Hyperparathyroidism
Hyperparathyroidism is an endocrine disorder characterized by excessive secretion of parathyroid hormone (PTH) from the parathyroid glands, resulting in dysregulation of calcium, phosphate, and bone metabolism. The pathogenesis involves either autonomous hyperfunction of one or more parathyroid glands, often due to adenoma, hyperplasia, or rarely carcinoma, or compensatory overproduction of PTH secondary to chronic hypocalcemia or vitamin D deficiency. Elevated PTH levels increase bone resorption, renal tubular reabsorption of calcium, and gastrointestinal absorption of calcium, leading to hypercalcemia and associated metabolic consequences. Health impacts include nephrolithiasis, osteoporosis, neuropsychiatric disturbances, cardiovascular complications, and, in severe or prolonged cases, end-organ damage. The disease can be asymptomatic or present with a spectrum ranging from mild biochemical abnormalities to life-threatening hypercalcemic crises.
Primary hyperparathyroidism is caused by intrinsic abnormalities of the parathyroid glands, most commonly a solitary benign adenoma, but also by glandular hyperplasia or, rarely, parathyroid carcinoma. This type is characterized by autonomous overproduction of PTH, leading to hypercalcemia and hypophosphatemia. Clinical manifestations are variable, ranging from asymptomatic hypercalcemia detected on routine biochemical screening to classic symptoms of bone pain, nephrolithiasis, gastrointestinal disturbances, and neuropsychiatric complaints. The majority of cases are sporadic, but familial forms exist, often associated with syndromes such as multiple endocrine neoplasia.
Secondary hyperparathyroidism arises as a physiological response to chronic hypocalcemia, most frequently due to chronic kidney disease (CKD), vitamin D deficiency, or malabsorption syndromes. In this context, persistent low calcium levels stimulate the parathyroid glands to increase PTH secretion in an attempt to restore normocalcemia. The resultant elevated PTH leads to bone demineralization and may contribute to renal osteodystrophy. Unlike primary hyperparathyroidism, serum calcium is typically low or normal, and phosphate levels may be elevated, particularly in CKD.
Tertiary hyperparathyroidism develops when secondary hyperparathyroidism, usually in the setting of longstanding CKD, progresses to autonomous parathyroid gland hyperfunction. The glands become hyperplastic and secrete PTH independent of serum calcium regulation, resulting in hypercalcemia. This type is most commonly observed following renal transplantation in patients with a history of severe secondary hyperparathyroidism, where the parathyroid glands fail to revert to normal function despite correction of the underlying cause.
Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting, with an estimated prevalence of 1–4 per 1,000 individuals in the general population and a higher incidence among postmenopausal women. The incidence increases with age, and the female-to-male ratio is approximately 3:1. Secondary hyperparathyroidism is particularly prevalent among patients with chronic kidney disease, affecting the majority of individuals with stage 4 or 5 CKD and those on long-term dialysis. Tertiary hyperparathyroidism is less common and occurs primarily in patients with end-stage renal disease who have undergone renal transplantation. The widespread use of serum calcium measurement has increased the detection of asymptomatic cases, altering the epidemiological landscape of the disease.
The diagnosis of hyperparathyroidism is established through a combination of biochemical, clinical, and imaging assessments. Initial laboratory evaluation reveals elevated serum calcium and parathyroid hormone levels in primary and tertiary hyperparathyroidism, while secondary hyperparathyroidism typically presents with elevated PTH and low or normal serum calcium. Additional laboratory findings may include hypophosphatemia in primary disease and hyperphosphatemia in secondary disease due to renal insufficiency. Measurement of 25-hydroxyvitamin D levels is essential to assess for concomitant deficiency. Renal function tests, urinary calcium excretion, and bone mineral density assessments are commonly performed to evaluate end-organ effects. Imaging studies such as neck ultrasonography, sestamibi parathyroid scintigraphy, and, in selected cases, cross-sectional imaging or four-dimensional CT are utilized for localization of abnormal parathyroid tissue, particularly when surgical intervention is considered. The diagnosis is confirmed by the presence of elevated or inappropriately normal PTH in the setting of hypercalcemia (for primary or tertiary forms) or elevated PTH in the context of hypocalcemia or normocalcemia (for secondary form), after exclusion of other causes of hypercalcemia or elevated PTH.
Several pharmacological agents are available for the management of hyperparathyroidism, each with distinct mechanisms of action. Upacicalcet sodium hydrate is utilized as a calcimimetic agent, modulating the calcium-sensing receptor on parathyroid cells to suppress PTH secretion. Evocalcet, another calcimimetic, is employed to control elevated PTH levels, particularly in patients with secondary hyperparathyroidism associated with chronic kidney disease. Etelcalcetide, a synthetic peptide calcimimetic, is administered intravenously to reduce PTH concentrations in patients undergoing hemodialysis. Cinacalcet hydrochloride is an oral calcimimetic that enhances the sensitivity of the calcium-sensing receptor to extracellular calcium, thereby reducing PTH secretion and serum calcium levels in both primary and secondary hyperparathyroidism. Falecalcitriol, a vitamin D analog, is used to suppress PTH synthesis and improve calcium homeostasis. Maxacalcitol (22-oxacalcitriol) serves as a vitamin D analog with selective action on parathyroid cells, effectively lowering PTH without causing significant hypercalcemia. Doxercalciferol, a synthetic vitamin D2 analog, is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, promoting intestinal calcium absorption and suppressing PTH synthesis. Paricalcitol, another vitamin D analog, is utilized to attenuate PTH levels in patients with CKD, with a reduced risk of hypercalcemia compared to other vitamin D compounds. Alfacalcidol (1-alpha-hydroxyvitamin D3) is converted in the liver to the active form of vitamin D, enhancing intestinal absorption of calcium and phosphate and suppressing PTH secretion. Calcifediol (25-hydroxyvitamin D3) is administered to correct vitamin D deficiency and indirectly reduce PTH levels by restoring normal calcium metabolism. These agents are integral to the medical management of hyperparathyroidism, particularly in patients for whom surgical intervention is not feasible or as adjunctive therapy in refractory cases.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | upacicalcet sodium hydrate (Rec INN) | C11 H13 Cl N3 O6 S . Na . H2 O | 391.76 | |
 | evocalcet (Rec INN) | 870964-67-3 | C24 H26 N2 O2 | 374.475 |
 | etelcalcetide (Rec INN; USAN); velcalcetide | 1262780-97-1 | C38 H73 N21 O10 S2 | 1048.251 |
 | cinacalcet hydrochloride (Rec INNM; USAN) | 226256-56-0 (free base); 364782-34-3 | C22 H22 F3 N . Cl H | 393.873 |
 | falecalcitriol (Prop INN); flocalcitriol; hexafluorocalcitriol | 83805-11-2 | C27 H38 F6 O3 | 524.579 |
 | 22-oxacalcitriol; maxacalcitol (Prop INN; USAN) | 103909-75-7 | C26 H42 O4 | 418.609 |
 | doxercalciferol (Rec INN; USAN) | 54573-75-0 | C28 H44 O2 | 412.648 |
 | paracalcin; paricalcitol (Prop INN; USAN) | 131918-61-1 | C27 H44 O3 | 416.636 |
 | 1-alpha-hydroxyvitamin D3; alfacalcidol (Rec INN; BAN; JAN); alpha-calcidol; oxydevit | 41294-56-8 | C27 H44 O2 | 400.637 |
 | 25-hydroxycholecalciferol; 25-hydroxyvitamin D3; calcidiol; calcifediol (Prop INN) | 19356-17-3 | C27 H44 O2 | 400.637 |
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