Significance and methodology of monitoring calcemia in disorders of mineral metabolism: challenges and prospects

Disorders of calcium and phosphorus metabolism can cause severe complications that require changing of therapeutic strategies and a long treatment in a hospital. The prevalence of diseases accompanied by calcium metabolism disorders varies from low to moderate. For example, primary hyperparathyroidism, as one of the most common causes of pathological changes in calcium metabolism due to parathyroid hormone hypersecretion, occurs with a frequency of 85 to 233 cases per 100 thousand people. In countries where blood calcium measurements are not routinely carried out, this disease and similar conditions are diagnosed less frequently, and at later stages, with a predominance of manifest and complicated forms. However, calcium metabolism disorders require timely detection and correction in order to prevent complications. At the same time, in a number of clinical situations, standard laboratory analysis is not the optimal diagnostic option due to the duration and complexity of its implementation. In particular, the development of acute hyper- and hypocalcemia requires faster obtaining of blood test results. It is promising to apply technologies allowing to quick assess the current level of calcium directly at a doctor’s appointment especially in cases of drug doses adjustment for patients with chronic disorders of calcium metabolism. In this regard, when long-term monitoring of calcemia is required or in emergency situations, the potential benefit can be obtained by using portable Point-of-Care (POC) devices or wearable biosensors. This review examines the clinical and methodological aspects of monitoring calcium levels, their capabilities and practical limitations, and also highlights the prospects for the development and implementation of POC devices and biosensors for ionized calcium.

1. Bilezikian JP, Brandi ML, Cusano NE, et al. Management of Hypoparathyroidism: Present and Future. J Clin Endocrinol Metab. 2016;101(6):2313-2324. doi: https://doi.org/10.1210/jc.2015-3910

2. Winter WE, Harris NS. Disorders of calcium metabolism. In: Winter WE, Holmquist B, Sokoll LJ, Bertholf RL, editors. Handbook of Diagnostic Endocrinology (Third Edition). Academic Press; 2021. p.309-388. doi: https://doi.org/10.1016/B978-0-12-818277-2.00010-8

3. Blaine J, Chonchol M, Levi M. Renal Control of Calcium, Phosphate, and Magnesium Homeostasis. Clin J Am Soc Nephrol CJASN. 2015;10(7):1257-1272. doi: https://doi.org/10.2215/CJN.09750913

4. Sun M, Wu X, Yu Y, et al. Disorders of Calcium and Phosphorus Metabolism and the Proteomics/MetabolomicsBased Research. Front Cell Dev Biol. 2020;8:576110. doi: https://doi.org/10.3389/fcell.2020.576110

5. Tonon CR, Silva TAAL, Pereira FWL, et al. A Review of Current Clinical Concepts in the Pathophysiology, Etiology, Diagnosis, and Management of Hypercalcemia. Med Sci Monit Int Med J Exp Clin Res. 2022;28:e935821. doi: https://doi.org/10.12659/MSM.935821

6. Bove-Fenderson E, Mannstadt M. Hypocalcemic disorders. Best Pract Res Clin Endocrinol Metab. 2018;32(5):639-656. doi: https://doi.org/10.1016/j.beem.2018.05.006

7. Mirzazadeh M, Morovat A, James T, et al. Point-of-care testing of electrolytes and calcium using blood gas analysers: it is time we trusted the results. Emerg Med J EMJ. 2016;33(3):181-186. doi: https://doi.org/10.1136/emermed-2015-204669

8. Guilmette J, Sadow PM. Parathyroid Pathology. Surg Pathol Clin. 2019;12(4):1007-1019. doi: https://doi.org/10.1016/j.path.2019.08.006

9. 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(3):1122-1129. doi: https://doi.org/10.1210/jc.2012-4022

10. Mokrysheva NG, Eremkina AK, Elfimova AR, et al. The Russian registry of primary hyperparathyroidism, latest update. Front Endocrinol. 2023;14:1203437. doi: https://doi.org/10.3389/fendo.2023.1203437

11. Bilezikian JP, Bandeira L, Khan A, et al. Hyperparathyroidism. Lancet Lond Engl. 2018;391(10116):168-178. doi: https://doi.org/10.1016/S0140-6736(17)31430-7

12. Mokrysheva NG, Eremkina AK, Mirnaya SS, et al. The clinical practice guidelines for primary hyperparathyroidism, short version. Problems of Endocrinology. 2021;67(4):94-124. (In Russ.)] doi: https://doi.org/10.14341/probl12801-9964

13. Dobreva EA, Mirnaya SS, Volodicheva VL, et al. Analysis of calcemic in residents of the cities of Khimki and Kolomna, Moscow region. Profil Meditsina. 2020;23(5):99. (In Russ.)]. doi: https://doi.org/10.17116/profmed20202305199

14. Clarke BL, Brown EM, Collins MT, et al. Epidemiology and Diagnosis of Hypoparathyroidism. J Clin Endocrinol Metab. 2016;101(6):2284-2299. doi: https://doi.org/10.1210/jc.2015-3908

15. Kovaleva EV, Eremkina AK, Krupinova JA, et al. Review of clinical practice guidelines for hypoparathyroidism. Problems of Endocrinology. 2021;67(4):68-83. (In Russ.)] doi: https://doi.org/10.14341/probl12800-9962

16. Kovaleva EV, Eremkina AK, Mokrysheva NG. Daily calcium profile in diagnosis of hypo- and hypercalcemia in patients with chronic hypoparathyroidism. clinical case series. Obesity and metabolism. 2021;18(2):175-179. (In Russ.)] doi: https://doi.org/10.14341/omet12729-9865

17. Chandran M, Wong J. Secondary and Tertiary Hyperparathyroidism in Chronic Kidney Disease: An Endocrine and Renal Perspective. Indian J Endocrinol Metab. 2019;23(4):391. doi: https://doi.org/10.4103/ijem.IJEM_292_19

18. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. 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):1-59. doi: https://doi.org/10.1016/j.kisu.2017.04.001

19. Makazan NV, Orlova EM, Tozliyan EV, et al. Variable phenotype of pseudohypoparathyroidism in children. Problems of Endocrinology. 2017;63(3):148-161. (In Russ.)] doi: https://doi.org/10.14341/probl8337-6447

20. Shchederkina IO, Orlova KA, Koltunov IE, et al. Difficulties in the differential diagnosis of epileptic and hypocalcemic seizures in children and adolescents. Neurology, Neuropsychiatry, Psychosomatics. 2018;10(1S):66-74. (In Russ.)] doi: https://doi.org/10.14412/2074-2711-2018-1S-66-74

21. Shao Y, Cai WJ, Wang XL, et al. Clinical data analysis of 22 cases with hypoparathyroidism misdiagnosed as epilepsy. Neuro Endocrinol Lett. 2022;43(2):113-118

22. Nardone R, Brigo F, Trinka E. Acute Symptomatic Seizures Caused by Electrolyte Disturbances. J Clin Neurol Seoul Korea. 2016;12(1):21-33. doi: https://doi.org/10.3988/jcn.2016.12.1.21

23. Li L, Yang H, Li J, et al. Misdiagnosis of idiopathic hypoparathyroidism: A case report and literature review. Medicine (Baltimore). 2018;97(9):e9884. doi: https://doi.org/10.1097/MD.0000000000009884

24. El-Hajj Fuleihan G, Clines GA, Hu MI, et al. Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2023;108(3):507-528. doi: https://doi.org/10.1210/clinem/dgac621

25. Gastanaga VM, Schwartzberg LS, Jain RK, et al. Prevalence of hypercalcemia among cancer patients in the United States. Cancer Med. 2016;5(8):2091-2100. doi: https://doi.org/10.1002/cam4.749

26. Asonitis N, Angelousi A, Zafeiris C, et al. Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature. Horm Metab Res Horm Stoffwechselforschung Horm Metab. 2019;51(12):770-778. doi: https://doi.org/10.1055/a-1049-0647

27. Bhandari S, Kumar R, Tripathi P, et al. Outcomes of hypercalcemia of malignancy in patients with solid cancer: a national inpatient analysis. Med Oncol Northwood Lond Engl. 2019;36(10):90. doi: https://doi.org/10.1007/s12032-019-1315-8

28. Ciosek Ż, Kot K, Kosik-Bogacka D, et al. The Effects of Calcium, Magnesium, Phosphorus, Fluoride, and Lead on Bone Tissue. Biomolecules. 2021;11(4):506. doi: https://doi.org/10.3390/biom11040506

29. Belaya ZE, Belova KYu, Biryukova EV, et al. Federal clinical guidelines for diagnosis, treatment and prevention of osteoporosis. Osteoporosis and Bone Diseases. 2021;24(2):4-47. (In Russ.)] doi: https://doi.org/10.14341/osteo12930

30. LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2022;33(10):2049-2102. doi: https://doi.org/10.1007/s00198-021-05900-y

31. Pekar JD, Grzych G, Durand G, et al. Calcium state estimation by total calcium: the evidence to end the neverending story. Clin Chem Lab Med. 2020;58(2):222-231. doi: https://doi.org/10.1515/cclm-2019-0568

32. Conrich-Wilks G, Ivison F, Kilpatrick ES. Factors influencing the derivation and clinical application of blood calcium adjustment equations. Ann Clin Biochem. 2023;60(1):54-62. doi: https://doi.org/10.1177/00045632221131673

33. Ridefelt P, Helmersson-Karlqvist J. Albumin adjustment of total calcium does not improve the estimation of calcium status. Scand J Clin Lab Invest. 2017;77(6):442-447. doi: https://doi.org/10.1080/00365513.2017.1336568

34. Bilezikian JP, Cusano NE, Khan AA, et al. Primary hyperparathyroidism. Nat Rev Dis Primer. 2016;2:16033. doi: https://doi.org/10.1038/nrdp.2016.33

35. Jassam N, O’Kane M. Harmonisation of adjusted calcium equation, is it a realistic aim: a narrative review. J Lab Precis Med. 2023;8(0). doi: https://doi.org/10.21037/jlpm-22-56

36. Jassam N, Thomas A, Hayden K, et al. The impact of the analytical performance specifications of calcium and albumin on adjusted calcium. Ann Clin Biochem. 2020;57(5):382-388. doi: https://doi.org/10.1177/0004563220944426

37. Rifai N. Tietz Textbook of Laboratory Medicine. 7th ed. Elsevier; 2022

38. Schini M, Hannan FM, Walsh JS, et al. Reference interval for albuminadjusted calcium based on a large UK population. Clin Endocrinol (Oxf ). 2021;94(1):34-39. doi: https://doi.org/10.1111/cen.14326

39. Li M, Wang C, Zhou EW, et al. Time to stop debating about the everlasting story: Some issues concerning serum total calcium and ionized calcium. Chin Med J (Engl). 2020;133(10):1251-1252. doi: https://doi.org/10.1097/CM9.0000000000000803

40. Minisola S, Pepe J, Cipriani C. Measuring serum calcium: Total, albumin-adjusted or ionized? Clin Endocrinol (Oxf ). 2021;95(2):267-268. doi: https://doi.org/10.1111/cen.14362

41. Hyperparathyroidism (Primary): Diagnosis, Assessment and Initial Management. London: National Institute for Health and Care Excellence (NICE); 2019. Accessed December 17, 2023. http://www.ncbi.nlm.nih.gov/books/NBK542087/

42. Tartaglia F. Is ionized calcium a reliable predictor of hypocalcemia after total thyroidectomy? A before and after study. G di Chir - J Surg. 2014. doi: https://doi.org/10.11138/gchir/2014.35.1.027

43. Tee MC, Holmes DT, Wiseman SM. Ionized vs serum calcium in the diagnosis and management of primary hyperparathyroidism: which is superior? Am J Surg. 2013;205(5):591-596. doi: https://doi.org/10.1016/j.amjsurg.2013.01.017

44. Gómez-Nieto B, Gismera MJ, Sevilla MT, et al. Micro-sampling method based on high-resolution continuum source graphite furnace atomic absorption spectrometry for calcium determination in blood and mitochondrial suspensions. Talanta. 2017;170:15-21. doi: https://doi.org/10.1016/j.talanta.2017.03.086

45. Zhao HJ, Ge ML, Yan Y, et al. Inductively Coupled Plasma Mass Spectrometry as a Reference Method to Evaluate Serum Calcium Measurement Bias and the Commutability of Processed Materials during Routine Measurements. Chin Med J (Engl). 2018;131(13):1584-1590. doi: https://doi.org/10.4103/0366-6999.235109

46. Yan Y, Ge M, Ma R, et al. A candidate reference method for serum calcium measurement by inductively coupled plasma mass spectrometry. Clin Chim Acta Int J Clin Chem. 2016;461:141-145. doi: https://doi.org/10.1016/j.cca.2016.07.004

47. Lyu Y, Gan S, Bao Y, et al. Solid-Contact Ion-Selective Electrodes: Response Mechanisms, Transducer Materials and Wearable Sensors. Membranes. 2020;10(6):128. doi: https://doi.org/10.3390/membranes10060128

48. Wang P, Kricka LJ. Current and Emerging Trends in Pointof-Care Technology and Strategies for Clinical Validation and Implementation. Clin Chem. 2018;64(10):1439-1452. doi: https://doi.org/10.1373/clinchem.2018.287052

49. Vashist SK. Point-of-Care Diagnostics: Recent Advances and Trends. Biosensors. 2017;7(4):62. doi: https://doi.org/10.3390/bios7040062

50. Jawa A, Motara F, Moolla M, Laher AE. A Comparative Assessment of the Nova Stat Profile Prime Plus® Critical Care Analyzer. Cureus. 2020;12(8):e9932. doi: https://doi.org/10.7759/cureus.9932

51. Leal Yepes FA, Behling-Kelly E, Caixeta LS, et al. Evaluation of a pointof-care calcium device in bovine plasma and serum. JDS Commun. 2023;4(5):390-393. doi: https://doi.org/10.3168/jdsc.2022-0346

52. Couto Serrenho R, Bruinjé TC, Morrison EI, et al. Validation of a point-of-care handheld blood total calcium analyzer in postpartum dairy cows. JDS Commun. 2021;2(1):41-45. doi: https://doi.org/10.3168/jdsc.2020-0006

53. Suzuki K, Kondo N, Takagi K, et al. Validation of the bovine blood calcium checker as a rapid and simple measuring tool for the ionized calcium concentration in cattle. J Vet Med Sci. 2021;83(5):767-774. doi: https://doi.org/10.1292/jvms.21-0001

54. Keresten V, Mikhelson K. Voltammetric Ion Sensing with IonophoreBased Ion-Selective Electrodes Containing Internal Aqueous Solution, Improving Lifetime of Sensors. Membranes (Basel). 2022;12(11):1048. doi: https://doi.org/10.3390/membranes12111048

55. Nyein HYY, Gao W, Shahpar Z, et al. A Wearable Electrochemical Platform for Noninvasive Simultaneous Monitoring of Ca(2+) and pH. ACS Nano. 2016;10(7):7216-7224. doi: https://doi.org/10.1021/acsnano.6b04005

56. Molinero-Fernández Á, Casanova A, Wang Q, et al. In Vivo Transdermal Multi-Ion Monitoring with a Potentiometric Microneedle-Based Sensor Patch. ACS Sens. 2023;8(1):158-166. doi: https://doi.org/10.1021/acssensors.2c01907

57. Lechner M, Moghul G, Chandrasekharan D, et al. Preoperative and postoperative optimisation of patients undergoing thyroid surgery: a multicentre quality improvement project at Barts Health NHS Trust. BMJ Open Qual. 2023;12(2):e001190. doi: https://doi.org/10.1136/bmjoq-2020-001190

58. Schwarzer P, Kuhn SO, Stracke S, et al. Discrepant post filter ionized calcium concentrations by common blood gas analyzers in CRRT using regional citrate anticoagulation. Crit Care. 2015;19(1):321. doi: https://doi.org/10.1186/s13054-015-1027-1