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 involved in the modulation of the biological effects of the IGFs. In order to obtain more insight into the clinical significance and regulation of IGFBP-4 in vivo we determined the levels of this protein by a specific radioimmunoassay in the human circulation under normal and various pathological conditions.


METHODS
Selected human biological fluids and plasma samples from 804 normal healthy males and females, ranging from 0 to 78 years of age, were analysed. In addition, plasma samples from patients with several disorders (i.e. hypothyroidism, hyperthyroidism, GH-deficiency, acromegaly, cancer, chronic renal failure corticosteroid-treatment) were investigated.


METHODS
A specific RIA for hIGFBP-4 was developed, using a rabbit polyclonal antibody raised against a synthetic peptide containing amino acids 80-103 of the mature hIGFBP-4 sequence.


RESULTS
In normal individuals circulating IGFBP-4 levels in males did not change with age. For females the values tended to increase slightly in older age. Overall, the mean +/- SD for males and females (189 +/- 83 microg/l and 193 +/- 72 microg/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 circulating IGFBP-4 levels since the levels were within the normal range. Both GH status and pharmacological doses of glucocorticoids, as employed in various chronic diseases, did not seriously affect plasma IGFBP-4 either. Under conditions with increased circulating PTH levels, i.e. dialysed adult patients with chronic renal failure (CRF) and subjects with hyperparathyroidism, a weak positive relationship was noted between the plasma contents of IGFBP-4 and PTH. An excess of IGFBP-4 was found in plasma of both nondialysed and dialysed prepubertal growth retarded children with chronic renal failure (CRF) (mean SDS: 10.75 and 5.78, respectively). IGFBP-4 levels were inversely related to glomerular filtration rate. Similar results were obtained for dialysed adults with CRF. In a group of CRF children who had undergone renal transplantation, circulating IGFBP-4 levels were markedly lower (mean SDS: 3.75). There was no evidence for an increased secretion of IGFBP-4 in the circulation of most of the cancer patients with solid tumours. Several children with acute lymphoblastic leukaemia, however, showed elevated plasma IGFBP-4 levels (mean SDS: 1.27). The presence of IGFBP-4 could also be demonstrated in other human biological fluids. The highest amounts were found in amniotic fluid (391-717 microg/l) and follicular fluid (249-500 microg/l).


CONCLUSIONS
Measurement of plasma IGFBP-4 has been shown so far to be of minor clinical relevance. However, the results indicate that different concentration gradients between plasma and various other body fluids may exist. Therefore, it may well be that certain pathophysiological stimuli induce significant alterations in the local turnover rate of IGFBP-4 but that they are not reflected by changes in the circulating levels. The possibility of quantifying IGFBP-4 by RIA will facilitate further in vitro and in vivo studies on its regulation and function in humans.
Van Doorn
J
J
Department of Paediatrics, Laboratory of Endocrinology, Wilhelmina Children's Hospital/University Medical Centre Utrecht, Utrecht, The Netherlands. J.vandoorn@lab.azu.nl
Cornelissen
A J
AJ
Van Buul-Offers
S C
SC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D000653:Amniotic Fluid / Q000737:chemistry; D001826:Body Fluids / Q000737:chemistry*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015571:Follicular Fluid / Q000737:chemistry; D005938:Glucocorticoids / Q000627:therapeutic use; D006130:Growth Disorders / Q000097:blood; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000032:analysis*; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007335:Insulin-Like Growth Factor II / Q000032:analysis; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008895:Milk, Human / Q000737:chemistry; D009369:Neoplasms / Q000097:blood; D011863:Radioimmunoassay; D013959:Thyroid Diseases / Q000097:blood
D005938:Glucocorticoids; D018974:Insulin-Like Growth Factor Binding Protein 4; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone