Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival.

BACKGROUND: Primary sclerosing cholangitis/autoimmune hepatitis (PSC/AIH) and primary biliary cirrhosis/AIH (PBC/AIH) overlap syndromes are poorly defined variants of AIH. Few large patient series exist, and there are little data on long-term outcomes. AIM: To compare presentation, clinical course and outcome of patients with PSC/AIH and PBC/AIH, with patients with definite AIH. Methods Two hundred and thirty-eight AIH patients were compared with 10 PBC/AIH patients and 16 PSC/AIH patients presenting consecutively between 1971 and 2005 at a single centre. RESULTS: Autoimmune hepatitis patients were significantly more likely to present with jaundice (69.4% vs. 25%; P = 0.0145) than PBC/AIH patients. Median serum aspartate aminotransferase activity at presentation was higher in AIH patients compared with PBC/AIH and PSC/AIH patients respectively (620 vs. 94 vs. 224 IU/L; P < 0.05). PBC/AIH patients demonstrated no response to standard AIH therapy more frequently than AIH patients (25% vs. 0.8%; P = 0.0057). Significant reduction in survival was identified between patients with PSC/AIH and those without (hazard ratio: PSC/AIH vs. AIH = 2.08, PSC/AIH vs. PBC/AIH = 2.14; P = 0.039). CONCLUSIONS: Patients with PSC/AIH have severe disease and significantly worse prognosis than patients with AIH or PBC/AIH. Recognition and close follow-up of this cohort are warranted.

Characteristics of autoimmune hepatitis in patients who are not of European Caucasoid ethnic origin.

BACKGROUND: Significant diversity in disease severity has been identified for autoimmune disorders among different ethnic groups but there is a lack of data on autoimmune hepatitis (AIH) in populations other than those of European Caucasoid (EC) or Japanese extraction. AIMS: To assess the clinical features, response to therapy, and eventual outcome in AIH patients of non-EC ethnicity. METHODS: A retrospective review of a regularly updated database of patients with AIH referred to liver outpatient clinics at King's College Hospital, London, since 1983. RESULTS: Twelve patients were identified (10 female; six African, five Asian, one Arabic; median age at presentation 30 years (range 12-58)) who satisfied international criteria for type 1 (11 cases) or type 2 (one case) AIH. Nine (75%) had cholestatic serum biochemistry and three (25%) had mild biliary changes on liver biopsy without definitive features of primary biliary cirrhosis or cholangiographic evidence of primary sclerosing cholangitis. Four showed a complete biochemical response to standard prednisolone with or without azathioprine therapy, three partial, and five no response. Four have required liver transplantation for intractable disease. By comparison with 180 EC patients with definite AIH attending during the same period, the non-EC patients were younger (p<0.05), presented with cholestatic biochemistry (p=0.014), and morphological biliary features more frequently (p<0.0005) and showed a poorer initial response to standard therapy (p<0.0005). CONCLUSIONS: Clinical expression of AIH in non-EC patients seems to differ in important respects from that in EC or Japanese patients. Management of such patients is challenging and may require alternative or more aggressive treatment strategies.

Autoimmune liver diseases.

The differential diagnosis of the three disorders that are usually classified as autoimmune liver diseases, namely autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), requires careful exclusion of other causes of chronic liver disease together with the finding of suggestive patterns of abnormalities of serum biochemical parameters, immunoglobulin isotypes and 'conventional' non-organ-specific autoantibodies. Antimitochondrial antibodies (particularly those reacting with epitopes on the E2 components of the pyruvate dehydrogenase and other 2-oxo-acid dehydrogenase complexes), and some sub-specificities of antinuclear antibodies, are virtually pathognomonic of PBC. Anti-liver-kidney microsomal antibodies reacting with defined epitopes on the cytochrome isoform P4502D6 are relatively specific for a small sub-group of (so-called 'type 2') AIH. However, most of the other serological parameters lack specificity. Additionally, within and between each disease group there is wide variability, even among patients with comparable severity of liver damage. Thus, in many cases, liver histology and/orcholangiography is still required for definitive diagnoses or for assessing stage and severity of these disorders. A number of autoantibodies that are more directly related to the liver than the 'conventional' autoantibodies are showing promise as possibly more specific diagnostic markers of AIH. Commercial tests for some of these are under development and it is hoped that they will soon become widely available.

Autoimmune hepatitis: Clinical manifestations and diagnostic criteria.

In 1998, the International Autoimmune Hepatitis Group--a panel of 40 hepatologists and hepatopathologists from 17 countries who have a particular interest in autoimmune hepatitis (AIH)--undertook a review, in light of subsequent experience, of the descriptive criteria and diagnostic scoring system that it had proposed in 1993 for the diagnosis of AIH. This review (published in 1999) noted that the original descriptive criteria appeared to be quite robust and required only relatively minor modifications to bring them up to date with developments and experience in diagnostic modalities for liver disease in general. Analysis of published data on the application of the original criteria in nearly 1000 patients revealed that the diagnostic scoring system had an overall diagnostic accuracy of 89.8%, with a sensitivity of 98.0%. Specificity for excluding definite AIH in patients with chronic viral hepatitis and circulating autoantibodies or patients with overlapping cholestatic syndromes was 98% to 100%, but specificity for excluding probable AIH in these disorders ranged from only 60% to 80%. Modifications, including adjustments to the weightings against biochemical and histological cholestatic features, have been made to the scoring system to improve its specificity.

Management and outcome of pregnancy in autoimmune hepatitis.

BACKGROUND: There is a paucity of data in the literature on the risks associated with, and optimal management of, pregnancy in patients with autoimmune hepatitis (AIH). AIMS: To assess maternal and fetal outcomes in relation to clinical management of pregnancy in a large cohort of patients with well defined AIH. METHODS: A review of all known pregnancies in 162 females with definite AIH attending our clinics between 1983 and 1998, with respect to treatment, natural history, and outcome. RESULTS: Thirty one live births (one twin) resulted from 35 pregnancies in 18 women (seven with cirrhosis). Median age at conception was 28 years (range 18-36). Two patients presented with AIH de novo during pregnancy. At conception, in 15 pregnancies patients had been receiving azathioprine alone or (in nine) with prednisolone, in seven prednisolone alone, and in one cyclosporin. Fetal loss at > or =20 weeks' gestation occurred in two instances. Flares in disease activity occurred during four pregnancies and within three months of delivery in a further four. Among the 31 children born (median follow up 10 years) only two abnormalities have been identified: Perthes' disease in one and severe mental and physical handicap in a second who was born prematurely following decompensation of the mother's liver disease. Neither mother was receiving azathioprine. CONCLUSIONS: Successful completion of pregnancy is a realistic expectation for patients with well controlled AIH. Treatment options vary, but azathioprine appears to be generally safe and without adverse outcomes for mother or baby. Vigilance is required, however, and patients need to be monitored carefully during pregnancy and for several months post partum.

HLA class II genotypes associated with chronic hepatitis C virus infection and response to alpha-interferon treatment in Poland.

AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.

Autoantibodies in alcoholic liver disease.

Despite many decades of research, the reasons why only a relatively small proportion of individuals who consume excessive quantities of alcohol develop clinically significant liver disease remain unknown. The association with features of autoimmune diseases, including hypergammaglobulinaemia, circulating autoantibodies, inheritance of certain immunogenetic (HLA) markers and response to corticosteroid therapy in some patients has led to a persistent impression that altered immune regulation with a relative loss of self-tolerance underlies susceptibility to the development of the more severe forms of alcoholic liver disease (alcoholic hepatitis and/or cirrhosis). However, review of the data from the numerous studies that have been conducted over the past 30 years fails to reveal sufficiently convincing evidence that autoimmunity plays a primary role in alcohol-related liver damage. In particular, most of the wide range of circulating autoantibodies that have been reported in patients are found mainly at low titres, are not confined to those with severe liver injury, and are probably more likely to be a response to the hepatic insult than causally related to liver damage. Additionally, an association with various HLA phenotypes has not been confirmed by meta-analysis. Interpretation is complicated by evidence that alcohol may have direct effects on some components of the immune system but, if there is an immunogenetic basis for alcoholic liver disease, the present evidence suggests that this might be related more to cytokine gene polymorphisms than to a predisposition to autoimmunity per se.

Pathogenesis of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an idiopathic disorder affecting the hepatic parenchyma. There are no morphological features that are pathognomonic of the condition but the characteristic histological picture is that of an interface hepatitis without other changes that are more typical of other liver diseases. It is associated with hypergammaglobulinaemia, high titres of a wide range of circulating auto-antibodies, often a family history of other disorders that are thought to have an autoimmune basis, and a striking response to immunosuppressive therapy. The pathogenetic mechanisms are not yet fully understood but there is now considerable circumstantial evidence suggesting that: (a) there is an underlying genetic predisposition to the disease; (b) this may relate to several defects in immunological control of autoreactivity, with consequent loss of self-tolerance to liver auto-antigens; (c) it is likely that an initiating factor, such as a hepatotropic viral infection or an idiosyncratic reaction to a drug or other hepatotoxin, is required to induce the disease in susceptible individuals; and, (d) the final effector mechanism of tissue damage probably involves auto-antibodies reacting with liver-specific antigens expressed on hepatocyte surfaces, rather than direct T-cell cytotoxicity against hepatocytes.

Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases.

OBJECTIVE: We report five cases (four male; median age 20 yr, range 14-38 yr) of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. The patients presented with jaundice, elevated serum aminotransferase and alkaline phosphatase activities, hyperglobulinemia with high immunoglobulin G (IgG) levels, circulating antinuclear and/or smooth muscle autoantibodies (> or = 1:40), and moderate to severe interface hepatitis on liver biopsy (with biliary features in four). METHODS: All five fulfilled criteria for diagnosis of "definite" autoimmune hepatitis and showed marked responses to prednisolone and azathioprine therapy, with relapses occurring during reduction or withdrawal of treatment. Cholangiographic features of primary sclerosing cholangitis were found in three patients at presentation and after intervals of 7 and 14 yr in the other two. Only two had evidence of inflammatory bowel disease. Diagnostic criteria for identifying those patients who may benefit from immunosuppressive therapy were reviewed. RESULTS: Review of the literature revealed only 11 similar cases that were sufficiently well described for comparison. However, in contrast to these and the present cases, preliminary data from other studies have suggested a marked association with ulcerative colitis and a poor response to immunosuppressive therapy. CONCLUSIONS: It is recommended that the possibility of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome responsive to immunosuppressive therapy should be considered in any patient presenting with a hepatitic illness with hyperglobulinemia, antinuclear or smooth muscle autoantibodies, and biliary changes on liver biopsy. Cholangiography should be considered in such patients.

Ultrasonography of the liver and spleen in Brazilian patients with hepatosplenic schistosomiasis and cirrhosis.

Ultrasonography is now widely used in the diagnosis and management of patients with chronic Schistosoma mansoni infections. The present study was undertaken to evaluate the use of ultrasonography in patients with hepatosplenic schistosomiasis (HSS) with and without cirrhosis. Ninety-seven patients (52 males; median age 38 years, range 19-68 years) with HSS, 65 with well compensated (HSSC) and 32 with decompensated (HSSD) disease and cirrhosis, were systematically examined by ultrasound. Hepatic fibrosis was graded according to WHO recommendations. Typical atrophy of the right hepatic lobe accompanied by hypertrophy of the left lobe, with a rounded inferior marginal edge, was seen in 86 (88.7%) patients. Periportal fibrosis was observed in 83 (85.6%) cases and confirmed histologically in all. In 66 patients (68.0%) thickening of the gallbladder wall, associated with periportal fibrosis and extending from the branches of the porta hepatis, was noted. No evidence of biliary disease was found in these patients and gallstones were present in only 3 cases. Fourteen (43.8%) of the HSSD patients could not be classified for grade of fibrosis because of the advanced stage of cirrhosis related to hepatitis B or C viral infection. Of the remaining 18 HSSD patients, none had only grade I fibrosis (vs. 10.8% of HSSC, P = 0.054) and only 6 had grade II (vs. 67.7% of HSSC, P < 0.0005), while the frequency of grade III was significantly higher in the HSSD patients than in those with HSSC (37.5% vs. 21.5%, P = 0.049). These findings indicate that although ultrasonography is a very valid technique for assessing patients with pure HSS, and should be considered the 'gold standard', it is not reliable for assessing periportal fibrosis in patients with concomitant cirrhosis due to other causes.

Screening of hepatoprotective plant components using a HepG2 cell cytotoxicity assay.

Identification of the active components of plants with hepatoprotective properties requires screening of large numbers of samples during fractionation and purification. A screening assay has been developed based on protection of human liver-derived HepG2 cells against toxic damage. Various hepatotoxins were incubated with HepG2 cells in 96-well microtitre plates (30,000 cells well-1) for 1 h and viability was determined by metabolism of the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS). Bromobenzene (10 mM) and 2,6-dimethyl-N-acetyl-p-quinoneimine (2,6-diMeNAPQI, 200 mM) had greater toxic effects than tert-butyl hydroperoxide (1.8 mM) or galactosamine (10 mM), reducing mean viability to 44.6 +/- 1.2% (s.e.m.) and 56.1 +/- 2.1% of control, respectively. Protection against toxic damage by these agents was tested using a crude extract of a known hepatoprotective Sri Lankan plant, Osbeckia aspera, and two pure established hepatoprotective plant compounds, (+)-catechin and silymarin (1 mg mL-1). Viability was significantly improved by Osbeckia (by 37.7 +/- 2.4%, P < 0.05, and 36.5 +/- 2.1%, P < 0.05, for bromobenzene and 2,6-diMeNAPQI toxicity, respectively). Comparable values for (+)-catechin were 68.6 +/- 2.9% and 63.5 +/- 1.1%, and for silymarin 24.9 +/- 1.4% and 25.0 +/- 1.6%. This rapid and reproducible assay should prove useful for the isolation and identification of active hepatoprotective compounds in crude plant extracts.

Specific liver autoreactivity in schistosomiasis mansoni.

To investigate the possible involvement of autoimmune mechanisms in the development of hepatosplenic schistosomiasis (HSS), 234 patients with chronic Schistosoma mansoni infections were screened for a wide range of non-organ-specific autoantibodies as well as for antibodies reacting with the GOR peptide and with a liver-specific autoantigen, the hepatic asialoglycoprotein receptor (ASGP-R). Thirty-five (15.0%) were seropositive for antinuclear, smooth muscle or gastric parietal cell antibodies at low titres (< or = 1:80), and 15/176 (8.5%) had anti-GOR, all of whom had concomitant hepatitis C viral (HCV) infections. Anti-ASGP-R was found in 64 (27.4%) of the 234 patients at titres similar to those found in 18 untreated auto-immune hepatitis patients studied concurrently. Anti-ASGP-R seropositivity occurred significantly (P < 0.005) more frequently in patients with HSS (62/190, 32.6%) than in those with hepatointestinal schistosomiasis (2/44, 4.5%), but did not correlate with severity of liver disease or with the presence of the non-organ-specific autoantibodies. Anti-ASGP-R was found significantly (P < < 0.0005) less frequently in HSS patients who had had a splenectomy for portal hypertension (5/86, 5.8%) than in those who had not had a splenectomy (57/104, 54.8%). The findings suggest that liver-specific autoreactivity may play a role in the development of HSS.

Alcohol dehydrogenase: a target of humoral autoimmune response in liver disease.

BACKGROUND & AIMS: Liver-specific membrane lipoprotein (LSP) is a heterogeneous liver preparation that has been widely used to study autoreactivity in liver disease. The aim of this study was to identify autoantigens in LSP. METHODS: Guinea pig anti-LSP serum was used to screen a human liver complementary DNA (cDNA) library. Humoral immune responses to isolated potential autoantigens were investigated by immunoblotting in 91 pediatric patients with various liver diseases, 20 adult patients with alcoholic liver disease and 20 with autoimmune thyroid disease, 37 healthy children, and 20 healthy adults. RESULTS: A 1.6-kilobase cDNA insert isolated from the cDNA library was found to encode amino acids 61-374 of the human alcohol dehydrogenase (ADH)-gamma 1 subunit. Antibodies to this or other ADH subunits were found significantly more frequently in autoimmune liver diseases (19 of 39 patients; 49%), Wilson's disease (5 of 13 patients; 38%), and alcoholic liver disease (10 of 20 patients; 50%) than in normal controls (P < 0.0001, P < 0.005, and P < 0.05, respectively) and correlated with disease activity in autoimmune liver disease. CONCLUSIONS: ADH has been identified as a new antigenic component of the LSP using a xenogeneic antiserum to immunoprobe a human cDNA liver library and seems to be a target autoantigen in liver disease. This approach may be useful in identifying other potential autoantigens.

Protective effects of Osbeckia octandra against galactosamine and tert-butyl hydroperoxide induced hepatocyte damage.

Ayurvedic and other 'traditional' medical practitioners in Sri Lanka use the mature leaves of the plant Osbeckia octandra for its hepatoprotective properties. In this study the effects of an aqueous extract of Osbeckia octandra against injury induced by D-galactosamine and tert-butyl hydroperoxide (TBH) were investigated in freshly isolated rat hepatocytes. The plant extract (500 micrograms/ml) significantly reduced the inhibition of protein synthesis (as assessed by the incorporation of 14C-leucine into protein) in hepatocytes incubated for 1 h with 10 mM galactosamine by a mean of 25.6 +/- 3.6% and decreased the release of cellular lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzyme activities into the medium by 55.3% and 32.8%, respectively. With TBH, the plant extract decreased lipid peroxidation (estimated from malondialdehyde formation) by a mean of 29.9 +/- 1.1% together with a 46.8% and 54.7% decrease in the release of LDH and AST, respectively into the incubation medium. Significant protection was also obtained when the Osbeckia extract was added to the incubation medium up to 30 min after pre-exposure of the hepatocytes to either galactosamine or, to a lesser extent, TBH. The results support the use of Osbeckia as a hepatoprotective agent.

Azathioprine for long-term maintenance of remission in autoimmune hepatitis.

BACKGROUND: In most patients with autoimmune hepatitis, remission can be maintained with prednisolone, usually in combination with azathioprine, but the majority of patients have a relapse when treatment is stopped and therefore require long-term therapy. Because prolonged corticosteroid therapy may have serious toxic effects, in 1984 we undertook a controlled trial of maintenance therapy with azathioprine alone. None of the 25 patients in that trial had relapses during the follow-up period of one year. We have now followed these 25 patients for 10 years and have treated an additional 47 patients in a similar manner. METHODS: The 72 patients (median age, 47 years; range, 14 to 71) had been in complete remission for at least one year with 5 to 15 mg of prednisolone per day and 1 mg of azathioprine per kilogram per day. The dose of azathioprine was increased to 2 mg per kilogram per day, and the prednisolone was gradually withdrawn. Remission was defined as the absence of symptoms suggestive of a relapse and serum globulin and aspartate aminotransferase concentrations within the normal range, with or without a liver biopsy showing only minimal inflammation. RESULTS: Sixty patients (83 percent) remained in remission while receiving azathioprine alone for a median of 67 months (range, 12 to 128). Of 48 follow-up liver biopsies in 42 patients, 45 showed inactive or minimal disease, and 3 showed moderate disease (2 after one year of therapy and 1 after eight years). After the prednisolone had been withdrawn, 26 patients lost their cushingoid facies, and 32 patients lost weight (median loss, 6.4 kg; range, 1.5 to 22.3). The most common adverse effect was arthralgia (in 38 patients). With the higher dose of azathioprine, four patients had myelosuppression, defined as a decrease in the leukocyte and platelet counts to less than 4000 and 150,000 per cubic millimeter, respectively. Two of these patients (both with pancytopenia) relapsed when the azathioprine was withdrawn; in the other two, remission was maintained with the resumption of prednisolone. Lymphopenia developed in 32 of 56 patients treated with 2 mg of azathioprine per kilogram per day for more than two years. During follow-up, nine patients died: one of liver failure and eight of causes not directly related to their liver disease. CONCLUSIONS: Many patients with autoimmune hepatitis who have been in complete remission for at least one year with prednisolone and azathioprine can remain in remission with a higher dose of azathioprine alone.