Effects of insulin-like growth factor-I administration on in vivo regulation of urea synthesis in normal subjects and patients with cirrhosis

Background: The anabolic effects of insulin‐like growth factor‐I (IGF‐I) may involve a decrease of hepatic nitrogen (N) clearance, but this has never been studied in humans. Patients with cirrhosis have low levels of IGF‐I and might benefit from IGF‐I therapy. Conversely, a possible decrease in hepatic N clearance by IGF‐I could increase the risk of hepatic encephalopathy. Aims: To examine the effects of 1‐week IGF‐I administration on the functional hepatic N clearance (FHNC), viz. the linear slope of the relationship between blood‐α‐amino‐N concentration and urea‐N synthesis rate as controlled by an infusion of alanine. Methods: A randomized sequence‐crossover placebo‐controlled study. Eight healthy volunteers and eight patients with alcoholic cirrhosis received injections of saline or IGF‐I twice daily (50 μg/kg) for 7 days. Results: IGF‐I levels at baseline were lower in the patients than those in the controls. The IGF‐I treatment normalized patient levels and caused an increase in the controls to supra‐physiological levels. FHNC was lower in patients compared with healthy subjects (23.0 vs 36.5 L/h, P=0.03). IGF‐I treatment reduced FHNC by 30% in healthy subjects (from 36.5 to 25.7 L/h, P=0.02), whereas no effect was found in the patients. Conclusion: IGF‐I downregulates urea synthesis in normal subjects. This may be part of the explanation behind the anabolic effects of IGF‐I. The normalization of IGF‐I in cirrhosis patients without an effect on urea synthesis implies that the patients were resistant to IGF‐I with regard to reduction of hepatic amino‐N elimination. IGF‐I treatment of cirrhosis patients evidently carries no risk of N accumulation.