Hypocalcemia

Basics

Description

Hypocalcemia refers to calcium levels below the normal range for age.
The severity of hypocalcemia varies from mild and asymptomatic to acutely life-threatening.
Identifying the etiology of hypocalcemia is important for appropriate long-term management.

Epidemiology

The prevalence of hypocalcemia varies depending on the patient’s age and underlying etiology.
Approximately one third of preterm infants and most very low-birth-weight infants will develop low serum calcium concentrations during the first 2 days of life.
The most common genetic cause of hypocalcemia is 22q11.2 deletion (DiGeorge) syndrome, which occurs in 1 in 4,000 to 5,950 live births.

General Prevention

Adequate dietary calcium intake
Vitamin D supplements should be given to breastfed infants and high-risk individuals.

Pathophysiology

Calcium is essential for many critical physiologic functions (i.e., nerve action potentials, muscle contractions), and its extracellular concentrations must be maintained within a narrow range.
There are three circulating forms of calcium in serum: protein bound (40%), complexed with serum anions (15%), and ionized form (45%). Calcium homeostasis involves intestinal, bone, and renal handling mediated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D.
Clinical symptoms of hypocalcemia result from lowered thresholds to nerve conduction and muscle action potentials, and range from mild to severe.

Etiology

Neonatal hypocalcemia
- Early transient hypocalcemia (within 72 hours of life): exaggeration of the normal decline in calcium concentrations after birth
  - Maternal factors: diabetes mellitus, toxemia, severe vitamin D deficiency, anticonvulsants, hyperparathyroidism
  - Neonatal factors: prematurity, low birth weight, perinatal stress/asphyxia, sepsis, respiratory distress syndrome
- Late transient hypocalcemia (5 to 10 days of life): due to relative PTH resistance of immature renal tubules
  - May be exacerbated by high phosphate intake from cow’s milk–based formula
- Persistent hypocalcemia: Cases of early or late neonatal hypocalcemia that fail to resolve should be investigated for additional etiologies (below).
Hypocalcemia with elevated PTH levels
- Insufficient calcium intake: malnutrition, malabsorption
- Hypovitaminosis D
  - Insufficient dietary intake and/or sun exposure
  - Malabsorption
  - Defects in vitamin D metabolism: liver or renal disease, hereditary resistance to vitamin D (VDR)
- Decreased vitamin D production: 1-α-hydroxylase deficiency
- PTH insensitivity: End-organ resistance results in appropriately high PTH in the setting of hypocalcemia and hyperphosphatemia.
  - Pseudohypoparathyroidism types IA (GNAS), IB (GNAS, STX16), and 2 (PRKAR1A)
Hypocalcemia with low or inappropriately normal PTH levels: hypoparathyroidism
- Parathyroid gland dysgenesis:
  - 22q11.2 deletion (DiGeorge) syndrome. Hypocalcemia may present in the neonatal period or later in life. Additional features include thymic aplasia, cardiac defects, and developmental delay (see “22q11.2 Deletion Syndrome [DiGeorge Syndrome, Velocardiofacial Syndrome]” chapter).
  - Hypoparathyroidism-retardation-dysmorphism, Kenny-Caffey, Sanjad-Sakati syndromes
  - Mitochondrial disorders (Kearns-Sayre; Pearson; mitochondrial encephalopathy, lactic acidosis, stroke-like episodes [MELAS])
- Reduced parathyroid hormone secretion:
  - Autosomal dominant hypocalcemic hypercalciuria (CaSR, GNA11)
- Autoimmune disorders:
  - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (AIRE1)
- Acquired causes:
  - Postsurgical (parathyroidectomy, thyroidectomy)
  - Iron overload (hemochromatosis, thalassemia, chronic transfusions)
  - Copper deposition (Wilson disease)
  - Granulomatous invasion (amyloidosis, sarcoidosis)
Miscellaneous
- Hypomagnesemia: impairs PTH release and decreases end-organ responsiveness to PTH action
- Hyperphosphatemia: decreases serum calcium availability due to calcium-phosphate precipitation in the tissues
  - Tumor lysis syndrome, rhabdomyolysis
  - Phosphate-containing enemas
- Hungry bone syndrome: mobilization of calcium from the serum during rapid bone remineralization
- Acute and critical illness (sepsis, acute pancreatitis, shock)
- Drug mediated:
  - Bisphosphonates
  - Bicarbonate
  - Loop diuretics
  - Denosumab
  - Citrated blood products
- Hypoalbuminemia: Decreased protein-bound calcium in the circulation results in “pseudohypocalcemia,” where total serum calcium levels are low, whereas ionized calcium levels are normal.

Risk Factors

Premature infants, low birth weight, or intrauterine growth restriction
Perinatal illness, asphyxia
Infants of mothers with diabetes
Inadequate nutrition, prolonged breastfeeding without vitamin D supplementation
Malabsorption

Diagnosis

History

For neonates and infants: detailed maternal and birth history
Dietary history (particularly calcium, vitamin D intake)
History of neck surgery/radiation
Family history of calcium disorders
Feeding problems, nausea, vomiting
Psychiatric manifestations
Apnea, jitteriness, irritability
Cardiac abnormalities or recurrent infections
Muscle cramps, twitching, or spasms
Circumoral or distal paresthesias
Seizures

Physical Exam

Neuromuscular irritability
- Tetany: perioral numbness, paresthesias of the hands and feet, muscle cramps or spasm
- Irritability, jitteriness, tremulousness
- Hyperreflexia
  - Chvostek sign: twitching of the orbicularis oris muscle with light tapping of the facial nerve at the anterior external auditory meatus
  - Trousseau sign: carpopedal spasm when BP cuff maintained 20 mm Hg above SBP for 3 minutes
- Laryngospasm, apnea
- Focal or generalized seizure
Rickets
- Widening at the wrists, knees, and/or ankles
- Bowing of the extremities
Features associated with genetic causes of hypocalcemia
- Dysmorphic features
- Hearing loss
- Congenital heart disease
- Mucocutaneous candidiasis, ectodermal dysplasia

Diagnostic Tests and Interpretation

Initial Tests

Total and ionized calcium, albumin, phosphorus, magnesium, alkaline phosphatase, creatinine
If hypoalbuminemia present, calculate corrected calcium: [0.8 (4 − albumin) + serum total calcium]
Intact PTH
1,25-dihydroxyvitamin D
25-hydroxyvitamin D
Urine calcium, creatinine, and urinalysis
12-lead ECG: evaluates for QTc interval prolongation

Treatment

Acute symptomatic hypocalcemia (all calcium doses expressed in respective salt amounts unless specified):
- Calcium gluconate (preferred) 100 to 200 mg/kg/dose (max 1 to 2 g/dose) IV over 5 to 10 minutes with cardiac monitoring
- Calcium chloride 20 mg/kg/dose (max 2 g/dose) can alternatively be given if readily available.
- IV calcium should not be infused more rapidly due to risk of cardiac dysfunction.
- Bolus should be immediately followed by a continuous infusion of calcium gluconate: 500 to 800 mg/kg/24 h or an intermittent infusion of calcium chloride of 10 to 20 mg/kg/dose (max 1 g/dose) q4–6h PRN.
- Calcium gluconate can be given via peripheral IV, but calcium chloride should only be given via central line due to risk of tissue necrosis with extravasation. Follow respective calcium salt product maximum concentration and rates for IV administration.
- Continue the IV infusion or intermittent doses until patient is on an effective oral regimen.
- Oral calcium 25 to 50 mg/kg/24 h elemental calcium (max 1 g elemental calcium per 24 hours) divided 3 to 4 times daily
- For patients with hypoparathyroidism, calcitriol should be initiated as soon as possible: infants 0.04 to 0.08 mcg/kg/24 h divided twice daily, >1 year 0.25 mcg/24 h and increase as needed up to a maximum of 2 mcg/24 h
- Magnesium supplements should be given as needed to correct hypomagnesemia.
- For patients with vitamin D deficiency, treat with high-dose oral cholecalciferol (vitamin D₃) over 8 to 12 weeks (goal total of ~200,000 to 400,000 IU).
  - Infants <1 month: 1,000 IU daily
  - Infants and children 1 month to 5 years: 1,000 to 2,000 IU daily
  - Children 5 years to adult: 5,000 to 6,000 IU daily
Mild asymptomatic or chronic hypocalcemia
- Oral calcium and calcitriol supplementation is preferred (see above).

Issue for Referral

Consult endocrinology for suspected hypoparathyroidism and/or genetic causes of hypocalcemia.

Inpatient Consideratons

Admission criteria
- Hypocalcemia can be managed in the outpatient setting; however inpatient admission should be considered if:
  - Symptoms of carpopedal spasm, tetany, or seizures
  - Prolonged QTc interval
  - Acute decrease in total corrected calcium to ≤7.5 mg/dL in asymptomatic patient
Discharge criteria
- Stable laboratory values
- Normalization in mental status and neurology exam

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

Regular serum and urine monitoring during initial therapy and dose adjustments
Ongoing monitoring as indicated depending on the etiology of hypocalcemia and risk factors for recurrence

Prognosis

Hypocalcemia typically improves with treatment; however, the long-term prognosis depends on the underlying etiology and risk factors for recurrence.

Complications

Tetany and seizures
Laryngospasm, apnea
Cardiac arrhythmia
If overtreated, patients can develop hypercalcemia and hypercalciuria that if unaddressed can lead to nephrocalcinosis, nephrolithiasis, and renal insufficiency.

Additional Reading

Liamis G, Milionis HJ, Elisaf M. A review of drug-induced hypocalcemia. J Bone Miner Metab. 2009;27(6):635–642. [PMID:19730969]
Lima K, Abrahamsen TG, Wolff AB, et al. Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome. Eur J Endocrinol. 2011;165(2):345–352. [PMID:21606191]
Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–58. [PMID:21118827]
Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med. 2008;359(4):391–403. [PMID:18650515]
Tafaj O, Jüppner H. Pseudohypoparathyroidism: one gene, several syndromes. J Endocrinol Invest. 2017;40(4):347–356. [PMID:27995443]

Codes

ICD-9

275.41 Hypocalcemia
775.4 Hypocalcemia and hypomagnesemia of newborn

ICD-10

E83.51 Hypocalcemia
P71.1 Other neonatal hypocalcemia
P71.0 Cow’s milk hypocalcemia in newborn
P71.8 Oth transitory neonatal disord of calcium & magnesium metab

SNOMED

5291005 Hypocalcemia (disorder)
268846006 Neonatal hypocalcemia (disorder)
63275006 Cow’s milk hypocalcemia of newborn (disorder)
240307008 Late neonatal hypocalcemia (disorder)

FAQ

Q: How can the phosphorus concentration help establish the cause of hypocalcemia?
A: In addition to increasing serum calcium, PTH results in renal phosphate wasting. Therefore, in settings of increased PTH secretion such as dietary calcium or vitamin D deficiency, the serum phosphorus will be low or in the normal range. However, in settings of PTH deficiency/resistance, the phosphorus level will be elevated.

Hormonal Problems	Serum Calcium	Serum Phosphate
Calcium/vitamin D deficiency	Low	Normal/low
Parathyroid hormone deficiency/resistance	Low	High

Q: When should patients be treated with parenteral versus oral calcium supplements?
A: Acute symptomatic hypocalcemia such as seizures or tetany should be treated with parenteral calcium bolus followed by continuous infusion. In addition, individuals who are unable to tolerate enteral feeding or have active malabsorption issues should be treated with parenteral calcium. The remainder of patients can be treated with oral calcium supplements and calcitriol if needed.
Q: What are the recommendations for calcium intake in infants and children?
A: Recommended calcium dietary allowances by age (mg/24 h):
- 0 to 6 months: 200
- 6 to 12 months: 260
- 1 to 3 years: 700
- 4 to 8 years: 1,000
- 9 to 18 years: 1,300

Authors

Mary Scott Ramnitz, MD

Alison Boyce, MD