Effects of serum aspartate aminotransferase levels in patients with autoimmune hepatitis influence disease course and outcome.

BACKGROUND & AIMS: Untreated patients with autoimmune hepatitis (AIH) who present with aspartate aminotransferase (AST) levels that are more than 5-fold greater than the upper limit of normal (UPLN) have a mortality rate of up to 80%. This study evaluated whether serum AST levels of patients, determined at presentation, are associated with disease course or outcome. METHODS: The records of 235 patients (median age, 46 y; range, 5-80 y) who presented with AIH, based on International AIH Group score (median, 22; range, 16-28), between 1970 and 2005, were examined. AST levels at presentation were available for 213 patients, who were assigned to 3 groups: group 1, AST less than 2x the UPLN, n = 26 (median, 62 IU; range, 23-97 IU); group 2, AST 2 to 10x the UPLN, n = 71 (median, 241 IU; range, 107-500 IU); and group 3, AST greater than 10x the UPLN, n = 116 (median, 1073 IU; range, 563-4603 IU). RESULTS: Patients in groups 1 and 2 had a significantly worse outcome (risk of liver transplantation or death) compared with those in group 3 (60% survival vs 82%; P = .01; odds ratio, 2.1). These patients were more likely to present with ascites (P < .001), hematemesis (P = .009), and cirrhosis or advanced fibrosis based on an index biopsy (P < .001). Patients in groups 1 and 2 also had lower bilirubin levels at presentation (P < .001) and were less likely to be symptomatic (P < .001). CONCLUSIONS: In patients with AIH, AST levels greater than 10x the UPLN at presentation were associated with a lower risk of cirrhosis and a better long-term outcome than those with AST levels that were less than 10x the UPLN.

Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis.

BACKGROUND/AIMS: Autoimmune hepatitis (AIH) predominantly affects women. Reasons for this are unclear and few series have assessed long-term outcomes of men with AIH. METHODS: To evaluate the clinical course and outcomes of 51 men from a total of 238 consecutive patients with definite AIH at a single centre from 1971 to 2005. The primary outcome measure was death or liver transplantation. RESULTS: Median age at diagnosis was 39 y in men and 49 y in women (p = 0.0589). HLA A1, B8 and DR3 allotypes and the HLA A1-B8-DR3 haplotype were more frequently expressed in men (63% vs. 45%, p = 0.049; 74% vs. 38%, p < 0.001; 62% vs. 44%, p = 0.058; and 50% vs. 23%, p = 0.003; respectively). There were no significant differences in clinical manifestations at presentation. Over 96% of patients demonstrated a complete initial response to treatment. A greater number of men experienced at least one relapse (71% vs. 55%, p = 0.0591). However, women were significantly more likely to die or require liver transplantation (Log rank test p = 0.024). CONCLUSIONS: Men with AIH appear to have a higher relapse rate and younger age of disease onset which may relate to increased prevalence of HLA A1-B8-DR3. Despite this, men have significantly better long-term survival and outcomes than women.

Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre.

BACKGROUND/AIMS: A few reports have suggested that AIH may be less severe in the elderly and may be underdiagnosed, but there is a paucity of data. METHODS: We have undertaken a systematic analysis of 164 consecutive patients (36 males, 128 females) with definite AIH (median score 23, range 18-28) attending our clinics, comparing those presenting at age >60 years (Group 1, n=43) with those presenting at <60 years (Group 2, n=121). RESULTS: Median (range) duration of follow-up was 9 years (1-28) in Group 1 and 14 years (1-33) in Group 2. Median ages (ranges) at presentation were: Group 1=65 (60-79) and Group 2=41 (6-59). Group 1 patients had a significantly increased incidence of ascites at presentation (p<0.001) and a lower incidence of relapse (42% vs. 70%, p=0.002), but there were no significant differences between the groups with respect to mode of onset (acute, insidious, asymptomatic), other clinical signs at presentation, biochemical parameters, types or titres of autoantibodies, incidence of histological cirrhosis, response to therapy or related side effects. There were also no significant differences in liver-related deaths or transplantation, or the frequencies of HLA DR3 or DR4 - although there was an increased frequency of the A1-B8-DR3/4 haplotype in Group 2 (40% vs. 22%, p=0.138). CONCLUSIONS: These findings suggest that AIH often presents in older patients, who frequently have severe disease. Active management in these patients can lead to a normal life expectancy.

Cost-effectiveness of pharmacotherapy for autoimmune hepatitis.

In > 80% of patients with autoimmune hepatitis, steroid therapy alone or in combination with azathioprine results in disease remission. Treatment response results in reversal of fibrosis and excellent long-term survival in many patients, whereas untreated patients may expect a 10-year survival of < 30%. The use of azathioprine monotherapy (2 mg/kg/day) has gained widespread acceptance in maintaining remission in clinical practice. Although all patients with autoimmune hepatitis may not need treatment, particularly those with mild disease, alternative strategies are required in patients who have failed to achieve remission on standard therapy of steroids with or without azathioprine, or patients with azathioprine-induced drug toxicity. In such circumstances, the use of salvage therapy in the form of ciclosporin, tacrolimus or mycophenolate mofetil may be warranted. Liver transplantation is the treatment of choice for patients who present with subacute liver failure or decompensated cirrhosis. Salvage therapy results in an exponential rise in cost with each increment in therapeutic escalation. As an alternative to standard therapy, it has also been suggested that novel therapies such as ciclosporin, tacrolimus or mycophenolate mofetil be initiated to achieve remission. However, a > 10-fold cost differential exists between the charges associated with more potent immunosuppression and standard therapy. Therefore, in evaluating novel immunosuppression in autoimmune hepatitis, it behoves clinicians not only to consider end points pertaining to efficacy, but also end points pertaining to cost-effectiveness. Moreover, the exact role of pharmacogenomics and genotyping of thiopurine methyltransferase in patients with autoimmune hepatitis needs to be fully defined.

Treatment challenges and investigational opportunities in autoimmune hepatitis.

New drugs and advances in molecular biology afford opportunities to upgrade the treatment of autoimmune hepatitis. The aims of this study were to define treatment problems, identify possible solutions, and stimulate investigations to improve patient care. A clinical subcommittee of the International Autoimmune Hepatitis Group reviewed current management difficulties and proposed corrective actions. The assessment of new front-line and salvage therapies for adults and children were given top priority. Cyclosporine and mycophenolate mofetil were endorsed as drugs worthy of rigorous study in severe disease, and budesonide was endorsed for study as front-line therapy in mild disease. Diagnostic criteria and treatment regimens for children required codification, and pharmacokinetic studies were encouraged to develop optimal dosing schedules based on therapeutic ranges. Collaborative efforts were proposed to help understand racial, geographical, and genetic factors affecting outcome and to establish definitions and therapies for variant syndromes and graft dysfunction after transplantation. The development of experimental animal models was deemed essential for the study of site-specific molecular interventions, and gene therapy was endorsed as a means of bolstering reparative processes. In conclusion, evolving pharmacological and technical advances promise to improve the treatment of autoimmune hepatitis, and investigations of these advances are timely, feasible, and necessary.

Autoimmunity and the female liver.

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.

Definition and classification of autoimmune hepatitis.

Autoimmune hepatitis (AIH) has been defined as "an unresolving, predominantly periportal hepatitis, usually with hypergammaglobulinemia and tissue autoantibodies, which is responsive to immunosuppressive therapy in most cases." It is a relatively rare disorder, with a preponderance of female patients, that can present at any age (although onset in most cases is after 40 years of age). There are no features that are pathognomonic of the condition. Diagnosis requires careful exclusion of other causes of liver disease together with the finding of a suggestive pattern of clinical and laboratory abnormalities. The marked heterogeneity of AIH with respect to presenting features, severity of disease, and response to therapy has led to several proposals for classification of the disease according to (mainly) immunologic parameters. These schemata may assist in diagnosis, and some may define different pathogenetic subgroups of the disease, but their utility for assessing prognosis or planning treatment strategies for the individual patient is still uncertain.

Interleukin-1, interleukin-10 and tumour necrosis factor-alpha gene polymorphisms in hepatitis C virus infection: an investigation of the relationships with spontaneous viral clearance and response to alpha-interferon therapy.

BACKGROUND/AIMS: Though there is a consensus that the HLA DQB1*0301 allele is important in untreated HCV clearance, this association is not universal and a number of genes outside the major histocompatibility complex may also play a role in host responses to HCV infection. Prime candidates, at present, are the genes encoding pro-inflammatory and immuno-regulatory cytokines. The aim of this study was to investigate the relationship between a number of these candidate genes and both spontaneous and treatment related clearance of hepatitis C virus infection. METHODS: Three members of the interleukin-1 gene family: IL-1A, IL-1B and IL-1RN, three polymorphic sites in the interleukin-10 gene promoter (- 1082, - 819, - 592) and two in the tumour necrosis factor-alpha promoter (- 308, - 238) were studied in two independent DNA banks, each with appropriate controls. Standard PCR-based genotyping techniques were used. RESULTS: No significant difference in the distribution of any of the polymorphisms was found in either study set. CONCLUSIONS: These findings in two large groups suggest that future investigations should focus on other candidate genes and may support the view that MHC-encoded susceptibility to chronic HCV infection may be determined by MHC class II rather than MHC class III genes.

Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features.

The diagnosis of AIH depends on the finding of several suggestive features together with careful exclusion of liver diseases of other etiologies. Wherever possible, the diagnosis should be confirmed histologically by an experienced hepatopathologist. Seronegativity for the conventional autoantibodies at presentation does not exclude a diagnosis of AIH. It is important to test for anti-LKM1 antibodies to avoid missing a diagnosis of type 2 AIH, with potentially serious consequences. Although the syndrome is associated with characteristic biochemical abnormalities, and biochemical parameters are commonly used for monitoring response to therapy, it should be borne in mind that neither these nor autoantibody titers are completely reliable indices of disease activity. Although the various systems that have been promulgated for classification of the disease may identify different groups of patients on pathogenetic or clinical criteria and are useful for research purposes, none is yet sufficiently exclusive in terms of defining prognosis or planning treatment strategies to be applicable to the individual patient seen in the clinic. Clinical management should therefore continue to be individually tailored.

Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis.

BACKGROUND/AIMS: Toxicity and efficacy of azathioprine is governed partly by the activity of thiopurine methyltransferase (TPMT). Azathioprine has been used for many years, with corticosteroids or alone, for the treatment of autoimmune hepatitis (AIH) but no studies of TPMT phenotype and genotype in relation to response to the drug in AIH have been published. METHODS: Erythrocyte TPMT activities were measured by a radioincorporation assay in 72 consecutive outpatients with AIH, 53 of whom were genotyped for the commonest defective alleles in Europeans (TPMT*3A, *3B and *3C) by restriction fragment length polymorphism analysis. RESULTS: TPMT activities were significantly lower in patients intolerant of azathioprine (group I, n=15) than in those who sustained remission on azathioprine alone (group II, n=28; P=0.003) and those who tolerated azathioprine but continued to require corticosteroids (group III, n=29; P<0.0001), and were higher in group III than in group II (P=0.034). Ten patients with defective alleles (all heterozygotes) had significantly lower TPMT activities (P=0.002). However, in 25% there was discordance between phenotype and/or genotype and response to azathioprine. CONCLUSIONS: TPMT phenotyping or genotyping may be advisable before institution of azathioprine therapy in AIH but neither approach invariably predicts response to the drug.

Type 1 autoimmune hepatitis in Turkish patients: absence of association with HLA B8.

BACKGROUND: There is very little information about autoimmune hepatitis (AIH) in populations other than of white European or Japanese descent. GOALS: To investigate the presenting features, immunogenetic background, and response to standard immunosuppressive therapy in native Turkish patients with AIH. METHODS: Retrospective analysis of all patients referred between 1994 and 2000 to our hepatology clinic in Ankara who fulfilled international criteria for definite or probable type 1 or type 2 AIH. RESULTS: Seventeen patients (15 female; median age, 31 years; range, 13-56 years) were identified. All had type 1 AIH. Clinical and laboratory features were broadly similar to those reported for white or Japanese patients. Five had the HLA DR3 allotype and 10 had DR4; however, in contrast to white and Japanese patients, DR4 was not associated with an older age at onset. Importantly, no patient had the B8 allotype (vs. 10.9% in 110 healthy Turkish subjects). Thus, none had the classic A1-B8-DR3 autoimmune haplotype: a major distinction from white individuals. CONCLUSIONS: There appears to be genetic differences in type 1 AIH between Turkish and other populations. Genotyping of Turkish patients to identify alleles that may confer susceptibility or resistance to AIH may progress understanding of the genetic basis of the disease.

Chronic hepatitis C infection: influence of the viral load, genotypes, and GBV-C/HGV coinfection on the severity of the disease in a Brazilian population.

The distributions of the different genotypes of the hepatitis C virus (HCV) and GBV-C virus (GBV-C/HGV) vary geographically and information worldwide is still incomplete. In particular, there are few data on the distribution of genotypes (and their relationship to the severity of liver disease) in South America. Findings are described in 114 consecutive patients from Northeast Brazil (median age 52 years, range 18-72 years) who had abnormal levels of serum aminotransferases and seropositivity for HCV RNA. The patients were recruited from an outpatient clinic between November 1997 and April 1998. Quantitative HCV RNA and GBV-C/HGV RNA estimations were carried out by double-nested polymerase chain reaction (PCR) using primers from the 5'-untranslated regions (UTRs) of the genomes. HCV genotypes were determined by restriction fragment length polymorphism (RFLP) analysis with 5'-UTR primers and by PCR with type-specific 5'-UTR primers. GBV-C/HGV-RNA genotypes were determined by RFLP with specific 5'-UTR primers and phylogenetic trees were constructed using the Neighbour-Joining and Drawtree programs. Histological features were graded and staged according to international criteria. Of the 114 patients, 35 (30.7%) patients had cirrhosis and 22 (27.8%) had mild, 51 (64.6%) had moderate, and 6 (7.6%) had severe chronic hepatitis. Median HCV viral load was 10(6) genome equivalents per millilitre (range 10(4)-10(9)/ml). Frequencies of genotypes were 5.3% type 1a, 44.7% type 1b, 3.5% type 2, 41.2% type 3, and 5.3% mixed types. GBV-C/HGV-RNA was detected in the sera of 12 (10.5%) patients and was distributed among three phylogenetic groups. There were no significant differences between patients with the predominant HCV genotypes (1b and 3) with respect to gender, age group, viral load, severity of liver disease, or coinfection with GBV-C/HGV.

Current and novel immunosuppressive therapy for autoimmune hepatitis.

Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in patients with autoimmune hepatitis (AIH) and results in remission induction in over 80% of patients. Sustained response to therapy may result in substantial regression of fibrosis even in advanced cases. The outcome of rapid withdrawal of immunosuppression is disease relapse in many patients. Consequently, the use of 2 mg/kg/d of azathioprine as a sole agent to maintain remission has been widely accepted in clinical practice. Persistent severe laboratory abnormalities or histologic abnormalities such as bridging necrosis or multilobular necrosis are absolute indications for treatment based on controlled clinical trials, but debate exists as to whether all patients with AIH need treatment. Examination of liver tissue remains the best method of evaluating both treatment response and need for treatment in patients who have little biochemical activity. Alternative strategies in patients who have failed to achieve remission on "standard therapy" of corticosteroids with or without azathioprine or patients with drug toxicity include the use of cyclosporine, tacrolimus, or mycophenolate mofetil. Liver transplantation is the treatment of choice in managing decompensated disease. In this review we examine current management strategies of AIH, and evaluate available data pertaining to the use of novel immunosuppressive agents in this condition.

Hepatites B e C na esquistossomose mansoni / B and C Hepatitis in schistosomiasis mansoni

Foram estudados 234 pacientes com essquistossomose mansoni, sendo 44 com a forma hepatintestinal (EHI), 143 com a forma hepatesplenica compensada (EHEC) e 47 com a forma descompensada (EHED), além de 50 individuos controles. Dos 234 pacientes, 133 (57por cento) tinham pelo menos um marcador sorológico dis HBV e hcv. A frequencia do HBsAg foi significativamente maior (21por cento vs. 6por cento vs. 2por cento) nos com EHED do que nos com EHEC ou nos com EHI (p<0,001. Dos 19 (8por cento) AgHBs positivos,14 (74por cento) foram ant-HBe (um com EHI, sete com EHEC e seis com EHED),incluindo sete (37 por cento) HBV-DNA positivos. Em relaçao ao HCV, 47 (20por cento) dos 234 pacientes foram anti-HCV poistivos, apresentaram também HCV-RNA no soro, sendo11 (69,8 por cento) dos 16 com EHEC,17 (56,7 por cento) dos com EHED e um com EHI. O HCV_DNA foi detectado tambem em cinco pacientes anti-HCV negativos com EHED, totalizando 22 pacientes cm infeccao pelo HCV. Nos 108 pacientes com EHE ( 13 HBsAg positivos, 25 anti-HCV positivos para ambos os marcadores submetidos a esplenectomia) em que foi realizada biópsia hepatica dos com EHEC apresentava hepatite cronica ativa. Os achados deste estudo sugerem que a infecçao concomitante pelos virus das hepatites B e C é importante fator contribuinte para a gravidade da doença hepatica na esquistossomose mansoni