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

• Granulomatous
• Hemochromatosis (see Hemochromatosis, [[Hemochromatosis]])
• Metastases
• Wilson’s Disease (see Wilson’s Disease, [[Wilsons Disease]])

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
    • Breast Cancer (see Breast Cancer, [[Breast Cancer]])
    • Prostate Cancer (see Prostate Cancer, [[Prostate Cancer]])
  • 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
    • Staphylococcal Toxic Shock Syndrome (TSS) (see Staphylococcal Toxic Shock Syndrome, [[Staphylococcal Toxic Shock Syndrome]])
    • Streptococcal Toxic Shock Syndrome (TSS) (see Streptococcal Toxic Shock Syndrome, [[Streptococcal Toxic Shock Syndrome]])
  • 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)

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

• Cataracts (see Cataracts, [[Cataracts]])

Pulmonary Manifestations

• Bronchospasm (see Obstructive Lung Disease, [[Obstructive Lung Disease]])

Other Manifestations

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

Oral Calcium Replacement

• Agents
  • Calcium Carbonate (Oscal, Tums) (see Calcium Carbonate, [[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, [[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