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.