Hypercalcaemia

• Calcium is the most abundant mineral in the body
• 1.5% of body weight
• Most of the calcium in bone is present with phosphate as Hydroxyapatite [Ca10(PO4)6OH2] crystals.
  • major structural component of bone
  • accounting for 65 % of bone weight
  • 1100g (27mol)
  • reservoir of calcium that is important for maintaining plasma calcium concentration
• Plasma Calcium is 2.5mmol/L

• 50% of Ca in ECF is bound to albumin

• 50% is ionised Calcium
  • active and freely diffusible
  • is a co-factor in production of fibrin by the clotting cascade

is needed in many other enzymes as co-factor : 

• myocardial/skeletal/smooth muscle contraction
• neural conduction
• synaptic signaling

ECF calcium concentration are maintained within a narrow range by feedback mechanisms that involve PTH and Vit D, which integrate signals btw the parathyroid glands, kidneys, intestines and bone.

↓ECF Ca²⁺ → ↑PTH secretion (1) 

PTH → ↑increased tubular reabsorption of Ca²⁺ by the kidney (2) 

        → resorption of Ca²⁺ from bone (2) 

        → stimulates renal 1,25(OH)₂D(calcitriol) production (3)

1,25(OH)₂D (calcitriol) → acts on the intestine → ↑Ca²⁺ absorption (4)

→ homeostatic mechanisms serve to restore serum calcium levels to normal

Vitamin D (Calciferol) Metabolism and Function:

1. Group of related sterols:
   • Vitamin D refers to a group of fat-soluble secosteroids, with the two major forms being Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol).
2. Synthesis and activation:
   • Cholecalciferol (Vitamin D3) is formed in the skin from 7-dehydrocholesterol upon exposure to ultraviolet (UV) light.
   • In the liver, cholecalciferol is hydroxylated to form 25-hydroxycholecalciferol (25(OH)D), also known as calcidiol.
   • In the kidney proximal tubules, 25-hydroxycholecalciferol is further hydroxylated to form 1,25-dihydroxycholecalciferol (1,25(OH)2D), also known as calcitriol, which is the active form of Vitamin D.
3. Functions:
   • Increases intestinal absorption of Ca2+: Calcitriol enhances the absorption of calcium (and phosphate) from the intestine.
   • Increases renal Ca2++ reabsorption: Calcitriol promotes the reabsorption of calcium in the kidneys, reducing its excretion.
   • Mobilizes bone Ca2+ and PO4: Calcitriol works with PTH to mobilize calcium and phosphate from bone, increasing blood calcium levels.
4. Regulation:
   • The synthesis of calcitriol in the kidneys is regulated by parathyroid hormone (PTH), which is secreted in response to low blood calcium levels. PTH increases the conversion of 25(OH)D to 1,25(OH)2D in the kidneys.

Parathyroid hormone (PTH) function and regulation:

1. Secretion increased by:
   • Hypocalcemia (low blood calcium levels)
   • Hypomagnesemia (low blood magnesium levels), though severe hypomagnesemia can impair PTH secretion and action.
2. Secretion decreased by:
   • Hypercalcemia (high blood calcium levels)
   • Hypermagnesemia (high blood magnesium levels)
3. Functions of PTH:
   • Mobilizes Ca2 from bone: PTH increases the release of calcium from bones into the bloodstream.
   • Increases renal Ca2+ reabsorption: PTH increases the reabsorption of calcium in the kidneys, reducing urinary calcium excretion.
   • Increases renal PO4 excretion: PTH increases the excretion of phosphate in the urine.
   • Increases formation of 1,25-dihydroxycholecalciferol (calcitriol): PTH stimulates the production of active vitamin D (calcitriol) in the kidneys, which enhances calcium absorption from the gut.

Calcitonin:

1. Antagonist of parathyroid hormone (PTH):
   • Calcitonin counteracts the effects of PTH by lowering blood calcium levels.
2. Secreted by the parafollicular cells (C cells) of the thyroid gland in response to:
   • Hypercalcemia (high blood calcium levels)
   • Catecholamines (e.g., adrenaline)
   • Gastrin (a hormone that stimulates the secretion of gastric acid)
3. Functions:
   • Inhibits the mobilization of bone Ca2+: Calcitonin inhibits osteoclast activity, thereby reducing the release of calcium from bones.
   • Increases renal Ca2+ and PO4 excretion: Calcitonin increases the excretion of calcium and phosphate in the urine.

To summarize, maintenance of normal plasma calcium concentration depends on:

1. diet containing adequate amounts of calcium
2. exposure to sunlight for endogenous production of vitamin D plus dietary source of vitamin D (both are required for optimum calcitriol production)
3. normal gastrointestinal function for absorption of dietary calcium and vitamin D
4. normal parathyroid function for appropriate secretion of PTH
5. normal renal function for secretion of calcitriol, and appropriate adjustment of calcium loss in urine
6. normal bone metabolism for appropriate movement of calcium between bone and blood

Aetiology

• The causes of hypercalcaemia are generally understood and classified according to the derangement in the normal calcium homeostatic mechanisms that regulate serum calcium levels.
• 90% of cases of hypercalcaemia are caused by primary hyperparathyroidism or malignancy.
• Primary hyperparathyroidism – mild and asymptomatic
• Malignancy – severe and symptomatic

Causes of hypercalcemia

• Parathyroid-Related:
  • Primary Hyperparathyroidism: Increased PTH secretion leading to secondary bone resorption.
• Malignancy-Related:
  • Solid Tumors with Metastasis: Breast, ovary, lung, kidney metastases.
  • Paraneoplastic Syndromes: Squamous cell carcinoma, renal cell carcinoma, transitional cell carcinoma, lymphoma, and myeloma.
• Vitamin-D–Related:
  • Vitamin D Intoxication: Excessive intake of vitamin D.
  • Sarcoidosis: Increased conversion of vitamin D to its active form.
  • Other Granulomatous Diseases: Such as tuberculosis and histoplasmosis.
• High Bone Turnover:
  • Hyperthyroidism: Increased bone resorption.
  • Paget Disease of Bone: Increased bone turnover.
  • Immobilization: Increased bone resorption due to lack of mechanical stress.
  • Vitamin A Intoxication: Excessive intake leading to increased bone resorption.
• Renal Failure:
  • Secondary Hyperparathyroidism: Due to chronic kidney disease and resultant hypocalcemia.
  • Aluminum Intoxication: Often associated with chronic kidney disease and dialysis.
• Other:
  • Thiazide Diuretics: Decrease urinary calcium excretion.
  • Milk-Alkali Syndrome: Excessive intake of calcium and absorbable alkali.
  • Familial Hypocalciuric Hypercalcemia: Genetic disorder causing altered calcium sensing.
  • Exogenous Intake: Excessive calcium or vitamin D intake.

Hypercalcaemia range

• Normal serum corrected calcium = 2.1 – 2.6 mmol/L
• Mild hypercalcaemia = 2.7 – 2.9 mmol/L
• Moderate hypercalcaemia = 3.0 – 3.4 mmol/L
• Severe hypercalcaemia = greater than 3.4 mmol/L

Clinical signs of hypercalcaemia

1. Mild hypercalcaemia
   1. Up to 11-11.5 mg/dL
   2. Usually asymptomatic (recognised only on routine calcium measurements)
   3. Vague neuropsychiatric symptoms: trouble concentrating, personality changes, depression
   4. Other symptoms can include:
      1. peptic ulcer disease
      2. nephrolithiasis
      3. ↑fracture risk
2. Severe hypercalcaemia
   1. > 12-13 mg/dL
   2. lethargy, stupor, coma
   3. GI symptoms: nausea, anorexia, constipation or pancreatitis
   4. ↓renal concentration abilities → polyuria and polydipsia
3. Chronic hyperparathyroidism
   1. Bone pain
   2. Pathological fractures

• Stones (Renal colic and hypercalcaemic stones)
• Bones (Increased osteolysis and fractures)
• Psychic moans (Depression, confusion, hallucinations and coma)
• Abdominal groans (Anorexia, N, V, constipation, PUD, pancreatitis)

Investigations

• Bloods

• EUC to assess renal function
• CMP
• LFT for albumin level to calculate corrected calcium
• PTH increased in primary hyperparathyroidism
• PTHrP increased in humoral hypercalcaemia of malignancy- don’t need to do if you know they have mets
• Vitamin D if no obvious malignancy and PTH and PTHrP normal

ECG changes: bradycardia, AV block and short QT level, Osborne Wave

• Urinary calcium level raised in hyperparathyroidism
  • Low urinary calcium suggests FHH→ screen family for hypercalcaemia or genetic testing

• CXR
  • Looking for malignancy (primary or mets) 
  • Sarcoidosis

• Other tests are targeted at finding malignancy
  • Mammogram
  • PSA
  • CT
  • Bone scan
  • Plasma and urine elctrophoresis for myeloma
  • ACE elevated in sarcoidosis

Assessing calcium status

Measurement:

• Total Calcium: The concentration of total calcium (the sum of protein-bound, complexed, and free ionized calcium) is measured in plasma or serum.
• Ionized Calcium: The physiological activity of calcium resides in the ionized fraction, which is the clinically significant component.

Clinical Considerations:

• Total Calcium vs. Ionized Calcium:
  • Total calcium concentration does not accurately reflect ionized calcium activity in patients with abnormal serum protein concentration or disturbances in acid-base balance.
  • Corrected calcium provides a better estimate of ionized calcium but is not entirely reliable for all patients.

Corrected Calcium Calculation:

• Formula: Corrected calcium (mg/dL) = measured total calcium (mg/dL) + 0.8 (4 – serum albumin (g/dL))
  • This correction accounts for the effect of abnormal serum protein concentration.

Reliability Issues:

• Studies have shown that corrected calcium may fail to accurately classify calcium status. For instance, in one study, corrected calcium misclassified calcium status in 38% of 110 intensive care patients, underestimating hypocalcemia and overestimating normocalcemia.

pH Dependence of Ionized Calcium:

• Alkalosis: Increases calcium binding to albumin, reducing active ionized calcium.
• Acidosis: Increases active ionized calcium.

Relationship of Calcium to Albumin:

• Ionized Calcium: Inversely related to serum albumin.
• Total Serum Calcium: Directly related to serum albumin.
  • Total serum calcium is adjusted by 0.8 mg/dL for every 1 g/dL change in serum albumin.
  • In hypoalbuminemia, serum calcium may measure low, but ionized calcium may be normal.

Ionized Calcium Concentration:

• Normal Range: Plasma ionized calcium concentration is maintained between approximately 1.15 and 1.30 mmol/L in healthy individuals.
• Hypercalcemia: Diagnosed if ionized calcium is >1.30 mmol/L; more common than hypocalcemia.
• Hypocalcemia: More prevalent among critically ill patients and neonates.

Diagnosis

1. Detailed medical Hx
2. Make sure that the alteration in serum calcium levels is not due to abnormal albumin concentrations
   1. Measure total calcium and albumin to ‘correct’ the serum calcium

→ establish that a true hyper/hypocalcaemic state exists

3. PTH level
   1. E.g. ↓PTH level in hypercalcaemia → aetiology: non-parathyroid mediated hypercalcaemia 
4. Serum creatinine → indication of renal fx

Correction of hypercalcaemia

Key to treatment is volume expansion

• Promote urinary excretion(if CVS and renal function adequate)
  • Forced saline Diuresis (plus magnesium and potassium) – 300-500ml N saline/hr
  • This replaces lost fluid and forces diuresis
  • Must monitor or replace K and Mg as these will be lost in the urine along with the calcium
  • NOTE do not give THIAZIDES, they will worsen condition
• Treatment with FRUSEMIDE is controversial as it promotes Calcium bone reuptake

1. Haemodialysis
   • Treatment of choice in CVS or renal compromise
2. Calcitonin/EDTA bisphosphonates
   • Reduce bone resorption and reduce GIT absorption of Calcium
   • Effect in 48 hours and last 15 days

1. Mild hypercalcaemia
   1. Immediate Tx is not as important
   2. Mx should be focused on diagnosing and appropriately managing the underlying cause

2. Significant, symptomatic hypercalcaemia

• Rehydration
  • May need 4-6 L Normal Saline over 24hrs, so start initially with 1L N/S over 4-6 hrs
  • Increases urinary excretion of sodium
  • Take care with patients who are older, heart failure, renal failure
    • May need CVP monitoring
  • Correct hypokalaemia/hypomagnesaemia
• Bisphosphonates
  • Disodium pamidronate 90mg IV over 4 hrs
  • Inhibits osteoclast activity and bone resorption
  • Causes a fall in calcium which is maximal at 2-3 days and lasts a week
  • If cause is not removed follow up with oral bisphosphate or repeat infusion
  • NB – failure to rehydrate before using bisphosphonates can lead to renal failure due to deposition of calcium complexes in kidney
• Other therapy
  • Frusemide 40mg IV/PO once rehydrated for forced diuresis, inhibits calcium reabsorption in loop of Henle
    • to prevent CHF from all the fluids you’re giving 
    • do NOT give thiazides as they will raise serum Ca2+ by inhibiting excretion in DCT 
  • Glucocorticoids:
    • effective in myeloma, sarcoidosis & Vit D excess, otherwise ineffective 
    • hydrocortisone 100 mg twice daily IV, or prednisolone 40mg daily
  • Calcitonin 8U/kg/8hrs IM or IV in life threatening situations to bring calcium down rapidly, inhibits osteoclasts, rarely used now
  • Dialysis
    • to get rid of excess Ca2
• Cease medications which will exacerbate hypercalcaemia
  • thiazide diuretics
  • calcium supplements / vitamin D / vitamin A