title: Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes.
abstract: It is uncertain whether patients with nonalcoholic fatty liver disease (NAFLD) and normal alanine aminotransferase (ALT) have a milder disease and should undergo liver biopsy. We reviewed the histological data of 458 Italian patients with NAFLD in whom liver biopsy was indicated by altered liver enzymes (395 cases, 86%), or persistently elevated ferritin or long-lasting severe steatosis (63 cases). Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis >/= 2 were identified by multivariate analysis. Patients with normal ALT were significantly older, had lower body mass index, fasting triglycerides, insulin resistance according to homeostasis model assessment (HOMA-IR), ALT, and gamma-glutamyltransferase, but a higher prevalence of hypertension. NASH was diagnosed in 59% and 74% of the patients with normal and increased ALT, respectively (P = 0.01). In the overall series of patients, NASH was independently predicted by ALT (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.04-1.19 per 10-IU/mL increase) and diabetes (OR, 1.5; 95% CI, 1.1-2.0). The same variables were selected in patients with increased ALT, whereas in those with normal ALT, HOMA-IR and ALT were independent predictors. Severe fibrosis was independently predicted by serum ferritin (OR, 1.04; 95% CI, 1.001-1.08 per 50-ng/mL increase), ALT (OR, 1.07; 95% CI, 1.02-1.14), and diabetes (OR, 1.8; 95% CI, 1.4-2.3) in the overall series, serum ferritin and diabetes in those with increased ALT, and only HOMA-IR (OR, 1.97; 95% CI, 1.2-3.7) in patients with normal ALT.
  
  
  CONCLUSIONS
  Normal ALT is not a valuable criterion to exclude patients from liver biopsy. Alterations in glucose metabolism and insulin resistance in subjects with normal ALT should also be considered in the selection of NAFLD cases for histological assessment of disease severity and progression.
authors.affiliation: Department of Internal Medicine, Scientific Institute of Recovery and Cure Foundation (IRCCS), Hospital Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
authors.forename: Marco
authors.initials: M
authors.lastname: Andreoletti
authors.forename: Agostino
authors.initials: A
authors.lastname: Colli
authors.forename: Ester
authors.initials: E
authors.lastname: Vanni
authors.forename: Cristina
authors.initials: C
authors.lastname: Bertelli
authors.forename: Erika
authors.initials: E
authors.lastname: Fatta
authors.forename: Daniela
authors.initials: D
authors.lastname: Bignamini
authors.forename: Giulio
authors.initials: G
authors.lastname: Marchesini
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion