Hypoparathyroidism

Hypoparathyroidism is a disorder of insufficient parathyroid hormone (PTH) secretion, leading to hypocalcaemia, hyperphosphataemia and disrupted calcium homeostasis. Its signature is a PTH that is inappropriately low or absent in the face of hypocalcaemia. That separates it from the more common secondary hyperparathyroidism, in which chronic hypocalcaemia drives PTH up.

How common. It is rare: 70,000-90,000 cases in the United States.

• Post-surgical - 75%. Iatrogenic, after thyroid or parathyroid surgery. Permanent hypoparathyroidism follows 1-2% of total thyroidectomies, and more after reoperative surgery or central neck dissection, up to 10%.
• Autoimmune. A substantial minority of cases, often as part of autoimmune polyglandular syndrome type 1.
• Genetic or congenital - 5-10%. Includes DiGeorge syndrome.

Why it reaches an orthopaedic list. Calcium that has not been optimised causes perioperative complications, hypocalcaemic seizures and arrhythmias among them. Chronic disease brings basal ganglia calcification, with its extrapyramidal movement disorders, and bone that is paradoxically dense because remodelling is reduced. Recognising the condition before surgery is what allows preoperative optimisation and avoids a metabolic crisis in theatre.

What PTH Normally Does

PTH acts on bone and kidney directly, and on the gut through vitamin D activation. Hypoparathyroidism is what happens when all of those actions are lost at once.

The net result is low serum calcium, high serum phosphate and low urine calcium.

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Why Calcium Falls and Phosphate Rises

Calcium. The losses all pull the same way. With no PTH-mediated osteoclast activation, calcium stays sequestered in bone; the distal tubule lets calcium go that it would have reclaimed; and with little calcitriol the gut absorbs poorly despite the low serum calcium. The result is a net calcium loss.

Phosphate. PTH normally promotes renal phosphate excretion by inhibiting the sodium-phosphate cotransporter in the proximal tubule, so without it phosphate is retained. The high serum phosphate then suppresses 1-alpha hydroxylase further, which worsens vitamin D activation.

Nerve and muscle. Ionised calcium is critical for normal neuronal and muscle function. Low calcium reduces the action potential threshold and increases neuronal excitability, and the result is tetany, seizures and cardiac conduction abnormalities.

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Causes of Hypoparathyroidism

Post-SurgicalAutoimmuneGenetic

How the glands are lost. By one of three routes:

• Gland removal - inadvertent excision during thyroidectomy, parathyroidectomy for hyperparathyroidism or radical neck dissection
• Vascular injury - devascularisation of the glands during surgery, temporary or permanent
• Autotransplantation failure - glands deliberately autotransplanted may not engraft

Who is left with permanent disease. The risk rises with:

• Total thyroidectomy (higher than hemithyroidectomy)
• Central lymph node dissection for thyroid cancer
• Reoperative surgery, through scar tissue and a difficult dissection
• Parathyroids not identified or preserved at operation
• Concurrent parathyroid pathology

Transient or permanent. Transient hypocalcaemia comes from temporary ischaemia or stunning of the glands: symptoms develop within 24-72 hours of surgery and resolve within 6 months. Permanent hypoparathyroidism follows gland removal, persists beyond that and needs lifelong replacement. Where the line falls has varied between 6 and 12 months from study to study, which inflates the heterogeneity in reported incidence; the 2022 international guideline sets it at more than 12 months.

Surveillance. After thyroid or parathyroid surgery, calcium is checked daily for 48-72 hours and supplemented as needed during recovery.

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Isolated autoimmune hypoparathyroidism. Antibodies are found against parathyroid tissue or the calcium-sensing receptor, and the parathyroid glands undergo progressive destruction. It presents in childhood or early adulthood and needs lifelong calcium and vitamin D supplementation.

Autoimmune polyglandular syndrome type 1 (APS-1). An autosomal recessive disorder caused by mutation of the AIRE gene. Its classic triad is chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency; hypoparathyroidism is often the first manifestation, in childhood, and there may be other autoimmune features such as alopecia, vitiligo and hepatitis.

An autoimmune cause means screening for the other autoimmune endocrinopathies.

DiGeorge syndrome (22q11.2 deletion). The most common genetic cause. A defect of the third and fourth pharyngeal pouches leaves the thymus and parathyroids hypoplastic, and the infant presents in the neonatal period with hypocalcaemia and tetany. Severity varies from complete absence of parathyroid function to partial function.

• Cardiac defects - tetralogy of Fallot, interrupted aortic arch
• Facial dysmorphism
• Immune deficiency

X-linked hypoparathyroidism (GCMB mutations). The mutation affects parathyroid development and produces isolated hypoparathyroidism without other features. Males are predominantly affected.

Autosomal dominant hypocalcaemia. Activating, gain-of-function mutations of the calcium-sensing receptor (CASR) gene make the glands perceive a normal calcium as high, so PTH is suppressed inappropriately. The picture resembles hypoparathyroidism with a slightly higher calcium set point, and it may present in childhood with seizures.

Mitochondrial disorders. Kearns-Sayre syndrome combines ophthalmoplegia, retinopathy and cardiac conduction defects with hypoparathyroidism.

Genetic counselling and family screening are important for all of these.

Acute Hypocalcaemia

Tetany. This is the neuromuscular irritability of hypocalcaemia. Tingling or numbness around the mouth and lips is often the earliest symptom, and carpopedal spasm the most characteristic finding.

• Perioral paraesthesia - often first
• Carpopedal spasm - wrist flexion, finger extension and thumb adduction, the obstetrician's hand
• Muscle cramps - painful, in the hands, feet, back and legs
• Laryngospasm - throat tightness and stridor, a high-pitched inspiratory sound; bronchospasm causes wheeze
• Seizures - generalised tonic-clonic, without focal features

Muscle and gut. Muscle weakness with a proximal myopathy and fatigue; abdominal cramps and diarrhoea (rare).

The heart. Arrhythmias are the lethal end of acute hypocalcaemia, and the ECG is covered under Investigations. Rarely, severe chronic hypocalcaemia causes a dilated cardiomyopathy and heart failure.

Mood and cognition. Anxiety, irritability, depression, cognitive impairment and confusion; psychosis is rare.

Examination

Chvostek's sign is tapping over the facial nerve (VII) in front of the ear. Beyond the three classic signs, the deep tendon reflexes are brisk, and tapping the ulnar nerve can elicit twitching of the hand muscles.

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Chronic Hypoparathyroidism

Skeleton. Bone turnover is low, with low alkaline phosphatase and low bone formation markers. Despite the high density, bone quality is abnormal and strength may be impaired, a static bone disease.

Brain. Basal ganglia calcification (see Imaging) can produce extrapyramidal disease: parkinsonism with tremor, rigidity and bradykinesia, chorea and dystonia. Seizures recur if calcium is not well controlled, and papilloedema from raised intracranial pressure (pseudotumour cerebri) is rare.

Eyes. Chronic hypocalcaemia causes posterior subcapsular cataracts, the lens calcium deposition visible on slit-lamp examination.

Teeth. Enamel hypoplasia follows if the disease is present while the teeth develop in childhood. Tooth eruption is delayed in congenital cases, and the risk of caries is increased.

Skin. Dry, coarse skin, brittle nails and hair loss (alopecia).

Acute Hypocalcaemia

Algorithm

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Chronic Hypoparathyroidism

The goals. Hold the serum calcium in the low-normal range, 2.0-2.2 mmol/L, and avoid hypercalciuria by keeping urine calcium below 300 mg/24 hours. Beyond the numbers, the aim is to prevent the long-term complications (nephrolithiasis, nephrocalcinosis, basal ganglia calcification) and to maintain quality of life.

Calcium. Calcium carbonate gives 1-3 g elemental calcium daily in divided doses with meals, because it needs acid to be absorbed; 1250 mg of calcium carbonate is 500 mg elemental calcium. Do not take it with levothyroxine, whose absorption it decreases. Calcium citrate does not need acid and is the alternative when gastric acid is poor. Titrate the dose to the serum and urine calcium.

Activated vitamin D - essential. Calcitriol (1,25-dihydroxy vitamin D), 0.25-1 mcg twice daily, is the active form and bypasses the PTH-mediated activation the patient no longer has. It increases intestinal calcium absorption and is more potent than cholecalciferol or ergocalciferol, but it carries a risk of hypercalciuria, so the 24-hour urine calcium is monitored. Alfacalcidol (1-alpha calcidiol) is the alternative.

Thiazides. Hydrochlorothiazide 25-50 mg daily increases renal calcium reabsorption and reduces urine calcium. It is useful if hypercalciuria develops despite dose optimisation, but may cause hypokalaemia, so the electrolytes are monitored.

PTH replacement. Teriparatide or rhPTH 1-84, by subcutaneous injection, improves calcium control and may reduce calcium and calcitriol requirements. It is expensive and not widely available, and is reserved for refractory cases not controlled on standard therapy.

Magnesium. Replace if deficient, with oral magnesium oxide 400-800 mg daily.

Monitoring. The schedule once the patient is stable:

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Before Surgery

Assessment. Confirm the diagnosis and the control:

• Confirm the diagnosis from the history, and that the patient is on calcium and calcitriol replacement
• Serum total and ionised calcium, phosphate and magnesium
• ECG for the baseline QT interval, since a prolonged QT increases anaesthetic risk
• Medication review for compliance
• Endocrinology consultation for complex or poorly controlled cases

On the day. Continue calcium and calcitriol on the day of surgery if oral intake is permitted. If the patient will be nil by mouth for more than 24 hours, IV calcium supplementation may be needed.

In Theatre

Monitoring. Continuous ECG for QT prolongation and arrhythmias. Consider ionised calcium monitoring in a prolonged case or with significant fluid shifts; large-volume transfusion of citrated blood products can chelate calcium (see Citrate-Related Hypocalcaemia below).

The anaesthetic. Muscle relaxants may act for longer in hypocalcaemia, so neuromuscular blockade is monitored. Rapid alkalosis is avoided (see the pearl below).

Rescue. Keep 10% calcium gluconate immediately available. If the calcium drops or tetany or an arrhythmia develops, give 10 mL IV over 10 minutes.

After Surgery

Monitoring. Check the ionised calcium on arrival in recovery, especially after a long period nil by mouth or a large fluid resuscitation. Continue cardiac monitoring if the QT is prolonged, and resume oral calcium and calcitriol as soon as oral intake is tolerated.

What to watch for. The acute complications of hypocalcaemia:

• Tetany - carpopedal spasm and perioral numbness; test Trousseau's and Chvostek's signs
• Seizures - especially if the calcium drops acutely
• Arrhythmias - torsades de pointes if the QT is prolonged

IV to oral. A patient nil by mouth for a prolonged period after surgery may need a temporary IV calcium infusion. Move to oral once medication is taken reliably, and check the calcium 24-48 hours after stopping IV calcium to confirm the oral therapy is adequate.

Not every hypocalcaemia after neck surgery is PTH deficiency. After parathyroidectomy the other major mechanism is hungry bone syndrome (HBS), and biochemically it is the mirror image.

Mechanism. After parathyroidectomy for severe or long-standing hyperparathyroidism, or occasionally after thyroidectomy for thyrotoxicosis with high-turnover bone, the abrupt fall in PTH removes the drive to bone resorption while osteoblastic bone formation continues. The demineralised, high-turnover "hungry" skeleton avidly re-mineralises, taking calcium, phosphate and magnesium out of the circulation. The result is a profound, prolonged hypocalcaemia, often lasting days to weeks.

Who gets it. The risk factors:

• Severe pre-operative hyperparathyroidism, with very high PTH and calcium
• Radiological or biochemical bone disease - osteitis fibrosa cystica, high alkaline phosphatase
• A large adenoma or parathyroid carcinoma
• Older age
• Vitamin D deficiency

Management. Aggressive and prolonged calcium, large intravenous doses then oral, with activated vitamin D and repletion of magnesium and phosphate, continued until the skeleton has re-mineralised. HBS is self-limiting as the bone refills; surgical hypoparathyroidism may be permanent.

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Citrate from transfused blood is the orthopaedic surgeon's commonest encounter with acute hypocalcaemia: revision arthroplasty, pelvic and spine surgery, polytrauma resuscitation.

Mechanism. Stored blood products contain citrate anticoagulant, which chelates ionised calcium. The liver normally metabolises citrate rapidly, to bicarbonate, so transfusion at an ordinary rate causes no problem. With rapid, massive transfusion (roughly one blood volume, or faster than the liver can clear the citrate), made worse by hypothermia, hepatic impairment or the low hepatic flow of shock, citrate accumulates and ionised calcium falls. The risks are those of any hypocalcaemia: tetany, QT prolongation and myocardial depression.

In hypoparathyroidism. There is no PTH reserve to defend the calcium, so the citrate load of major surgery hits harder and faster. Anticipate it and pre-empt it.

Management. During massive transfusion, monitor the ionised calcium and give intravenous calcium, chloride or gluconate, to keep it normal; this is the calcium limb of the lethal-triad and massive-transfusion protocols. Keep the patient warm to preserve citrate clearance. Detailed transfusion protocols belong to the blood-loss-management topic.

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Global Epidemiology

• Prevalence: roughly 25-40 per 100,000 population in Western registry data; defined as an orphan/rare disease in Europe and the US
• Dominant cause worldwide: post-surgical, accounting for around 75% of chronic cases; permanent hypoparathyroidism follows about 1-3% of total thyroidectomies and more after central neck dissection or reoperation
• Non-surgical causes (autoimmune, genetic, infiltrative, hypomagnesaemia-related) predominate in regions with lower thyroid-surgery volumes and in paediatric cohorts
• Idiopathic/non-surgical disease is relatively more represented in South Asian and Middle Eastern series, where it presents with prominent basal ganglia calcification and seizures

Major Guidelines Side by Side

Registry and Database Signals

National registries are emerging rather than mature for hypoparathyroidism, but population datasets are informative. Danish national-registry cohorts (Underbjerg and colleagues) link postsurgical disease to excess infection and neuropsychiatric morbidity and to increased renal stones/insufficiency in idiopathic disease, while showing no overall fracture excess despite high bone mineral density. The international PARADIGHM observational registry tracks long-term outcomes and PTH-replacement safety across multiple countries.

High- vs Limited-Resource Practice Variation

• High-resource settings: intraoperative or early postoperative PTH-guided protocols, ionised calcium assays, calcitriol availability, and access to PTH analogues (rhPTH 1-84 / palopegteriparatide) for refractory disease
• Limited-resource settings: reliance on total serum calcium with albumin correction, plain (parent) vitamin D or alfacalcidol where calcitriol is scarce, and greater burden of late-presenting idiopathic disease with established basal ganglia calcification, cataract and seizures
• Universal priorities: surgeon experience and meticulous parathyroid preservation remain the single most effective preventive measure regardless of resource level

• Is PTH replacement disease-modifying? rhPTH(1-84) and the long-acting prodrug palopegteriparatide reduce calcium/calcitriol requirements and improve biochemistry, but whether they prevent hard endpoints (renal impairment, basal ganglia calcification, fractures) is unproven. PTH analogues also carry a historical osteosarcoma class warning from rodent data.
• Optimal calcium target: guidelines recommend low-normal calcium, yet no trial links any specific target to clinical outcomes. The balance between symptom relief and hypercalciuria/nephrocalcinosis is individualised.
• Phosphate versus calcium control: calcium-phosphate product, not calcium alone, drives basal ganglia and ectopic calcification, but routine phosphate-lowering strategies are not standardised.
• Bone paradox: bone mineral density is high and fracture risk is not increased in cohort data, but bone is low-turnover with abnormal microarchitecture; the true fracture and quality implications remain debated.
• Routine post-thyroidectomy PTH protocols: early PTH measurement can triage supplementation and discharge, but cost-effectiveness and the best cut-offs differ between surgical units.