Hypocalcemia – MD Nexus

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

Granulomatous
Hemochromatosis (see Hemochromatosis)
Metastases
Wilson’s Disease (see Wilson’s Disease)

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
  - Breast Cancer (see Breast Cancer)
  - Prostate Cancer (see Prostate Cancer)
- 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
  - Staphylococcal Toxic Shock Syndrome (TSS) (see Staphylococcal Toxic Shock Syndrome)
  - Streptococcal Toxic Shock Syndrome (TSS) (see Streptococcal Toxic Shock Syndrome)
- 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

Arrhythmias
- Clinical
  - XXXX
Congestive Heart Failure (CHF) (see Congestive Heart Failure)
- Epidemiology
  - Cases of Hypocalcemia-Associated Heart Failure Have Been Extensively Reported (Anesth Analg, 1976) [MEDLINE] (Am J Nephrol, 1990) [MEDLINE] (Am J Kidney Dis, 1994) [MEDLINE] (Clin Nephrol, 2006) [MEDLINE] (Am J Med Sci, 2007) [MEDLINE] (Am J Kidney Dis, 2015) [MEDLINE]
Hypotension (see Hypotension)
- Epidemiology
  - Cases of Hypocalcemia-Associated Hypotension Have Been Extensively Reported (Am J Kidney Dis, 1994) [MEDLINE] (Am J Kidney Dis, 2015) [MEDLINE] (Hemodial Int, 2016) [MEDLINE]
  - Hypocalcemia-Associated Hypotension is Most Commonly Seen When it is Rapidly Induced by Ethylenediaminetetraacetic Acid (EDTA), Transfusion of Citrated Blood, Products, or with the Use of Low Calcium Dialysate in Patients Undergoing Dialysis
- Physiology
  - XXXX
Prolonged Q-T with Increased Risk of Torsade (see Torsade)
- Clinical
  - XXXX
Syncope (see Syncope)
- Epidemiology
  - XXXX

Neurologic Manifestations

Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) (see Pseudotumor Cerebri)
- Clinical
  - Papilledema (see Papilledema)
Seizures (see Seizures)
Tetany (Neuromuscular Irritability) (see Tetany)
- Epidemiology
  - Patients with a Gradual Decline in Serum Calcium Tend to Have Fewer Symptoms at the Same Calcium Level than Patients with Acute Hypocalcemia (Endocrinol Metab Clin North Am, 1993) [MEDLINE]
  - Tetany Usually Only Occurs when Ionized Calcium Falls to Below 1.1 mmol/L (Corresponding to a Total Serum Calcium of Approximately 7-7.5 mg/dL)
- Physiology
  - Acute Hypocalcemia Increases Neuromuscular Irritability (Brain, 1991) [MEDLINE]: hyperexcitability occurs at central nervous system level, spinal reflex level, and motor endplate level
  - Hypocalcemia and Alkalosis Act Synergistically to Cause Tetany (see Metabolic Alkalosis] and Respiratory Alkalosis)
    - Respiratory Alkalosis Can Cause Tetany Even in the Absence of Hypocalcemia
- Diagnosis
  - Electromyogram (EMG) (see Electromyogram-Nerve Conduction Velocity)
    - Repetitive, High-Frequency Discharges After a Single Stimulus are Noted
- Clinical
  - General Comments
    - Tetany Manifests as Both Sensory and Motor Dysfunction (Endocrinol Metab Clin North Am, 1993) [MEDLINE]
  - Autonomic Manifestations
    - Biliary Colic (see Abdominal Pain)
    - Bronchospasm (see Bronchospasm and Obstructive Lung Disease)
    - Diaphoresis (see Diaphoresis)
  - Chvostek’s Sign (see Chvostek’s Sign)
    - Tapping of the Facial Nerve Hust Anterior to the Ear Elicits Contraction of the Ipsilateral Facial Muscles
    - Sensitivity for Hypocalcemia: 29%
    - Chvostek’s Sign Occurs in Approximately 10% of Normal Subjects
  - Clumsiness
  - Hyperreflexia (see Hyperreflexia)
  - Laryngospasm (Laryngismus Stridulus) (see Laryngospasm) (J Emerg Med, 2015) [MEDLINE] (BMJ Case Rep, 2018) [MEDLINE] (Front Horm Res, 2019) [MEDLINE]
  - Muscle Cramps (see Muscle Cramps)
    - Abdominal Cramps (see Abdominal Pain)
  - Muscle Spasms/Twitching
  - Myalgias (see Myalgias)
  - Perioral/Acral Paresthesias (see Paresthesias)
    - These Symptoms Can Cause Hyperventilation, Resulting in Respiratory Alkalosis, Which Exacerbates the Paresthesias
  - Stiffness
  - Trousseau’s Sign (see Trousseau Sign)
    - 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
    - Inflated Blood Pressure Cuff for 3 min Elicits Carpopedal Spasm in the Hand/Forearm
    - Sensitivity for Hypocalcemia: 94%

Chronic Hypocalcemia

Neuropsychiatric

Dementia/Impaired Memory
Extrapyramidal Symptoms (see Extrapyramidal Symptoms)
- Akathisia (see Akathisia)
  - Clinical: motor restlessness
- Dystonia (see Dystonia)
  - Clinical: continuous spasms and muscle contractions
- Parkinsonism (see Parkinson’s Disease)
  - Clinical: rigidity, bradykinesia, tremor
- Tardive Dyskinesia (see Tardive Dyskinesia)
  - Clinical: irregular, jerky movements
Psychosis (see Psychosis)

Other

Abnormal Dentition
Cataracts (see Cataracts)
Metastatic Calcification
- Pseudogout (see Pseudogout)
- Chondrocalcinosis (see Chondrocalcinosis)
Macrocytic Anemia (see Anemia)
- Clinical
  - Abnormal Schilling Test

Treatment

Oral Calcium Replacement

Agents
- Calcium Carbonate (Oscal, Tums) (see Calcium Carbonate)

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): 1 amp over 30-60 min
- Calcium Gluconate (see Calcium Gluconate): 1 amp IV over 30-60 min
  - Avoid Use in Liver Disease
Adverse Effects
- Carpopedal Spasm: with rapid infusion

References

General

Massive blood replacement: correlation of ionized calcium, citrate, and hydrogen ion concentration. Anesth Analg 1979; 58:274-278 [MEDLINE]
Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons. Brain. 1991;114 ( Pt 1B):527 [MEDLINE]
Hypocalcemic emergencies. Endocrinol Metab Clin North Am. 1993;22(2):363 [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]

Clinical Manifestations

Laryngospasm (see Laryngospasm)

Acute dyspnea caused by hypocalcemia-related laryngospasm. J Emerg Med. 2015 Jan;48(1):29-30. doi: 10.1016/j.jemermed.2014.09.034 [MEDLINE]
Hypocalcaemia in an adult: the importance of not overlooking the cause. BMJ Case Rep. 2018 Apr 5;2018. pii: bcr-2017-224108. doi: 10.1136/bcr-2017-224108 [MEDLINE]
Clinical Presentation of Hypoparathyroidism. Front Horm Res. 2019;51:139-146. doi: 10.1159/000491044 [MEDLINE]

Other

Cardiac failure associated with hypocalcemia. Anesth Analg. 1976;55(1):34 [MEDLINE]
Hypocalcemic heart failure in end-stage renal disease. Am J Nephrol 1990;10(2):167-70. doi: 10.1159/000168073 [MEDLINE]
Hypocalcemic emergencies. Endocrinol Metab Clin North Am. 1993;22(2):363 [MEDLINE]
Refractory hypotension associated with hypocalcemia and renal disease. Am J Kidney Dis 1994 Mar;23(3):430-2. doi: 10.1016/s0272-6386(12)81007-9 [MEDLINE]
Reversible hypocalcemic heart failure with T wave alternans and increased QTc dispersion in a patient with chronic renal failure after parathyroidectomy. Clin Nephrol 2006 Jan;65(1):65-70. doi: 10.5414/cnp65065 [MEDLINE]
Reversible congestive heart failure related to profound hypocalcemia secondary to hypoparathyroidism. Am J Med Sci 2007 Apr;333(4):226-9. doi: 10.1097/MAJ.0b013e318039b9c6 [MEDLINE]
Facility Dialysate Calcium Practices and Clinical Outcomes Among Patients Receiving Hemodialysis: A Retrospective Observational Study. Am J Kidney Dis. 2015 Oct;66(4):655-65 [MEDLINE]
Dialysate-induced hypocalcemia presenting as acute intradialytic hypotension: A case report, safety review, and recommendations. Hemodial Int. 2016;20(2):E8 [MEDLINE]

Treatment

Choice of calcium salt. A comparison of the effects of calcium chloride and gluconate on plasma ionized calcium. Anaesthesia. 1984 Nov;39(11):1079-82 [MEDLINE]
Calcium chloride versus calcium gluconate: comparison of ionization and cardiovascular effects in children and dogs. Anesthesiology. 1987 Apr;66(4):465-70 [MEDLINE]
Ionization and hemodynamic effects of calcium chloride and calcium gluconate in the absence of hepatic function. Anesthesiology. 1990 Jul;73(1):62-5 [MEDLINE]