Indication - Disorders of the parathyroids or parathyroid hormone system
Parathyroid hormone (PTH)
Facility level:
Assay formats
Status history
First added in 2022
Purpose type
To aid in the evaluation of the causes of calcium homeostasis disorders and monitor the effects of treatment
Specimen types
Serum, Plasma
WHO prequalified or recommended products
WHO supporting documents
Technical specifications for procurements
ICD11 code: 5A5Z

Summary of evidence evaluation

The role between PTH assays differs, and for that reason the needed accuracy and clinical impact will differ. Therefore, it is difficult to know which test is being appraised in the context of this application (second generation or third generation). Clinical guidelines agreed upon testing for PTH for several indications, so for that reason PTH assays will have a positive impact on health in LMICs. Systematic review of the role of PTH for several indications and the potential clinical impact are given. However, systematic reviews on the accuracy of PTH testing are not given for each of the indications. In general: ■ First-generation assays are no longer in clinical use because of issues with clinical sensitivity and specificity due to cross-reactivity with inactive PTH fragments. ■ Challenges in determining the diagnostic accuracy include: (i) the lack of a reference method, (ii) the lack of standardization of the assays, (iii) on some occasions the lack of consistent reference range and (iv) stability problems/large intra-individual variation. How accurately can we assess the levels of PTH (with second- or third-generation assays) and for which indication does it matter the most? ■ For classic primary hyperparathyroidism (PHPT), the type of PTH assay used will not affect diagnosis or management because the precise concentration of PTH is less relevant. ■ In CKD, the guideline recommends treating secondary hyperparathyroidism above a twofold to ninefold PTH increase, which will result in different clinical decisions depending on the assay used. ■ For patients after bariatric surgery, guidelines state absolute cutoff values for PTH, but the impact of different-generation assays is unknown because direct comparison of PTH assays has never been performed. ■ During parathyroid surgery, PTH measurements with a third- generation assay reflect treatment success more rapidly than second- generation assays. Increased awareness among clinicians regarding the complexity of PTH measurements is warranted because it can affect clinical decisions. Diagnostic accuracy measures: ■ Regarding the utility of PTH levels in predicting temporary post- thyroidectomy hypocalcaemia for an absolute PTH threshold, the median accuracy, sensitivity and specificity were 86%, 85% and 86%, respectively. For a percentage change over time, the median accuracy, sensitivity and specificity were 89%, 88% and 90%, respectively (QUADAS-2: moderate to high quality). However, there was considerable selection bias among the studies. The studies included diverse populations. ■ Pooled sensitivity and specificity of selective parathyroid venous sampling (sPVS) in PHPT patients was 0.74 (95% CI: 0.70–0.77) and 0.41 (95% CI: 0.33–0.48), respectively. Summary performance estimates of positive likelihood ratio for sPVS was 1.55 (95% CI: 1.33–1.82) and for negative likelihood ratio was 0.47 (95% CI: 0.39–0.58). The area under the receiver operating characteristic curve was 0.684, indicating an average discriminatory ability of sPVS (QUADAS-2: moderate to high quality). Sensitivity issues: ■ Assay less sensitive at lower concentrations. ■ Percutaneous blood sampling for parathyroid gland localization showed poor sensitivity.

Summary of SAGE IVD deliberations

SAGE IVD agreed that PTH is an important test that needs to be available. However, it is expensive (a single test may cost US$ 20 to US$ 25) and as such should only be included in reference laboratories for second-level evaluation of changes in calcium or phosphorus, including kidney failure. The group also noted that there are different generations of tests, but that the application did not provide a good sense for how to use the second- and third-generation tests. Members of the group noted that generation (active, bioactive and so forth) probably matters more for procurement decisions made at the country or laboratory manager level. One SAGE IVD member pointed out that earlier- generation diagnostics are generally offered to countries in low-income settings, and that clarifying the generational differences enables countries to make better decisions. After discussion, the experts agreed to add a footnote specifying that the test is approved for both the second-generation (intact) and third-generation (bioactive or bio-intact) forms of the assay. Literature cited in the discussion: Smit MA, van Kinschot CM, van der Linden J, van Noord C, Kos S. Clinical guidelines and PTH measurement: does assay generation matter: Endocrine Rev. 2019;40(6):1468–80 (https://academic.oup.com/edrv/article/40/6/1468/5487988, accessed 14 December 2022).

SAGE IVD recommendation

SAGE IVD recommended listing the parathyroid hormone (PTH) test category in EDL 4 ■ as a disease-specific IVD for use in clinical laboratories (EDL 4, Section II.b); ■ using an immunoassay format; ■ using plasma and serum as specimen types; ■ to aid in the evaluation of the causes of calcium homeostasis disorders and monitor the effects of treatment. SAGE IVD also recommended adding a footnote to the test category stating that the test is approved for both the second-generation (intact) and third-generation (bioactive or bio-intact) forms of PTH.

Details of submission from 2022


Disease condition and impact on patients PTH is an essential hormone which is central to maintaining the integrity and physiological function of the skeletal system. The skeletal system is one of the largest organs in the body responsible for providing structural integrity across the lifespan; facilitating movement through the network of joints, connective tissue and muscles; protecting and supporting vital organs, including the brain, heart, lungs, liver and kidneys; and storage of essential minerals such as calcium and phosphate. The skeleton also contains bone marrow, which is responsible for haematopoiesis. The normal physiological functioning of the various organ systems is dependent on a healthy skeleton; conversely, skeletal health is a barometer of overall health. The PTH assay is used to diagnose and monitor disorders of PTH secretion, including hyperparathyroidism (primary, secondary and tertiary), pseudohypoparathyroidism and hypoparathyroidism. These disorders are associated with a significant health and economic burden worldwide such as chronic kidney disease (CKD) and osteoporosis. Bone mineral density (BMD) is predominantly determined by genetics, but adequate physical activity and nutrition both play vital role in attaining optimal peak BMD by young adulthood. Malnutrition is a significant problem affecting children in developing countries which affects growth and survival. In 2020, for children under 5 years of age, WHO estimated that 149 million had stunted growth (short for age), 45 million were underweight, and 45% of deaths were related to undernutrition. CKD is a significant cause of metabolic bone disease too. Causes of primary hyperparathyroidism include solitary adenomas, hyperplasia of the parathyroid glands and parathyroid cancer. The rates of primary hyperparathyroidism have been shown to be increased in populations characterized by social deprivation. Unlike developed countries, where identification and optimal management of predominantly asymptomatic cases of primary hyperparathyroidism are the focus, in developing countries over 70% are symptomatic at presentation with worse clinical outcomes. The widespread availability of PTH assays is important to narrow the gap caused by social disadvantage. Anterior neck surgery is the most common cause of acquired hypoparathyroidism, accounting for 75% of cases, with autoimmune and infiltrative disease also contributing to disease burden in adults. Genetic conditions such as 22q11 deletions are commonly responsible for hypoparathyroidism in the paediatric population. Hypoparathyroidism has been associated with a twofold increase in rates of fractures. Severe vitamin D deficiency with or without hypocalcaemia is characterized by hyperparathyroidism as a homeostatic response. The rates of nutritional rickets in children from developing countries has been estimated to be over 50% and represents a significant disease burden. Does the test meet a medical need? Measurement of PTH will facilitate the diagnosis and assist in the management of conditions which are prevalent and have significant economic costs in both developed and developing countries. These include CKD and osteoporosis, and other causes of abnormal PTH secretion leading to disorders of bone and mineral metabolism. How the test is used Determination of PTH level is useful in the differential diagnosis of both hypercalcaemia and hypocalcaemia, for assessing parathyroid function in CKD and for evaluating parathyroid function in bone and mineral disorders. Readers can refer directly to the application to review diagnostic algorithms on hypercalcaemia, hypocalcaemia, nonsurgical hypoparathyroidism, secondary osteoporosis and hyperparathyroidism. Note: the algorithms mentioned above were provided by the applicant as part of this application and are not WHO algorithms. The original application and the reviews are available in full at: https://www.dropbox.com/sh/dm1026anops6fe8/ AACmVfzPz9Tpn_eT1KGJ1h0Ya?dl=0 (accessed 14 April 2023). ■ CKD – use of PTH in guiding management of CKD In CKD, PTH measurement is utilized to assess parathyroid function, estimating bone turnover and guiding management. Established clinical practice guidelines are available (KDIGO – Kidney Disease Improving Global Outcomes) for the management of CKD mineral and bone disorder. Intact PTH levels are used to guide treatment in CKD, with current recommendations for evaluating modifiable factors (including hyperphosphataemia, hypocalcaemia, high phosphate intake and vitamin D deficiency) if levels are progressively rising or persistently above the upper range of normal in patients with CKD G1–G5, suggesting secondary hyperparathyroidism. Patients with high bone turnover caused by secondary hyperparathyroidism (advanced osteitis fibrosa) have the highest concentrations of PTH, whereas those with low-turnover, adynamic bone disease, including osteomalacia, have the lowest concentrations whether measured by whole or intact PTH assays. ■ Hypoparathyroidism – assessing completeness of parathyroidectomy In parathyroid surgery, intraoperative PTH is used to assess the effectiveness of removal as well as the risk of hypocalcaemia. Because of the short half-life of PTH (< 5 minutes), intraoperative intact PTH is often measured (just before incision and again 20 minutes after resection of hyperfunctioning parathyroid) to assess the completeness of parathyroidectomy. A decline of ≥ 50% or more suggests adequate removal.

Public health relevance

Prevalence In a comprehensive systematic review and meta-analysis, the global prevalence of osteoporosis in adults, defined by WHO criteria as BMD that lies 2.5 standard deviations or more below average for age and gender, was estimated to be 18.3% (95% CI: 16.2–20.7) with an age range of 15–105 years and a sample size of 103 334 579 people. In 2017, the GBD Chronic Kidney Disease Collaboration estimated 697.5 million (95% CI: 649.2–752.0) cases of all-stage CKD for a global prevalence of 9.1%. CKD resulted in 35.8 million (95% CI: 33.7–38) DALYs. The burden of CKD was predominantly concentrated in the three lowest quintiles of the sociodemographic index. Socioeconomic impact Not provided.

WHO or other clinical guidelines relevant to the test

Primary hyperparathyroidism: Khan AA, Hanley DA, Rizzoli R, Bollerslev J, Young JE, Rejnmark L et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos Int. 2017;28(1):1–19. Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151(10):959–68. Asymptomatic primary hyperparathyroidism: Bilezikian JP, Brandi ML, Eastell R, Silverberg SH, Udelsman R, Marcocci C et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3561–9. Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570–9. Secondary hyperparathyroidism in CKD: Executive summary of the 2017 KDIGO Chronic Kidney Disease – Mineral and Bone Disorder (CKDMBD) Guideline Update: what’s changed and why it matters [published correction appears in Kidney Int. 2017;92(6):1558]. Kidney Int. 2017;92(1):26–36. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD 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 Suppl. 2009:S1–130. Secondary hyperparathyroidism after bariatric surgery: Fried M, Yumuk V, Oppert JM, Scopinaro N, Torres A, Weiner R et al. Interdisciplinary European guidelines on metabolic and bariatric surgery. Obes Surg. 2014;24(1):42–55. Heber D, Greenway FL, Kaplan LM, Livingston E, Salvador J, Still C et al. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(11):4823–43. Mechanick JI, Youdim A, Jones DB, Garvey WT, Hurley DL, McMahon MM et al. American Association of Clinical Endocrinologists; Obesity Society; American Society for Metabolic & Bariatric Surgery. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient – 2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Endocr Pract. 2013;19(2):337–72. Parrott J, Frank L, Rabena R, Craggs-Dino L, Isom KA, Greiman L. American Society for Metabolic and Bariatric Surgery integrated health nutritional guidelines for the surgical weight loss patient 2016 update: micronutrients. Surg Obes Relat Dis. 2017;13(5):727–41. Perioperative use of PTH measurement: AES Guidelines 06/01 Group. Australian Endocrine Surgeons Guidelines AES06/01. Postoperative parathyroid hormone measurement and early discharge after total thyroidectomy: analysis of Australian data and management recommendations. ANZ J Surg. 2007;77(4):199–202. Orloff LA, Wiseman SM, Bernet VJ, Fahey TJ 3rd, Shaha AR, Shindo ML et al. American thyroid association statement on postoperative hypoparathyroidism: diagnosis, prevention, and management in adults. Thyroid. 2018;28(7):830–41. Pseudohypoparathyroidism: Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018;14(8):476–500.

Evidence for diagnostic accuracy

PTH is currently measured by immunoassays, with liquid chromatography- tandem mass spectrometry methods only available in a research capacity. The circulating PTH forms detected by immunoassays include both intact hormone and “inactive” fragments. These fragments, which are devoid of N-terminal regions, are conventionally thought not to possess classic PTH activity. However, more recently, separate receptors for C-terminal PTH have been identified in bone cells and the actions of these fragments may affect the maturation and biological activity of these cells. C-terminal fragments have a very short half-life (< 1 hour) owing to rapid renal clearance via glomerular filtration. In individuals with normal renal function, 5–25% of total circulating PTH is intact hormone and 75–95% is C-terminal fragments. The half-life and circulating concentrations of fragments are increased in individuals with impaired renal function. Three generations of PTH assays have been developed (Henrich et al., 2006), necessitated by the heterogeneity of the PTH molecule in both the physiological state and various pathophysiological conditions (especially CKD). Antibodies used in immunoassays may be monoclonal or polyclonal antibodies purified by affinity chromatography to produce sequence-specific antibodies. For the quantitation of intact PTH (1–84), the carboxyl or middle region of the molecule (e.g. amino acid sequences 39–84, 44–84) are the usual targets of the capture antibody, while signal antibody is directed at the N-terminal amino acid sequence (1–34). However, the detection strategy is reversed in a number of methods, using capture antibodies against the N-terminal amino acid sequence (e.g. amino acids 26–32) and signal antibodies against the middle or C-terminal amino acid sequence (e.g. 55–64). A summary of the main characteristics of each generation of PTH assays follows. First generation (radioimmunoassays; no longer in clinical use): ■ First used in the 1960s. ■ Competitive immunoassay. ■ Used single polyclonal antibodies directed against the mid-, C-terminal portion of PTH. ■ Had issues with clinical sensitivity and specificity due to cross- reactivity with inactive PTH fragments. Second generation: ■ Developed with aim to measure only the intact molecule of PTH (1–84), collectively known as intact assays. ■ Noncompetitive (sandwich) immunometric assays with the capture and signal antibodies directed at different regions, either against the C-terminus or N-terminus (amino acids 1–34). ■ Use in diagnosis of primary hyperparathyroidism and in monitoring secondary hyperparathyroidism is well-established. ■ Overestimates the severity of PTH-related bone disease due to cross-reactivity with N-terminal-truncated fragments (PTH 7–84), which increases with worsening CKD. Third generation: ■ The epitope of N-terminally binding antibody consists of the first four to six amino acids of the PTH molecule. ■ Collectively known as true intact PTH assays, whole PTH assays, bioactive PTH assays or cyclase-activating PTH assays. ■ Currently no clear clinical advantage over second-generation assays. ■ Thought to also detect amino PTH (D’Amour et al., 2003), which has its amino-terminal serine residue in a phosphorylated form. Because early (first-generation) intact PTH assays measured N-terminal- truncated PTH, they overestimated the concentration of biologically intact hormone. The degree of overestimation is method dependent, with intact PTH 50% higher on average than PTH (1–8) measured by third-generation assays in patients with primary hyperparathyroidism or stage 5 CKD (Gao et al., 2001). There is a lack of harmonization between commercial PTH assays (Reichel et al., 2003), especially when measuring samples from patients with CKD or receiving haemodialysis. This has highlighted the importance of the production and implementation of a commutable international standard material (IS 95/646), an endeavour which has been adopted by a committee of the International Federation of Clinical Chemistry and Laboratory Medicine. Optimal sampling conditions: sample tube with EDTA is preferred, though some assays require serum (due to interference from EDTA of assay signal by chelation of divalent cations required for enzymatic action of alkaline phosphatase label). Storage: analysis within 72 hours if stored at 4°C. There is no consensus on the effects of storing samples at –20°C or –80°C. Reference intervals: reference intervals vary significantly with the method used. Typical intervals are: ■ intact PTH: 10–65 pg/mL or 1.1–68 pmol/L; and ■ PTH (1–84): 6–40 pg/mL or 0.6–42 pmol/L.

Evidence for clinical usefulness and impact

Ahmadieh H, Kreidieh O, Akl EA, Fuleihan GEH. Minimally invasive parathyroidectomy guided by intraoperative parathyroid hormone monitoring (IOPTH) and preoperative imaging versus bilateral neck exploration for primary hyperparathyroidism in adults. Cochrane Database Syst Rev. 2020;10(10):CD010787. Chen L, Wang K, Yu S, Lai L, Zhang X, Yuan J et al. Long-term mortality after parathyroidectomy among chronic kidney disease patients with secondary hyperparathyroidism: a systematic review and meta-analysis. Ren Fail. 2016;38(7):1050–8. Covic A, Kothawala P, Bernal M, Robbins S, Chalian A, Goldsmith D et al. Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. Nephrol Dial Transplant. 2009;24(5):1506–23. Desai AA, Nissenson A, Chertow GM, Farid M, Singh I, Van Oijen MGH et al. The relationship between laboratory-based outcome measures and mortality in end-stage renal disease: a systematic review. Hemodial Int. 2009;13(3):347–59. Goldsmith D, Kothawala P, Chalian A, Bernal M, Robbins S, Covic A et al. Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of fracture and need for parathyroidectomy in CKD. Am J Kidney Dis. 2009;53(6):1002–13. Gunn IR, Gaffney D. Effect of ascorbic acid on mineral and bone disorders in hemodialysis patients: a systematic review and meta-analysis. Ann Clin Biochem. 2004;41(Pt 6):441–58. Ibraheem K, Toraih EA, Haddad AB, Farag M, Randolph GW, Emad Kandil. Selective parathyroid venous sampling in primary hyperparathyroidism: a systematic review and meta-analysis. Laryngoscope. 2018;128(11):2662–7. Jaruvongvanich V, Vantanasiri K, Upala S, Ungprasert P. Changes in bone mineral density and bone metabolism after sleeve gastrectomy: a systematic review and meta-analysis. Surg Obes Relat Dis. 2019;15(8):1252–60. Leere JS, Karmisholt J, Robaczyk M, Vestergaard. Contemporary medical management of primary hyperparathyroidism: a systematic review. Front Endocrinol (Lausanne). 2017;8:79. Lotito A, Teramoto M, Cheung M, Becker K, Sukumar D. Serum parathyroid hormone responses to vitamin D supplementation in overweight/obese adults: a systematic review and meta-analysis of randomized clinical trials. Nutrients. 2017;9(3):241. Mathur A, Nagarajan N, Kahan S, Schneider EB, Zeiger MA. Association of parathyroid hormone level with postthyroidectomy hypocalcemia: a systematic review. JAMA Surg. 2018;153(1):69–76. Moslehi N, Shab-Bidar S, Mirmiran P, Hosseinpanah F, Azizi F et al. Determinants of parathyroid hormone response to vitamin D supplementation: a systematic review and meta-analysis of randomised controlled trials. Br J Nutr. 2015;114(9):1360–74. Natoli JL, Boer R, Nathanson BH, Miller RM, Chiroli S, Goodman WG et al. Is there an association between elevated or low serum levels of phosphorus, parathyroid hormone, and calcium and mortality in patients with end stage renal disease? A meta-analysis. BMC Nephrol. 2013 Apr 17;14:88. Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA. 2011;305(11):1119–27. Quinn AJ, Ryan ÉJ, Garry S, James DL, Boland MR, Young O et al. Use of intraoperative parathyroid hormone in minimally invasive parathyroidectomy for primary hyperparathyroidism: a systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2021 Feb 1;147(2):135–43. Roy DJ, Pande SD, Liew ZH, Roy D. Role of parathyroid hormone assay and bedside ultrasound in the emergency department in differentiating acute kidney injury from chronic kidney disease: a systematic review. Emerg Med Int. 2019;2019:2102390. Seamans KM, Cashman KD. Existing and potentially novel functional markers of vitamin D status: a systematic review. Am J Clin Nutr. 2009;89(6):1997S–2008S. Spiegel BM, Melmed G, Robbins S, Esrailian E. Biomarkers and health-related quality of life in end-stage renal disease: a systematic review. Clin J Am Soc Nephrol. 2008;3(6):1759–68. Switzer NJ, Marcil G, Prasad S, Debru E, Church N, Mitchell P et al. Long-term hypovitaminosis D and secondary hyperparathyroidism outcomes of the Roux- en-Y gastric bypass: a systematic review. Obes Rev. 2017;18(5):560–6. Van Ballegooijen AJ, Reinders I, Visser M, Brouwer IA. Parathyroid hormone and cardiovascular disease events: a systematic review and meta-analysis of prospective studies. Am Heart J. 2013 May;165(5):655–64, 664.e1–5.

Evidence for economic impact and/or cost–effectiveness

No cost–effectiveness data are available.

Ethical issues, equity and human rights issues

Diagnosis and management of disorders of PTH secretion and action, including hyperparathyroidism, hypoparathyroidism, CKD and osteoporosis are significantly compromised in developing countries compared to developed countries, resulting in much worse outcomes. The availability of PTH measurement will go a long way to addressing some of these inequities. There are no ethical considerations.
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