Hypoparathyroidism

Hypoparathyroidism is deficient parathyroid hormone secretion or action. It most commonly results from inadvertent surgical damage to or removal of the parathyroid glands during thyroid or other neck surgery (post surgical hypoparathyroidism, see thyroid surgery).

It produces hypocalcaemia with inappropriately low or absent parathyroid hormone. Management is centred on lifelong calcium and active vitamin D replacement and, for selected patients, recombinant parathyroid hormone therapy.

Less common causes are:

• autoimmune destruction, in isolation or as part of a broader autoimmune polyendocrine syndrome
• genetic causes, including developmental syndromes affecting parathyroid gland formation
• rarely, pseudohypoparathyroidism, which is parathyroid hormone resistance rather than deficiency, from a genetic defect in the parathyroid hormone receptor signalling pathway

Pathophysiology and classification

• Post surgical hypoparathyroidism is the commonest cause overall. It reflects inadvertent removal, devascularisation or direct surgical trauma to the parathyroid glands during thyroid or other neck surgery.
• It is transient in most affected patients, reflecting temporary devascularisation or trauma with subsequent recovery of function. It is permanent in a meaningful minority, particularly after more extensive surgery with central compartment lymph node dissection.
• Autoimmune hypoparathyroidism reflects immune mediated destruction of the parathyroid glands. It occurs in isolation or, in a proportion of cases, as part of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome.
• That syndrome is a rare, genetically determined autoimmune polyendocrine syndrome, additionally associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency among other manifestations. Recognise it where such features are present.
• Pseudohypoparathyroidism reflects genetic resistance to parathyroid hormone action at the target tissue receptor. It produces hypocalcaemia with elevated, not low, parathyroid hormone, an appropriate but ineffective attempt to compensate for hormone resistance.
• In a proportion of genetic subtypes there are additional physical features (short stature, brachydactyly and other skeletal abnormalities), collectively termed Albright hereditary osteodystrophy.

• The typical acute presentation is symptoms and signs of hypocalcaemia: perioral and peripheral paraesthesia and muscle cramping. In more significant or acute hypocalcaemia there is carpopedal spasm and tetany.
• Severe cases bring seizures and cardiac arrhythmia, including a prolonged corrected QT interval predisposing to potentially life threatening ventricular arrhythmia.
• Chvostek sign (facial muscle twitching elicited by tapping over the facial nerve anterior to the ear) and Trousseau sign (carpopedal spasm induced by inflation of a blood pressure cuff above systolic pressure for several minutes) are classic signs supporting significant hypocalcaemia.
• Both have imperfect sensitivity and specificity, so their absence does not exclude clinically significant hypocalcaemia.
• Chronic, longstanding hypoparathyroidism can cause cataracts (chronic hypocalcaemia related lens changes) and basal ganglia calcification. Basal ganglia calcification may be found incidentally on neuroimaging and can, in some patients, be associated with movement disorder or other neurological manifestations.
• Dental abnormalities occur where onset is during childhood tooth development.
• The clinical context guides the underlying cause: recent neck surgery, symptoms or history suggesting a broader autoimmune polyendocrine syndrome, or, in pseudohypoparathyroidism, the characteristic physical features of Albright hereditary osteodystrophy.

• Serum calcium with intact parathyroid hormone is the essential diagnostic approach. True hypoparathyroidism shows hypocalcaemia with an inappropriately low or undetectable parathyroid hormone level.
• This distinguishes it from hypocalcaemia due to another cause (such as vitamin D deficiency or chronic kidney disease), where parathyroid hormone is elevated as an appropriate physiological response.
• It also distinguishes it from pseudohypoparathyroidism, where hypocalcaemia with elevated parathyroid hormone reflects hormone resistance rather than deficiency.
• Serum phosphate is typically elevated in hypoparathyroidism, reflecting loss of the phosphaturic effect of parathyroid hormone. This is a further supportive biochemical feature.
• Assess magnesium. Significant hypomagnesaemia can itself impair parathyroid hormone secretion and produce a functional, reversible hypoparathyroid state, a readily correctable cause to exclude or address.
• Where the cause is not apparent from the context (such as a clear history of recent relevant neck surgery), further evaluation supports definitive diagnosis and classification. Screen for associated autoimmune conditions where autoimmune polyendocrine syndrome is suspected. Use genetic testing where the biochemical pattern and any physical features suggest pseudohypoparathyroidism.
• Electrocardiography to assess for corrected QT interval prolongation is appropriate in significant hypocalcaemia, given the arrhythmia risk.
• Cranial imaging, where done for another indication or for relevant neurological symptoms, may incidentally show the basal ganglia calcification of chronic, longstanding hypoparathyroidism.

• Acute, severe, symptomatic hypocalcaemia (tetany, seizure, significant cardiac arrhythmia) needs emergency intravenous calcium gluconate. Give it as a slow infusion with cardiac monitoring, because overly rapid administration risks arrhythmia.
• Once acute symptoms resolve and the patient can tolerate oral intake, transition to oral calcium and active vitamin D supplementation.
• Chronic management is oral calcium supplementation with active vitamin D analogues (alfacalcidol or calcitriol). These bypass the renal hydroxylation step needed to activate standard vitamin D, which itself depends on adequate parathyroid hormone action. Standard, inactive vitamin D preparations are therefore generally inadequate as sole treatment.
• Titrate doses by regular serum calcium monitoring.
• The target serum calcium is generally the low normal range or, in some cases, slightly below the normal reference range but sufficient to control symptoms. Do not aim for the mid to upper normal range typical of other contexts.
• More aggressive correction risks hypercalciuria and nephrocalcinosis or renal stone formation. Without parathyroid hormone mediated renal calcium reabsorption, the kidney lacks its usual protection against this complication.
• Monitor renal function and, particularly, twenty four hour urinary calcium excretion, with periodic renal imaging where indicated. This allows early identification of hypercalciuria and renal complications and treatment adjustment.
• Consider a thiazide diuretic, which reduces urinary calcium excretion, as an adjunct where hypercalciuria occurs despite calcium levels within the target range.
• Recombinant human parathyroid hormone, given as a subcutaneous injection, is an important option for chronic hypoparathyroidism inadequately controlled with conventional calcium and active vitamin D alone, or with significant treatment related complications (marked hypercalciuria, renal impairment).
• It restores more physiological calcium and phosphate homeostasis and, in selected patients, allows meaningful reduction in the dose of conventional calcium and active vitamin D.
• Magnesium replacement is essential where significant hypomagnesaemia is a contributing or causative factor, because correcting magnesium deficiency restores parathyroid hormone secretion and calcium homeostasis.
• Lifelong endocrinology follow up monitors calcium, phosphate, renal function and urinary calcium excretion. Assess periodically for chronic complications of longstanding hypoparathyroidism (cataracts, basal ganglia calcification, renal complications).
• Post surgical hypoparathyroidism needs reassessment over the initial months after surgery. In a meaningful proportion parathyroid function recovers, allowing eventual discontinuation of replacement therapy.