SEQUENTIAL-CHANGES IN INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) AND IGF-BINDING PROTEINS IN CHILDREN WITH END-STAGE LIVER-DISEASE BEFORE AND AFTER SUCCESSFUL ORTHOTOPIC LIVER-TRANSPLANTATION

Pediatric end-stage liver disease (ESLD) leads to poor linear growth a nd wasting. After orthotopic liver transplantation (OLT), catch-up gro wth occurs unpredictably and with a delay. The bulk of circulating ins ulin-like growth factor I(IGF-I) and its major circulating binding pro tein, IGF-binding protein-3 (IGFBP-3), is derived from the liver. We h ypothesized that growth failure in ESLD, both before and after OLT, ma y result from abnormalities in the IGF-IGFBP axis. Serum IGF-I, IGFBP- 1, and insulin were measured by RIA, and IGFBP-3 was determined by imm unoradiometric assay in 26 children with ESLD (mean of 3.7 samples pre -OLT and 4.2 samples post-OLT per patient) and 30 age-matched controls . In addition, serum IGFBPs were visualized by Western ligand blotting . IGFBP-3 and IGFBP-2 were also observed by immunoblotting with specif ic antisera. IGFBP-3 protease activity was determined by protease gels using recombinant human IGFBP-3 label as substrate. Anthropometric me asurements were performed according to standard techniques. Pre-OLT, I GF-I(32.7 +/- 4.8 mu g/L), and IGFBP-3 (1.11 +/- 0.10 mg/L) were signi ficantly lower than control values [IGF-I, 168.3 +/- 16.5 mu g/L (P = 0.0001); IGFBP-3, 2.57 +/- 0.17 mu g/L (P = 0.0001)]. Post-OLT, IGF-I( 179.2 +/- 19.7 mu g/L; P = NS) rose to control levels, whereas IGFBP-3 (3.49 +/- 0.14 mg/L; P = 0.002) became significantly greater than the control value. IGFBP-1 was significantly higher pre-OLT (78.9 +/- 9.6 mu g/L; P = 0.0001) than post-OLT (45.7 +/- 6.9 mu g/L), and both wer e significantly higher than control values (18.5 +/- 2.5 mu g/L; P = 0 .0001 us. pre-OLT and P = 0.0002 us. post-OLT). There was a trend towa rd higher insulin levels both pre-OLT (15.5 +/-1 1.8 mU/L) and post-OL T(12.5 +/- 1.4 mU/L) compared with control values (9.7 +/- 1.1 mU/L; P = 0.06 vs. pre-OLT). IGFBP-1 was negatively correlated with serum ins ulin post-OLT (P = 0.008), but there was no correlation pre-OLT. Weste rn ligand blotting confirmed the changes in IGFBP-3 pre- and post-OLT. Immunoblotting demonstrated a reduction in all mol wt forms of IGFBP- 3 pre-OLT. Protease assays demonstrated the appearance of IGFBP-3 prot eolysis only at a time coincidental with the operative stress of OLT; overall, there was no difference in protease activity pre- and post-OL T. IGFBP-2 was unchanged post-OLT compared with pre-OLT, although leve ls were higher than control values. Mid upper arm circumference and tr iceps skin fold thickness so score 3 months post-OLT and weight so sco re 1 yr post-OLT were significantly higher than those at OLT. In concl usion, IGF-I and IGFBP-3 are reduced, and IGFBP-1 and IGFBP-2 are incr eased in children with ESLD. After OLT, IGF-I levels return to normal, but marked abnormalities in IGFBPs remain. These changes may help to explain at least in part the growth failure seen in pediatric ESLD bot h before and after successful OLT.