The Association Between IGF-1 Levels and the Histologic Severity of Nonalcoholic Fatty Liver Disease

Abstract

Objectives: The mechanisms responsible for the development of nonalcoholic fatty liver disease (NAFLD) and progression to nonalcoholic steatohepatitis (NASH) are incompletely understood. Growing evidence suggests that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may have roles in the development and progression of NAFLD. We hypothesized that lower serum IGF-1 levels would be associated with increased liver fat accumulation, inflammation, and fibrosis in a group of meticulously phenotyped obese subjects with liver biopsies.

Methods: A retrospective, cross-sectional study was performed at Massachusetts General Hospital, Boston, MA, USA and St. Mary's Hospital, Richmond, VA, USA. Liver biopsies were performed in 142 subjects during NAFLD work-up or bariatric surgery and were graded by a single, blinded pathologist. Main outcome measures included liver histology and serum IGF-1.

Results: Mean age was 52±10 years and body mass index (BMI) was 43±9 kg/m². Mean serum IGF-1 was lower in subjects with lobular inflammation (112±47 vs. 136±57 ng/ml, P=0.01), hepatocyte ballooning (115±48 vs. 135±57 ng/ml, P=0.05), higher fibrosis stage (stage 2-4 vs. 0-1; 96±40 vs. 125±51 ng/ml, P=0.005), and NASH (109±45 vs. 136±57 ng/ml, P=0.002). All results remained significant after controlling for age, BMI, and a diagnosis of diabetes, and all but hepatocyte ballooning (trend, P=0.06) remained significant after excluding individuals with cirrhosis. Steatosis was not significantly associated with mean serum IGF-1 levels.

Conclusions: Low serum IGF-1 levels are associated with increased histologic severity of NAFLD when rigorously controlled for age, BMI, the presence of diabetes, and after the exclusion of subjects with cirrhosis. Further investigation is warranted to determine the differential effects of GH and IGF-1 on the development and progression of NAFLD, which could further elucidate pathophysiology and identify therapeutic targets.

Figure 1

Reported as mean serum insulin-like growth factor-I (IGF-1) in ng/ml±s.e.m. *P<0.05 as specified below. (a) Mean serum IGF-1 was significantly lower in subjects with the presence (“present”) vs. the absence (“absent”) of lobular inflammation (P=0.01). (b) Subjects with hepatocyte ballooning had significantly lower mean serum IGF-1 levels than those without (P<0.05). (c) Subjects with nonalcoholic steatohepatitis (NASH) (“present”) had significantly lower mean serum IGF-1 when compared with those without NASH (“absent”)(P=0.002). (d) Subjects with more severe fibrosis (Stages 2–4) had significantly lower mean serum IGF-1 levels than those with less severe fibrosis (Stages 0–1) (P<0.005). All results remained significant when excluding individuals with cirrhosis with the exception of hepatocyte ballooning, which remained a trend at P=0.06. (e) Mean serum IGF-1 level was not significantly different in subjects with steatosis (“present”) vs. controls without steatosis (“absent”) (P=NS), which was unchanged after excluding those with cirrhosis. (f) Mean serum IGF-1 was lower in subjects with cirrhosis (“present”) vs. those without cirrhosis (“absent”) (P<0.05).