Prognosis of acute severe autoimmune hepatitis (AS-AIH): the role of corticosteroids in modifying outcome.

BACKGROUND & AIMS: No standardised definition exists for acute, severe AIH (AS-AIH). However, rapid identification of AS-AIH and early corticosteroid therapy may prevent the need for liver transplantation (LT). We set out to determine the clinical outcomes of patients with AS-AIH presenting to our institution with particular focus on the role of corticosteroids. METHODS: Retrospective analysis of a prospectively collated database identified patients presenting with AS-AIH from 1999 to 2009. We defined AS-AIH as an acute presentation with an INR of ⩾1.5 at any time without histological evidence of cirrhosis. RESULTS: 32 patients were identified with AS-AIH. Among the 32 AS-AIH patients 23 were treated with corticosteroids of whom 10 (48%) required LT, whilst all 9 untreated patients required LT (p = 0.01). Untreated patients demonstrated higher MELD scores at presentation (34 vs. 28 p = 0.01) and a non-significant decrease in episodes of sepsis but no difference in sepsis or mortality was observed between untreated or treated patients (11% vs. 26% p = 0.6 and 22% vs. 17% p = 0.99 respectively). Among treated patients, no difference in MELD scores was observed between responders or failures. Despite 59% undergoing LT, six deaths (19%) occurred. CONCLUSION: In a well characterised cohort of patients with AS-AIH, almost 60% required LT and 20% died. There was no difference in prognostic scores between steroid responders and failures and steroid exposure did not appear to jeopardise survival. Patients with AS-AIH should be considered for a trial of corticosteroids expediently whilst a thorough search for sepsis and assessment for LT should occur if clinical deterioration or encephalopathy develops.

Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group (IAIHG) criteria in acute and chronic liver disease.

UNLABELLED: Diagnostic criteria for autoimmune hepatitis (AIH) have been created and revised by the International Autoimmune Hepatitis Group (IAIHG). Simplified criteria have been created, but remain independently unvalidated. We report on the diagnostic accuracy of the simplified criteria in patients across a range of diagnoses, including a subset of patients presenting with fulminant liver failure who required liver transplant. Patients with AIH and non-AIH etiologies of liver disease were identified from dedicated patient databases. Parameters relevant to the simplified and 1999 IAIHG criteria were recorded, and sensitivity, specificity, and positive and negative predictive values for scores of >or=6 (probable AIH) and >or=7 (definite AIH) were calculated. A total of 549 patients with chronic liver disease were evaluated, (221 with AIH, 26 with variant syndromes, and 302 with non-AIH). For scores >or=6, sensitivity was 90%, and specificity was 98% with positive and negative predictive values of 97% and 92%, respectively. For scores >or=7; sensitivity was 70%, and specificity was 100% with positive and negative predictive values of 100% and 74%, respectively. Seven false positive diagnoses of AIH occurred, all with simplified scores of 6. Concordance with 1999 criteria was 90% for probable and 61% for definite AIH. The frequency of an overall diagnosis of AIH (probable or definite AIH) among the 70 patients with fulminant liver failure was 24% for simplified criteria and 40% for 1999 criteria, respectively. CONCLUSION: The simplified criteria retain high specificity but exhibit lower sensitivity for scores of >or=7. The explanations for this are unclear but may relate to loss of such discriminating information as response to corticosteroids. Prospective evaluation of these criteria is required to corroborate these observations.

Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening.

UNLABELLED: Hepatocellular carcinoma (HCC) has traditionally been considered a rare complication of cirrhosis secondary to autoimmune hepatitis (AIH), yet the true incidence remains unknown due to a lack of published data. Consequently, some professional guidelines do not mandate routine surveillance for HCC in this condition. Our aims were to evaluate the rate at which HCC develops among a large, prospectively obtained cohort of patients with AIH at a single center. Demographic, clinical, and laboratory indices associated with the development of HCC were also identified. HCC was discovered in 15 of 243 patients with AIH, all of whom had type 1 AIH equating to 1090 cases per 100,000 patient follow-up years. HCC occurred in the same proportion of females as males, 6.1% versus 6.4%, P = 0.95. HCC occurred more frequently in patients who had cirrhosis at presentation, 9.3% versus 3.4%, P = 0.048, or who had a variceal bleed as the index presentation of AIH, 20% versus 5.3%, P = 0.003. The median duration from time of confirmed cirrhosis to a diagnosis of HCC was 102.5 months, range 12-195 months. Median survival in patients whose HCC was diagnosed on surveillance was 19 months (range 6-36 months) compared with 2 months (range 0-14 months) for patients presenting symptomatically (P = 0.042). CONCLUSION: Cirrhosis in AIH is the sine qua non for HCC development, which subsequently occurs at a rate of 1.1% per year and affects men and women in equal proportions.

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.

Remission in autoimmune hepatitis: what is it, and can it ever be achieved?

The goals of therapy in autoimmune hepatitis (AIH) are to dampen inflammation within the liver, with the aim of inducing remission, improving symptoms, and prolonging survival. Ideally, treatment could be stopped once remission has been achieved. However, cessation of therapy may be complicated by relapse in substantial numbers of patients and although as many as 30% of patients could remain in remission, it is impossible to predict which patients can stop therapy safely and avoid unnecessary prolongation of immunosuppression therapy. A retrospective analysis of data from a large single centre has assessed parameters that could predict maintenance of remission following withdrawal of therapy. Importantly, it has been shown that therapy should not be withdrawn in any patient who has not achieved complete normalization of biochemistry in the presence of normal histology, nonspecific portal hepatitis, or inactive cirrhosis. The results illustrate the difficulties in relation to defining remission and relapse in patients with AIH and highlight the need for consistency in terminology.

Liver transplantation in patients over 60 and 65 years: an evaluation of long-term outcomes and survival.

With increased demand for liver transplantation (LT), outcomes of older recipients have been subjected to greater scrutiny, as previous studies have demonstrated poorer survival outcomes. Outcomes of 77 patients aged>65 yr (group 1) who underwent transplantation between 1988 and 2003 at King's College Hospital, London, were compared with all recipients aged between 60 and 64 yr (group 2, n=137) and 202 time-matched control patients with chronic liver disease aged between 18-59 yr (group 3). Patient survival at 30-days for groups 1, 2, and 3 were 99%, 94%, and 94%, respectively (P=not significant [NS]). At 1-yr, survival in the 3 groups was 82%, 86%, and 83%, respectively (P=NS), and at 5-yr patient survival was comparable (73%, 80%, and 78%, respectively) (P=NS). Episodes of acute cellular rejection (ACR) were fewer in the older cohorts (43% vs. 45% vs. 61%, P=0.0016), although there was no significant difference identified in the numbers of patients in each group who experienced ACR (P=0.16). A similar but nonsignificant trend was identified for rates of chronic rejection among the groups. In conclusion, these data suggest that survival of patients over 60 and 65 yr undergoing LT is satisfactory, at least in the first 5-yr posttransplantation. In addition, patients over 65 yr experience less rejection, with good graft survival. Thus, LT should not be denied to patients>65 yr on the basis of age alone, once a comprehensive screen for comorbidity has been undertaken.

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.

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.

Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipients.

Infertility is common in women with end-stage liver disease. Successful liver transplant (LT), however, can restore childbearing potential. Controversy exists regarding the most appropriate immunosuppressive regimen and timing of conception following LT. We report the outcomes of a review of all pregnancies occurring following LT at King's College Hospital, London, from 1988 to 2004. Seventy-one pregnancies were recorded in 45 women. Tacrolimus (60%) and cyclosporin A (38%) were the predominant primary immunosuppressive agents used. Median age at conception was 29 years (range, 19-42), with a median time from LT to conception of 40 months (range, 1-111). There were 50 live births, and no maternal or fetal deaths related to pregnancy. There were no graft losses. Median gestation was 37 weeks (range, 24-42) with a median birth weight of 2,690 g (range, 554-4,260). Caesarean section was performed in 40% of pregnancies. Complications included pregnancy-induced hypertension in 20%, preeclampsia in 13%, acute cellular rejection in 17%, and renal impairment in 11%. There was no statistically significant difference in complication rates observed between immunosuppressive groups. Pregnancies occurring within 1-year posttransplant had an increased incidence of prematurity, low birth weight, and acute cellular rejection compared to those occurring later than 1 year. In conclusion, this study confirms that favorable outcomes of pregnancy post-LT can be expected for the majority of patients. However, delaying pregnancy until after 1-year post-LT is advisable, since doing so maybe associated with a lower risk of prematurity.