Hypocalcemia

Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Patients can exhibit symptoms from neuromuscular irritability (tetany, Chvostek sign, Trousseau sign) to cardiovascular dysfunction (arrhythmia). Confirmation of hypocalcemia is required with correction of the value depending on albumin level or ionized calcium (the metabolically active form), followed by PTH level, and determination of the underlying cause. Correction of calcium is dictated by the degree of severity of hypocalcemia. In severe cases, IV calcium administration is required. Treatment of the underlying cause is recommended.

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Calcium Homeostasis

Calcium

Calcium is the most abundant mineral in the human body; 99% is found in bone. Calcium in the blood exists in 3 forms:

  • 15% is bound to small anions (citrate, phosphate).
  • 45% is protein-bound calcium (mostly with albumin).
  • 40% is ionized or free calcium (metabolically active or able to be transported into cells).

Levels:

  • Normal serum total calcium: 8.5–10.5 mg/dL (2.12–2.62 mmol/L)
  • Normal ionized calcium: 4.65–5.25 mg/dL (1.16–1.31 mmol/L)

Importance of calcium:

  • Bone mineralization
  • Cofactor of enzymes
  • Cardiac and nerve function
  • Muscle contraction
  • Regulation of clotting mechanisms
  • Effective intracellular messenger for a variety of substances (e.g., insulin)

Calcium regulation

Bone, intestine, and kidneys are involved in homeostasis.

Key elements of calcium regulation:

  • Parathyroid hormone (PTH) (from parathyroid glands):
    • ↑ Vitamin D production in the kidneys, ↑ reabsorption of calcium in distal tubule
    • ↑ Calcium absorption in the intestines
    • ↑ Bone resorption (release of calcium and phosphate from the bones)
  • Vitamin D:
    • With sunlight exposure, 7-dehydrocholesterol is converted into cholecalciferol (vitamin D3) in the skin. 
    • Vitamin D3 is converted into 25-hydroxyvitamin D (calcidiol) in the liver. 
    • Calcidiol goes to the kidney and is converted into 1,25-dihydroxyvitamin D (calcitriol), which is the active form.
    • Effects:
      • Activation of osteoclasts to release calcium and phosphorus
      • Intestinal calcium and phosphate absorption
  • pH: 
    • ↑ pH (alkalosis) will ↑ the binding of calcium to albumin = ↓ ionized calcium
    • ↓ pH (acidosis) will ↓ the binding of calcium to albumin = ↑ ionized calcium
  • Albumin:
    • ↓ Serum protein/albumin (i.e., nephrotic syndrome) = ↓ serum calcium (pseudohypocalcemia)
    • ↑ Serum protein/albumin (i.e., multiple myeloma) = ↑ serum calcium (pseudohypercalcemia)
    • In the above cases, ionized calcium is normal.
    • For every ↓ in albumin by 1 g/dL → ↓ in calcium by 0.8 mg/dL
    • Corrected Ca²+ (mg/dL) = measured total Ca²+ (mg/dL) + [0.8 x (4.0 – albumin concentration in g/dL)]
  • Other factors:
    • Calcitonin from the thyroid gland (opposes PTH → ↓ calcium)
    • Hyperphosphatemia (↑ phosphate binding, ↓ ionized calcium)
    • Hypomagnesemia (↓ PTH release → ↓ calcium)
Calcium Metabolism

Schematic diagram of calcium regulation:
Low plasma calcium stimulates the release of parathyroid hormone (PTH), which increases calcium and phosphate release from bones, calcium absorption in the GI tract, and vitamin D production in the kidneys. In turn, active vitamin D increases calcium release from bones and calcium absorption in the small intestine.

Image by Lecturio.

Etiology

Associated with ↑ PTH:

  • Vitamin D deficiency:
    • Malabsorption
    • Reduced exposure to sunlight
    • Renal failure
    • Liver failure
  • Hyperphosphatemia:
    • Tumor lysis syndrome
    • Rhabdomyolysis
  • PTH resistance:
    • Altered postreceptor PTH signaling pathway
    • Effect: Target organ is unresponsive to PTH.
  • Acute pancreatitis: Calcium binds free fatty acids (released by pancreatic enzymes).
  • Osteoblastic metastasis (i.e., breast cancer): Calcium is deposited in the bone around the tumor.

Hypoparathyroidism (↓ PTH):

  • Complication of thyroid/parathyroidectomy, or neck surgery/trauma/radiation
  • Congenital causes (e.g., DiGeorge syndrome, familial hypoparathyroidism)
  • Autoimmune hypoparathyroidism (antibodies to calcium-sensing receptors)
  • Parathyroid gland infiltration

Drug induced:

  • Loop diuretics
  • Glucocorticoids
  • Calcitonin
  • Chemotherapy
  • Bisphosphonates
  • Fluoride poisoning

Others:

  • Multiple blood transfusions (high concentrations of citric acid, which bind to serum calcium)
  • Inadequate oral intake of calcium
  • Hypomagnesemia
  • Alkalosis
  • Hungry bone syndrome

Clinical Presentation

Manifestations depend on the level and onset of hypocalcemia:

  • Mild disease is asymptomatic, but serum total calcium of < 7.0–7.5 mg/dL will produce symptoms.
  • Acute decline hypocalcemia produces more symptoms than gradual onset hypocalcemia.

Symptoms:

  • Increased neuromuscular excitability:
    • Tetany:
      • Sensory: perioral and acral paresthesias
      • Motor: carpopedal spasms, muscle cramps, spasm of the respiratory muscle and glottis
      • Autonomic: biliary colic, diaphoresis, bronchospasm
    • Classic physical findings of tetany:
      • Chvostek sign: Tapping on the facial nerve in the area of the cheek results in ipsilateral twitching of the lip and facial musculature.
      • Trousseau sign: Carpal spasms (“claw hand”) are induced by inflation of the blood pressure cuff above the systolic pressure for 3 minutes.
  • Seizures:
    • Generalized tonic-clonic
    • Focal
    • Generalized absence
  • Papilledema ± increased intracranial pressure (severe hypocalcemia)
  • Neuropsychiatric symptoms (reversible):
    • Depression
    • Psychotic disorders
    • Anxiety
  • Cardiovascular:
    • Myocardial dysfunction → hypotension, congestive heart failure
    • ECG changes: long QT interval with risk of torsades de pointes
  • Chronic changes:
    • Hypoparathyroidism: cataracts, dental abnormalities, dementia
    • Vitamin D deficiency: osteomalacia, osteopenia, hypotonia, stunted growth in children

Diagnosis

  • Review clinical history and manifestation.
  • Laboratory tests:
    • Serum calcium concentration  
    • Confirm true hypocalcemia:
      • Repeat test.
      • Obtain serum albumin and calculate corrected Ca2+ (mg/dL). 
      • Ionized calcium level
    • Serum PTH levels:
      • ↓ PTH indicates hypoparathyroidism.
      • ↑ PTH indicates kidney disease, vitamin D deficiency, or pseudohypoparathyroidism.
    • Serum phosphate levels: 
      • Decreased or normal in vitamin D deficiency
      • Elevated in hypoparathyroidism, pseudohypoparathyroidism, or chronic kidney disease
    • Serum magnesium levels: Hypocalcemia from ↓ magnesium resolves with correction of low magnesium.
    • Serum vitamin D levels: 
      • Measure calcidiol or 25(OH)D.
      • Hypocalcemia increases PTH, which increases renal production of 1,25-dihydroxyvitamin D (appears normal or high).
    • Comprehensive metabolic panel to exclude any renal or hepatic diseases
  • Others:
    • Alkaline phosphatase: ↑ in osteomalacia from severe vitamin D deficiency
    • Amylase: if pancreatitis suspected
    • Urinary calcium: low in vitamin D deficiency or hypoparathyroidism
    • ECG: prolonged QT interval, possible ventricular arrhythmias
Table: Laboratory findings in hypocalcemia
DiagnosisHypoparathyroidismVitamin D deficiencyMagnesium deficiencyChronic kidney disease
PTHLowHighNormal/lowHigh
PhosHighLowNormalHigh
25(OH)DNormalLow*NormalNormal/low
1,25(OH)2DNormal/lowNormal/high*NormalLow
MgNormalNormalLowNormal/high
Clinical clues
  • Neck surgery
  • Autoimmune disease
  • Bone tenderness
  • Osteomalacia
  • Alcohol use
  • Diuretics
  • Associated with hypokalemia
Abnormal creatinine
PTH: parathyroid hormone
Phos: phosphate
25(OH)D: 25-hydroxyvitamin D/calcidiol
1,25(OH)2D: 1,25-dihydroxyvitamin D/calcitriol
Mg: magnesium
*25(OH)D is a better measurement for vitamin D deficiency because 1,25(OH)2D increases with low calcium, triggering ↑ PTH → ↑ renal production of calcitriol

Management

Management depends on the underlying cause and severity.

Mild hypocalcemia

Approach for:

  • Asymptomatic patients
  • Patients with mild symptoms (i.e., oral paresthesia)
  • Patients with chronic hypocalcemia

Treatment:

  • Oral replacement with 1,500–2,000 mg of elemental calcium/day
  • Either calcium citrate or calcium carbonate

Severe hypocalcemia/acute hypocalcemia

Approach for:

  • Patients with tetany, carpopedal spasm, or seizures
  • Patients with prolonged QT
  • Patients with acute decline to ≤ 7.5 mg/dL (i.e., post head or neck surgery)

Treatment:

  • IV calcium gluconate, OR
  • IV calcium chloride

Additional considerations

  • Hypomagnesemia:
    • Correct deficient magnesium.
    • IV magnesium sulfate
  • Chronic kidney disease (individualized treatment): 
    • Oral calcium is given as a phosphate binder.
    • Vitamin D replacement may be needed in some patients.
  • Vitamin D deficiency: vitamin D supplementation
  • Chronic liver disease: Calcidiol is given because it does not require 25-hydroxylation in the liver.

Clinical Relevance

The following are conditions related to hypocalcemia:

  • Vitamin D deficiency: vitamin D is a fat-soluble, substance vitamin essential for proper function of the human body, especially for skeletal health. Demineralization of the bones leads to osteomalacia in adults and rickets with osteomalacia in children. Other manifestations include bone tenderness, muscle weakness, and fracture(s). Deficiency is determined by obtaining a 25-hydroxyvitamin D (calcidiol) concentration. Management includes vitamin D replenishment.
  • Osteomalacia and rickets: softening of the bones due to bone demineralization, mostly related to deficiency of vitamin D. Rickets presents in children, who have open and growing epiphyseal growth plates. Osteomalacia presents commonly in adults, whose growth plates generally have already closed. Rickets manifests with skeletal deformities and growth abnormalities. Osteomalacia patients exhibit bone pain and pathologic fractures. Diagnosis is made based on a combination of clinical findings, laboratory tests, and imaging. Treatment includes vitamin D, calcium, and phosphorus supplementation.
  • Acute pancreatitis: an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients present with epigastric pain radiating to the back. Diagnosis requires 2 of 3 criteria, including characteristic abdominal pain, serum amylase, and lipase 3x the upper limit of normal, or characteristic radiology findings. Low calcium is a Ranson criteria factor and commonly used to assess severity. Management includes aggressive IV hydration, analgesia, nutrition support, and treatment of the underlying cause.
  • Chronic kidney disease (CKD): kidney impairment lasting for at least 3 months, which implies CKD is irreversible. Hypertension and diabetes are the most common causes; however, a multitude of other diseases can also be the etiology. One of the complications of CKD (especially in the later stages) is secondary hyperparathyroidism (mineral and bone disorder). Increased phosphate overwhelms the regulatory system, and calcium binding with phosphate lowers the ionized calcium, leading to symptomatic hypocalcemia.
  • Cirrhosis: a late stage of hepatic necrosis and scarring. Chronic cellular damage causes extensive distortion of the normal hepatic architecture, which can lead to impairment of normal blood flow through the liver. Common causes are chronic, excessive alcohol use, viral hepatitis, and nonalcoholic steatohepatitis (NASH). Chronic liver disease leads to impaired vitamin D production. Calcidiol, which does not require hepatic 25-hydroxylation, can be given to patients with hypocalcemia.
  • Hypoparathyroidism: reduced PTH levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic, following neck surgery. Parathyroid hormone deficiency results in low serum calcium levels, causing increased neuromuscular excitability. Acute onset (usually postsurgical) is treated with emergent IV administration of calcium gluconate. Chronic hypoparathroidism requires long-term calcium and vitamin D supplementation and monitoring.
  • DiGeorge syndrome: a condition caused by a microdeletion at location q11.2 of chromosome 22. DiGeorge syndrome is also known as 22q11.2 syndrome. A defective development of the 3rd and 4th pharyngeal pouches leads to thymic and parathyroid hypoplasia, causing T cell immunodeficiency and hypocalcemia, respectively. Diagnosis is made with clinical findings, laboratory tests (low calcium), echocardiogram, and genetic analysis. Treatment can include calcium supplementation, surgery (for heart defects and palate abnormalities), and thymus or hematopoietic cell transplantation.
  • Rhabdomyolysis: a condition characterized by muscle necrosis and the release of myoglobin, which has nephrotoxic effects. Rhabdomyolysis may be caused by trauma or direct muscle compression; or, rhabdomyolysis can be nontraumatic (e.g., intense exertional activity). Creatine kinase elevation with presentation of myalgias and dark urine are highly suggestive of the diagnosis. Hyperphosphatemia results from necrotic muscles, which leads to hypocalcemia. The formation of calcium phosphate salts contribute to renal failure. Management is with IV fluid resuscitation.

References

  1. Dawson-Hughes, B. (2021). Vitamin D deficiency in adults. UpToDate. Retrieved May 7, 2021, from https://www.uptodate.com/contents/vitamin-d-deficiency-in-adults-definition-clinical-manifestations-and-treatment
  2. Goltzman, D. (2021). Clinical manifestations of hypocalcemia. UpToDate. Retrieved May 7, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-hypocalcemia
  3. Goltzman, D. (2021). Diagnostic approach to hypocalcemia. UpToDate. Retrieved May 7, 2021, from https://www.uptodate.com/contents/diagnostic-approach-to-hypocalcemia
  4. Goltzman, D. (2021). Etiology of hypocalcemia in adults. UpToDate. Retrieved May 7, 2021, from https://www.uptodate.com/contents/etiology-of-hypocalcemia-in-adults
  5. Gotlzman, D. (2021). Treatment of hypocalcemia. UpToDate. Retrieved May 7, 2021, from https://www.uptodate.com/contents/treatment-of-hypocalcemia
  6. Goyal A, Singh S. (2020). Hypocalcemia. StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK430912/

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