The insulin-like growth factor and binding protein axis in children with end-stage liver disease before and after orthotopic liver transplantation

Over 50% of children with established cirrhosis have evidence of growth failure and malnutrition. Orthotopic liver transplantation (OLT) is a successful treatment for many children and leads to improved growth and nutrition. Most of the anabolic actions of GH are mediated through the generation of the mitogenic polypeptide insulin-like growth factor-I (IGF-I). Although this is synthesised ubiquitously, the bulk of circulating IGF-I is derived from the liver. The actions of IGF-I are modulated by a family of at least six high-affinity binding proteins (IGFBPs). Growth failure in end-stage liver disease, both before and after OLT, may result from abnormalities in the IGF-IGFBP axis. Children who had undergone successful OLT were studied before and after OLT. Anthropometry was measured by standard techniques. Serum IGFs, IGFBPs and acid labile subunit (ALS) were measured by RIA, IRMA, ELISA, Western ligand and immunoblotting. The most severely affected anthropometric parameters were skin fold thickness and mid-arm circumference. After OLT there was a marked improvement in these parameters. Chronic liver disease was characterised by low serum IGF-I, IGF-II, IGFBP-3 and ALS levels with raised IGFBP-1 and -2 levels. Serum IGFBP-1 and -2 were negatively correlated with pre-OLT anthropometric parameters. After OLT, there was a rapid normalisation of serum IGF-I, while IGF-II and IGFBP-3 overshot to supranormal levels. ALS levels post-OLT remained below control levels. By 3 years post-OLT, IGFBP-3 had fallen to levels which were insignificantly different from controls. IGFBP-1 fell but remained above normal, while there was no significant change in IGFBP-2. Growth post-OLT correlated positively with serum IGF-I and negatively with IGFBP-1. In conclusion, chronic liver disease is associated with marked changes in body composition. These changes are associated with and may be caused by an impaired generation of IGF-I and altered production of IGFBPs. After OLT there is a marked improvement in growth associated with partial normalisation of the IGF-IGFBP axis. However, there are persistent abnormalities in this axis which may explain growth failure post-OLT.