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Hypocalcemia, Pediatric

Basics

Description

• Severity varies from asymptomatic to acute life-threatening condition.
• Etiology is important for appropriate management.
• Neonates
  • Term/premature >1,500 g: total calcium <8 mg/dL (2 mmol/L) if serum protein normal (ionized < 1.1 mmol/L)
  • Premature <1,500 g: total calcium <7 mg/dL (1.75 mmol/L); ionized <0.8 mmol/L
• Children: total serum calcium <8.5 mg/dL (2.1 mmol/L) and ionized calcium <4.5 mg/dL (ionized <1.1 mmol/L).

Epidemiology

• Many normal neonates have serum calcium <8 mg/dL during first 3 weeks of life owing to physiologic transient hypoparathyroidism.
• Parathyroid gland (PTG) immaturity can lead to deficient PTH release and exaggerated fall in calcium during the first 3 days of life.
• Relative immaturity of renal phosphorus handling and PTH response can lead to late neonatal hypocalcemia precipitated by a high-phosphate diet.
• Prevalence of vitamin D deficiency in neonate with mother at risk or maternal vitamin D deficiency is about 52-90%.
• Following total thyroidectomy, 10% develop transient hypoparathyroidism; of these, <50% remain permanently hypoparathyroid.

Risk Factors

• Neonate
  • Maternal disorders: diabetes mellitus, toxemia, preeclampsia, hyperparathyroidism, severe vitamin D deficiency
  • Maternal drugs; anticonvulsants, high intake of alkali, magnesium sulfate antacid
  • Prematurity, low birth weight, IUGR, perinatal stress/asphyxia, sepsis
  • Hyperbilirubinemia, phototherapy, citrated blood product use, exchange transfusion
  • Nutrients/drugs; lipid infusion, phosphate therapy, phytate, aminoglycosides, bicarbonate, loop diuretics, glucocorticosteroids, anticonvulsants
  • Osteopetrosis type II
  • Phosphate load; high dietary phosphate (such as cow's milk), phosphate enema, chronic renal insufficiency
  • Hypomagnesemia rarely hypermagnesemia
  • Vitamin D deficiency: malabsorption, renal insufficiency, and liver disease
  • Osteopenia of prematurity
• Hypoparathyroidism
  • Transient neonatal hypoparathyroidism
  • PTG dysgenesis/agenesis
    • Several identified genetic causes including isolated hypoparathyroidism (GCM2, PTH, SOX3), DiGeorge syndrome (DGS) (TBX1), mitochondrial fatty acid disorders (Kearns-Sayre, Pearson, mitochondrial encephalopathy, lactic acidosis, stroke-like-MELAS)
  • PTH insensitivity
    • Blomstrand chondrodysplasia (PTHR1)
    • Pseudohypoparathyroidism type IA (PHP IA)
  • Dyshormonogenesis
  • Autoimmune hypoparathyroidism
    • Autoimmune polyglandular syndrome type I (AIRE1)
    • Activating antibodies to the calcium sensing receptor (CaSR)
  • Acquired
    • Postsurgical, PTG radiation destruction
    • PTG infiltrative disease (excessive iron or copper deposition, granulomatous or neoplastic invasion)
  • Enzyme deficiencies
    • Deficiency of 25-hydroxylase (CYP2R1)
    • Deficiency of 25OH-vitamin D3-1-hydroxylase (CYP27B1)
  • Loss of function vitamin D receptor mutations
• Calcium deficiency
  • Nutritional deprivation
  • Hypercalciuria
• Hypomagnesemia
  • Malabsorption
  • Hypermagnesuria
    • Primary (CLDN16)
    • Bartter syndrome type V (CaSR)
  • Renal tubular acidosis
  • Acute renal failure
  • Chronic inflammatory bowel disease, intestinal resection
  • Diuretics
• Hyperphosphatemia
  • Renal failure
  • Phosphate administration
  • Tumor lysis syndrome
  • Rhabdomyolysis

Commonly Associated Conditions

• Hypoproteinemia
• Hyperventilation
• Drugs: furosemide, bisphosphonates, calcitonin, anticonvulsants, ketoconazole, antineoplastic agents, citrated blood products
• "Hungry bone syndrome"�
• Sepsis, acute pancreatitis, shock
• Organic acidemia

Pathophysiology

• Calcium is most abundant mineral ion in body; 99% of total body calcium is deposited in bone. Three forms of calcium in serum: protein-bound (50%), complex with serum anions (5%), and ionized form (45%).
• Calcium homeostasis is regulated by many factors: hormones and their receptors (PTH/PTHR, vitamin D/VDR, calcitonin), organs (bone, kidneys, PTGs, intestine, and liver), CaSR (the serum calcium set point), and others such as serum pH.
• Tetany is a manifestation of neuromuscular irritability in patients with hypocalcemia.
• Hypocalcemia may present with seizure or other nonspecific symptoms.

Etiology

• Abnormal hormonal response
  • Hypoparathyroidism
    • Abnormal PTH production: PTG agenesis/dysfunction, acquired hypoparathyroidism, abnormal PTH secretion
    • Pseudohypoparathyroidism
  • Vitamin D disorder: deficiency/resistance
• Abnormality of calcium-regulating organs
  • Kidneys, bone, intestine
• Abnormal CaSR
  • Gain of function mutation of CaSR gene
  • Antibodies to the CaSR
• Other causes of hypocalcemia
  • Phosphate load
  • Calcium sequestration or clearance
  • Decreased ionized calcium

Diagnosis

History

• In neonates and infants, include relevant maternal history, prematurity, nutrition, IUGR, perinatal illness
• Other nonspecific symptoms; apnea, poor feeding
• Family history of calcium disorders
• Current illness and drug use
• History of neck surgery
• Recurrent infection
• History of seizure
• Muscle cramps
• Paresthesia, a tingling sensation, usually present around the mouth, fingers, and toes

Physical Exam

• Neuromuscular irritabilities
  • Tetany, hyperreflexia
    • Chvostek sign (usually in 1 month to 2 years of age): twitching of the orbicularis oris muscle with light tapping at anterior external auditory meatus on the CN VII
    • Peroneal sign: dorsiflexion and abduction of the foot on tapping the peroneal nerve on the lateral surface of the fibula just before the knee
    • Trousseau sign: carpopedal spasm when BP cuff maintained 20 mm Hg above SBP for 3 minutes
  • Lethargy
  • Muscle weakness
  • Focal or generalized seizure
  • In neonate: laryngospasm, apnea, bradycardia/ tachycardia, hypotension, cyanosis, emesis
• Prolonged hypocalcemia
  • Basal ganglia calcification
  • Subcapsular cataracts
  • Papilledema (occasional)
  • Dental enamel hypoplasia, particularly of the primary teeth
• Features associated with genetic syndrome/inherited causes of hypocalcemia
  • Dysmorphic features
  • Hearing loss
  • Congenital heart disease
  • Clinical signs of rickets, alopecia
  • Mucocutaneous candidiasis, ectodermal dysplasia, vitiligo
  • Albright hereditary osteodystrophy (AHO)
  • PHP IA has AHO features: short stature, husky-obese body habitus, shortening of the 3rd-5th metacarpal bones and distal phalanx of the 1st finger (brachydactyly), syndactyly between the 2nd and 3rd toes, round face, flat nasal bridge, short neck, subcutaneous calcifications (heterotopic ossification), cataract, and developmental delay in some patients.

Diagnostic Tests & Interpretation

Initial Lab Tests

• Blood: total and ionized calcium, albumin, arterial pH, phosphate, intact PTH, Mg, alkaline phosphatase, creatinine, 25-hydroxyvitamin D; consider 1,25-dihydroxyvitamin D
• Urine: calcium, creatinine
• 12-lead ECG
  • Prolonged QT interval associated with early after-repolarizations and triggered dysrhythmias
  • ECG abnormalities common but serious dysrhythmias infrequent
• If hypoalbuminemia present: correction calculated by: calcium measured + 0.8 [4 - albumin (mg/dL)]
• When serum pH increased (alkalosis), Ca2+ bound to protein
• Phosphate is an indirect index of PTH activity; low and high phosphate levels may reflect a raised and a reduced PTH, respectively.
• Hypoparathyroidism: low/subnormal serum calcium and high serum phosphate with normal or inappropriately low serum iPTH after ruled out hypo/hypermagnesemia
• Parathyroid hormone insensitivity
  • In PHP IA, low serum calcium, high serum and urine phosphate, and elevated PTH
  • No increased serum calcium, urinary cyclic AMP or phosphate after rhPTH1-34 (unresponsive to exogenous PTH)
• Hypomagnesemia inhibits PTH secretion and activity.
• Hypermagnesemia suppresses PTH secretion and decreases renal tubular calcium reabsorption.
• Urine calcium/urine creatinine: normal values for spot collections vary by age. For 0-6, 7-12, and >24 months are <0.8, <0.6, and <0.21 mg/mg, respectively.
• Alkaline phosphatase: bone formation marker
• Serum Cr is used to exclude renal failure.
• Vitamin D disorders: low/ subnormal serum calcium, low/normal phosphate with secondary hyperparathyroidism. In vitamin D deficiency, serum 25-hydroxyvitamin D <30 ng/mL. Serum 1,25-dihydroxyvitamin D3 inappropriately low in patients with severely compromised renal function, hypoparathyroidism, and deficiency of 25OH-vitamin D3-1-hydroxylase.

Treatment

Medication

Neonatal hypocalcemia �

• Asymptomatic neonatal hypocalcemia
  • Increased oral calcium intake, calcium glubionate/carbonate 50-100 mg of elemental Ca/kg/day divided q4-6h if no feeding intolerance (be careful, high osmolality of oral calcium in whom at risk of necrotizing enterocolitis), or 10% calcium gluconate continuous IV infusion for 48 hours. Calcium glubionate is preferable in neonates.
  • Once serum calcium normalizes, can taper supplements
• Symptomatic neonatal hypocalcemia
  • 10% calcium gluconate IV over 10 minutes (elemental Ca 9.3 mg/mL), 18.6 mg elemental Ca (2 mL)/kg/dose (max. 20 mg elemental Ca/kg), diluted 1:1 with 5% dextrose, with cardiac monitoring
  • If severe hypocalcemia with poor cardiac function, may give calcium chloride 20 mg/kg via central line over 10-30 minutes
  • Maintenance of 50-100 mg of elemental Ca/kg/day, continuous IV infusion for 48 hours
  • If serum calcium is normal at 48 hours, taper to 50% dose for next 24 hours and then stop/continue depending on etiology; may switch to oral calcium on the last day before stopping or for continued treatment
  • Avoid extravascular extravasation.
• Treatment for specific causes
  • Calcium supplement doses depend on patient requirement and cause of hypocalcemia.
  • Hypomagnesemia: Give 50% (500 mg/mL) MgSO4 50-100 mg/kg (0.1-0.2 mL/kg) IV/IM q12h for 2 doses with cardiac monitoring. A maintenance dose is 100 mg (0.2 mL)/kg/day PO for 3 days.
  • Phosphate load: Encourage exclusive breastfeeding or use low-phosphate formula (similac PM 60/40, Ca : P = 1.6:1). Phosphate-binding gels are not recommended.
  • Hypoparathyroidism: Supplement 1, 25(OH)2 vitamin D3/calcitriol 20-60 ng/kg/day or 0.5-1 mcg/day PO.
  • Vitamin D deficiency: Supplement vitamin D2 or D3 (age 0-1 year) 2,000 IU daily for 6 weeks to achieve level above 30 ng/mL, then maintenance therapy 400-1,000 IU daily.

Hypocalcemia in childhood and adolescence �

• Asymptomatic hypocalcemia
  • Likely long-standing; may not require immediate treatment
  • Supplement oral calcium 25-100 mg of elemental Ca/kg/day q4-6h. Calcium citrate may be preferable.
• Symptomatic hypocalcemia
  • Give 10% (100 mg/mL) calcium gluconate 200 mg (2 mL)/kg/dose IV, slow rate over 10 minutes with cardiac monitoring; may repeat dose q6-8h
  • Maintenance by 20-80 mg of elemental Ca/kg/day, continuous IV infusion for 48 hours
  • If hypocalcemia is caused by hypomagnesemia, give 50% (500 mg/mL) MgSO4 50-100 mg (0.1-0.2 mL)/kg IM with cardiac monitoring.
• Higher supplemental calcium doses required in patient with severe bone demineralization (hungry bone syndrome)
• In hypoparathyroidism: calcitriol 20-60 ng/kg/day PO and calcium 30-75 mg elemental Ca/kg/day q4-6h
• Additional medication: Thiazide (hydrochlorothiazide [HCTZ] 0.2 mg/kg/day) combined with a low-salt diet may increase renal tubular reabsorption of Ca and lower calcitriol requirement.
• Others: Recombinant human PTH therapy in adults can be considered; black box warning in children
• In chronic hypocalcemia, goals are to control symptoms and avoid complications. Maintain serum calcium at the lower end of normal range, Ca � phosphate < 55 (higher products could precipitate calcium phosphate in soft tissue: kidney, lens, and basal ganglia), and urine Ca/urine creatinine < 0.2 to avoid hypercalcemia, hypercalciuria, nephrocalcinosis, and nephrolithiasis, especially in hypoparathyroidism.

Ongoing Care

Follow-up Recommendations

Patient Monitoring

• Regular serum and urine monitoring during initial therapy and dose adjustment and 3-6-month interval if stabilized
• Annual renal ultrasound, slit-lamp, and ophthalmoscopic examination are recommended.

Prognosis

Depends on etiology �

Complications

Precipitation of calcium-phosphate salts in soft tissues (e.g., kidney, lens, and basal ganglia), hypercalcemia, hypercalciuria, nephrocalcinosis, nephrolithiasis, renal insufficiency �

Additional Reading

• Cusano �NE, Rubin �MR, McMahon �DJ, et al. Therapy of hypoparathyroidism with PTH (1-84). J Clin Endocrinol Metab.  2013;98(1):137-144. �[View Abstract]
• Liamis �G, Milionis �HJ, Elisaf �M. A review of drug-induced hypocalcemia. J Bone Miner Metab.  2009;27(6):635-642. �[View Abstract]
• 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. �[View Abstract]
• Malloy �PJ, Feldman �D. Genetic disorders and defects in vitamin D action. Endocrinol Metab Clin North Am.  2010;39(2):333-346. �[View Abstract]
• Nhan �C, Dolev �Y, Mijovic �T, et al. Vitamin D deficiency and the risk of hypocalcemia following total thyroidectomy. J Otolaryngol Head Neck Surg.  2012;41(6):401-406. �[View Abstract]
• Shoback �D. Clinical practice: hypoparathyroidism. N Eng J Med.  2008;359(4):391-403. �[View Abstract]

Codes

ICD09

• 275.41 Hypocalcemia
• 775.4 Hypocalcemia and hypomagnesemia of newborn

ICD10

• 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: What is the relationship between calcium and phosphate in hypocalcemic setting?
• A: It depends on abnormal hormonal regulation and etiology of hypocalcemia.
  �
  View LargeHormonal problemsSerum calciumSerum phosphateParathyroid hormone deficiency/resistantLowHighVitamin D deficiency/resistantNormal/ lowNormal/ low
• Q: When should parenteral or oral calcium supplement be used?
• A: Every patient can be treated with oral calcium supplement except in acute symptomatic hypocalcemia such as seizure and individuals who temporally hold on enteral feeding or have active malabsorption issue.
• Q: What is the treatment goal of hypocalcemia in children?
• A: Keep serum calcium level in the lower normal range without symptoms of hypocalcemia to reduce the long-term complications, especially nephrocalcinosis.

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