Regulation of the growth hormone receptor/binding protein, insulin-like growth factor ternary complex system in human cirrhosis

Background/Aims: The liver is the central organ of the endocrine growth hormone/insulin-like growth factor I (GH/IGF-I) axis and cirrhosis effects a state of acquired GH resistance. Low IGF-I levels are associated with adverse clinical outcomes in cirrhotic patients and may be pathogenic to the complications of cirrhosis. We examined the impact of cirrhosis on hepatic mRNA and serum protein levels for the GH receptor (GHR)/binding protein (GHBP), IGF-I, IGF binding protein (IGFBP)-3 and the acid-labile subunit (ALS). Methods: Fifty patients with cirrhosis were studied and liver tissue was obtained from 18. Gene expression was assessed by Northern analysis and serum protein levels by immunoassay. Results: In cirrhotic liver GHR mRNA and GH binding to microsomal membranes were decreased by 61 and 56%, respectively. Serum GHBP levels were decreased only in severe disease, not correlating with GHR mRNA or GH binding. Hepatic IGF-I and ALS mRNA were significantly decreased by 84 and 68%, respectively, in parallel with serum protein, suggesting transcriptional regulation. Hepatic IGFBP-3 mRNA was unchanged but low serum IGFBP-3 suggested post-transcriptional regulation. Conclusions: The decreased mRNA and serum levels for the GH-dependent, hepatocyte produced proteins IGF-I and ALS confirm the importance of GH receptor loss to the GH resistance of cirrhosis.