Aetiology

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

  • Parathyroid adenomas are the most common aetiology. 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] A history of family members with PHPT should prompt suspicion of multi-gland disease. These disorders include multiple endocrine neoplasia (MEN) 1, MEN 2, and MEN 4; HPT-jaw tumour 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 multi-gland parathyroid disease, pancreatic neuroendocrine tumours, and anterior pituitary tumours.[7]​ In MEN 2A, PHPT occurs in around 20% of patients.[18]​ The PHPT disease is either multi-gland or an adenoma. Other manifestations of MEN 2A include medullary thyroid cancer and phaeochromocytomas.[18]​ MEN 4 is characterised by the occurrence of parathyroid, anterior pituitary tumours, and pancreatic neuroendocrine tumours in association with gonadal, adrenal, renal and thyroid tumours that have CDNK1B mutations.[18]​​

    • HPT-jaw tumour syndrome characteristically includes parathyroid adenomas or carcinomas, in association with mandibular or maxillary fibro-osseous lesions, uterine tumours in women, and renal cysts and tumours.[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 the over-stimulation 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 over-stimulation 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.

Over-stimulation 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 non-specific symptoms.

Normocalcaemic PHPT: an asymptomatic biochemical phenotype with normal calcium levels and a mildly elevated PTH level (usually similar or slightly lower than in the hypercalcaemic 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]

Use of this content is subject to our disclaimer