Abstract
PurposeObese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR.ObjectiveTo assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent.MethodsThis cross-sectional study included 78 obese subjects (mean age 46 ± 11 years; BMI 42.2 ± 4.7 kg/m2). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD.ResultsA positive association between overall NAFLD Activity Score and HOMA-IR was found (r s = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR.ConclusionIn this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances.
Highlights
An important complication of obesity is the development of nonalcoholic fatty liver disease (NAFLD), which covers a broad histological spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH), and can progress to fibrosis, cirrhosis and even hepatocellular carcinoma
The difference in HOMA-insulin resistance (IR) levels between fibrosis groups was independent of age and BMI (F(2,68) = 3620; P = 0.032); age, BMI and TG (F(2,66) = 3323; P = 0.042); and age, BMI and sex (F(2,67) = 3424; P = 0.038) but lost its significance when controlling for age, BMI and type 2 diabetes (T2D) status (F(2,67) = 2422, P = 0.097) and age, BMI and inflammation score (F(2,65) = 1061; P = 0.352). In this population of severely obese subjects, NAFLD severity according to NAFLD Activity Score (NAS) is associated with higher IR
From the four histopathological components, lobular inflammation shows the strongest link with IR, whereas grade of fibrosis is no longer related to IR after controlling for inflammation score
Summary
An important complication of obesity is the development of nonalcoholic fatty liver disease (NAFLD), which covers a broad histological spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH), and can progress to fibrosis, cirrhosis and even hepatocellular carcinoma. The pathogenesis of NAFLD is complex whereby the historical two-hit hypothesis is replaced by a multiple parallel hits hypothesis considering the impact of an altered adipokine secretory pattern, inflammation, gut microbiota, nutritional factors, genetic and epigenetic factors, and IR on the development and progression of NAFLD [5, 6]. Few human studies investigated the association between IR and individual histological components of NAFLD (steatosis, lobular inflammation, ballooning and fibrosis) [9, 10, 11, 12, 13, 14, 15] Most of these studies were not primarily designed to investigate IR, included non-obese or paediatric subjects, and yielded contradictory overall results. As an increase in knowledge and understanding of the complex relation between IR and NAFLD could lead to possible new therapeutic pathways or targets, we addressed this association in a high-risk, severely obese population with histological evaluation of NAFLD
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