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.

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.

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.

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.

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.

Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.

BACKGROUND & AIMS: Prevalence of nonalcoholic fatty liver disease (NAFLD) has not been well established. The purpose of this study was to prospectively define the prevalence of both NAFLD and nonalcoholic steatohepatitis (NASH). METHODS: Outpatients 18 to 70 years old were recruited from Brooke Army Medical Center. All patients completed a baseline questionnaire and ultrasound. If fatty liver was identified, then laboratory data and a liver biopsy were obtained. RESULTS: Four hundred patients were enrolled. Three hundred and twenty-eight patients completed the questionnaire and ultrasound. Mean age (range, 28-70 years) was 54.6 years (7.35); 62.5% Caucasian, 22% Hispanic, and 11.3% African American; 50.9% female; mean body mass index (BMI) (calculated as kg/m(2)) was 29.8 (5.64); and diabetes and hypertension prevalence 16.5% and 49.7%, respectively. Prevalence of NAFLD was 46%. NASH was confirmed in 40 patients (12.2% of total cohort, 29.9% of ultrasound positive patients). Hispanics had the highest prevalence of NAFLD (58.3%), then Caucasians (44.4%) and African Americans (35.1%). NAFLD patients were more likely to be male (58.9%), older (P = .004), hypertensive (P < .00005), and diabetic (P < .00005). They had a higher BMI (P < .0005), ate fast food more often (P = .049), and exercised less (P = 0.02) than their non-NAFLD counterparts. Hispanics had a higher prevalence of NASH compared with Caucasians (19.4% vs 9.8%; P = .03). Alanine aminotransferase, aspartate aminotransferase, BMI, insulin, Quantitative Insulin-Sensitivity Check Index, and cytokeratin-18 correlated with NASH. Among the 54 diabetic patients, NAFLD was found in 74% and NASH in 22.2%. CONCLUSION: Prevalence of NAFLD and NASH is higher than estimated previously. Hispanics and patients with diabetes are at greatest risk for both NAFLD and NASH.

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.

Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy.

UNLABELLED: Elevated low-density lipoprotein (LDL) levels and statin use have been associated with higher sustained virological response (SVR) rates in patients receiving chronic hepatitis C therapy. However, these relationships have not been well characterized in randomized controlled trials. Furthermore, little is known about the relationship between high-density lipoprotein (HDL) and virological response. To determine whether baseline LDL or HDL levels and statin use affect SVR rates, we retrospectively evaluated the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial, in which 3070 treatment-naive, hepatitis C virus (HCV) genotype 1-infected patients were treated for up to 48 weeks in one of the following arms: (1) peginterferon (PEG-IFN) alfa-2b at 1.5 microg/kg/week with ribavirin (RBV) at 800 to 1400 mg/day, (2) PEG-IFN alfa-2b at 1.0 microg/kg/week with RBV at 800 to 1400 mg/day, or (3) PEG-IFN alfa-2a at 180 microg/week with RBV at 1000 to 1200 mg/day. Virological responses were assessed by pretreatment statin use and baseline elevated LDL levels (> or =130 mg/dL) or low HDL levels (<40 mg/dL for men and <50 mg/dL for women). In 1464 patients with baseline elevated LDL levels or low HDL levels, the SVR rate was significantly higher than that in patients with normal levels (44.9% versus 34.0%, P < 0.001). In 66 patients receiving a statin pretreatment, the SVR rate was higher than the rate of those not receiving it (53.0% versus 39.3%, P = 0.02). In a multivariate logistic regression analysis using the stepwise selection method with baseline characteristics, a high LDL level [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4-1.8, P < 0.001], a low HDL level (OR = 0.5, 95% CI = 0.3-0.8, P = 0.004), and statin use (OR = 2.0, 95% CI = 1.1-3.7, P = 0.02) were independently associated with SVR. CONCLUSION: Baseline elevated LDL levels or low HDL levels and preemptive statin usage were associated with higher SVR rates. Prospective studies may be considered to explore the biological impact of these factors on HCV RNA replication and treatment response.

Induction pegylated interferon alfa-2b in combination with ribavirin in patients with genotypes 1 and 4 chronic hepatitis C: a prospective, randomized, multicenter, open-label study.

BACKGROUND & AIMS: Standard of care (SOC) treatment for chronic hepatitis C (CHC) involves weekly pegylated (PEG) interferon plus weight-based ribavirin with resultant sustained virologic response (SVR) rates at or near 50% for genotypes 1 and 4 virus. Induction therapy with higher doses of PEG interferon may improve first-phase viral kinetics and thus improve the overall SVR in genotypes 1 and 4 patients. METHODS: This multicenter, randomized, open-label trial enrolled treatment-naive genotypes 1- and 4-infected CHC patients to either initial induction therapy versus SOC. The induction group received PEG interferon alfa-2b 3.0 mcg/kg/wk for 12 weeks followed by PEG interferon alfa-2b 1.5 mcg/kg/wk for 36 weeks and 13 +/- 2 mg/kg ribavirin daily for 48 weeks. SOC patients received PEG interferon alfa-2b 1.5 mcg/kg weekly for 48 weeks and 13 +/- 2 mg/kg ribavirin daily for 48 weeks. The primary end point was SVR. RESULTS: There were 610 patients enrolled throughout the United States. Complete early virologic response was 62.6% versus 57.7% in induction versus SOC (NS). Overall SVR was 32% in induction versus 29% in SOC group (NS). Dose reduction of either PEG interferon (24.1% vs 23.8%) or ribavirin (26.8% vs 25.1%) was similar between the 2 groups. There was a trend toward a significant difference when comparing the SVR in induction therapy in patients weighing more than 85 kg versus those receiving SOC (38% vs 28%; P = .08). CONCLUSIONS: Induction therapy does not enhance complete early virologic response or SVR rates in a predominantly genotype 1 CHC population compared with SOC therapy.

Diagnosis and therapy of nonalcoholic steatohepatitis.

The increasing prevalence of obesity, insulin resistance, and the metabolic syndrome has significant implications for the future of chronic liver disease. The resultant increase in the number of patients with nonalcoholic fatty liver disease (NAFLD) is expected to translate into increased numbers of patients with end-stage liver disease (cirrhosis), liver failure, and hepatocellular carcinoma. It is particularly important to identify the patients who are at greatest risk of these aforementioned complications of chronic liver disease, those nonalcoholic fatty liver disease patients with nonalcoholic steatohepatitis. Currently liver biopsy is the gold standard for diagnosis, but less invasive, highly accurate, and affordable screening tools are required. These tools may include radiologic or laboratory studies to identify patients noninvasively who may benefit from therapeutic interventions. Clinical scoring systems that may be used in general practice as initial screening tools also may prove useful. Most therapeutic modalities available or under development target the major pathways thought essential in the pathogenesis of nonalcoholic steatohepatitis and often are directed at reducing body mass index and improving insulin resistance via pharmacologic, surgical, dietary, or exercise regimens. Other potential therapeutic agents directed at cytoprotection or reduction of fibrosis are under investigation. This article focuses on diagnosis and therapy available and under development for this chronic liver disease.

Effect of weight loss on nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common causes of liver disease worldwide and has grown proportionately with the rise in obesity. The prevalence of NAFLD is now thought to be around 20% to 40% of the entire population in industrialized Western countries. Insulin resistance, a product of obesity, is central to the pathogenesis of NAFLD, and is improved with weight loss, making this modality the primary goal of therapy. A combination of dietary modifications and increased physical activity, although hard to maintain, is thought to have significant long-term benefits, although further study is required to determine the best and most effective approaches to lifestyle modification. Alternatively, for those individuals who are unable to lose weight despite aggressive efforts, bariatric surgery, which has been shown rather convincingly to improve underlying fatty liver disease, may offer a solution. This review discusses dietary modification, exercise, weight loss pharmacotherapy, and surgical intervention as potential options for patients with NAFLD.

A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: A randomized placebo-controlled trial.

GOALS: This study was designed to assess the utility of statin therapy in patients with biopsy proven nonalcoholic steatohepatitis (NASH) and hyperlipidemia. BACKGROUND: Nonalcoholic fatty liver disease, as the hepatic manifestation of the metabolic syndrome, has become a growing public health concern. Nonalcoholic steatohepatitis (NASH) represents a subset of nonalcoholic fatty liver disease manifested by hepatic fatty infiltration and inflammation which may progress to cirrhosis and its subsequent complications, to include hepatocellular carcinoma. As the metabolic syndrome is thought to be central in the pathogenesis of NASH, it has been speculated that medications that improve metabolic profiles may be beneficial in treatment. In fact, recent studies have demonstrated potential benefit of 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), which are used in clinical practice to improve lipid panels. STUDY: This double-blinded randomized placebo-controlled trial compared the HMG-CoA reductase inhibitor, simvastatin, with placebo in the treatment of NASH over a 12-month period using serum aminotransferases and repeat liver biopsy to assess for improvement. RESULTS: Sixteen patients with biopsy proven NASH were enrolled: 14 completed the study and 10 underwent 1-year repeat liver biopsy. Mean age: 53 years (+/-10.1), mean body mass index: 32.4 (+/-6.1) with 11 male and 5 female patients. Although a 26% reduction in low-density lipoprotein was seen in the simvastatin group compared with placebo, there was no statistically significant improvement in serum aminotransferases, hepatic steatosis, necroinflammatory activity or stage of fibrosis within or between groups. CONCLUSIONS: In this pilot trial, monotherapy with simvastatin does not seem to be an effective treatment for NASH.

HCV replication and statin pleotropism: an adjuvant treatment panacea?

With optimal treatment regimens for hepatitis C still under investigation, novel agents that may improve sustained virologic response (SVR) are needed. The targeting of host lipid metabolism, particularly via the cholesterol-lowering 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins, represents a novel approach to hepatitis C therapy and has been proven beneficial in vitro. The study in this issue of the Journal is the first prospective trial that shows benefit, albeit modest, of statin therapy in vivo. While limited by heterogeneous patient population and overall small numbers, this study provides hope that use of statins in combination with standard therapy pegylated interferon and ribavirin may improve SVR.

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.