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.

Insulin‐like growth factor‐1 is inversely associated with liver fibrotic markers in patients with type 2 diabetes mellitus

“…In contrast, Sumida et al 26 investigated the SDS of IGF-1 by age and sex in 199 NAFLD patients, and showed that the IGF-1 SDS decreased significantly with increasing lobular inflammation and fibrosis, and showed in the multivariate logistic regression analysis the significant association between the IGF-1 SDS values and the severity of NAFLD (NASH vs NAFL or fibrosis stage 0-2 vs 3-4) after adjusting for age, sex and insulin resistance. Additionally, Dichtel et al 32 examined 21 controls with no steatosis, lobular inflammation or fibrosis and 121 NAFLD patients, and showed that IGF-1 was lower in individuals with lobular inflammation, hepatocyte ballooning, higher fibrosis stages (stage 2-4 vs 0-1) and NASH; all factors examined remained significant after controlling for age, BMI and the diagnosis of diabetes. However, these studies did not examine the relationship between IGF-1 and liver fibrosis among type 2 diabetes mellitus, which are high-risk groups of advanced liver disease; hence, this was our primary outcome measure.…”

Hepatic steatosis in patients with acromegaly

“…22 Indeed, lower GH concentrations have been reported in human studies with participants diagnosed with NAFLD. 25,26 A recent study showed hepatic steatosis (as assessed by a surrogate marker, the hepatic steatosis index) to be related to insulin resistance and the reduction of IGF-1 and GH levels; after 12 months of follow-up, improvements to insulin sensitivity paralleled reductions of hepatic steatosis. 25,26 A recent study showed hepatic steatosis (as assessed by a surrogate marker, the hepatic steatosis index) to be related to insulin resistance and the reduction of IGF-1 and GH levels; after 12 months of follow-up, improvements to insulin sensitivity paralleled reductions of hepatic steatosis.…”

“…23,24 Moreover, low serum IGF-1 concentrations have also been associated with NAFLD and it has been suggested that hepatic insulin resistance modulates hepatic GH production and thus IGF-1 concentrations. 25,26 A recent study showed hepatic steatosis (as assessed by a surrogate marker, the hepatic steatosis index) to be related to insulin resistance and the reduction of IGF-1 and GH levels; after 12 months of follow-up, improvements to insulin sensitivity paralleled reductions of hepatic steatosis. 20 The observed risk with GH and IGF-1 deficiencies would imply that treated patients with acromegaly might be prone to develop NAFLD, because treatment does, in some cases, lead to the development of GH deficiency, as illustrated in a recently published case study.…”

A narrative review of factors associated with the development and progression if non‐alcoholic fatty liver disease

“…The increase in GH, IGF‐1 and insulin concentrations during adolescence ensure anabolism and thereby protect against steatosis. Circulating GH and IGF‐1 levels are lower in NAFLD patients than in controls . Patients with GH deficiency have an increased NAFLD prevalence .…”

“…Circulating GH and IGF-1 levels are lower in NAFLD patients than in controls. 72,73 Patients with GH deficiency have an increased NAFLD prevalence. 72 Moreover, GH secretion is reduced in obesity, 74 without a proportional decrease in IGF-1 concentrations, 70 maintaining a negative feedback loop for GH.…”