13.5 Calcium Regulation & Hypercalcaemia

Extracellular calcium is vital for neuromuscular transmission, myocardial excitation-contraction coupling, blood coagulation, and skeletal mineralization. The parathyroid glands, kidneys, skeleton, and gastrointestinal tract interact via parathyroid hormone (PTH), calcitriol, and fibroblast growth factor 23 (FGF23) to maintain ionized calcium within a narrow physiological window. Mastery of calcium emergencies and metabolic bone disorders is central to MRCP(UK) Part 1.

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1. Calcium Regulation & Corrected Calcium

Fractional Calcium & The Albumin Correction Formula

Circulating total serum calcium comprises three distinct physicochemical fractions:

1. Ionized Calcium ($\sim 45\text{–}50%$): The biologically active, strictly regulated fraction.
2. Protein-Bound Calcium ($\sim 40\text{–}45%$): Bound predominantly to albumin ($\sim 80%$) and globulins ($\sim 20%$).
3. Complexed Calcium ($\sim 10%$): Chelation complexes with citrate, phosphate, and bicarbonate.

Because total calcium fluctuates with alterations in serum albumin, laboratories report adjusted (corrected) calcium: $\text{Corrected Calcium (mmol/L)} = \text{Total Calcium (mmol/L)} + 0.02 \times \big(40 - \text{Serum Albumin [g/L]}\big)$

MRCP Acid-Base Pearl: Systemic pH alters ionized calcium without changing total calcium. Acidosis displaces calcium from albumin binding sites, increasing free ionized calcium. Conversely, acute alkalosis (e.g. hyperventilation / panic attack) increases negative charges on albumin, driving calcium binding and triggering acute hypocalcaemic tetany and carpopedal spasm despite a completely normal total serum calcium.

Hormonal Control of Calcium & Phosphate

• Parathyroid Hormone (PTH): An 84-amino-acid peptide secreted by parathyroid chief cells in response to reduced ionized calcium sensed by cell-surface G-protein coupled calcium-sensing receptors (CaSR). Actions:
  1. Bone: Stimulates osteoblast expression of RANKL, which binds RANK on osteoclast precursors, activating osteoclastic bone resorption and releasing calcium and phosphate.
  2. Kidney: Increases distal convoluted tubule calcium reabsorption (via TRPV5 channels); downregulates NaPi-2a/NaPi-2c cotransporters in the proximal tubule to promote phosphaturia; and stimulates renal $1\alpha$-hydroxylase ($CYP27B1$) to convert 25-hydroxyvitamin D into active $1,25$-dihydroxyvitamin D3 (calcitriol).
  3. Net Effect: $\uparrow \text{Serum Calcium}$, $\downarrow \text{Serum Phosphate}$, $\uparrow \text{Urinary Phosphate}$, $\uparrow \text{Calcitriol}$.
• Calcitriol ($1,25\text{-(OH)}_2\text{-D}_3$): Steroid hormone synthesized in the renal proximal tubule. Binds nuclear vitamin D receptors (VDR), upregulating intestinal calbindin-D9k and epithelial calcium channels (TRPV6) to dramatically increase intestinal absorption of both calcium and phosphate. Net effect: $\uparrow \text{Serum Calcium}$, $\uparrow \text{Serum Phosphate}$.
• Fibroblast Growth Factor 23 (FGF23): Secreted by osteocytes in response to hyperphosphataemia. Binds FGFR1/Klotho complexes in the proximal tubule to induce massive phosphaturia and inhibit $1\alpha$-hydroxylase, preventing hyperphosphataemia.

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2. Hypercalcaemia: Etiology, Differential & Crisis Protocols

More than $90%$ of all hypercalcaemic cases are attributable to either Primary Hyperparathyroidism (most common in outpatients) or Malignancy (most common in hospitalized patients).

Primary Hyperparathyroidism (PHPT)

• Etiology: Autonomous parathyroid oversecretion caused by a single solitary parathyroid adenoma (80–85%), four-gland primary hyperplasia ($15%$, frequently linked to MEN1 or MEN2A), or parathyroid carcinoma ($< 1%$).
• Clinical Presentation: Classically remembered as 'stones, bones, abdominal groans, and psychiatric moans':
  • Stones: Nephrolithiasis (calcium oxalate/phosphate stones in $15\text{–}20%$) and nephrocalcinosis.
  • Bones: Bone pain, osteopenia/osteoporosis (predominantly cortical bone loss at the distal radius), and severe subperiosteal bone resorption (osteitis fibrosa cystica, brown tumors, and 'salt-and-pepper' skull).
  • Abdominal Groans: Constipation, anorexia, nausea, peptic ulcer disease (calcium stimulates gastrin secretion), and acute pancreatitis (calcium activates pancreatic trypsinogen).
  • Psychiatric Moans: Depression, cognitive slowing, fatigue, and psychosis.
• Biochemical Profile: Elevated corrected calcium, low or low-normal serum phosphate, elevated or inappropriately normal intact PTH (in the setting of hypercalcaemia, any detectable PTH $> 1.5\text{–}2.0\text{ pmol/L}$ is pathologically inappropriate), elevated alkaline phosphatase (in high-turnover bone disease), and elevated 24-hour urinary calcium excretion.
• Pre-operative Localization: Technetium-99m sestamibi SPECT-CT scan and high-resolution neck ultrasonography.
• Surgical Indications (Parathyroidectomy): Symptomatic disease, or asymptomatic patients meeting any NICE/international consensus criterion:
  • Age $< 50$ years
  • Serum adjusted calcium $> 0.25\text{ mmol/L}$ above upper reference limit ($> 2.85\text{ mmol/L}$)
  • T-score $\le -2.5$ at lumbar spine, total hip, femoral neck, or distal radius, or previous fragility fracture
  • Estimated GFR $< 60\text{ mL/min/1.73 m}^2$ or nephrolithiasis/nephrocalcinosis on imaging
  • 24-hour urinary calcium excretion $> 10\text{ mmol/day}$ ($> 400\text{ mg/day}$)

Familial Hypocalciuric Hypercalcaemia (FHH)

• Genetics & Pathophysiology: Autosomal dominant condition caused by heterozygous inactivating mutations in the calcium-sensing receptor gene (CaSR) on chromosome 3q. The mutated parathyroid and renal CaSRs perceive normal calcium concentrations as hypocalcaemic; the set-point for calcium-mediated PTH suppression is shifted upward. Patients exhibit lifelong, benign, asymptomatic mild hypercalcaemia with normal or mildly elevated PTH.
• Distinction from PHPT: In FHH, renal tubular calcium reabsorption is abnormally elevated despite hypercalcaemia, leading to profound hypocalciuria. The diagnostic differentiator is the Calcium-to-Creatinine Clearance Ratio (CCCR): $\text{CCCR} = \frac{\text{Urinary Calcium [mmol/L]} \times \text{Serum Creatinine [umol/L]}}{\text{Serum Calcium [mmol/L]} \times \text{Urinary Creatinine [umol/L]}}$
  • $\text{CCCR} < 0.01$ ($< 1%$): Highly diagnostic of Familial Hypocalciuric Hypercalcaemia (FHH). Parathyroidectomy is completely ineffective and strictly contraindicated! Reassure the patient and perform cascade family screening.
  • $\text{CCCR} > 0.02$ ($> 2%$): Confirms Primary Hyperparathyroidism.
  • $\text{CCCR } 0.01\text{–}0.02$: Indeterminate grey zone; requires genetic testing for CaSR mutations.

Hypercalcaemia of Malignancy

Malignancy causes rapid, symptomatic hypercalcaemia through three principal mechanisms:

1. Humoral Hypercalcaemia of Malignancy (HHM, ~80%): Secretion of PTH-related protein (PTHrP) by solid tumors, particularly squamous cell carcinomas (lung, head and neck, oesophagus), renal cell carcinoma, and breast cancer. PTHrP binds the common PTH1 receptor, stimulating osteolysis and renal calcium reabsorption: corrected calcium is elevated, phosphate is low, PTHrP is elevated, but intact PTH is completely suppressed ($< 1.0\text{ pmol/L}$).
2. Local Osteolytic Hypercalcaemia (~20%): Extensive bone metastases or haematological malignancy (multiple myeloma, breast carcinoma) release local osteoclast-activating cytokines (IL-1, IL-6, TNF-$\alpha$, RANKL). PTH is suppressed.
3. $1\alpha$-Hydroxylase Overproduction ($< 1%$): Unregulated extra-renal conversion of 25-OH-D to calcitriol by tumor-associated macrophages in Hodgkin and non-Hodgkin lymphomas (and non-malignant granulomatous diseases: sarcoidosis, tuberculosis). Both calcium and phosphate are elevated; PTH is suppressed.

Emergency Management of Acute Hypercalcaemic Crisis

Severe hypercalcaemia (corrected calcium $> 3.5\text{ mmol/L}$) or hypercalcaemic crisis (polyuria, dehydration, delirium, cardiac arrhythmias, shortened QTc) is a medical emergency:

1. Aggressive Fluid Resuscitation (First-Line): Infuse intravenous 0.9% normal saline at 3 to 4 liters per 24 hours ($200\text{–}300\text{ mL/hour}$ titrated to cardiovascular status and urine output). Re-expands profound intravascular volume depletion, restores GFR, and promotes proximal tubular calcium excretion. (Loop diuretics such as furosemide are strictly restricted to patients developing fluid overload/pulmonary oedema; they are no longer used routinely due to worsening dehydration).
2. Intravenous Bisphosphonates (Second-Line): Following initial hydration, administer intravenous Zoledronic acid (4 mg over 15 minutes) or pamidronate ($60\text{–}90\text{ mg}$). Inhibits osteoclastic farnesyl pyrophosphate synthase, halting bone resorption. Onset of action takes 48 to 72 hours, with nadir calcium achieved at 4 to 7 days. Dose reduction required in severe renal impairment.
3. Calcitonin: Subcutaneous or IM salmon calcitonin ($4\text{–}8\text{ IU/kg}$ 12-hourly). Provides rapid onset ($2\text{–}4\text{ hours}$) of calcium reduction by promoting renal excretion and inhibiting osteoclasts, serving as an acute bridge while awaiting bisphosphonate effect. Efficacy is limited by tachyphylaxis (receptor downregulation) within 48 hours.
4. Refractory or Renal Failure Cases: Denosumab (monoclonal antibody targeting RANKL; $120\text{ mg}$ SC) is highly effective for bisphosphonate-refractory hypercalcaemia and safe in advanced chronic kidney disease. Glucocorticoids (oral prednisolone 30–60 mg daily) are specifically effective in lymphoma, sarcoidosis, and vitamin D toxicity by suppressing macrophage $1\alpha$-hydroxylase activity. Emergency low-calcium haemodialysis is reserved for refractory hypercalcaemia complicated by acute oliguric renal failure.

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