Search

UNLABELLED Postmenopausal women with nonalcoholic steatohepatitis are at an increased risk of hepatic fibrosis compared with premenopausal women. Whether duration of estrogen deficiency in postmenopausal state dictates an individual's fibrosis risk remains uninvestigated. We assessed the associations of age at menopause and time from menopause with fibrosis severity in postmenopausal women with nonalcoholic fatty liver disease. Data from 488 postmenopausal women with (1) histologic diagnosis of nonalcoholic fatty liver disease and (2) self-reported information on age at menopause were analyzed. The associations of premature menopause (age at menopause of

Non-alcoholic fatty liver disease (NAFLD) contributes to premature death along with obesity, diabetes, and cardiovascular disease. We examined whether hepatic steatosis on ultrasound and liver enzyme activities were associated with increased liver disease mortality in the U.S. National Health and Nutrition Examination Survey (NHANES), 1988-1994, with up to 23 years of linked-mortality data. Survey-linked National Death Index records were analyzed among 14,527 adult participants who were negative for viral hepatitis B and C and iron overload. Hepatic steatosis on ultrasound was categorized as normal, mild, moderate, or severe. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GGT) elevation was defined as the highest sex-specific decile. Cumulative mortality was 36.2% from all causes, including 16.3% from cardiovascular disease, 10.8% from cancer, 5.4% from diabetes, and 1.1% from liver disease. Severe hepatic steatosis was associated with increased liver disease mortality in both age-adjusted (hazard ratio [HR], 3.92; 95% confidence interval [CI], 1.49-10.27, p for trend, 0.011) and multivariate-adjusted analyses (HR, 2.68; 95% CI, 1.02-7.03; p for trend, 0.072). Hepatic steatosis was not independently associated with mortality from all-causes, cardiovascular disease, cancer, or diabetes. Higher liver disease mortality was found with elevated ALT (HR, 4.08; 95% CI,1.99-8.33), AST (HR, 4.33; 95% CI, 2.18-8.59), and GGT (HR, 7.91; 95% CI, 3.06-20.46). GGT elevation was associated with increased overall mortality (HR, 1.45; 95% CI, 1.21-1.74). Liver enzymes were, otherwise, unrelated to overall or cause-specific mortality. In the U.S. population, severe hepatic steatosis on ultrasound and liver enzyme elevation were associated with increased liver disease mortality, but were not independently associated with mortality from all causes (except for GGT), cardiovascular disease, cancer, or diabetes. This article is protected by copyright. All rights reserved.

The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (−15.7 versus −1.91; P = 0.02), but this effect did not persist at 96 weeks (−3.25 versus −4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). Conclusion: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis. (HEPATOLOGY 2012)

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the United States; however, few data are available about racial and ethnic variation. We investigated relationships between ethnicity, NAFLD severity, metabolic derangements, and sociodemographic characteristics in a well-characterized cohort of adults with biopsy-proven NAFLD. Data were analyzed from 1,026 adults (≥18 years) in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) from 2004 to 2008, for whom liver histology data were available within 6 months of enrollment. Associations between ethnicity (i.e., Latino versus non-Latino white) and NAFLD severity (i.e., NASH versus non-NASH histology and mild versus advanced fibrosis) were explored with multiple logistic regression analysis. We also investigated effect modification of ethnicity on metabolic derangements for NAFLD severity. Within the NASH CRN, 77% (N = 785) were non-Latino white and 12% (N = 118) were Latino. Sixty-one percent (N = 628) had NASH histology and 28% (N = 291) had advanced fibrosis. Latinos with NASH were younger, performed less physical activity, and had higher carbohydrate intake, compared to non-Latino whites with NASH. Gender, diabetes, hypertension, hypertriglyceridemia, aspartate aminotransferase (AST), platelets, and the homeostasis model assessment of insulin resistance (HOMA-IR) were significantly associated with NASH. Age, gender, AST, alanine aminotransferase, alkaline phosphatase, platelets, total cholesterol, hypertension, and HOMA-IR, but not ethnicity, were significantly associated with advanced fibrosis. The effect of HOMA-IR on the risk of NASH was modified by ethnicity: HOMA-IR was not a significant risk factor for NASH among Latinos (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.85-1.02), but was significant among non-Latino whites (OR, 1.06; 95% CI: 1.01-1.11).Metabolic risk factors and sociodemographic characteristics associated with NASH differ by ethnicity. Additional insights into NASH pathogenesis may come from further studies focused on understanding ethnic differences in this disease.

The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was formed to conduct multicenter studies on the etiology, contributing factors, natural history, and treatment of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine the associations of readily available demographic, clinical, and laboratory variables with the diagnosis of NASH and its key histological features, and determine the ability of these variables to predict the severity of nonalcoholic fatty liver disease (NAFLD). A total of 1266 adults were enrolled in NASH CRN studies between October 2004 and February 2008, of whom 1101 had available liver histology. The median age was 50 years; 82% were white and 12% Hispanic. The median body mass index was 33 kg/m(2); 49% had hypertension and 31% had type 2 diabetes. On liver biopsy, 57% were judged to have definite NASH and 31% bridging fibrosis or cirrhosis. Using data from the 698 patients with liver biopsies within 6 months of clinical data, patients with definite NASH were more likely to be female and have diabetes, higher levels of aspartate and alanine aminotransferases, alkaline phosphatase, gamma glutamyl transpeptidase, and homeostasis model assessment of insulin resistance (HOMA-IR). Progressive models for predicting histological diagnoses performed modestly for predicting steatohepatitis or ballooning (area under receiver operating characteristic curves [AUROC] ranged from 0.70-0.79), and better for advanced fibrosis (AUROC 0.73-0.85).Readily available clinical and laboratory variables can predict advanced fibrosis in adults with NAFLD, but additional information is needed to reliably predict the presence and severity of NASH. Prospective studies of this well-characterized population and associated tissue bank samples offer a unique opportunity to better understand the cause and natural history of NAFLD and develop more precise means for noninvasive diagnosis.