hypocalcemia

Introduction

Most cases of hypocalcemia are due to low plasma albumin

• albumin binds 45% of serum Ca+2, thus a low Ca+2 in the face of hypoalbuminemia may not reflect true hypocalcemia
• if ionized Ca+2 is normal, then no disorder of calcium metabolism is present.
• if ionized Ca+2 cannot be measured, a corrected calcium can be estimated by adding 0.8 mg/dL for every g/dL decrease in serum albumin below 4.0 g/dL.
  • the percentage of calcium bound to albumin varies, especially in critically ill patients, particularly at extremes of pH & osmolality
  • acidemia increases ionized Ca+2 whereas alkalemia dimimishes it
  • in these conditions the correction formula may not be useful.

Etiology

(causes of true hypocalcemia)

• hypoparathyroidism (most common)
  • surgical excision or vascular injury to the parathyroids during neck surgery
  • polyglandular autoimmune syndrome type 1
• calcium malabsorption
  • vitamin D deficiency
    • IV bisphosphonate may precipitate hypocalcemia*
    • celiac disease may cause vitamin D deficiency thus hypocalcemia
  • vitamin D resistance
• pseudohypoparathyroidism (PTH resistance)
• renal failure
• hypomagnesemia (severe)
  • hypokalemia likely present
  • hypocalcemia difficult to correct in a malnourished patient
• hypermagnesemia
• acute pancreatitis
• hyperphosphatemia
  • rhabdomyolysis
  • tumor lysis syndrome
  • renal failure
• osteoblastic metastases
  • prostatic carcinoma
  • breast carcinoma
• citrated blood transfusions (multiple) or plasmapheresis
• idiopathic (common in critically ill patients)
• sepsis syndrome
• hungry bone syndrome (s/p parathyroidectomy for hyperparathyroidism)
• acute respiratory alkalosis
• pharmacologic causes:
  • antineoplastic agents
    • cisplatin
    • cytosine arabinoside
    • doxorubicin
    • 5-fluorouracil
  • antibiotics
    • pentamidine
    • ketoconazole
    • foscarnet
    • isoniazid
    • rifampin
  • anticonvulsants
    • phenytoin
    • phenobarbital
  • hypocalcemic agents used to treat Paget's disease or hypercalcemia
    • calcitonin
    • plicamycin
    • bisphosphonates
      • IV bisphosphonate may precipitate hypocalcemia*
  • phosphates
  • theophylline
• ethylene glycol toxicity from precipitation of calcium oxylate

* when serum calcium is maintained by resorption of bone, IV bisphosphonate may precipitate hypocalcemia

Clinical manifestations

• positive Trousseau's sign
• positive Chvostek's sign
• mild symptoms include perioral numbness & acral paresthesias (extremities)
• musculoskeletal manifestations
  • muscle cramping
  • carpopedal spasm
  • tetany
  • laryngospasm (rare)
• central nervous system manifestations
  • tremor
  • lethargy
  • anxiety, depression
  • confusion
  • psychosis
  • hyper-irritability
  • seizures (rare)
• gastrointestinal: vomiting
• cardiac manifestations:
  • prolonged QT interval*
  • hypotension
  • bradycardia
  • congestive heart failure
• manifestations of chronic hypocalcemia
  • cataracts
  • basal ganglia calcification

Laboratory

• serum calcium (8.1-10.9 mg/dL)
• serum albumin
• ionized calcium if indicated
  • ref seems to imply that ionized calcium is only clinically useful in assessment of hypercalcemia
  • corrections for low albumin to estimate ionized calcium may or may not substitute for an actual measurement
• serum magnesium
  • next test if hypokalemia
  • if low serum albumin
• serum creatinine to rule out renal insufficiency
• serum 25-hydroxyvitamin D3 better indicator of vitamin D status than serum 1,25-dihydroxyvitamin D3
• serum phosphorus
  • low with vitamin D deficiency
  • high with hypoparathyroidism
• serum parathyroid hormone (serum PTH) if true hypocalcemia
• calcium/creatinine in urine (assess hypercalciuria)
• see ARUP consult

Diagnostic procedures

• electrocardiogram: prolonged QT interval*

Differential diagnosis

• hypoparathyroidism
  • hypocalcemia, hyperphosphatemia, low serum PTH, variable serum 25-hydroxyvitamin D3
• pseudohypoparathyroidism
  • hypocalcemia, hyperphosphatemia, elevated serum PTH, normal serum 25-hydroxyvitamin D3
• chronic kidney disease
  • hypocalcemia, hyperphosphatemia, elevated serum PTH, low serum calcitriol
• vitamin D deficiency
  • hypocalcemia, hypophosphatemia, osteomalacia, weakness, gait ataxia, bone tenderness or fibromyalgia-like syndrome
• impaired PTH secretion/PTH resistance
  • hypocalcemia, magnesium deficiency, diarrhea, alcoholism, diuretics
  • small bowel bypass
• hungry bone syndrome
  • hypocalcemia after parathyroidectomy
• ethylene glycol toxicity
  • high osmolal gap
  • calcium oxalate crystals in urine

Management

acute hypocalcemia

• calcium gluconate (10%) 2 ampules 20 mL IV over 10 minutes, followed by infusion of 60 mL of calcium gluconate in 500 mL D5W (1 mg/mL) at 0.5-2.0 mg/kg/hr
• correct hypomagnesemia
• 1,25-dihydroxyvitamin D3 (calcitriol)
  • 0.25 ug PO QD (initially)
  • 0.5-2.0 mg PO QD (maintenance)
• monitor ECG in patients taking digoxin, since hypocalcemia potentiates digitalis toxicity

chronic hypocalcemia (also see hypoparathyroidism)

• generally well tolerated if mild
  • goal for most patients is serum calcium at or just below normal range without hypercalciuria
• supplemental calcium
  • 1-2 g of elemental calcium PO TID (initially)
  • 0.5-1 g PO TID with meals (maintenance)
• vitamin D, 25-hydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 (calcitriol)
  • calcitriol
    • 0.25 ug PO QD (initially)
    • 0.5-2.0 mg PO QD (maintenance)
    • dose may be increased at 2-4 week intervals
    • indicated with renal failure (hydroxylation of 25-OH vitamin D occurs in the kidney)
  • ergocalciferol 50,000 IU orally weekly for 6-12 weeks
  • 25-OH vitamin D3 indicated in liver failure (vitamin D hydroxylated to 25-OH vitamin D in liver)
  • vitamin D
    • requires weeks to achieve full effect
    • 50,000 IU (1.25 mg) PO QD (initially)
    • 50,000-100,000 IU PO QD (maintenance)
    • dose may be increased at 4-6 week intervals
• if hypercalcemia develops, stop vitamin D, then restart at a lower dose
• calcium acetate (Phoslo) as needed to maintain serum phosphorus < 6.5 mg/dL
• thiazide diuretics to inhibit urinary Ca+2 excretion
  • main adverse effect of therapy is hypercalciuria & nephrolithiasis
• correct magnesium deficiency
  • if hypoparathyroidism is the cause of hypocalcemia, serum magnesium must be corrected to 2.0 mg/dL or higher
  • hypocalcemia difficult to correct if hypomagnesemia

More general terms

• electrolyte disorder
• sign/symptom
• disorder of calcium metabolism

More specific terms

• hungry bone syndrome
• hypoparathyroidism

Additional terms

• calcium (Ca+2) in serum/plasma
• Chvostek's sign
• hypercalcemia
• magnesium (Mg+2) in serum
• parathyroid hormone (PTH) intact in serum/plasma
• pseudohypoparathyroidism
• Trousseau's sign