Introduction: Acid-labile subunit (ALS) is a glycoprotein, which is produced in the liver in response to growth hormone (GH), with its main role being the formation of a complex with insulin-like growth factor 1 (IGF-1) and IGF-binding-protein-3 (IGFBP-3) in order to extend their circulating half-life and thus support the action of GH. Acid-labile subunit-deficient patients are of research interest because of the unclear incidence of the condition among the short-statured population and the need of specific therapeutic approach.
Aim: The aim of this study is to assess the prevalence of ALS deficiency in a cohort of patients with GH deficiency (GHD) followed up in a tertiary university pediatric endocrinology center.
Design: The study participants were 71 children (76% boys, age range 2–18 years), diagnosed with GHD by 2 standard GH-stimulation tests (max GH < 10 ng/mL), on GH therapy, and at mean age at the time of collection of samples: 11.6 ± 3.3 years. Blood serum samples were collected from each patient during the routine visits at the center, and then were stored frozen at -80℃ in 0.5 mL aliquots until analysis.
Results: Acid-labile subunit deficiency screening identified serum ALS levels with range from 2.2 to 60 mg/L, with a mean of 17.4 ± 8.7 mg/L. The mean ALS levels were significantly lower than the published ones from subjects without short stature but close to the levels in the referred for GHD patients (6.5 ± 4.8 mg/L). Very low ALS levels (< 4.0 mg/L) were detected in 3 (4.2%) of the patients. The low ALS levels corresponded with low SDSheight (-2.8 ± 1.2) and low SDSIGF-1 (-1.4 ± 1.0) before therapy. In one of the 3 patients, the ALS level (2.2 mg/L) was close to that in patients with IGFALS gene mutations (< 1.0 mg/L).
Conclusion: The present results show the prevalence of ALS deficiency in the current GH treated cohort and support the evidence that investigation of ALS levels could be helpful in the differential diagnosis of growth disorders.
Zaidman V. Analysis of acid-labile subunit and its usefulness in pediatrics. Arch Argent Pediatr. 2017;115(4):391-8. doi: 10.5546/aap.2017.eng.391.
Twigg S, Kiefer M, Zapf J, Baxter R. Insulin-like growth factor-binding protein 5 complexes with the acid-labile subunit. Role of the carboxyl-terminal domain. J Biol Chem. 1998;273(44):28791-8. doi: 10.1074/jbc.273.44.28791.
Kim H, Fu Y, Hong H, Lee S, Lee D, Kim H. Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex. Nat Commun. 2022;13(1):4434. doi: 10.1038/s41467-022-32214-2.
Domené H, Hwa V, Argente J, Wit J, Camacho-Hübner C, Jasper H, et al. International ALS Collaborative Group. Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences. Horm Res. 2009;72(3):129-41. doi: 10.1159/000232486.
Baxter R, Martin J, Beniac V. High molecular weight insulin-like growth factor binding protein complex. Purification and properties of the acid-labile subunit from human serum. J Biol Chem. 1989;264(20):11843-8.
Baxter R. Circulating levels and molecular distribution of the acid-labile (alpha) subunit of the high molecular weight insulin-like growth factor-binding protein complex. J Clin Endocrinol Metab. 1990;70(5):1347-53. doi: 10.1210/jcem-70-5-1347.
David A, Kelley L, Sternberg M. A new structural model of the acid-labile subunit: pathogenetic mechanisms of short stature-causing mutations. J Mol Endocrinol. 2012;49(3):213-20. doi: 10.1530/JME-12-0086.
Fukuda I, Hotta M, Hizuka N, Takano K, Ishikawa Y, Asakawa-Yasumoto K, et al.. Decreased serum levels of acid-labile subunit in patients with anorexia nervosa. J Clin Endocrinol Metab. 1999;84(6):2034-6. doi: 10.1210/jcem.84.6.5737.
Barrios V, Argente J, Muñoz M, Pozo J, Chowen J, Hernández M. Diagnostic interest of acid-labile subunit measurement in relationship to other components of the IGF system in pediatric patients with growth or eating disorders. Eur J Endocrinol. 2001;144(3):245-50. doi: 10.1530/eje.0.1440245.
Domené H, Scaglia P, Martínez A, Keselman A, Karabatas L, Pipman V, et al. Heterozygous IGFALS gene variants in idiopathic short stature and normal children: impact on height and the IGF system. Horm Res Paediatr. 2013;80(6):413-23. doi: 10.1159/000355412.
Domené S, Domené H. The role of acid-labile subunit (ALS) in the modulation of GH-IGF-I action. Mol Cell Endocrinol. 2020;518:111006. doi: 10.1016/j.mce.2020.111006.
Işık E, Haliloglu B, van Doorn J, Demirbilek H, Scheltinga S, Losekoot M, Wit J. Clinical and biochemical characteristics and bone mineral density of homozygous, compound heterozygous and heterozygous carriers of three novel IGFALS mutations. Eur J Endocrinol. 2017;176(6):657-67. doi: 10.1530/EJE-16-0999.
Baxter R. Insulin-like growth factor binding proteins in the human circulation: a review. Horm Res. 1994;42(4-5):140-4. doi: 10.1159/000184186.
Juul A, Møller S, Mosfeldt-Laursen E, Rasmussen M, Scheike T, Pedersen S, et al. The acid-labile subunit of human ternary insulin-like growth factor binding protein complex in serum: hepatosplanchnic release, diurnal variation, circulating concentrations in healthy subjects, and diagnostic use in patients with growth hormone deficiency. J Clin Endocrinol Metab. 1998;83(12):4408-15. doi: 10.1210/jcem.83.12.5311.
Barrios V, Pozo J, Muñoz M, Buño M, Argente J. Normative data for total and free acid-labile subunit of the human insulin-like growth factor-binding protein complex in pre- and full-term newborns and healthy boys and girls throughout postnatal development. Horm Res. 2000;53(3):148-53. doi: 10.1159/000023554.
Ertl D, Chen J, Gleiss A, Janu D, Sagmeister S, Raimann A, et al. Diagnostic Value of Serum Acid-Labile Subunit Alone and in combination with IGF-I and IGFBP-3 in the Diagnosis of Growth Hormone Deficiency. Horm Res Paediatr. 2020;93(6):371-9. doi: 10.1159/000512336.
Grimberg A, DiVall S, Polychronakos C, Allen D, Cohen L, Quintos J, et al. Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society. Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. Horm Res Paediatr. 2016;86(6):361-97. doi: 10.1159/000452150.
Friedrich N, Wolthers O, Arafat A, et al. Age- and sex-specific reference intervals across life span for insulin-like growth factor binding protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 ratio measured by new automated chemiluminescence assays. J Clin Endocrinol Metab. 2014;99(5):1675-86. doi: 10.1210/jc.2013-3060.
Yakar S, Rosen C, Beamer W, Ackert-Bicknell C, Wu Y, Liu J, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002;110(6):771-81. doi: 10.1172/JCI15463.
Storr H, Prasad R, Temple I, Metherell L, Savage M, Walker J. Heterogeneity of the growth phenotype and birth size in acid-labile subunit (ALS) deficiency. J Endocrinol Invest. 2015;38(4):407-12. doi: 10.1007/s40618-014-0195-1.
Khosravi M, Diamandi A, Mistry J, Krishna R, Khare A. Acid-labile subunit of human insulin-like growth factor-binding protein complex: measurement, molecular, and clinical evaluation. J Clin Endocrinol Metab. 1997;82(12):3944-51. doi: 10.1210/jcem.82.12.4415.
van Dommelen P, van Zoonen R, Vlasblom E, Wit J, Beltman M; Expert Committee. Guideline for referring short or tall children in preventive child health care. Acta Paediatr. 2021;110(4):1231-8. doi: 10.1111/apa.15625.
Poyrazoğlu Ş, Hwa V, Baş F, Dauber A, Rosenfeld R, Darendeliler F. A novel homozygous mutation of the acid-labile subunit (IGFALS) gene in a male adolescent. J Clin Res Pediatr Endocrinol. 2019;11(4):432-8. doi: 10.4274/jcrpe.galenos.2019.2018.0301.
Fofanova-Gambetti O, Hwa V, Wit J, Domene H, Argente J, Bang P, et al. Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium. J Clin Endocrinol Metab. 2010;95(9):4184-91. doi: 10.1210/jc.2010-0489.
Schilbach K, Olsson D, Boguszewski M, Bidlingmaier M, Johannsson G, Jørgensen J. Biomarkers of GH action in children and adults. Growth Horm IGF Res. 2018;40:1-8. doi: 10.1016/j.ghir.2018.03.005.
Nimura A, Katsumata N, Horikawa R, Tanae A, Tanaka T. Acid-labile subunit (ALS) measurements in children. Endocr J. 2000;47 Suppl:S111-4. doi: 10.1507/endocrj.47.supplmarch_s111.
Fukuda I, Hizuka N, Itoh E, Yasumoto K, Ishikawa Y, Murakami Y, et al. Acid-labile subunit in growth hormone excess and deficiency in adults: evaluation of its diagnostic value in comparison with insulin-like growth factor (IGF)-I and IGF-binding protein-3. Endocr J. 2002;49(3):379-86. doi: 10.1507/endocrj.49.379.
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