Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis.

OBJECTIVES: Biochemical remission is widely considered a satisfactory treatment end point in autoimmune hepatitis (AIH). The significance of persisting histological activity despite biochemical remission is unknown. We aimed to assess the frequency and prognostic significance of persisting histological inflammation in patients with AIH who had achieved biochemical remission with treatment. METHODS: We studied 120 patients (median age at diagnosis 57 years; 81% female) with AIH by International Criteria (59% definite), who received immunosuppressive treatment and underwent a follow-up liver biopsy after at least 6 months of sustained biochemical remission (defined as normal serum ALT and globulin). RESULTS: Fifty-five patients (46%) had persisting histological activity (Ishak histological activity index (HAI) ≥4). These patients had higher serum ALT (24 vs. 18 IU/l, P=0.003) and AST (27 vs. 23 IU/l, P=0.03) at the time of follow-up biopsy, compared with patients who achieved histological remission (HAI ≤3). They had less frequent regression of fibrosis on follow-up biopsy compared with those achieving histological remission (32 vs. 60%, P=0.004) and had excess mortality (standardized mortality ratio 1.4 vs. 0.7, P<0.05). The excess mortality was due to liver disease. On multivariate analysis, persisting histological activity was independently associated with all-cause death/transplantation (HR 3.1 (95% CI 1.2-8.1); P=0.02); an association with liver-related death/transplantation fell short of significance (HR 9.7 (95% CI 0.84-111.6; P=0.07). CONCLUSIONS: Persisting histological activity, despite biochemical remission, is frequent in patients with treated AIH and is associated with lower rates of fibrosis regression and reduced long-term survival.

Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis.

UNLABELLED: Azathioprine (AZA) is used to maintain remission in autoimmune hepatitis (AIH), but up to 18% of patients are unresponsive. AZA is a prodrug, and the formation of active thioguanine nucleotide (TGN) metabolites varies widely. We aimed to assess the relationship between AZA metabolite concentrations (i.e., TGNs and methylmercaptopurine nucleotides [MeMPNs]), thiopurine methyltransferase (TPMT) activity, therapeutic response, and toxicity in adult patients with AIH prescribed a stable dose of AZA for the maintenance of remission. Red blood cell (RBC) TGNs and MeMPNs were measured in serial blood samples over a 2-year period. The average TGNs (avTGNs) and MeMPNs (avMeMPNs) concentrations for each patient were used for analysis. Therapeutic response was defined as the ability to maintain remission, defined as a normal serum alanine aminotransferase (ALT) level (ALT <33 IU/mL). Patients who maintained remission (n = 53), compared to those who did not (n = 17), tended to be on lower doses of AZA (1.7 versus 2.0 mg/kg/day; P = 0.08), but had significantly higher concentrations of avTGN (237 versus 177 pmol/8 × 10(8) RBCs; P = 0.025). There was no difference in MeMPN concentrations or TPMT activities between the two groups. There was a negative correlation between ALT and avTGN (r(s) = -0.32; P = 0.007). An avTGN concentration of >220 pmol/8 × 10(8) RBCs best predicted remission, with an odds ratio of 7.7 (P = 0.003). There was no association between TGN, MeMPN, or TPMT activity and the development of leucopenia. Two patients developed AZA-induced cholestasis and the avMeMPN concentration was higher in those patients, compared to those who did not (14,277 versus 1,416 pmol/8 × 10(8) RBCs). CONCLUSION: TGN concentrations of >220 pmol/8 × 10(8) RBCs are associated with remission. TGN measurement may help identify inadequate immunosupression. AZA-induced cholestasis was associated with increased MeMPN concentrations.

Long-term outcomes of patients with autoimmune hepatitis managed at a nontransplant center.

BACKGROUND & AIMS: The long-term outcomes of patients treated for autoimmune hepatitis (AIH) are considered to be good. However, follow-up data beyond 10 years are limited and confined to tertiary referral centers. We assessed long-term outcomes and determinants of outcome in patients with AIH from a nontransplant center. METHODS: We studied 245 patients (204 women; median age, 56 years; range, 2.5-87 years) with AIH (167 definite by International AIH Group criteria) managed at a single nontransplant center from 1971 to 2007. RESULTS: 229 patients (93%) achieved normal serum levels of alanine aminotransferase within 12 months after treatment. After a median follow-up period of 9.4 years (range, 0.01-36 years), 11 patients received liver transplants (2 subsequently died). Seventy other patients died (30 from liver disease), 15 were censored (moved away, defaulted, or developed primary biliary cirrhosis), and 149 were still being followed up on December 31, 2007. Survival rates from all-cause death or transplantation were 82%±3% and 48%±5% after 10 and 20 years, respectively, and from liver-related death or transplantation were 91%±2% and 70%±5%, respectively. The standardized mortality ratio was 1.63 for all-cause death (95% confidence interval [CI], 1.25-2.02), 1.86 also considering liver transplant as "death" (95% CI, 1.49-2.26), and 0.91 for non-liver-related death (95% CI, 0.62-1.19). By Cox regression analysis, liver decompensation, cirrhosis at any time, failure to normalize levels of alanine aminotransferase within 12 months, and >4 relapses per decade were significantly associated with liver-related death or transplant. CONCLUSIONS: Despite a good initial response to immunosuppression, long-term mortality of patients with AIH is greater than that of the general population.

Severity of alcohol dependence in decompensated alcoholic liver disease: comparison with heavy drinkers without liver disease and relationship to family drinking history.

AIM: The aim of this study was to compare alcohol dependence severity in patients with severe alcoholic liver disease (ALD) with that in heavy drinkers without liver disease. METHODS: Short alcohol dependence data and lifetime alcohol questionnaires applied to unselected heavy alcohol drinkers (>60 units/week (M) or 40 units/week (F) for >5 years) with either (a) decompensated ALD (patients n = 136) or (b) no evidence of serious liver disease by clinical, biochemical and ultrasound evaluation ('controls' n = 148). RESULTS: The SADD alcohol dependence severity score (range 0-42) in patients with ALD was >28 (severe dependence) in 36 cases (26%); slightly higher than that in heavy-drinking controls taken as a whole; similar to that in controls who were seeking healthcare but higher than that in controls who were not; and lower than that in controls who attended specialist alcohol services. In ALD patients and controls, the SADD score was higher in those with three or more heavy-drinking first-degree relatives than in those with none. In multiple regression analysis, the SADD score showed independent associations with young age, clinically manifest alcohol dependence, seeking healthcare and the presence of multiple heavy drinking relatives, but not with ALD. CONCLUSIONS: Alcohol dependence severity in patients with ALD varies and tends to be lower than that in heavy drinkers seeking treatment at alcohol treatment centres but is not as low as implied in some previous studies. Alcohol dependence severity is associated with young age and family drinking history but is not specifically associated with the development of liver disease.

Spectrum of liver histology in presumed decompensated alcoholic liver disease.

BACKGROUND: In presumed decompensated alcoholic liver disease (ALD; liver decompensation, heavy alcohol intake, and negative results of noninvasive screening for other causes), liver biopsy is often performed to assess severity of liver injury and to rule out other liver diseases. AIM: The aim of the study is to describe the spectrum of liver histology in such patients. METHODS: We reviewed all patients with presumed decompensated ALD seen between 1998 and 2004, in whom liver tissue was available for histology (N = 110). RESULTS: A total of 104 of the 110 patients had at least one of the histological features suggestive of ALD: fat, Mallory's hyalin, neutrophilic infiltrate, and hepatocyte ballooning. These features were more prevalent in tissue obtained within a month after presentation with decompensation than in that obtained before decompensation or more than 1 month after. These features were also associated with more severe liver dysfunction. Histology revealed a major additional diagnosis (Budd-Chiari syndrome) in only one case. In 41 patients biopsied within a month of first presentation with decompensation, Child score and Maddrey discriminant function (DF), but none of the histological features, were predictive of survival by Cox multivariate analysis. Of the 26 of these 41 patients with a Maddrey DF >32, 22 (85%) had alcoholic hepatitis. CONCLUSIONS: In patients with presumed decompensated ALD, other liver diseases are uncommon. Routine liver biopsy is of limited added value but biopsy should be considered in those in whom the noninvasive workup, or failure to recover despite abstinence, raises the possibility of other liver diseases.

Effectiveness of an upper-gastrointestinal haemorrhage unit: a prospective analysis of 900 consecutive cases using the Rockall score as a method of risk standardisation.

OBJECTIVES: To assess the effectiveness of a centralised upper-gastrointestinal haemorrhage (UGIH) unit. METHODS: The UK Audit of acute UGIH resulted in the formulation of a simple numerical scoring system. The Rockall score categorises patients by risk factors for death and allows case-mix comparisons. A total of 900 consecutive patients admitted to a UGIH unit between October 1995 and July 1998 were analysed prospectively. Patients were given an initial Rockall score and, if endoscopy was performed, a complete score. This method of risk stratification allowed the proportion of deaths (in our study) to be compared with the National Audit using risk standardised mortality ratios. RESULTS: The distribution of both initial and final Rockall scores was significantly higher in our study than in the National Audit. A total of 73 (8.1%) patients died, compared with the National Audit mortality of 14%. Risk-standardised mortality ratios using both initial and complete Rockall scores were significantly lower in our study when compared with those in the National Audit. CONCLUSION: A specialised UGIH unit is associated with a lower proportion of deaths from UGIH, despite comprising a greater number of high-risk patients than the National Audit. This lower mortality therefore cannot be attributed to a more favourable case mix and demonstrates that further improvements in mortality for UGIH can be made.