Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities

BACKGROUND AND AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid beta oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. METHODS: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU. m(-2). min(-1)) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-(13)C]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid beta oxidation from serum [beta-OH butyrate], release of water-soluble radioactivity from (3)H-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 3-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6). RESULTS: NASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1.6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 micromol. kg(-1). min(-1); P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU. m(-2). min(-1). NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid beta oxidation was noted in any group. Also, mean [beta-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 micromol/L; P < 0.04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. CONCLUSIONS: These data indicate that peripheral insulin resistance, increased fatty acid beta oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but NASH alone is associated with mitochondrial structural defects.     

Salazopyrin in the treatment of scleroderma

Following reports of successful treatment of various forms of scleroderma with salazopyrin, 13 selected patients were treated, 8 with acrosclerosis, one with sclerodermatomyositis and four with generalized morphoea. No effect was observed except in two cases of generalized morphoea which were in the acute stage of spreading to involve most of body surface. These two were more or less cured. This observation seems to warrant further trials with salazopyrin in this rare but serious form of scleroderma.     

Benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis is a rare autosomal recessive disorder characterized by repeated episodes of intense pruritus, profound elevations in serum alkaline phosphatase and bilirubin, with normal or nearly normal values for serum gamma-glutamyl transferase. Attack lasts from several weeks to months and resolve spontaneously. Between attacks patients remain asymptomatic for months to years. The disorder does not lead to progressive liver injury and is not fatal. Genetic studies have demonstrated that the disorder is the result of a mutation in ATP8BI, a gene that codes for the FIC1 (familial intrahepatic cholestasis) protein, which is also affected in other forms of familial intrahepatic cholestasis. It is believed this protein plays a role in bile acid secretion, in aminophospholid transport, and in maintaining fluidity of the cell membrane. Therapy is supportive and aimed at relieving pruritus and other complications of severe cholestasis until the episode resolves spontaneously.     

Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay

Primary biliary cirrhosis (PBC) is sometimes diagnosed based on a positive antimitochondrial antibody in the appropriate clinical setting without a liver biopsy. Although a liver biopsy can assess the extent of liver fibrosis and provide prognostic information, serum fibrosis markers avoid biopsy complications and sampling error and provide results as a continuous variable, which may be more precise than categorical histological stages. The current study was undertaken to evaluate serum fibrosis markers as predictors of clinical progression in a large cohort of PBC patients. Serial liver biopsy specimens and serum samples were collected every 2 years in 161 PBC subjects for a median of 7.3 years. Clinical progression was defined as development of one or more of the following events: varices, variceal bleed, ascites, encephalopathy, liver transplantation, or liver-related death. Serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and procollagen III aminopeptide were measured and entered into the previously validated enhanced liver fibrosis (ELF) algorithm. The ability of ELF, histological fibrosis, bilirubin, Model for End-Stage Liver Disease (MELD), and Mayo Risk Score to differentiate between individuals who would experience a clinical event from those who would not was evaluated at different time points. Event-free survival was significantly lower in those with high baseline ELF. Each 1-point increase in ELF was associated with a threefold increase in future complications. The prognostic performance of all tests was similar when performed close to the time of the first event. However, at earlier times in the disease process (4 and 6 years before the first event), the prognostic performance of ELF was significantly better than MELD or Mayo R score. CONCLUSION: The ELF algorithm is a highly accurate noninvasive measure of PBC disease severity that provides useful long-term prognostic information.     

The effect of major depression on participation in preventive health care activities

Background  

The objective of this study was to determine whether major depressive episodes (MDE) contribute to a lower rate of participation in three prevention activities: blood pressure checks, mammograms and Pap tests.     

Differences between Caucasian, African American, and Hispanic patients with primary biliary cirrhosis in the United States

Primary biliary cirrhosis (PBC) is an uncommon chronic cholestatic liver disease that primarily afflicts young and middle-aged Caucasian women; there are limited data on the clinical presentation and disease severity among non-Caucasian patients with this disease. The goal of this study was to examine differences in the severity of liver disease between Caucasian and non-Caucasian patients with PBC screened for enrollment in a large national multicenter clinical trial. Demographic features, symptoms, physical findings, and laboratory tests obtained during screening were examined in 535 patients with PBC with respect to ethnicity, gender, and antimitochondrial antibody (AMA) status; 73 of 535 (13.6%) were non-Caucasian (21 were African American, and 42 were Hispanic). Non-Caucasians were more likely than Caucasians to be ineligible for participation in the clinical trial (46.5% versus 25.1%, P = 0.0001), primarily because of greater disease severity. African Americans and Hispanics were also more likely to have a lower activity level, more severe pruritus, and more advanced disease. However, the mean age, male-to-female ratio, and seroprevalence of AMA positivity were similar between the 2 groups. CONCLUSION: Liver disease severity at clinical presentation is higher among non-Caucasians than Caucasians with PBC, and this cannot be explained by demographic or serologic features alone. Possible mechanisms underlying this health discrepancy are not clear, but increased awareness of PBC as a cause of chronic cholestatic liver disease is critical in evaluating non-Caucasian patients in the United States.     

The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome

The patterns of fat distribution and their relationship to severity of nonalcoholic fatty liver disease (NAFLD) are unknown. The objectives of this study were to define the fat distribution patterns and their relationship to histological severity and metabolic parameters in subjects with NAFLD. Anthropometric indices and total body fat were measured in 123 subjects. Fat distribution patterns were defined as: general, abdominal, limb, truncal, and dorsocervical lipohypertrophy (DCL) a novel finding in NAFLD. Eighty-one (66%) of the subjects were obese, and 94 (76%) had abdominal obesity. Thirty-five (28.5%) had DCL. Whereas body mass index (BMI) correlated best with the presence of diabetes (r = 0.22, P < 0.05), waist circumference (WC) correlated best with hypertension (r = 0.2, P < 0.05), hypertriglyceridemia (r = 0.37, P < 0.001), and insulin resistance (homeostasis model of assessment for insulin resistance [r = 0.68, P < 0.0001]). None of the patterns of fat distribution were significantly associated with severity of hepatic steatosis. Abdominal obesity (WC) correlated with inflammation (r = 0.2, P < 0.05) only. DCL correlated significantly with the severity of all histological parameters except steatosis. Whereas DCL was the single greatest contributor to the variability in severity of histological parameters, a model combining BMI, WC, and DCL showed the greatest contribution to the variability in severity of individual histological parameters. The addition of steatosis grade to the model significantly increased its contribution to the range of lobular inflammation. CONCLUSION: WC predicts metabolic risk profile with the most significance. However, DCL is most strongly associated with severity of steatohepatitis. WC and BMI added modestly to the contribution of DCL to severity of nonalcoholic steatohepatitis.