International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Sulphur amino acid metabolism, oxidative stress and pancreatitis

The observation that mice fed a diet that blocks the recycling and metabolism of methionine develop fulminant pancreatitis, attests to the dependence of the pancreatic acinar cell on methionine transsulphuration. S-adenosylmethionine (SAMe), the first intermediate of transsulphuration, is the principle metabolic methyl group donor.  Glutathione (GSH) a final product of transsulphuration is a vital intracellular antioxidant.  N-acetylcysteine (NAC), an antioxidant in its own right potentially bolsters GSH levels.  Thus, the combination of SAMe and NAC could be expected to ameliorate and/or accelerate recovery from acute pancreatitis.  However, intravenous SAMe and NAC for the first 24 hours of acute pancreatitis, proved to be of no advantage over optimal conventional care in a randomised trial.  Low blood folate levels were identified as a potential for treatment failure, as also was vitamin C. Plasma methionine concentration was similar in healthy controls and patients with quiescent recurrent acute (RAP) or chronic (CP) pancreatitis.  Oral loading and methionine or NAC exposed no differences between these groups in methionine pharmacokinetics, or the concentration of (i) amino acids whose metabolism is linked with methionine or (ii) transsulphuration intermediates, except for plasma GSH, which is low in pancreatitis.  Serum selenium and vitamin C were low in patients with pancreatitis, as was urinary inorganic sulphate excretion in CP.  These vitamin deficiencies are corrected within 10 weeks by oral antioxidant supplementation therapy [Bioantox i.q.i.d. PharmaNord] (AOT).  AOT did not alter blood levels or pharmacokinetic characteristics of methionine, GSH or other amino acids measured. Irrefutable evidence implicates oxidative stress and/or a disruption of methionine metabolism in the genesis of pancreatitis.  Further studies to elucidate the mechanisms that initiate and prevent/reverse these metabolic perturbations should facilitate the development of an antioxidant cocktail with prophylactic and therapeutic activity against this condition.</p

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

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. METHODS We 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. FINDINGS 2703 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<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<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). INTERPRETATION We 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. FUNDING UK Medical Research Council and University of Milan-Bicocca