5 Primary Hyperparathyroidism

Suggested citation: Endocrine Society. Endocrine Facts and Figures: Bone and Mineral. First Edition. 2016.

Primary hyperparathyroidism (PHPT) results from an excess of parathyroid hormone (PTH) secreted by one or more of the four parathyroid glands due to parathyroid adenoma, parathyroid hyperplasia, or (very rarely) parathyroid carcinoma.

5.1 PREVALENCE AND INCIDENCE

The most recent prevalence estimates of PHPT are 1-4 per 1,000, with a 3-fold higher prevalence in women than men.92 The Rochester-Olmsted County Epidemiology Project observed a rise and fall in the annual incidence of PHPT from 1965 to 2010.93 A significant increase was noted in 1974, following the implementation of routine testing of serum calcium. Interestingly, a second peak started in 1998 in conjunction with the introduction of national osteoporosis screening guidelines. During the most recent period examined (1998-2010), the overall age- and sex-adjusted incidence rate has been reported to be 50.4 per 100,000.93 Trends in PHPT incidence in this cohort are summarized in Table 26.

Table 26. Age- and sex-adjusted annual incidence of primary hyperparathyroidism.
Data Source Population Years Incidence Per 100,00 Person-Years
Rochester-Olmsted County Epidemiology Project medical records Residents of Olmsted County, Minnesota 1965-1974 15
1974-1984 121.7
1984 37.3
1998-2007 86.2
2007 31.3

Source: Griebeler et al. 201593

5.2 DEMOGRAPHIC DIFFERENCES

Overall, PHPT is more prevalent in women than men, with the highest incidence in postmenopausal women.94

The introduction of the multichannel screening test into clinical medicine is primarily responsible for the change in recognition of PHPT in the 1970s. As countries implemented biochemical screening, which routinely measured serum calcium, PHPT became commonly recognized as noted above. Most of these “newly discovered” individuals were asymptomatic women in their middle years.95 Researchers at a large tertiary referral center examined electronic medical records of 2.7 million patients over a 2-year period and identified 95 with a recorded diagnosis of PHPT, of whom 16 underwent parathyroidectomy.96 Among hypercalcemic patients identified in the electronic medical records, PTH values were not obtained from 67%, which (the authors conclude) led to underdiagnosis and undertreatment of PHPT.

Analysis of active enrollees in Kaiser Permanente Southern California showed some racial and ethnic differences in the epidemiology of PHPT (Table 27). Incidence was highest among African American patients, and racial/ethnic differences were more pronounced among older patients.

Table 27. Age-adjusted incidence and prevalence of primary hyperparathyroidism by sex and race/ethnicity.
  Incidence (per 100,000) Prevalence (per 100,000)
Race/Ethnicity Women Men Women Men
Caucasian 81.0 29.4 201.0 69.1
African American 92.0 46.0 321.7 138.4
Asian 51.8 27.9 103.1 63.1
Hispanic 48.6 17.1 118.3 39.9
Other 25.4 5.9 50.1 10.3

Source: Yeh et al. 201397

5.3 LIFE EXPECTANCY AND MORTALITY

The ability to recognize asymptomatic hyperparathyroidism95 has led to discussions about how to manage this disease. A 1998 population-based study by researchers at the Mayo Clinic that examined data between 1965 and 1992, identified 435 cases of PHPT; of those, 126 patients underwent parathyroid surgery.98 Patients who underwent surgery had higher serum calcium levels than those who were observed without surgery (mean ± SD 11.3 ± 0.7 vs. 10.7 ± 0.4 mg/dL, respectively, P < .001), and age-adjusted multivariate analysis showed that the highest quartile of serum calcium levels was an independent predictor of mortality (RR = 1.3 per mg/dL, 95% CI 1.1-1.6, P < .02). An Australian study found significantly greater mortality (P < .001) among a group of 561 patients with PHPT than in the general population.99 Mortality rates were similar regardless of whether the patients’ serum calcium levels were above or below 12 mg/dL.

Among 1,049 patients with overt PHPT and 388 matched patients with mild PHPT, 62.2% and 53.3% were cured at 5 months following surgery (P ≤ .01) and had equivalent Kaplan-Meier disease-free survival following surgery.100

5.4 KEY TRENDS AND HEALTH OUTCOMES

Revised guidelines for the management of asymptomatic PHPT were published in 2014 and included recommendations for the extensive evaluation of patients’ skeletal and renal systems, inclusion of these results in surgery guidelines, and the development of specific guidelines regarding parathyroid surgery.101 More data are now becoming available about the clinical presentation of a new variant of hyperparathyroidism, normocalcemic PHPT, in which PTH levels are elevated, while serum calcium levels are consistently normal. This occurs in the absence of secondary causes of hyperparathyroidism, such as renal disease or vitamin D deficiency.102 We are also seeing improvements in imaging and analytical techniques for detecting skeletal and renal involvement in asymptomatic hyperparathyroidism.103 In patients who do not meet guidelines for parathyroidectomy, a conservative, non-interventional follow-up regimen is recommended as a reasonable option. However, the recent workshop on the management of asymptomatic PHPT noted that parathyroid surgery can be performed in patients who don’t meet guidelines for surgery if they and/or their physician make that decision, as long as there are no medical contraindications.104 While it has been suggested that cardiovascular morbidity and mortality may be related to PHPT, most of these observations come from a time when PHPT was a symptomatic disease. The extent to which the cardiovascular system is involved and associated with increased morbidity and mortality in PHPT is not known. The consequences of successful parathyroidectomy on this and other “off target” manifestations of PHPT remain uncertain.104

Current guidelines recommend parathyroid surgery for patients with symptomatic PHPT or with asymptomatic PHPT who meet one of the following guidelines: serum calcium > 1mg/dL above the upper limit of normal, calculated creatinine clearance < 60mL/min, evidence for kidney stones or nephrocalcinosis by history or by imaging studies, osteoporosis by T-score, previous fragility fracture, and age < 50 years.105,106

Patients with asymptomatic PHPT who do not meet the guidelines for surgery or with contraindications for surgery should be followed. In those who meet densitometric surgical guidelines but who are not going to have parathyroid surgery, antiresorptive therapy and the monitoring of biochemical data and bone densitometry is appropriate.105 For individuals who meet surgical guidelines by virtue of the serum calcium level but who do not undergo parathyroid surgery, calcimimetic therapy has been proven to be helpful.107-114

In an Australian multicenter retrospective cohort study, 4,569 patients (3,585 women) underwent either focused parathyroidectomy or open four-gland parathyroid exploration.108 The former was associated with fewer operative complications but higher persistence rates that nonetheless were resolved by early reoperation, and both procedures had similarly low long-term recurrence rates (5-year recurrence rates of 0.6% vs. 0.4%, respectively, P=0.08). Other researchers compared minimally invasive parathyroidectomy with open four-gland parathyroid exploration in a cohort of 1,083 patients and reported that patients undergoing open four-gland parathyroid exploration experienced more post-operative transient hypocalcemia. In comparison, patients undergoing minimally invasive parathyroidectomy appeared to have a greater long-term recurrence rate. Therefore, proper patient selection and counseling of these risks is necessary for either approach.109

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