Best Practice & Research Clinical Endocrinology & Metabolism
Primary hyperparathyroidism
Introduction
Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. It is caused by excessive synthesis and secretion of PTH by one or more of the four parathyroid glands [1], [2].
When PHPT was first described almost a century ago, in the 1930's, the disease was associated with severe hypercalcemia and serious skeletal and renal complications. The indelible association of PHPT with signs (kidney stones and fractures) and symptoms (due to hypercalcemia) persisted until the 1970's when biochemical screening tests became routinely employed, first in the United States and then elsewhere. The clinical phenotype of PHPT changed from overt bone and renal involvement to asymptomatic hypercalcemia. These patients were discovered essentially in the context of biochemical screening and not for any signs or symptoms that would have prompted the health care provider to measure the serum calcium. Four more decades passed when yet another phenotype of PHPT emerged, namely a normocalcemic variant in which albumin-corrected and ionized serum calcium concentrations were persistently normal but the PTH level was persistently elevated. Of course, all known secondary causes for a high PTH have to be ruled out [3]. Not the subject of this discussion, but it is noteworthy that patients have recently been recognized with PHPT but only by pathological examination of parathyroid tissue. The calcium and PTH levels are normal [4], [5].
These different clinical phenotypes of PHPT have raised many issues with regard to parathyroid surgery, the definitive management of the disease. In the hands of expert parathyroid surgeons, parathyroidectomy (PTX) offers very high cure rates [6], but in patients who are completely asymptomatic, a surgical option is not necessarily the obvious one. The normocalcemic variant of PHPT presents yet another challenge in the decision to recommend parathyroid surgery or not. To this end, the Fourth International Workshop on Asymptomatic PHPT [7], recently revisited by others [8], [9], [10], offers reasonable evidence-based guidance as to who is best advised to have parathyroid surgery.
In this article, we review these different profiles of PHPT with particular emphasis on recent publications.
Section snippets
Epidemiology
The peak incidence of PHPT is in the early postmenopausal years, coincident with the loss of estrogen [11]. Many more women than men develop this disease with a ratio of approximately 4:1. In the United States, the prevalence is 0.86% [12]. Racial predilection favors African Americans [13]. While there is wide variability in prevalence estimates for the classic hypercalcemic form of PHPT, there are even more widely variant prevalence estimates of normocalcemic PHPT (0.4–11%). To a certain
Etiology and risk factors
The vast majority of patients with PHPT harbor a single, benign, parathyroid adenoma. It accounts for approximately 80% of cases of PHPT. Multiglandular disease, in which 4-gland parathyroid hyperplasia is the predominant form, is seen in 15–20% of cases. Multiglandular disease can also be manifest as two and, very rarely, three adenomas. Parathyroid carcinoma accounts for well under 1% of all cases of PHPT [2]. Parathyroid cancer presents in a very different manner than its benign counterpart.
Clinical presentation
When hypercalcemia is high enough, generally over 12 mg/dL, or if it rises rapidly, over several days, signs and symptoms of PHPT may be due to the hypercalcemia itself. Symptoms include polyuria, polydipsia, constipation, anorexia, vomiting, dehydration, arrhythmias, and altered mental status.
The clinical presentation of PHPT can also include the key target organs, kidney and bone. With regard to the kidney, any combination of hypercalciuria, nephrolithiasis, nephrocalcinosis and reduced renal
A world view of how PHPT can present
These three different presentations of PHPT were described chronologically with the symptomatic variant described first, following by the discovery of asymptomatic PHPT via the use of biochemical screening, and most recently by the normocalcemic variant in which the routine measurement of PTH among those with normal serum calcium levels was prompted initially by the proactive approach to the evaluation of low bone density. However, these three forms of PHPT exist concurrently in the world
Diagnosis and evaluation
Classical PHPT is diagnosed readily by hypercalcemia in association with a frankly elevated PTH or inappropriately ‘normal’ PTH. A PTH level within the normal range is clearly not a normal value physiologically when someone is hypercalcemic. The question then arises, how low can the PTH be when hypercalcemia is present and have it still be compatible with the diagnosis of PHPT? A level of 20–25 pg/mL or higher in the setting of hypercalcemia is considered to be compatible with the diagnosis of
Surgical management
The definitive cure of PHPT is surgical removal of hyperfunctioning parathyroid tissue. Successful PTX leads to normalization of all biochemical indices and eventually to higher BMD, reduced fracture risk and reduced risk of kidney stones *[21], [55], [56], [57], *[75], *[76]. Even in NPHPT, PTX has been associated with beneficial outcomes [77], [78]. In patients who are symptomatic of hypercalcemia or who have sustained target organ issues (e.g., fractures, stones), surgery is clearly
Natural history of PHPT with and without surgery
Based upon a number of studies, comparing PTX with non-operative management *[21], [55], [56], [57], *[75], *[76], BMD significantly improves after PTX while it remains stable or declines in those without surgical intervention. The longest observational study to date followed patients with or without PTX for 15 years. In the non-surgical group [21], biochemical indices remained stable for 15 years, the only exception being the serum calcium that trended upwards between years 13 and 15. After
Summary
The three clinical forms of PHPT present in frequency as a function of several factors: the presence of routine biochemical screening; endogenous vitamin D deficiency; the use of PTH in the evaluation of reduced bone mass even if the serum calcium is normal. Even among those whose PHPT is discovered incidentally, signs of skeletal and renal involvement can often be demonstrated. Successful PTX cures the disease. It is recommended in those with symptomatic disease and for those who are
Acknowledgments
This work was supported, in part, by NIH grant DK 32333.
References (106)
- et al.
Hyperparathyroidism
Lancet
(2018) - et al.
Epidemiology of primary hyperparathyroidism
- et al.
New insights into the effects of primary hyperparathyroidism on the cortical and trabecular compartments of bone
Bone
(2013) - et al.
Neuromuscular involvement in mild, asymptomatic primary hyperparathyroidism
Am J Med
(1989) - et al.
Non-traditional manifestations of primary hyperparathyroidism
- et al.
Characterization of normocalcemic primary hyperparathyroidism
Am J Med
(2004) - et al.
The 2011 IOM report on vitamin D and calcium requirements for north America: clinical implications for providers treating patients with low bone mineral density
J Clin Densitom
(2011) - et al.
Silent renal stones in primary hyperparathyroidism: prevalence and clinical features
Endocr Pract
(2014) - et al.
Seasonal changes in serum calcium, PTH and vitamin D levels in patients with primary hyperparathyroidism
Bone
(2016) - et al.
Alendronate therapy in men with primary hyperparathyroidism
Endocr Pract
(2009)
Primary hyperparathyroidism
Nat Rev Dis Prim
Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop
J Clin Endocrinol Metabol
Use of calcium and parathyroid hormone nomogram to distinguish between atypical primary hyperparathyroidism and normal patients
World J Surg
Primary hyperparathyroidism with normal calcium and PTH
World J Surg
The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop
J Clin Endocrinol Metabol
Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop
J Clin Endocrinol Metabol
Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and International consensus
Osteoporos Int
Indications for surgical management of hyperparathyroidism: a review
JAMA Surg
The American association of endocrine surgeons guidelines for definitive management of primary hyperparathyroidism
JAMA Surg
The prevalence of undiagnosed and unrecognized primary hyperparathyroidism: a population-based analysis from the electronic medical record
Surgery
Incidence and prevalence of primary hyperparathyroidism in a racially mixed population
J Clin Endocrinol Metabol
Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations
J Clin Endocrinol Metabol
Normocalcemic primary hyperparathyroidism: a survey in a small village of Southern Italy
Endocr Connect
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
Increasing incidence of primary hyperparathyroidism in Denmark
Dan Med J
Epidemiology of primary hyperparathyroidism in Europe
J Bone Miner Res
Primary hyperparathyroidism: increasing prevalence, social deprivation, and surgery
Endocr Res
Characteristics, management, and outcome of primary hyperparathyroidism at a single clinical center from 2005 to 2016
Osteoporos Int
The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years
J Clin Endocrinol Metabol
Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype
J Clin Endocrinol Metabol
Systematic review of primary hyperparathyroidism in India: the past, present, and the future trends
Int J Endocrinol
Primary hyperparathyroidism: 11-year experience in a single institute in Thailand
Int J Endocrinol
Primary hyperparathyroidism: a tale of two cities revisited – New York and Shanghai
Bone Res
From mild to severe primary hyperparathyroidism: the Brazilian experience
Arq Bras Endocrinol Metabol
Epidemiology of primary hyperparathyroidism and its non-classical manifestations in the city of Recife, Brazil
Clin Med Insights Endocrinol Diabetes
Primary hyperparathyroidism: postoperative long-term evolution
Medicina (B Aires)
Sex difference in the clinical presentation of primary hyperparathyroidism: influence of menopausal status
J Clin Endocrinol Metabol
Trends in the incidence and treatment of parathyroid cancer in the United States
Cancer
Genetics of parathyroid tumours
J Intern Med
Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features
PLoS One
Hypercalcemic disorders in children
J Bone Miner Res
Calcium intake and risk of primary hyperparathyroidism in women: prospective cohort study
BMJ
Physical activity and the risk of primary hyperparathyroidism
J Clin Endocrinol Metabol
Body size and the risk of primary hyperparathyroidism in women: a cohort study
J Bone Miner Res
Hypertension, antihypertensive medications, and risk of incident primary hyperparathyroidism
J Clin Endocrinol Metabol
The parathyroid as a target for radiation damage
N Engl J Med
A prospective study of hyperparathyroidism in individuals exposed to radiation in childhood
Jama
Lithium-associated hyperparathyroidism: report of four cases and review of the literature
Eur J Endocrinol
Thiazide-associated hypercalcemia: incidence and association with primary hyperparathyroidism over two decades
J Clin Endocrinol Metabol
Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop
J Clin Endocrinol Metabol
Cited by (85)
Severe hypercalcemia secondary to parathyroid adenoma: Series of four consecutive cases at a tertiary care hospital in Qatar
2023, International Journal of Surgery Case ReportsMaximizing Opportunities: Primary Hyperparathyroidism in the Older Adult
2023, Journal for Nurse PractitionersCitation Excerpt :If serum 25-hydroxyvitamin D is low, clinicians should cautiously and slowly replete the stores with close monitoring of serum Ca2+ because comorbid chronic renal disease is common in older adults.3 A 24-hour urinary Ca2+ should be normal or elevated (>200-300 mg/d with calcium/creatinine > 0.02).11 Preoperative imaging is not recommended for diagnostic confirmation but is accepted as standard of care and recommended by society guidelines for lesion localization.18,22,25,26
Insights into Hyperparathyroidism–Jaw Tumour Syndrome: From Endocrine Acumen to the Spectrum of CDC73 Gene and Parafibromin-Deficient Tumours
2024, International Journal of Molecular SciencesThe calcium-clot connection: investigating the association between primary hyperparathyroidism and acute venous thromboembolism
2024, Journal of Thrombosis and Thrombolysis