Background/Aims: Ultrasound is used to screen for hepatic steatosis, the most common liver disease in the United States. However, few studies have prospectively evaluated the accuracy of ultrasound to diagnose hepatic steatosis. Therefore, a double blinded prospective study was performed in consecutive patients undergoing liver biopsy to evaluate the accuracy of ultrasound to diagnose hepatic steatosis. Methods: Real time ultrasound was performed just prior to the biopsy by a single investigator masked to the clinical diagnosis. The liver biopsy was reviewed by a pathologist masked to the clinical indication or sonographic findings Results: Of 73 consecutive patients studied,macrovesicular steatosis of any severity on biopsy was found in 46 (63%) and micro vesicular fat found in 51 (69.9%). The overall impression of the sonographer for the presence of macrovesicular hepatic steatosis of any degree had a sensitivity of 60.9% and a specificity of 100%. The sensitivity increased to 100% and the specificity to 90% when there was ≥ 20% of fat. The zonular distribution of the fat did not alter the diagnostic accuracy of ultrasound. Ultrasound had a poor yield in the diagnosis of microvesicular fat with an overall sensitivity of 43% and a specificity of 73%. The combination of increased echogenicity and portal vein blurring on ultrasound had the greatest sensitivity in the diagnosis of hepatic steatosis. Conclusion: Real time ultrasound using a combination of sonographic findings has a high specificity but underestimates the prevalence of hepatic steatosis when there is less than ≥ 20% fat.

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Background Nonalcoholic steatohepatitis (NASH) is common and severe in patients with diabetes mellitus. Although, there are no effective treatments for NASH in diabetic patients, preliminary reports suggest that polyunsaturated fatty acids (PUFA) may be beneficial in these patients. Aim A prospective, randomized, double blind placebo controlled study (NCT 00323414) was performed in NASH patients with diabetes. Methods 37 patients (50.6±9.8y) with well controlled diabetes (HbA1C<8.5%) were randomized to receive either PUFA containing eicosapentaenoic acid 2160 mg and docosahexaenoic acid 1440 mg daily or an isocaloric, identical placebo containing corn oil for 48 weeks under CONSORT guidelines. Clinical, demographics, biochemical laboratory tests, body composition using DEXA® and liver biopsy were done at randomization and at the end of treatment. Liver biopsy was scored by the NASH CRN criteria. An intention to treat analysis was performed. Results At inclusion, gender, age, body weight, biochemical tests, glucose control and liver histology were similar in the 2 treatment groups. There was no change in liver enzymes, body weight or body composition during the study in either group. At the end of treatment, hepatic steatosis and the activity score improved (p<0.05) and lobular inflammation worsened (p<0.001) with placebo but was unchanged with PUFA. At the end of treatment, insulin resistance (serum glucose and HOMA) worsened with PUFA but not placebo. Conclusions PUFA provided no benefit over placebo in NASH patients with diabetes. The effects of PUFA on histology and insulin resistance were inferior to placebo. These data provide no support for PUFA supplements in NASH.

Background Hypovitaminosis D is common in obesity and insulin resistant states. Increased fat mass in patients with non-alcoholic fatty liver disease (NAFLD) may contribute to hypovitaminosis D. Aims To determine the relation between plasma vitamin D concentration, severity of disease and body composition in NAFLD. Methods Plasma vitamin D concentration was quantified in 148 consecutive biopsy proven patients with NAFLD (non alcoholic steatohepatitis-NASH: n=81; and hepatic steatosis n=67) and healthy controls (n=39). NAFLD was scored using the NASH CRN criteria. Body composition was quantified by bioelectrical impedance analysis and abdominal CT image analysis. Results Plasma vitamin D concentration was significantly lower in NAFLD (21.2±10.4 ng/ml) compared to healthy controls (35.7±6.0 ng/ml). Higher NAFLD activity scores were associated with lower plasma concentration of vitamin D (r2=0.29; p<0.001). Subgroup analysis among patients with NAFLD showed that patients with NASH had significantly lower (p<0.01) vitamin D levels than those with steatosis alone (18.1±8.4 vs. 25.0±11.3 ng/ml). Low concentrations of vitamin D were associated with greater severity of steatosis, hepatocyte ballooning and fibrosis (p<0.05). On multivariate regression analysis, only severity of hepatocyte ballooning was independently associated (p=0.02) with low vitamin D concentrations. Plasma vitamin D (p=0.004) and insulin concentrations (p=0.03) were independent predictors of the NAFLD activity score on biopsy. Patients with NAFLD had higher fat mass that correlated with low vitamin D (r2=0.26; p=0.008). Conclusions Low plasma vitamin D concentration is an independent predictor of the severity of NAFLD. Further prospective studies demonstrating the impact of vitamin D replacement in NAFLD patients are required.

Uncomplicated pregnancy in humans is associated with a higher rate of transsulfuration early in gestation and a higher rate of transmethylation of methionine in late gestation. These data may have implications for understanding the role of methionine and homocysteine in complications of pregnancy and for the nutritional care of pregnant women.

Background Identifying changes in the epidemiology of liver disease is critical for establishing health-care priorities and allocating resources to develop therapies. The projected contribution of different etiologies towards development of cirrhosis in the United States was estimated based on current publications on epidemiological data and advances in therapy. Given the heterogeneity of published reports and the different perceptions, that are not always reconcilable, a critical overview rather than a formal meta-analysis of the existing data and projections for the next decade were performed. Methods Data from the World Health Organization (WHO) Global Status Report on Alcohol and Health of 2014, Scientific Registry of Transplant Recipients (SRTR) from 1999 to 2012, National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Centers for Disease Control and Prevention were inquired to determine future changes in the epidemiology of liver disease. Results Alcohol consumption has increased over the past 60 years. In 2010, transplant related costs for liver recipients were the highest for hepatitis C (~$124 million) followed by alcohol related cirrhosis (~$86 million). We anticipate a significant reduction in incidence cirrhosis due to causes other than alcohol because of the availability of high efficiency antiviral agents for hepatitis C, universal and effective vaccination for hepatitis B, relative stabilization of the obesity trends in the United States and novel, potentially effective therapies for non-alcoholic steatohepatitis (NASH). The proportion of alcohol related liver disease (ALD) is therefore likely to increase in both the population as a whole and in the liver transplant wait-list. Conclusions Alcohol related cirrhosis and alcohol related liver disorders will be the major cause of liver disease in the coming decades. There is an urgent need to allocate resources aimed towards understanding the pathogenesis of the disease and its complications so that effective therapies can be developed.

Despite advances in treatment of alcohol use disorders that focus on increasing abstinence and reducing recidivism, alcoholic liver disease is projected to be the major cause of cirrhosis and its complications. Malnutrition is recognized as the most frequent complication in alcoholic liver disease (ALD) and despite the high clinical significance, there are no effective therapies to reverse malnutrition in ALD. Malnutrition is a relatively imprecise term and sarcopenia or skeletal muscle loss, the major component of malnutrition, is primarily responsible for the adverse clinical consequences in patients with liver disease. It is, therefore, critical to define the specific abnormality (sarcopenia) rather than malnutrition in ALD, so that therapies targeting sarcopenia can be developed. Skeletal muscle mass is maintained by a balance between protein synthesis and proteolysis. Both direct effects of ethanol and its metabolites on the skeletal muscle and the consequences of liver disease result in disturbed proteostasis (protein homeostasis) and consequent sarcopenia. Once cirrhosis develops in patients with alcoholic liver disease, abstinence is unlikely to be effective in completely reversing sarcopenia, since other contributors including hyperammonemia, hormonal and cytokine abnormalities aggravate sarcopenia and maintain a state of anabolic resistance initiated by ethanol. Cirrhosis is also a state of accelerated starvation, with increased gluconeogenesis that requires amino acid diversion from signaling and substrate functions. Novel therapeutic options are being recognized that are likely to supplant the current “deficiency replacement” approach and instead focus on specific molecular perturbations, given the increasing availability of small molecules that can target specific signaling components. Myostatin antagonists, leucine supplementation, and mitochondrial protective agents are currently in various stages of evaluation in preclinical studies to prevent and reverse sarcopenia, in cirrhosis in general, and alcoholic liver disease, specifically. Translation of these data to human studies and clinical application requires priority for allocation of resources.

Hypertensive patients with NAFLD on baseline RAS blockers had less advanced hepatic fibrosis suggesting a beneficial effect of RAS blockers in NAFLD.