Calcium Disorders

Calcium Disorders

• 99% of total body calcium is stored in bone.
• Extracellular calcium is a small fraction; 50% is bound to albumin, with 40% available as physiologically active, free (ionized) calcium.
• Serum/plasma calcium concentration is measured as either total or ionized calcium.
• Total calcium includes ionized, complexed, and bound calcium, measured via colorimetric assay.
• Ionized calcium, measured by a calcium-specific electrode, represents physiologically regulated calcium.
• Total and ionized calcium can be expressed in mg/dL, mEq/L, or mmol/L (SI units). SI units (mmol/L) are converted to mg/dL by multiplying by 4.
• Plasma-ionized calcium is regulated by a complex interplay of parathyroid hormone (PTH) and vitamin D3 (calcitriol) in the intestine, bone, and kidney.
• The parathyroid gland senses extracellular fluid (ECF)-ionized calcium concentration via a calcium-sensing receptor.
• The parathyroid gland responds rapidly (within minutes) to ECF-ionized calcium changes.
• High ECF calcium inhibits PTH release.
• Low ECF calcium stimulates PTH secretion, and increases parathyroid gland mass.
• An inverse sigmoid relationship exists between ECF calcium concentration and PTH secretion.
• In bone, PTH, in the presence of calcitriol, increases osteoclastic activity, promoting calcium reabsorption.
• In the intestine, PTH indirectly enhances calcium and phosphate absorption by promoting calcitriol formation.
• In the kidney, PTH increases distal tubular calcium reabsorption and inhibits proximal tubular phosphate and bicarbonate reabsorption, while stimulating calcitriol formation in the proximal tubule.
• Calcitriol is produced in the proximal tubule through 1-alpha-hydroxylation of 25(OH) vitamin D3 (calcidiol).
• PTH and hypophosphatemia are the key stimulators of 1-alpha-hydroxylase.
• The primary function of calcitriol is to increase calcium and phosphate availability for bone formation and to prevent symptomatic hypocalcemia/hypophosphatemia.
• Calcitriol increases calcium-binding protein (calbindin) production in the intestine and kidney, aiding transcellular calcium movement.
• Calcitriol potentiates PTH activity in bone, inducing osteoclast differentiation, and stimulating osteoclastic reabsorption.
• Gut calcium absorption is regulated by calcitriol (active vitamin D).
• Falling calcium activates parathyroid calcium-sensing receptors, triggering parathyroid hormone (PTH) release.
• PTH increases renal tubular calcium reabsorption and vitamin D3 hydroxylation to the active metabolite, which enhances intestinal calcium uptake.
• PTH also increases bone osteoclastic activity.

Hypercalcemia

• Three factors cause hypercalcemia: increased calcium absorption from the gastrointestinal tract, decreased renal calcium excretion, and increased bone calcium resorption.

• Increased Calcium Absorption from the Gastrointestinal Tract:

  • Milk-alkali syndrome caused by excessive calcium and alkali intake.
  • Hypercalcemia in chronic kidney disease (CKD).
  • Vitamin D intoxication.
  • Granulomatous disorders (e.g., sarcoidosis).

• Milk-alkali syndrome:

  • Historically, treated with milk and sodium bicarbonate.
  • Now less common with usage of histamine antagonists and proton pump inhibitors.
  • Commonly occurs in elderly women taking excess calcium carbonate or calcium citrate for osteoporosis treatment.
  • Alkalosis decreases renal calcium excretion, causing hypercalcemia, nephrocalcinosis, and renal dysfunction, which then prevents correction of alkalosis.
  • Patients often also receive vitamin D supplements, increasing intestinal calcium absorption.

• Hypercalcemia in CKD: Typically occurs with calcium and vitamin D supplements. Hypercalcemia from dietary calcium ingestion alone rarely occurs without renal impairment.

• Vitamin D Intoxication: Excess vitamin D leads to hypercalcemia as calcium is primarily absorbed in the small intestine, stimulated by calcitriol.

• Granulomatous disorders: Activated macrophages produce calcitriol, increasing intestinal calcium absorption.

• Causes of Increased Bone Calcium Resorption:

  • Hyperparathyroidism
  • Malignancy
  • Hyperthyroidism
  • Immobilization
  • Paget's disease
  • Thiazide diuretics

Signs and Symptoms of Hypercalcemia

• Signs and symptoms are related to severity and rate of plasma-ionized calcium rise.
• Mild hypercalcemia is often asymptomatic, detected during routine blood chemistries.
• Severe hypercalcemia leads to polyuria, polydipsia, neurological and gastrointestinal symptoms.
• Neurological symptoms (e.g., mental status changes, depression, confusion, coma).
• Gastrointestinal symptoms (e.g., constipation, anorexia, nausea, vomiting, abdominal pain due to peptic ulcer or pancreatitis).

Hypocalcemia

• Causes of Hypocalcemia:
  • Vitamin D deficiency
  • Malnutrition
  • Malabsorption
  • Chronic renal failure (CRF)
  • Vitamin D-dependent rickets
  • Hypoparathyroidism
  • Hyperphosphatemia
  • Acute pancreatitis
  • Hypomagnesemia

Symptoms and Signs of Hypocalcemia

• Depression, anxiety, irritability, circumoral/distal extremity paresthesia, carpopedal spasm, tetany, convulsions, arrhythmias.
• Chronic hypocalcemia may cause cataracts, dental changes, bone pain, and muscle weakness/skeletal deformities.
• Chvostek's and Trousseau's signs.