Skip to main content

Advertisement

SpringerLink
Log in

How the reference values for serum parathyroid hormone concentration are (or should be) established?

  • Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Well-validated reference values are necessary for a correct interpretation of a serum PTH concentration. Establishing PTH reference values needs recruiting a large reference population. Exclusion criteria for this population can be defined as any situation possibly inducing an increase or a decrease in PTH concentration. As recommended in the recent guidelines on the diagnosis and management of asymptomatic primary hyperparathyroidism, PTH reference values should be established in vitamin D-replete subjects with a normal renal function with possible stratification according to various factors such as age, gender, menopausal status, body mass index, and race. A consensus about analytical/pre-analytical aspects of PTH measurement is also needed with special emphasis on the nature of the sample (plasma or serum), the time and the fasting/non-fasting status of the blood sample. Our opinion is that blood sample for PTH measurement should be obtained in the morning after an overnight fast. Furthermore, despite longer stability of the PTH molecule in EDTA plasma, we prefer serum as it allows to measure calcium, a prerequisite for a correct interpretation of a PTH concentration, on the same sample. Once a consensus is reached, we believe an important international multicentre work should be performed to recruit a very extensive reference population of apparently healthy vitamin D-replete subjects with a normal renal function in order to establish the PTH normative data. Due to the huge inter-method variability in PTH measurement, a sufficient quantity of blood sample should be obtained to allow measurement with as many PTH kits as possible.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Souberbielle JC, Cormier C, Cavalier E (2015) How to manage an isolated elevated PTH? Ann Endocrinol 76:134–141

    Article  Google Scholar 

  2. Eastell R, Arnold A, Brandi ML, Brown EM, D’Amour P, Hanley D et al (2009) Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 94:340–350

    Article  CAS  PubMed  Google Scholar 

  3. Bilezikian J, Brandi ML, Eastell R, Silverberg S, Udelsman R, Marcocci C et al (2014) Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the fourth international workshop. J Clin Endocrinol Metab 99:3561–3569

    Article  CAS  PubMed  Google Scholar 

  4. Nussbaum SR, Zahradnik RJ, Lavigne JR, Brennan GL, Nozawa-Ung K, Kim LY et al (1987) Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 33:1364–1367

    CAS  PubMed  Google Scholar 

  5. Lepage R, Roy L, Brossard JH, Rousseau L, Dorais C, Lazure C et al (1998) A non (1–84) circulating parathyroid hormone fragment interferes significantly with intact PTH commercial assay in uremic samples. Clin Chem 44:4287–4290

    Google Scholar 

  6. John M, Goodman W, Gao P, Cantor T, Salusky I, Juppner H (1999) A novel immunoradiometric assay detects full-length human PTH but not amino-terminally truncated fragments: implications for PTH measurements in renal failure. J Clin Endocrinol Metab 84:4287–4290

    Article  CAS  PubMed  Google Scholar 

  7. Cavalier E, Daly AF, Betea D, Pruteanu-Apetrii P, Delanaye P, Stubbs P et al (2010) The ratio of parathyroid hormone as measured by third- and second-generation assays as a marker for parathyroid carcinoma. J Clin Endocrinol Metab 95:3745–3749

    Article  CAS  PubMed  Google Scholar 

  8. Souberbielle JC, Boutten A, Carlier MC, Chevenne D, Coumaros G, Lawson-Body E et al (2006) Inter-method variability in PTH measurement: implication for the care of CKD patients. Kidney Int 70:345–350

    Article  CAS  PubMed  Google Scholar 

  9. Joly D, Drueke T, Alberti C, Houillier P, Lawson-Body E, Martin K et al (2008) Variation in serum and plasma PTH levels in second-generation assays in hemodialysis patients: a cross-sectional study. Am J Kidney Dis 51:987–995

    Article  CAS  PubMed  Google Scholar 

  10. Touvier M, Deschasaux M, Montourcy M, Sutton A, Charnuax N, Kess-Guyot E et al (2014) Interpretation of plasma PTH concentrations according to 25OHD status, gender, age, weight status, and calcium intake: importance of the reference values. J Clin Endocrinol Metab 99:1196–1203

    Article  CAS  PubMed  Google Scholar 

  11. Björkman M, Sorva A, Tilvis R (2009) Responses of parathyroid hormone to vitamin D supplementation: a systematic review of clinical trials. Arch Gerontol Geriatr 48:160–166

    Article  PubMed  Google Scholar 

  12. Blind E, Schmidt-Gayk H, Scharla S, Flentje D, Fischer S, Göhring U et al (1988) Two-site assay of intact parathyroid hormone in the investigation of primary hyperparathyroidism and other disorders of calcium metabolism compared with a mid-region assay. J Clin Endocrinol Metab 67:353–360

    Article  CAS  PubMed  Google Scholar 

  13. Endres D, Villanueva R, Sharp C Jr, Singer F (1991) Immunochemiluminometric and immunoradiometric determinations of intact and total immunoreactive parathyrin: performance in the differential diagnosis of hypercalcemia and hypoparathyroidism. Clin Chem 37:162–168

    CAS  PubMed  Google Scholar 

  14. Ratcliffe W, Heath D, Ryan M, Jones S (1989) Performance and diagnostic application of a two-site immunometric assay for parathyrin in serum. Clin Chem 35:1957–1961

    CAS  PubMed  Google Scholar 

  15. Gao P, Scheibel S, D’Amour P, John M, Rao S, Schmidt-Gayk H et al (2001) Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1–84: implication for improvement of accurate assessment of parathyroid function. J Bone Miner Res 16:605–614

    Article  CAS  PubMed  Google Scholar 

  16. Souberbielle JC, Cormier C, Kindermans C, Gao P, Cantor T, Forette F et al (2001) Vitamin D status and redefining serum parathyroid hormone reference range. J Clin Endocrinol Metab 86:3086–3090

    CAS  PubMed  Google Scholar 

  17. Glendenning P, Vasikaran S (2002) Comment on: Vitamin D status and redefining serum PTH reference range in the elderly. J Clin Endocrinol Metab 97:946–947

    Article  Google Scholar 

  18. Souberbielle JC, Fayol V, Sault C, Lawson-Body E, Kahan A, Cormier A (2005) Assay-specific decision limits for two new automated parathyroid hormone and 25-hydroxyvitamin D assays. Clin Chem 51:395–400

    Article  CAS  PubMed  Google Scholar 

  19. Aloia J, Feuerman M, Yeh J (2006) Reference range for serum parathyroid hormone. Endocr Pract 12:137–144

    Article  PubMed  PubMed Central  Google Scholar 

  20. La’ulu S, Roberts W (2010) Performance characteristics of six intact parathyroid hormone assays. Am J Clin Pathol 134:930–938

    Article  PubMed  Google Scholar 

  21. Rejnmark L, Vestergaard P, Heickendorff L, Mosekilde L (2011) Determinants of plasma PTH and their implication for defining a reference interval. Clin Endocrinol 74:37–43

    Article  CAS  Google Scholar 

  22. Fillée C, Keller T, Mourad M, Brikman T, Ketelslegers JM (2012) Impact of vitamin D-related serum PTH reference values on the diagnosis of mild primary hyperparathyroidism, using bivariate calcium/PTH reference regions. Clin Endocrinol 76:785–789

    Article  Google Scholar 

  23. Cavalier E, Delanaye P, Vranken L, Bekaert AC, Carlisi A, Chapelle JP et al (2012) Interpretation of serum PTH concentrations with different kits in dialysis patients according to the KDIGO guidelines: importance of the reference (normal) values. Nephrol Dial Transpl 27:1950–1956

    Article  CAS  Google Scholar 

  24. Deckers M, de Jongh R, Lips P, Penninx B, Milaschi Y, Smit J et al (2013) Prevalence of vitamin D deficiency and consequences for PTH reference values. Clin Chim Acta 426:41–45

    Article  CAS  PubMed  Google Scholar 

  25. Djennane M, Lebbah S, Roux C, Djoudi H, Cavalier E, Souberbielle JC (2014) Vitamin D status of schoolchildren in Northern Algeria, seasonal variations and determinants of vitamin D deficiency. Osteoporos Int 25:1493–1502

    Article  CAS  PubMed  Google Scholar 

  26. Li M, Lv F, Zhang Z, Deng W, Li Y, Deng Z et al (2016) Establishment of a normal reference value of parathyroid hormone in a large healthy Chinese population and evaluation of its relation to bone turnover and bone mineral density. Osteoporos Int 27:1907–1916

    Article  CAS  PubMed  Google Scholar 

  27. Souberbielle JC, Massart C, Brailly-Tabard S, Cormier C, Cavalier E, Delanaye P et al (2016) 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. Eu J Endocrinol 174:315–323

    Article  CAS  Google Scholar 

  28. Ross C, Manson JE, Abrams S, Aloia J, Brannon P, Clinton S et al (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 96:53–58

    Article  CAS  PubMed  Google Scholar 

  29. Holick M, Binkley N, Bischoff-Ferrari H, Gordon C, Hanley D, Heaney R et al (2011) Evaluation, treatment and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930

    Article  CAS  PubMed  Google Scholar 

  30. KDIGO C-M (2009) Work Group KDIGO Clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone disorder (CKD-MBD). Kidney Int 76(Suppl 113):S1–130

    Google Scholar 

  31. Bell NH, Greene A, Epstein S, Oexmann MJ, Shaw S, Shary JR (1985) Evidence for alteration of the vitamin D-endocrine system in blacks. J Clin Invest 76:470–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Quesada JM, Coopmans W, Ruiz B, Aljam P, Jans I, Bouillon R (1992) Influence of vitamin D on parathyroid hormone in the elderly. J Clin Endocrinol Metab 75:494–501

    CAS  PubMed  Google Scholar 

  33. Valcour A, Blocki F, Hawkins DM, Rao SD (2012) Effects of age and serum 25OHD-vitamin D levels on serum parathyroid hormone levels. J Clin Endocrinol Metab 97:3989–3995

    Article  CAS  PubMed  Google Scholar 

  34. Bailey D, Colantino D, Kuriakopoulou L, Cohen A, Chan MK, Armbruster D et al (2013) Marked biological variance in endocrine and biochemical markers in childhood: establishment of pediatric reference intervals using healthy community children from CALIPER cohort. Clin Chem 59:1393–1405

    Article  CAS  PubMed  Google Scholar 

  35. Soldin O, Dahlin J, Gresham E, King J, Soldin S (2008) Immulite 2000 age and sex-specific reference intervals for alpha fetoprotein, homocysteine, insulin, insulin-like growth factor-1, insulin-like growth factor binding protein-3, C-peptide, immunoglobulin E and intact parathyroid hormone. Clin Biochem 41:937–942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kovacs C, Kronenberg H (1997) Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev 18:832–872

    CAS  PubMed  Google Scholar 

  37. Frolich A, Rudnicki M, Fischer-Rasmussen W, Olofsson K (1991) Serum concentration of intact parathyroid hormone during late human pregnancy: a longitudinal study. Eur J Obstet Gynecol Reprod Biol 42:85–87

    Article  CAS  PubMed  Google Scholar 

  38. Seely EW, Brown E, DeMaggio D, Weldon D, Graves S (1997) A prospective study of calciotropic hormones in pregnancy and post partum: reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D. Am J Obstet Gynecol 176:214–217

    Article  CAS  PubMed  Google Scholar 

  39. Saggese G, Baroncelli GI, Bertelloni S, Cipolloni C (1991) Intact parathyroid hormone levels during pregnancy, in healthy term neonates and in hypocalcemic preterm infants. Acta Paediatr Scand 80:36–41

    Article  CAS  PubMed  Google Scholar 

  40. Cross N, Hillman L, Allen S, Krause G, Vieira N (1995) Calcium homeostasis and bone metabolism during pregnancy, lactation, and postweaning: a longitudinal study. Am J Clin Nutr 61:514–523

    CAS  PubMed  Google Scholar 

  41. More C, Bhattoa HP, Bettembuk P, Balogh A (2003) The effect of pregnancy and lactation on hormonal status and biochemical markers of bone turnover. Eur J Obstet Gynecol Reprod Biol 106:209–213

    Article  CAS  PubMed  Google Scholar 

  42. Uemura H, Yasui T, Kiyokawa M, Kuwahara A, Ikawa H, Matsuzaki T et al (2002) Serum osteoprotegerin/osteoclastogenesis-inhibitory factor during pregnancy and lactation and the relationship with calcium-regulating hormones and bone turnover markers. J Endocrinol 174:353–359

    Article  CAS  PubMed  Google Scholar 

  43. Kramer C, Ye C, Hanley A, Connelly P, Sermer M, Zinman B et al (2016) The relationship between parathyroid hormone and 25-hydroxyvitamin D during and after pregnancy. J Clin Endocrinol Metab 101:1729–1736

    Article  PubMed  Google Scholar 

  44. Fuleihan GEH, Klerman E, Brown E, Choe Y, Brown E, Czeisler C (1997) The parathyroid hormone circadian rhythm is truly endogenous—a general clinical research center study. J Clin Endocrinol Metab 82:281–286

    CAS  Google Scholar 

  45. Rejnmark L, Lauridsen A, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L (2002) Diurnal rhythm of plasma 1,25-dihydroxyvitamin D and vitamin D-binding protein in postmenopausal women: relationship to plasma parathyroid hormone and calcium and phosphate metabolism. Eur J Endocrinol 146:635–642

    Article  CAS  PubMed  Google Scholar 

  46. Smith E, Cai M, McMahon L, Holt S (2012) Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab 97:3501–3504

    Google Scholar 

  47. Horn PS, Feng L, Li Y, Pesce AJ (2001) Effect of outliers and nonhealthy individuals on reference interval estimation. Clin Chem 47:2137–2145

    CAS  PubMed  Google Scholar 

  48. Souberbielle JC, Lawson-Body E, Hammadi B, Sarfati E, Kahan A, Cormier C (2003) The use in clinical practice of parathyroid hormone normative values established in vitamin D-sufficient subjects. J Clin Endocrinol Metab 88:3501–3504

    Article  CAS  PubMed  Google Scholar 

  49. Koumakis E, Souberbielle JC, Sarfati E, Meunier M, Maury E, Gallimard E et al (2013) Bone mineral density evolution after successful parathyroidectomy in patients with normocalcemic primary hyperparathyroidism. J Clin Endocrinol Metab 98:3213–3220

    Article  CAS  PubMed  Google Scholar 

  50. van Ballegooijen A, Reinders I, Visser M, Brouwer I (2013) Parathyroid hormone and cardiovascular disease events: a systematic review and meta-analysis of prospective studies. Am Heart J 165:655–664

    Article  PubMed  Google Scholar 

  51. Yang B, Lu C, Wu Q, Zhang J, Zhao H, Cao Y (2016) Parathyroid hormone, cardiovascular and all-cause mortality: a meta-analysis. Clin Chim Acta 455:154–160

    Article  CAS  PubMed  Google Scholar 

  52. Minisola S, Pepe J, Piemonte S, Cipriani C (2015) The diagnosis and management of hypercalcemia. BMJ 2(350):h2723. doi:10.1136/bmj.h2723

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Service des Explorations Fonctionnelles, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015, Paris, France

    J.-C. Souberbielle, F. Brazier & M.-L. Piketty

  2. Université René Descartes, 75015, Paris, France

    J.-C. Souberbielle, F. Brazier & M.-L. Piketty

  3. Rheumatology Department, Cochin University Hospital, 75014, Paris, France

    C. Cormier

  4. Ordinario di Medicina Interna, Responsabile UOC Medicina Interna e Malattie Metaboliche dell’Osso (TMC 04), « Sapienza » Università di Roma, Rome, Italy

    S. Minisola

  5. Clinical Chemistry Department, Sart Tilman University Hospital, Liège, Belgium

    E. Cavalier

Authors
  1. J.-C. Souberbielle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Brazier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M.-L. Piketty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Cormier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Minisola
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Cavalier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J.-C. Souberbielle.

Ethics declarations

Conflict of interest

JCS reports lecture fees and/or travel/hotel expenses from DiaSorin, Roche Diagnostics, Abbott, Amgen, Shire, MSD, Lilly, Rottapharm, Meda. EC is consultant for IDS and DiaSorin and has received lecture fees from IDS, DiaSorin, Roche, Abbott, and Amgen. SM served as a speaker for Abiogen, Amgen, Diasorin, Eli Lilly, Italfarmaco, Fujii, Merck Sharp and Dohme, Takeda. He also served in advisory board of Amgen and Eli Lilly. FB, MLP, and CC have nothing to declare.

Ethical approval

Not applicable to this review article.

Informed consent

Not applicable to this review article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Souberbielle, JC., Brazier, F., Piketty, ML. et al. How the reference values for serum parathyroid hormone concentration are (or should be) established?. J Endocrinol Invest 40, 241–256 (2017). https://doi.org/10.1007/s40618-016-0553-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-016-0553-2

Keywords

Search

Navigation