Etiology

Primary hyperparathyroidism is caused by the inappropriate secretion of parathyroid hormone (PTH), leading to hypercalcemia.

  • Parathyroid adenomas are the most common etiology. Around 85% are a single, benign adenoma, which in most cases is sporadic.[1]​ Multiple adenomas and hypertrophy of all 4 glands are less common.

  • Inherited forms, affecting 5% to 10% of patients, lead to hyperfunctioning parathyroid glands.[17] These disorders include multiple endocrine neoplasia (MEN) 1, MEN 2, and MEN 4; HPT-jaw tumor syndrome; and familial isolated hyperparathyroidism.[18]​

    • MEN 1, MEN 2, and MEN 4 are autosomal dominant traits. PHPT affects 90% of patients with MEN 1.[7]​ Clinical features of MEN 1 include multigland parathyroid disease, pancreatic neuroendocrine tumors, and anterior pituitary tumors.[7]​ In MEN 2A, PHPT occurs in around 20% of patients.[18]​ The PHPT disease is either multigland or an adenoma. Other manifestations of MEN 2A include medullary thyroid cancer and pheochromocytomas.[18]​ MEN 4 is characterized by the occurrence of parathyroid, anterior pituitary tumors, and pancreatic neuroendocrine tumors in association with gonadal, adrenal, renal and thyroid tumors that have CDNK1B mutations.[18]​​

    • HPT-jaw tumor syndrome characteristically includes parathyroid adenomas or carcinomas, in association with mandibular or maxillary fibro-osseous lesions, uterine tumors in women, and renal cysts and tumors.[18]​ Inherited in an autosomal dominant fashion.

    • Familial isolated PHPT is a genetic mutation similar to MEN, but without manifestations of other endocrinopathies.[18] It has different modes of inheritance and different patterns of parathyroid pathology.[9]​​

  • Only ≤1% of cases are due to parathyroid malignancies.[3]​​

  • Hyperparathyroidism may also result from external neck irradiation.[19]​​

  • Lithium therapy, often used to treat patients with bipolar disorder, can lead to overstimulation of parathyroid glands, by altering feedback inhibition of PTH secretion, known as the PTH set point.[20]​ This phenomenon may persist after the drug is stopped if parathyroid hormone production has become autonomous.[20]​​

Pathophysiology

Low serum calcium ordinarily stimulates parathyroid hormone (PTH) secretion, whereas high calcium levels suppress PTH secretion. In primary hyperparathyroidism, PTH secretion is not suppressed (as would typically be expected) by high calcium levels. Excessive PTH leads to overstimulation of bone resorption, with cortical bone affected more than cancellous bone.[6] PTH also stimulates the kidneys to reabsorb calcium and to convert 25-hydroxyvitamin D3 to its more active form of 1,25-dihydroxyvitamin D3. This active vitamin D is responsible for the gastrointestinal absorption of calcium.

Overstimulation of PTH receptors, specifically type-2 PTH receptors, is thought to play a role in the subjective neurocognitive and affective symptoms.[21] Hypercalciuria may also lead to nephrolithiasis.[6]

Classification

Primary hyperparathyroidism: clinical phenotypes[1]

The clinical presentation of primary hyperparathyroidism has changed over the years and varies across countries, depending on availability of biochemical screening tests.

Symptomatic PHPT: the patient overtly exhibits "classic" symptoms of renal (e.g., reduced kidney function, nephrolithiasis) and skeletal (e.g. fragility fractures, skeletal deformities) complications. The neuromuscular system (e.g., proximal neuromuscular weakness) can also be involved. Other “non-classical” manifestations attributed to PHPT include the cardiovascular system (e.g., hypertension, atherosclerotic heart disease) and neurocognitive features (e.g., anxiety, poor concentrating ability, cognitive decline). Gastrointestinal symptoms may be present.

Asymptomatic PHPT: the patient has biochemical evidence of the disease and may have manifestations of PHPT, but does not exhibit any of the classic symptoms. Usually an incidental finding of mildly elevated calcium and/or PTH levels (typically within two times the upper limit of normal). The patient may exhibit a constellation of subjective nonspecific symptoms.

Normocalcemic PHPT: an asymptomatic biochemical phenotype with normal calcium levels and a mildly elevated PTH level (usually similar or slightly lower than in the hypercalcemic form of asymptomatic PHPT).[4]​ The clinical features can be similar to the classical form, including nephrolithiasis and low bone mineral density. The exact proportion of patients that will go on to develop PHPT is unknown, but current evidence suggests only small numbers.[5]

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