Masi, MD, PhD
Metabolic Bone Diseases Unit, University Hospital of Florence, AOU-Careggi
Largo Palagi, 1
IT–50134 Florence (Italy)
E-Mail [email protected]
Brandi ML (ed): Parathyroid Disorders. Focusing on Unmet Needs.
Front Horm Res. Basel, Karger, 2019, vol 51, pp 13–22 (DOI: 10.1159/000491035)
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Asymptomatic Primary Hyperparathyroidism
Bart L. Clarke
Mayo Clinic, Rochester, MN, USA
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Abstract
Asymptomatic primary hyperparathyroidism has become the most common presentation of primary hyperparathyroidism in Europe and North America, and an increasingly common presentation in other parts of the world. As many as 25% of asymptomatic patients may develop indications for parathyroidectomy when followed long-term for up to 15 years. Patients who remain asymptomatic should be monitored for the development of complications that justify surgery. Patients who become symptomatic should be referred for surgery. Surgery may improve quality of life even in patients who remain asymptomatic.
© 2019 S. Karger AG, Basel
Asymptomatic primary hyperparathyroidism (PHPT) is viewed as a milder presentation of classical PHPT [1]. Despite meeting biochemical criteria for the diagnosis, asymptomatic patients often do not meet other criteria for surgery, and many patients without symptoms are observed without surgery. Over time, some of these patients progress to symptomatic PHPT and require surgery, whereas others remain asymptomatic. Asymptomatic patients who meet other criteria for surgery at the initial evaluation, such as having osteoporosis or low-trauma fractures, calcium-containing kidney stones, hypercalciuria, or serum calcium more than 1.0 mg/dL above the normal range, are usually advised to have surgery [2]. Most patients in Europe and North America present with asymptomatic PHPT in the modern era, whereas patients elsewhere in the world more commonly have symptomatic PHPT [3].
Epidemiology
PHPT is the most common cause of hypercalcemia in the outpatient setting [3, 4]. The incidence of this disorder is estimated to be 27–30 per 100,000 person-years in the USA, the UK, and Sweden [5, 6], with prevalence estimated at 1:1,000 in men and 2–3:1,000 in women. No studies have specifically evaluated the incidence or prevalence of asymptomatic PHPT.
Griebeler et al. [7] evaluated population-based secular trends in the incidence of PHPT in a mostly Caucasian population in Rochester, MN, USA, to determine if there had been a significant change in the incidence of PHPT between 2002 and 2010, and, if possible, to identify any changes in clinical practice that might be responsible. The findings were added to the historical cohort of patients that has been followed since 1965, and incidence rates adjusted to the 2010 US white population. A total of 1,142 Rochester residents had been diagnosed with PHPT since 1965, with 341 newly diagnosed cases in 2002–2010. Two periods of increased incidence occurred, one beginning in 1974, with a peak of 121.7 per 100,000 person-years, and a second peak of 86.2 per 100,000 person-years, beginning in 1998.
Yeh et al. [8] evaluated the incidence and prevalence of PHPT in a racially mixed population including 3.5 million enrollees within the Kaiser Permanente Southern California health system. The incidence of PHPT fluctuated from 34 to 120 per 100,000 person-years (mean 66 per 100,000) among women, and from 13 to 36 (mean 25 per 100,000) among men. With advancing age, the incidence increased and sex differences became pronounced, with the incidence estimated at 12–24 per 100,000 for both sexes younger than 50 years, 80 and 36 per 100,000 for women and men aged 50–59 years, respectively, and 196 and 95 per 100,000 for women and men aged 70–79 years, respectively. The incidence of PHPT was highest among blacks, with 92 and 46 per 100,000 for women and men (p < 0.0001), followed by whites, with 81 and 29 per 100,000 for women and men, with rates for Asians (52 and 28 per 100,000 for women and men), Hispanics (49 and 17 per 100,000 for women and men), and other races (25 and 6 per 100,000 for women and men) lower than that for whites (p < 0.0001).
Yu et al. [9] evaluated the prevalence and incidence of diagnosed PHPT in adults in a population-based study between 1997 and 2006 in Tayside, UK. The prevalence of diagnosed PHPT increased from 1.82 per 1,000 population in 1997 to 6.72 per 1,000 population in 2006 (p < 0.001). The prevalence of PHPT was higher in females, and the female preponderance increased with age. The annual prevalence ratio between women and men was stable at around 2.5 each year. The higher prevalence figures obtained in this study compared to other studies is likely to be due to differences in methodology.
Diagnosis and Clinical Features
Asymptomatic PHPT is caused by inappropriate secretion or oversecretion of parathyroid hormone (PTH) [10]. Solitary parathyroid adenomas cause PHPT 80–85% of the time, whereas multigland hyperplasia is found in 15–20% of cases, and parathyroid cancer is noted in less than 0.5% of cases [11]. As with other endocrine tumors, pathologic diagnosis of parathyroid carcinoma is difficult and is usually based on the examination of local tissue, presence of vascular invasion, or detection of metastatic disease [12]. Most single adenomas are due to sporadic disease, whereas 4-gland hyperplasia implies a familial disorder, most commonly MEN1 or 2A, or familial isolated PHPT [13].
The causes of asymptomatic sporadic PHPT are not well understood. It is presumed that causes of asymptomatic PHPT are similar to those causing symptomatic PHPT. Previous exposure to neck irradiation contributes in a minority of cases, typically 20–30 years after such exposure [14]. More commonly, adenomas represent clonal expansion of a single or several abnormal cells, attributable to a genetic abnormality that results in either stimulation of cell proliferation or loss of inhibition of cell proliferation [15].
Normocalcemic, or “incipient,” hyperparathyroidism occurs when serum calcium is normal but PTH is increased, without evidence of vitamin D deficiency, hypercalciuria, or other causes of hyperparathyroidism [16]. This condition requires documentation of normal serum 25-hydroxyvitamin D and 24-h urine calcium levels to rule out other causes of physiological hyperparathyroidism. It may be due to an early stage of evolving PHPT or very mild PHPT, with more complications than expected for asymptomatic PHPT [17].
Most current patients with PHPT in Europe and the USA are asymptomatic, typically