Primary hyperparathyroidism is excessive parathyroid hormone secretion caused by a parathyroid adenoma (most common), multigland hyperplasia, or rarely carcinoma, leading to hypercalcemia and its systemic complications.

Exam domain	One-glance essentials
Definition / diagnosis	Primary hyperparathyroidism (PHPT) is autonomous PTH secretion with hypercalcaemia and an inappropriately non-suppressed PTH ^[1] Common pathology: solitary adenoma; less often multigland hyperplasia; carcinoma is rare ^[1]
Epidemiology / risks	Consider MEN1, MEN2A, HPT-jaw tumour syndrome or familial disease in young, recurrent or multigland PHPT ^[1] Relevant acquired risks include previous neck irradiation, lithium and thiazide therapy ^[1]
Core mechanism	PTH raises serum calcium via bone resorption, renal calcium reabsorption and increased calcitriol; it lowers phosphate through phosphaturia ^[1] Cortical bone is preferentially lost; renal calcium load causes hypercalciuria, stones and nephrocalcinosis ^[1] Carcinoma should be suspected with severe hypercalcaemia, often > 3.5 mmol/L, and a palpable neck mass ^[1]
Clinical picture	Often incidental; symptomatic disease causes stones, polyuria/polydipsia, fatigue, weakness and bone pain ^[1] Skeletal disease may include osteoporosis, fractures or osteitis fibrosa cystica ^[1] Pseudogout/CPPD and chondrocalcinosis are recognised associations ^[1]
Investigations	Confirm raised corrected or ionised calcium with non-suppressed PTH on repeat testing; assess phosphate, ALP, vitamin D and renal function ^[1] Check urine calcium/CCCR: < 0.01 suggests FHH; > 0.02 supports PHPT ^[1] DEXA should include distal 1/3 radius; ultrasound and sestamibi are for localisation after biochemical diagnosis, not diagnosis ^[1]
Management	Parathyroidectomy is the only curative treatment; focused excision suits a localised single adenoma ^[1] Multigland hyperplasia generally requires bilateral exploration with subtotal 3.5-gland resection; MEN1 also needs cervical thymectomy ^[1] Carcinoma requires en bloc resection with ipsilateral central neck dissection when indicated ^[1] Severe symptomatic hypercalcaemia requires IV saline, calcitonin and bisphosphonate, followed by surgery ^[1]
Complications	Disease complications: nephrolithiasis, nephrocalcinosis, CKD, osteoporosis, fractures, pseudogout and hypercalcaemic crisis ^[1] Postoperative hungry bone syndrome causes prolonged hypocalcaemia; risk is higher with raised preoperative ALP ^[1] Surgical risks include RLN injury and permanent hypoparathyroidism ^[1]
Prevention / follow-up	Maintain hydration and avoid precipitating drugs such as thiazides, lithium and excess calcium/vitamin D when clinically appropriate ^[1] After non-operative management, monitor calcium, renal function, urinary complications and bone density ^[1] After surgery, monitor calcium closely and provide calcium/vitamin D replacement when hypocalcaemia or hungry bone develops ^[1]
Exam traps	A normal PTH is abnormal when calcium is high: it should be suppressed ^[1] Exclude FHH before surgery; low urinary calcium is a discriminator and FHH does not benefit from parathyroidectomy ^[1] A negative sestamibi scan does not exclude PHPT, particularly with hyperplasia or multigland disease ^[1] Never give loop diuretics before adequate rehydration in hypercalcaemic crisis ^[1]

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (pp. 41, 132–133)

Primary Hyperparathyroidism (PHPT)

Primary hyperparathyroidism (PHPT) is a condition of autonomous, excessive secretion of parathyroid hormone (PTH) from one or more parathyroid glands, independent of the normal calcium-sensing feedback mechanism ^[1]^[2]. This leads to hypercalcaemia (elevated serum calcium), which is the biochemical hallmark.

Let's break down the name:

Primary = the problem originates in the parathyroid gland itself (cf. secondary = reactive to hypocalcaemia from renal failure/vitamin D deficiency; tertiary = autonomous secretion that has evolved from long-standing secondary hyperparathyroidism)
Hyper = excessive
Parathyroidism = function of the parathyroid glands

The key distinction: in PHPT, PTH is inappropriately elevated (or non-suppressed) in the setting of hypercalcaemia. Normally, hypercalcaemia should suppress PTH via the calcium-sensing receptor (CaSR) — in PHPT, this feedback loop is broken ^[1]^[2].

PHPT is the most common cause of hypercalcaemia in the outpatient/ambulatory setting ^[1]^[2].

Parameter	Detail
Prevalence	~1–2 per 1,000 in the general population ^[1]
Peak age	6th–7th decade (average age ~59 years) ^[1]
Sex ratio	M:F ≈ 1:2–3 (female predominance, especially postmenopausal women) ^[1]
Discovery	Majority (~80%) now discovered incidentally on routine blood tests (asymptomatic hypercalcaemia) rather than with classic "stones, bones, moans" — this is a shift from historical presentation
Incidence	Roughly 20–66 per 100,000 person-years in Western populations; lower reported incidence in Hong Kong/East Asia but likely underdiagnosed

Hong Kong context: In Hong Kong, PHPT is increasingly recognised due to routine inclusion of calcium in biochemical panels. It remains less common than in Western populations, but awareness is growing. A significant proportion present late with symptomatic disease (renal stones, osteoporosis) compared to Western centres where asymptomatic PHPT predominates ^[1].

Risk Factor	Explanation
Female sex	2–3× more common in women, especially postmenopausal (loss of oestrogen → ↑bone resorption → may unmask/promote PHPT)
Age > 50	Incidence rises with age
Previous head and neck irradiation	Radiation to the neck (e.g. childhood leukaemia treatment, total body irradiation for bone marrow transplant, environmental radiation exposure) increases parathyroid cell mutagenesis ^[3]
Lithium therapy	Lithium shifts the calcium-PTH set point to the right → parathyroid glands require a higher calcium level to suppress PTH → chronic stimulation → hyperplasia/adenoma
Thiazide diuretics	Can unmask mild PHPT (thiazides ↓urinary Ca excretion → ↑serum Ca)
Familial/genetic syndromes	MEN1, MEN2A, hyperparathyroidism-jaw tumour (HPT-JT) syndrome, familial isolated hyperparathyroidism (FIHP) ^[1]^[3]
Vitamin D deficiency	Co-existing vitamin D deficiency is common and can mask the degree of hypercalcaemia while worsening bone disease

4. Anatomy and Physiology of the Parathyroid Glands

Number: Typically four parathyroid glands (two superior, two inferior), though 5–13% of people have supernumerary glands (important for surgery — missed gland = persistent disease)
Location:
- Superior glands: posterolateral to the upper thyroid poles, relatively constant position (derived from the 4th pharyngeal pouch)
- Inferior glands: more variable position (derived from the 3rd pharyngeal pouch, migrating with the thymus) — can be found anywhere from the angle of the mandible to the anterior mediastinum
Size: Each gland is ~5 mm × 3 mm × 1 mm, weighing ~30–50 mg (a normal gland is about the size of a grain of rice)
Blood supply: Inferior thyroid artery (primarily), with contributions from superior thyroid artery
Histology: Two main cell types:
- Chief cells: secrete PTH (the workhorse)
- Oxyphil cells: larger, packed with mitochondria (this is why they retain sestamibi on nuclear scans — critical for parathyroid scintigraphy) ^[2]^[4]

PTH is an 84-amino acid polypeptide. Its net effect is to ↑ serum calcium and ↓ serum phosphate ^[5].

Three target organs of PTH action:

Target	Action	Mechanism
Bone	↑ Osteoclastic bone resorption (and ↑ osteoblastic activity → ↑ ALP) — net effect is bone resorption	PTH binds PTH1R on osteoblasts → osteoblasts release RANKL → RANKL activates osteoclasts via RANK → ↑ bone resorption → releases Ca²⁺ and PO₄³⁻ into blood
Kidney (DCT)	↑ Calcium reabsorption at the distal convoluted tubule (DCT), ↓ phosphate reabsorption at the proximal convoluted tubule (PCT)	Upregulates TRPV5 channels in DCT for Ca²⁺; downregulates NaPi-IIa cotransporter in PCT for PO₄³⁻
Kidney (vitamin D)	↑ 1α-hydroxylation of 25-(OH)-D → ↑ 1,25-(OH)₂-D (calcitriol) → ↑ intestinal calcium absorption	Stimulates 1α-hydroxylase enzyme in PCT cells

Why does PTH raise calcium but lower phosphate? Because PTH simultaneously causes phosphaturia (renal phosphate wasting) while increasing calcium reabsorption. The phosphaturic effect ensures that the calcium × phosphate product doesn't rise dangerously (which would cause metastatic calcification). Clever homeostasis!

Three calciotropic hormones:

PTH: ↑Ca, ↓PO₄, ↑ALP
Calcitriol (1,25-(OH)₂-D₃): ↑Ca, ↑PO₄, ↑ALP (↑intestinal absorption of both Ca and PO₄; at high doses also ↑bone resorption)
Calcitonin (from thyroid parafollicular C cells): ↓Ca, ↓PO₄ — physiologically negligible (thyroidectomy does NOT significantly affect serum Ca) ^[5]

Important modifiers of total serum calcium:

Albumin: ~50% of plasma Ca is albumin-bound → hypoalbuminaemia causes a factitiously low total Ca
- Corrected Ca (mmol/L) = total Ca + 0.02 × (40 – albumin in g/L) ^[5]
Phosphate: can precipitate Ca out of serum
pH: alkalosis → ↓ionised Ca (H⁺ normally competes with Ca²⁺ for albumin binding sites; in alkalosis, fewer H⁺ → more Ca²⁺ binds albumin → ↓free ionised Ca) ^[5]

The Calcium-Sensing Receptor (CaSR)

The CaSR on parathyroid chief cells is the gatekeeper. When serum Ca rises, CaSR is activated → suppresses PTH secretion. In PHPT, the parathyroid cells (adenoma/hyperplastic) have a shifted set point — they require a higher Ca level to suppress PTH, or in some cases, ignore the signal entirely. This is why PTH remains elevated or non-suppressed despite hypercalcaemia. Contrast this with Familial Hypocalciuric Hypercalcaemia (FHH), where an inactivating mutation of the CaSR throughout the body (including parathyroids and kidneys) leads to mild hypercalcaemia with inappropriately normal PTH — a critical mimic of PHPT.

5. Etiology

Cause	Frequency	Key Features
Solitary parathyroid adenoma	~80–85%	Single enlarged gland; remaining glands are normal/atrophic. Most common cause of sporadic PHPT
Parathyroid hyperplasia (multigland disease)	~10–15%	All four glands enlarged. Think MEN1 or MEN2A or lithium use
Double adenomas	~1–5%	Two abnormal glands; distinction from asymmetric hyperplasia is debated
Parathyroid carcinoma	< 1% (up to 5% in some series)	Rare but important — suspect if Ca > 3.5 mmol/L, very high PTH (often > 5–10× ULN), palpable neck mass, hoarseness (RLN invasion)

5.2 Sporadic vs Familial PHPT

No identifiable genetic syndrome
Risk factor: previous head and neck irradiation ^[2]
Molecular: somatic mutations in CCND1 (cyclin D1 overexpression), MEN1 gene, CDC73/HRPT2 gene

Associated with Multiple Endocrine Neoplasia (MEN) syndromes:

Syndrome	Gene	Parathyroid Pathology	Other Features
MEN1	MEN1 gene (encoding menin) at 11q13	Parathyroid hyperplasia/adenoma (almost 100% penetrance by age 40–50)	Pancreatic NETs (gastrinoma 60%, insulinoma 10%), pituitary adenoma (prolactinoma most common)
MEN2A	RET proto-oncogene (ch10)	Parathyroid hyperplasia/adenoma (10–25% penetrance, usually mild)	Medullary thyroid carcinoma (100%), phaeochromocytoma (50%)
MEN2B	RET proto-oncogene	Rare/not typically associated	MTC, phaeochromocytoma, mucosal neuromas, Marfanoid habitus
HPT-JT syndrome	CDC73 (HRPT2) gene	Parathyroid adenoma/carcinoma (higher risk of carcinoma!)	Ossifying fibromas of jaw, renal cysts/tumours, uterine tumours
Familial isolated HPT (FIHP)	Various (MEN1, CDC73, CaSR, GCM2)	Adenoma or hyperplasia	No other endocrine tumours

MEN Syndromes – High Yield Mnemonic

MEN1 = 3 P's: Parathyroid, Pituitary, Pancreatic (tumour)
MEN2A = 2 P's + 1 M: Phaeochromocytoma, Parathyroid hyperplasia, Medullary thyroid carcinoma
MEN2B = 2 P's + 1 M + neuromas: Phaeochromocytoma, (no Parathyroid), Medullary thyroid carcinoma + Mucosal neuromas + Marfanoid habitus

MEN1 has the highest penetrance for PHPT (~100% by age 40–50). Typically presents with multiple parathyroid adenomas with a high recurrence rate (> 50% in 12 years if subtotal parathyroidectomy). Management favours subtotal parathyroidectomy (3.5 glands) + cervical thymectomy (to reduce risk of thymic carcinoid) ^[7].

MEN2A PHPT is usually mild and asymptomatic; management is similar to sporadic PHPT. NOT indicated for prophylactic parathyroidectomy during thyroidectomy (as PHPT is usually asymptomatic in MEN2A) ^[7].

Accounts for < 1% of PHPT ^[1]^[2]
Suspect when:
- Markedly elevated calcium ( > 3.5 mmol/L)
- Very high PTH (often > 5–10× upper limit of normal)
- Palpable neck mass (parathyroid adenomas are almost never palpable)
- Hoarseness (recurrent laryngeal nerve invasion)
- Associated with CDC73/HRPT2 gene mutations (HPT-JT syndrome)
En bloc resection is the treatment of choice (not simple parathyroidectomy)
Prognosis is variable; local recurrence is common

6. Pathophysiology of PHPT

The core problem: autonomous PTH secretion → persistent hypercalcaemia.

Pathology	Mechanism
Parathyroid adenoma	Clonal proliferation of a single abnormal parathyroid cell. Common molecular alterations: CCND1 rearrangement (overexpression of cyclin D1 → cell cycle progression), somatic MEN1 mutations (loss of tumour suppressor menin). The abnormal cells have a shifted calcium set point — requiring higher Ca²⁺ to suppress PTH secretion, plus increased proliferative capacity
Parathyroid hyperplasia	Polyclonal (or oligoclonal) proliferation of all four glands. Driven by germline mutations in MEN1, RET, or other genes. The increased cell mass → increased total PTH output, even if individual cells may still partially respond to Ca²⁺
Parathyroid carcinoma	Loss of CDC73/HRPT2 gene (encodes parafibromin, a tumour suppressor) → uncontrolled cell growth. May also have CCND1 overexpression. Markedly autonomous PTH secretion with very high PTH levels

6.2 Downstream Pathophysiology (Organ-by-Organ)

Let's trace each downstream effect:

↑ PTH → ↑ osteoclast activity → ↑ bone resorption
- Cortical bone preferentially affected (PTH has catabolic effect on cortical bone but can be anabolic to trabecular bone — this is why the distal 1/3 radius BMD drops first)
- In severe/prolonged disease: osteitis fibrosa cystica — subperiosteal bone resorption (classically at radial aspect of middle phalanges), brown tumours (focal collections of osteoclasts and fibrous tissue), "salt and pepper" skull on X-ray, bone cysts
- ↑ osteoblastic activity → ↑ ALP (alkaline phosphatase) — ALP level reflects bone turnover and predicts risk of hungry bone syndrome post-operatively ^[2]

Hypercalcaemia → hypercalciuria → calcium-containing renal stones (calcium oxalate and calcium phosphate)
- Despite PTH's action to reabsorb Ca in DCT, the filtered load of Ca²⁺ overwhelms reabsorption → net hypercalciuria
- Long-standing → nephrocalcinosis (calcium deposition in renal parenchyma)
- Nephrogenic diabetes insipidus (NDI): hypercalcaemia inhibits adenylyl cyclase → ↓cAMP → ↓aquaporin-2 insertion in collecting duct → concentrating defect → polyuria and polydipsia ^[6]
- Chronic hypercalcaemia can cause renal impairment from nephrocalcinosis and tubular damage

Hypercalcaemia → smooth muscle dysfunction:
- Constipation (↓GI motility — Ca²⁺ interferes with smooth muscle contraction/relaxation cycle)
- Anorexia, nausea, vomiting (central and peripheral effects)
- Abdominal pain
- Peptic ulcer disease: ↑Ca²⁺ stimulates gastrin secretion → ↑gastric acid
- Acute pancreatitis: Ca²⁺ may activate trypsinogen within pancreatic duct → autodigestion (though association is somewhat controversial)

Hypercalcaemia → ↑ membrane threshold potential:
- Ca²⁺ stabilises neuronal membranes → neurons require a greater stimulus to fire
- This causes: fatigue, lethargy, depression, impaired concentration, confusion
- Severe: psychosis, coma
- Proximal muscle weakness (often subtle)

Short QT interval on ECG (↑Ca²⁺ accelerates phase 2 repolarisation → shortens action potential)
Hypertension (~40% of PHPT patients; mechanism multifactorial: vascular smooth muscle tone, renal effects, RAAS activation)
Long-standing: vascular and valvular calcification, LVH

CPPD deposition disease (pseudogout): PHPT is a recognised secondary cause of calcium pyrophosphate crystal deposition (hyperPTH odds ratio ~3.35× for CPPD) ^[8]
Band keratopathy: calcium deposition in the cornea (medial and lateral limbus) — seen on slit-lamp examination
Chondrocalcinosis: radiographic calcification in cartilage

Stones, Bones, Moans, Thrones, Psychic Overtones

This is the classic mnemonic for hypercalcaemia symptoms, not just PHPT. But the vast majority of PHPT patients today are asymptomatic — picked up incidentally on routine blood tests. Only ~20% present with classic symptomatic disease.

Stones = renal stones, nephrocalcinosis
Bones = bone pain, osteoporosis, osteitis fibrosa cystica, fractures
Moans = constipation, nausea, abdominal pain, peptic ulcer, pancreatitis
Thrones = polyuria (nephrogenic DI), polydipsia, dehydration
Psychic overtones = depression, confusion, lethargy, psychosis

7. Classification

Type	Frequency	Characteristics
Solitary adenoma	~80–85%	Single enlarged gland; remaining 3 glands normal/suppressed
Double adenoma	~1–5%	Two abnormal glands
Multigland hyperplasia	~10–15%	All 4 glands enlarged; strongly associated with MEN syndromes and lithium
Parathyroid carcinoma	< 1%	Very high Ca/PTH, palpable mass, RLN invasion, CDC73 mutations

Category	Description
Symptomatic PHPT	Classic presentation with end-organ complications (stones, bones, moans, etc.)
Asymptomatic PHPT	Hypercalcaemia discovered incidentally on routine bloodwork; no overt symptoms
Normocalcaemic PHPT	Persistently elevated PTH with consistently normal total and ionised calcium, after excluding all secondary causes of elevated PTH (vitamin D deficiency, CKD, medications). This is a recognised entity and may represent the earliest phase of PHPT

Category	Examples
Sporadic (~90–95%)	No identifiable genetic syndrome
Familial (~5–10%)	MEN1, MEN2A, HPT-JT, FIHP

8. Clinical Features

The majority of patients today are asymptomatic (picked up incidentally). When symptoms occur, they are attributable to hypercalcaemia and/or end-organ damage from chronically elevated PTH.

System	Symptom	Pathophysiological Basis
General	Fatigue, malaise, weakness	Hypercalcaemia stabilises neuronal and muscle cell membranes → ↑threshold for depolarisation → reduced excitability → generalised weakness and lethargy
Renal ("Thrones")	Polyuria, polydipsia, nocturia	Hypercalcaemia inhibits adenylyl cyclase in collecting duct → ↓cAMP → ↓aquaporin-2 expression → nephrogenic diabetes insipidus ^[6]
	Renal colic (flank pain)	Hypercalciuria → calcium stone formation → ureteric obstruction
	Recurrent urinary tract infections	Secondary to nephrolithiasis/stasis
Skeletal ("Bones")	Bone pain, backache	↑ PTH → ↑ osteoclastic resorption → cortical bone thinning, microfractures
	Pathological fractures	Osteoporosis/osteitis fibrosa cystica → structural weakness
	Joint pain	CPPD crystal deposition (pseudogout) secondary to ↑Ca and ↑PPi
GI ("Moans")	Constipation	Hypercalcaemia → ↓smooth muscle motility in GI tract (Ca²⁺ impairs normal contractile cycling)
	Anorexia, nausea, vomiting	Central and peripheral neuronal effects of hypercalcaemia, ↑gastric acid
	Abdominal pain	Peptic ulceration (↑Ca²⁺ → ↑gastrin → ↑acid), pancreatitis, constipation
Neuropsychiatric ("Psychic Overtones")	Depression, anxiety, cognitive impairment	Ca²⁺ affects neurotransmitter release and neuronal excitability; also vascular effects on cerebral blood flow
	Confusion, drowsiness (if severe)	Severe hypercalcaemia → global cerebral depression
	Hallucinations (rare, severe)	Severe hypercalcaemia > 3.5 mmol/L
Cardiovascular	Hypertension (often asymptomatic)	Multifactorial: ↑vascular smooth muscle tone (Ca²⁺-dependent), ↑RAAS, renal impairment
	Palpitations	Short QT → potential arrhythmia substrate

System	Sign	Pathophysiological Basis
Neck	Palpable neck mass (rare, concerning)	Parathyroid adenomas are almost never palpable. A palpable mass should raise suspicion for parathyroid carcinoma
Eyes	Band keratopathy	Calcium phosphate deposition in the cornea (medial and lateral limbus) — occurs when Ca × PO₄ product is chronically elevated; seen on slit-lamp exam
Musculoskeletal	Proximal muscle weakness (subtle)	Hypercalcaemia → ↑membrane threshold → reduced muscle fibre excitability
	Bone tenderness	Subperiosteal resorption, pathological fractures
	Joint swelling/warmth (pseudogout)	CPPD crystal-induced synovitis (PHPT is a recognised metabolic cause of pseudogout) ^[8]
Skin	Pruritus (uncommon)	Metastatic calcification in skin
Cardiovascular	Hypertension	As above
	Short QT interval on ECG	Hypercalcaemia shortens phase 2 (plateau) of cardiac action potential → shortened QT
Abdominal	Epigastric tenderness	Peptic ulcer disease or acute pancreatitis
Neurological	Decreased deep tendon reflexes	Hypercalcaemia → ↑neuronal membrane threshold → hyporeflexia
	Altered mental status (severe)	Severe hypercalcaemia → CNS depression
Renal	Signs of dehydration	Polyuria → volume depletion (if compensatory intake is insufficient)

Clinical Pearl — Hypercalcaemic Crisis

Severe hypercalcaemia ( > 3.5 mmol/L) is a medical emergency. It creates a vicious cycle: hypercalcaemia → polyuria → dehydration → ↓GFR → ↓renal Ca excretion → worsening hypercalcaemia. Patients may present with severe dehydration, confusion, oliguria, and cardiac arrhythmias. This requires urgent IV normal saline rehydration as the first step.

Parameter	Expected Finding	Why
Serum calcium	↑ (or high-normal in normocalcaemic PHPT)	Autonomous PTH → ↑bone resorption, ↑renal Ca reabsorption, ↑calcitriol → ↑gut absorption
Serum PTH	↑ or inappropriately normal	Even a "normal" PTH in the setting of hypercalcaemia is abnormal — it should be suppressed. This counts as "inappropriately non-suppressed" ^[2]^[6]
Serum phosphate	↓ (or low-normal)	PTH causes phosphaturia (↓PO₄ reabsorption at PCT)
ALP	↑ (if significant bone involvement)	↑ osteoblastic activity in response to ↑ bone resorption → ↑ALP ^[2]
Chloride	↑ (mild hyperchloraemic metabolic acidosis)	PTH inhibits bicarbonate reabsorption in PCT → mild RTA-like picture → compensatory Cl⁻ retention
24-hour urine calcium	↑ (> 250 mg/day in women, > 300 mg/day in men)	Filtered Ca load overwhelms tubular reabsorption; must check to rule out FHH ^[2]
Vitamin D (25-OH-D)	Variable (often low)	Coincident vitamin D deficiency is common; if present, correcting it may unmask the full degree of hypercalcaemia
1,25-(OH)₂-D (calcitriol)	↑ (or high-normal)	PTH stimulates 1α-hydroxylase → ↑calcitriol production

Biochemical diagnosis of PHPT = hypercalcaemia + high or inappropriately normal PTH ^[2]

Familial Hypocalciuric Hypercalcaemia (FHH) — The Critical Mimic

FHH must be excluded before diagnosing PHPT. FHH is caused by an inactivating mutation in the calcium-sensing receptor (CaSR). Both the parathyroids and the kidneys fail to "sense" calcium properly:

Parathyroids: PTH remains normal or mildly elevated despite hypercalcaemia
Kidneys: Avid reabsorption of calcium → low urinary calcium excretion

Key differentiator: 24-hour urine calcium:

PHPT: urine calcium is elevated (calcium:creatinine clearance ratio > 0.02)
FHH: urine calcium is low (calcium:creatinine clearance ratio < 0.01)

FHH is benign — it does NOT require surgery. Misdiagnosing FHH as PHPT leads to unnecessary parathyroidectomy with persistent hypercalcaemia post-op.

The calcium:creatinine clearance ratio (CCCR) = (urine Ca / serum Ca) ÷ (urine Cr / serum Cr).

CCCR < 0.01: likely FHH
CCCR 0.01–0.02: indeterminate (consider genetic testing)
CCCR > 0.02: likely PHPT

Feature	Adenoma	Hyperplasia	Carcinoma
Frequency	80–85%	10–15%	< 1%
Glands involved	Usually single	All four	Usually single
Serum calcium	Mild–moderate ↑	Mild–moderate ↑	Often markedly ↑ ( > 3.5 mmol/L)
PTH level	↑	↑	Very high (often > 5–10× ULN)
Palpable mass	Almost never	No	May be palpable
Genetic association	Sporadic; MEN2A	MEN1, MEN2A, lithium	HPT-JT syndrome (CDC73)
Surgery	Focused parathyroidectomy	Subtotal (3.5 glands) or total + autotransplant	En bloc resection
Recurrence	Low (~1–4%)	Higher (especially MEN1 > 50% in 12y)	High (local recurrence common)

High Yield Summary

PHPT = autonomous PTH secretion → hypercalcaemia — most commonly from a solitary parathyroid adenoma (~85%)
Most common cause of hypercalcaemia in ambulatory patients (vs malignancy in inpatients)
Demographics: F > M (2–3:1), peaks 6th–7th decade
Biochemical hallmark: ↑Ca + ↑/inappropriately normal PTH + ↓PO₄ + ↑ALP (if bone disease)
Must check 24h urine calcium to rule out FHH (CCCR < 0.01 = FHH; > 0.02 = PHPT)
Even a "normal" PTH in the setting of hypercalcaemia is abnormal — should be suppressed
Clinical features: Majority asymptomatic; symptomatic = "Stones, Bones, Moans, Thrones, Psychic Overtones"
MEN associations: MEN1 (parathyroid hyperplasia, ~100% penetrance), MEN2A (10–25%, usually mild)
Parathyroid carcinoma: < 1%, suspect if Ca > 3.5, very high PTH, palpable mass, hoarseness, CDC73 mutation
Localisation (NOT diagnosis): USG + sestamibi scan — sestamibi retained by mitochondria-rich oxyphil cells
Parathyroid scintigraphy: dual-phase technique — early (20 min) and delayed (2h) images; faster thyroid washout makes parathyroid more apparent on delayed images
ALP level predicts risk of hungry bone syndrome post-parathyroidectomy

Active Recall - Primary Hyperparathyroidism (Definition to Clinical Features)

^[1] Senior notes: Ryan Ho Endocrine.pdf (pp. 41, 132–133) ^[2] Senior notes: maxim.md (Primary hyperparathyroidism section) ^[3] Senior notes: felixlai.md (Hyperparathyroidism section, pp. 1469–1470, 1506–1521) ^[4] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p. 60 — Parathyroid Scintigraphy) ^[5] Senior notes: Adrian Lui Pediatrics.pdf (pp. 276–278 — Physiology of Serum Calcium) ^[6] Senior notes: Ryan Ho Fundamentals.pdf (pp. 430–438 — Hypercalcemia) ^[7] Senior notes: Ryan Ho Endocrine.pdf (pp. 132–133 — MEN syndromes) ^[8] Senior notes: Ryan Ho Rheumatology.pdf (p. 41 — CPPD Crystal Deposition Disease)

Differential Diagnosis of Primary Hyperparathyroidism

The differential diagnosis of PHPT is really a two-step problem. First, you're usually starting from the finding of hypercalcaemia — so you need to work through the DDx of hypercalcaemia. Second, even once you've identified PTH-dependent hypercalcaemia, there are a few conditions that can mimic PHPT. Let's think through this systematically from first principles.

The single most important investigation when you encounter hypercalcaemia is the serum PTH level. This splits the entire differential into two clean branches ^[6]^[9]:

PTH-dependent (PTH elevated or inappropriately normal): The parathyroid glands are driving the hypercalcaemia.
PTH-independent (PTH suppressed): Something else is raising calcium, and the parathyroids are appropriately shutting down.

Why does this work? Because the calcium-sensing receptor (CaSR) on parathyroid chief cells normally suppresses PTH when serum Ca²⁺ rises. If PTH is NOT suppressed in the setting of hypercalcaemia, either the parathyroid glands are autonomous (PHPT/tertiary) or the set point is shifted (FHH, lithium) ^[9]^[10].

Even if PTH is within the reference range, a hypercalcaemia of non-parathyroid cause should be accompanied by appropriately suppressed PTH. A "normal" PTH in the face of hypercalcaemia is inappropriately non-suppressed and should trigger workup for primary hyperparathyroidism ^[10].

Step 3: Detailed Differential Diagnosis

Condition	Key Distinguishing Features	Why PTH is Elevated/Non-Suppressed
Primary hyperparathyroidism	Most common outpatient cause of hyperCa. ↑Ca, ↑/N PTH, ↓PO₄, ↑ALP. 24h urine Ca elevated (CCCR > 0.02). Adenoma ~85%, hyperplasia ~10–15%, carcinoma < 1%	Autonomous secretion from abnormal parathyroid tissue — the adenomatous/hyperplastic cells have a shifted calcium set point and proliferate beyond normal feedback control
Tertiary hyperparathyroidism	History of chronic renal failure (often on dialysis). Previously had secondary hyperPTH → prolonged parathyroid stimulation → glands become autonomous. Hypercalcaemia persists even after correction of the underlying cause (e.g. post-renal transplant) ^[3]	Long-standing secondary hyperparathyroidism → parathyroid hyperplasia → eventually some cells acquire autonomous (monoclonal) growth → adenoma formation within hyperplastic glands. The glands no longer respond to normalised calcium levels
Familial hypocalciuric hypercalcaemia (FHH)	AD inheritance. Mild, usually asymptomatic hypercalcaemia. Normal or mildly ↑PTH. Low urine Ca, CCCR < 0.01. Normal PO₄. Family history of mild hypercalcaemia. Does NOT require surgery ^[2]^[10]	Inactivating mutation of CaSR → both the parathyroids and the kidneys "think" calcium is lower than it really is. Parathyroids don't suppress PTH; kidneys avidly reabsorb calcium (low urinary Ca). This is NOT a disease — it's a benign reset of the calcium thermostat
Lithium-induced hyperparathyroidism	Patient on lithium therapy (for bipolar disorder). Should stop lithium to evaluate (if safe to do so) ^[1]	Lithium shifts the calcium-PTH set point to the right (similar mechanism to FHH but pharmacological rather than genetic). The parathyroids require a higher Ca²⁺ to suppress PTH → chronic overstimulation → may cause hyperplasia or adenoma over time
Thiazide-unmasked PHPT	Patient on thiazide diuretics with hypercalcaemia. Should stop thiazide to evaluate (if safe) ^[1]	Thiazides ↓renal calcium excretion (enhance Ca²⁺ reabsorption in DCT via NCC-related mechanisms). In a patient with subclinical PHPT, thiazide use can tip them over into overt hypercalcaemia. The thiazide itself doesn't cause PHPT but unmasks it. If hypercalcaemia persists after stopping the thiazide, the patient has true PHPT

FHH — The Trap You Must Not Fall Into

FHH is the most important differential to exclude before committing a patient to parathyroidectomy. It mimics PHPT biochemically (↑Ca, ↑/N PTH) but is a benign, lifelong condition requiring NO treatment. Operating on FHH patients does NOT cure the hypercalcaemia (because the renal CaSR is also mutated — they will continue to reabsorb calcium avidly). The key test is the 24-hour urine calcium and calcium-creatinine clearance ratio (CCCR):

CCCR < 0.01 → FHH
CCCR > 0.02 → PHPT
CCCR 0.01–0.02 → indeterminate; consider genetic testing for CaSR mutation

Always check family history — FHH is autosomal dominant, so multiple family members may have mild asymptomatic hypercalcaemia.

These are the conditions where something other than the parathyroid glands is raising calcium. The intact parathyroid feedback loop correctly suppresses PTH in response.

Condition	Frequency	Key Features	Mechanism of Hypercalcaemia
Hypercalcaemia of malignancy	Most common cause of hyperCa in hospitalised patients. HyperCa in ~20% of cancer patients	PTH suppressed. Ca usually much higher and symptomatic (cf. PHPT which is often mild). Common cancers: breast, lung, kidney, prostate, multiple myeloma, lymphoma ^[10]	Several mechanisms: (1) Ectopic PTHrP production (humoral hypercalcaemia of malignancy — "HHM"): PTHrP mimics PTH action on bone and kidney but is NOT detected by standard PTH assays, hence PTH is suppressed. Common in SCC lung, HCC, breast cancer. (2) Local osteolysis: bone metastases directly destroy bone via mechanical compression + local cytokines (IL-6, TNF-β) — common in breast cancer, multiple myeloma. (3) Ectopic calcitriol production: lymphoma cells contain 1α-hydroxylase → ↑1,25-(OH)₂-D
Granulomatous disease	Uncommon	↑1,25-(OH)₂-D level. TB, sarcoidosis, histoplasmosis, coccidioidomycosis, leprosy, berylliosis. In HK, think TB and sarcoidosis	Activated macrophages within granulomas express 1α-hydroxylase → unregulated conversion of 25-(OH)-D to 1,25-(OH)₂-D (calcitriol) → ↑intestinal Ca absorption and ↑bone resorption. This is extra-renal and NOT regulated by normal feedback ^[6]
Vitamin D intoxication	Uncommon	↑25-(OH)-D level, normal or ↑1,25-(OH)₂-D	Excessive exogenous vitamin D supplementation (or consumption of fortified foods) → ↑25-(OH)-D → substrate-driven ↑calcitriol production → ↑Ca absorption. Can also directly act at high concentrations
Milk-alkali syndrome	Uncommon	History of excessive calcium + absorbable alkali intake (e.g. calcium carbonate antacids). ↑Ca, metabolic alkalosis, renal impairment	Large oral Ca load → mild hyperCa → ↑renal Ca excretion → but alkali component → metabolic alkalosis → ↑renal Ca reabsorption (alkalosis enhances DCT Ca transport) → vicious cycle of worsening hyperCa and renal impairment
Drugs	Variable	Thiazides (usually unmask PHPT rather than cause de novo hyperCa), lithium (shifts set point), ranitidine (rare), calcium supplements, vitamin A intoxication	Drug-specific mechanisms; always take a thorough drug history
Increased bone resorption (non-malignant)	Uncommon	Thyrotoxicosis (↑bone turnover from excess T3/T4), Paget's disease (especially if immobilised), prolonged immobilisation (e.g. spinal cord injury, bedbound patient)	Accelerated osteoclastic activity from various stimuli → release of skeletal calcium stores faster than renal excretion can compensate. Usually mild unless coexisting renal impairment
Adrenal insufficiency	Rare	Features of Addison's disease; ↑Ca usually mild	Mechanism multifactorial: haemoconcentration (↓intravascular volume), ↑renal Ca reabsorption (loss of cortisol's calciuretic effect), ↑bone resorption
Paraproteinaemia (e.g. MGUS, myeloma)	Uncommon	↑total protein with normal albumin → ↑globulin. Apparent high Ca may be factitious (paraproteins bind calcium → ↑total Ca but normal ionised Ca). Check serum protein electrophoresis ^[10]	Paraproteins can bind calcium, inflating the total calcium measurement without changing the biologically active ionised fraction. Also, in myeloma, true hyperCa occurs via osteoclast activation (RANKL:OPG imbalance). Mnemonic for myeloma: CRAB — Ca↑, Renal insufficiency, Anaemia, Bone lytic lesions ^[10]

PHPT vs Malignancy — The Two Giants

These two account for > 90% of all hypercalcaemia cases combined. The clinical distinction is usually straightforward:

Feature	PHPT	Malignancy
Setting	Outpatient, incidental	Inpatient, symptomatic
Calcium level	Usually mild (< 3.0 mmol/L)	Often markedly elevated ( > 3.0 mmol/L)
PTH	↑ or inappropriately normal	Suppressed
Patient	Looks well	Looks unwell (weight loss, cachexia)
PO₄	↓ (PTH-driven phosphaturia)	Variable (↓ if PTHrP; ↑ if bone mets)
ALP	↑ if bone disease	↑ if bone mets or PTHrP
Chronicity	Chronic, indolent	Acute/subacute onset
Urine Ca	↑	↑

A suppressed PTH with hypercalcaemia should trigger workup for occult malignancy ^[6]^[10].

Once PHPT is confirmed (↑Ca + ↑/N PTH + ↑urine Ca + normal RFT), you need to think about the underlying pathology:

Feature	Solitary Adenoma	Double Adenoma	Multigland Hyperplasia	Parathyroid Carcinoma
Frequency	~80–85%	~1–5%	~10–15%	< 1%
Ca level	Mild–moderate ↑	Mild–moderate ↑	Mild–moderate ↑	Often markedly ↑ ( > 3.5 mmol/L)
PTH	↑	↑	↑	Very high ( > 5–10× ULN)
Palpable mass	No (too small)	No	No	May be palpable
Hoarseness	No	No	No	Yes (RLN invasion)
Genetic association	Sporadic; MEN2A	Sporadic	MEN1, MEN2A, lithium	CDC73/HPT-JT
Family history	Usually negative	Usually negative	May be positive (MEN)	May be positive (HPT-JT)
Localisation imaging	Single focus on USG + sestamibi	Two foci	Diffuse uptake / multigland on sestamibi (may be negative)	Single focus, may show invasion
Surgery	Focused parathyroidectomy	Bilateral exploration	Subtotal (3.5 glands) ± thymectomy	En bloc resection

A negative sestamibi scan does NOT preclude the diagnosis of PHPT — it can be unrevealing in parathyroid hyperplasia, multiple adenomas, or coexisting thyroid disease ^[3]^[4]. Localisation studies are for surgical planning, NOT for diagnosis ^[3]^[4].

This is a conceptual distinction that examiners love:

Feature	Primary	Secondary	Tertiary
Definition	Autonomous PTH secretion from abnormal parathyroid tissue	Physiological ↑PTH as a response to chronic hypocalcaemia	Autonomous PTH secretion that has evolved FROM prolonged secondary hyperPTH
Serum Ca	↑	↓ or low-normal	↑
Serum PTH	↑ or inappropriately N	↑ (appropriately)	↑
Serum PO₄	↓	↑ (in CKD) or ↓ (in vit D deficiency)	Variable
RFT	Normal	Usually abnormal (CKD)	History of CKD, often post-transplant
Key cause	Adenoma, hyperplasia, carcinoma	CKD (↑PO₄ → ↓ionised Ca → ↓1,25-D), vitamin D deficiency, dietary Ca deficiency ^[3]	Prolonged secondary hyperPTH → parathyroid hyperplasia → glands acquire autonomy (adenoma formation within hyperplastic glands). Glands do NOT respond to Ca²⁺ level in blood ^[3]
Pathology	Usually adenoma	Diffuse hyperplasia (reactive)	Nodular hyperplasia with possible adenomatous transformation

Why does tertiary hyperPTH develop? Think of it as a "point of no return." In secondary hyperPTH, all four glands undergo diffuse hyperplasia in response to chronic hypocalcaemia. Over years (especially in dialysis patients), some hyperplastic cells acquire further mutations (somatic MEN1 or CCND1 changes) and become monoclonal — essentially forming adenomas within the hyperplastic glands. These cells no longer respond to calcium feedback and continue to secrete PTH autonomously, even if the patient receives a renal transplant and calcium normalises ^[3].

Before going down the entire pathway, always rule out factitious (spurious) hypercalcaemia ^[6]:

Cause	Mechanism	How to Detect
Hypoalbuminaemia	↓albumin → ↓total Ca but normal ionised Ca. NOT true hypercalcaemia	Check albumin-corrected Ca or ionised Ca
Paraproteinaemia	↑globulin binds Ca → ↑total Ca but normal ionised Ca ^[10]	Check ionised Ca (will be normal), serum protein electrophoresis
Prolonged tourniquet	Venous stasis → haemoconcentration → spuriously ↑Ca	Repeat sample with proper venepuncture technique
Dehydration	Haemoconcentration → ↑total Ca	Recheck after rehydration

When you encounter hypercalcaemia, think in three steps:

Is it real? Rule out factitious causes (check corrected/ionised Ca, albumin, protein electrophoresis)

Is it PTH-dependent? Measure PTH → splits into two clean categories

If PTH-dependent — is it PHPT or a mimic? Check 24h urine Ca (CCCR) to exclude FHH; check RFT to exclude tertiary hyperPTH; review drug history (lithium, thiazides)

High Yield Summary — Differential Diagnosis of PHPT

PTH is the pivot: ↑/N PTH + hyperCa = PTH-dependent; ↓PTH + hyperCa = PTH-independent
Two most common causes of hypercalcaemia overall: PHPT (outpatient) and malignancy (inpatient)
FHH is the critical mimic: inactivating CaSR mutation → mild hyperCa + normal/↑PTH + LOW urine Ca (CCCR < 0.01). Benign, does NOT need surgery. Missing this → unnecessary failed parathyroidectomy
Malignancy: PTH is suppressed, Ca usually markedly elevated, patient looks unwell. Mechanisms: PTHrP (HHM), local osteolysis, ectopic calcitriol (lymphoma)
Lithium and thiazides should be stopped (if safe) before confirming PHPT diagnosis
Tertiary hyperPTH: distinguish from PHPT by history of CKD/dialysis
Paraproteinaemia can cause factitious hypercalcaemia (↑total Ca, normal ionised Ca) — check SPE
Within PHPT: suspect carcinoma if Ca > 3.5, PTH > 5–10× ULN, palpable mass, hoarseness
Negative sestamibi does NOT exclude PHPT — localisation studies are for surgical planning, not diagnosis

Active Recall - Differential Diagnosis of PHPT

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (p. 42 — D/dx of PHPT) ^[2] Senior notes: maxim.md (Primary hyperparathyroidism section) ^[3] Senior notes: felixlai.md (Hyperparathyroidism section — types of hyperPTH, pp. 1506–1521) ^[4] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p. 60 — Parathyroid Scintigraphy) ^[6] Senior notes: Ryan Ho Fundamentals.pdf (p. 430 — Hypercalcemia approach and DDx table) ^[9] Senior notes: Ryan Ho Cardiology.pdf (p. 177 — Secondary HTN, hyperPTH as cause) ^[10] Senior notes: Ryan Ho Chemical Path.pdf (p. 23 — Causes of hypercalcaemia)

Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities

1. Diagnostic Criteria for Primary Hyperparathyroidism

PHPT does not have a single "set of criteria" like, say, the Jones criteria for rheumatic fever. Instead, the diagnosis is biochemical — it rests on demonstrating a characteristic laboratory pattern and then systematically excluding mimics. Let's build the diagnostic requirements from first principles.

The diagnosis of PHPT = elevated serum calcium + inappropriately elevated (or non-suppressed) PTH, in the setting of normal renal function.

This can be broken down into three mandatory components:

Component	Requirement	Rationale
1. Confirmed true hypercalcaemia	Albumin-corrected Ca elevated (typically > 2.55–2.60 mmol/L, lab-specific) OR elevated ionised Ca, on at least two occasions	A single elevated reading can be spurious (tourniquet, dehydration, lab error). Always correct for albumin: corrected Ca = total Ca + 0.02 × (40 − albumin in g/L). Alternatively, ionised Ca directly measures the biologically active fraction and bypasses albumin/paraprotein confounders ^[6]
2. Inappropriately elevated or non-suppressed PTH	PTH elevated above the reference range, OR PTH "normal" in the context of hypercalcaemia	This is the conceptual lynchpin. Normally, hypercalcaemia activates the CaSR on parathyroid chief cells → suppresses PTH. If PTH is not suppressed, the feedback loop is broken. Even a PTH in the "normal range" (e.g. 3.5 pmol/L in a patient with Ca 2.85 mmol/L) is inappropriately non-suppressed — it should be low/undetectable. This counts as PHPT ^[10]
3. Normal renal function	Normal urea, creatinine, eGFR	To exclude tertiary hyperparathyroidism (autonomous PTH from prolonged CKD-related secondary hyperPTH). If the patient has CKD with ↑Ca and ↑PTH, the diagnosis shifts to tertiary, not primary ^[1]^[3]

Exclusion	How	Why
Rule out FHH	24-hour urine calcium and calcium-creatinine clearance ratio (CCCR) ^[2]	FHH mimics PHPT biochemically. CCCR < 0.01 → FHH likely (benign, no surgery needed). CCCR > 0.02 → PHPT. 0.01–0.02 → indeterminate, consider genetic testing for CaSR mutation
Rule out vitamin D deficiency	Serum 25-(OH)-D ^[1]^[2]	Vitamin D deficiency causes secondary hyperPTH (↑PTH is a physiological response to ↓Ca from ↓intestinal Ca absorption). It can also coexist with PHPT and mask the degree of hypercalcaemia. If 25-(OH)-D is low, replete it first, then reassess Ca and PTH
Rule out drug causes	Medication review: stop lithium and thiazides if safe ^[1]	Lithium shifts the CaSR set point → ↑PTH. Thiazides ↓renal Ca excretion → can unmask subclinical PHPT. Must stop and recheck before confirming diagnosis

Normocalcaemic PHPT — The Emerging Entity

Normocalcaemic PHPT is defined as persistently elevated PTH with consistently normal total and ionised calcium, after all secondary causes of elevated PTH have been rigorously excluded (vitamin D deficiency, CKD, medications, malabsorption). This is thought to represent the earliest form of PHPT. It is a diagnosis of exclusion — you cannot make this diagnosis without first ensuring 25-(OH)-D is > 50 nmol/L (ideally > 75 nmol/L), eGFR is > 60, and no offending drugs are present. These patients may eventually progress to classical hypercalcaemic PHPT and should be monitored.

3. Investigation Modalities — Systematic Approach

The investigations in PHPT serve three distinct purposes, and it is critical to understand why each test is ordered:

Confirm the biochemical diagnosis (is it really PHPT?)
Screen for complications (has the disease damaged anything?)
Localise the abnormal gland (where is it, to guide surgery?)

Localisation studies are NOT used for diagnosis of PHPT NOR to determine the need for surgery. They are indicated ONLY when PHPT is biochemically confirmed AND a decision for surgery has been made ^[3]^[4].

Investigation	Key Findings in PHPT	Interpretation / Why It's Ordered
Serum calcium (total + corrected)	↑ (typically 2.6–3.0 mmol/L in most cases; > 3.5 mmol/L raises concern for carcinoma)	The albumin-corrected Ca accounts for the ~50% of calcium that is protein-bound. In hypoalbuminaemia, total Ca is falsely low; in hyperproteinaemia (e.g. myeloma), total Ca is falsely high. Corrected Ca = total Ca + 0.02 × (40 − albumin) ^[6]
Ionised calcium	↑	Directly measures the biologically active (free) fraction. Unaffected by albumin or acid-base status. Most accurate but not always available. Particularly useful when albumin is very abnormal or acid-base disturbance present ^[6]
Serum intact PTH	↑ or inappropriately normal	The "intact" PTH assay measures the whole 1-84 PTH molecule. Even a mid-range "normal" PTH is pathological if calcium is elevated — it should be suppressed to < lower limit of normal ^[10]. Third-generation PTH assays (1-84 specific) are preferred over second-generation (which may cross-react with PTH fragments in CKD)
Serum phosphate	↓ or low-normal	PTH causes phosphaturia by downregulating NaPi-IIa cotransporter in PCT → renal phosphate wasting. A low PO₄ in the setting of ↑Ca + ↑PTH is the classic triad. ↑PTH + ↑Ca + ↓PO₄ suggests hyperparathyroidism ^[3]
Serum ALP (alkaline phosphatase)	↑ (if bone involvement)	Reflects osteoblastic activity (osteoblasts produce ALP). In hyperparathyroid bone disease, there is ↑osteoclastic resorption and compensatory ↑osteoblastic activity → ↑ALP. ↑ALP level predicts risk of hungry bone syndrome post-operatively ^[2] — the higher the ALP, the greater the expected post-op calcium "crash" as bone suddenly shifts from net resorption to net formation
Serum 25-(OH)-vitamin D	Variable; often ↓	Must check to rule out vitamin D deficiency ^[2], which can: (1) be a secondary cause of ↑PTH mimicking PHPT, or (2) coexist with PHPT and mask the true severity of hypercalcaemia. If deficient, replete cautiously (may worsen hypercalcaemia if true PHPT is present) then reassess
24-hour urine calcium	↑ (> 250 mg/day women, > 300 mg/day men)	Must check to rule out FHH ^[2]. The filtered calcium load in PHPT overwhelms tubular reabsorption → net hypercalciuria. In FHH, the mutant renal CaSR causes avid Ca reabsorption → paradoxically low urine Ca
Calcium-creatinine clearance ratio (CCCR)	> 0.02 in PHPT; < 0.01 in FHH	CCCR = (urine Ca / serum Ca) ÷ (urine Cr / serum Cr). This ratio corrects for GFR and is more discriminating than 24h urine Ca alone. Essential to calculate ^[2]
Urea, creatinine, eGFR (RFT)	Normal in PHPT (unless complicated by nephrocalcinosis)	Rules out tertiary hyperparathyroidism (CKD + autonomous PTH) ^[1]. Also establishes baseline renal function for surgical planning and to assess if renal impairment is a complication of PHPT itself
Serum magnesium	Usually normal	Severe hypomagnesaemia can impair PTH secretion and action → low Ca refractory to replacement. Not a typical finding in PHPT but should be checked if calcium/PTH levels are discordant
Serum chloride	↑ (mild hyperchloraemic acidosis)	PTH inhibits bicarbonate reabsorption in PCT → mild non-anion-gap metabolic acidosis with compensatory chloride retention. A Cl:PO₄ ratio > 33 was historically used (rarely relied upon now)

Summary biochemical profile of PHPT ^[1]^[3]^[6]:

↑Ca, ↑PTH (or inappropriately normal), ↓PO₄, ↑ALP, ↑urine Ca (CCCR > 0.02), normal RFT

These are ordered once the diagnosis of PHPT is confirmed — they document end-organ damage and help determine whether surgery is indicated (especially in asymptomatic patients).

Investigation	Target Complication	Key Findings	Clinical Significance
DEXA bone densitometry	Osteoporosis	T-score ≤ −2.5 at any site is a surgical indication. PHPT preferentially affects cortical bone → measure at three sites: lumbar spine, hip (femoral neck), and distal 1/3 radius ^[1]^[3]	PTH causes cortical > trabecular bone loss. The distal 1/3 radius is predominantly cortical bone and may show the earliest/most severe ↓BMD, whereas the lumbar spine (predominantly trabecular) may be relatively preserved or even paradoxically increased (intermittent PTH has anabolic effects on trabecular bone, but continuous elevation does not)
Abdominal X-ray (KUB) / USG kidneys	Nephrolithiasis, nephrocalcinosis	Renal calculi (radio-opaque calcium stones on KUB), nephrocalcinosis (diffuse renal parenchymal calcification on USG) ^[2]	Presence of stones or nephrocalcinosis = surgical indication even in asymptomatic patients. Calcium stones (oxalate and phosphate) are the most common stone type in PHPT
Lateral thoracolumbar spine X-ray or VFA	Vertebral fracture	Vertebral compression fractures may be asymptomatic and occlude on plain X-ray; Vertebral Fracture Assessment (VFA) on DEXA can also detect these	Presence of vertebral fracture = surgical indication (per 2022 international guidelines)
ECG	Cardiac effects of hypercalcaemia	Short QT interval (↑Ca²⁺ shortens phase 2 plateau of cardiac AP → shortens overall QT). In severe cases: ST elevation mimicking MI, Osborne/J waves, arrhythmias	Baseline ECG recommended especially if Ca > 3.0 mmol/L. Short QT is the earliest ECG sign
Serum creatinine / eGFR	Renal impairment	eGFR < 60 mL/min is a surgical indication	CKD can result from chronic hypercalcaemia-induced nephrocalcinosis, tubular damage, and dehydration

Should perform workup for MEN in every PHPT patient, especially if ^[1]^[7]^[10]:

Age < 40
Multigland disease
Family history of PHPT, MEN, or related tumours
Parathyroid carcinoma (→ CDC73 testing)

Investigation	When to Order	What You're Looking For
Detailed family history	All PHPT patients	FHH, MEN1, MEN2A, HPT-JT syndrome
Genetic testing: MEN1 gene	Young onset, multigland, positive FHx	MEN1 = parathyroid hyperplasia/adenoma + pancreatic NETs + pituitary adenoma ^[7]
Genetic testing: RET proto-oncogene	Positive FHx, coexisting MTC or phaeochromocytoma	MEN2A = MTC + phaeochromocytoma + parathyroid hyperplasia ^[7]
Genetic testing: CDC73/HRPT2	Suspected parathyroid carcinoma, HPT-JT syndrome	CDC73 mutations → ↑risk of parathyroid carcinoma, ossifying fibromas of jaw
Genetic testing: CaSR	CCCR 0.01–0.02 (indeterminate) or suspected FHH	Inactivating CaSR mutation confirms FHH
Serum prolactin, IGF-1	Suspected MEN1	Screen for pituitary adenoma (prolactinoma most common in MEN1)
Fasting gastrin	Suspected MEN1, symptoms of ZES	Zollinger-Ellison syndrome (gastrinoma, 60% of MEN1)
Urine/plasma metanephrines	Suspected MEN2A/2B	Screen for phaeochromocytoma (50% in MEN2) — must exclude phaeochromocytoma before any surgery to avoid intraoperative HTN crisis
Serum calcitonin, CEA	Suspected MEN2A/2B	Screen for medullary thyroid carcinoma

Must Exclude Phaeochromocytoma Before Surgery

In any patient with suspected MEN2, always screen for phaeochromocytoma (urine/plasma metanephrines) BEFORE proceeding to parathyroidectomy or any surgery. An undiagnosed phaeochromocytoma can cause a fatal intraoperative hypertensive crisis during anaesthesia induction. If positive, the phaeochromocytoma must be treated first (alpha-blockade → adrenalectomy) before addressing the parathyroid disease.

3.4 Localisation Studies — For Surgical Planning Only

This is one of the most commonly tested concepts. Let me emphasise again:

Localisation studies are NOT for diagnosis. They are NOT used to determine the need for surgery. They are performed ONLY after PHPT is biochemically confirmed and the decision for surgery has been made, to guide the surgical approach ^[3]^[4].

The role of localisation is to determine:

Whether a focused/minimally invasive parathyroidectomy (MIP) is feasible (requires a single, clearly identified adenoma)
Whether there is multigland disease (→ bilateral neck exploration needed)
Whether an ectopic parathyroid is present (mediastinal, intrathymic, retroesophageal)

Modality	Technique / Mechanism	Key Findings	Strengths and Limitations
USG neck	High-frequency linear probe; operator-dependent	Parathyroid adenomas appear as homogeneous hypoechoic nodules posterior to the thyroid, often with an extra-thyroidal feeding vessel with peripheral vascularity on Doppler ^[3]	Strengths: non-invasive, no radiation, inexpensive, can be done at bedside, good for neck lesions. Limitations: operator-dependent, poor for mediastinal/ectopic glands, sensitivity ↓ in coexisting multinodular goitre, misses small adenomas and hyperplasia
⁹⁹ᵐTc-Sestamibi scintigraphy	Radiotracer that accumulates in mitochondria. Parathyroid adenomas are rich in oxyphilic cells (which have abundant mitochondria) → slow washout compared to thyroid tissue. Dual-phase technique: early image at ~10–20 min (tracer in both thyroid + parathyroid), delayed image at 2h (faster thyroid washout → parathyroid more apparent) ^[2]^[4]	Persistent focal uptake on delayed images localises the hyperfunctioning gland. Can be performed as: (1) single isotope dual-phase scan, (2) dual isotope subtraction imaging (⁹⁹ᵐTc-sestamibi minus ⁹⁹ᵐTc-pertechnetate to subtract thyroid signal) ^[2]	Strengths: functional imaging (identifies hyperfunctioning tissue, not just anatomy), can detect ectopic glands (mediastinal), sensitivity ~75–90% for single adenomas. Limitations: false positive: Hürthle cell adenoma (also mitochondria-rich) ^[2]; poor sensitivity for hyperplasia, double adenomas, and small adenomas; negative sestamibi does NOT preclude the diagnosis of PHPT ^[3]
SPECT/CT (Single-photon emission CT)	3D sestamibi scan fused with CT for anatomical co-registration	Better spatial resolution than planar sestamibi; precise anatomical localisation	Higher sensitivity than planar sestamibi alone (~85–90%); better for ectopic and small glands; ↑radiation dose
4D CT scan	Multiphase CT imaging (non-contrast, arterial, venous, delayed phases). The "4th dimension" is time — perfusion characteristics over multiple phases	Parathyroid adenomas show characteristic rapid arterial enhancement with washout pattern, distinguishable from lymph nodes and thyroid nodules	High spatial resolution, excellent for re-operative cases and when USG/sestamibi are discordant. Limitation: high radiation dose ^[2]. Increasingly used as first-line in some centres
MRI	Multiplanar imaging without radiation	Parathyroid adenomas: low signal on T1, high signal on T2 ^[3]	Useful when CT is contraindicated (e.g. pregnancy, radiation concerns), good for mediastinal glands. Less commonly used as first-line
PET scan	¹¹C-methionine or ¹⁸F-fluorocholine PET/CT	Increased amino acid / choline uptake in hyperfunctioning parathyroid tissue	Emerging modality with high sensitivity, especially for re-operative cases and when conventional imaging is negative. ¹⁸F-fluorocholine PET/CT increasingly used ^[3]

The Standard First-Line Localisation Package

USG neck + sestamibi scan (± SPECT/CT) is the standard first-line localisation strategy ^[2]^[4]. The two modalities are complementary:

USG provides anatomical detail and is excellent for intrathyroidal or perithyroidal adenomas
Sestamibi provides functional information and can detect ectopic glands
When both agree ("concordant"), there is > 95% likelihood of finding a single adenoma at surgery → patient is a good candidate for focused/minimally invasive parathyroidectomy
When discordant or negative, consider 4D CT, SPECT/CT, or ¹⁸F-choline PET/CT

Modality	Technique	When to Use
Selective venous sampling	Catheterisation of cervical veins (superior/middle/inferior thyroid, thymic, vertebral veins). PTH measured at each location. A ≥ 1.5–2× increase in PTH compared to peripheral sample is considered abnormal and localises the gland ^[3]	Most common invasive modality for parathyroid localisation. Reserved for patients with prior neck surgery or unrevealing non-invasive tests ^[2]^[3]
Selective arteriography with transarterial hypocalcaemic stimulation	Injection of sodium citrate into feeding arteries → induces local hypocalcaemia → stimulates PTH release from the hyperfunctioning gland → measured in effluent veins	Reserved for re-operative cases or when non-invasive and venous sampling are inconclusive ^[3]
Intraoperative ultrasound	USG probe applied directly to neck tissues during surgery	Adjunct during bilateral exploration; helps identify glands not found by standard dissection
Imaging-guided FNAC with PTH washout	USG-guided FNA of a suspected parathyroid lesion → aspirate sent for PTH level (not cytology)	Can confirm a lesion is parathyroid tissue (PTH in aspirate >> serum PTH). Useful when a nodule's identity is ambiguous on imaging

Investigation	Technique	Significance
Intraoperative PTH assay (ioPTH)	Takes advantage of the short half-life of PTH (~3–5 minutes). Serum PTH measured pre-incision and at 5 and 10 minutes after excision of the suspected adenoma. Miami criteria: PTH drops to normal range AND falls > 50% of the maximum pre-excision value by 10 minutes post-excision ^[2]^[3]	Confirms that all hyperfunctioning tissue has been removed. If criteria are met → surgery successful, can close. If criteria NOT met → suspect multigland disease → convert to bilateral neck exploration ^[2]
Frozen section	Intraoperative histological examination of excised tissue	Confirms tissue is parathyroid (not lymph node, thyroid, fat). Especially important during subtotal parathyroidectomy (3.5 gland resection) to confirm the remnant tissue is indeed parathyroid ^[2]

Why ioPTH Works

PTH has a half-life of only ~3–5 minutes. After removing the hyperfunctioning adenoma, serum PTH should plummet rapidly. If you measure PTH at 10 minutes post-excision and it has dropped by > 50% and fallen into the normal range, you can be confident that:

The removed gland was indeed the source of excess PTH
There is no second hyperfunctioning gland remaining (i.e. no double adenoma or hyperplasia)

If PTH does NOT fall adequately, the surgeon should suspect multigland disease and convert from focused parathyroidectomy to bilateral neck exploration. This is one of the most elegant uses of a rapid biochemical assay in surgery.

While not used for diagnosis per se, recognising the radiological features of advanced PHPT is high-yield for exams ^[1]:

Finding	Location	Description	Pathophysiology
Subperiosteal bone resorption	Radial aspect of middle phalanges (most sensitive site)	Thinning/irregularity of the bony cortex at the subperiosteal surface	PTH → ↑osteoclastic resorption preferentially at cortical bone surfaces
"Salt and pepper" skull	Skull vault	Multiple tiny well-defined lucencies on skull X-ray/CT	Resorption of trabecular bone within the diploë of the skull vault
Brown tumours	Jaw, long bones, ribs, pelvis	Well-defined lytic lesions with fibrous tissue and hemosiderin (brown colour)	Osteoclastic aggregations intermixed with fibrous tissue and poorly mineralised woven bone; brown due to hemosiderin from microhaemorrhages ^[1]
Bone cysts	MCP shafts, ribs, pelvis	Central medullary lucencies	Focal areas of intense resorption
Tapering of distal clavicles	Acromioclavicular joints	Loss of the normal rounded distal clavicular end	Subperiosteal/subchondral resorption
Chondrocalcinosis	Knee (meniscus), wrist (TFCC), pubic symphysis	Linear calcification in cartilage on X-ray	CPPD crystal deposition secondary to hypercalcaemia (PHPT is a metabolic cause of pseudogout)
Osteopenia / osteoporosis	Cortical sites: distal 1/3 radius, femoral neck > lumbar spine	↓BMD on DEXA	Continuous PTH elevation → net cortical bone loss (cortical > trabecular) ^[1]
"Rugger-jersey" spine	Thoracolumbar spine	Alternating bands of sclerosis and lucency	More characteristic of secondary/tertiary hyperPTH (renal osteodystrophy) than primary, but can occur

The classical osteitis fibrosa cystica (the full triad of subperiosteal resorption + brown tumours + bone cysts) is uncommon today because most PHPT is caught early on biochemical screening before advanced bone disease develops ^[1].

Per JCEM/AES 2022 guidelines (updated from JCEM 2014 referenced in the notes) ^[1]:

Category	Investigations
Confirm PHPT	Serum total Ca (corrected for albumin), ionised Ca, intact PTH, serum PO₄, serum ALP
Rule out other causes	Serum 25-(OH)-D (vitamin D deficiency), urea/Cr/eGFR (CKD → tertiary), 24h urine Ca and CCCR (FHH), medication review (lithium, thiazides)
Screen for complications	DEXA at 3 sites (lumbar spine, hip, distal 1/3 radius), KUB / USG kidneys (stones, nephrocalcinosis), lateral spine X-ray or VFA (vertebral fracture), ECG, baseline RFT
Screen for MEN	Family history, ± genetic testing (MEN1, RET, CDC73), ± biochemical screening (prolactin, gastrin, metanephrines, calcitonin)
Localisation (if surgery planned)	USG neck + ⁹⁹ᵐTc-sestamibi scan (± SPECT/CT) ^[2]^[4]. If discordant/negative: 4D CT, choline PET/CT, or invasive methods

High Yield Summary — Diagnostics

Diagnosis = ↑Ca + ↑/inappropriately normal PTH + normal RFT. That's the core.
"Normal" PTH with hypercalcaemia IS abnormal — it should be suppressed → workup for PHPT.
Must check 24h urine Ca and CCCR in ALL patients to exclude FHH (CCCR < 0.01 = FHH; > 0.02 = PHPT).
Must check 25-(OH)-D to exclude vitamin D deficiency as cause of secondary ↑PTH.
ALP predicts hungry bone syndrome risk post-op: higher ALP = worse post-op hypoCa.
DEXA at THREE sites (spine, hip, distal 1/3 radius) — cortical bone loss earliest at radius.
Localisation studies are for surgical planning, NOT diagnosis, NOT to determine need for surgery.
Standard localisation: USG + sestamibi (± SPECT/CT).
Sestamibi works because oxyphilic cells are rich in mitochondria → slow tracer washout. Dual-phase: 10–20 min early, 2h delayed.
False positive for sestamibi: Hürthle cell adenoma (also mitochondria-rich).
Negative sestamibi does NOT exclude PHPT — poor for hyperplasia and multigland disease.
ioPTH: PTH t½ ~3–5 min. Miami criteria: > 50% drop + return to normal range at 10 min post-excision.
If ioPTH criteria NOT met → suspect multigland disease → convert to bilateral exploration.

Active Recall - Diagnosis and Investigation of PHPT

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (pp. 41–42 — PHPT diagnosis, standard Ix, bone disease) ^[2] Senior notes: maxim.md (Primary hyperparathyroidism — investigations, localisation, surgical criteria) ^[3] Senior notes: felixlai.md (Hyperparathyroidism — localisation studies, case study, pp. 1516–1522) ^[4] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p. 60 — Parathyroid Scintigraphy) ^[6] Senior notes: Ryan Ho Fundamentals.pdf (p. 430 — Hypercalcaemia approach) ^[7] Senior notes: Ryan Ho Endocrine.pdf (pp. 132–133 — MEN syndromes) ^[10] Senior notes: Ryan Ho Chemical Path.pdf (p. 23 — Causes of hypercalcaemia, PTH interpretation)

Management of Primary Hyperparathyroidism

The management of PHPT follows a clear decision tree: Is the patient a candidate for surgery? If yes, operate. If not, monitor and manage medically. Surgery is the only curative treatment. Let's walk through the entire management framework systematically.

Before discussing definitive surgery, any patient presenting with severe symptomatic hypercalcaemia (Ca > 3.5 mmol/L) — sometimes called "parathyroid crisis" — needs urgent medical stabilisation ^[1]:

Clinical setting: often associated with dehydration (hypercalcaemia → polyuria → volume depletion → ↓GFR → ↓renal Ca excretion → worsening hypercalcaemia — a vicious cycle) ^[1].

Management aims: (1) rapid control of severe hypercalcaemia, (2) early diagnosis of cause ^[1].

Step	Treatment	Dose / Regimen	Mechanism	Notes
1. Stop precipitants	Remove offending drugs	Stop calcium supplements, vitamin D, thiazides, lithium, ranitidine	These drugs all contribute to ↑Ca via different mechanisms	Always take a drug history first ^[1]
2. Rehydrate	IV normal saline (NS)	100–500 mL/h until euvolaemic (est. 3–4 L/day)	Restores intravascular volume → ↓Na resorption in PCT/Loop → ↓Ca resorption (majority of Ca reabsorption in the kidney is Na-dependent and passive-paracellular in the PCT and thick ascending Loop of Henle) ^[1]	The single most important first step. Most patients are significantly dehydrated
3. Loop diuretic	Furosemide (lasix)	20–40 mg IV Q4–12H (only AFTER adequate hydration)	Inhibits Na⁺/K⁺/2Cl⁻ cotransporter in thick ascending LoH → ↓lumen-positive potential → ↓paracellular Ca²⁺ reabsorption → ↑urinary Ca excretion ^[1]	Must give ONLY after adequate hydration — otherwise worsens dehydration and hypercalcaemia. Monitor U/O (~200 mL/h target), Na/K/Ca/Mg
4a. ↓ Bone resorption (rapid onset)	Salmon calcitonin	4 U/kg IM/SC Q12H	Directly inhibits osteoclast activity → ↓bone resorption → ↓Ca release	Onset ≤ 2–3h (fast!) but tachyphylaxis sets in within 2–3 days → use as a bridge while waiting for bisphosphonate to take effect ^[1]
4b. ↓ Bone resorption (sustained)	IV bisphosphonate	Pamidronate 30–90 mg in 250–500 mL NS over 4–6 h OR zoledronate 4 mg IV over 15 min	Bisphosphonates are pyrophosphate analogues incorporated into bone matrix → taken up by osteoclasts during resorption → induce osteoclast apoptosis → ↓bone resorption	Pamidronate: max effect in several days, do NOT repeat before 7 days, effect lasts 2–4 weeks. Zoledronate: max effect at 72h. Precaution: C/I if eGFR < 30; renal dosing if eGFR < 60 ^[1]
5. Special situations	Corticosteroids	Hydrocortisone 50 mg IV Q8H then PO 40–60 mg/day	↓calcitriol production — inhibit macrophage 1α-hydroxylase	Onset 3–5 days. Mainly for haem malignancy, vitamin D intoxication, granulomatous disease — NOT first-line for PHPT ^[1]
6. Refractory / CKD	Denosumab	Dose uncertain	RANKL inhibitor → ↓osteoclast activation	Especially useful in renal impairment (not renally cleared) ^[1]
	Cinacalcet	Calcimimetic	Allosteric agonist of CaSR → ↑CaSR sensitivity to Ca²⁺ → ↓PTH secretion	Powerful hypocalcaemic effect; can bridge to surgery ^[1]^[3]
	Haemodialysis	Zero/low Ca dialysate	Physically removes Ca from blood	Treatment of last resort ^[1]

	Pamidronate	Calcitonin
Onset	Slow (several days)	Rapid (2–3 hours)
Duration	Long (2–4 weeks)	Short (tachyphylaxis in 2–3 days)
Clinical use	Mainstay — most potent	Bridge at the beginning while awaiting bisphosphonate effect
Renal precaution	C/I eGFR < 30; dose adjust eGFR < 60	None

Strategy: give calcitonin + bisphosphonate simultaneously at the start. Calcitonin provides rapid Ca lowering in the first 2–3 days while bisphosphonate's effect builds up. By the time calcitonin loses efficacy from tachyphylaxis, bisphosphonate has taken over ^[1].

3. Surgical Management — The Definitive Cure

Surgery (parathyroidectomy) is the only curative treatment for PHPT. It has a cure rate of ~95–98% and provides durable normalisation of calcium, improvement in BMD, reduction in fracture risk, and resolution of symptoms ^[1]^[3].

3.1 Indications for Surgery

This is straightforward — any patient with symptoms attributable to PHPT should be offered surgery:

Renal stones / nephrocalcinosis
Symptomatic bone disease (fractures, significant bone pain)
Symptomatic hypercalcaemia (psychic overtones, GI symptoms, polyuria)
Parathyroid crisis

Most PHPT patients today are asymptomatic. The question becomes: who among these should still be offered surgery? The guidelines (based on 5th International Workshop on PHPT, 2022, building on JCEM 2014) identify patients at highest risk of developing complications if left untreated:

Surgical Indications for Asymptomatic PHPT — Mnemonic: CASR

CASR (like the calcium-sensing receptor!) ^[2]:

C — Calcium: adjusted Ca ≥ 0.25 mmol/L (1 mg/dL) above upper limit of normal (i.e. typically ≥ 2.85 mmol/L)
A — Age: < 50 years (longer lifetime exposure to PTH → cumulative skeletal and renal damage)
S — Skeletal: DEXA T-score ≤ −2.5 at lumbar spine, total hip, femoral neck, or distal 1/3 radius; OR vertebral fracture on imaging (XR, CT, MRI, or VFA)
R — Renal: any of the following:
- CrCl < 60 mL/min (eGFR < 60)
- 24h urine Ca > 400 mg/day (10 mmol/day) + ↑stone risk by biochemical stone risk analysis
- Nephrolithiasis or nephrocalcinosis on imaging (XR, USG, or CT)

Persistent or recurrent PHPT (after previous surgery)
Familial PHPT (MEN1, MEN2A, HPT-JT)
Parathyroid carcinoma (suspected or confirmed)
Parathyroid crisis (severe hypercalcaemia with haemodynamic compromise)

The logic behind these criteria: we are trying to identify patients who will progress to end-organ damage. A young patient (< 50) has decades of PTH exposure ahead. Markedly elevated calcium (≥ 2.85 mmol/L) predicts faster disease progression. Skeletal and renal damage, once established, may be partially irreversible. Surgery before damage accumulates is therefore recommended ^[1]^[3].

Contraindication	Rationale
Familial hypocalciuric hypercalcaemia (FHH)	Not PHPT. Surgery does not cure FHH because the CaSR defect is systemic (including renal). Patient will remain hypercalcaemic post-op
Known contralateral recurrent laryngeal nerve (RLN) injury	Bilateral RLN injury is life-threatening — causes bilateral vocal cord paralysis → airway obstruction requiring tracheostomy. If one RLN is already damaged, operating on the other side carries unacceptable risk
Patient medically unfit for surgery	Severe comorbidities precluding general/regional anaesthesia. These patients should be managed medically (calcimimetics, bisphosphonates)
Symptomatic cervical disc disease (relative)	May complicate neck positioning during surgery

Pre-operative localisation studies — USG neck + sestamibi scan (± SPECT/CT, 4D CT) — to guide surgical strategy, NOT for diagnosis ^[3]^[4]
Review of vocal cord function (indirect laryngoscopy) — baseline RLN assessment
Optimise calcium if severely hypercalcaemic — IV hydration, calcitonin, bisphosphonate as needed
If MEN2 suspected: exclude phaeochromocytoma BEFORE any surgery (urine/plasma metanephrines)
Vitamin D repletion: if deficient, replete pre-op (reduces severity of post-op hungry bone syndrome)

3.4 Surgical Options

This is the preferred approach when a single adenoma is identified on pre-operative localisation ^[2].

Feature	Detail
Indication	Adenoma identified on pre-op localisation studies (concordant USG + sestamibi) ^[2]
Rationale	Based on the premise that ~80–85% of PHPT is due to a single adenoma ^[2]
Approach	Open with < 3 cm incision (fig.), video-assisted, or imaging-guided. Can be done under local/regional anaesthesia ^[1]
Key requirement	Intraoperative PTH (ioPTH) assay to confirm all hyperfunctioning tissue has been removed
ioPTH — Miami criteria	PTH must drop to normal range AND fall > 50% of the maximum pre-excision value, measured at 10 min post-gland excision (comparing pre-skin-incision or pre-manipulation level with 10 min post-excision level). This works because PTH half-life is only ~3–5 minutes ^[2]^[3]
If Miami criteria NOT met	Suspect multigland disease → convert to bilateral neck exploration (BCE) ^[2]
Benefits	↓surgery time, ↓dissection, ↓cost, smaller incision, ↓post-op hypocalcaemia (remaining normal glands are not disturbed), equal cure rate (~97–98%) when compared with BCE ^[3]
Cure rate	~98% curative, < 1% nerve injury ^[1]

Feature	Detail
Indications	Conversion from focused parathyroidectomy (failed ioPTH criteria), MEN1/MEN2A, uncertain/discordant imaging (USG not consistent with sestamibi), suspected multigland disease, negative localisation
Approach	Kocher's incision (transverse collar scar ~2 cm above sternal notch) ^[2]
Goal	Identify all four glands, determine which are abnormal, and remove appropriately

Within BCE, the extent of resection depends on the pathology:

i. Subtotal parathyroidectomy ("3.5 gland resection") ^[2]^[3]

3 glands completely resected
Fourth gland: half excised for frozen section (to confirm the tissue is indeed parathyroid), remaining half left in situ, marked with non-absorbable sutures (to aid identification if re-operation is needed) ^[2]
50–80 mg of vascularised gland preserved ^[1]
Advantage: ↓ risk of permanent hypoparathyroidism (some functioning tissue remains)
Disadvantage: ↑ risk of persistent/recurrent hyperparathyroidism; re-operation in the neck is technically difficult if recurrence occurs

ii. Total parathyroidectomy with autotransplantation ^[3]

All identifiable parathyroid glands removed
A small portion (~60 mg) of the most normal-appearing gland is diced into 1 mm³ fragments and autotransplanted into the non-dominant forearm (brachioradialis muscle) or neck (SCM) ^[2]^[3]
Rationale for forearm placement:
- Allows easy re-exploration under local anaesthesia if graft becomes hyperplastic/recurrent ^[3]
- Graft function can be monitored by comparing PTH levels in ipsilateral vs contralateral forearm veins — a gradient confirms functioning graft ^[3]
- Cryopreservation of remaining tissue allows delayed autotransplantation if graft fails ^[1]^[3]
Advantage: Lower recurrence than subtotal; better symptom improvement ^[3]
Disadvantage: Risk of profound hypoparathyroidism if autograft fails (countered by cryopreserved tissue); period of transient hypoparathyroidism before graft takes (~2–4 weeks)

iii. Total parathyroidectomy without autotransplantation

Highest risk of permanent hypocalcaemia → reserved for severe cases where risk of leaving any parathyroid tissue is deemed too high (e.g. severe recurrent tertiary hyperPTH) ^[3]

Performed in both total and subtotal parathyroidectomy (especially in MEN1)
Rationale: Supernumerary parathyroid glands (5th, 6th glands) are most commonly located within the thymus (because inferior parathyroid glands and thymus share embryological origin from the 3rd pharyngeal pouch and co-migrate during development) ^[3]
Indicated if MEN1 to resect supernumerary glands + also reduces risk of thymic carcinoid (a MEN1-associated tumour) ^[2]^[7]
Important for patients with a missing inferior parathyroid gland or suspected supernumerary glands ^[3]

Suspected parathyroid carcinoma (markedly ↑Ca, very high PTH, palpable mass, adherent to surrounding structures) requires en bloc resection of the tumour with the ipsilateral thyroid lobe, isthmus, and any adherent tissue
Do NOT simply shell out the tumour — capsular rupture risks local seeding (parathyromatosis)
Ipsilateral central neck dissection if lymph nodes are involved

MEN Syndrome	Surgical Approach	Key Points
MEN1	Subtotal parathyroidectomy (3.5 glands) + cervical thymectomy	Indications same as sporadic. High recurrence rate ( > 50% in 12 years) due to multiple adenomas/hyperplasia. Cervical thymectomy to ↓thymic carcinoid risk and remove supernumerary glands ^[7]
MEN2A	Similar to sporadic (focused or BCE depending on extent)	Usually mild, asymptomatic. NOT for prophylactic parathyroidectomy during thyroidectomy (as PHPT is usually mild in MEN2A). Manage only if symptomatic or meets criteria ^[7]

4. Conservative / Medical Management

Medical management is for patients who do not meet surgical criteria OR are surgically unfit ^[1]^[2].

Asymptomatic PHPT not meeting any surgical criteria
Patient medically unfit for surgery (severe comorbidities, advanced age with limited life expectancy)
Patient declines surgery

Measure	Rationale
Adequate hydration (≥ 2 L/day)	Prevents dehydration → maintains renal Ca excretion
Avoid dehydration, immobilisation	Both worsen hypercalcaemia (dehydration → ↓GFR → ↓Ca excretion; immobilisation → ↑bone resorption)
Moderate calcium intake (~1000 mg/day)	Neither restrict nor load — restriction paradoxically stimulates PTH further; excess loads Ca into the system
Replete vitamin D (if deficient)	Co-existing vitamin D deficiency worsens hyperPTH and bone disease. Cautious repletion with monitoring of serum Ca
Avoid thiazide diuretics	Thiazides ↓urinary Ca excretion → worsen hypercalcaemia
Exercise	Weight-bearing exercise ↓bone resorption

Agent	Mechanism	Effect in PHPT	Indications / Notes
Cinacalcet (calcimimetic)	Mimics action of Ca²⁺ on tissues by allosteric activation of the CaSR → ↑CaSR sensitivity → ↓PTH secretion ^[1]^[3]	Effective in lowering/normalising serum Ca but less consistent effect on serum PTH and NO consistent improvement in BMD ^[1]	Indicated when parathyroidectomy is indicated but surgery is contraindicated or refused ^[1]^[3]. Can be used as a bridge to surgery in hypercalcaemic crisis
Bisphosphonates (e.g. alendronate)	Inhibit osteoclast-mediated bone resorption	↑BMD (especially at lumbar spine), but minimal effect on serum Ca or PTH	Primarily to address skeletal complications (osteoporosis) in non-surgical PHPT patients
Denosumab	RANKL inhibitor → ↓osteoclast activation → ↓bone resorption	↑BMD, may ↓serum Ca	Emerging option, especially useful in renal impairment (not renally cleared). Monitor for rebound hypercalcaemia on cessation
SERMs (e.g. raloxifene)	Selective oestrogen receptor modulators → ↓bone resorption	Modest ↑BMD, modest ↓Ca	Limited evidence; occasionally used in postmenopausal women ^[2]
HRT (oestrogen replacement)	↓bone resorption via oestrogen action on osteoblasts/osteoclasts	↓Ca, ↑BMD	Historical option; now rarely used due to HRT-related risks (VTE, breast cancer)

Cinacalcet — The Key Medical Agent

"Cinacalcet" → "cina" = mimics calcium; "calcet" = calcium-related. It is a calcimimetic — it fools the CaSR into thinking calcium is higher than it really is.

How it works from first principles: Cinacalcet binds to an allosteric site on the CaSR (not the Ca²⁺-binding site itself). This makes the CaSR more sensitive to circulating Ca²⁺ → at any given Ca²⁺ level, the receptor signals more strongly → PTH secretion is suppressed → serum Ca drops.

Why doesn't it improve BMD? Because while it lowers Ca and partially ↓PTH, the remaining PTH that is still secreted continues to drive bone turnover. The bone benefits of surgery (complete PTH normalisation) are not fully replicated.

Bottom line: cinacalcet normalises calcium, but surgery normalises everything (Ca, PTH, and BMD).

Regular monitoring is mandatory for any patient with PHPT not undergoing surgery:

Parameter	Frequency	Rationale
Serum calcium	Annually	Detect worsening hypercalcaemia
Serum creatinine / eGFR	Annually	Detect progressive renal impairment
DEXA at 3 sites (L-spine, hip, distal 1/3 radius)	Every 1–2 years	Detect progressive bone loss (T-score ≤ −2.5 triggers surgical referral)
Spine imaging (XR/VFA)	If clinically indicated (height loss, back pain)	Detect new vertebral fractures
Renal imaging (USG/CT) + 24h urine	If stone symptoms or biochemical stone risk analysis changes	Detect new nephrolithiasis

If at any point during surveillance the patient meets surgical criteria → refer for surgery ^[1].

5. Post-Operative Management and Monitoring

Issue	Management
Serum Ca monitoring	Routinely check Ca on post-op Day 1 ^[2]. In high-risk patients (high pre-op ALP, large adenoma, severe bone disease), check Ca Q6–8h
Hypocalcaemia (most common post-op complication)	Expected and usually transient. Causes: (1) Transient suppression of remaining normal parathyroid glands — they have been chronically suppressed by the adenoma's autonomous PTH secretion and need time to "wake up" (days to weeks) ^[2]; (2) Hungry bone syndrome
Hungry bone syndrome	Rapid, profound hypocalcaemia due to sudden drop in PTH → abrupt shift from net bone resorption to net bone formation → calcium, phosphate, and magnesium are rapidly deposited into demineralised bone → serum Ca crashes ^[2]^[5]. Predicted by high pre-op ALP ^[2]. Mx: aggressive IV Ca gluconate + oral calcium + calcitriol
Airway monitoring	Watch for neck haematoma (reactionary haemorrhage) → can cause airway compression. Keep clip removers at bedside
Voice assessment	Assess for hoarseness (RLN injury)

Monitoring	Details
Serum Ca, PTH	Confirm cure (normalised Ca and PTH). Check at 6 months and annually
DEXA	Repeat at 1–2 years to document BMD improvement (expected to improve after curative surgery)
Renal function	Annual Cr/eGFR
Permanent hypoparathyroidism	Defined as requirement for calcium and/or vitamin D supplementation at 1 year post-op ^[2]. Occurs in < 1–3% after focused parathyroidectomy; higher risk after total parathyroidectomy

Term	Definition	Usual Cause	Management
Persistent PHPT	Hypercalcaemia persisting < 6 months post-op	Missed pathology (unidentified second adenoma, ectopic gland, supernumerary gland)	Re-localisation imaging (sestamibi, 4D CT) → bilateral neck exploration
Recurrent PHPT	Hypercalcaemia recurring > 6 months post-op (after initial documented cure)	Missed pathology; parathyromatosis (disseminated parathyroid tissue seeded during initial surgery from capsule rupture — rare but troublesome)	Re-localisation → targeted re-exploration; parathyromatosis is very difficult to cure ^[2]

High Yield Summary — Management of PHPT

Surgery is the only cure. Cure rate ~95–98%.
ALL symptomatic patients → surgery.
Asymptomatic surgical criteria (CASR): Ca ≥ 2.85 (0.25 above ULN), Age < 50, Skeletal (T ≤ −2.5 or vertebral fracture), Renal (CrCl < 60 / urine Ca > 400 mg/d / stones on imaging).
Other absolute indications: parathyroid carcinoma, parathyroid crisis, familial PHPT, persistent/recurrent PHPT.
Contraindications: FHH (surgery won't cure it), contralateral RLN injury, medically unfit.
Focused parathyroidectomy: when single adenoma identified on concordant USG + sestamibi. Small incision, ioPTH monitoring, ↓complications.
ioPTH Miami criteria: PTH drops > 50% of max AND returns to normal at 10 min post-excision. If NOT met → convert to BCE.
MEN1: subtotal (3.5 glands) + cervical thymectomy. High recurrence ( > 50% in 12y).
MEN2A: NOT prophylactic PTHectomy during thyroidectomy (usually mild/asymptomatic).
Medical Mx: Cinacalcet (normalises Ca, not BMD), bisphosphonates (↑BMD), denosumab. For non-surgical candidates.
Surveillance: annual Ca, Cr; DEXA Q1–2y at 3 sites; spine/renal imaging prn. Refer for surgery if criteria develop.
Post-op: watch for hypocalcaemia (transient gland suppression, hungry bone syndrome). Check Ca Day 1. ↑ALP pre-op predicts hungry bone.
Hungry bone syndrome: sudden ↓PTH → bone shifts from resorption to formation → Ca/PO₄/Mg crash. Mx: IV Ca + calcitriol.
Persistent ( < 6 mo) vs recurrent ( > 6 mo) PHPT: usually missed pathology. Parathyromatosis from capsule rupture is rare but devastating.
Permanent hypoparathyroidism: needing Ca/vitamin D at 1 year post-op. < 1–3% after focused PTHectomy.

Active Recall - Management of PHPT

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (pp. 41–43 — Management of severe hypercalcaemia, PHPT surgical indications, conservative Tx) ^[2] Senior notes: maxim.md (Primary hyperparathyroidism — surgical indications CASR, focused PTHectomy, BCE, complications) ^[3] Senior notes: felixlai.md (Hyperparathyroidism — medical Tx, surgical indications, focused PTHectomy, BCE, subtotal/total, thymectomy, pp. 1517–1519) ^[4] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p. 60 — Parathyroid scintigraphy, localisation) ^[5] Senior notes: Adrian Lui Pediatrics.pdf (p. 278 — Hungry bone syndrome definition) ^[7] Senior notes: Ryan Ho Endocrine.pdf (pp. 132–133 — MEN1 and MEN2 surgical management)

Complications of Primary Hyperparathyroidism

Complications in PHPT fall into two broad categories that you must keep mentally distinct:

Complications of the disease itself (i.e. end-organ damage from chronic hypercalcaemia and excessive PTH)
Complications of treatment (i.e. surgical and post-operative complications of parathyroidectomy)

Both are examinable and both are linked by a common thread: calcium homeostasis gone awry — too much calcium before surgery, and often too little calcium immediately after.

A. Complications of the Disease (Untreated / Undertreated PHPT)

These are the downstream consequences of chronic autonomous PTH hypersecretion and the resultant hypercalcaemia, hypercalciuria, and hypophosphataemia. Think of them as the "why we operate" list — each of these is a reason to intervene.

Complication	Mechanism	Clinical Details
Nephrolithiasis (renal stones)	Hypercalcaemia → hypercalciuria (filtered load overwhelms tubular reabsorption) → supersaturation of urine with calcium salts → crystal nucleation → calcium oxalate and calcium phosphate stone formation	Commonest symptomatic presentation of PHPT. Presents as renal colic (flank pain radiating to groin), haematuria. ~15–20% of PHPT patients have stones at diagnosis ^[1]^[3]
Nephrocalcinosis	Long-standing hypercalciuria → diffuse calcium deposition within the renal parenchyma (medullary interstitium) rather than discrete stones	Detected on USG or CT as diffuse medullary calcification. More insidious than stones; associated with progressive renal impairment ^[1]
Chronic kidney disease (CKD)	Multiple mechanisms: (1) nephrocalcinosis → tubulointerstitial damage, (2) recurrent stones → obstructive uropathy, (3) direct tubular toxicity of hypercalcaemia, (4) renal vasoconstriction from hypercalcaemia	eGFR < 60 mL/min is a surgical indication ^[1]^[3]. CKD may not be fully reversible even after parathyroidectomy if chronic damage has occurred
Nephrogenic diabetes insipidus	Hypercalcaemia inhibits adenylyl cyclase in collecting duct → ↓cAMP → ↓aquaporin-2 expression → inability to concentrate urine ^[6]	Presents as polyuria, polydipsia, nocturia. Creates a vicious cycle: polyuria → dehydration → ↓GFR → ↓Ca excretion → worsening hypercalcaemia
Tubular dysfunction	Chronic hypercalcaemia damages proximal tubular cells → impaired reabsorption	May contribute to mild metabolic acidosis and wasting of electrolytes

Complication	Mechanism	Clinical Details
Osteoporosis	Continuously ↑PTH → cortical bone resorption > trabecular bone resorption ^[1] → demineralisation → ↓BMD	More pronounced at cortical sites (distal 1/3 radius, femoral neck, hip) than trabecular sites (lumbar spine). DEXA T-score ≤ −2.5 at any of these sites is a surgical indication ^[1]
Pathological fractures	Demineralised bone → structural weakening → fracture under physiological load	2–3× risk of vertebral, distal forearm, and pelvic fractures ^[1]. May be the presenting feature
Osteitis fibrosa cystica	The classical but now uncommon bone lesion of PHPT. Continuous ↑PTH → intense osteoclastic resorption + fibrous replacement	Includes: brown tumours (osteoclastic aggregations + fibrous tissue + hemosiderin in jaw, long bones, ribs), subperiosteal bone resorption (radial aspect of middle phalanges), bone cysts (MCP, ribs, pelvis), "salt and pepper" skull, tapering of distal clavicles ^[1]
Bone pain	↑ Bone resorption, microfractures, periosteal stretching	Diffuse or localised; may be presenting complaint

Osteitis fibrosa cystica is now uncommon because most PHPT is caught incidentally on biochemical screening before advanced bone disease develops ^[1]. When it does occur, it indicates long-standing, severe disease.

Complication	Mechanism	Clinical Details
Constipation	Hypercalcaemia → ↓GI smooth muscle motility (Ca²⁺ interferes with normal contractile cycling of smooth muscle)	Extremely common; often dismissed as a non-specific symptom
Peptic ulcer disease	↑Serum Ca²⁺ → ↑gastrin secretion by G cells → ↑gastric acid secretion	Epigastric pain, dyspepsia. If the patient has MEN1, also consider Zollinger-Ellison syndrome (gastrinoma → massive acid hypersecretion)
Acute pancreatitis	↑Ca²⁺ in pancreatic duct → premature activation of trypsinogen → autodigestion. Also: Ca²⁺ can obstruct pancreatic ducts via calcification	Uncommon (~1–2% of PHPT), but association is well-described. Severe abdominal pain radiating to back, elevated lipase
Anorexia, nausea, vomiting	Central and peripheral neuronal effects of hypercalcaemia, ↑gastric acid	Non-specific but common

Complication	Mechanism	Clinical Details
Depression, cognitive impairment	Hypercalcaemia affects neurotransmitter release, neuronal excitability, and cerebral blood flow	Common and often subtle; may improve after parathyroidectomy. Underrecognised as a complication of PHPT
Fatigue, lethargy	↑Ca²⁺ stabilises neuronal membranes → ↑threshold for depolarisation → ↓neuronal excitability	Non-specific but very common
Confusion, psychosis, coma	Severe hypercalcaemia ( > 3.5 mmol/L) → global cerebral depression	Medical emergency; part of parathyroid crisis
Proximal muscle weakness	Hypercalcaemia → ↓neuromuscular excitability	Often subtle; tested clinically by asking patient to stand from sitting without arms

Complication	Mechanism	Clinical Details
Hypertension	Multifactorial: ↑vascular smooth muscle tone (Ca²⁺-dependent contraction), RAAS activation, renal effects of hypercalcaemia, possible endothelial dysfunction	Present in ~40% of PHPT patients ^[1]. Hypercalcaemia is a recognised secondary cause of hypertension ^[9]. May not fully resolve after surgery
Left ventricular hypertrophy (LVH)	Secondary to chronic hypertension and possibly direct calcium-mediated myocardial effects	Detected on echocardiography ^[1]
Short QT interval	Hypercalcaemia shortens phase 2 (plateau) of the cardiac action potential → accelerated repolarisation → shortened QT	Earliest and most characteristic ECG finding. In extreme cases → risk of arrhythmia ^[1]
Vascular and valvular calcification	Chronic elevation of Ca × PO₄ product → ectite deposition in vessel walls and cardiac valves	Contributes to cardiovascular morbidity; may include coronary artery calcification ^[1]
Arrhythmias	Short QT substrate + direct myocardial Ca²⁺ effects	Risk increases with severity of hypercalcaemia

Complication	Mechanism	Clinical Details
Pseudogout (CPPD crystal disease)	PHPT is a recognised metabolic cause of CPPD crystal deposition (odds ratio ~3.35× for CPPD). ↑Ca²⁺ + pyrophosphate → calcium pyrophosphate dihydrate crystal formation in cartilage	Acute joint inflammation (pseudogout attacks) or chronic arthropathy. Chondrocalcinosis on X-ray (linear calcification in cartilage, especially knee menisci, TFCC of wrist, pubic symphysis) ^[1]^[8]
Gout	↑Uric acid from ↓renal urate clearance (hypercalcaemia-induced tubular dysfunction)	Less common than pseudogout; can coexist

A life-threatening complication of severe, acute-on-chronic hypercalcaemia (Ca typically > 3.5 mmol/L)
Clinical features: severe dehydration, confusion/coma, oliguria, cardiac arrhythmias, abdominal pain, nausea/vomiting
Vicious cycle: severe hypercalcaemia → polyuria → dehydration → ↓GFR → ↓renal Ca excretion → worsening hypercalcaemia
Triggers: intercurrent illness, dehydration (e.g. vomiting, hot weather), immobilisation, thiazide initiation
Management: emergency IV NS rehydration, calcitonin, bisphosphonate, ± cinacalcet, ± haemodialysis → followed by urgent parathyroidectomy once stabilised ^[1]

B. Complications of Treatment (Post-Parathyroidectomy)

These are the complications that arise from the surgical procedure itself and from the abrupt change in calcium-PTH dynamics after removal of the hyperfunctioning gland. The complications of parathyroidectomy are similar to those of thyroidectomy (the anatomy is shared) plus unique metabolic consequences ^[2]^[11].

This is the complication you will be asked about most often. There are three distinct mechanisms:

Type	Mechanism	Timing	Course
Transient suppression of remaining normal glands	The adenoma was autonomously secreting massive amounts of PTH → remaining 3 normal parathyroid glands have been chronically suppressed (negative feedback from hypercalcaemia) and are effectively "asleep." When the adenoma is removed, PTH drops suddenly, and the dormant glands need days to weeks to "wake up" and resume secretion	Hours to days post-op	Transient — resolves as remaining glands recover. Most common cause after focused parathyroidectomy ^[2]
Hungry bone syndrome	Rapid, profound hypocalcaemia immediately following parathyroidectomy due to sudden loss of stimulation for bone resorption → bone formation >>> bone resorption → calcium, phosphate, and magnesium are rapidly deposited into previously demineralised bone ^[2]^[5]	Hours to days post-op (can persist for days to weeks)	Can be prolonged and severe. Predicted by elevated pre-operative ALP (high ALP = high bone turnover = more "hungry" bone waiting to absorb calcium) ^[2]
Permanent hypoparathyroidism	Inadvertent removal of or damage to all remaining parathyroid tissue, or devascularisation (compromise of inferior thyroid artery during surgery)	Persists	Defined as requiring calcium and/or vitamin D supplementation at 1 year post-op ^[2]. Risk: < 1–3% after focused parathyroidectomy; higher after total parathyroidectomy or extensive bilateral exploration

Clinical features of post-op hypocalcaemia (mnemonic: CATS GO NUMB) ^[11]:

Convulsions
Arrhythmias (long QT → torsades de pointes)
Tetany
Spasms (laryngospasm — can be fatal if airway compromised)
GO
NUMBNESS (perioral and acral paraesthesia — earliest symptom)
Unusual muscle cramps
Muscle spasms
Bronchospasm (rare)

Clinical signs:

Trousseau's sign: inflate BP cuff above systolic for 3 minutes → carpopedal spasm (flexion of wrist and MCP joints, extension of IP joints, adduction of thumb). This is the more sensitive sign
Chvostek's sign: tapping the facial nerve anterior to the ear → twitching of ipsilateral facial muscles. Less specific (present in ~10% of normal population)

ECG: Prolonged QT interval (↓Ca²⁺ lengthens phase 2 of cardiac action potential — opposite of hypercalcaemia which shortens QT)

Management of post-op hypocalcaemia ^[2]^[5]^[11]:

Severity	Treatment
Severe or symptomatic (tetany, laryngospasm, seizures, cardiac arrhythmias)	IV 10% calcium gluconate 10–20 mL over 10 min (slow bolus), then continuous infusion if needed. ECG and cardiac monitoring. Close monitoring of serum Ca (Q6–8h) ^[5]^[11]
Mild or asymptomatic	Oral calcium carbonate (e.g. 1–2 g TDS) + calcitriol (1,25-(OH)₂-D₃, the active form of vitamin D) ^[2]^[11]
Hungry bone syndrome	Aggressive IV calcium ± oral calcium + calcitriol. May require large doses and prolonged supplementation (weeks). Also replete magnesium and phosphate as needed ^[2]^[5]

Why calcium gluconate and not calcium chloride? Calcium chloride contains more elemental Ca per mL (27 mg/mL vs 9 mg/mL) but has much higher osmolality (2000 mOsm/L vs 680 mOsm/L) → causes severe venous irritation and tissue necrosis if extravasated ^[5]. Therefore calcium gluconate is preferred for peripheral IV infusion. Calcium chloride is reserved for central line administration in emergencies.

Hungry Bone Syndrome — Why ALP Predicts It

The logic is elegant: in chronic PHPT, persistently elevated PTH drives ↑↑osteoclast activity and reactive ↑↑osteoblast activity (trying to keep up). This reactive osteoblast activity produces elevated ALP (ALP is an osteoblast enzyme). When the adenoma is removed, PTH plummets, and osteoclasts suddenly stop resorbing bone. But the osteoblasts are still revved up and continue forming bone at a high rate → they pull calcium, phosphate, and magnesium out of the blood and deposit it into the demineralised skeleton. The higher the pre-op ALP, the more osteoblast activity is primed, and the more dramatic the post-op calcium crash. This is why ALP level predicts risk of hungry bone syndrome ^[2].

Key biochemical features of hungry bone syndrome (vs hypoparathyroidism):

Both: ↓Ca, ↓Mg
Hungry bone: ↓PO₄ (phosphate is also deposited into bone)
Hypoparathyroidism: ↑PO₄ (loss of PTH's phosphaturic effect → phosphate retention)

This PO₄ difference helps distinguish the two in the post-op period.

Feature	Detail
Anatomy	The RLN (a branch of the vagus) runs in the tracheoesophageal groove, close to the inferior thyroid artery and posterior to the thyroid/parathyroid glands. It supplies all intrinsic laryngeal muscles except the cricothyroid
Risk	< 1% for focused parathyroidectomy, higher for bilateral exploration and re-operative surgery ^[1]
Unilateral RLN injury	Unilateral vocal cord paralysis → hoarseness, breathy voice, ineffective cough, ↑risk of aspiration pneumonia ^[11]
Bilateral RLN injury	Bilateral vocal cord paralysis → stridor, dyspnoea, AIRWAY OBSTRUCTION. This is life-threatening and may require immediate re-intubation ± tracheostomy ^[11]
Why it matters for surgical planning	Known contralateral RLN injury is a contraindication to parathyroidectomy — bilateral RLN injury can be fatal ^[3]
Management	Transient (tractional neuropraxia): observation, usually recovers in weeks to months. Permanent (transection/severe thermal injury): unilateral → medialization thyroplasty (inject fat/silicone into paralysed cord); bilateral → tracheostomy ± later cord lateralisation

Feature	Detail
Incidence	~1.25%, uncommon but potentially fatal ^[11]
Significance	Bleeding usually occurs in the paratracheal region below the strap muscles → venous obstruction → acute laryngeal oedema → airway compromise ^[11]
Presentation	Large, tense, firm, immobile neck swelling + progressive SOB + stridor
Management	Emergency: cut subcuticular stitches and stitches holding strap muscles to evacuate haematoma at the bedside → call seniors for intubation → return to theatre for surgical haemostasis ^[11]. Keep clip/stitch removers at the bedside of all post-neck-surgery patients

Bedside Emergency — Post-Thyroidectomy/Parathyroidectomy Neck Haematoma

This is a surgical emergency that every medical student and junior doctor must know. If a patient post-neck surgery develops a rapidly expanding, tense neck swelling with respiratory distress:

Do NOT wait — open the wound at the bedside by cutting all stitches (skin and deep)
Evacuate the haematoma
Call for senior help for definitive airway management
Return to theatre for haemostasis

A few minutes' delay can result in death from airway obstruction. This is why stitch removers are kept at the bedside.

Term	Definition	Causes	Management
Persistent PHPT	Hypercalcaemia persisting < 6 months post-op	Missed pathology: unidentified second adenoma, ectopic gland (mediastinal, intrathymic), supernumerary gland	Re-localisation imaging (sestamibi, 4D CT, choline PET/CT) → bilateral neck exploration ^[2]
Recurrent PHPT	Hypercalcaemia recurring > 6 months post-op (after initial documented cure)	Missed pathology (as above), parathyromatosis	Re-localisation → targeted re-exploration. Parathyromatosis is difficult to cure ^[2]

Parathyromatosis deserves special mention ^[2]:

Definition: Disseminated parathyroid tissue within the soft tissue of the neck and mediastinum
Cause: Rupture of a parathyroid gland during initial operation → seeding of viable parathyroid cells into surrounding tissues → multiple foci of autonomous PTH-secreting tissue
Significance: Very difficult to identify and excise completely; a recognised cause of refractory recurrent hyperparathyroidism
Prevention: Gentle handling of parathyroid glands during surgery; avoid rupturing the capsule

Complication	Details
Superior laryngeal nerve (SLN) injury	The external branch of the SLN supplies the cricothyroid muscle (which tenses the vocal cord for high-pitched sounds). Injury → vocal fatigue, inability to sing high notes, weak/monotonous voice. Important to ask if the patient is a professional singer pre-op ^[11]
Wound infection	Standard surgical site infection; uncommon in clean neck surgery
Seroma	Superficial, mobile fluid collection; usually self-limiting
Scar complications	Hypertrophic scar, keloid formation (more common in certain populations)
Oesophageal or tracheal injury	Very rare; intraoperative complication from inadvertent dissection

Category	Complications
Disease — Renal	Nephrolithiasis, nephrocalcinosis, CKD, nephrogenic DI, tubular dysfunction
Disease — Skeletal	Osteoporosis, pathological fractures, osteitis fibrosa cystica (brown tumours, subperiosteal resorption, bone cysts, salt-and-pepper skull)
Disease — GI	Constipation, PUD, pancreatitis, anorexia/nausea
Disease — Neuropsych	Depression, cognitive impairment, fatigue, confusion, coma
Disease — CVS	Hypertension, LVH, short QT, arrhythmias, vascular calcification
Disease — MSK	Pseudogout (CPPD), chondrocalcinosis, gout
Disease — Acute	Hypercalcaemic crisis (parathyroid crisis)
Surgery — Metabolic	Hypocalcaemia (transient gland suppression, hungry bone syndrome, permanent hypoparathyroidism)
Surgery — Nerve	RLN injury (unilateral → hoarseness; bilateral → airway obstruction), SLN injury (weak voice)
Surgery — Bleeding	Reactionary haemorrhage / neck haematoma (potentially fatal)
Surgery — Persistent/Recurrent	Persistent ( < 6 mo) or recurrent ( > 6 mo) PHPT; parathyromatosis
Surgery — Other	Wound infection, seroma, scar complications

High Yield Summary — Complications of PHPT

Disease complications = "Stones, Bones, Moans, Thrones, Psychic Overtones" — these are also the reasons to operate
Most common symptomatic presentation: renal stones (~15–20% at diagnosis)
Osteoporosis: cortical > trabecular bone loss; distal 1/3 radius affected most. T ≤ −2.5 = surgical indication
Osteitis fibrosa cystica: now uncommon (early detection); includes brown tumours, subperiosteal resorption, "salt and pepper" skull
Hypertension: present in ~40%; hypercalcaemia is a secondary cause of HTN; may not fully resolve post-op
Pseudogout (CPPD): PHPT is a recognised metabolic cause (OR ~3.35×)
Hypercalcaemic crisis: Ca > 3.5, vicious cycle of dehydration → ↓GFR → worsening hyperCa; medical emergency
Post-op hypocalcaemia: MOST COMMON post-op complication. Three mechanisms: transient gland suppression, hungry bone syndrome, permanent hypoparathyroidism
Hungry bone syndrome: ↓Ca, ↓PO₄, ↓Mg; predicted by high pre-op ALP; Mx: aggressive IV Ca + calcitriol
Distinguish hungry bone from hypoparathyroidism by PO₄: hungry bone = ↓PO₄; hypoparathyroidism = ↑PO₄
Permanent hypoparathyroidism: requiring Ca/vitamin D at 1 year post-op. Risk < 1–3% after focused PTHectomy
RLN injury: < 1% for focused PTHectomy. Unilateral = hoarseness; bilateral = airway obstruction (life-threatening)
Neck haematoma: rare but fatal → open wound at bedside, evacuate, intubate, return to theatre
Persistent PHPT ( < 6 mo): missed pathology. Recurrent ( > 6 mo): missed pathology or parathyromatosis
Parathyromatosis: seeded parathyroid cells from capsular rupture during surgery → refractory recurrent disease
CATS GO NUMB: mnemonic for hypocalcaemia symptoms (Convulsions, Arrhythmias, Tetany, Spasm, Numbness)

Active Recall - Complications of PHPT

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (pp. 41–43 — PHPT complications, bone disease, CVS) ^[2] Senior notes: maxim.md (Primary hyperparathyroidism — specific complications, persistent/recurrent, parathyromatosis) ^[3] Senior notes: felixlai.md (Hyperparathyroidism — complications, bone involvement, surgical Ix, pp. 1518–1522) ^[5] Senior notes: Adrian Lui Pediatrics.pdf (p. 278 — Hungry bone syndrome definition, Ca gluconate vs chloride) ^[6] Senior notes: Ryan Ho Fundamentals.pdf (p. 430 — Hypercalcaemia S/S, nephrogenic DI mechanism) ^[8] Senior notes: Ryan Ho Rheumatology.pdf (p. 41 — CPPD and hyperPTH association) ^[9] Senior notes: Ryan Ho Cardiology.pdf (p. 177 — Hypercalcaemia as secondary cause of HTN) ^[11] Senior notes: Ryan Ho Endocrine.pdf (p. 22 — Thyroidectomy/parathyroidectomy complications, RLN injury, haematoma, hypoCa)

Primary Hyperparathyroidism (adenoma, Hyperplasia, Carcinoma)

References

Primary Hyperparathyroidism (PHPT)

4. Anatomy and Physiology of the Parathyroid Glands

5. Etiology

5.2 Sporadic vs Familial PHPT

6. Pathophysiology of PHPT

6.2 Downstream Pathophysiology (Organ-by-Organ)

7. Classification

8. Clinical Features

Active Recall - Primary Hyperparathyroidism (Definition to Clinical Features)

Differential Diagnosis of Primary Hyperparathyroidism

Step 3: Detailed Differential Diagnosis

Active Recall - Differential Diagnosis of PHPT

References

Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities

1. Diagnostic Criteria for Primary Hyperparathyroidism

3. Investigation Modalities — Systematic Approach

3.4 Localisation Studies — For Surgical Planning Only

Active Recall - Diagnosis and Investigation of PHPT

References

Management of Primary Hyperparathyroidism

3. Surgical Management — The Definitive Cure

3.1 Indications for Surgery

3.4 Surgical Options

4. Conservative / Medical Management

5. Post-Operative Management and Monitoring

Active Recall - Management of PHPT

References

Complications of Primary Hyperparathyroidism

A. Complications of the Disease (Untreated / Undertreated PHPT)

B. Complications of Treatment (Post-Parathyroidectomy)

Active Recall - Complications of PHPT

References

On this page

Primary Hyperparathyroidism (adenoma, Hyperplasia, Carcinoma)

1. Definition

2. Epidemiology

3. Risk Factors

4. Anatomy and Physiology of the Parathyroid Glands

4.1 Anatomy

4.2 Parathyroid Hormone (PTH) — Physiology

4.3 Calcium Homeostasis Overview [5]

5. Etiology

5.1 Causes of PHPT [1][2][6]

5.2 Sporadic vs Familial PHPT

Sporadic PHPT (~90–95%)

Familial PHPT (~5–10%) [1][3][7]

5.3 Parathyroid Carcinoma — Special Mention

6. Pathophysiology of PHPT

6.1 Molecular Pathogenesis

6.2 Downstream Pathophysiology (Organ-by-Organ)

A. Bones

B. Kidneys (Stones)

C. GI tract (Moans)

D. Neuromuscular / Psychiatric (Psychic Overtones)

E. Cardiovascular

F. Other

7. Classification

7.1 By Pathological Subtype

7.2 By Clinical Presentation

7.3 By Genetic Context

8. Clinical Features

8.1 Symptoms (with Pathophysiological Basis)

8.2 Signs (with Pathophysiological Basis)

8.3 Biochemical Profile of PHPT

9. Approach to Suspected PHPT — Logical Clinical Framework

10. Summary of Pathology-Specific Features

Active Recall - Primary Hyperparathyroidism (Definition to Clinical Features)

References

Step 1: The PTH Pivot — PTH-Dependent vs PTH-Independent Hypercalcaemia

Step 2: Differential Diagnosis Algorithm

Step 3: Detailed Differential Diagnosis

A. PTH-Dependent Causes (↑ or inappropriately normal PTH) [6][9]

B. PTH-Independent Causes (↓ PTH — appropriately suppressed) [6][9][10]

Step 4: Differentiating Subtypes Within PHPT

Step 5: Differentiating Primary vs Secondary vs Tertiary Hyperparathyroidism

Step 6: Don't Forget Factitious Hypercalcaemia

Summary: A Logical Approach to the Differential

Active Recall - Differential Diagnosis of PHPT

1. Diagnostic Criteria for Primary Hyperparathyroidism

1.1 Core Biochemical Diagnosis [1][2][6]

1.2 Additional Required Exclusions

2. Complete Diagnostic Algorithm

3. Investigation Modalities — Systematic Approach

3.1 Investigations to Confirm the Diagnosis

3.2 Investigations to Screen for Complications

3.3 Investigations to Screen for Genetic/MEN Syndromes

3.4 Localisation Studies — For Surgical Planning Only

A. Non-Invasive Localisation

B. Invasive Localisation — Reserved for Re-operative or Challenging Cases

3.5 Intraoperative Investigations

3.6 Radiological Findings of Hyperparathyroid Bone Disease

4. Standard Investigation Set — Putting It All Together

Active Recall - Diagnosis and Investigation of PHPT

1. Overall Management Algorithm

2. Emergency Management of Severe Hypercalcaemia / Parathyroid Crisis

3. Surgical Management — The Definitive Cure

3.1 Indications for Surgery

A. ALL symptomatic patients [2][3]

B. Asymptomatic patients meeting specific criteria [1][2][3]

C. Other absolute surgical indications [3]

3.2 Contraindications to Surgery [3]

3.3 Pre-operative Preparation

3.4 Surgical Options

A. Focused Parathyroidectomy (Minimally Invasive Parathyroidectomy — MIP) [2][3]

B. Bilateral Neck Exploration (BCE) [2][3]

C. Cervical Thymectomy [2][3][7]

D. En Bloc Resection — For Parathyroid Carcinoma

3.5 MEN-Specific Surgical Considerations [7]

4. Conservative / Medical Management

4.1 Indications for Conservative Management

4.2 General Measures

4.3 Pharmacological Options [1][2]

4.4 Active Surveillance Protocol for Non-Surgical Patients [1]