https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.20973

Nonalcoholic fatty liver disease: From steatosis to cirrhosis

Importance Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30% and 5%, respectively, of the US population. In patients with nonalcoholic steatohepatitis, half of deaths are due to cardiovascular disease and malignancy, yet awareness of this remains low. Cirrhosis, the third leading cause of death in patients with nonalcoholic fatty liver disease, is predicted to become the most common indication for liver transplantation. Objectives To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease. Evidence Review PubMed was queried for published articles through February 28, 2015, using the search termsNAFLD and cirrhosis, mortality, biomarkers,andtreatment. A total of 88 references were selected, including 14 randomized clinical trials, 19 cohort or case-control studies, 1 population-based study, 2 practice guidelines, 7 meta-analyses, 43 classified as other, and 2 webpages. Findings Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis. Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest ( Conclusions and Relevance Between 75 million and 100 million individuals in the United States are estimated to have nonalcoholic fatty liver disease and its potential morbidity extends beyond the liver. It is important that primary care physicians, endocrinologists, and other specialists be aware of the scope and long-term effects of the disease. Early identification of patients with nonalcoholic steatohepatitis may help improve patient outcomes through treatment intervention, including transplantation for those with decompensated cirrhosis.

https://jamanetwork.com/journals/JAMA/articlepdf/2319168/jrv150008.pdf

Nonalcoholic Fatty Liver Disease: A Systematic Review

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.27368

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.

BACKGROUND No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus. METHODS We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy–confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([ 14 C]glucose given with the oral glucose load and [ 3 H]glucose given by intravenous infusion). RESULTS Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P = 0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P = 0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (P = 0.003), ballooning necrosis (P = 0.02), and inflammation (P = 0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P = 0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group (P = 0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed. CONCLUSIONS In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110.)

/pdf/a-placebo-controlled-trial-of-pioglitazone-in-subjects-with-1xq8whw720.pdf

A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis

NONALCOHOLIC FATTY LIVER DISEASE is emerging as the most common chronic liver condition in the Western world. It is associated with insulin resistance and frequently occurs with features of the metabolic syndrome. Disease presentation ranges from asymptomatic elevated liver enzyme levels to cirrhosis with complications of liver failure and hepatocellular carcinoma. Current treatment recommendations are limited to weight loss and exercise, although several promising medications are on the horizon. In this article we discuss the etiology, pathogenesis and diagnosis of nonalcoholic fatty liver disease as well as approaches to its management.

/pdf/nonalcoholic-fatty-liver-disease-2fji4cqr7g.pdf

Nonalcoholic fatty liver disease

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1053/jhep.2003.50229

Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values

Non-alcoholic fatty liver disease (NAFLD) is a common disorder in the Western hemisphere. It encompasses two histological lesions: fatty liver and steatohepatitis. A large body of literature indicates that insulin resistance is a key pathophysiological abnormality in patients with NAFLD. Insulin resistance results from a complex interplay between the major targets of insulin action, i.e. muscle, adipose tissue and liver, versus the ability of the pancreatic islet beta cells to compensate for insulin resistance by increasing insulin production. The metabolic and clinical profile associated with insulin resistance is thus defined by the factors that produce and maintain insulin resistance and the effects of decreased insulin sensitivity on various insulin-dependent pathways. The major metabolic defects associated with insulin resistance are increased peripheral lipolysis, increased hepatic glucose output due to increased gluconeogenesis and increased lipid oxidation. This is associated with an oxidative stress in the liver that may be compounded by additional pathophysiological abnormalities. While much work remains to be done, the current understanding of the pathogenesis of NAFLD provides direction for both future investigation and development of therapeutic trials.

Mahmadul Haque

Papers

Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values

The metabolic abnormalities associated with non-alcoholic fatty liver disease.