Nonalcoholic Steatohepatitis and Endpoints in Clinical Trials.

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of liver disease in developed countries, and the rates of NAFLD continue to rise in conjunction with the obesity pandemic. While the majority of patients with isolated steatosis generally have a benign course, a diagnosis of nonalcoholic steatohepatitis (NASH) carries a significantly higher risk for progression of disease, cirrhosis, and death. Pharmacologic therapeutic interventions in NASH have largely proven to be ineffective or unappealing due to long-term side-effect profiles, and the majority of patients cannot achieve or sustain targeted weight loss goals, necessitating an urgent need for therapeutic trials and drug development. The complex molecular mechanisms leading to NASH and the long duration of time to develop complications of disease are challenges to developing meaningful clinical endpoints. Because of these challenges, surrogate endpoints that are linked to all-cause mortality, liver-related death, and complications of cirrhosis are much more likely to be beneficial in the majority of patients.

Review of treatment options for nonalcoholic fatty liver disease.

Although the future of NAFLD and NASH treatment has many promising agents, clinicians are currently faced with limited options with an emphasis on lifestyle modification. Figs. 1 and 2 summarize current practices for the diagnosis and treatment of NAFLD with the understanding that each patient's treatment must be customized to their comorbidities, exercise tolerance, and willingness to comply with therapy.

Nutrition in cirrhosis and chronic liver disease.

Nutrition has not been a primary focus of many medical conditions despite its importance in the development and the severity of these diseases. This is certainly the case with nutrition and end-stage liver disease despite the well-established association of nutritional deficiencies and increased rates of complications and mortality in cirrhosis. This review provides an overview of nutrition in chronic liver disease with an emphasis on its pathogenesis as well as ways to assess nutritional status and intervene in an effort to improve nutrition.

Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is now recognized as part of the metabolic syndrome, and is specifically related to obesity and insulin resistance. Lifestyle modification is advocated for the treatment of NAFLD, but few studies have evaluated its impact on liver histology. The purpose of this study was to investigate which, if any, specific diet and exercise recommendations are associated with histopathologic changes. METHODS: A total of 56 participants were randomly assigned to 1 of 4 lifestyle modification subgroups for 6 months: standard care, low-fat diet and moderate exercise, moderate-fat/low-processed-carbohydrate diet and moderate exercise, or moderate exercise only. All subjects had biopsy-proven NAFLD, to include nonalcoholic steatohepatitis (NASH), and received a repeat 6-month biopsy to detect histopathologic changes. Other measures included blood assay of liver enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase), fasting glucose, serum insulin, lipid panel, body weight, dietary intake, fat mass, and fitness level. RESULTS: Among the 41 participants who completed the study (88% with NASH), a significant change was found in pre- to post-NAFLD activity score in the group as a whole (p < 0.001) with no difference detected between subgroups (p = 0.31). Our results confirm that lifestyle modification is effective in improving NAFLD and NASH. CONCLUSIONS: Regardless of intervention group, lifestyle modification improved liver histology, as verified by repeat biopsy, after a 6-month intervention. This study reinforces the importance of lifestyle modification as the primary treatment strategy for patients with NAFLD.

NAFLD: Predictive value of ALT levels for NASH and advanced fibrosis.

With expanding waistlines, the prevalence of NAFLD has burgeoned to become the leading cause of chronic liver disease in the USA. A subset of patients with NAFLD meet criteria for NASH with its inherent risk of progression to cirrhosis. Verma et al. addressed the utility of alanine aminotransferase levels for predicting NASH or advanced fibrosis to decide who would benefit from the definitive test of liver biopsy.

Killing two birds with one stone: screening for chronic hepatitis C at the time of colonoscopy in the baby boomer cohort.

Colonoscopy is a well-accepted colon cancer screening modality that is recommended by the United States Multi-Society Task Force on all individuals greater than 50 years of age. Chronic hepatitis C (CHC) is a common cause of chronic liver disease with notably increased rates of infection in individuals born between 1945 and 1965. The Centers for Disease Control recently recommended all individuals of this "Baby Boomer" cohort undergo one time screening for CHC. As gastroenterologists interface with these patients for screening colonoscopy, this represents a unique opportunity to complete this screening and identify CHC patients at risk for advanced liver disease.

Vitamin D and nonalcoholic fatty liver disease (NAFLD): is it more than just an association?

Vitamin D is a secosteroid with known effects on calcium homeostasis that has recently been shown to have other significant functions regarding immune modulation, cell differentiation and proliferation, and the inflammatory response. As our understanding of the many functions of vitamin D has grown, the presence of vitamin D deficiency (VDD) has become more evident in Western populations. Concomitantly, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease. NAFLD and VDD are often found together, and while this is not unexpected, given their similar associations with obesity and sedentary lifestyle, a growing body of evidence points to a closely linked and potentially causative relationship between VDD and NAFLD. The epidemiologic association between VDD and NAFLD as well as the role of VDD in the pathogenesis of NAFLD and the available evidence on the clinical utility of vitamin D replacement in NAFLD populations are discussed.

Physical activity: an essential component of lifestyle modification in NAFLD.

NAFLD encompasses a spectrum of liver diseases pertaining to fat accumulation in the liver in the absence of significant alcohol consumption. NASH is the most clinically relevant subset of NAFLD, and patients with NASH have an increased risk of progression to cirrhosis or developing liver cancer. No pharmacotherapy is currently approved for NAFLD, and lifestyle modification via diet and exercise is most commonly recommended. The optimal physical activity regimen in terms of both effectiveness and compliance remains to be determined and is the focus of this Review.

Nonalcoholic fatty liver disease.

As the hepatic manifestation of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of asymptomatic liver enzyme elevations in Western nations. Although it is easy to diagnose NAFLD, a liver biopsy is currently required to diagnose nonalcoholic steatohepatitis (NASH). Patients with NASH are those at greatest risk of progression to cirrhosis and, thus, treatment efforts are targeted to these individuals. Although currently there are no FDA-approved treatments for NASH, a multidisciplinary approach that addresses comorbid conditions and promotes modest weight loss comprises the backbone of therapy.

Features, diagnosis, and treatment of nonalcoholic fatty liver disease.

As the global incidence of obesity has increased, nonalcoholic fatty liver disease (NAFLD) has become a worldwide health concern. NAFLD occurs in children and adults of all ethnicities and includes isolated fatty liver and nonalcoholic steatohepatitis (NASH). Patients with NASH are at risk for developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma and have increased all-cause mortality. NAFLD is associated with a variety of clinical conditions and is an independent risk factor for hepatocellular carcinoma. The pathogenesis of NAFLD and the specific steps that lead to NASH and advanced fibrosis are not fully understood, although researchers have found that a combination of environmental, genetic, and metabolic factors lead to advanced disease. There have been improvements in noninvasive radiographic methods to diagnose NAFLD, especially for advanced disease. However, liver biopsy is still the standard method of diagnosis for NASH. There are many challenges to treating patients with NASH, and no therapies have been approved by the U.S. Food and Drug Administration; multimodal approaches are being developed and becoming the standard of care. We review pathogenesis and treatment approaches for the West's largest liver-related public health concern.

Nonalcoholic steatohepatitis and noncirrhotic hepatocellular carcinoma: fertile soil.

Nonalcoholic fatty liver disease (NAFLD) is easily the most common cause of chronic liver disease in the United States (U.S.) as the hepatic manifestation of the metabolic syndrome. Although only 5 to 20% of patients with NAFLD are generally considered to meet criteria for nonalcoholic steatohepatitis (NASH), with its inherent risk for progression to cirrhosis, this still represents an alarmingly large number of individuals. The exponentially growing rates of hepatocellular carcinoma (HCC) in the U.S. may be partially attributable to increased numbers of NASH cirrhotics, although recent evidence has suggested that NAFLD may directly promote hepatic carcinogenesis independent of cirrhosis. This review focuses on HCC in noncirrhotic NASH with an emphasis on clinical presentation, pathogenesis, and implications for screening.

Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis.

UNLABELLED: Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not-NASH to those with NASH stage 0-1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0-1 to those with NASH stage 2-4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = -0.215; P = 0.035). CONCLUSION: Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients.

Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial.

UNLABELLED: Medication combinations that improve the efficacy of thiazolidinediones or ameliorate weight-gain side effects of therapy represent an attractive potential treatment for (NASH). The aim of this randomized, open-label trial was to assess the efficacy of rosiglitazone and metformin in combination versus rosiglitazone and losartan, compared to rosiglitazone alone, after 48 weeks of therapy. A total of 137 subjects with biopsy-proven NASH were enrolled and randomly assigned to receive either 4 mg twice-daily of rosiglitazone, 4 mg of rosiglitazone and 500 mg of metformin twice-daily, or 4 mg of rosiglitazone twice-daily and 50 mg of losartan once-daily for 48 weeks. Patients were screened for other etiologies of chronic liver disease, including daily alcohol intake in excess of 20 g. Repeat liver biopsy was performed after 48 weeks of therapy and reviewed in a blinded fashion by a single expert hepatopathologist. The primary aim of the study was to assess for differences between treatment groups in the improvement of steatosis, hepatocellular inflammation, and fibrosis. In total, 108 subjects completed the trial. Primary outcome revealed no significant difference between treatment groups in all histologic parameters (steatosis, P = 0.137; hepatocellular inflammation, P = 0.320; fibrosis, P = 0.229). Overall improvement in steatosis, hepatocellular inflammation, ballooning degeneration, and fibrosis was observed (P ≤ 0.001). Serum aminotransferases were reduced in all three groups (P < 0.001 within treatment, P > 0.05 between groups). Metformin did not significantly mitigate weight gain (P = 0.051). CONCLUSIONS: Forty-eight weeks of combination therapy with rosiglitazone and metformin or rosiglitazone and losartan confers no greater benefit than rosiglitazone alone with respect to histopathology.