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NAFLD is becoming much more common, and will soon be the major underlying aetiology for liver transplantation. This article discusses the evidence that NAFLD is a multisystem disease and outlines the factors that determine interindividual variation in the development and progression of NAFLD. NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease). Key Points NAFLD is a spectrum of progressive liver disease that includes steatosis, NASH, fibrosis, cirrhosis and hepatocellular carcinoma NAFLD is a common and underdiagnosed condition that is strongly associated with features of the metabolic syndrome, particularly abdominal obesity and type 2 diabetes mellitus NAFLD, and especially NASH, are associated with an increased risk of morbidity and mortality related to the liver and cardiovascular system NAFLD is also associated with an increased risk of developing type 2 diabetes mellitus Considerable interindividual variation exists in the severity of NAFLD and the risk of morbidity and mortality that might be influenced by a combination of genetic and environmental factors

ObjectiveLiver 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 peroxisome proliferator-activated receptor gamma (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.DesignPatients 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 alcoholic liver disease (ALD) were also subjected to plasma DNA and LCM pyrosequencing.Results26 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.ConclusionsDifferential 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 non-invasively stratify liver fibrosis severity in patients with NAFLD. Plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease.

In this randomized trial in patients hospitalized with alcoholic hepatitis, pentoxifylline did not improve survival. The 28-day survival advantage in patients treated with prednisolone did not reach significance and was not sustained at 90 days or 1 year. Alcoholic hepatitis is a distinct manifestation of alcoholic liver disease that is characterized by jaundice and liver failure. This condition develops in persons with a history of prolonged and heavy alcohol use. 1 The severity of alcoholic hepatitis is conventionally defined by Maddrey’s discriminant function, which is calculated as 4.6×(patient’s prothrombin time in seconds−control’s prothrombin time in seconds)+patient’s serum bilirubin level in milligrams per deciliter; a value of 32 or higher indicates severe alcoholic hepatitis that carries an adverse prognosis, with mortality of 20 to 30% within 1 month after presentation and 30 to 40% within 6 months after presentation. 2 A . . .

Nonalcoholic fatty liver disease (NAFLD) encompasses a range of manifestations, including steatosis and cirrhosis. Progressive disease is characterized by hepatic leukocyte accumulation in the form of steatohepatitis. The adhesion molecule vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase that promotes leukocyte recruitment to the liver, and the soluble form (sVAP-1) accounts for most circulating monoamine oxidase activity, has insulin-like effects, and can initiate oxidative stress. Here, we determined that hepatic VAP-1 expression is increased in patients with chronic liver disease and that serum sVAP-1 levels are elevated in patients with NAFLD compared with those in control individuals. In 4 murine hepatic injury models, an absence or blockade of functional VAP-1 reduced inflammatory cell recruitment to the liver and attenuated fibrosis. Moreover, disease was reduced in animals expressing a catalytically inactive form of VAP-1, implicating enzyme activity in the disease pathogenesis. Within the liver, hepatic stromal cells expressed functional VAP-1, and evaluation of cultured cells revealed that sVAP-1 promotes leukocyte migration through catalytic generation of ROS, which depended on VAP-1 enzyme activity. VAP-1 enhanced stromal cell spreading and wound closure and modulated expression of profibrotic genes. Together, these results link the amine oxidase activity of VAP-1 with hepatic inflammation and fibrosis and suggest that targeting VAP-1 has therapeutic potential for NAFLD and other chronic fibrotic liver diseases.

Growing evidence suggests that nonalcoholic fatty liver disease is associated with an increased risk of cardiovascular disease beyond that conferred by established risk factors. Nonalcoholic fatty liver disease encompasses a spectrum of pathologic conditions, ranging from simple steatosis to nonalcoholic steatohepatitis and cirrhosis. The disease has reached epidemic proportions and is the most common cause of chronic liver disease in Western countries. 1 – 4 Approximately 20 to 30% of adults in the general population in Western countries have nonalcoholic fatty liver disease, and its prevalence increases to 70 to 90% among persons who are obese or have diabetes; such patients are also at increased risk for the development of advanced fibrosis and cirrhosis. 1 – 4 Recognition of the importance of nonalcoholic fatty liver disease and its . . .

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide. Experimental and small clinical trials have demonstrated that angiotensin II blockers (ARB) may be anti-fibrotic in the liver. The aim of this randomised controlled trial was to assess whether treatment with Losartan for 96 weeks slowed, halted or reversed the progression of fibrosis in patients with non-alcoholic steatohepatitis (NASH). Double-blind randomised-controlled trial of Losartan 50 mg once a day versus placebo for 96 weeks in patients with histological evidence of NASH. The primary outcome for the study was change in histological fibrosis stage from pre-treatment to end-of-treatment. The study planned to recruit 214 patients. However, recruitment was slower than expected, and after 45 patients were randomised (median age 55; 56% male; 60% diabetic; median fibrosis stage 2), enrolment was suspended. Thirty-two patients (15 losartan and 17 placebo) completed follow up period: one patient (6.7%) treated with losartan and 4 patients (23.5%) in the placebo group were \"responders\" (lower fibrosis stage at follow up compared with baseline). The major reason for slow recruitment was that 39% of potentially eligible patients were already taking an ARB or angiotensin converting enzyme inhibitor (ACEI), and 15% were taking other prohibited medications. Due to the widespread use of ACEI and ARB in patients with NASH this trial failed to recruit sufficient patients to determine whether losartan has anti-fibrotic effects in the liver. ISRCTN 57849521.

Background: Non-alcoholic fatty liver disease (NAFLD) is principally a disease of middle and old age. Previous studies reported it to be benign in old age, however more recent studies suggest an increased mortality in the >60-year-olds. Objectives: To define the prevalence of risk factors and the laboratory and histological differences between different age groups with NAFLD, in order to confirm/refute findings in previous smaller studies. Methods: Retrospective, cohort study set in a tertiary liver clinic in the UK. 351 consecutive patients with biopsy-proven NAFLD were divided into an older (≥60), a middle-aged (≥50 to <60) and a younger (<50) group. Blood pressure, body mass index, serum lipids, glucose, HbA1C, albumin, liver enzymes, bilirubin, mean cell volume (MCV), platelets, and insulin resistance were recorded. In addition, liver biopsy was analyzed for steatosis, inflammation and fibrosis. Results: Older patients had significantly more risk factors (hypertension, obesity, diabetes, hyperlipidaemia). Albumin, alanine aminotransferase (ALT), ALT/aspartate aminotransferase ratio and platelets significantly reduced with advancing age. MCV and alkaline phosphatase significantly increased with increasing age. Older patients had significantly greater fibrosis on biopsy with less percentage fat, with the cirrhotic patients being significantly older than non-cirrhotics. Insulin resistance was similar in younger and older groups. Conclusion: NAFLD affects mainly the middle-aged and the elderly. With advancing age come more risk factors for its development. Older patients show more severe biochemical, haematological and histological changes, with cirrhotics having a significantly greater age than those with milder disease.

NAFLD is a complex disease. Considerable variability exists in the severity and risk of morbidity and mortality among individuals with NAFLD, which could be influenced by genetic and environmental factors. Here, the authors discuss the latest knowledge on the genetics of NAFLD and how this genetic variation might determine disease phenotype and progression. NAFLD is a disease spectrum ranging from simple steatosis, through steatohepatitis to fibrosis and, ultimately, cirrhosis. This condition is characterized by considerable interpatient variability in terms of severity and rate of progression: although a substantial proportion of the population is at risk of progressive disease, only a minority experience associated morbidity. As such, NAFLD is best considered a complex disease trait resulting from environmental exposures acting on a susceptible polygenic background and comprising multiple independent modifiers. Much ongoing research is focused on identifying the genetic factors that contribute to NAFLD pathogenesis. This Review describes the current status of the field, discussing specific genetic and epigenetic modifiers, including the mechanisms through which genes identified by genome-wide association studies, including PNPLA3 , influence disease progression. Key Points NAFLD is a spectrum of progressive liver disease encompassing steatosis, NASH, fibrosis and cirrhosis NAFLD is a common and underdiagnosed condition that is strongly associated with features of the metabolic syndrome, particularly abdominal obesity and type 2 diabetes mellitus Considerable interindividual variation exists in terms of NAFLD severity and risk of morbidity and mortality that might be influenced by a combination of genetic and environmental factors Candidate-gene studies and hypothesis-generating genome-wide association studies have provided key insights into the pathogenesis of NAFLD, with multiple genetic modifiers being described PNPLA3 remains the most well-validated gene associated with all aspects of the NAFLD spectrum Although considerable progress has been made in elucidating how the PNPLA3 rs738409 (encoding Ile148Met) variant promotes NAFLD, it remains unclear why this gene also associates so strongly with inflammatory and fibrosis

Background Emerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. This study aimed to examine the importance of serum endotoxin and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) patients, with and without type 2 diabetes mellitus (T2DM), and to explore the effect of treatment with a lipase inhibitor, Orlistat, on their inflammatory status. Methods Fasted serum from 155 patients with biopsy proven NAFLD and 23 control subjects were analysed for endotoxin, soluble CD14 (sCD14), soluble tumour necrosis factor receptor II (sTNFRII) and various metabolic parameters. A subgroup of NAFLD patients were re-assessed 6 and 12 months after treatment with diet alone (n = 6) or diet plus Orlistat (n = 8). Results Endotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008). Both sCD14 (p < 0.01) and sTNFRII (p < 0.001) increased with severity of fibrosis. A positive correlation was also noted between sTNFRII and sCD14 in the NAFLD subjects (r = 0.29, p = 0.004). Sub-cohort treatment with Orlistat in patients with NAFLD showed significant decreases in ALT (p = 0.006), weight (p = 0.005) and endotoxin (p = 0.004) compared with the NAFLD, non-Orlistat treated control cohort at 6 and 12 months post therapy, respectively. Conclusions Endotoxin levels were considerably increased in NAFLD patients, with marked increases noted in early stage fibrosis compared with controls. These results suggest elevated endotoxin may serve as an early indicator of potential liver damage, perhaps negating the need for invasive liver biopsy. As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden.