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Diagnostic Value of the Acid-Labile Subunit in Acromegaly: Evaluation in Comparison with Insulin-Like Growth Factor (IGF) I, and IGF-Binding Protein-1, -2, and -3¹

Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore Istituto Ricovero e Cura a Carattere Scientifico (M.A., G.F.), I-20122 Milan; and Department of Endocrinology and Metabolism, University of Genova (S.G., A.C., F.M., A.B.), and Unit of Clinical Epidemiology and Trials, National Institute for Cancer Research (P.B.), I-16132 Genova, Italy

Address all correspondence and requests for reprints to: Dr. A. Barreca, Department of Endocrinology and Metabolism, University of Genova, Viale Benedetto XV, no 6. I-16132 Genova, Italy. E-mail: barreca{at}unige.it

In normal subjects the main form of circulating insulin-like growth factor (IGF) is the 150-kDa complex. This complex is formed by the IGF peptide, the acid-stable IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS). Experimental and clinical data have demonstrated that ALS is primarily under the control of GH and plays a critical role in maintaining constant levels of circulating IGF-I. In this study we evaluated ALS, IGF-I, and IGFBP-1, -2, and -3 in 45 acromegalic patients in basal conditions and, in 37 of these, twice after surgical therapy compared with 100 age- and sex-matched control subjects to estimate their value as parameter of GH secretory state.

The results demonstrated that in acromegaly before treatment all parameters (ALS, 523 ± 26; IGF-I, 129 ± 6; IGFBP-1, 0.7 ± 0.1; IGFBP-3, 234 ± 21; nmol/L; mean ± SEM) but IGFBP-2 were significantly different (P < 0.0001) from those in healthy subjects (ALS, 281 ± 4; IGF-I, 22 ± 1; IGFBP-1, 1.6 ± 0.1; IGFBP-3, 91 ± 3). IGF-I was more sensitive (100%) than ALS (89%), and both were more predictive of disease status than IGFBP-3, in that 27% of the patients had IGFBP-3 levels within the normal range. Considering the ALS/IGFBP-3 molar ratio, almost 55% of ALS circulated in a free form in active acromegaly. Before treatment, the IGF-I/IGFBPs (-1 + -2 + -3) molar ratio, which can be regarded as free, biologically active, IGF-I, was greatly increased (0.77 ± 0.06; P < 0.0001) compared with that in control subjects (0.23 ± 0.01).

After surgery, all 10 patients with controlled disease showed normalization of ALS (100% sensitivity), whereas 9 of them had normal IGFBP-3; reevaluation after varying lengths of time showed all these parameters within the normal range. In the 27 patients with active disease, IGF-I and ALS were more predictive of disease status (91% and 83% negative predictive values, respectively) than IGFBP-3 (53%).

The basal ALS concentration correlated only with IGFBP-3 (r = 0.70; P < 0.001). In postsurgery samples (first control) a statistically significant (P < 0.001) correlation was found between mean GH values as well as minimum GH after oral glucose tolerance test and ALS (r = 0.72 and 0.83, respectively), IGF-I (r = 0.69 and 0.77), IGFBP-3 (r = 0.50 and 0.72), and IGFBP-2 (r = -0.36 and -0.63). Similarly, IGF-I, IGFBP-3, and ALS were positively correlated among themselves and negatively correlated with IGFBP-2 (P < 0.001).

In conclusion, in the diagnosis of acromegaly, the measurement of total IGF-I appears to be the most sensitive parameter among the subunits of the 150K complex, and IGFBP-3 the least sensitive. For ALS, this subunit is quite sensitive and appears to be a useful parameter in reassessment after surgical treatment.

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