Plasma levels of insulin-like growth factor binding protein-4 (IGFBP-4) under normal and pathological conditions

OBJECTIVE Insulin-like growth factor binding protein-4 (IGFBP-4) belongs to a family of six structurally related IGF-binding proteins that are involve d in the modulation of the biological effects of the IGFs. In order to obta in more insight into the clinical significance and regulation of IGFBP-4 in vivo we determined the levels of this protein by a specific radioimmunoass ay in the human circulation under normal and various pathological condition s. DESIGN AND PATIENTS Selected human biological fluids and plasma samples fro m 804 normal healthy males and females, ranging from 0 to 78 years of age, were analysed. In addition, plasma samples from patients with several disor ders (i.e. hypothyroidism, hyperthyroidism, GH-deficiency, acromegaly, canc er, chronic renal failure corticosteroid-treatment) were investigated. MEASUREMENTS A specific RIA for hIGFBP-4 was developed, using a rabbit poly clonal antibody raised against a synthetic peptide containing amino acids 8 0-103 of the mature hIGFBP-4 sequence. RESULTS In normal individuals circulating IGFBP-4 levels in males did not c hange with age. For females the values tended to increase slightly in older age. Overall, the mean +/- SD for males and females (189 +/- 83 mug/l and 193 +/- 72 mug/l, respectively) were not different. Normative range values of IGFBP-4 correlated weakly with those of IGF-II (r = 0.31, P < 0.001). Neither hypothyroidism nor hyperthyroidism appeared to influence circulatin g IGFBP-4 levels since the levels were within the normal range. Both GH sta tus and pharmacological doses of glucocorticoids, as employed in various ch ronic diseases, did not seriously affect plasma IGFBP-4 either. Under condi tions with increased circulating PTH levels, i.e. dialysed adult patients w ith chronic renal failure (CRF) and subjects with hyperparathyroidism, a we ak positive relationship was noted between the plasma contents of IGFBP-4 a nd PTH. An excess of IGFBP-4 was found in plasma of both nondialysed and di alysed prepubertal growth retarded children with chronic renal failure (CRF ) (mean SDS: 10.75 and 5.78, respectively). IGFBP-4 levels were inversely r elated to glomerular filtration rate. Similar results were obtained for dia lysed adults with CRF. In a group of CRF children who had undergone renal t ransplantation, circulating IGFBP-4 levels were markedly lower (mean SDS: 3 .75). There was no evidence for an increased secretion of IGFBP-4 in the ci rculation of most of the cancer patients with solid tumours. Several childr en with acute lymphoblastic leukaemia, however, showed elevated plasma IGFB P-4 levels (mean SDS: 1.27). The presence of IGFBP-4 could also be demonstr ated in other human biological fluids. The highest amounts were found in am niotic fluid (391-717 mug/l) and follicular fluid (249-500 mug/l). CONCLUSIONS MEASUREMENT of plasma IGFBP-4 has been shown so far to be of mi nor clinical relevance. However, the results indicate that different concen tration gradients between plasma and various other body fluids may exist. T herefore, it may well be that certain pathophysiological stimuli induce sig nificant alterations in the local turnover rate of IGFBP-4 but that they ar e not reflected by changes in the circulating levels. The possibility of qu antifying IGFBP-4 by RIA will facilitate further in vitro and in vivo studi es on its regulation and function in humans.