Major changes in serum levels of insulin-like growth factor
After secretion from the anterior pituitary gland, growth hormone (GH) binds to specific cell-surface receptors I (IGF-I) and IGF-binding proteins (IGFBPs) occur in children with end-stage liver disease in association with changes in (GHRs) through which it exerts its actions. GH has both metabolic and anabolic actions, 1 but the bulk of its anabolic body composition. We hypothesized that these changes would be associated with changes in hepatic messenger RNA actions are mediated through the generation of the mitogenic polypeptide insulin-like growth factor (IGF)-I. 2 IGF-I and (mRNA) expression. Eleven children with end-stage extrahepatic biliary atresia and 11 controls (liver donors) were stud-IGF-II have profound effects on the regulation of proliferation and differentiation of many cell types, acting through ied. Serum samples were obtained from the children with biliary atresia immediately before orthotopic liver transplanta-autocrine, paracrine, and classical endocrine mechanisms. 3 Although IGF-I is synthesized widely, the majority of circu-tion. Serum IGF-I, IGFBP-1, and IGFBP-2 levels were measured by radioimmunoassay, and IGFBP-3 by immunoradio-lating IGF-I is derived from the liver. 4 The IGFs are present in the circulation and throughout metric assay. In both groups, growth hormone receptor mRNA expression was examined by quantitative reverse transcrip-the extracellular space almost entirely bound to members of a family of high-affinity IGF-binding proteins (IGFBP-1 to tion-polymerase chain reaction, IGF-I mRNA expression by ribonuclease protection assay, and IGFBP-1 to -4 mRNA ex--6) that are essential to coordinate and regulate the biological functions of the IGFs; the IGFBPs 1) transport IGFs and pression by Northern analysis. Growth hormone receptor and IGF-I mRNA levels were reduced 1.7-fold (P Γ
.003) and 9.6-control their efflux from the circulation; 2) prolong the halflives of IGFs and regulate their metabolic clearance; 3) pro-fold (P Γ
.0001) in biliary atresia compared with levels in controls. Despite increased serum IGFBP-1 levels and reduced vide a means of tissue and cell type specificity; and 4) directly modulate the interactions of IGFs with their receptors. 5 IGFBP-3 levels in biliary atresia, there was no change in either IGFBP-1 or IGFBP-3 mRNA expression. In contrast, serum Fifty percent of children with established cirrhosis have abnormal growth or malnutrition, which is associated with levels and mRNA expression of IGFBP-2 were increased 1.6fold (P Γ
.003) and twofold (P Γ
.0001), respectively, com-a poor quality of life from frequent complications and hospitalization and ultimately death. 6 Previous studies have found pared with controls. Gene expression did not correlate with liver dysfunction or body composition. Changes in growth major abnormalities in the GH-IGF-IGFBP axis in cirrhosis. 7,8 Serum GH levels are raised, whereas IGF-I levels are hormone receptor and IGF-I mRNA expression may account for the reduction in serum IGF-I found in pediatric liver dis-universally low in liver failure, suggesting the acquisition of a GH resistant state. Marked changes in serum IGFBPs occur, ease. In contrast, the marked alteration in circulating IGFBP levels was not accompanied by changes in hepatic IGFBP gene leading to an increase in IGFBP-1 and IGFBP-2 and a decrease in IGFBP-3. expression, suggesting that posttranslational mechanisms may be important. (HEPATOLOGY 1997;26:1600-1606.)
The underlying mechanisms of these changes are unknown, but reduced synthetic capacity secondary to hepatocellular dysfunction and malnutrition may contribute to a derangement of the growth axis. In rat models of liver dis-Abbreviations: GH, growth hormone; GHRs, GH receptors; IGF, insulin-like growth ease, there is a poor correlation between changes in serum factor; IGFBP, IGF binding protein; EHBA, extrahepatic biliary atresia; OLT, orthotopic levels of IGFBPs and hepatic gene expression. 9 liver transplantation; MAC, midarm circumference; TSF, triceps skinfold thickness;
To assess whether changes in serum levels of IGF-I and cRNA, control RNA; bp, base pair; GAPDH, glyceraldehyde-3-phosphate dehydroge-IGFBPs are associated with underlying changes in hepatic nase; cDNA, complementary DNA; RT, reverse transcription; PCR, polymerase chain reaction; mRNA, messenger RNA; SDS, sodium dodecyl sulfate; SSC, salt-sodium ci-gene expression in children, this study examined steady-state trate; SD, standard deviation. hepatic gene expression of GHR, IGF-I, and IGFBP-1 to From the Departments of 1 Medicine and 2 Child Health and the 3 Institute of Liver -4 in 11 children with end-stage extrahepatic biliary atresia Studies, King'