Hypocalcemia


Etiology

Pseudohypocalcemia

  • Interference with Colorimetric Laboratory Calcium Assay
    • Gadodiamide MRI Angiography Contrast: in addition, since the contrast is excreted renally, it may be retained for prolonged periods after the MRI
    • Gadoversetamide MRI Angiography Contrast: in addition, since the contrast is excreted renally, it may be retained for prolonged periods after the MRI

Hypoparathyroidism (Low Parathyroid Hormone)

Genetic

  • Abnormal Parathyroid Gland Development
    • DiGeorge Syndrome
    • Mutations in the Transcription Factor Glial-Cell Missing B (GCMB)
  • Abnormal Parathyroid Hormone Synthesis
  • Activating Mutations of Calcium-Sensing Receptor (CaSR)
    • Autosomal Dominant Hypocalcemia
    • Sporadic Isolated Hypoparathyroidism

Autoimmune

  • Polyglandular Autoimmune Syndrome Type I: associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency
  • Isolated Hypoparathyroidism Due to Activating Antibodies to Calcium-Sensing Receptor (CaSR)

Postoperative

  • General Comments
    • Surgical Etiologies are the Most Common Causes of Hypoparathyroidism
  • Parathyroidectomy
  • Radical Neck Dissection (for Head and Neck Cancer)
  • Thyroidectomy

Infiltration of Parathyroid Gland

Other

  • Radiation-Induced Destruction of Parathyroid Gland
  • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
  • Hungry Bone Syndrome (Post-Parathyroidectomy)

Secondary Hyperparathyroidism in Response to Hypocalcemia (High Parathyroid Hormone)

Vitamin D Deficiency/Resistance

  • Etiology
    • Nutritional Vitamin D Deficiency and Decreased Cutaneous Vitamin D Synthesis
    • Vitamin D Deficiency Due to Abnormal Synthesis and Catabolism
      • Chronic Kidney Disease (CKD): low calcitriol (1,25 dihydroxyvitamin D) production due to decreased glomerular filtration rate, loss of the 1-alpha-hydroxylase enzyme secondary to structural renal disease, and suppression of enzyme activity due to hyperphosphatemia and resultant increased circulating FGF23 levels
      • Drugs (Inducers of P-450 enzyme, Which Metabolizes Calcidiol to Inactive Vitamin D Metabolites): phenytoin, phenobarbital, carbamazepine, oxcarbazepine, isoniazid, theophylline, rifampin
      • Cirrhosis/Liver Disease (see Cirrhosis)
      • Nephrotic Syndrome: due to loss of calcidiol (25-hydroxyvitamin D) bound to vitamin D-binding protein
      • Vitamin D-Dependent Rickets Type I
    • Vitamin D Resistance
      • Hereditary Vitamin D-Resistant Rickets (HVDRR)
  • Physiology
    • Decreased Synthesis or Action of Vitamin D, Resulting in Hypocalcemia with a High PTH

Parathyroid Hormone Resistance

  • Hypomagnesemia (see Hypomagnesemia)
    • Epidemiology
      • Interestingly, a few patients with magnesium-responsive hypocalcemia but normal serum magnesium levels have also been reported
    • Physiology: hypomagnesemia can decrease PTH secretion or cause PTH resistance
      • PTH resistance occurs when serum magnesium concentration falls below 0.8 mEq/L (1 mg/dL or 0.4 mmol/L)
    • Diagnosis: associated with low/normal/high parathyroid levels
      • Most patients have low-normal serum phosphate levels: probably due to poor phosphate intake
  • Missense Mutation in Parathyroid Hormone
  • Pseudohypoparathyroidism

Renal Disease

  • Acute Kidney Injury (AKI) (see Acute Kidney Injury)
  • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)
    • Epidemiology: hypocalcemia does not occur until GFR <15 mL/min
    • Physiology
      • Decrease in Renal Production of 1,25-Dihydroxyvitamin D
      • Hyperphosphatemia Also Contributes to Development of Hypocalcemia

Loss of Calcium from Circulation

  • Acute Pancreatitis (see Acute Pancreatitis)
    • Physiology
      • Saponification of Calcium Soaps within the Inflamed Pancreas and Abdominal Cavity
  • Acute Respiratory Alkalosis (see Respiratory Alkalosis)
    • Physiology:
  • Acute Severe Illness
    • Epidemiology
      • Hypocalcemia is Common in Critical Illness (Approaching 80-90% of Cases)
    • Physiology
      • Sue to impaired PTH secretion of PTH, decreased calcitriol production, and end-organ PTH resistance
  • Hyperphosphatemia (see Hyperphosphatemia)
    • Epidemiology:
      • Acute hyperphosphatemia, resulting from increased phosphate intake (phosphate enemas, oral phosphate replacement) in the setting of renal failure, can result in acute hypocalcemia
      • Chronic hyperphosphatemia is usually due to decreased phosphate clearance in chronic kidney disease; in these cases, primary impairment of calcitriol synthesis (resulting in decreased intestinal calcium absorption) further excaerbates the hypocalcemia
    • Physiology: hyperphosphatemia results in calcium deposition, mostly in bone (but also in extraskeletal tissues)
  • Osteoblastic Bone Metastases
    • Etiology
    • Physiology
      • Due to Deposition of Calcium in the Newly Formed Bone Around the Tumor
  • Rhabdomyolysis (see Rhabdomyolysis): patients are typically hypocalcemic during the oliguric phase of acute kidney injury (due to acute tubular necrosis)
    • Physiology: in setting of decreased renal excretion of phosphate, hyperphosphatemia from tissue breakdown results in calcium deposition, mostly in bone (but also in extraskeletal tissues)
  • Sepsis (see Sepsis)
    • Epidemiology
      • Hypocalcemia is Common in Critical Illness (Approaching 80-90% of Cases)
    • Commonly Associated Etiologies
    • Physiology: due to impaired PTH secretion of PTH, decreased calcitriol production, and end-organ PTH resistance
  • Severe Burns (see Burns)
  • Tumor Lysis Syndrome (see Tumor Lysis Syndrome)
    • Physiology
      • In the Setting of Decreased Renal Excretion of Phosphate, Hyperphosphatemia from Tumor Breakdown Results in Calcium Deposition, Mostly in Bone (But Also in Extraskeletal Tissues)

Drugs/Toxins

Inhibitors of Bone Resorption

  • Bisphosphonates (see Bisphosphonates)
    • Epidemiology: more frequently seen when potent bisphosphonates (such as zoledronate) are used and in patients with underlying vitamin D deficiency, unrecognized hypoparathyroidism, or chronic kidney disease
    • Pharmacology: reduce osteoclastic bone resorption
  • Calcitonin (see Calcitonin)
    • Pharmacology:
  • Denosumab (Xgeva, Prolia) (see Denosumab)
    • Pharmacology: fully human monoclonal antibody to the receptor activator of nuclear factor kappaB ligand (RANKL), which is an osteoclast differentiating factor

Other Drugs/Toxins

  • 5-Fluorouracil and Leucovorin (see 5-Fluorouracil)
    • Epidemiology: hypocalcemia occured in 65% of cases (in one series)
    • Physiology: probably by decreasing calcitriol production
  • Calcium Chelators
    • EDTA
    • Citrate (see Citrate)
      • Massive Blood Product Transfusion (see Packed Red Blood Cells): due to citrate binding of calcium
        • Diagnosis: in cases due to large-volume blood product transfusion, total calcium is normal but ionized calcium is decreased
        • Clinical: hypocalcemia is usually transient and there is no evidence that the treatment of hypocalcemia in this setting is beneficial
      • Plasmapheresis (see Plasmapheresis): hypocalcemia is common during plasmapheresis
    • Phosphate
  • Cinacalcet (Sensipar) (see Cinacalcet)
    • Pharmacology: calcimimetic drug
  • Fluoride Intoxication (see Fluoride)
    • Physiology: formation of fluorapatite
  • Foscarnet (Foscavir) (see Foscarnet): due to intravascular complexing with calcium
  • Phenytoin (Dilantin) (see Phenytoin): due to conversion of vitamin D to inactive metabolites
  • Sorafenib (Nexavar) (see Sorafenib)
  • White Phosphorus Toxicity (see White Phosphorus)
    • Epidemiology: associated with systemic toxicity
    • Clinical: hypocalcemia may be severe

Other

  • Ethylene Glycol Intoxication (see Ethylene Glycol): due to calcium oxalate formation
  • Hydrofluoric Acid Inhalation (see Hydrofluoric Acid)
  • Hypomagnesemia (see Hypomagnesemia)
    • Epidemiology
      • Interestingly, a few patients with magnesium-responsive hypocalcemia but normal serum magnesium levels have also been reported
    • Physiology: hypomagnesemia can decrease PTH secretion or cause PTH resistance
      • PTH resistance occurs when serum magnesium <0.8 mEq/L (1 mg/dL or 0.4 mmol/L)
    • Diagnosis: associated with low/normal/high parathyroid levels
      • Most patients have low-normal serum phosphate levels: probably due to poor phosphate intake
  • Post-Surgery
    • Epidemiology: hypocalcemia may occur post-operatively even in cases where no blood products are given
    • Physiology: due to volume expansion and hypoalbuminemia
    • Diagnosis: ionized calcium is normal in most of these cases
  • Severe Hypermagnesemia (see Hypermagnesemia)
    • Epidemiology
      • During aggressive magnesium therapy in pre-eclampsia
      • During magnesium replacement in the setting of aneurysmal subarachnoid hemorrhage (Neurocrit Care, 2008) [MEDLINE]
    • Physiology: suppression of PTH secretion
    • Diagnosis: occurs with serum magnesium concentration >5 mEq/L (6 mg/dL or 2.5 mmol/L)


Clinical Manifestations

Acute Hypocalcemia

Cardiovascular Manifestations

Neurologic Manifestations

Chronic Hypocalcemia

Neuropsychiatric

Other


Treatment

Oral Calcium Replacement

Intravenous Calcium Replacement


References

General

Clinical Manifestations

Laryngospasm (see Laryngospasm)

Other

Treatment