Ductular reaction is an independent predictor of advanced fibrosis in NAFLD

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury in Western countries and non-alcoholic steatohepatits (NASH) represents its form potentially progressive to cirrhosis and hepatocellular carcinoma. The mechanisms leading to advanced liver injury in NASH are still unknown. Insulin resistance (IR) is an independent predictor of NAFLD-related histological damage. Ductular reaction (DR) may occur during chronic liver injury and represents a potential fibrogenic mechanism by the recruitment of myofibroblasts; its role in NASH has been only partially investigated. Aims of the study were 1. To evaluate the relationship between DR, histological features and parameters of IR in patients with NAFLD and 2. To compare it with DR in age, BMI and sex-matched patients with Chronic Hepatitis C (CHC). Patients and Methods: Eighty-five consecutive NAFLD patients (mean age 44 ± 10, M/F 66/10) underwent liver biopsy and anthropometric, clinical and biochemical evaluation, including assessment of IR by the oral glucose insulin sensitivity (OGIS) test. Liver injury was determined by Kleiner’s score, and citokeratin-7 (CK7) was assessed by immunohistochemistry as a marker of DR. DR elements were stratified into its components, namely reactive ductular cells (RDCs), hepatic progenitor cells (HPCs) and intermediate hepatobiliary cells (IHBCs). Results: In NAFLD patients at univariate analysis DR was associated with increased liver fibrosis (p=0.011), while NAS score ≥5 was related to increased liver ALT (p=0.003), reduced insulin sensitivity according to OGIS (p=0.04) and increased fibrosis (p=0.05). The presence of significant (staging ≥2) fibrosis was associated with total CK7 (p=0.032) and NAS score (p=0.043). At logistic regression analysis, total CK7 was not associated with the NAS score and its individual components (steatosis, inflammation, ballooning). By multivariate analysis, NAS score and CK7 were independent predictors of hepatic fibrosis. Compared with CHC patients, total CK7 was similar although its HPCs component was reduced by 50% in NAFLD (0.76 ± 0.30 vs 2.45 ± 2.50 in CHC, p < 0.0001). Conclusion: DR is significantly associated with liver fibrosis in patients with NAFLD, and its contribution appears independent from IR and its histological features (steatosis and necroinflammation).