Objective Liver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of PPARγ gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD. Design Patients with biopsy- proven NAFLD, and age-matched controls were recruited from the Liver and Gastroenterology Clinics at the Newcastle upon Tyne Hospitals NHS Foundation Trust. Plasma cell free circulating DNA methylation of PPARγ was quantitatively assessed by pyrosequencing. Liver DNA methylation was quantitatively assessed by pyrosequencing NAFLD explant tissue, subjected to laser capture microdissection (LCM). Patients with ALD were also subjected to plasma DNA and LCM pyrosequencing. Results 26 patients with biopsy-proven NAFLD were included. Quantitative Plasma DNA methylation of PPARγ stratified patients into mild (Kleiner 1-2) and severe (Kleiner 3-4) fibrosis (CpG1: 63% vs 86%, p<0.05; CpG2: 51% vs 65% p>0.05). Hypermethylation at the PPARγ promoter of plasma DNA correlated with changes in hepatocellular rather than myofibroblast DNA methylation. Similar results were demonstrated in patients with ALD cirrhosis. Conclusions Differential DNA methylation at the PPARγ promoter can be detected within the pool of cell-free DNA of human plasma. With further validation, plasma DNA methylation of PPARγ could potentially be used to noninvasively stratify liver fibrosis severity in patients with NAFLD. Plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease.

SummaryBackgroundSince 1970, there has been a 400% increase in liver‐related deaths due to the increasing prevalence of chronic liver disease in the United Kingdom (UK). The 2013 UK National Confidential Enquiry into Patient Outcome and Death report found that only 47% of patients who died from alcohol‐related liver disease received ‘good care’ during their hospital stay.AimTo develop a ‘care bundle’ for patients with decompensated cirrhosis, aiming to ensure that evidence‐based treatments are delivered within the first 24 h of hospital admission.MethodsThis work gives practical advice about how to implement the bundle and examines its effects on patient care at three National Health Service Hospital Trusts in the UK by collecting data on patient care before and after introduction of the bundle.ResultsData were collected on 228 patients across three centres (59% male, median age 53 years). Alcohol‐related liver disease was the aetiology of chronic liver disease in 85% of patients. The overall mortality rate during hospital admission was 15%. The audits demonstrated improvements in patient care for patients with a completed care bundle who were significantly more likely to have a diagnostic ascitic performed within the first 24 h (P = 0.020), have an accurate alcohol history documented (P < 0.0001) and be given antibiotics as prophylaxis against infection following a variceal haemorrhage (P = 0.0096). In Newcastle, the bundle completion rate increased from 25% to 90% during the review periods.ConclusionsThe introduction of a care bundle was associated with increased rates of diagnostic paracentesis and antibiotic prophylaxis with variceal haemorrhage in patients with decompensated cirrhosis.

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