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Primary hyperparathyroidism: Epidemiology, diagnosis and clinical picture

Abstract

Primary hyperparathyroidism (HPT) is a common disorder that mainly afflicts elderly women. It can be diagnosed in at least 1% of all postmenopausal females and autopsy studies indicate an even higher frequency. Although the widespread use of automated serum calcium analyses has increased the awareness of HPT, only 10% of all cases seem to be identified. The diagnosis relies on the demonstration of an inappropriately elevated serum concentration of parathyroid hormone (PTH) relative to the serum calcium value, which need not be markedly raised. Measurements of intact PTH with immunometric methods have considerably improved the diagnostic precision but it is still difficult to evaluate patients with only marginal hypercalcemia. Few patients with diagnosed HPT are completely without symptoms. Symptoms commonly encountered are psychiatric and neuromuscular disturbances. Subclinical bone disease might be relevant but there is insufficient information about its importance in otherwise asymptomatic individuals. Various cardiovascular risk factors appear more commonly in patients with HPT and untreated disease is associated with an increased risk of premature death.

Résumé

L'hyperparathyroÏdie primitive (HPT) est une affection relativement fréquente qui touche essentiellement la femme âgée. Elle se voit chez au moins 1% des femmes ménopausées: sa fréquence d'après les études autopsiques serait encore plus élevée. Bien que le dosage de la calcémie par automate soit répandue actuellement, sensibilisant la détection de l'HPT, on ne fait le diagnostic que de 10% des cas. Le diagnostic repose sur la mise en évidence d'un taux anormalement élevé de parathormone par rapport à la calcémie, qui n'est pas forcement élevée. Le dosage de la parathormone complète par des méthodes immunologiques a considérablement amélioré la précision diagnostique, mais il demeure toujours difficile d'évaluer les patients qui n'ont qu'une hypercalcémie minime. Il existe également un certain nombre de patients avec une véritable HPT qui semblent Être asymptomatiques, exception faite de troubles psychiatriques ou neuromusculaires divers. Il se peut que ces patients présentent des anomalies osseuses infracliniques, mais on ne possède pas encore suffisamment d'information sur ce sujet. Le risque cardiovasculaire est augmenté par l'HPT. Le risque de mort prématurée semble plus élevé chez les patients ayant une HPT non traitée.

Resumen

El hiperparatiroidismo primario (HPT) es una entidad clínica comÚn que afecta principalmente a mujeres de edad avanzada. Puede ser diagnosticado por lo menos en 1% de todas las mujeres postmenopáusicas, pero estudios de autopsia revelan una incidencia todavía mayor. Aunque la generalización de las determinaciones automatizadas del calcio sérico ha incrementado el reconocimineto del HPT, todavía apenas un 10% de los casos es debidamente indentificado. El diagnóstico se fundamenta en la demostración de concentraciones inapropiadamente elevadas, en relatión a la calcemia, de la hormona paratiroidea (PTH) en el suero. La medición de la PTh intacta por métodos inmunométricos ha mejorado considerablemente la précision diagnóstica, pero aün es difícil diagnosticar los pacientes con sólo hipercalcemia marginal. Muy pocos patientes con HPT diagnosticado aparecen totalmente libres de síntomas; los síntomas más comunes son las diversas alteraciones psiquiátricas y neuromusclares. La enfermedad ósea subclínica puede ser relevante, pero la informatión disponible sobre su importancia es insuficiente en pacientes por lo demás asintomáticos. Diversos riesgos cardiovasculares se presentan frecuentemente en pacientes con HPT no tratado y se asocian con un riesgo aumentado de muerte prematura.

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References

  1. Åkerström, G., Rudberg, C., Grimelius, L., Bergström, R., Johansson, H., Ljunghall, S., Rastad, J.: Histologic parathyroid abnormalities in an autopsy series. Hum. Pathol.17:520, 1986

    Google Scholar 

  2. Joborn, C., Ljunghall, S., Larsson, K., Lindh, E., Naessen, T., Wide, L., Åkerström, G., Rastad, J.: Skeletal responsiveness to parathyroid hormone in healthy females: Relationship to menopause and estrogen replacement. Clin. Endocr.34:335, 1991

    Google Scholar 

  3. Christensson, T., Hellström, K., Wengle, B., Alveryd, A., Wikland, B.: Prevalence of hypercalcaemia in a health screening in Stockholm. Acta Med. Scand.200:131, 1976

    Google Scholar 

  4. Ljunghall, S., Hedstrand, H.: Epidemiology of renal stones in a middle-aged male population. Acta Med. Scanda.197:439, 1975

    Google Scholar 

  5. Palmér, M., Jakobsson, S., Åkerström, G., Ljunghall, S.: Prevalence of hypercalcemia in a health survey: A 14-year follow-up of serum calcium values. Eur. J. Clin. Invest.118:39, 1988

    Google Scholar 

  6. Heath H. III, Hodgson, S.F., Kennedy, M.A.: Primary hyperparathyroidism: Incidence, morbidity and economic impact in a community. N. Engl. J. Med.302:189, 1980

    Google Scholar 

  7. Stenström, G., Hedman, P.A.: Clinical findings in patients with hypercalcaemia: A final investigation based on biochemical screening. Acta Med. Scand.195:473, 1974

    Google Scholar 

  8. Melton, L.J.: Epidemiology of primary hyperparathyroidism: National Institutes of Health Consensus Development Conference, October 29–31, 1990. J. Bone Miner. Res.6(suppl 2): 1991

  9. Yendt, E.R., Gagné, R.J.A.: Detection of primary hyperparathyroidism with special reference to its occurrence in hypercalciuric females with normal or bordeline serum calcium. Can. Med. Assoc. J.98:331, 1968

    Google Scholar 

  10. Wills, M.R., Pak, C.Y.C., Hammon, W.G., Bartter, F.C.: Normocalcemic primary hyperparathyroidism. Am. J. Med.47:384, 1969

    Google Scholar 

  11. Johansson, H., Thorén, L., Werner, I.: Normocalcaemic hyperparathyroidism, kidney stone and idiopathic hypercalciuria. Surgery77:691, 1975

    Google Scholar 

  12. Ljunghall, S., Källsen, R., Backman, U., Danielson, B.G., Grimelius, L., Johansson, H., Thorén, L., Werner, I.: Clinical effects of parathyroid surgery in normocalcaemic patients with recurrent renal stones. Acta Chir. Scand.146:161, 1980

    Google Scholar 

  13. Broadus, A.E., Horst, R.L., Littledike, E.T., Mahaffey, J.E., Rasmussen, H.: Primary hyperparathyroidism with intermittent hypercalcemia: Serial determinations and simple diagnosis by means of an oral calcium tolerance test. N. Engl. J. Med.12:225, 1980

    Google Scholar 

  14. Benson, L., Ljunghall, S., Groth, T., Falk, H., Hvarfner, A., Rastad, J., Wide, L., Åkerström, G.: Optimal discrimination of mild hyperparathyroidism with serum calcium, ionized calcium and parathyroid hormone measurements. Ups. J. Med. Sci.92:147, 1987

    Google Scholar 

  15. Groth, T.L., Ljunghall, S., DeVerdier, C.H.: Optimal screening for patients with hyperparathyroidism with use of serum calcium observations: A decision-theoretical analysis. Scand. J. Clin. Lab. Invest.43:699, 1983

    Google Scholar 

  16. Edmonson, J.W., Li, F.T.: The relationship between ionized and total serum calcium in primary hyperparathyroidism. J. Lab. Clin. Med.87:624, 1976

    Google Scholar 

  17. Ladenson, J.H., Lewis, J.W., MacDonald, J.M., Slatopolsky, E., Boyd, J.C.: Relationship of free and total calcium in hypercalcaemic conditions. J. Clin. Endocrinol. Metab.48:393, 1978

    Google Scholar 

  18. McLeod, M.K., Monchik, J.M., Martin, H.F.: The role of ionized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery95:667, 1985

    Google Scholar 

  19. Ladenson, J.H.: Blood calcium determination in primary hyperparathyroidism: National Institutes of Health Concensus Development Conference, October 29–31, 1990. J. Bone Miner. Res.6(suppl 2): 1991

  20. Ladenson, J.H., Lewis, J.W., Boyd, J.C.: Failure of total calcium corrected for protein, albumin and pH to correctly assess free calcium status. J. Clin. Endocrinol. Metab.46:986, 1978

    Google Scholar 

  21. Nussbaum, S.R., Zahradnik, R.J., Lavigne, J.R., Brennan, G.L., Nozawa-Ung, K., Kim, L.Y., Keutmann, H.T., Wang, C.-A., Potts, J.T. Jr., Segre, G.V.: Highly sensitive two-site immunoradiometric assay of parathyrin and its clinical utility in evaluating patients with hypercalcemia. Clin. Chem.33:1364, 1987

    Google Scholar 

  22. Nussbaum, S.R.: Sensitive immunometric assays for parathyroid hormone and their impact on the diagnosis and management of hyperparathyroidism: National Institutes of Health Consensus Development Conference, October 29–31, 1990. J. Bone Miner. Res.6(suppl 2): 1991

  23. Blind, E., Schmidt-Gayk, H., Scharla, S., Flentje, S., Fischer, S., Göhring, U., Hitzler, W.: Two-site assay of intact of parathyroid hormone in the investigation of primary hyperparathyroidism and other disorders of calcium metabolism compared with a midregion assay. J. Clin. Endocrinol. Metab.67:353, 1988

    Google Scholar 

  24. Ljunghall, S., Larsson, K., Lindh, E., Lindqvist, U., Rastad, J., Åkerström, G., Wide, L.: Disturbance of basal and stimulated serum levels of intact parathyroid hormone in primary hyperparathyroidism. Surgery110:47, 1991

    Google Scholar 

  25. Rutledge, R., Stiegel, M., Thomas, C.G., Wild, R.E.: The relation of serum calcium and immunoparathormone levels to parathyroid size and weight in primary hyperparathyroidism. Surgery98:1107, 1985

    Google Scholar 

  26. Åkerström, G., Bergström, R., Grimelius, L., Johansson, H., Ljunghall, S., Lundström, B., Palmér, M., Rastad, J., Rudberg, C.: Relation between changes in clinical and histopathological features of primary hyperparathyroidism. World J. Surg.10:696, 1986

    Google Scholar 

  27. Wallfelt, C., Gylfe, E., Larsson, R., Ljunghall, S., Rastad, J., Åkerström, G.: Relation between external and cytoplasmic calcium concentrations, parathyroid hormone release and glandular weight in hyperparathyroidism. J. Endocrinol.116:457, 1988

    Google Scholar 

  28. Wallfelt, C., Ljunghall, S., Bergström, R., Rastad, J., Åkerström, G.: Clinical characteristics and surgical treatment of sporadic primary hyperparathyroidism. Surgery107:13, 1990

    Google Scholar 

  29. Nussbaum, S.R., Gaz, R.D., Arnold, A.: Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N. Engl. J. Med.323:1324, 1990

    Google Scholar 

  30. Burtis, W.J., Brady, T.G., Orloff, J.J., Ersbak, J.B., Warrell, R.P., Olson, B.R., Wu, T.L., Mitnick, M.E., Broadus, A.E., Stewart, A.F.: Immunochemical characterization of circulating parathyroidrelated protein in patients with humoral hypercalcemia of cancer. N. Engl. J. Med.322:1106, 1990

    Google Scholar 

  31. Rudberg, C., Åkerström, G., Ljunghall, S., Grimelius, L., Johansson, H., Pertoft, H., Wide, L.: Regulation of parathyroid hormone release in primary and secondary hyperparathyroidism: Studies in vivo and in vitro. Acta Endocrinol.101:408, 1982

    Google Scholar 

  32. Benson, L., Wide, L., Åkerström, G., Ljunghall, S.: A stimulation test with calcitonin for the differential diagnosis of hypercalcaemia. Acta Endocrinol.107:237, 1984

    Google Scholar 

  33. Benson, L., Rastad, J., Wide, L., Åkerström, G., Ljunghall, S.: Stimulation of parathyroid hormone secretion by EDTA infusion: A test for the differential diagnosis of hypecalcaemia. Acta Endocrinol.111:498, 1986

    Google Scholar 

  34. Ljunghall, S., Benson, L., Rastad, J., Wide, L., Åkerström, G.: Dynamic tests of parathyroid function for diagnosis of primary hyperparathyroidism in malignancy. Clin. Endocrinol.27:163, 1987

    Google Scholar 

  35. Ljunghall, S., Benson, L., Wide, L., Åkerström, G., Rastad, J.: Improved differential diagnosis of hypercalcemia by hypocalcemic stimulation of parathyroid hormone secretion. World J. Surg.12:496, 1988

    Google Scholar 

  36. Lafferty, F.W.: Primary hyperparathyroidism: Changing clinical spectrum, prevalence of hypertension, and a discriminant analysis of laboratory tests. Arch. Intern. Med.141:1761, 1981

    Google Scholar 

  37. Lafferty, F.W.: Differential diagnosis of hypercalcemia: National Institutes of Health Concensus Development Conference, October 29–31, 1990. J. Bone Miner. Res.6(suppl 2): 1991

  38. Broadus, A.E., Horst, R.L., Lang, R., Littledike, E.T., Rasmussen, H.: The importance of circulating 1,25(OH)2D in the pathogenesis of hypercalciuria and renal stone formation in primary hyperparathyroidism. N. Engl. J. Med.302:421, 1980

    Google Scholar 

  39. Palmer, M., Ljunghall, S., Åkerström, G., Adami, H.-O., Bergström, R., Grimelius, L., Rudberg, C., Johansson, H.: Patients with primary hyperparathyroidism operated on over a 24-year period: Temporal trends of clinical and laboratory findings. J. Chronic Dis.40:121, 1987

    Google Scholar 

  40. Parisien, M., Silverberg, S.J., Shane, E., Dempster, D., Bilezikian, J.P.: Bone disease in primary hyperparathyroidism. Endocrinol. Metab. Clin. North Am.19:19, 1990

    Google Scholar 

  41. Parisien, M., Silverberg, S., Shane, E., DeLaCruz, L., Lindsay, R., Bilezikian, J.P., Dempster, D.: The histomorphometry of bone in primary hyperparathyroidism: Preservation of cancellous bone structure. J. Clin. Endocrinol. Metab.70:930, 1990

    Google Scholar 

  42. Silverberg, S.J., Shane, E., DeLaCruz, L., Dempster, D., Feldman, F., Seldin, D., Jacobs, T., Siris, E.S., Cafferty, M., Parisien, M.V., Lindsay, R., Clemens, T.L., Bilezikian, J.P.: Skeletal disease in primary hyperparathyroidism. J. Bone Miner. Res.4:283, 1989

    Google Scholar 

  43. Eriksen, E.F., Mosekilde, L., Melsen, F.: Trabecular bone remodelling and balance in primary hyperparathyroidism. Bone7:213, 1986

    Google Scholar 

  44. Larsson, K., Lindh, E., Lind, L., Persson, I., Ljunghall, S.: Increased fracture risk in hypercalcemia: Bone mineral content measured in hyperparathyroidism. Acta Orthop. (Scand.)60:268, 1989

    Google Scholar 

  45. Martin, P., Bergmann, P., Gillet, C., Fuss, M., Kinnaert, P., Corvilain, J., Van Geertruyden, J.: Long-term irreversibility of bone loss after surgery for primary hyperparathyroidism. Arch. Intern. Med.150:1495, 1990

    Google Scholar 

  46. Rao, S.D., Wilson, R.J., Kleerekoper, M., Parfitt, A.M.: Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: Evidence for biphasic disease course. J. Clin. Endocrinol. Metab.67:1294, 1988

    Google Scholar 

  47. Mautalen, C., Reyes, H.R., Ghiringelli, G., Fromm, G.: Cortical bone mineral content in primary hyperparathyroidism: Changes after parathyroidectomy. Acta Endocrinol. (Copenh)111:494, 1986

    Google Scholar 

  48. Block, M.A., Dailey, G.E., Muchmore, D.E.: Bone demineralization, a factor of increasing significance in the management of primary hyperparathyroidism. Surgery106:1063, 1989

    Google Scholar 

  49. Peacock, M., Horsman, A., Aaron, J.E., Marshall, D.H., Selby, P.L., Simpson, M.: The role of parathyroid hormone in bone loss. In Osteoporosis 1, C. Christianses, C.D. Arnaud, B.E.C. Nordin, editors, Denmark, Aalborg Stiftsbogtrykkers, 1984, pp. 463–468

    Google Scholar 

  50. Kochersberger, G., Buckley, N.J., Leight, G.S., Martinex, S., Stdenski, S., Vogler, J., Lyles, K.W.: What is the clinical significance of bone loss in primary hyperparathyroidism? Arch. Intern. Med.147:1951, 1987

    Google Scholar 

  51. Wilson, R.J., Rao, S.D., Ellis, B., Kleerekoper, M., Parfitt, A.M.: Mild asymptomatic hyperparathyroidism is not a risk factor for vertebral fractures. Ann. Intern. Med.109:959, 1988

    Google Scholar 

  52. Backman, U., Danielson, B.G., Johansson, G., Ljunghall, S., Wikström, B.: Incidence and clinical importance of renal tubular defects in recurrent renal stone formers. Nephron25:96, 1980

    Google Scholar 

  53. Backman, U., Danielson, B.G., Fellström, B., Johansson, G., Ljunghall, S., Wikström, B.: Clinical and laboratory findings in patients with medullary sponge kidney. In Urolithiasis: Clinical and Basic Research, L.H. Smith, editor, New York, Plenum Publishing Corporation, 1981, pp. 113–120

    Google Scholar 

  54. Silverberg, S.J., Shane, E., Jacobs, T.P., Siris, E.S., Gartenberg, F., Seldin, D., Clemens, T.L., Bilezikian, J.P.: Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am. J. Med.89:327, 1990

    Google Scholar 

  55. Ljunghall, S., Danielson, B.G., Johansson, G., Wibell, L.: Renal stone formation in primary hyperparathyroidism: Role of tubular dysfunction. In Urolithiasis: Clinical and Basic Research, L.H. Smith, editor, New York, Plenum Publishing Corporation, 1981, pp. 89–92

    Google Scholar 

  56. Pak, C.Y.C.: Effect of parathyroidectomy on crystallization of calcium salts in urine of patients with primary hyperparathyroidism. Invest. Urol.17:146, 1979

    Google Scholar 

  57. Joborn, C., Hetta, J., Rastad, J., Ågren, H., Åkerström, G., Ljunghall, S.: Psychiatric symptoms and cerebrospinal fluid monoamine metabolites in patients with primary hyperparathyroidism. Biol. Psychiatry23:149, 1988

    Google Scholar 

  58. Joborn, C., Hetta, J., Johansson, H., Rastad, J., Ågren, H., Åkerström, G., Ljunghall, S.: Psychiatric morbidity in primary hyperparathyroidism. World J. Surg.12:476, 1988.

    Google Scholar 

  59. Joborn, C., Hetta, J., Lind, L., Rastad, J., Åkerström, G., Ljunghall, S.: Self-rated psychiatric symptoms in patients with primary hyperparathyroidism. Surgery105:72, 1989

    Google Scholar 

  60. Joborn, C., Hetta, J., Niklasson, F., Rastad, J., Ågren, H., Åkerström, G., Ljunghall, S.: Cerebrospinal fluid calcium, parathyroid hormone and the blood-brain barrier in primary hyperparathyroidism: Relation to CSF monoamine and purine metabolism. Psychoneuroendocrinology (in press)

  61. Joborn, C., Joborn, H., Rastad, J., Åkerström, G., Ljunghall, S.: Maximal isokinetic muscle strength in patients with primary hyperparathyroidism before and after parathyroid surgery. Br. J. Surg.75:77, 1988

    Google Scholar 

  62. Joborn, C., Rastad, J., StÅlberg, E., Åkerström, G., Ljunghall, S.: Muscle function in patients with primary hyperparathyroidism. Muscle Nerve12:87, 1989

    Google Scholar 

  63. Joborn, C., Hetta, J., Palmér, M., Åkerström, G., Ljunghall, S.: Psychiatric symptomatology in patients with primary hyperparathyroidism. Ups. J. Med. Sci.91:77, 1986

    Google Scholar 

  64. Turken, S.A., Cafferty, M., Silverbeerg, S.J., DeLaCruz, L., Cimino, C., Lange, D.J., Lovelace, R.E., Bilezikian, J.P.: Neuromuscular involvement in mild, asymptomatic primary hyperparathyroidism Am. J. Med.87:553, 1989

    Google Scholar 

  65. Brown, G.G., Preisman, R.C., Kleerekoper, M.: Neurobehavioral symptoms in mild primary hyperparathyroidism: Related to hypercalcemia but not improved by parathyroidectomy. Henry Ford Hosp. Med. J.35:211, 1987

    Google Scholar 

  66. Joborn, C., Hetta, J., Frisk, P., Palmér, M., Åkerström, G., Ljunghall, S.: Primary hyperparathyroidism in patients with organic brain syndrome. Acta Med. Scand.219:91, 1985

    Google Scholar 

  67. Palmér, M., Adami, H.-O., Bergström, R., Jakobsson, S., Åkerström, G., Ljunghall, S.: Survival and renal function in persons with untreated hypercalcaemia: A population-based cohort study with 14 years of follow-up. Lancet1:59, 1987

    Google Scholar 

  68. Lind, L., Wengle, B., Wide, L., Ljunghall, S.: Hypertension in primary hyperparathyroidism: Reduction of blood pressure by long-term treatment with vitamin D (alphacalcidol). A double-blind, placebo-controlled study. Am. J. Hypertens.2:397, 1988

    Google Scholar 

  69. Ljunghall, S., Lithell, H., Vessby, B., Wide, L.: Glucose and lipoprotein metabolism in primary hyperparathyroidism: Effects of parathyroidectomy. Acta Endocrinol. (Kbh)89:580, 1978

    Google Scholar 

  70. Ljunghall, S., Palmér, M., Åkerström, G., Wide, L.: Diabetes mellitus, glucose tolerance and insulin response to glucose in patients with primary hyperparathyroidism before and after parathyroidectomy. Eur. J. Clin. Invest.13:373, 1983

    Google Scholar 

  71. Ljunghall, S., Åkerström, G.: Urate metabolism in primary hyperparathyroidism. Urol. Int.37:73, 1982

    Google Scholar 

  72. Palmér, M., Adami, H.-O., Bergström, R., Åkerström, G., Ljunghall, S.: Mortality after operation for primary hyperparathyroidism: A follow-up of patients operated on during 1956–1979. Surgery102:1, 1987

    Google Scholar 

  73. Palmér, M., Adami, H.-O., Krusemo, U.-B., Ljunghall, S.: Increased risk of malignant disease after operation for primary hyperparathyroidism: A nation-wide cohort study. Am. J. Epidemiol.127:1031, 1988

    Google Scholar 

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Ljunghall, S., Per Hellman, Rastad, J. et al. Primary hyperparathyroidism: Epidemiology, diagnosis and clinical picture. World J. Surg. 15, 681–687 (1991). https://doi.org/10.1007/BF01665300

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Keywords

  • Serum Calcium
  • Bone Disease
  • Hypercalcemia
  • Primary Hyperparathyroidism
  • Affection Relativement