Hypoparathyroidism and pseudohypoparathyroidism

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

PTH deficiency is most commonly acquired through thyroid, parathyroid or other neck surgery, but autoimmune destruction, infiltrative disease, radiotherapy and genetic syndromes also occur. During low calcium, an intact gland should raise PTH; failure to do so is the defining feedback abnormality. High phosphate reflects loss of renal phosphaturic action. Establish chronicity and review operative records, magnesium, renal function, vitamin D and medicines such as calcimimetics. Autoimmune hypoparathyroidism with candidiasis or adrenal disease and congenital cases with cardiac, immune, renal, hearing or facial features need syndrome-aware specialist assessment. Treatment differs from ordinary nutritional deficiency because colecalciferol alone may not reliably generate enough active hormone when PTH-dependent renal activation is absent.

Pseudohypoparathyroidism is a group of GNAS-related disorders in which renal proximal tubules resist PTH, so PTH rises while calcium falls and phosphate accumulates. Phenotypes and terminology are evolving; some patients have Albright hereditary osteodystrophy, early-onset obesity, ectopic ossification, learning difficulties or additional TSH resistance, while related variants inherited through the paternal line can produce the skeletal phenotype without the same biochemical resistance. Diagnosis combines serial physiology, phenotype and specialist molecular or methylation testing. Chronic management again uses activated vitamin D and calcium, but endogenous high PTH may still protect distal renal calcium conservation, making urinary behaviour different from complete gland absence. Both groups need oral-health, cataract, renal and quality-of-life review. Pregnancy, childhood growth and complex genetics require specialised services, and recombinant PTH approaches remain restricted and locally commissioned rather than routine primary-care escalation.

Key points

Hypoparathyroidism produces low calcium and high phosphate with PTH that is low or inappropriately normal, most often after anterior neck surgery.
Pseudohypoparathyroidism produces a similar calcium-phosphate pattern but PTH is raised because target tissues resist its signal.
Severe magnesium depletion can suppress PTH secretion and action, so it must be corrected before declaring permanent gland failure.
Albright hereditary osteodystrophy features can include short stature, round face, brachydactyly and subcutaneous ossification, but their absence does not exclude a GNAS-related disorder.
Some GNAS disorders cause resistance to TSH and other hormones as well as PTH, making thyroid and developmental assessment part of specialist care.
Conventional hypoparathyroid therapy uses oral calcium plus activated vitamin D because absent PTH impairs renal activation of native vitamin D.
Aim for symptom control with calcium in a safe low-normal range; normalising serum calcium aggressively can cause hypercalciuria, stones and nephrocalcinosis.
Genetic testing is phenotype-led through an NHS genomic service, and inheritance can depend on parental origin because GNAS is an imprinted locus.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Acquired PTH deficiency

Thyroid, parathyroid or other neck surgery is the common acquired cause, while autoimmune destruction, radiotherapy and infiltrative disease also reduce gland function.

Genetic parathyroid disease

Congenital and syndromic disorders can impair parathyroid development or function, sometimes alongside cardiac, immune, renal, hearing or adrenal features.

GNAS-related PTH resistance

Pseudohypoparathyroidism arises when target tissues, especially renal proximal tubules, do not respond normally to circulating PTH despite an intact gland.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
PTH effect becomes inadequate
Deficient hormone secretion or end-organ resistance reduces renal calcium conservation, phosphate excretion and activation of vitamin D.
2
Calcium falls and phosphate rises
Reduced active vitamin D and impaired renal handling lower extracellular calcium while phosphate accumulates, increasing neuromuscular excitability.
3
Feedback distinguishes the mechanism
PTH remains low or inappropriately normal with gland failure but rises in pseudohypoparathyroidism as the gland responds to hypocalcaemia.
4
Chronic replacement alters renal risk
Calcium and active vitamin D bypass some normal regulation, so symptom control can coexist with hypercalciuria and renal mineral deposition.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

True PTH deficiency

Low calcium, raised phosphate and PTH that fails to rise appropriately after neck surgery or in autoimmune disease supports hypoparathyroidism once magnesium is adequate.

PTH resistance

Low calcium and high phosphate with clearly raised PTH, preserved renal function and no simpler vitamin D explanation suggests pseudohypoparathyroidism.

Albright phenotype

Short metacarpals or metatarsals, round facial appearance, reduced stature, obesity or subcutaneous ossification can indicate a GNAS-related disorder and justify genomic referral.

Multi-hormone resistance

Raised TSH with an atypical thyroid pattern, growth or pubertal disturbance alongside PTH resistance indicates broader G-protein signalling involvement rather than isolated calcium disease.

Chronic treatment complication

Polyuria, stones, nephrocalcinosis or falling eGFR despite acceptable serum calcium suggests excess urinary calcium from conventional replacement and requires regimen reassessment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Concurrent calcium, phosphate and PTHFirst step
Why
Distinguish inadequate PTH secretion from an appropriately raised but ineffective PTH response.
Interpretation and limitations
Low PTH with hypocalcaemia supports gland failure; high PTH with hyperphosphataemia suggests resistance after CKD and vitamin D-related secondary causes are excluded.
02
Magnesium and renal function
Why
Identify reversible functional hypoparathyroidism and kidney explanations for phosphate-PTH disturbance.
Interpretation and limitations
Severe low magnesium can suppress PTH and must be corrected; advanced CKD causes high phosphate and secondary PTH, so preserved renal function is important in pseudohypoparathyroid interpretation.
03
25-hydroxyvitamin D
Why
Detect coexisting nutritional deficiency that can raise PTH and increase replacement requirements.
Interpretation and limitations
Correct deficiency cautiously, but recognise that native vitamin D does not replace the activated preparation needed for established absent PTH physiology.
04
Urine calcium and renal imaging
Why
Detect hypercalciuria, nephrolithiasis or nephrocalcinosis caused by chronic replacement.
Interpretation and limitations
High urine calcium despite a low-normal serum target supports reducing calcium exposure, dietary sodium review or specialist thiazide strategy while preserving symptom control.
05
TSH, free thyroxine and phenotype assessment
Why
Identify additional hormone resistance and syndromic features in suspected GNAS disease.
Interpretation and limitations
Biochemical TSH resistance or characteristic skeletal, developmental and ossification features strengthens the case for a genomic pathway and multidisciplinary follow-up.
06
NHS genomic and methylation testing
Why
Confirm a GNAS-related or other genetic hypoparathyroid disorder when eligibility and phenotype support testing.
Interpretation and limitations
Results require specialist interpretation of variant, imprinting and parental origin; a variant of uncertain significance does not by itself establish the diagnosis or family risk.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Vitamin D deficiency

Low calcium with raised PTH and low vitamin stores favours secondary hyperparathyroidism rather than gland failure, usually with different phosphate behaviour.

Hypomagnesaemia

Severe magnesium deficiency suppresses PTH secretion and action, producing a reversible biochemical imitation of hypoparathyroidism when combined with the history and other findings.

Chronic kidney disease

Reduced phosphate excretion and vitamin D activation cause hypocalcaemia with high PTH as part of renal mineral-bone disorder.

Hungry bone syndrome

Recent parathyroid surgery after high-turnover disease causes prolonged skeletal mineral uptake, often with an appropriate postoperative PTH response.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01ClassifyRead PTH in contextFirst stepPersistent hypocalcaemia and hyperphosphataemia suggest parathyroid-axis disease.

1Confirm true low calcium and measure PTH, phosphate, magnesium, kidney function and vitamin D from the same physiological period.
2Correct significant magnesium deficiency and review surgery, autoimmune history, CKD and medicines before concluding gland loss or resistance.
3If PTH is raised with preserved renal function, assess Albright and multi-hormone features and refer through a specialist genomic pathway.

02ReplaceBuild safe chronic therapyHypoparathyroidism or PTH resistance is confirmed after acute symptoms have been controlled.

1Use activated vitamin D with divided oral calcium, titrating to symptom relief and a specialist-agreed safe calcium range rather than the upper normal interval.
2Correct nutritional vitamin D and magnesium separately, review dietary calcium and sodium, and explain interaction spacing and missed-dose risks.
3Measure urinary calcium and renal function as well as serum chemistry, adjusting treatment or adding a specialist thiazide approach when renal calcium loss is excessive.

03SyndromicManage beyond serum calciumGenetic, autoimmune or multi-hormone features accompany parathyroid dysfunction.

1Map thyroid, adrenal, growth, pubertal, renal, immune, hearing, cognitive and ectopic-ossification features according to the suspected syndrome.
2Coordinate clinical genetics, endocrinology and relevant organ specialists and offer consented family testing only after an actionable result is confirmed.
3Create pregnancy, illness and procedure plans and provide an emergency summary that states the diagnosis, usual therapy and acute calcium pathway.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Provides active vitamin D signalling despite absent PTH-dependent renal activation and increases intestinal calcium absorption.

Calcitriol or alfacalcidol

Begin and adjust the activated vitamin D preparation in small specialist-guided increments according to symptoms, calcium, phosphate, kidney function and urine calcium, following the local product-specific regimen.

The preparations differ and dosing errors can cause prolonged hypercalcaemia, hyperphosphataemia and kidney damage. Monitor closely after changes and during intercurrent illness; do not substitute nutritional vitamin D casually.

Supplies absorbable calcium for chronic symptom control and acute-to-oral transition.

Oral calcium

Use a divided elemental-calcium regimen selected for dietary intake, symptoms and activated vitamin D dose, with product and timing documented because different salts contain different elemental amounts.

High doses cause constipation and hypercalciuria and interfere with levothyroxine, iron and some antibiotics. Serum calcium alone cannot detect renal calcium toxicity.

Reduces urinary calcium loss in selected people whose conventional replacement causes persistent hypercalciuria.

Thiazide diuretic for hypercalciuria

Use only through an endocrine or renal plan at a low licensed regimen combined with dietary sodium review and follow-up electrolytes and blood pressure.

Hyponatraemia, hypokalaemia, hypotension, gout and glucose effects occur. It is not a substitute for reducing excessive calcium or activated vitamin D and is unsafe without monitoring.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Tetany and seizure

Low ionised calcium causes paraesthesia, cramps and carpopedal spasm; severe deficiency may progress to laryngospasm or seizure.

Renal calcification

Long-term calcium and active vitamin D treatment can increase urinary calcium, causing stones, nephrocalcinosis and declining renal function.

Cataract and dental disease

Chronic calcium-phosphate disturbance can affect lens clarity and tooth development or integrity, particularly in longstanding or childhood-onset disease.

Additional hormone resistance

Some GNAS-related disorders also impair TSH or other signalling, so untreated multi-hormone disease can compound growth and metabolic morbidity.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During titration, check calcium, phosphate, magnesium and renal function frequently enough to catch both recurrent symptoms and overshoot.
Once stable, maintain scheduled serum and urine calcium surveillance and investigate stones, polyuria, haematuria or declining eGFR promptly.
For GNAS-related disease, monitor thyroid function, growth or reproductive axes and ectopic ossification according to phenotype and age.
Review dental health, cataract symptoms, neurocognitive function and quality of life because biochemical stability does not capture the full burden.
After any formulation or dose change, reconcile exact units and preparation across primary, specialist and pharmacy records to prevent active-vitamin-D errors.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

PTH must be appropriate

A laboratory-normal PTH is pathological when calcium is low enough to demand a strong response. Feedback expectation matters more than the reference flag.

Phosphate separates mechanisms

Absent or resisted PTH reduces renal phosphate excretion, whereas vitamin D deficiency with intact PTH often lowers phosphate through secondary phosphaturia.

Imprinting changes inheritance

The same GNAS region can produce different skeletal and hormone-resistance phenotypes depending on parental origin, so a simple dominant pedigree may mislead.

Serum success can hide renal harm

Without PTH-mediated distal calcium conservation, conventional therapy may normalise blood calcium while urine calcium remains high and damages kidneys.

Native and active vitamin D differ

Colecalciferol replenishes stores; calcitriol or alfacalcidol provides active hormonal effect. They serve complementary, not interchangeable, purposes in established hypoparathyroidism.

11Common pitfallsFrequent interpretation and management errors.

01
Calling postoperative hypocalcaemia permanent hypoparathyroidism before recovery and magnesium status are assessed.
02
Diagnosing pseudohypoparathyroidism from high PTH without excluding CKD and vitamin D deficiency.
03
Titrating activated vitamin D to upper-normal serum calcium while ignoring urine calcium and renal imaging.
04
Confusing colecalciferol with calcitriol or alfacalcidol during medicines reconciliation.
05
Assuming every short fourth metacarpal proves GNAS disease without biochemical and genetic context.
06
Offering family predictive testing for a variant of uncertain significance as though pathogenicity were established.