The risk of severe liver disease in NAFLD with normal aminotransferase levels: A role for insulin resistance and diabetes

Background 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. Materials & Methods We reviewed the histological data of 458 Italian patients with NAFLD in whom liver biopsy was indicated because of altered liver enzymes (395 cases, 86%) or persistently elevated ferritin or long-lasting severe steatosis in (63 cases). Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis ≥ 2 were identified by logistic regression analysis. Results Patients with normal ALT were significantly older, had lower body mass index, fasting triglycerides, insulin resistance (homeostasis model assessment – HOMA), ALT and gamma-glutamyltransferase (GGT), but a higher prevalence of hypertension. NASH was diagnosed in 59% and 74% patients with normal and increased ALT, respectively (p=0.01). In the overall series of patients, NASH was independently predicted by ALT (Odd 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% CI1.02-1.14), 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. Conclusion Alterations in glucose metabolism and insulin resistance should be considered in the selection of NAFLD cases for the histological assessment of disease severity and progression, also in subjects with normal ALT.