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)

Post-Operative

  • 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, [[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
      • Liver Disease (see End-Stage Liver Disease, [[End-Stage Liver Disease]])
      • 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 -> hypocalcemia with a high PTH

Parathyroid Hormone Resistance

  • Hypomagnesemia (see Hypomagnesemia, [[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, [[Acute Kidney Injury]])
  • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[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, [[Acute Pancreatitis]])
    • Physiology: saponification of calcium soaps within the inflammed pancreas and abdominal cavity
  • Acute Respiratory Alkalosis (see Respiratory Alkalosis, [[Respiratory Alkalosis]])
    • Physiology:
  • Acute Severe Illness
    • Epidemiology: hypocalcemia is common in critical illness (approaching 80-90%)
    • Physiology: due to impaired PTH secretion of PTH, decreased calcitriol production, and end-organ PTH resistance
  • Hyperphosphatemia (see Hyperphosphatemia, [[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, [[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, [[Sepsis]])
    • Epidemiology: hypocalcemia is common in critical illness (approaching 80-90%)
    • Commonly Associated Etiologies
    • Physiology: due to impaired PTH secretion of PTH, decreased calcitriol production, and end-organ PTH resistance
  • Severe Burns (see Burns, [[Burns]])
  • Tumor Lysis Syndrome (see Tumor Lysis Syndrome, [[Tumor Lysis Syndrome]])
    • Physiology: in 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, [[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, [[Calcitonin]])
    • Pharmacology:
  • Denosumab (Xgeva, Prolia) (see Denosumab, [[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, [[5-Fluorouracil]])
    • Epidemiology: hypocalcemia occured in 65% of cases (in one series)
    • Physiology: probably by decreasing calcitriol production
  • Calcium Chelators
    • EDTA
    • Citrate (see Citrate, [[Citrate]])
      • Massive Blood Product Transfusion (see Packed Red Blood Cells, [[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, [[Plasmapheresis]]): hypocalcemia is common during plasmapheresis
    • Phosphate
  • Cinacalcet (Sensipar) (see Cinacalcet, [[Cinacalcet]])
    • Pharmacology: calcimimetic drug
  • Fluoride Intoxication (see Fluoride, [[Fluoride]])
    • Physiology: formation of fluorapatite
  • Foscarnet (Foscavir) (see Foscarnet, [[Foscarnet]]): due to intravascular complexing with calcium
  • Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]]): due to conversion of vitamin D to inactive metabolites
  • Sorafenib (Nexavar) (see Sorafenib, [[Sorafenib]])
  • White Phosphorus Toxicity (see White Phosphorus, [[White Phosphorus]])
    • Epidemiology: associated with systemic toxicity
    • Clinical: hypocalcemia may be severe

Other

  • Ethylene Glycol Intoxication (see Ethylene Glycol, [[Ethylene Glycol]]): due to calcium oxalate formation
  • Hydrofluoric Acid Inhalation (see Hydrofluoric Acid, [[Hydrofluoric Acid]])
  • Hypomagnesemia (see Hypomagnesemia, [[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, [[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

Cardiovascular Manifestations

  • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
  • Hypotension (see Hypotension, [[Hypotension]])
  • Prolonged Q-T with Increased Risk of Torsade (see Torsade, [[Torsade]])
  • Syncope (see Syncope, [[Syncope]])

Neurologic Manifestations

  • Abdominal Cramps (see Abdominal Pain, [[Abdominal Pain]])
  • Chvostek Sign (see Chvostek Sign, [[Chvostek Sign]])
    • Sensitivity for Hypocalcemia: 29%
  • Extrapyramidal Symptoms (see Extrapyramidal Symptoms, [[Extrapyramidal Symptoms]])
    • Akathisia (see Akathisia, [[Akathisia]]): motor restlessness
    • Dystonia (see Dystonia, [[Dystonia]]): continuous spasms and muscle contractions
    • Parkinsonism (see Parkinson’s Disease, [[Parkinsons Disease]]): rigidity, bradykinesia, tremor
    • Tardive Dyskinesia (see Tardive Dyskinesia, [[Tardive Dyskinesia]]): irregular, jerky movements
  • Hyperreflexia (see Hyperreflexia, [[Hyperreflexia]])
  • Impaired Memory
  • Laryngospasm (see Laryngospasm, [[Laryngospasm]])
  • Papilledema (see Papilledema, [[Papilledema]])
  • Parasthesias (see Parasthesias, [[Parasthesias]])
  • Pseudotumor Cerebri (see Pseudotumor Cerebri, [[Pseudotumor Cerebri]])
  • Psychosis (see Psychosis, [[Psychosis]])
  • Seizures (see Seizures, [[Seizures]])
  • Trousseau Sign (see Trousseau Sign, [[Trousseau Sign]]): inflated blood pressure cuff for 3 min will elicit carpopedal spasm in hand/forearm
    • Other Name for Sign: “main d’accoucheur” (French for “hand of the obstetrician”) because it resembles the position of an obstetrician’s hand in delivering a baby
    • Sensitivity for Hypocalcemia: 94%

Opthalmologic Manifestations

Pulmonary Manifestations

Other Manifestations

  • Metastatic Calcification
    • Pseudogout
    • Chondrocalcinosis
  • Macrocytic Anemia (see Anemia, [[Anemia]]): with abnormal Schilling test

Treatment

Oral Calcium Replacement

  • Agents

Intravenous Calcium Replacement

  • Clinical Efficacy
    • Systematic Review of Parenteral Calcium Replacement in Critical Care Patients (Cochrane Database Syst Rev, 2008) [MEDLINE]: no evidence that parenteral calcium replacement improves outcome in critically ill patients
  • Agents
    • Calcium Chloride (in 10 ml = 10%) (see Calcium Chloride, [[Calcium Chloride]]): 1 amp over 30-60 min
    • Calcium Gluconate (see Calcium Gluconate, [[Calcium Gluconate]]): 1 amp IV over 30-60 min
      • Avoid Use in Liver Disease
  • Adverse Effects
    • Carpopedal Spasm: with rapid infusion

References

  • Massive blood replacement: correlation of ionized calcium, citrate, and hydrogen ion concentration.  Anesth Analg 1979; 58:274-278 [MEDLINE]
  • Ionized hypocalcemia during sepsis. Crit Care Med 2000; 28:266-268 [MEDLINE]
  • Electrolyte disturbances in the intensive care unit.  Semin Dial 2006; 19:496-501 [MEDLINE]
  • Parenteral calcium for intensive care unit patients.  Cochrane Database Syst Rev 2008 Oct 8; (4):CD006163.  DOI:  1002/14651858.CD006163.pub2 [MEDLINE]
  • Calcium homeostasis during magnesium treatment in aneurysmal subarachnoid hemorrhage. Neurocrit Care 2008;8(3):413 [MEDLINE]