Hypocalcaemia
Description
- Corrected calcium <2.10 mmol/L; ionised calcium is what matters
- `Corrected Ca = measured Ca + 0.02 x (40 - albumin)`
- *Alkalosis increases protein binding -> ionised calcium falls with a normal total* - the mechanism of hyperventilation tetany
Clinical - neuromuscular irritability
- Perioral and acral paraesthesia -> cramps, carpopedal spasm, tetany -> laryngospasm, bronchospasm, seizures
- Chvostek sign - tap over the facial nerve anterior to the ear -> ipsilateral facial twitch (present in ~10-25% of normal people - poorly specific)
- Trousseau sign - BP cuff above systolic for 3 minutes -> carpopedal spasm: wrist and MCP flexion, IP extension, thumb adduction (more specific)
- Cardiac: prolonged QT, hypotension, heart failure (reversible cardiomyopathy)
- Chronic: cataract, basal ganglia calcification, papilloedema, dry skin, brittle nails, enamel hypoplasia, extrapyramidal features, anxiety/depression
Epidemiology
- Post-surgical hypoparathyroidism causes ~75% of chronic hypoparathyroidism
- Transient after total thyroidectomy in up to 30%; permanent in 1-3% (higher after central node dissection or re-operation)
- Hypocalcaemia in up to 15-20% of hospital inpatients (mostly mild, multifactorial, critical illness)
- Vitamin D deficiency is the commonest community cause
Aetiopathogenesis
Divide by PTH - the same branch point as hypercalcaemia
### A. PTH low or inappropriately normal - hypoparathyroidism
- Post-surgical - thyroidectomy, parathyroidectomy, radical neck dissection
- Autoimmune - isolated, or APS-1 (AIRE) with candidiasis and Addison
- Infiltration - haemochromatosis, Wilson disease, metastases, radiation
- Genetic
- DiGeorge / 22q11.2 deletion - cardiac outflow defects, cleft palate, thymic aplasia, immunodeficiency
- Activating CASR mutation (autosomal dominant hypocalcaemia) - set-point reset downward; hypercalciuria for the calcium level - treating to a normal calcium causes nephrocalcinosis
- GATA3 (HDR: hypoparathyroidism, deafness, renal dysplasia), mitochondrial (Kearns-Sayre)
- Functional
- *Hypomagnesaemia - the one to remember*. Mg is required both for PTH secretion and for PTH action
- Causes PTH-resistant, calcium-resistant hypocalcaemia. The calcium will not correct until the magnesium does**
- PPIs, alcohol, diuretics, diarrhoea, cisplatin, aminoglycosides, calcineurin inhibitors
- Severe hypermagnesaemia also suppresses PTH (obstetric magnesium infusions)
- *Hypomagnesaemia - the one to remember*. Mg is required both for PTH secretion and for PTH action
### B. PTH high - appropriate secondary response
- Vitamin D deficiency or resistance - low sunlight, malabsorption (coeliac, bariatric surgery, pancreatic insufficiency), liver disease (dec 25-hydroxylation), CKD (dec 1-alpha-hydroxylation), anticonvulsants (inc catabolism)
- CKD - dec calcitriol + phosphate retention
- Pseudohypoparathyroidism - end-organ resistance to PTH
- Calcium sequestration or loss
- Acute pancreatitis (saponification), rhabdomyolysis, tumour lysis syndrome, osteoblastic metastases (prostate, breast)
- *Hungry bone syndrome - after parathyroidectomy or thyroidectomy for thyrotoxicosis; profound, prolonged, with low phosphate and magnesium too*
- Drugs - bisphosphonates and denosumab (especially with unrecognised vitamin D deficiency or CKD), cinacalcet, foscarnet, citrate (massive transfusion, apheresis, regional citrate anticoagulation in CRRT), phosphate
Pseudohypoparathyroidism
- Resistance to PTH at the renal tubule despite normal or hyperplastic parathyroids
- Biochemistry: *low calcium + HIGH phosphate + HIGH PTH* - the same picture as hypoparathyroidism except the PTH is high
| Genetics | Phenotype | |
|---|---|---|
| Type 1a (majority) | Maternally inherited GNAS loss-of-function | Albright hereditary osteodystrophy: short stature, round face, brachydactyly (short 4th/5th metacarpals), subcutaneous ossification, obesity, intellectual disability. Also resistance to TSH, gonadotrophins, GHRH - hence hypothyroidism and, occasionally, precocious puberty |
| Type 1b | GNAS imprinting defect | Normal phenotype, renal PTH resistance only |
| Pseudopseudohypoparathyroidism | Paternally inherited GNAS | Albright phenotype with NORMAL biochemistry |
Diagnosis
- Confirm with ionised calcium or repeat corrected calcium
- PTH, magnesium, phosphate, creatinine, ALP, 25-OH vitamin D
- ECG for QT prolongation
- 24-hour urinary calcium before starting treatment in hypoparathyroidism (and to detect activating CASR mutation)
| PTH | Phosphate | Mg | 25-OH D | |
|---|---|---|---|---|
| Hypoparathyroidism | Low/normal | High | Normal | Normal |
| Pseudohypoparathyroidism | High | High | Normal | Normal |
| Vitamin D deficiency | High | Low | Normal | Low |
| CKD | High | High | Variable | Low-normal |
| Hypomagnesaemia | Low/normal | Normal | Low | Normal |
| Hungry bone | Low (post-op) | Low | Low | Normal |
- *High phosphate points to a PTH problem; low phosphate points to a vitamin D problem*
- Genetic testing (GNAS, CASR, 22q11 FISH/microarray, AIRE) where the picture fits
Management
Acute symptomatic hypocalcaemia - tetany, seizure, laryngospasm, long QT
- 10 mL of 10% calcium gluconate IV over 10 minutes, repeat until symptoms settle
- Then infusion: ~100 mL of 10% calcium gluconate in 1 L of 5% dextrose or saline at 50-100 mL/h, titrated
- Calcium chloride only via a central line - it is sclerosant and causes tissue necrosis
- Continuous cardiac monitoring; extreme caution if on digoxin
- *Correct magnesium at the same time* - hypocalcaemia will not respond otherwise
- Start oral calcium and calcitriol immediately - the IV is only a bridge
Chronic hypoparathyroidism - conventional therapy
- Elemental calcium 1-2 g/day in divided doses + calcitriol 0.25-2 microg/day (the active form - the 1-alpha-hydroxylation step is what is missing)
- *Target: serum calcium at the LOW end of normal or just below (~2.0-2.1), with the patient asymptomatic*
- Normalising the calcium without PTH causes hypercalciuria, nephrolithiasis, nephrocalcinosis and CKD - PTH is what normally keeps urinary calcium low
- Monitor: calcium, phosphate, magnesium, creatinine, and 24-hour urinary calcium; renal imaging periodically
- Keep the calcium-phosphate product <4.4 mmol2/L2; low-phosphate diet or phosphate binder
- Thiazide + low-salt diet reduces urinary calcium loss where hypercalciuria limits treatment
PTH replacement - the field has changed
- Palopegteriparatide (TransCon PTH) - a long-acting prodrug of PTH(1-34) giving sustained physiological levels from a single daily subcutaneous injection
- Starting dose 18 microg daily, titrated to eucalcaemia
- *Normalises serum calcium, phosphate AND urinary calcium, and allows most patients to stop calcium and active vitamin D altogether*
- For patients inadequately controlled on, or intolerant of, conventional therapy - persistent symptoms, hypercalciuria, renal impairment, high supplement burden
- Approved in the US and EU; check Australian TGA/PBS availability
- rhPTH(1-84) (natpara) has been withdrawn; teriparatide twice daily is an off-label alternative
Other
- Vitamin D deficiency - colecalciferol loading then maintenance; plain colecalciferol, not calcitriol, unless the 1-alpha-hydroxylase step is impaired
- Hypomagnesaemia - IV or oral magnesium, and remove the cause (stop the PPI)
- Hungry bone syndrome - large doses of calcium and calcitriol for weeks; anticipate it after removing a large adenoma with a high ALP
- Before a bisphosphonate or denosumab: check and correct calcium, vitamin D and renal function
Associations
- APS-1 (APECED) - hypoparathyroidism + mucocutaneous candidiasis + Addison disease
- 22q11.2 deletion (DiGeorge) - conotruncal cardiac defects, thymic hypoplasia, cleft palate, immunodeficiency, psychiatric disease
- Autoimmune Addison disease - hypoparathyroidism is the commonest associated endocrinopathy in APS-1
- Thyroid and parathyroid surgery; radioiodine; neck irradiation
- Haemochromatosis, Wilson disease, thalassaemia (iron-loading)
- Chronic PPI use and alcohol -> hypomagnesaemia
- Acute pancreatitis, rhabdomyolysis, tumour lysis, massive transfusion
- Osteomalacia and rickets - proximal myopathy, Looser zones, waddling gait, bone pain
Natural history & complications
- Post-thyroidectomy hypocalcaemia is usually transient - retest before committing to lifelong therapy
- Chronic hypoparathyroidism is under-treated as a disease: nephrocalcinosis and CKD in up to 40% on long-term conventional therapy, basal ganglia calcification, cataract, reduced quality of life
- Complications come as much from the treatment as from the disease - the reason PTH replacement matters
- Untreated severe hypocalcaemia -> laryngospasm, seizure, arrhythmia, reversible dilated cardiomyopathy
- Pseudohypoparathyroidism type 1a - hormone resistance broadens with age; monitor TSH and gonadal function
- Vitamin D deficiency corrects fully; osteomalacia takes months of repletion to remineralise
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