Calcium is critical for neuromuscular excitability, cardiac conduction, coagulation, bone mineralisation, and intracellular signalling. The body maintains serum calcium within a very narrow range (~2.1–2.55 mmol/L) because even small deviations cause life-threatening symptoms — arrhythmias, seizures, tetany, confusion. ^[1]

High-Yield — PTH Physiological Effects (directly from lecture slides):

• Increase calcium release from bone indirectly: PTH binds receptors on osteoblast-lineage cells, increases RANKL signalling, and thereby recruits/activates osteoclasts
• Increase reabsorption of calcium from distal convoluted tubules
• Increase uptake of calcium from intestine via its effect on the formation of 1,25(OH)₂D₃
• Decrease phosphate reabsorption from proximal convoluted tubules ^[1]

The homeostatic diagram is a negative-feedback loop: falling ionised extracellular calcium stimulates PTH; PTH increases renal calcium retention, phosphate excretion, calcitriol formation, and bone calcium release; calcitriol increases gut calcium absorption; the restored calcium then suppresses PTH. A “normal” PTH during hypercalcaemia is therefore not normal physiology—it is inappropriately non-suppressed.

Do not confuse vitamin D tests: 25-hydroxyvitamin D [25(OH)D, calcidiol] is the main circulating store and the routine test of vitamin D status. 1,25-dihydroxyvitamin D [1,25(OH)₂D, calcitriol] is the active hormone and is measured selectively, for example when lymphoma or granulomatous calcitriol production is suspected.

Why PTH lowers phosphate: PTH inhibits the NaPi-IIa cotransporter in the proximal tubule → phosphaturia. This is crucial because if both Ca and PO₄ rise simultaneously, calcium-phosphate product increases → metastatic soft-tissue calcification. Nature designed PTH to raise Ca without raising PO₄.

High-Yield — Vitamin D Physiological Effects:

• Increase calcium uptake in intestine by increasing calcium-binding protein (calbindin)
• Increase intestinal absorption of phosphate
• Increase calcium resorption from bone (if in high doses) ^[1]

High-Yield — Calcitonin Physiological Effects:

• Decrease osteoclast-mediated bone resorption
• Decrease reabsorption of calcium from kidney ^[1]

High-Yield — Calcium Homeostasis: Other Factors (from lecture):

• Albumin: 50% of plasma calcium is protein-bound (mostly albumin). Low albumin → low total Ca, but ionised Ca is normal = pseudohypocalcaemia
• Phosphate: Affects ionic balance of calcium
• pH: Alkalosis increases protein binding of Ca²⁺ → lower ionised Ca → symptoms of hypocalcaemia even with normal total Ca. Acidosis does the opposite. ^[1]

Why pH matters clinically: A hyperventilating anxious patient develops respiratory alkalosis → increased Ca-albumin binding → reduced ionised Ca → perioral tingling and carpopedal spasm. This is not true hypocalcaemia — total Ca is normal.

The fractions shown by the physiology slides are approximate: about 45–50% ionised (biologically active), 40–45% protein-bound, and roughly 10% complexed to anions such as phosphate or citrate. These proportions vary with albumin, pH, and illness.

High-Yield — Classification of Hypercalcaemia (from lecture):

Severity	Serum Ca (corrected)	Clinical State
Mild	< 3.0 mmol/L	Asymptomatic or mildly symptomatic
Moderate	3.0–3.5 mmol/L	Symptomatic, needs active management
Severe	> 3.5 mmol/L	Medical emergency
[1]

These bands are a triage aid, not stand-alone treatment rules. Symptoms, rate of rise, ECG changes, renal function, and volume status determine urgency; a rapidly rising calcium with confusion or arrhythmia needs emergency management even before a numerical threshold is crossed.

High-Yield — Slide-Based Differential:

Why TB/sarcoidosis cause hypercalcaemia: Activated macrophages in granulomas express 1α-hydroxylase independently of PTH → unregulated production of 1,25-(OH)₂D₃ → increased intestinal Ca absorption and bone resorption. This is why glucocorticoids are the specific treatment — they suppress macrophage calcitriol production.

Adrenal Insufficiency and Hypercalcaemia (from lecture): Proposed mechanisms (the evidence is incomplete):

1. Hypovolaemia → ↓ GFR → ↓ calcium filtered → ↑ renal calcium reabsorption
2. ↑ 1α-hydroxylase activity → ↑ intestinal calcium absorption ^[1]

High-Yield Mnemonic from Lecture: "Bones, Stones, Abdominal Groans & Psychiatric Overtones" ^[1]

The key discriminator is PTH level — this divides hypercalcaemia into PTH-mediated and PTH-independent causes.

Slide-based diagnostic sequence:

1. Confirm hypercalcaemia with total and ionised calcium. If the result is normal, consider haemoconcentration or a serum protein abnormality.
2. Perform clinical evaluation and measure electrolytes, BUN, creatinine, phosphate, and ALP.
3. Measure serum PTH—the pivotal branching test:
   • Normal or high: PTH-dependent hypercalcaemia; proceed with the PTH-dependent work-up.
   • Low: PTH-independent hypercalcaemia.
4. Investigate the suppressed-PTH branch selectively, guided by history and examination: PTHrP when humoral malignancy is plausible; 25(OH)D for intoxication; 1,25(OH)₂D for lymphoma/granulomatous disease; serum/urine electrophoresis plus free light chains for myeloma; and TSH, cortisol, or imaging when clinically indicated. The lecture's broad occult-malignancy panel is a historical framework, not a mandate to scan every patient. ^[1]

High-Yield — Common Clinical Scenarios Table (from lecture slide 70): ^[1]

From lecture:

• Avoid factors that could aggravate hypercalcaemia
• Maintain adequate hydration
• The slide advises avoiding a high-calcium diet; current PHPT guidance instead recommends normal age-appropriate calcium intake, not aggressive restriction ^[13]

Also review thiazides, lithium, non-essential calcium/vitamin D excess, and immobilisation; maintain hydration and treat the cause. In confirmed PHPT, keep calcium intake consistent with nutritional guidance and replete vitamin D cautiously rather than reflexively stopping all calcium and vitamin D. ^[13]

High-Yield — Principles (from lecture):

1. Rapid control of calcium levels esp. for moderate and severe hypercalcaemia
2. Early diagnosis of the cause ^[1]

Step-by-Step Management Algorithm

For hypercalcaemia of malignancy, the current Endocrine Society guideline recommends an IV bisphosphonate or denosumab and suggests denosumab over an IV bisphosphonate. In severe disease (calcium above 3.5 mmol/L), add calcitonin initially, but stop it after 48–72 hours. Calcitriol-mediated malignancy is treated first with a glucocorticoid; add an antiresorptive if severe or symptomatic hypercalcaemia persists. ^[14]

Glucocorticoids are cause-specific, not routine acute therapy. In suspected infection-associated granulomatous disease such as tuberculosis, investigate and treat the infection appropriately rather than giving empiric steroids without a diagnostic plan.

High-Yield (from lecture):

• Most common cause of hypercalcaemia
• Prevalence ~1–2/1000
• Peak incidence: 6th–7th decade
• F:M ~2–3:1
• Causes:
  • Solitary parathyroid adenoma (~85%)
  • Hyperplasia (~10–15%)
  • Double adenomas (1–2%)
  • Parathyroid carcinoma (~1%) ^[1]

Why a single adenoma is the most common: This is usually a sporadic somatic mutation in one gland. Hyperplasia (all four glands) should prompt investigation for MEN syndromes (MEN1 or MEN2A).

From lecture (most common modern presentation):

• Incidental finding of mild hypercalcaemia — this is how most patients present today ^[1]

The lecture's historical comparison makes the shift visible: older series (1930–1970) reported nephrolithiasis in roughly 51–57% and overt skeletal disease in 10–23%, whereas later series (1970–2000) reported more asymptomatic disease (22–80%) and less nephrolithiasis (17–37%) or overt skeletal disease (1.4–14%). Treat these broad ranges as historical, cohort-dependent data—the durable teaching point is the move from symptomatic end-organ disease to biochemical detection.

For symptomatic patients: weakness, tiredness, anorexia, nausea, vomiting, constipation, thirst, polyuria, dry mouth, confusion, drowsiness, renal stones, nephrocalcinosis, hypertension, renal failure, osteoporosis, bone pain, fractures, epigastric pain, joint pain (chondrocalcinosis), and rarely multiple endocrine neoplasia. ^[1]

From lecture:

• Continuously high PTH (e.g. PHPTH) → Bone resorption (cortical bone worse than trabecular bone)
• Intermittent low dose PTH (e.g. Teriparatide) → Anabolic action with increase in BMD ^[1]

Why this matters: This is why teriparatide (recombinant PTH 1-34) is used to TREAT osteoporosis — pulsatile PTH stimulates osteoblasts preferentially. But the constant elevation in PHPTH drives net resorption. Cortical bone (e.g. distal radius) is preferentially affected over trabecular bone (e.g. lumbar spine).

From lecture:

• Osteitis fibrosa cystica — rarely seen now
• Subperiosteal resorption — most evident on phalanges (radial side of middle phalanges)
• Bone cysts — central medullary portions of MCP shafts, ribs, pelvis
• Brown tumours (osteoclastomas) — multinucleated osteoclasts in jaw, long bones, ribs
• Skull "salt and pepper" appearance
• Pathological fractures
• Low BMD especially in cortical bone (e.g. distal 1/3 forearm) — more common presentation now ^[1]

How to read the hand radiograph: look for irregular subperiosteal cortical resorption along the radial sides of the middle phalanges, tuft/resorptive change, and expansile lucent “brown tumour” lesions. Brown tumours are reparative giant-cell lesions of severe hyperparathyroidism—not neoplasms—and can mimic primary bone tumours or metastases. The skull counterpart is diffuse granular demineralisation, the “salt-and-pepper” skull.

From lecture (JCEM 2018 guidelines):

Biochemistry panel:

• Ca, PO₄, ALP
• Urea, Creatinine, eGFR
• 25-OH Vitamin D (disease more active when insufficient < 20 ng/mL or deficient < 10 ng/mL)
• PTH (2nd or 3rd generation immunoassay)

Bone assessment:

• DXA for BMD at lumbar spine, hip, AND distal one-third radius (cortical site preferentially affected)
  • T-score ≤ −2.5 for postmenopausal women and men ≥ 50
  • For premenopausal women and men younger than 50, report Z-scores; a Z-score of −2.0 or lower is “below the expected range for age.” Do not diagnose osteoporosis in a man younger than 50 from BMD alone. ^[20]
• Vertebral spine assessment (X-ray or VFA by DXA)

Renal assessment:

• 24-hour urine for calcium and creatinine → calculate the calcium–creatinine clearance ratio (CCCR) when FHH is a concern. A CCCR below 0.01 favours FHH and 0.02 or above favours PHPT, but there is substantial overlap; interpret with family history, renal function, vitamin D status, thiazide use, and genetic testing where appropriate. ^[13]
• Abdominal imaging (KUB, USG, CT) for urinary stones ^[1]

Key surgical indications (from lecture/JBMR 2022):

• Serum calcium > 0.25 mmol/L (1 mg/dL) above upper limit of normal
• T-score ≤ −2.5 at lumbar spine, total hip, femoral neck, or distal one-third radius; or vertebral fracture
• eGFR < 60 mL/min/1.73m²
• Nephrolithiasis or nephrocalcinosis
• 24-hour urine calcium above 6.25 mmol/day (250 mg/day) in women or 7.5 mmol/day (300 mg/day) in men (2022 sex-specific thresholds) ^[1][13]
• Age < 50 years ^[1]

Meeting any one criterion is sufficient to advise surgery, and symptomatic PHPT (stones, fracture, marked hypercalcaemia) is a clear indication. The older 400 mg/day-plus-stone-risk rule shown in earlier guidance has been replaced by the sex-specific 2022 thresholds above. ^[13]

Key lecture point: Localisation is to GUIDE the surgeon, NOT a diagnostic procedure. Negative or discordant imaging should NOT inhibit referral to an experienced parathyroid surgeon. ^[1]

The sestamibi images illustrate the recognition rule: thyroid activity washes out on delayed imaging while a persistent focal hotspot inferior/posterior to a thyroid lobe suggests hyperfunctioning parathyroid tissue. This localises a gland for operative planning; it does not establish the biochemical diagnosis. Most people have four glands on the posterior thyroid, but ectopic retro-oesophageal or mediastinal glands explain why ultrasound can be negative.

Minimally invasive parathyroidectomy (from lecture):

• Image-guided, focused operation
• Under local/regional anaesthesia, small incisions
• Curative results > 98%, nerve injury < 1%
• Prerequisites: preoperative localisation + intraoperative PTH assay

Intraoperative PTH Assay Monitoring (from lecture):

• PTH half-life: 3.5–4 minutes (normal renal function)
• Drop in PTH: 5–10 minutes
• Drop in Ca: 24–48 hours
• Miami Criterion: Fall of 50% in PTH compared to the highest of either pre-manipulation or pre-excision sample ^[1]

For multi-gland disease (e.g. MEN1):

• Subtotal parathyroidectomy: resection of 3½ glands; preserve 50–80 mg vascularised gland
• Total parathyroidectomy with immediate autotransplantation to forearm + cryopreservation for possible delayed autotransplantation ^[1][5]

Post-operative complications (from surgery notes):

• RLN injury
• Reactionary haemorrhage
• Hungry bone syndrome: rapid, profound hypocalcaemia due to sudden PTH drop → rapid Ca deposition into demineralised bone → treat with Ca + Vit D ^[5]
• Transient or permanent hypoparathyroidism

Cinacalcet (Calcimimetic) — from lecture:

• Allosteric activator of calcium-sensing receptor (CaSR) → makes parathyroid think Ca is higher → reduces PTH secretion
• Indications: Patients where parathyroidectomy is indicated but surgery is NOT clinically appropriate or is contraindicated
• Effective at lowering/normalising serum calcium
• Effects on PTH less pronounced
• No consistent effects on BMD ^[1]

Monitoring when surgery is not performed (from the lecture):

• Serum calcium and 25(OH)D annually; PTH as clinically indicated.
• Renal function annually; the Fifth Workshop prefers creatinine clearance, although eGFR is commonly reported.
• Skeletal assessment at 1–2-year intervals, including DXA at three sites; obtain spinal X-ray or vertebral fracture assessment if clinically indicated, such as with height loss or back pain.
• Renal imaging and 24-hour urine calcium if clinically indicated, for example when stones are suspected. ^[1][13]

For osteoporosis in PHPTH: bisphosphonates or denosumab can be used if surgery not pursued.

From lecture:

• Secondary hyperparathyroidism: Physiological PTH response to chronic hypocalcaemia (e.g. CKD, Vit D deficiency)
• Tertiary hyperparathyroidism: Prolonged secondary HPT → parathyroid hyperplasia → autonomous PTH secretion → hypercalcaemia (even after the initial stimulus is removed, e.g. post-renal transplant) ^[1]

From lecture: F/52, history of total thyroidectomy a few weeks ago, bilateral hand and perioral numbness, normal kidney function, low serum calcium, high phosphate, PTH at low normal range → Post-surgical hypoparathyroidism ^[1]

Here, a “low-normal” PTH is again inappropriate: true hypocalcaemia should strongly stimulate PTH. The photographed serial panel confirms genuine hypocalcaemia (total calcium down to 1.69 mmol/L, adjusted calcium 1.57 mmol/L) with phosphate about 1.59–1.60 mmol/L. The combination of low calcium, high phosphate, and non-elevated PTH after neck surgery localises the defect to the parathyroids. The displayed 24-hour urinary calcium of 9.6 mmol/day also reminds you to monitor for treatment-related hypercalciuria in hypoparathyroidism.

At only a few weeks after surgery this may still be transient postoperative hypoparathyroidism. Current international guidance defines chronic postsurgical hypoparathyroidism as persisting for more than 12 months. ^[19]

From lecture: Symptoms typically develop when adjusted serum calcium falls below 1.9 mmol/L, although this threshold varies. Also depends on the rate of fall of serum calcium. ^[1]

A rapid fall (e.g. post-thyroidectomy) produces symptoms at higher levels than a chronic, slow decline (e.g. CKD).

Complete list from lecture:

Most important: To confirm genuine hypocalcaemia! Look at serum albumin levels; measured ionised calcium ^[1]

From lecture:

• Perioral and digital paraesthesiae
• Neuromuscular irritability:
  • Trousseau's sign: Inflate BP cuff above systolic for 3 minutes → carpopedal spasm (more specific)
  • Chvostek's sign: Tap facial nerve anterior to ear → ipsilateral facial muscle twitching (less specific — positive in 10% normal people)
• Tetany and carpopedal spasm
• Convulsions
• Laryngeal spasm (life-threatening)
• ECG: Prolonged QT interval ^[1]

Why these signs occur: Low ionised Ca²⁺ increases neuronal membrane excitability by lowering the threshold for action potential firing. Voltage-gated Na⁺ channels open more easily → spontaneous depolarisation of motor neurons → muscle spasm.

High-Yield — Treatment Algorithm from Lecture:

Severe or Symptomatic (Adjusted Ca below 1.9 mmol/L, or symptomatic at any level below range):

• ECG and cardiac monitoring
• IV calcium gluconate by infusion
  • Current Society for Endocrinology emergency guidance: 10–20 mL of 10% calcium gluconate in 50–100 mL 5% dextrose over 10 minutes with ECG monitoring, repeat until symptoms settle, then
  • 100 mL of 10% calcium gluconate in 1 L normal saline or 5% dextrose at 50–100 mL/hour, titrated to calcium and symptoms. Follow the local hospital protocol and check the actual preparation concentration. ^[15]
• Monitor calcium frequently and correct the cause, especially magnesium deficiency; start active vitamin D early when hypoparathyroidism is the cause. ^[15]

Mild (Adjusted Ca above 1.9 mmol/L and asymptomatic):

• Oral calcium replacement:
  • Caltrate = 600 mg elemental Ca per tab
  • Oscal = 250 mg elemental Ca per tab
  • Calcium gluconate = 27 mg elemental Ca per tab
• The slide's instruction to wait for failure of 2–4 g elemental calcium before adding vitamin D should not be applied to hypoparathyroidism: use active vitamin D (calcitriol or alfacalcidol) with oral calcium because PTH-dependent renal activation is impaired. ^[15][19]

"Most important: Look out for Causes and Treat Accordingly" ^[1]

From the GC Interactive Tutorial (Endo-Hypoparathyroidism): A 49-year-old woman with paraesthesia and painful muscle cramps 2 weeks after thyroidectomy. ^[8]

Why this happens: During thyroidectomy, the parathyroid glands (located behind the thyroid lobes) may be inadvertently removed, devascularised, or bruised. This leads to transient or permanent hypoparathyroidism → ↓ PTH → ↓ Ca, ↑ PO₄.

Management approach:

1. Confirm genuine hypocalcaemia (corrected Ca or ionised Ca)
2. Check PTH — if low → hypoparathyroidism confirmed
3. Check Mg²⁺ — correct if low
4. Treat as per severity algorithm above
5. Long-term: oral calcium + active vitamin D (calcitriol/alfacalcidol) — because renal conversion of 25(OH)D to 1,25(OH)₂D₃ is impaired without PTH stimulation

For chronic hypoparathyroidism, aim for symptom control with serum calcium in the lower half of the normal range or just below it, while avoiding hypercalciuria; monitor renal function, magnesium, phosphate, 25(OH)D, and 24-hour urine calcium. Conventional first-line treatment is calcium plus an active vitamin D metabolite. ^[19]