Subscribe to RSS
DOI: 10.1055/a-2690-6416
The Application of Assay- and Age-Specific Parathyroid Hormone (PTH) Reference Intervals Decreases the Diagnosis of Normocalcaemic Primary Hyperparathyroidism and Improves Diagnostic Concordance of PTH Assays

Abstract
Parathyroid hormone (PTH) assays are not standardized and therefore PTH results are interpreted using manufacturer-provided assay-specific reference intervals. Assay-specific PTH reference intervals, however, do not account for between-assay differences and lead to discordance in the diagnosis of normocalcaemic primary hyperparathyroidism (NCPHPT). PTH increases with age independent of vitamin D, renal function, phosphate and ionized calcium. The observed variations in age-nonspecific PTH reference intervals may, in part, be attributed to the varying proportions of individuals from different age sub-sets included in the direct sampling reference interval studies. We assessed the impact of recently derived age-specific reference intervals for Abbott and Roche PTH assays on the diagnosis and diagnostic concordance of previously identified NCPHPT individuals. Of the 46 NCPHPT individuals identified using elevated Abbott PTH, only 16 (35%) were concordant for NCPHPT whereas 30 (65%) had normal PTH when samples were analysed by the Roche method and results were interpreted using the manufacturer-provided reference intervals for both methods. However, interpreting results using the method-specific age-related PTH reference intervals resulted in 31 (67%) individuals having a concordant normal PTH, eight (17%) having concordant NCPHPT and only seven (15%) remaining discordant (NCPHPT by Abbott and normal by Roche methods). Application of assay- and age-specific reference intervals decreases the diagnosis of NCPHPT and improves diagnostic concordance between PTH assays. We suggest that the diagnosis of NCPHPT should be based on assay- and age-specific PTH reference intervals. Until PTH assays are harmonized, subsequent PTH measurements for NCPHPT patients should ideally be performed using the same assay.
Keywords
normocalcaemic hyperparathyroidism - age-specific PTH reference intervals - discordance - intact PTHPublication History
Received: 30 January 2025
Accepted after revision: 22 August 2025
Article published online:
08 September 2025
© 2025. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
-
References
- 1 Bilezikian JP, Bandeira L, Khan A. et al. Hyperparathyroidism. Lancet 2018; 391: 168-178
- 2 Yeh MW, Ituarte PHG, Zhou HC. et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab 2013; 98: 1122-1129
- 3 Bilezikian JP, Khan AA, Silverberg SJ. et al. Evaluation and management of primary hyperparathyroidism: summary statement and guidelines from the fifth international workshop. J Bone Miner Res 2022; 37: 2293-2314
- 4 Zavatta G, Clarke BL. Normocalcemic hyperparathyroidism: a heterogeneous disorder often misdiagnosed?. JBMR Plus 2020; 4: e10391
- 5 Schini M, Jacques RM, Oakes E. et al. Normocalcemic hyperparathyroidism: study of its prevalence and natural history. J Clin Endocrinol Metab 2020; 105: e1171-e1186
- 6 Cusano NE, Cipriani C, Bilezikian JP. Management of normocalcemic primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab 2018; 32: 837-845
- 7 Vignali E, Cetani F, Chiavistelli S. et al. Normocalcemic primary hyperparathyroidism: a survey in a small village of Southern Italy. Endocr Connect 2015; 4: 172-178
- 8 García-Martín A, Reyes-García R, Muñoz-Torres M. Normocalcemic primary hyperparathyroidism: one-year follow-up in one hundred postmenopausal women. Endocrine 2012; 42: 764-766
- 9 Kontogeorgos G, Trimpou P, Laine CM. et al. Normocalcaemic, vitamin D-sufficient hyperparathyroidism – high prevalence and low morbidity in the general population: a long-term follow-up study, the WHO MONICA project, Gothenburg, Sweden. Clin Endocrinol (Oxf) 2015; 83: 277-284
- 10 Kalaria T, Fenn J, Sanders A. et al. The diagnosis of normocalcaemic hyperparathyroidism is strikingly dissimilar using different commercial laboratory assays. Horm Metab Res 2022; 54: 429-434
- 11 Kalaria T, Lawson AJ, Duffy J. et al. Age-specific reference intervals of Abbott intact PTH-potential impacts on clinical care. J Endocr Soc 2024; 8: bvae004
- 12 Eastell R, Brandi ML, Costa AG. et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the fourth international workshop. J Clin Endocrinol Metab 2014; 99: 3570-3579
- 13 Sturgeon CM, Sprague S, Almond A. et al. Perspective and priorities for improvement of parathyroid hormone (PTH) measurement – a view from the IFCC working group for PTH. Clin Chim Acta 2017; 467: 42-47
- 14 Souberbielle J-C, Brazier F, Piketty M-L. et al. How the reference values for serum parathyroid hormone concentration are (or should be) established?. J Endocrinol Invest 2017; 40: 241-256
- 15 KDIGO. 2017 Clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2017; 7: 1-59
- 16 Quesada JM, Coopmans W, Ruiz B. et al. Influence of vitamin D on parathyroid function in the elderly. J Clin Endocrinol Metab 1992; 75: 494-501
- 17 Bell NH, Greene A, Epstein S. et al. Evidence for alteration of the vitamin D-endocrine system in blacks. J Clin Invest 1985; 76: 470-473
- 18 Ebeling PR, Sandgren ME, DiMagno EP. et al. Evidence of an age-related decrease in intestinal responsiveness to vitamin D: relationship between serum 1,25-dihydroxyvitamin D3 and intestinal vitamin D receptor concentrations in normal women. J Clin Endocrinol Metab 1992; 75: 176-182
- 19 Slovik DM, Adams JS, Neer RM. et al. Deficient production of 1,25-dihydroxyvitamin D in elderly osteoporotic patients. N Engl J Med 1981; 305: 372-374
- 20 Irsik DL, Bollag WB, Isales CM. Renal contributions to age-related changes in mineral metabolism. JBMR Plus 2021; 5: e10517
- 21 Gonzalez Pardo V, Russo de Boland A. Age-related changes in the response of intestinal cells to 1α,25(OH)2-vitamin D3. Ageing Res Rev 2013; 12: 76-89
- 22 Nordin BEC, Need AG, Morris HA. et al. Effect of age on calcium absorption in postmenopausal women. Am J Clin Nutr 2004; 80: 998-1002
- 23 Carrivick SJ, Walsh JP, Brown SJ. et al. Brief report: does PTH increase with age, independent of 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium?. J Clin Endocrinol Metab 2015; 100: 2131-2134
- 24 Souberbielle J-C, Massart C, Brailly-Tabard S. et al. Serum PTH reference values established by an automated third-generation assay in vitamin D-replete subjects with normal renal function: consequences of diagnosing primary hyperparathyroidism and the classification of dialysis patients. Eur J Endocrinol 2016; 174: 315-323
- 25 Cavalcante LBCP, Brandão CMÁ, Chiamolera MI. et al. Big data-based parathyroid hormone (PTH) values emphasize need for age correction. J Endocrinol Invest 2023; 46: 2525-2533
- 26 Farrell C-JL, Nguyen L, Carter AC. Parathyroid hormone: data mining for age-related reference intervals in adults. Clin Endocrinol (Oxf) 2018; 88: 311-317
- 27 Delgado JA, Bauça JM, Pastor MI. et al. Use of data mining in the establishment of age-adjusted reference intervals for parathyroid hormone. Clin Chim Acta. 2020 508. 217-220
- 28 Khalil H, Borai A, Dakhakhni M. et al. Stability and validity of intact parathyroid hormone levels in different sample types and storage conditions. J Clin Lab Anal 2021; 35: e23771
- 29 Cusano NE, Maalouf NM, Wang PY. et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab 2013; 98: 2734-2741
- 30 Maruani G, Hertig A, Paillard M. et al. Normocalcemic primary hyperparathyroidism: evidence for a generalized target-tissue resistance to parathyroid hormone. J Clin Endocrinol Metab 2003; 88: 4641-4648
- 31 Palermo A, Naciu AM, Tabacco G. et al. Clinical, biochemical, and radiological profile of normocalcemic primary hyperparathyroidism. J Clin Endocrinol Metab 2020; 105: dgaa174
- 32 Hanon EA, Sturgeon CM, Lamb EJ. Sampling and storage conditions influencing the measurement of parathyroid hormone in blood samples: a systematic review. Clin Chem Lab Med 2013; 51: 1925-1941
- 33 Lorde N, Elgharably A, Kalaria T. Impact of variation between assays and reference intervals in the diagnosis of endocrine disorders. Diagnostics (Basel, Switzerland) 2023; 13: 3453
- 34 Souberbielle JC, Cormier C, Kindermans C. et al. Vitamin D status and redefining serum parathyroid hormone reference range in the elderly. J Clin Endocrinol Metab 2001; 86: 3086-3090
- 35 Aloia JF, Feuerman M, Yeh JK. Reference range for serum parathyroid hormone. Endocr Pract 2006; 12: 137-144
- 36 Eastell R, Arnold A, Brandi ML. et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009; 94: 340-350
- 37 Mirzazadeh M, Webster C, Weerasinghe G. et al. UK reference intervals for parathyroid hormone using Abbott methods. Br J Biomed Sci. 2023 8011224.