Parathyroid & Calcium Metabolism Disorders
Pathology · Endocrine · lean revision notes
Parathyroid & Calcium Metabolism Disorders
Calcium homeostasis is governed by a tight feedback loop between parathyroid hormone (PTH), vitamin D (calcitriol), and calcitonin, acting on bone, gut, and kidney. Disorders of the parathyroid glands sit at the crossroads of pathology, biochemistry, and endocrine surgery, and they are a perennial NEET PG favourite — especially the MEN syndrome tables, brown tumours, and the lab-pattern grids that separate primary from secondary from tertiary disease.
Calcium physiology in one frame
PTH is secreted by the chief cells of the parathyroid glands in response to a fall in ionised serum calcium, sensed by the calcium-sensing receptor (CaSR) on the chief-cell surface. PTH then:
- Bone → activates osteoclasts (indirectly, via RANK-L on osteoblasts) → mobilises calcium and phosphate.
- Kidney → increases distal tubular calcium reabsorption, decreases phosphate reabsorption (phosphaturia), and stimulates 1-α-hydroxylase → more calcitriol.
- Gut → indirect (via calcitriol) → increases calcium and phosphate absorption.
Net PTH effect: serum calcium up, serum phosphate down. Hold this rule — it decodes almost every lab grid in this chapter.
High-yield: PTH raises calcium but lowers phosphate. Any disorder where calcium and phosphate move together (both up, both down) is usually NOT a primary PTH problem.
Classification of parathyroid disorders
| Category | Core defect | Calcium | PTH |
|---|---|---|---|
| Primary hyperparathyroidism | Autonomous PTH excess (adenoma/hyperplasia/carcinoma) | High | High (or inappropriately normal) |
| Secondary hyperparathyroidism | Compensatory PTH rise to low calcium (CKD, vit-D deficiency) | Low/normal | High |
| Tertiary hyperparathyroidism | Autonomous gland after long-standing secondary | High | Very high |
| Hypoparathyroidism | PTH deficiency | Low | Low/undetectable |
| Pseudohypoparathyroidism | PTH resistance (Gsα defect) | Low | High |
Primary hyperparathyroidism (PHPT)
Etiology
- Solitary chief-cell adenoma — ~80–85% (most common cause overall).
- Primary (4-gland) hyperplasia — ~10–15%, often in MEN syndromes.
- Parathyroid carcinoma — <1%, but produces the highest calcium levels and a palpable neck mass.
High-yield: The single commonest cause of PHPT is a solitary parathyroid adenoma of chief cells. The commonest cause of hypercalcaemia in an ambulatory/outpatient setting is PHPT; in a hospitalised patient it is malignancy (PTHrP, lytic mets, myeloma).
Pathology — gross & microscopy
- Adenoma: solitary, soft, tan-brown, well-circumscribed nodule; the remaining glands are normal/atrophic (suppressed by hypercalcaemia). Composed predominantly of chief cells, often with a rim of compressed normal parathyroid at the edge and absent stromal fat.
- Hyperplasia: all four glands enlarged (though asymmetrically); no normal suppressed gland, diffuse chief-cell proliferation, reduced stromal fat.
- Carcinoma: capsular/vascular invasion is the only reliable malignancy criterion; dense fibrous bands, mitoses, trabecular pattern.
High-yield: Distinguishing adenoma from hyperplasia at surgery hinges on the other glands — a normal/atrophic second gland favours adenoma; uniformly enlarged glands favour hyperplasia (think MEN).
Skeletal disease — osteitis fibrosa cystica (von Recklinghausen disease of bone)
Chronic PTH excess drives osteoclastic bone resorption, producing the classic skeletal triad:
- Subperiosteal resorption — earliest and most specific radiological sign, best seen on the radial side of the middle phalanges of the index and middle fingers; also lamina dura of teeth and distal clavicles.
- "Salt-and-pepper" skull — granular demineralisation.
- Brown tumours — focal collections of osteoclasts, haemorrhage, and reactive fibrous tissue (giant-cell reparative lesions). They are brown due to haemosiderin and vascularity, are radiolucent/lytic, and can mimic giant-cell tumour or metastasis. They regress after parathyroidectomy.
High-yield: Brown tumour = osteoclasts + haemosiderin + fibrous stroma; brown colour from haemosiderin, NOT bilirubin. It is the visual signature of osteitis fibrosa cystica.
Clinical features — "Stones, Bones, Abdominal Groans, Psychic Moans"
- Stones — nephrolithiasis (calcium oxalate/phosphate), nephrocalcinosis.
- Bones — bone pain, fractures, osteitis fibrosa cystica, osteoporosis (especially cortical bone at the distal radius).
- Abdominal groans — constipation, peptic ulcer (hypercalcaemia stimulates gastrin), acute pancreatitis.
- Psychic moans — fatigue, depression, confusion; severe hypercalcaemia → lethargy, coma.
- Polyuria/polydipsia (nephrogenic DI), short QT on ECG, band keratopathy.
Most modern cases are asymptomatic, detected on routine calcium screening.
Diagnosis & investigation of choice
- Biochemistry: high serum calcium + inappropriately high/non-suppressed PTH is diagnostic. Phosphate low, ALP raised, urinary calcium raised, low serum 25-OH if coexistent deficiency; chloride:phosphate ratio >33 is a classic clue.
- Localisation (only after biochemical diagnosis): Tc-99m sestamibi scan is the investigation of choice to localise an adenoma pre-operatively; combined with neck ultrasound and 4D-CT.
- Intra-operative PTH monitoring (>50% fall after excision confirms cure, half-life of PTH ~3–5 min).
High-yield: Sestamibi scan = localisation investigation of choice for parathyroid adenoma. Diagnosis is biochemical (Ca + PTH); imaging is to guide the surgeon, not to confirm disease.
Management / drug of choice
- Definitive: parathyroidectomy (adenoma excision, or subtotal/3½-gland resection for hyperplasia).
- Medical (non-operable or refractory): cinacalcet — a calcimimetic that allosterically activates the CaSR, lowering PTH and calcium; it is the drug of choice for medical control. Bisphosphonates for bone protection.
- Acute hypercalcaemic crisis: IV normal saline + loop diuretic (after rehydration) → bisphosphonate (zoledronate) → calcitonin for rapid (transient) lowering; consider denosumab/dialysis in refractory cases.
Secondary hyperparathyroidism
A compensatory rise in PTH driven by chronic hypocalcaemia, most often chronic kidney disease (CKD) and vitamin-D deficiency.
Mechanism in CKD (flow): Failing kidney → phosphate retention + reduced 1-α-hydroxylase → low calcitriol → low gut calcium absorption → hypocalcaemia → CaSR-driven PTH surge → 4-gland hyperplasia. FGF-23 rises early and further suppresses calcitriol.
- Labs: low/normal calcium, high phosphate (in CKD), high PTH, high ALP.
- Bone disease = renal osteodystrophy (osteitis fibrosa cystica + osteomalacia + adynamic bone + osteosclerosis → "rugger-jersey spine").
- Management: control phosphate (dietary restriction, non-calcium phosphate binders — sevelamer/lanthanum), active vitamin-D analogues (calcitriol, paricalcitol), and cinacalcet.
High-yield: In secondary HPT of CKD, phosphate is HIGH (kidney can't excrete it) — contrast with primary HPT where phosphate is LOW. This single value distinguishes the two on a lab grid.
Tertiary hyperparathyroidism
After long-standing secondary stimulation, the hyperplastic glands become autonomous and keep oversecreting PTH even after the calcium stimulus is corrected (classically post-renal-transplant). Result: hypercalcaemia + very high PTH. Treatment is subtotal/total parathyroidectomy with autotransplantation (forearm) or cinacalcet.
Hypoparathyroidism
Etiology
- Surgical (commonest) — inadvertent removal/devascularisation during thyroidectomy/neck surgery.
- Autoimmune — isolated or part of APS-1/APECED (autoimmune polyendocrine syndrome type 1: hypoparathyroidism + Addison + mucocutaneous candidiasis; AIRE gene).
- DiGeorge syndrome — 22q11.2 deletion → failure of development of 3rd & 4th pharyngeal pouches → absent parathyroids + thymic aplasia (T-cell immunodeficiency, cardiac outflow defects, hypocalcaemic tetany in neonate).
- Magnesium depletion (impairs PTH secretion and action), infiltration (Wilson, haemochromatosis), activating CaSR mutations (autosomal dominant hypocalcaemia).
Clinical features (hypocalcaemia)
- Neuromuscular irritability: perioral and acral paraesthesiae, carpopedal spasm, tetany, laryngospasm, seizures.
- Chvostek sign — tapping the facial nerve anterior to the ear → ipsilateral facial twitch.
- Trousseau sign — carpal spasm on inflating a BP cuff above systolic for 3 min (more specific).
- ECG: prolonged QT interval.
- Chronic: cataracts, basal ganglia calcification, dental enamel hypoplasia, dry skin, papilloedema.
Diagnosis
Low calcium + low/inappropriately normal PTH + high phosphate. Check magnesium (correct it first — hypomagnesaemia causes functional hypoparathyroidism). Vitamin D and renal function help exclude mimics.
Management
- Acute symptomatic hypocalcaemia / tetany: slow IV calcium gluconate (drug of choice; calcium chloride is more irritant/sclerosant peripherally).
- Chronic: oral calcium + active vitamin D (calcitriol/alfacalcidol); recombinant PTH (1-84) in refractory cases; correct magnesium.
High-yield: DiGeorge = 22q11 deletion → 3rd & 4th pharyngeal pouch failure → absent parathyroids + thymus. Neonatal hypocalcaemic tetany + immunodeficiency + conotruncal cardiac defect is the classic vignette.
Pseudohypoparathyroidism (PHP type 1a — Albright hereditary osteodystrophy)
End-organ resistance to PTH from a defective Gsα subunit (GNAS gene). Labs mimic hypoparathyroidism (low calcium, high phosphate) but PTH is HIGH. Phenotype: short stature, round face, shortened 4th & 5th metacarpals, obesity, mental subnormality. Pseudopseudohypoparathyroidism has the same phenotype but normal biochemistry.
| Condition | Calcium | Phosphate | PTH | Defect |
|---|---|---|---|---|
| Hypoparathyroidism | Low | High | Low | PTH deficiency |
| Pseudohypoparathyroidism | Low | High | High | Gsα/PTH resistance |
| Pseudopseudohypoparathyroidism | Normal | Normal | Normal | Gsα (phenotype only) |
MEN syndromes — the high-yield grid
Multiple endocrine neoplasia syndromes are autosomal dominant, and parathyroid involvement features in MEN1 and MEN2A. Know the gene, the chromosome, and the component organs cold.
| Feature | MEN1 (Wermer) | MEN2A (Sipple) | MEN2B |
|---|---|---|---|
| Gene | MEN1 (menin) | RET | RET |
| Chromosome | 11q13 | 10q11 | 10q11 |
| Parathyroid | Hyperplasia (~90%) | Hyperplasia (~20–30%) | Usually absent |
| Pituitary | Adenoma (prolactinoma) | — | — |
| Pancreas/GI | Islet-cell tumours (gastrinoma → Zollinger-Ellison, insulinoma) | — | — |
| Adrenal | — | Phaeochromocytoma | Phaeochromocytoma |
| Thyroid | — | Medullary carcinoma (MTC) | Medullary carcinoma (MTC) |
| Distinctive | "3 Ps" | MTC + phaeo + parathyroid | Mucosal neuromas, marfanoid habitus, ganglioneuromatosis |
Mnemonics:
- MEN1 = "3 Ps" → Parathyroid, Pituitary, Pancreas.
- MEN2A = "2 Ps + 1 M" → Parathyroid, Phaeochromocytoma, Medullary thyroid carcinoma.
- MEN2B = "1 P + 2 Ms + neuromas" → Phaeochromocytoma, Medullary carcinoma, Marfanoid habitus + mucosal neuromas (NO parathyroid).
High-yield: MEN1 → MEN1/menin gene (tumour suppressor, chr 11). MEN2A & MEN2B → RET proto-oncogene (chr 10). Parathyroid disease is most prominent in MEN1; absent in MEN2B.
High-yield: In MEN2, do adrenal imaging/plasma metanephrines first — always exclude and treat phaeochromocytoma before any thyroid/parathyroid surgery to avoid a fatal intra-operative hypertensive crisis. Prophylactic thyroidectomy is offered based on the RET codon (e.g., codon 918 in MEN2B = highest risk, operate in infancy).
Familial hypocalciuric hypercalcaemia (FHH) — the must-not-miss mimic
An autosomal dominant inactivating CaSR mutation → the gland "thinks" calcium is low → mild hypercalcaemia with inappropriately normal/high PTH — looks exactly like PHPT. The discriminator is urine calcium.
| Parameter | Primary HPT | FHH |
|---|---|---|
| Serum calcium | High | High (mild, lifelong) |
| PTH | High/normal | Normal/mildly high |
| 24-h urinary calcium | High | Low |
| Calcium:creatinine clearance ratio | >0.02 | <0.01 |
| Treatment | Surgery | None (surgery contraindicated) |
High-yield: Urinary calcium is LOW in FHH and HIGH in primary HPT. Operating on FHH is a classic error — calculate the Ca/Cr clearance ratio (<0.01 = FHH) before sending for parathyroidectomy.
Key differentials of hypercalcaemia
Approach (flow): Hypercalcaemia confirmed → measure PTH → PTH high/inappropriately normal → PHPT, tertiary HPT, FHH, lithium → PTH low (suppressed) → check PTHrP (malignancy/squamous tumours), 1,25-vit D (granulomatous disease, lymphoma), and consider bony mets/myeloma, thyrotoxicosis, immobilisation, milk-alkali, vitamin-D toxicity.
- Malignancy: commonest cause of hypercalcaemia in hospital; via PTHrP (humoral), osteolytic mets, or myeloma cytokines. PTH is suppressed.
- Granulomatous disease (sarcoidosis, TB): macrophage 1-α-hydroxylase → high calcitriol; PTH suppressed.
- Milk-alkali, thiazides, vitamin A/D toxicity, immobilisation, Paget, thyrotoxicosis.
Complications recap
- PHPT: nephrolithiasis, nephrocalcinosis, CKD, fragility fractures, peptic ulcer, pancreatitis, hypercalcaemic crisis.
- Hypoparathyroidism: tetany, laryngospasm, seizures, cataract, basal ganglia calcification.
- Renal osteodystrophy and vascular calcification in secondary/tertiary HPT.
- Post-parathyroidectomy: "hungry bone syndrome" — rapid bone re-mineralisation → severe hypocalcaemia and hypophosphataemia.
High-yield: Hungry bone syndrome = profound prolonged hypocalcaemia + hypophosphataemia + hypomagnesaemia after parathyroidectomy in long-standing severe HPT, due to avid skeletal uptake of minerals.
Recently asked / exam angle
- Lab-grid MCQs are the bread and butter: given Ca/PO₄/PTH/ALP values, identify primary vs secondary vs tertiary HPT vs hypoparathyroidism vs PHP. The phosphate direction and PTH are the deciding cells.
- MEN component matching — "Which tumour is NOT a feature of MEN2B?" (answer: parathyroid hyperplasia) and "Gene for MEN1?" (menin, chr 11) recur almost every year.
- Brown tumour histology/identity and its association with osteitis fibrosa cystica — frequently paired with a giant-cell lesion image.
- Subperiosteal resorption site (radial side of middle phalanges) as the earliest radiological sign of PHPT.
- Sestamibi scan as localisation investigation of choice; cinacalcet mechanism (calcimimetic, CaSR agonist).
- FHH vs PHPT discrimination by urinary calcium / Ca:Cr clearance ratio — a recurring "do-not-operate" trap.
- DiGeorge (22q11, 3rd & 4th pouch) and APS-1/AIRE as causes of hypoparathyroidism.
- Chvostek vs Trousseau signs and short QT (hypercalcaemia) vs long QT (hypocalcaemia) on ECG.
Rapid revision
- PTH raises calcium, lowers phosphate — the master rule.
- Commonest cause of PHPT = solitary chief-cell adenoma; commonest cause of hypercalcaemia in OPD = PHPT, in hospital = malignancy.
- Osteitis fibrosa cystica = subperiosteal resorption + salt-and-pepper skull + brown tumours (osteoclasts + haemosiderin + fibrous stroma).
- Earliest radiological sign of PHPT = subperiosteal resorption on radial side of middle phalanges.
- Localisation IOC = Tc-99m sestamibi; diagnosis is biochemical (Ca + non-suppressed PTH).
- Drug for medical control of HPT = cinacalcet (calcimimetic, CaSR agonist).
- Secondary HPT (CKD): low Ca, HIGH phosphate, high PTH; tertiary HPT: HIGH Ca + very high PTH (post-transplant).
- MEN1 = menin gene (chr 11), 3 Ps; MEN2A/2B = RET (chr 10); parathyroid absent in MEN2B.
- FHH: AD inactivating CaSR mutation → LOW urinary calcium, Ca/Cr clearance ratio <0.01 → never operate.
- Hypoparathyroidism: low Ca, high PO₄, low PTH; pseudohypoparathyroidism: same but PTH HIGH (Gsα/GNAS defect, Albright osteodystrophy, short 4th–5th metacarpals).
- DiGeorge = 22q11 deletion → 3rd & 4th pharyngeal pouch failure → absent parathyroid + thymus.
- Chvostek/Trousseau + long QT = hypocalcaemia; treat acute tetany with IV calcium gluconate; beware hungry bone syndrome post-op.