EVALUATION OF INSULIN-LIKE GROWTH FACTOR-1 AND INSULINLIKE GROWTH FACTOR BINDING PROTEIN-3 IN DIAGNOSIS OF GROWTH HORMONE DEFICIENCY IN SHORT-STATURE CHILDREN
Abstract
Background: Growth Hormone Deficiency (GHD) is conventionally diagnosed and confirmed bydiminished peak Growth Hormone (GH) levels to provocative testing. Serum Insulin-like growthfactor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are under the influence ofGH and reflect the spontaneous endogenous GH secretion. Owing to the absence of a circadian rhythm,it is possible to take individual measurements of IGF-1 and IGFBP-3 at any time of the day forevaluation of GH status instead of subjecting the individual to cumbersome provocative tests.Objectives of this study were to compare IGF-1 and IGFBP-3 assays with Exercise and L-Dopastimulation tests in the diagnosis of growth hormone deficiency in short stature children using ITT asgold standard. Methods: This validation study was conducted at Department of Chemical Pathologyand Endocrinology, AFIP, Rawalpindi, from November 2005 to October 2006. Fifty-two short staturechildren were included in the study. Basal samples for GH levels and simultaneous IGF-1 and IGFBP-3measurements were obtained and afterwards all children were subjected to sequential exercise and LDopa stimulation tests. Insulin Tolerance Test (ITT) was performed one week later with all thenecessary precautionary measures. On the basis of ITT results, children were divided into two groups,i.e., 31 growth hormone deficient and 21 Normal Variant Short Stature (NVSS). Results: Thediagnostic value of exercise stimulation test remained highest with sensitivity 90.3%, specificity 76.0%,Positive Predictive Value (PPV) 84.84%, Negative Predictive Value (NPV) 84.2% and accuracy84.6%. The conventional L-Dopa stimulation had sensitivity 96.7%, specificity 38.0%, PPV 69.7%,NPV 88.8 % and accuracy 73.0%. The serum IGF-1 and IGFBP-3 levels were positively correlatedwith post ITT peak GH levels (r= 0.527, r=0.464 respectively, both p<0.001). The diagnostic value ofIGF-1 had sensitivity 83.87%, specificity 76.2%, PPV 83.87%, NPV 76.2% and accuracy 80.76%. Thediagnostic value of IGFBP-3 had sensitivity 54.83%, specificity 90.47%, PPV 89.47%, NPV 57.57%and accuracy 69.23%. With combined use of IGF-1 and IGFBP-3 diagnostic value had sensitivity69.35%, specificity 83.33% PPV 86%, NPV 64.81% and accuracy 75%. Conclusion GrowthHormones provocative tests still remain the most useful investigations for the diagnosis of GHD.Measurements of IGF-1 and IGFBP-3 have shown comparable diagnostic performance with growthhormone stimulation tests and are valuable for patients’ convenience and ease of performance and canbe useful in the initial workup of short stature.Keywords: Growth Hormone Deficiency, Insulin-like Growth Factor-1, IGF-1, Insulin-like GrowthFactor Binding Protein-3, Normal Variant Short StatureReferences
Agarwal YP, Lewandrowski K. Laboratory evaluation of
pituitary disorders, adrenal cortex and medulla and selected
neuroendocrine tumours. In: Lewandrowski K. Clinical
chemistry; Laboratory management and clinical correlations.
Philadelphia: Lippincot Williams and Wilkins; 2002. p. 607–8.
Styne DM. Growth. In: Greenspoon FS, Gardener DG. Basic
and clinical endocrinology. 7th ed. New york: Mc Graw Hill;
p. 177–213.
Awan TM, Sattar A, Khattak EG. Frequency of growth
hormone deficiency in short stature children. J Coll
Physicians Surg Pak 2005;15:295–8.
Styne DM. Growth disorders. In: Fitzgerald PA. Handbook
of clinical endocrinology. 2nd ed. London: Prentice-Hall Int;
p.100–18.
Shah A, Stanhope R, Mathew D. Hazards of pharmacological
tests of growth hormone secretion in childhood. BMJ
;304:173–4.
Ranke MB, Schweizer R, Lindberg A, Price DA, Reiter EO,
Albertson-Wikland K, et al. Insulin-like growth factors as
diagnostic tools in growth hormone deficiency during
childhood and adolescence: the KIGS experience. Horm Res
;62(suppl 1):17–25.
Dehiya RK, Bhartiya D, Kapadia C, Desai MP. Insulin-like
growth factor-1, insulin-like growth factor binding protein-3
and acid labile subunit levels in healthy children and
adolescents residing in Mumbai Suburbs. Indian Pediatr
;37:990–7.
Rosen JC. Serum insulin-like growth factors and insulin-like
growth factor binding proteins: clinical implications. Clin
Chem 1999;45:1384–90.
Blum WF, Albertson-Wikland K, Rosberg S, Ranke MB.
Insulin like growth factor-1 (IGF-1) and IGF binding protein-
(IGFBP-3) reflect spontaneous growth hormone (GH)
secretion. J Clin Endocrinol Metab 1993;76:1610–6.
Jaruratanasirikul S. The usefulness of serum insulin-like
growth factor-1 (IGF-1) and insulin-like growth factor
binding pritein-3 (IGFBP-3) for evaluation of children with
short stature. J Med Assoc Thai 2000;83:619–26.
Elmlinger MW, Zwimer, Kuhnel W. Stability of Insulin-Like
Growth Factor (IGF)-I and IGF Binding Protein-3 (IGFBP)-3
measured by the Immulite® automated Chemi-Luminescence
assay system in different blood specimens. Clin Lab
;51:145–52.
IMMULITE Growth Hormone (hGH), Technical Instructions
for use on Immulite 1000 systems. Diagnostic Products
Corporation (DPC), Los Angeles, USA 2005:1–6.
IMMULITE IGF-1, Technical Instructions for use on
Immulite 1000 systems. Diagnostic Products Corporation
(DPC), Los Angeles, USA 2005:1–7.
IMMULITE IGFBP-3, Technical Instructions for use on
Immulite1000 systems. Diagnostic Products Corporation
(DPC), Los Angeles, USA 2005:1–7.
Nicoll AG, Smail PJ, Forsyth CC. Exercise test for growth
hormone deficiency. Arch Dis Child 1984;59:1177–8.
Liberman B, Cesar FP, Wajchenberg BL. Human growth
hormone (hGH) stimulation tests: the sequential exercise and
L-dopa procedure. Clin Endocrinol (Oxf) 1979;10:649–54.
Demers LM, Vance ML. Pituitary function. In: Burtis CA,
Ashwood ER, Burns DE. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 4th ed. Missouri:
Saunders; 2006.p. 1967–2002.
Eddy RL, Jones AL, Chakmakjian ZH, Silverthorne MC.
Effects of levodopa (L-Dopa) on human hypophyseal tropic
hormone release. J Clin Endocrinol Metab 1971;33:709–12.
Biller Beverly MK, Samuels MH, Zagar A, Cook DM,
Arafah BM, Bonert V, et al. Sensitivity and specificity of six
tests for the diagnosis of adult GH Deficiency. J Clin
Endocrinol Metab 2002;87:2067–79.
Blum WF, Ranke MB. Use of insulin-like growth factorbinding protein-3 for the evaluation of growth disorders.
Horm Res 1990;33(Suppl 4):31–7.
Blum WF, Ranke MB. Insulin-like growth factor binding
proteins (IGFBPs) with special reference to IGFBP-3. Acta
Pediatr Scand 1990;367(Suppl):55–62.
Hasegawa Y, Hasegawa T, Tadaka M, Tsuchiya Y. Plasma
free insulin-like growth factor-1 concentrations in growth
hormone deficiency in children and adolescents. Eur J
Endocrinol 1996;134:184–9.
Granada ML, Murillo J, Lucas A, Salinas I, Lopis MA,
Castells I, et al. Diagnostic efficiency of serum IGF-1, IGFbinding protein-3 (IGFBP-3), IGF-1/IGFBP-3 molar ratio
and urinary GH measurements in the diagnosis of adult GH
deficiency: importance of an appropriate reference
population. Eur J Endocrinol 2000;142:243–53.
Juul A, Kastrup KW, Pederson SA, Skakkebaek NE. Growth
hormone (GH) provocative retesting of 108 young adults
with childhood-onset GH deficiency and the diagnostic value
of insulin-like growth factor-1 and IGF-binding protein-3. J
Clin Endocrinol Metab 1997;82:1195–201.
Cianfarani S, Liguori A, Boemi S, Maghnie M, Iughetti L,
Wasniewska M, et al. Inaccuracy of insulin-like growth
factor binding protein-3 (IGFBP-3) assessment in the
diagnosis of growth hormone deficiency from childhood to
young adulthood: association to low GH dependency of IGFII and presence of circulating IGFBP-3 18- kilodalton
fragment. J Clin Endocrinol Metab 2005;90:6028–34.
Milani D, Carmichael JD, Welkowitz J, Ferris S, Reitz RE,
Danoff A, et al. Variability and reliability of single serum
IGF-I measurements: impact on determining predictability of
risk ratios in disease development. J Clin Endocrinol Metab
;89:2271–74.
Harrela M, Koistinen H, Kaprio J, Lehtovirta M, Tuomilehto J,
Eriksson J, et al. Genetic and environmental components of
inter-individual variation in circulating levels of IGF-I, IGF-II,
IGFBP-1, and IGFBP-3. J Clin Invest 1996;98:2612–5.
Cianfarani S, Boemi S, Spagnoli A, Cappa M, Argirò G,
Vaccaro F, et al. Is IGF binding protein-3 assessment helpful
for the diagnosis of GH deficiency? Clin Endocrinol
;43:43–7.
Cianfarani S, Tondinelli T, Spadoni GL, Scirè G, Boemi S,
Boscherinia B. Height velocity and IGF-1 assessment in the
diagnosis of childhood-onset GH insufficiency: do we still
need second GH stimulation test? Clin Endocrinol
;57:161–7.
Boquete HR, Sobrado PGV, Fideleff HL, Sequera AM,
Giaccio AV, et al. Evaluation of diagnostic accuracy of
insulin-like growth factor-1 and IGF-binding protein-3 in
growth hormone-deficient children and adults using ROC
plot analysis. J Clin Endocrinol Metab 2003;88:4702–8.
Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ,
Bierich JR. A specific radioimmunoassay for the growth
hormone (GH)-dependent somatomedin binding protein: its
use for diagnosis of GH deficiency. J Clin Endocrinol Metab
;70:1292–8.
J Ayub Med Coll Abbottabad 2009;21(3)
http://www.ayubmed.edu.pk/JAMC/PAST/21-3/Asif.pdf 45
Hasegawa Y, Hasegawa T, Aso T, Kotoh S, Nose O, Ohyama
Y, et al. Clinical utility of insulin-like growth factor binding
protein-3 in the evaluation and treatment of short children
with suspected growth hormone deficiency. Eur J Endocrinol
;131:27–32.
Nunez AB, Municchi G, Barnes KM, Rose SR. Insulin-like
growth factor-1 and IGF-binding protein-3 concentrations
compared to stimulated and night growth hormone in the
evaluation of short children- a clinical research centre study.
J Clin Endocrinol Metab 1996;81:1927–32.
Juul A, Skakkebaek NE. Prediction of the outcome of growth
hormone provocative testing in short children by
measurement of serum levels of insulin-like growth factor-1
and insulin-like growth factor binding protein 3. J Pediatr
;130:197–204.
Tillman V, Buckler JMH, Kibirige MS, Price DA, Shalet
SM, Wales JKH, et al. Biochemical tests in the diagnosis of
childhood growth hormone deficiency. J Clin Endocrinol
Metab 1997;82:531–35.
Rikken B, van Doorn J, Ringeling A, van den Brande JL,
Massa G, Wit JM. Plasma levels of insulin-like growth factor
(IGF)-I, IGF-II and IGF-binding protein-3 in the evaluation
of childhood growth hormone deficiency. Horm Res
;50:166–76.
Baxter RC. Circulating binding proteins for the insulin-like
growth factors. Trends Endocrinol Metab 1993;4:91–6.
Rosenfeld RG, Wilson DM, Lee PDK, Hintz RL. Insulin-like
growth factors I and II in evaluation of growth retardation. J
Pediatr 1986;109:428–33.
Hossenlopp P, Sergovia B, Lassarre C, Roghani M, Bredon
M, Binoux M. Evidence of enzymatic degradation of insulinlike growth factor binding proteins (IGFBPs) in the 150 K
complex during pregnancy. J Clin Endocrinol Metab
;71:797–805.
Mitchell H, Dattani MT, Nanduri V, Hindmarsh PC, Preece MA,
Brook CGD. Failure of IGF-I and IGFBP-3 to diagnose growth
hormone insufficiency. Arch Dis Child 1999;80:443–7.
Thissen JP, Ketelslegers JM. Underwood LE. Nutritional
regulation of the insulin-like growth factors. Endocr Rev
;5:80–101.
Miell JP, Taylor AM. Zini M. Maheshwari HG. Ross RJM,
Valcavi R. Effects of hypothyroidism and hyperthyroidism
on insulin-like growth factors and growth hormone and IGFbinding protein. J Clin Endocrinol Metab 1993:76:950–5.
Tonshoff B, Blum WF, Wingren AM, Mehls O. Serum
insulin-like growth factors and IGF binding protein 1, 2 and
in children with chronic renal failure: relationship to height
and glomerular filtration rate. J Clin Endocrinol Metab
;80:2684–91.
Downloads
Published
Issue
Section
License
Journal of Ayub Medical College, Abbottabad is an OPEN ACCESS JOURNAL which means that all content is FREELY available without charge to all users whether registered with the journal or not. The work published by J Ayub Med Coll Abbottabad is licensed and distributed under the creative commons License CC BY ND Attribution-NoDerivs. Material printed in this journal is OPEN to access, and are FREE for use in academic and research work with proper citation. J Ayub Med Coll Abbottabad accepts only original material for publication with the understanding that except for abstracts, no part of the data has been published or will be submitted for publication elsewhere before appearing in J Ayub Med Coll Abbottabad. The Editorial Board of J Ayub Med Coll Abbottabad makes every effort to ensure the accuracy and authenticity of material printed in J Ayub Med Coll Abbottabad. However, conclusions and statements expressed are views of the authors and do not reflect the opinion/policy of J Ayub Med Coll Abbottabad or the Editorial Board.
USERS are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. This is in accordance with the BOAI definition of open access.
AUTHORS retain the rights of free downloading/unlimited e-print of full text and sharing/disseminating the article without any restriction, by any means including twitter, scholarly collaboration networks such as ResearchGate, Academia.eu, and social media sites such as Twitter, LinkedIn, Google Scholar and any other professional or academic networking site.
