Hyperparathyroidism

A condition of excess parathyroid hormone secretion, classified as primary, secondary, or tertiary.

• Primary: autonomous parathyroid hormone overproduction, most commonly from a solitary parathyroid adenoma.
• Secondary: appropriate, physiological parathyroid hormone elevation in response to chronic hypocalcaemia, most commonly from chronic kidney disease or vitamin D deficiency.
• Tertiary: autonomous parathyroid hormone hypersecretion developing after a prolonged period of secondary hyperparathyroidism, typically in the context of longstanding chronic kidney disease, where the chronically stimulated parathyroid glands develop autonomous function persisting even after the original stimulus is corrected.

Accurate classification is essential given the fundamentally different underlying pathophysiology and management approach required for each.

Pathophysiology and classification

• Primary hyperparathyroidism most commonly results from a solitary parathyroid adenoma, accounting for the great majority of cases.
• Parathyroid hyperplasia (affecting multiple glands) and, rarely, parathyroid carcinoma account for the remaining minority.
• Hyperplasia has a recognised association with certain hereditary syndromes, including multiple endocrine neoplasia type one and type two a.
• The characteristic biochemical pattern is elevated or inappropriately normal parathyroid hormone in the context of hypercalcaemia, reflecting autonomous, calcium independent hormone secretion.
• Secondary hyperparathyroidism reflects an appropriate physiological parathyroid response to chronic hypocalcaemia.
• In chronic kidney disease, the stimulus is the combined effect of reduced renal activation of vitamin D, phosphate retention, and resulting chronic hypocalcaemia.
• The parathyroid hormone elevation is an appropriate compensatory response rather than autonomous gland dysfunction.
• Treatment is therefore directed at correcting the underlying cause of the chronic hypocalcaemic stimulus rather than at the parathyroid glands themselves.
• Tertiary hyperparathyroidism is the development of autonomous parathyroid hormone hypersecretion following a prolonged period of secondary hyperparathyroidism, most classically in longstanding chronic kidney disease or following renal transplantation.
• The chronically stimulated parathyroid glands develop autonomous, calcium independent function.
• This function persists, and can produce frank hypercalcaemia, even after the original underlying stimulus (such as renal failure, following successful transplantation) has been corrected.

• Primary hyperparathyroidism is frequently identified incidentally through routine biochemical testing revealing hypercalcaemia in an otherwise asymptomatic patient, reflecting the now common practice of biochemical screening in many healthcare settings.
• A proportion of patients present with symptoms of hypercalcaemia: polyuria, polydipsia, constipation, fatigue and, in more severe or longstanding cases, nephrolithiasis (renal stone disease) and reduced bone density.
• Bone involvement was historically associated with osteitis fibrosa cystica, a classical though now uncommon severe manifestation.
• In contemporary practice it more typically presents as subclinical reduction in bone mineral density, particularly affecting cortical bone sites, identified on formal bone density assessment.
• There is an associated increased fracture risk over time if the underlying hyperparathyroidism remains untreated.
• Secondary hyperparathyroidism in the context of chronic kidney disease is generally identified through routine biochemical monitoring in this population, rather than presenting with specific symptoms directly attributable to the parathyroid hormone elevation itself.
• It contributes to the broader spectrum of chronic kidney disease mineral and bone disorder, addressed further under chronic kidney disease elsewhere.
• Tertiary hyperparathyroidism presents with hypercalcaemia, sometimes significant, together with the specific relevant clinical context of longstanding chronic kidney disease or a history of previous renal transplantation, distinguishing this specific scenario from de novo primary hyperparathyroidism occurring without this particular preceding clinical history.

• Serum calcium together with intact parathyroid hormone measurement is the essential initial diagnostic approach.
• Primary hyperparathyroidism is characterised by elevated or inappropriately normal (given the concurrent hypercalcaemia) parathyroid hormone in the context of confirmed hypercalcaemia.
• This distinguishes it from the appropriately suppressed parathyroid hormone expected in hypercalcaemia from other, non parathyroid causes (such as malignancy related hypercalcaemia).
• Twenty four hour urinary calcium excretion, together with assessment of renal function and vitamin D status, supports the diagnostic evaluation.
• It helps exclude the important differential diagnosis of familial hypocalciuric hypercalcaemia.
• Familial hypocalciuric hypercalcaemia is a benign, generally non progressive condition caused by a calcium sensing receptor mutation, characterised by mild hypercalcaemia with inappropriately low urinary calcium excretion.
• It requires no specific parathyroid directed treatment, and is important to distinguish from genuine primary hyperparathyroidism given the fundamentally different management implications.
• Parathyroid imaging is performed to localise the abnormal parathyroid gland or glands: ultrasound and, commonly, sestamibi scintigraphy, with four dimensional computed tomography as a further, increasingly used localisation technique, particularly for more diagnostically challenging cases.
• Localisation is essential for guiding surgical planning once the diagnosis of primary hyperparathyroidism requiring surgical treatment has been established.
• It is not required to establish the diagnosis itself, which rests on the biochemical findings.
• Bone mineral density assessment (dual energy x ray absorptiometry) supports assessment of the end organ consequences of confirmed primary hyperparathyroidism.
• Where relevant based on symptoms or risk factors, renal imaging for nephrolithiasis is added.
• Both inform severity assessment and the specific indications for surgical treatment.

• Parathyroidectomy, surgical excision of the identified abnormal parathyroid gland or glands, is the definitive, curative treatment for primary hyperparathyroidism.
• It is indicated for symptomatic disease: nephrolithiasis, significant bone disease, or other clear symptoms attributable to hypercalcaemia.
• In asymptomatic patients it is indicated according to established criteria:
  • the degree of hypercalcaemia
  • evidence of reduced bone density on formal assessment
  • evidence of renal involvement (reduced renal function or nephrolithiasis)
  • age under fifty years
• This reflects the generally favourable long term outcome and low surgical morbidity of parathyroidectomy in appropriately selected patients.
• Asymptomatic patients not meeting surgical criteria may be managed with observation, including regular monitoring of serum calcium, renal function and bone density over time, given the generally slow, often non progressive natural history of mild, asymptomatic primary hyperparathyroidism in a substantial proportion of such patients.
• Cinacalcet is a calcimimetic agent that increases the sensitivity of the calcium sensing receptor to circulating calcium, thereby reducing parathyroid hormone secretion.
• It is a medical treatment option for patients with primary hyperparathyroidism not suitable for, or declining, surgical treatment.
• It is also an important component of management for secondary and tertiary hyperparathyroidism in the chronic kidney disease population.
• Secondary hyperparathyroidism is managed by addressing the underlying cause of the chronic hypocalcaemic stimulus, including vitamin D replacement where deficiency is identified.
• In chronic kidney disease, management uses phosphate binders, active vitamin D analogues and, where indicated, cinacalcet.
• This forms part of the broader, full management approach to chronic kidney disease mineral and bone disorder.
• Tertiary hyperparathyroidism, where persistent and clinically significant following renal transplantation or in ongoing dialysis dependent chronic kidney disease, may require surgical parathyroidectomy where medical management with cinacalcet proves inadequate.
• Surgical principles are broadly similar to those in primary hyperparathyroidism, with specific additional considerations relevant to the underlying chronic kidney disease context and any transplant related factors.
• Postoperative monitoring following parathyroidectomy includes assessment for hypocalcaemia, together with confirmation of biochemical cure through postoperative calcium and parathyroid hormone measurement.
• Hypocalcaemia can be particularly pronounced and prolonged in "hungry bone syndrome": rapid, avid bone uptake of calcium following correction of longstanding hyperparathyroidism.
• This is particularly relevant in patients with more severe, longstanding disease and significant preoperative bone involvement.
• It requires proactive, sometimes substantial and prolonged, calcium and active vitamin D supplementation.