tolerance and induction of autoreactivity—particularly in PBC, but also in some forms of AIH [30,49]. However, due to the latency of clinical onset, these initiating events (which may be crucial to understanding pathogenesis) are usually missed. Other confounding factors include the heterogeneity of patient populations with respect to disease severity. There is also accumulating evidence to suggest that the clinical manifestations of these disorders, at least in AIH, may arise through different pathogenetic mechanisms in different patients [50] and that this may be due partly to differences in genetic susceptibility [51,52]. Perhaps these differences are modulated by hormonal factors. To quote Whitacre et al. [53]: “It is not known whether there is a genetic basis for gender differences in autoimmunity. If there is, then this will be the focus of much future research. However, the notion that
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176
genes conferring susceptibility to autoimmune disease may themselves be regulated by sex hormones also needs to be seriously considered.” References [1] Manns MP. The concept of autoimmune liver diseases. In: Krawitt EL, Wiesner RH, Nishioka M, editors. Autoimmune liver diseases. 2nd ed. Amsterdam: Elsevier; 1998. p. 21–34. [2] Dienes HP, Erberich H, Dries V, Schirmacher P, Lohse A. Autoimmune hepatitis and overlap syndromes. Clin Liver Dis 2002;6:349– 62. [3] International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929–38. [4] Donaldson PT. Immunogenetics in liver disease. Baillieres Clin Gastroenterol 1996;10:533–49. [5] Whitacre CC. Sex differences in autoimmune disease. Nat Immunol 2001;2:777–80. [6] Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol 2002;97:2051–7. [7] Lucey MR, Neuberger JM, Williams R. Primary biliary cirrhosis in men. Gut 1986;27:1373–6. [8] Prince M, Chetwynd A, Newman W, Metcalf JV, James OF. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 2002;123:1044–51. [9] Poynard T, Mathurin P, Lai C-L, et al. A comparison of fibrosis progression in chronic liver diseases. J Hepatol 2003;38:257–65. [10] Nalbandian G, Van de Water J, Gish R, et al. Is there a serological difference between men and women with primary biliary cirrhosis. Am J Gastroenterol 1999;94:2482–6. [11] Tessitore L, Sesca E, Pani P, Dianzani MU. Sexual dimorphism in the regulation of cell turnover during liver hyperplasia. Chemic-Biol Interact 1995;97:1–10. [12] Gasbarrini A, Addolorato G, Di Campli C. Gender affects reperfusion injury in rat liver. Dig Dis Sci 2001;46:1305–12. [13] Sakuma T, Takai M, Endo Y, et al. A novel female-specific member of the CYP3A gene subfamily in the mouse liver. Arch Biochem Biophys 2000;377:153–62. [14] Jarukamjorn K, Sakuma T, Yamamoto M, Ohara A, Nemoto N. Sex-associated expression of mouse hepatic and renal CYP2B enzymes by glucocorticoid hormones. Biochem Pharmacol 2001;62: 161–9. [15] Villa E, Grottola A, Colantoni A, et al. Hepatocellular carcinoma: role of estrogen receptors in the liver. Ann N Y Acad Sci USA 2002;963:37–45. [16] Marino IR, Doyle HR, Aldrighetti L, et al. Effect of donor age and sex on the outcome of liver transplantation. Hepatology 1995;22:1754– 62. [17] Brooks BK, Levy MF, Jennings LW, et al. Influence of donor and recipient gender on the outcome of liver transplantation. Transplantation 1996;62:1784–7. [18] Candinas D, Gunson BK, Nightingale P, Hubscher S, McMaster P, Neuberger JM. Sex mismatch as a risk factor for chronic rejection of liver allografts. Lancet 1995;346:1117–21. [19] Pillay P, Van Thiel DH, Gavaler JS, Starzl TE. Donor gender does not affect liver transplantation outcome in children. Dig Dis Sci 1990;35:686–9. [20] Gupta P, Hart J, Cronin D, Kelly S, Millis JM, Brady L. Risk factors for chronic rejection after pediatric liver transplantation. Transplantation 2001;72:1098–102. [21] Francavilla R, Hadzic N, Heaton ND, et al. Gender matching and outcome after pediatric liver transplantation. Transplantation 1998;66:602–5.
175
[22] Vergani D, Mieli-Vergani G. Autoimmunity after liver transplantation. Hepatology 2002;36:271–6. [23] Kerkar N, Hadzic N, Davies ET, et al. De-novo autoimmune hepatitis after liver transplantation. Lancet 1998;351:409–13. [24] Heneghan MA, Portmann BC, Norris SM, et al. Graft dysfunction mimicking autoimmune hepatitis following liver transplantation in adults. Hepatology 2001;34:464–70. [25] Andries S, Casamayou L, Sempoux C, et al. Posttransplant immune hepatitis in pediatric liver transplant recipients: incidence and maintenance therapy with azathioprine. Transplantation 2001;72:267–72. [26] Gupta P, Hart J, Millis JM, Cronin D, Bray L. De novo hepatitis with autoimmune antibodies and atypical histology: a rare cause of late graft dysfunction after pediatric liver transplantation. Transplantation 2001;71:664–8. [27] Hernandez HM, Kovarik P, Whitingtion PF, Alonso EM. Autoimmune hepatitis as a late complication of liver transplantation. J Ped Gastroenterol Nutr 2001;32:131–6. [28] Spada M, Bertani A, Sonzogni A, et al. A cause of late graft dysfunction after liver transplantation in children: de-novo autoimmune hepatitis. Transplant Proc 2001;33:1747–8. [29] Salcedo M, Vaquero J, Banares R, et al. Response to steroids in de novo autoimmune hepatitis after liver transplantation. Hepatology 2002;35:349–56. [30] Mackay IR, Gershwin ME. Pathogenesis of primary biliary cirrhosis. In: Krawitt EL, Wiesner RH, Nishioka M, editors. Autoimmune liver diseases. 2nd ed. Amsterdam: Elsevier; 1998. p. 49–69. [31] McFarlane IG. The relationship between autoimmune markers and different clinical syndromes in autoimmune hepatitis. Gut 1998;42: 599–602. [32] Rose NR. Fundamental concepts of autoimmunity and autoimmune disease. In: Krawitt EL, Wiesner RH, Nishioka M, editors. Autoimmune liver diseases. 2nd ed. Amsterdam: Elsevier; 1998. p. 1–20. [33] Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T-helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989;170:2081–95. [34] Gilmore W, Weiner LP, Correale J. Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1997;158:446–51. [35] Bassendine MF, Jones DEJ, Yeaman SJ. Biochemistry and autoimmune response to the 2-oxoacid dehydrogenase complexes in primary biliary cirrhosis. Semin Liver Dis 1997;17:49–60. [36] Ishibashi H, Nakamura M, Shimoda S, Gershwin ME. T cell immunity in primary biliary cirrhosis. Autoimmun Rev 2003;2:19–24. [37] McFarlane IG. Pathogenesis of autoimmune hepatitis. Biomed Pharmacother 1999;53:255–63. [38] Colle I, Hautekeete M. Remission of autoimmune hepatitis during pregnancy: a report of two cases. Liver 1999;19:55–7. [39] Muratori P, Loffreda S, Muratori L, et al. Spontaneous remission of autoimmune hepatitis during pregnancy. Dig Liver Dis 2002;34:608– 9. [40] Heneghan MA, Norris SM, O’Grady JG, Harrison PM, McFarlane IG. Management and outcome of pregnancy in autoimmune hepatitis. Gut 2001;48:97–102. [41] Nir A, Sorokin Y, Abramovici H, Theodor E. Prenancy and primary biliary cirrhosis. Int J Gynaecol Obstet 1989;28:279–82. [42] Wong KK, Goh KL. Pregnancy in primary biliary cirrhosis. Eur J Obstet Gynecol Reprod Biol 1992;45:149–51. [43] Olsson R, Loof L, Wallerstedt S. Pregnancy in patients with primary biliary cirrhosis—a case for dissuasion? The Swedish Internal Medicine Liver Club. Liver 1993;13:316–8. [44] Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children. Clin Liver Dis 2002;6:335–46. [45] Metcalf VV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OFW. Natural history of early primary biliary cirrhosis. Lancet 1996;348:1399–402.
176
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176
[46] McFarlane IG. Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features. Clin Liver Dis 2002;6:317–33. [47] Vento S, Garofano T, Di Perri G, Concia E, Bassetti D. Identification of hepatitis A virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 1991;337:1183–7. [48] Vento S, Guealla L, Mirandola F, et al. Epstein–Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 1995;346:608–9. [49] Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis. Clin Liver Dis 2002;6:439–49.
[50] McFarlane IG. Definition and classification of autoimmune hepatitis. Semin Liver Dis 2002;22:317–24. [51] Bittencourt PL, Goldberg AC, Cancado ELR, et al. Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am J Gastroenterol 1999;94:1906–13. [52] Pando M, Larriba J, Fernandez GC, et al. Pediatric and adult forms of type 1 autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology 1999;20:1374–80. [53] Whitacre CC, Reingold SC, O’Looney PA, et al. A gender gap in autoimmunity. Science 1999;283:1277–8.
Review
Autoimmunity and the female liver Ian G. McFarlane∗ , Michael A. Heneghan Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK Received 14 October 2003; accepted 12 December 2003
Abstract In common with several other autoimmune diseases, there is a marked female preponderance in both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Whether this is due to gender differences relating specifically to the liver or more generally to the female constitution is unknown. The clinical expression of these disorders provides few clues to explain their predilection for females. Sexual dimorphism in the metabolic functions of the liver is well recognised, and several studies have suggested that donor-recipient gender matching/mismatching has a major impact on the outcome of orthotopic liver transplantation (OLT) but, overall, the available evidence does not support the concept that the female liver is inherently more susceptible to immune mediated damage. Since the majority of patients present peri-menopausally and endocrinopathy is frequently associated with these conditions, it seems more likely that hormonal factors may be involved. Review of the available information about hormonal effects on the immune system and how they might impact on what is known about the pathogenetic mechanisms, and interact with genetic factors, in the two conditions unfortunately provides no definitive explanation for the predilection of these disorders for females. However, this is clearly a potentially fruitful area for further research. © 2004 Elsevier B.V. All rights reserved. Keywords: Autoimmune hepatitis; Primary biliary cirrhosis; Sexual dimorphism
Three chronic diseases of the liver are thought to be autoimmune mediated: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) [1]. Although patients have been described with overlapping features of AIH and PBC or PSC [2], in most cases each condition is associated with distinct serological profiles, hepatic morphological changes, course of disease and response to therapy. AIH is a disease characterised by inflammation and destruction of the hepatic parenchyma which shows a striking response to immunosuppressive therapy, while PBC and PSC are primarily diseases of the biliary tract [3]. In PBC, damage is confined to the small intralobular bile ducts whereas, in PSC, the extrahepatic and/or intrahepatic ducts may be affected. Part of the evidence for an autoimmune diathesis derives from the association of these disorders with a high frequency of hypergammaglobulinemia and the presence in serum of a variety of autoantibodies—some of which, such as antimitochondrial antibodies (AMA) in PBC, are relatively disease-specific but most others, such as anti-nuclear antibodies, are non-specific markers. Addition∗ Corresponding author. Tel.: +44-207-346-3253; fax: +44-207-346-3167. E-mail address: [email protected] (I.G. McFarlane).
1386-6346/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.hepres.2003.12.002
ally, between 40 and 70% of patients with these conditions have at least one concomitant extrahepatic immunological disorder, most frequently Sjögren’s syndrome, thyroiditis, rheumatoid arthritis, diabetes or ulcerative colitis [1]. Although familial AIH, PBC, or PSC is rare, there appears to be an underlying genetic susceptibility to each condition as evidenced by well established associations with various HLA haplotypes or allotypes, several of which are also associated with other autoimmune disorders [4]. These include the A1-B8-DR3 haplotype and DR3 and DR4 allotypes in AIH; DR8 in PBC; B8, DR3 and DR2 in PSC. Also in common with many other autoimmune diseases [5], there is a marked female preponderance in AIH (4:1, F:M) and especially in PBC (9:1). In PSC, however, males predominate. The present discussion will therefore focus on AIH and PBC as paradigms of autoimmune liver disease in females. Perhaps because of the rarity of AIH and PBC, especially in males, there is a relative paucity of information about gender differences in the clinical expression of these conditions. The most recent comprehensive study of a large cohort of well-defined patients failed to find many significant differences between males and females with AIH [6]. The few differences which were identified appeared to be related mainly to genetic (HLA) factors rather than
172
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176
to gender per se and, as might be expected, females had a higher frequency of concurrent immunological disorders at presentation than males. But, importantly, there were no significant differences in other clinical or laboratory features, including severity of disease, response to treatment, or long-term outcome. In PBC, an early study from our Institute described the presenting features and clinical course of 39 men and 191 women seen between 1970 and 1984 [7]. Of note, pruritus was significantly less common in men than in women, both at diagnosis and throughout the period of follow up. The difference in incidence of pruritus was most evident when the male group were compared with a group of pre-menopausal women, an observation consistent with the involvement of sex steroid metabolism in the origin of pruritus. Autoimmune associated conditions, such as sicca syndrome were more common in women. Although survival was similar among men and women, hepatocellular carcinoma developed with greater frequency amongst men [7]. In a more recent study of patients with PBC, overall survival was found to be similar in males and females, although liver-related deaths were reportedly significantly higher in females [8]. However, the latter observation conflicts with a subsequent report that progression of fibrosis is significantly slower in females with PBC [9]. Other studies have shown that there are no significant gender differences in titers or sub-specificities of AMA in patients with PBC [10]. Overall, therefore, the clinical expression of these diseases provides few clues to explain their female preponderance. This begs the question of whether there is something different about the female liver that makes it more susceptible to immune-mediated damage, or whether the predilection of these diseases for females is related more to the female constitution in general? In other words, is it the female liver or is it the female herself? Studies in humans and animals have established that there is undoubtedly marked sexual dimorphism in the metabolic functions of the liver. To cite only a few examples, the female organ reportedly regenerates faster after partial hepatectomy and has a lower apoptotic index [11], but is more susceptible to oxidative stress [12] than the male liver. There are female-specific cytochrome P450 isoenzymes that appear to be under hormonal control and may be involved in different metabolic pathways, especially in the disposal of drugs and other xenobiotics [13,14]. Females have a higher liver cytosolic estrogen:androgen receptor ratio than males but a lower frequency of variant estrogen receptors (which may have implications for malignancy) [15]. But the data are complex, sometimes confusing, occasionally conflicting, and difficult to interpret in the present context. Can more useful information be gleaned from studies of what may be described as a unique human experimental situation, namely liver transplantation? Several investigations of the effects of donor:recipient gender matching and mismatching on the outcome of orthotopic liver transplantation (OLT) have been undertaken in large series of patients. Two studies in the USA found that male:female grafts had the
most, and female:male grafts the least, favourable outcomes in terms of both patient and graft survival in adults [16,17], although this was not confirmed by a comparable study in the UK [18]. In children undergoing OLT, two similar studies found no significant differences in outcome between the four possible combinations of donor:recipient gender matching or mismatching [19,20] but a third report agreed with the American studies in adults that female:male grafts had the worst outcome [21]. Although these data are somewhat conflicting, on balance they suggest that perhaps the female liver may be more susceptible to immune-mediated damage. If so, do PBC and AIH recur after OLT more frequently in patients receiving grafts from female donors than those with other donor:recipient gender combinations ? The issue of PBC recurrence is still somewhat controversial but most studies support the concept of AIH recurrence [22]. Unfortunately, very few reports of such studies have included the genders of the donors, and the numbers of patients documented with possible recurrence of either disease is still too small for meaningful analysis. There have, however, been several recent reports of AIH developing in patients who were transplanted for other conditions [23–29]. This has been termed “de novo” AIH, defined as an AIH-like syndrome developing in patients receiving grafts for non-AIH disorders [22]. Some investigators prefer the terms “graft dysfunction mimicking autoimmune hepatitis” or “post-transplantation immune hepatitis”. Nonetheless, the syndrome does appear to have all of the features of AIH [3], including elevated serum IgG concentrations, high titers of autoantibodies and the morphological changes of interface hepatitis with a lymphoplasmacytic infiltration without the characteristic changes associated with rejection, and it responds to conventional AIH therapy with corticosteroids and azathioprine. Again, unfortunately, most of the reports of this syndrome do not include the genders of the donors. But two of the largest series, one in adults [24] and the other in children [23], were undertaken in our Institute and it has been possible to obtain the information. It transpires that, far from there being a high incidence of gender mismatching, most of the patients developing de novo AIH in these studies had actually received gender-matched grafts (Table 1). Furthermore, only two of the fourteen reported cases had female:male grafts, most of the patients were male, and there was no correlation between rapidity of development of de novo AIH and either the primary disease or the genders of the donors or recipients. From the above, it would appear that there is little evidence to support the concept that there is something different about the female liver that makes it more susceptible to the development of AIH or PBC. So, is the predilection of these disorders for females related more to the female constitution in general? The large majority of patients with AIH and PBC presenting to general gastroenterology and hepatology clinics around the world are peri- or post-menopausal females [3,30], and the age distribution at presentation of the more severe cases of AIH seen in tertiary referral centres shows a
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176 Table 1 “De novo autoimmune hepatitis” following orthotopic liver transplantation (OLT) Primary disease
Gender Donor
Recipient
Years to AIH onset post-OLT
Adultsa Alcoholic liver disease Primary sclerosing cholangitis Cryptogenic cirrhosis Primary sclerosing cholangitis Primary biliary cirrhosis Chronic hepatitis C Drug-induced liver disease
Male Male Male Female Female Male Female
Male Male Male Female Female Female Male
1.8 7.2 0.3 5.0 4.3 1.1 3.4
Childrenb Alpha-1-antitrypsin deficiency Alagille’s syndrome Biliary atresia Biliary atresia Biliary atresia Biliary atresia Drug-induced liver disease
Male Male Male Male Female Female Male
Male Male Male Male Female Male Female
3.8 0.8 2.0 0.5 3.4 1.5 1.6
OLT: orthotopic liver transplantation. a Heneghan et al. [24]. b Kerkar et al. [23].
second (smaller) peak around puberty [31]. Additionally, endocrinopathy is frequently associated with both conditions. These observations strongly suggest that hormonal factors may be important. It is known that the immune system is under some form of hormonal influence, but the interactions between the neuroendocrine and immune systems are complex and are still poorly understood. Background genetic susceptibility, modulated by environmental agents and neuroendocrine factors may all contribute to the outcome of an immune response [5]. Before discussing the possible influence of hormonal factors in the development of AIH and PBC, it is necessary first to consider the mechanisms involved in the development of a potentially tissue-damaging autoimmune reaction. Initiation of such a reaction requires the presentation of an autopeptide Low estrogen Prolactin
TH 1
TH 0
173
by a professional antigen presenting cell to an uncommitted helper T cell (TH 0) in the context of a major histocompatibility complex (MHC) class II molecule. The resulting activation of the TH 0 cell leads to its differentiation into one of two functional phenotypes, TH 1 or TH 2, and triggers a whole cascade of immune responses. Which phenotype results from the activation of TH 0 depends on the nature of the autopeptide, the affinity of binding between the T-cell receptor and the MHC/peptide complex, and the cytokines in the microenvironment [32]. Interleukin-12 (IL-12) promotes differentiation of TH 0 into TH 1, while IL-4 favours differentiation into TH 2 cells. TH 1 cells produce IL-2 and interferon-gamma (IFN-␥) which promote cell-mediated cytotoxicity through activation of macrophages and cytotoxic T-lymphocytes, while TH 2 cells release IL-4, IL-5 and IL-10 which promote co-operation with B cells to produce antibodies. Thus autoreactive tissue injury may arise via either the TH 1 pathway (leading to cell-mediated cytotoxic reactions) or the TH 2 pathway (resulting in antibody-mediated cell damage). These processes are under some form of immunoregulatory control which normally maintains self-tolerance by “switching off” the autoimmune response—although whether this involves discrete subsets of “suppressor” T lymphocytes is still somewhat controversial. The cytokines produced by each type of activated T cell are counteractive. Thus, TH 1 cytokines suppress production of TH 2 cytokines and vice versa, resulting in one pathway usually predominating over the other [33]. Which pathway predominates is profoundly influenced by the effects of sex hormones on cytokine production (Fig. 1). Estrogens have a biphasic effect, with low concentrations favouring production of TH 1 cytokines and high concentrations promoting secretion of TH 2 cytokines [34]. High prolactin concentrations favour a TH 1 response while progesterone and testosterone tend to promote TH 2 cytokine production [5]. Evidence of this can be most strikingly seen in the changes in disease activity that occur during pregnancy in different autoimmune disorders. In multiple sclerosis and rheumatoid arthritis, TNF-alpha IL-2 IFN-gamma
Cell-mediated cytotoxicity
Cross-inhibition Progesterone Testosterone High estrogen
TH 2
IL-4 IL-5 IL-6 IL-10
Antibodymediated cytotoxicity
Fig. 1. Hormonal influences on the immune system: Activation of an uncommitted helper T lymphocyte (TH 0) leads to its differentiation into one of two functional phenotypes, TH 1 or TH 2, and triggers a cascade of immune responses. In an autoimmune disease, this may lead to either cell-mediated cytotoxic (TH 1) or antibody-mediated (TH 2) tissue damage. The different cytokines produced by each phenotype are counteractive, with TH 1 cytokines suppressing production of TH 2 cytokines and vice versa. Thus, one pathway usually predominates over the other. Which pathway predominates depends on a number of factors (see text) but is also strongly influenced by the relative concentrations of various hormones (adapted from Whitacre et al. [53], with kind permission of the authors and publishers. Copyright 1999 AAAS).
174
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176
which are thought to be primarily TH 1-mediated, disease activity often decreases during pregnancy—particularly during the third trimester when estrogen and progesterone concentrations are at their highest [5]. This is in keeping with a sex hormone induced shift towards increased TH 2 cytokine production, with consequent suppression of the TH 1 pathway. When the levels of these hormones fall during the post-partum period there is often a flare of disease activity, which may be explained by a shift back towards a TH 1 response. In contrast, in systemic lupus erythematosus, which is thought to be a TH 2-mediated condition, disease activity either remains unchanged or worsens during pregnancy [5]. Whether the above can shed light on the predilection of AIH and PBC for females is uncertain, in part because the pathogenetic mechanisms underlying the development of these two conditions are poorly understood. In PBC, its unique association with AMA notwithstanding, there is some evidence to suggest that biliary epithelial cell damage is mediated by direct T-cell cytotoxicity (at least in the early stages of the disease), i.e. via the TH 1 pathway [30,35,36]. In AIH, the picture is less clear. Studies in some animal models and other artificial systems have suggested that AIH is TH 1-mediated but this has not been supported by studies in patients, which have failed to implicate direct T-cell cytotoxicity as the prime mechanism of hepatocellular injury [37]. On the contrary, most such studies in patients have indicated that antibody-dependent cellular cytotoxic (ADCC) reactions appear to be important in liver cell damage in AIH, suggesting that it is predominantly a TH 2-mediated condition [37]. The defects in immunoregulation that lead to loss of self-tolerance in PBC have not been defined but, in AIH, there is evidence to indicate that there are at least two defects in this regulatory mechanism which might account for persistence of the autoimmune response. These genetic defects cannot, however, explain the female preponderance of AIH because they are not X-linked (they are inherited in an autosomal recessive mode) [37]. Can anything be learned from evidence relating to hormonal changes in these conditions, as in the other autoimmune disorders discussed above? No comprehensive studies of hormonal profiles in either AIH or PBC appear to have been reported, but prolactin does not seem to be a factor in AIH. We have recently measured plasma prolactin concentrations in 30 female patients before treatment and all had completely normal prolactin levels (McFarlane, unpublished observations). There is, however, a substantial amount of information about changes in disease activity in AIH during pregnancy. There are well documented case reports of treated patients showing marked improvement during pregnancy and requiring lower doses of immunosuppressive drugs to sustain remission, and of untreated patients having spontaneous remissions during pregnancy but experiencing exacerbations of disease post-partum [38,39]. This scenario would suggest that the TH 1 pathway predominates in AIH. But there are equally well documented reports of treated patients in remission who suffer relapses of their disease
during pregnancy and even of previously asymptomatic patients presenting for the first time during the second or third trimesters of pregnancy when estrogen levels are highest [40], which suggests that the TH 2 pathway predominates. Pregnancy in women with pre-existing PBC is rare but, as in AIH, the available evidence on changes in disease activity during pregnancy is conflicting. Early observations indicated a worsening of the liver disease during pregnancy [41] but this has not been supported by later reports that there is no significant change in liver function during or after pregnancy in PBC [42,43]. If hormonal factors are involved in the development of these disorders, it might be expected that their influence may be less in pre-pubertal children. PBC has not been reported in children, but both AIH and PSC occur in the paediatric age groups. It transpires, however, that the female preponderance in children with AIH and the male preponderance in children with PSC is the same as in adults with these diseases [44]. Interestingly, females also predominate in autoimmune sclerosing cholangitis (a paediatric disorder with features of both AIH and PSC) but to a lesser degree (55:45, F:M) than in AIH [44]. It will be apparent from the above discussion that there is no concrete information which provides an explanation for the predilection of AIH and PBC for females. In part, this is because of a lack of knowledge of the precise pathogenetic mechanisms in these conditions, which is compounded by a number of confounding factors. One of the latter is the recognition that in both disorders (and, indeed, also in PSC) there is a prolonged presymptomatic phase before the diseases become clinically manifest [45,46]. The development of an autoimmune disorder is thought to require a triggering event to initiate the condition in a genetically susceptible individual. Environmental agents, including infections with viruses or bacteria, or exposure to drugs and other chemicals, have been implicated as initiating factors. The hepatitis A and Epstein–Barr viruses have been reported to trigger AIH in genetically susceptible subjects [47,48]. Molecular mimicry between self antigens and antigens expressed on microorganisms is a popular hypothesis which has been proposed to account for the breakdown of tolerance and induction of autoreactivity—particularly in PBC, but also in some forms of AIH [30,49]. However, due to the latency of clinical onset, these initiating events (which may be crucial to understanding pathogenesis) are usually missed. Other confounding factors include the heterogeneity of patient populations with respect to disease severity. There is also accumulating evidence to suggest that the clinical manifestations of these disorders, at least in AIH, may arise through different pathogenetic mechanisms in different patients [50] and that this may be due partly to differences in genetic susceptibility [51,52]. Perhaps these differences are modulated by hormonal factors. To quote Whitacre et al. [53]: “It is not known whether there is a genetic basis for gender differences in autoimmunity. If there is, then this will be the focus of much future research. However, the notion that
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176
genes conferring susceptibility to autoimmune disease may themselves be regulated by sex hormones also needs to be seriously considered.” References [1] Manns MP. The concept of autoimmune liver diseases. In: Krawitt EL, Wiesner RH, Nishioka M, editors. Autoimmune liver diseases. 2nd ed. Amsterdam: Elsevier; 1998. p. 21–34. [2] Dienes HP, Erberich H, Dries V, Schirmacher P, Lohse A. Autoimmune hepatitis and overlap syndromes. Clin Liver Dis 2002;6:349– 62. [3] International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929–38. [4] Donaldson PT. Immunogenetics in liver disease. Baillieres Clin Gastroenterol 1996;10:533–49. [5] Whitacre CC. Sex differences in autoimmune disease. Nat Immunol 2001;2:777–80. [6] Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol 2002;97:2051–7. [7] Lucey MR, Neuberger JM, Williams R. Primary biliary cirrhosis in men. Gut 1986;27:1373–6. [8] Prince M, Chetwynd A, Newman W, Metcalf JV, James OF. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 2002;123:1044–51. [9] Poynard T, Mathurin P, Lai C-L, et al. A comparison of fibrosis progression in chronic liver diseases. J Hepatol 2003;38:257–65. [10] Nalbandian G, Van de Water J, Gish R, et al. Is there a serological difference between men and women with primary biliary cirrhosis. Am J Gastroenterol 1999;94:2482–6. [11] Tessitore L, Sesca E, Pani P, Dianzani MU. Sexual dimorphism in the regulation of cell turnover during liver hyperplasia. Chemic-Biol Interact 1995;97:1–10. [12] Gasbarrini A, Addolorato G, Di Campli C. Gender affects reperfusion injury in rat liver. Dig Dis Sci 2001;46:1305–12. [13] Sakuma T, Takai M, Endo Y, et al. A novel female-specific member of the CYP3A gene subfamily in the mouse liver. Arch Biochem Biophys 2000;377:153–62. [14] Jarukamjorn K, Sakuma T, Yamamoto M, Ohara A, Nemoto N. Sex-associated expression of mouse hepatic and renal CYP2B enzymes by glucocorticoid hormones. Biochem Pharmacol 2001;62: 161–9. [15] Villa E, Grottola A, Colantoni A, et al. Hepatocellular carcinoma: role of estrogen receptors in the liver. Ann N Y Acad Sci USA 2002;963:37–45. [16] Marino IR, Doyle HR, Aldrighetti L, et al. Effect of donor age and sex on the outcome of liver transplantation. Hepatology 1995;22:1754– 62. [17] Brooks BK, Levy MF, Jennings LW, et al. Influence of donor and recipient gender on the outcome of liver transplantation. Transplantation 1996;62:1784–7. [18] Candinas D, Gunson BK, Nightingale P, Hubscher S, McMaster P, Neuberger JM. Sex mismatch as a risk factor for chronic rejection of liver allografts. Lancet 1995;346:1117–21. [19] Pillay P, Van Thiel DH, Gavaler JS, Starzl TE. Donor gender does not affect liver transplantation outcome in children. Dig Dis Sci 1990;35:686–9. [20] Gupta P, Hart J, Cronin D, Kelly S, Millis JM, Brady L. Risk factors for chronic rejection after pediatric liver transplantation. Transplantation 2001;72:1098–102. [21] Francavilla R, Hadzic N, Heaton ND, et al. Gender matching and outcome after pediatric liver transplantation. Transplantation 1998;66:602–5.
175
[22] Vergani D, Mieli-Vergani G. Autoimmunity after liver transplantation. Hepatology 2002;36:271–6. [23] Kerkar N, Hadzic N, Davies ET, et al. De-novo autoimmune hepatitis after liver transplantation. Lancet 1998;351:409–13. [24] Heneghan MA, Portmann BC, Norris SM, et al. Graft dysfunction mimicking autoimmune hepatitis following liver transplantation in adults. Hepatology 2001;34:464–70. [25] Andries S, Casamayou L, Sempoux C, et al. Posttransplant immune hepatitis in pediatric liver transplant recipients: incidence and maintenance therapy with azathioprine. Transplantation 2001;72:267–72. [26] Gupta P, Hart J, Millis JM, Cronin D, Bray L. De novo hepatitis with autoimmune antibodies and atypical histology: a rare cause of late graft dysfunction after pediatric liver transplantation. Transplantation 2001;71:664–8. [27] Hernandez HM, Kovarik P, Whitingtion PF, Alonso EM. Autoimmune hepatitis as a late complication of liver transplantation. J Ped Gastroenterol Nutr 2001;32:131–6. [28] Spada M, Bertani A, Sonzogni A, et al. A cause of late graft dysfunction after liver transplantation in children: de-novo autoimmune hepatitis. Transplant Proc 2001;33:1747–8. [29] Salcedo M, Vaquero J, Banares R, et al. Response to steroids in de novo autoimmune hepatitis after liver transplantation. Hepatology 2002;35:349–56. [30] Mackay IR, Gershwin ME. Pathogenesis of primary biliary cirrhosis. In: Krawitt EL, Wiesner RH, Nishioka M, editors. Autoimmune liver diseases. 2nd ed. Amsterdam: Elsevier; 1998. p. 49–69. [31] McFarlane IG. The relationship between autoimmune markers and different clinical syndromes in autoimmune hepatitis. Gut 1998;42: 599–602. [32] Rose NR. Fundamental concepts of autoimmunity and autoimmune disease. In: Krawitt EL, Wiesner RH, Nishioka M, editors. Autoimmune liver diseases. 2nd ed. Amsterdam: Elsevier; 1998. p. 1–20. [33] Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T-helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989;170:2081–95. [34] Gilmore W, Weiner LP, Correale J. Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1997;158:446–51. [35] Bassendine MF, Jones DEJ, Yeaman SJ. Biochemistry and autoimmune response to the 2-oxoacid dehydrogenase complexes in primary biliary cirrhosis. Semin Liver Dis 1997;17:49–60. [36] Ishibashi H, Nakamura M, Shimoda S, Gershwin ME. T cell immunity in primary biliary cirrhosis. Autoimmun Rev 2003;2:19–24. [37] McFarlane IG. Pathogenesis of autoimmune hepatitis. Biomed Pharmacother 1999;53:255–63. [38] Colle I, Hautekeete M. Remission of autoimmune hepatitis during pregnancy: a report of two cases. Liver 1999;19:55–7. [39] Muratori P, Loffreda S, Muratori L, et al. Spontaneous remission of autoimmune hepatitis during pregnancy. Dig Liver Dis 2002;34:608– 9. [40] Heneghan MA, Norris SM, O’Grady JG, Harrison PM, McFarlane IG. Management and outcome of pregnancy in autoimmune hepatitis. Gut 2001;48:97–102. [41] Nir A, Sorokin Y, Abramovici H, Theodor E. Prenancy and primary biliary cirrhosis. Int J Gynaecol Obstet 1989;28:279–82. [42] Wong KK, Goh KL. Pregnancy in primary biliary cirrhosis. Eur J Obstet Gynecol Reprod Biol 1992;45:149–51. [43] Olsson R, Loof L, Wallerstedt S. Pregnancy in patients with primary biliary cirrhosis—a case for dissuasion? The Swedish Internal Medicine Liver Club. Liver 1993;13:316–8. [44] Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children. Clin Liver Dis 2002;6:335–46. [45] Metcalf VV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OFW. Natural history of early primary biliary cirrhosis. Lancet 1996;348:1399–402.
176
I.G. McFarlane, M.A. Heneghan / Hepatology Research 28 (2004) 171–176
[46] McFarlane IG. Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features. Clin Liver Dis 2002;6:317–33. [47] Vento S, Garofano T, Di Perri G, Concia E, Bassetti D. Identification of hepatitis A virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 1991;337:1183–7. [48] Vento S, Guealla L, Mirandola F, et al. Epstein–Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 1995;346:608–9. [49] Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis. Clin Liver Dis 2002;6:439–49.
[50] McFarlane IG. Definition and classification of autoimmune hepatitis. Semin Liver Dis 2002;22:317–24. [51] Bittencourt PL, Goldberg AC, Cancado ELR, et al. Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am J Gastroenterol 1999;94:1906–13. [52] Pando M, Larriba J, Fernandez GC, et al. Pediatric and adult forms of type 1 autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology 1999;20:1374–80. [53] Whitacre CC, Reingold SC, O’Looney PA, et al. A gender gap in autoimmunity. Science 1999;283:1277–8.