Hyaluronic acid and endothelial damage due to paracetamol-induced hepatotoxicity.

BACKGROUND: Damage to endothelial cells may be an important factor in the complications of acute liver failure, resulting in multi-organ failure. The aim of this study was to assess endothelial cell function in patients with severe hepatotoxicity due to paracetamol ingestion. PATIENTS AND METHODS: Fifty-eight patients with paracetamol-induced hepatotoxicity were studied for up to 7 days. Serum hyaluronic acid (HA), as a marker of hepatic sinusoidal endothelial cell function, was determined using an enzyme-linked binding assay. Plasma von Willebrand Factor, thrombomodulin and interleukin-8 were also determined using ELISA. RESULTS: Serum HA on admission was significantly increased (median 6777 ng/ml, range 24-50 967 ng/ml) as compared to normal controls (n = 10, median 21 ng/ml, range 0-50 ng/ml; P < 0.001). In non-survivors (n = 21) HA levels peaked on day 2 after admission (P = 0.044), and then decreased. In the survivors (n = 37) the levels of HA did not increase further. Plasma von Willebrand Factor, plasma thrombomodulin and serum interleukin-8 were significantly increased in the patients as compared to the normal controls (P < 0.001). Serum interleukin-8 was significantly higher in non-survivors in the first 2 days. CONCLUSIONS: Endothelial function is abnormal in paracetamol-induced hepatotoxicity. Damage to hepatic sinusoidal endothelial cells assessed by serum HA was greater in non-survivors than survivors.

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.