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]])
- 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]])
- 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
Other Manifestations
- Metastatic Calcification
- Pseudogout
- Chondrocalcinosis
- Macrocytic Anemia (see Anemia, [[Anemia]]): with abnormal Schilling test
Treatment
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]