The Relevance of Insulin-Like Growth Factor-1 and Insulin-Like Growth FactorBinding Protein-3 Concentrations as a Screening Test for Diagnosis of Growth Hormone Deficiency

Abstract

Background and objective: Growth hormone deficiency (GHD) is one of the most important endocrine and treatable causes of short stature. Reports regarding the sensitivity and specificity of insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-3) are not consistent. The aim of our study was to analyze the relevance of IGF-1 and IGFBP-3 concentrations as a screening test for diagnosis of GHD. Design: We retrospectively studied 40 patients whom were evaluated for short stature at the Endocrinology Department of King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia between January 2015 to December 2018. For IGF-1 and IGFBP-3 concentrations, laboratory reference ranges were based on age and sex. For all eligible patients, IGF-1 and IGFBP-3 concentrations were determined and an insulin tolerance test (ITT) was performed. Patients with a peak GH of ≤5.0 ng/ml were considered to be GHD. Results: We retrospectively included 40 patients evaluated for SS for analysis. Mean age was 14.7 ±1.7 years. There were 38 males (80.9%) and 9 females (19.1%) and mean IGF-1 concentration was 146.4 ±69.4 ng/dl. The observed male to female ratio was 4.2:1. Results from the ITT indicated that 27 (57.4%) had GHD. Age was not statistically significant different between GHD (14.7 ±1.8 years) and non-GHD (14.8 ±1.6 years), p=0.9. Moreover, there was non statistical significant more males (59%) than females (50%) in the GHD patients, P=0.7. In addition, there were not statistically significantly different between GHD and non-GHD patients in mean IGF-1 concentration (156.0 ±71.1 ng/dl vs. 140.8 ±68.1 ng/dl, p=0.5) and IGFBP-3 concentration (3752.9 ±1295.9mcg/L vs. 3816.8 ±867.0mcg/L, p=0.9). The mean peak for GH concentration was significantly lower in patients with GHD than without GHD (2.2 ±1.3 ng/ml vs. 9.9 ±5.6 ng/ml, p<0.0001). Peak GH concentration was not significantly positively correlated with IGF-1 concentration (r=0.181, P=0.3) and IGFBP-3 concentration (r=0.103, P=0.5). With a threshold of IGF-1 concentration, sensitivity was 48% (95% confidence interval (95%CI); 26%, 70%), specificity was 37% (95%CI; 16%, 62%) and the negative predictive value for the diagnosis of GHD was 39% (95% CI; 24%, 57%). With a threshold of IGF-1+IGFBP-3 concentration, the sensitivity was 19% (95% CI; 5%, 42%) and the specificity was 89% (95%CI; 67%, 99%). A positive predictive value of 67% (95% CI; 29%, 91%) but a negative predictive value of 50% (95%CI; 44%, 56%). 17 of the patients with IGF-1+IGFBP-3 concentration above the threshold (N = 34) were normal and 17 had GH deficiency. These 17 GHD patients had IGF-1+IGFBP-3 concentration below the reference range for age and sex that did not differ significantly from those of their GH-sufficient counterparts (66.7% vs 50% , P=0.7) respectively. If IGF1+IGFBP-3 concentration was used as a screening test (with a concentration threshold below the reference range for age and sex) and ITT as a confirmatory test, 34 (85%) out of 40 ITT would not have been performed, leading to the misdiagnosis of 17 GH-deficient adults. Thus, in our study population, such a procedure would misdiagnose 17 out of 21 GHD patients (81%) and yield a sensitivity of 19%. Conclusion: Our study demonstrated the good negative predictive value of IGF-1+IGFBP-3 concentration for the diagnosis of GHD, making it possible to minimize the use of the “reference test” method ITT. This observation remains to be validated by population-based studies.