Hepatic Steatosis and Fibrosis in Obese, Dysmetabolic and Diabetic Nonhuman Primates Quantified by Noninvasive Echography

Abstract

Purpose: Patients with obesity and type 2 diabetes (T2D) are more susceptible to the occurrence of nonalcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH). Although liver biopsy is still reviewed as a gold standard for the diagnosis, due to its invasiveness, high cost and variable readouts, it has limited application in large scale clinical investigation and long term following up the therapeutic benefits. This study was to apply a clinically used noninvasive echography to quantitatively evaluate the NAFLD/NASH model in dysmetabolic nonhuman primates. Method: Noninvasive echography with computer-assisted imaging analysis was used to quantify hepatic pathological changes in 36 cynolmolgus monkeys at different dysmetabolic stage. Result: Both hepatic/renal echo-intensity ratio (H/R=1.69 +/- 0.12 vs 1.36 +/- 0.09) and hepatic echo-intensity attenuation rate (HA=25.7 +/- 5.7 vs 12.0 +/- 3.2 kHz/cm) were significantly higher in obese (n=14) compared to control (n=22) monkeys, which were highly correlated with multiple metabolic risks such as obese, hyperlipidemia and liver fibrosis indices including body mass index (BMI), Alanine/Aspartate Transaminase (AST/ALT) and diabetes (BARD) score, fibrosis-4 (FIB4), AST to platelet ratio index (APRI), etc. Postmortem examination of liver biopsy tissue revealed liver pathology resembling human NAFLD/NASH and higher triglycerides (245 +/- 26 vs 101 +/- 32 mg/100 g tissue) in diabetic than control monkeys. Conclusion: The data demonstrate for the first time that obese, dysmetabolic and diabetic monkeys can develop NAFLD/NASH assembling to human disease. The noninvasive and quantitative echography along with the nonhuman primate model can be used as a powerful translational tool for following-up disease progression, and evaluation of novel therapies for NAFLD/NASH both clinically and pre-clinically.