Valério Lucidi

BACKGROUND: A 6-month abstinence from alcohol is usually required before patients with severe alcoholic hepatitis are considered for liver transplantation. Patients whose hepatitis is not responding to medical therapy have a 6-month survival rate of approximately 30%. Since most alcoholic hepatitis deaths occur within 2 months, early liver transplantation is attractive but controversial. METHODS: We selected patients from seven centers for early liver transplantation. The patients had no prior episodes of alcoholic hepatitis and had scores of 0.45 or higher according to the Lille model (which calculates scores ranging from 0 to 1, with a score ≥ 0.45 indicating nonresponse to medical therapy and an increased risk of death in the absence of transplantation) or rapid worsening of liver function despite medical therapy. Selected patients also had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence. Survival was compared between patients who underwent early liver transplantation and matched patients who did not. RESULTS: In all, 26 patients with severe alcoholic hepatitis at high risk of death (median Lille score, 0.88) were selected and placed on the list for a liver transplant within a median of 13 days after nonresponse to medical therapy. Fewer than 2% of patients admitted for an episode of severe alcoholic hepatitis were selected. The centers used 2.9% of available grafts for this indication. The cumulative 6-month survival rate (±SE) was higher among patients who received early transplantation than among those who did not (77 ± 8% vs. 23 ± 8%, P<0.001). This benefit of early transplantation was maintained through 2 years of follow-up (hazard ratio, 6.08; P = 0.004). Three patients resumed drinking alcohol: one at 720 days, one at 740 days, and one at 1140 days after transplantation. CONCLUSIONS: Early liver transplantation can improve survival in patients with a first episode of severe alcoholic hepatitis not responding to medical therapy. (Funded by Société Nationale Française de Gastroentérologie.).

Background Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters.MethodsWe did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples.Findings2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p&lt;0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p&lt;0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p&lt;0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p&lt;0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).InterpretationWe have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis.