Calcium Metabolism Disorders

Calcium homeostasis is a tightly regulated balance between parathyroid hormone (PTH), vitamin D (calcitriol) and calcitonin, acting on gut, bone and kidney. Disorders manifest as hypercalcaemia (CNS depression, "stones, bones, groans, psychic moans") or hypocalcaemia (neuromuscular irritability, tetany). This is a perennial NEET PG favourite for both diagnosis-of-cause and ECG/clinical-sign matching.

Physiology recap — the three regulators

Normal serum total calcium is 8.5–10.5 mg/dL (2.12–2.62 mmol/L); ionised (physiologically active) calcium is 4.5–5.3 mg/dL (~1.1–1.3 mmol/L). About 45% of calcium is protein-bound (mainly albumin), 45% ionised, 10% complexed.

• PTH ↑ when calcium falls. It raises calcium by: bone resorption (osteoclast activation via RANKL), distal tubular Ca reabsorption, and stimulating renal 1-α-hydroxylase → ↑ calcitriol. PTH also causes phosphaturia (↓ phosphate).
• Calcitriol (1,25-(OH)₂-D₃) ↑ gut absorption of both calcium and phosphate, and permits bone mineralisation.
• Calcitonin (from thyroid C-cells) lowers calcium by inhibiting osteoclasts — minor physiological role in humans.
• Calcium-sensing receptor (CaSR) on parathyroid and renal tubule senses serum calcium and is the master "set-point".

High-yield: PTH raises calcium but lowers phosphate; vitamin D raises both calcium and phosphate. This phosphate behaviour is the single best discriminator between PTH-driven and vitamin-D-driven disorders.

Albumin correction — must-know formula

Because total calcium tracks albumin, hypoalbuminaemia gives spurious "hypocalcaemia" while ionised calcium is normal.

Corrected Ca (mg/dL) = measured Ca + 0.8 × (4 − serum albumin in g/dL)

So a patient with calcium 8.0 mg/dL and albumin 2 g/dL has a corrected calcium of 8.0 + 0.8×2 = 9.6 mg/dL — i.e. normal. When in doubt, measure ionised calcium directly (unaffected by albumin). Acidosis raises ionised Ca; alkalosis (e.g. hyperventilation) lowers it and precipitates tetany.

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HYPERCALCAEMIA

Definition and severity

Grade	Total Ca (mg/dL)	Typical picture
Mild	10.5–12	Often asymptomatic
Moderate	12–14	Polyuria, constipation, fatigue
Severe / crisis	>14	Dehydration, confusion, coma, arrhythmia

Causes — the 90% rule

High-yield: ~90% of all hypercalcaemia is due to either primary hyperparathyroidism (commonest in outpatients/asymptomatic) or malignancy (commonest in inpatients/symptomatic). PTH level splits these instantly.

Mechanism	Examples	PTH	Phosphate
PTH-mediated	Primary HPT (adenoma 80–85%), tertiary HPT, FHH, lithium	↑ or inappropriately normal	↓
PTHrP / osteolytic	Squamous cell Ca lung, breast, renal cell, myeloma, lymphoma	↓ (suppressed)	variable
Vitamin D excess	Granulomatous disease (sarcoidosis, TB), vitamin D toxicity, lymphoma	↓	↑
High bone turnover	Thyrotoxicosis, immobilisation, Paget's	↓	normal
Other	Milk-alkali syndrome, thiazides, vitamin A toxicity, Addison's	↓	variable

Mnemonic for causes — "CHIMPANZEES": Calcium supplements/Ca-alkali, Hyperparathyroid/Hyperthyroid, Iatrogenic (thiazide/lithium), Milk-alkali, Paget's, Addison's/Acromegaly, Neoplasm, Zollinger-Ellison (MEN1), Excess vitamin D, Excess vitamin A, Sarcoidosis.

Primary hyperparathyroidism (PHPT)

• Cause: solitary parathyroid adenoma (80–85%) > hyperplasia (4 glands, MEN) > carcinoma (<1%).
• Classic biochemistry: ↑ Ca, ↓ PO₄, ↑ PTH, ↑ urinary cAMP, ↑ alkaline phosphatase, ↑ chloride (hyperchloraemic metabolic acidosis; Cl/PO₄ ratio >33).
• Bone disease: osteitis fibrosa cystica, subperiosteal resorption of radial border of middle phalanges, "salt-and-pepper" skull, brown tumours.
• Associations: MEN 1 (parathyroid + pancreas + pituitary) and MEN 2A (medullary thyroid Ca + phaeo + parathyroid).

High-yield: Localisation of choice for a parathyroid adenoma before surgery = 99mTc-sestamibi scan (often with SPECT/CT or 4D-CT). Definitive cure = parathyroidectomy.

FHH (Familial Hypocalciuric Hypercalcaemia)

Autosomal-dominant inactivating CaSR mutation. Mild hypercalcaemia, inappropriately normal/high PTH, but the giveaway is LOW urinary calcium → 24-h urine Ca:creatinine clearance ratio <0.01. Crucial because it mimics PHPT but must NOT be operated.

Clinical features

"Stones, bones, abdominal groans, psychic moans, with fatigue overtones."

• Renal: polyuria/polydipsia (nephrogenic DI), nephrolithiasis, nephrocalcinosis.
• GI: anorexia, constipation, nausea, peptic ulcer, pancreatitis.
• Neuro: lethargy, confusion, depression, coma.
• Cardiac: hypertension, short QT interval, bradyarrhythmia; digoxin sensitivity.

High-yield (ECG): Hypercalcaemia → SHORT QT interval. Severe hypercalcaemia can produce an Osborn (J) wave, also seen in hypothermia.

Investigation flow

Confirm with corrected/ionised Ca → measure intact PTH →

1. PTH high/normal → PHPT or FHH → check 24-h urine Ca (low = FHH; high/normal = PHPT → sestamibi → surgery).
2. PTH low (suppressed) → measure PTHrP (malignancy), 25-OH-D and 1,25-(OH)₂-D (toxicity vs granuloma), SPEP/serum free light chains (myeloma), TSH, vitamin A, cortisol → image for malignancy.

Management of hypercalcaemia

Aggressiveness depends on level and symptoms. Treat if Ca >14 mg/dL or symptomatic.

Step-wise: IV fluids → calcitonin → bisphosphonate → (denosumab) → dialysis if needed.

1. IV isotonic saline (0.9% NaCl) — first and most important step; restores volume and promotes calciuresis. Loop diuretics only AFTER euvolaemia (and not routinely now).
2. Calcitonin (4 IU/kg) — works fastest (within hours) but tachyphylaxis after 48 h; a bridging agent.
3. Bisphosphonate — zoledronic acid (preferred in malignancy) or pamidronate; onset 2–4 days, durable. Watch renal function and osteonecrosis of jaw.
4. Denosumab — RANKL inhibitor, useful in bisphosphonate-refractory or renal failure.
5. Glucocorticoids — for vitamin-D-mediated causes (sarcoidosis, lymphoma, vitamin D toxicity) by inhibiting 1-α-hydroxylase.
6. Haemodialysis — for renal failure or life-threatening crisis.
7. Cinacalcet (calcimimetic) — for parathyroid carcinoma, inoperable PHPT, tertiary HPT.

High-yield: In hypercalcaemic crisis, the immediate priority is aggressive IV saline hydration; bisphosphonates give the durable control. Avoid thiazides and digoxin.

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HYPOCALCAEMIA

Definition

Corrected total Ca <8.5 mg/dL or ionised Ca <4.5 mg/dL. Always recheck against albumin and pH.

Causes

Category	Examples	PTH	Phosphate
Low PTH (hypoparathyroidism)	Post-thyroidectomy/parathyroidectomy (commonest acquired), autoimmune, DiGeorge, hypomagnesaemia	↓	↑
PTH resistance	Pseudohypoparathyroidism (Albright)	↑	↑
Vitamin D deficiency/resistance	Nutritional, malabsorption, CKD, anticonvulsants	↑ (secondary)	↓ (deficiency) or ↑ (CKD)
Sequestration / other	Acute pancreatitis, rhabdomyolysis, tumour lysis, hungry bone syndrome, citrate (massive transfusion), alkalosis	variable	↑

High-yield: Hypomagnesaemia causes hypocalcaemia by both impairing PTH secretion and causing PTH resistance — calcium will NOT correct until magnesium is replaced. Always check Mg in refractory hypocalcaemia (classic in chronic alcoholics, PPI use, aminoglycosides).

Hypoparathyroidism vs Pseudohypoparathyroidism

• Hypoparathyroidism: ↓ Ca, ↑ PO₄, ↓ PTH. Commonest cause is inadvertent removal/devascularisation of parathyroids during thyroid surgery.
• Pseudohypoparathyroidism type 1a (Albright hereditary osteodystrophy): end-organ resistance to PTH (Gsα defect, GNAS). ↓ Ca, ↑ PO₄, ↑ PTH. Phenotype: short stature, round face, short 4th/5th metacarpals, obesity, subcutaneous ossification.
• Pseudo-pseudohypoparathyroidism: same phenotype but normal biochemistry.

Clinical features — neuromuscular irritability

• Tetany, perioral numbness, paraesthesiae (fingers/toes), carpopedal spasm, laryngospasm, bronchospasm.
• Chvostek sign — tapping the facial nerve anterior to the ear → ipsilateral facial twitch (less specific; positive in ~10% normals).
• Trousseau sign — inflating a BP cuff above systolic for 3 minutes → carpopedal spasm (more specific).
• Seizures, papilloedema, basal ganglia calcification (Fahr syndrome) in chronic cases; dental and cataract changes; prolonged QT.

High-yield (ECG): Hypocalcaemia → PROLONGED QT interval (risk of torsades). Remember mirror image: high Ca = short QT, low Ca = long QT.

Mnemonic for hypocalcaemia features — "CATs go numb": Convulsions, Arrhythmias, Tetany, numbness/paraesthesiae.

Investigation flow

Confirm corrected/ionised Ca → check Mg → measure PTH →

1. PTH low → hypoparathyroidism (surgical history? autoimmune? check Mg).
2. PTH high → measure phosphate + vitamin D: ↓ PO₄ + low vitamin D = deficiency/malabsorption; ↑ PO₄ with normal/high vitamin D and no renal failure = pseudohypoparathyroidism (confirm with Ellsworth-Howard test); ↑ PO₄ + renal failure = CKD-MBD.

Management

Acute symptomatic (tetany, seizure, QT prolongation):

1. IV calcium gluconate 10% — 10–20 mL over 10 min, then infusion. (Calcium gluconate preferred peripherally over calcium chloride, which is more sclerosant.)
2. Correct magnesium simultaneously if low.
3. Continuous ECG monitoring; caution in digoxin-treated patients.

Chronic:

• Oral calcium + active vitamin D (calcitriol/alfacalciferol) — calcitriol preferred in hypoparathyroidism and renal failure (bypasses 1-α-hydroxylation).
• Treat underlying cause; thiazide diuretic can reduce hypercalciuria in hypoparathyroidism. Recombinant PTH (1-84) for refractory hypoparathyroidism.
• Vitamin D deficiency: cholecalciferol/ergocalciferol loading then maintenance.

High-yield: "Hungry bone syndrome" — profound, prolonged hypocalcaemia AFTER parathyroidectomy (or thyroidectomy in thyrotoxicosis) due to rapid skeletal re-uptake of calcium and phosphate; needs aggressive calcium + calcitriol.

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Key differentials and discriminators

Disorder	Ca	PO₄	PTH	Urine Ca	Clue
Primary HPT	↑	↓	↑	↑	Adenoma, sestamibi +ve
FHH	↑	↓/N	↑/N	↓	Ca:Cr clearance <0.01
Malignancy (PTHrP)	↑	↓/N	↓	↑	Known cancer, weight loss
Sarcoidosis	↑	↑	↓	↑	↑1,25-D, ACE, hilar nodes
Hypoparathyroidism	↓	↑	↓	↓	Post-surgery
Pseudohypoparathyroidism	↓	↑	↑	↓	AHO phenotype
Vitamin D deficiency	↓	↓	↑	↓	↓25-OH-D, ↑ALP
CKD-MBD	↓	↑	↑	↓	Renal failure

High-yield: Two diseases give ↑ Ca + ↓ PO₄ + ↑ PTH — PHPT and FHH — and urinary calcium is the deciding test (high in PHPT, low in FHH).

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Complications

• Hypercalcaemia: nephrolithiasis, nephrocalcinosis, chronic kidney disease, peptic ulcer, acute pancreatitis, osteoporosis/fractures, arrhythmia, coma.
• Hypocalcaemia: laryngospasm and respiratory arrest (acute), seizures, torsades de pointes, cataracts, basal ganglia calcification, dental hypoplasia, papilloedema.
• Iatrogenic: bisphosphonate-induced osteonecrosis of jaw, atypical femoral fractures; calcitonin tachyphylaxis; over-correction of hypocalcaemia → hypercalciuria and stones.

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Recently asked / exam angle

• ECG matching: "Short QT" = hypercalcaemia; "Long QT" = hypocalcaemia — a recurring one-liner. Osborn (J) wave links hypercalcaemia and hypothermia.
• Sign attribution: Trousseau (BP cuff → carpopedal spasm, more specific) and Chvostek (facial tap) for hypocalcaemia.
• Biochemistry vignette: ↑Ca ↓PO₄ ↑PTH with low urine Ca → answer FHH, do NOT operate.
• Best localising investigation for parathyroid adenoma → 99mTc-sestamibi.
• First step in hypercalcaemic crisis → IV normal saline (not bisphosphonate first).
• Refractory hypocalcaemia not responding to calcium → check and replace magnesium.
• Granulomatous disease hypercalcaemia mechanism → macrophage 1-α-hydroxylase → ↑1,25-D; treatment = steroids.
• Albright hereditary osteodystrophy with short 4th metacarpal + ↑PTH → pseudohypoparathyroidism 1a.
• Corrected calcium calculation from given albumin (the 0.8 factor) is a frequent numerical.
• Drug causes: thiazide → hypercalcaemia; loop diuretics → hypocalcaemia; lithium → hypercalcaemia.

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Rapid revision

1. Normal total Ca 8.5–10.5 mg/dL; correct +0.8 mg/dL per 1 g/dL fall in albumin below 4.
2. PTH lowers phosphate; vitamin D raises phosphate — best discriminator.
3. 90% of hypercalcaemia = primary HPT or malignancy; check PTH to split them.
4. PHPT = adenoma; biochem ↑Ca ↓PO₄ ↑PTH; localise with sestamibi; cure = parathyroidectomy.
5. FHH = inactivating CaSR mutation, low urine Ca (Ca:Cr clearance <0.01) — never operate.
6. Hypercalcaemia ECG = short QT (± Osborn wave); hypocalcaemia ECG = long QT.
7. Hypercalcaemia treatment order: saline → calcitonin (fast, tachyphylaxis) → zoledronate (durable); steroids for vitamin-D causes.
8. Hypocalcaemia: Trousseau (specific, cuff) and Chvostek (facial tap); tetany, laryngospasm.
9. Commonest acquired hypoparathyroidism = post-thyroidectomy; biochem ↓Ca ↑PO₄ ↓PTH.
10. Pseudohypoparathyroidism = ↑PTH with resistance + Albright osteodystrophy (short 4th/5th metacarpal).
11. Replace magnesium in refractory hypocalcaemia; acute tetany → IV calcium gluconate.
12. "Hungry bone syndrome" = severe post-parathyroidectomy hypocalcaemia from rapid skeletal uptake.