Parathyroid Disorders

The parathyroid glands are the master regulators of calcium, and their disorders span benign adenomas, multi-gland hyperplasia, renal-driven secondary disease, and the dreaded post-thyroidectomy hypoparathyroidism. This topic sits at the crossroads of endocrine surgery, biochemistry, and medicine — a favourite for NEET PG because one MCQ can test localisation imaging, biochemistry, and operative strategy at once.

Applied anatomy & physiology you must own

Most people have four parathyroid glands (two superior, two inferior), each ~5–7 mm, weighing 30–50 mg, tan-yellow. Roughly 13% of people have a fifth (supernumerary) gland — a classic cause of persistent disease.

• Superior glands arise from the 4th pharyngeal pouch (along with the C-cells/ultimobranchial body). They are more constant in position, found near the cricothyroid junction, dorsal to the recurrent laryngeal nerve (RLN), above the inferior thyroid artery.
• Inferior glands arise from the 3rd pharyngeal pouch (with the thymus). They migrate more, are more variable, and lie ventral to the RLN. Ectopic locations: thymus/mediastinum, thyrothymic ligament, intrathyroidal.
• Blood supply: predominantly the inferior thyroid artery (a branch of the thyrocervical trunk) for both superior and inferior glands. This is why ligating the inferior thyroid artery on the main trunk during thyroidectomy risks devascularising parathyroids.

PTH is secreted by chief cells. It raises serum calcium by: (1) increasing osteoclastic bone resorption, (2) increasing renal distal-tubule calcium reabsorption while promoting phosphate excretion (phosphaturia), and (3) stimulating renal 1-α-hydroxylase → more 1,25-(OH)₂-vitamin D → increased gut calcium absorption. The net biochemical signature of PTH excess: high calcium, low phosphate.

High-yield: Superior parathyroid = 4th pouch, dorsal to RLN; Inferior parathyroid = 3rd pouch (with thymus), ventral to RLN. The inferior gland's longer embryonic migration explains its ectopic positions.

Classification of parathyroid disorders

Type	Calcium	PTH	Phosphate	Core mechanism
Primary hyperparathyroidism (PHPT)	High	High (or inappropriately normal)	Low	Autonomous PTH (adenoma/hyperplasia)
Secondary HPT	Low/Normal	High	High (in CKD)	Compensatory to hypocalcaemia/CKD
Tertiary HPT	High	Very high	Variable	Autonomous gland after long-standing secondary HPT
Hypoparathyroidism	Low	Low	High	Loss/damage of glands (commonly post-surgical)
Pseudohypoparathyroidism	Low	High	High	End-organ PTH resistance (Gsα defect)
FHH	High	Normal/mildly high	Variable	Inactivating CaSR mutation

Primary hyperparathyroidism (PHPT)

Etiology

• Single adenoma — ~80–85% (most common cause).
• Four-gland hyperplasia — ~10–15% (think MEN syndromes).
• Double adenoma — ~2–4%.
• Parathyroid carcinoma — <1%.

MEN syndrome associations (commonly tested)

• MEN 1 (Wermer): Parathyroid hyperplasia (earliest & most common manifestation, ~95%) + Pancreatic islet tumours + Pituitary adenoma → "3 Ps". Gene: MEN1 (menin, chromosome 11q13).
• MEN 2A (Sipple): Medullary thyroid carcinoma + Phaeochromocytoma + Parathyroid hyperplasia. Gene: RET (chromosome 10).
• MEN 2B: MTC + Phaeo + mucosal neuromas/marfanoid habitus — parathyroid usually NOT involved.

High-yield: In MEN-associated PHPT the disease is four-gland hyperplasia, so a focused single-gland removal fails — these patients need subtotal (3½-gland) parathyroidectomy or total parathyroidectomy with autotransplantation.

Clinical features — "Stones, Bones, Abdominal groans, Psychic moans"

• Stones: renal calculi (calcium oxalate/phosphate), nephrocalcinosis, polyuria/polydipsia.
• Bones: osteitis fibrosa cystica (subperiosteal resorption of radial side of middle phalanges, "salt-and-pepper" skull, brown tumours — osteoclastic giant-cell lesions), osteoporosis (cortical/distal radius predominantly).
• Abdominal groans: peptic ulcer disease, pancreatitis, constipation.
• Psychic moans: depression, fatigue, lethargy, cognitive slowing.
• Today, most PHPT in developed settings is asymptomatic, detected on routine calcium screening. In India, symptomatic disease (stones/bones) is still common.

High-yield: Subperiosteal bone resorption on the radial aspect of the middle phalanx of the index/middle finger is the classic radiological sign of hyperparathyroidism.

Diagnosis & investigation of choice

Biochemistry establishes the diagnosis; imaging is only for localisation, never for diagnosis.

1. Serum calcium ↑ (correct for albumin: corrected Ca = measured Ca + 0.8 × [4 − albumin g/dL]) — ionised calcium is most accurate.
2. PTH high or inappropriately normal in the face of hypercalcaemia (intact PTH assay).
3. Phosphate low, chloride high (Cl:PO₄ ratio > 33 suggests PHPT), mild hyperchloraemic metabolic acidosis.
4. 24-hour urinary calcium — to exclude FHH (which is low).
5. Vitamin D and renal function.

Localisation (pre-operative, only once diagnosis is biochemically confirmed):

• ⁹⁹ᵐTc-Sestamibi scan — investigation of choice for localising a parathyroid adenoma; sestamibi is retained longer by hyperfunctioning parathyroid tissue (mitochondria-rich oxyphil cells) than by thyroid. SPECT/CT improves anatomical detail.
• High-resolution USG neck — first-line/complementary, operator-dependent.
• 4D-CT — increasingly used, excellent for ectopic/re-operative cases.
• Sestamibi + USG concordance allows a minimally invasive (focused) parathyroidectomy.

High-yield: Sestamibi (⁹⁹ᵐTc-MIBI) is the localisation study of choice for a parathyroid adenoma. Imaging does NOT diagnose PHPT — biochemistry does.

Stepwise approach to suspected PHPT:

High/borderline calcium → repeat with ionised Ca + intact PTH → if PTH high/inappropriate → check 24-h urinary calcium (rule out FHH) → confirm PHPT → localise with sestamibi ± USG → decide surgery vs surveillance.

Management

Surgery (parathyroidectomy) is the only curative treatment. Indications for surgery in asymptomatic PHPT (modified guidelines):

Parameter	Threshold for surgery
Serum calcium	> 1 mg/dL above upper limit of normal
Age	< 50 years
Renal	eGFR < 60; 24-h urine Ca > 400 mg; nephrolithiasis/nephrocalcinosis
Bone	T-score ≤ −2.5 at any site; or vertebral fracture

• Single adenoma: focused/minimally invasive parathyroidectomy guided by imaging + intra-operative PTH (IOPTH) monitoring. A >50% drop in IOPTH from baseline at 10 minutes after excision (the Miami criterion) confirms cure.
• Four-gland hyperplasia (MEN): subtotal (3½ gland) parathyroidectomy OR total parathyroidectomy + autotransplantation of ~50 mg into the forearm/sternocleidomastoid (allows easy re-access if recurrence).
• Medical (when surgery not possible): hydration, cinacalcet (calcimimetic — activates CaSR, lowers PTH and calcium), bisphosphonates for bone protection.

High-yield: Miami criterion = ≥50% fall in intra-operative PTH at 10 min post-excision (PTH half-life ~3–5 min) confirms successful removal.

Parathyroid carcinoma

Suspect with very high calcium (>14 mg/dL), markedly elevated PTH (often >3–10× normal), a palpable neck mass, and bone + renal involvement together. Associated with HRPT2 (CDC73/parafibromin) mutation (also Hyperparathyroidism-Jaw Tumour syndrome). Treatment: en bloc resection (gland + ipsilateral thyroid lobe + involved structures); avoid capsular rupture. Chemo/radiotherapy largely ineffective.

Secondary hyperparathyroidism

Compensatory parathyroid hyperplasia driven by chronic hypocalcaemia — overwhelmingly due to chronic kidney disease (CKD):

• Reduced renal 1-α-hydroxylase → ↓1,25-(OH)₂-vitamin D → ↓gut calcium → hypocalcaemia.
• Phosphate retention (failing kidney) → hyperphosphataemia → further lowers calcium and directly stimulates PTH; FGF23 rises.
• Result: low/normal calcium, high phosphate, high PTH, leading to renal osteodystrophy.

Management: dietary phosphate restriction, phosphate binders (sevelamer, calcium acetate; lanthanum), active vitamin D analogues (calcitriol, paricalcitol), and calcimimetics (cinacalcet). Surgery (subtotal/total parathyroidectomy + autotransplant) reserved for refractory disease, calciphylaxis, or intractable pruritus/bone pain.

Tertiary hyperparathyroidism

Long-standing secondary HPT in which the glands become autonomous — they keep secreting PTH even after the stimulus is corrected (classically after renal transplantation). Biochemistry flips to HIGH calcium + HIGH PTH (resembling primary). Treatment: cinacalcet, or subtotal/total parathyroidectomy with autotransplantation if persistent post-transplant hypercalcaemia.

Feature	Secondary HPT	Tertiary HPT
Calcium	Low/normal	High
PTH	High	Very high
Gland behaviour	Responsive (compensatory)	Autonomous
Setting	Active CKD	After prolonged 2° HPT / post-transplant

Hypercalcaemia — acute management

Causes are dominated by primary hyperparathyroidism (outpatient) and malignancy (inpatient) — together ~90%.

Stepwise treatment of severe symptomatic hypercalcaemia (>14 mg/dL):

1. IV isotonic saline — aggressive volume repletion (corrects dehydration, promotes calciuresis). First and most important step.
2. Calcitonin — rapid but short-lived (tachyphylaxis after 48 h); useful as a bridge.
3. IV bisphosphonate (zoledronic acid / pamidronate) — most effective for sustained reduction; onset 2–4 days.
4. Denosumab — for bisphosphonate-refractory or renal-impaired patients.
5. Glucocorticoids — for vitamin-D-mediated/granulomatous/lymphoma hypercalcaemia.
6. Haemodialysis — for renal failure or life-threatening levels.
7. Loop diuretics (furosemide) only after adequate hydration; routine use discouraged.

High-yield: First step in acute hypercalcaemia is IV normal saline, NOT furosemide. Bisphosphonates give the most durable control.

Hypoparathyroidism (esp. post-thyroidectomy)

The single most common cause of acquired hypoparathyroidism is iatrogenic — post-thyroid/parathyroid surgery (inadvertent removal or devascularisation). Biochemistry: low calcium, high phosphate, low PTH.

Clinical features (neuromuscular hyperexcitability):

• Perioral & acral paraesthesiae, carpopedal spasm, tetany, laryngospasm, seizures.
• Chvostek's sign: tapping over the facial nerve (anterior to ear) → ipsilateral facial twitch.
• Trousseau's sign: BP cuff inflated above systolic for 3 min → carpopedal spasm (more specific).
• ECG: prolonged QT interval.
• Chronic: cataracts, basal ganglia calcification, dental defects.

Acute management of symptomatic hypocalcaemia: IV calcium gluconate (10 mL of 10% over 10 min, then infusion); replace magnesium (hypomagnesaemia causes refractory hypocalcaemia). Chronic: oral calcium + active vitamin D (calcitriol); recombinant PTH (1-84) for refractory cases.

High-yield: Trousseau's sign (carpopedal spasm on BP-cuff inflation) is more specific than Chvostek's sign for latent tetany/hypocalcaemia. Always check and correct magnesium in refractory hypocalcaemia.

Differentiating low-calcium states:

Condition	Calcium	PTH	Phosphate	Key point
Post-surgical hypoPTH	Low	Low	High	Most common acquired cause
Pseudohypoparathyroidism (Albright osteodystrophy)	Low	High	High	PTH resistance; short 4th/5th metacarpals
Vitamin D deficiency	Low	High (2°)	Low	Reduced gut absorption
Hypomagnesaemia	Low	Low/inappropriate	Variable	Impairs PTH secretion & action

Key differentials of PHPT — Familial Hypocalciuric Hypercalcaemia (FHH)

FHH is the must-exclude mimic before any parathyroid surgery. Autosomal dominant inactivating mutation of the calcium-sensing receptor (CaSR) → the body "thinks" calcium is low, so it retains calcium renally.

• Mild hypercalcaemia + inappropriately normal/mildly high PTH (looks like PHPT) BUT low urinary calcium.
• Calcium-to-creatinine clearance ratio (CCCR) < 0.01 strongly suggests FHH (PHPT usually > 0.02).
• Lifelong, benign, asymptomatic — surgery is contraindicated (parathyroidectomy does not cure it).

High-yield: Hypercalcaemia + high PTH + LOW urinary calcium = FHH, not PHPT. Operating on FHH is a classic exam trap.

Complications

• Of PHPT: nephrolithiasis/nephrocalcinosis, renal failure, osteoporosis & fractures, pancreatitis, peptic ulcer, hypercalcaemic crisis.
• Of parathyroidectomy: RLN injury (hoarseness), transient hypocalcaemia, and the classic "hungry bone syndrome" — after removing the source of chronic high PTH, demineralised bone avidly re-uptakes calcium, phosphate and magnesium → prolonged severe hypocalcaemia + hypophosphataemia (distinguished from hypoparathyroidism, where phosphate is HIGH and PTH is low). Higher risk after surgery for severe/secondary/tertiary HPT.

High-yield: Hungry bone syndrome = low Ca + low phosphate post-parathyroidectomy. Post-surgical hypoparathyroidism = low Ca + high phosphate. The phosphate level differentiates them.

Mnemonics

• PHPT symptoms: "Stones, Bones, Abdominal Groans, Psychic Moans" (+ painful bones, renal stones, psychic overtones).
• MEN 1 = 3 Ps (Parathyroid, Pancreas, Pituitary).
• Hypercalcaemia ladder: "Saline, then Calcitonin, then Bisphosphonate" (Fluids first, drugs after).

Recently asked / exam angle

• Localisation of choice for parathyroid adenoma → ⁹⁹ᵐTc-Sestamibi scan (with SPECT/CT). Diagnosis is biochemical, not imaging.
• First step in acute hypercalcaemia → IV normal saline.
• Most common cause of PHPT → solitary adenoma (~85%).
• Embryology: superior parathyroid → 4th pouch; inferior → 3rd pouch (with thymus) — frequently asked as a single-line MCQ.
• MEN syndrome with parathyroid hyperplasia as earliest feature → MEN 1 (menin gene).
• Hypercalcaemia + low urinary calcium → FHH (CaSR mutation), surgery contraindicated.
• Intra-operative PTH ≥50% drop (Miami criterion) confirms cure.
• Post-thyroidectomy tetany / Trousseau's & Chvostek's signs → hypoparathyroidism, treat with IV calcium gluconate; check magnesium.
• Brown tumour / osteitis fibrosa cystica / subperiosteal resorption = radiological hallmark of hyperparathyroidism.
• Parathyroid carcinoma → HRPT2/CDC73 (parafibromin), very high calcium + palpable mass, treat by en bloc resection.
• Hungry bone syndrome (low Ca + low PO₄) vs hypoPTH (low Ca + high PO₄) — phosphate distinguishes.

Rapid revision

1. PTH raises calcium, lowers phosphate (phosphaturic); activates renal 1-α-hydroxylase.
2. Most common cause of PHPT = solitary adenoma (~85%); MEN cases = four-gland hyperplasia.
3. PHPT biochemistry: high Ca, high/inappropriate PTH, low phosphate, high chloride.
4. Diagnosis of PHPT is biochemical; sestamibi scan is only for localisation.
5. Asymptomatic PHPT surgery: Ca >1 mg/dL above normal, age <50, eGFR <60, stones, T-score ≤ −2.5.
6. Miami criterion = ≥50% intra-operative PTH drop at 10 min confirms cure.
7. MEN management = subtotal (3½-gland) or total parathyroidectomy + forearm autotransplant.
8. Secondary HPT (CKD): low/normal Ca, HIGH phosphate, high PTH; treat with phosphate binders, calcitriol, cinacalcet.
9. Tertiary HPT (post-transplant): autonomous glands → HIGH Ca + HIGH PTH.
10. Acute hypercalcaemia: IV saline first → calcitonin (bridge) → bisphosphonate (durable).
11. FHH: high Ca + normal PTH + LOW urinary Ca (CCCR <0.01), CaSR mutation — never operate.
12. Post-thyroidectomy hypocalcaemia → IV calcium gluconate + correct magnesium; hungry bone (low Ca + low PO₄) vs hypoPTH (low Ca + high PO₄).