PHPT is a common disorder of mineral metabolism that is due to excessive secretion of PTH from 1 or more of the 4 parathyroid glands. The clinical consequences of abnormally active parathyroid tissue are typically hypercalcemia and concentrations of PTH that are either clearly elevated above the normal range or inappropriately normal in the context of hypercalcemia.
Epidemiology
PHPT mainly affects women, with a female to male ratio of 3–4:1 [2, 3]. When the first several hundred individuals with PHPT were described in the 1930s at Massachusetts General Hospital, 57% had kidney stones, 8% had peptic ulcer disease, and 23% had bone complications [4]. Over the past 5 decades, the clinical presentation of PHPT has changed in several regions of the world. The clinical evolution of PHPT from symptomatic to asymptomatic has occurred primarily in the USA and Europe, although other countries have more recently appreciated this change as well. Similar to the epidemiology in North America, PHPT in Europe most often presents as an asymptomatic disorder. Both in Sweden and Denmark, the incidence of PHPT appears to be increasing, perhaps because of an increase in the use of screening methods [6, 15, 16].
Etiopathogenesis and Diagnosis
PHPT is most commonly due to a single benign parathyroid adenoma (approximately 80% of patients), with multiglandular disease seen in approximately 15–20% of patients [6]. PHPT is due to multiglandular involvement consisting of either multiple adenomas or hyperplasia of all 4 glands (5–10%), and very rarely by parathyroid carcinoma (<1%) [4]. Very rarely, PHPT may be caused by ectopic secretion of PTH by a nonparathyroid tumor. In most patients with PHPT, the disease is sporadic, without a personal or family history of PHPT [6, 17]. The genetic syndromes associated with PHPT are considered major risk factors and include MEN1, 2A, and 4, hyperparathyroidism-jaw tumor syndrome, familial isolated PHPT, familial hypocalciuric hypercalcemia (FHH), and neonatal severe hyperparathyroidism [6]. The combination of hypercalcemia and an elevated or inappropriately normal PTH level makes PHPT the most likely diagnosis [18]. The genetics of PHPT is usually monoclonal when a single gland is involved, which implies that the tumors derive from a single abnormal cell [4], and polyclonal when multiglandular disease is present. The genes that have been implicated in PHPT include proto-oncogenes and tumor-suppressor genes [4]. Hyperplastic parathyroid glands probably originate from a stimulus for generalized (polyclonal) parathyroid cell proliferation, even though monoclonal tumors may also occur in this context. Thus, in some cases, apparently hyperplastic glands are in fact adenomas. The clonality of parathyroid tumors has also been shown in MEN1 [4].
If the corrected serum calcium is normal and PTH is elevated, serum ionized calcium should be measured, as PHPT can present with an elevated ionized calcium despite a normal albumin-adjusted serum calcium [18, 19]. Ionized calcium measurements are reliable if samples are collected under anaerobic conditions maintaining the original pH of the specimen, as acidosis is associated with an increase in ionized calcium. The differential diagnosis of hypercalcemia includes conditions which mimic PHPT, including FHH and certain non-PTH-related forms of hypercalcemia (see above in the section Hypercalcemia and Differential Diagnosis). An elevated serum PTH in the presence of consistently normal albumin-adjusted calcium and ionized calcium, normal serum 25-hydroxyvitamin D [25(OH)D >20 ng/mL or 50 nmol/L], and well-maintained renal function (eGFR >60 mL/min/1.73 m2) supports this diagnosis [18, 19]. In the evaluation of PHPT, the calcium to creatinine clearance ratio is determined in order to exclude FHH, a rare, autosomal-dominant disorder with 3 identified variants with very low urinary calcium excretion and mild hypercalcemia with normal or slightly elevated PTH levels. FHH1 is due to an inactivating mutation of the calcium-sensing receptor (CaSR) gene. FHH2 is caused by inactivating mutations of the G-protein alpha 11 subunit (Gα11), and FHH3 is due to inactivating mutations of the adaptor protein-2 sigma subunit (AP2S1) [18, 20, 21]. Urinary calcium excretion is usually expressed as the “calcium clearance to creatinine ratio” (CCa/CCr), which is rather the sensitive index of renal calcium excretion than total urinary calcium. The CCa/CCr in FHH is usually less than 0.01, allowing discrimination from PHPT [11, 21]. However, approximately 20% have a CCa/CCr between 0.01 and 0.02, which can overlap with PHPT [21]. Finally, a low CCa/CCr may be observed in PHPT with renal insufficiency or severe calcium and/or vitamin D deficiency [18, 20].
Other genetic disorders that should be considered in the differential diagnosis of PHPT include MEN1 and 2. Screening is justified in settings of familial glandular secretory syndromes that involve the pituitary glands and pancreas, or the thyroid or adrenal glands, or both. If the patient also has a history suggestive of MEN1 or 2, screening for these familial syndromes is important. The clinical presentation of parathyroid cancer is very different from the presentation of typical PHPT. Patients with parathyroid cancer tend to be younger by about a decade – between 40 and 50 years of age – and the prevalence is roughly the same in women and men. Serum calcium and PTH concentrations are usually much higher than in typical PHPT [6, 22].
Parathyroid imaging has become a standard preoperative procedure to locate abnormal parathyroid tissue [18]. The value of imaging rests with accurate identification of abnormal parathyroid tissue in order to assist in planning the appropriate parathyroid surgery. The imaging techniques most frequently used are 99mTc-sestamibi scintigraphy, ultrasound, and computed tomography (CT) [18]. In the presence of concordance between scintigraphy and ultrasound, the positive predictive value for correct side localization of a parathyroid adenoma can be as high as 97% [18]. 11C-methionine PET/CT scintigraphy is another method of imaging based on the uptake and incorporation of the essential amino acid methionine in parathyroid tissue in PTH synthesis. It may have a high sensitivity