Caused of Hypocalcemia

Definition and Clinical Features

Diagnostic Thresholds

• Hypocalcemia in older infants and children is generally defined as a serum total calcium concentration of less than 8.5 mg/dL or an ionized calcium level of less than 4.4 mg/dL (<1.1 mmol/L).
• In neonates, the definition varies by birth weight: total calcium <7.5 to 8.0 mg/dL (ionized <4.4 mg/dL) in term or >1500 g infants, and total calcium <7.0 mg/dL (ionized <3.6 mg/dL) in very low birth weight (<1500 g) infants.
• Serum total calcium must be interpreted alongside serum albumin, as a 1 g/dL decrease in albumin lowers total calcium by 0.8 mg/dL without affecting the biologically active ionized calcium fraction.

Clinical Manifestations

• In neonates and infants, clinical features are often subtle and include lethargy, jitteriness, tremulousness, hyperacusis, poor feeding, apnea, cyanosis, and focal or generalized seizures.
• Beyond infancy, the hallmark presentation is tetany, characterized by carpopedal spasm (adduction of thumbs, flexion of metacarpophalangeal joints, and extension of interphalangeal joints).
• Latent tetany can be elicited by physical signs: the Chvostek sign (twitching of facial muscles upon tapping the facial nerve at the angle of the jaw) and the Trousseau sign (carpopedal spasm induced by inflating a blood pressure cuff above systolic pressure for 3 minutes).
• Cardiovascular manifestations include a prolonged QT interval on the electrocardiogram (QTc >0.45 seconds), dilated cardiomyopathy, bradycardia, and occasionally congestive heart failure.
• Severe hypocalcemia can present as a life-threatening emergency with laryngospasm, bronchospasm, or altered sensorium.

Etiology of Hypocalcemia

Neonatal Hypocalcemia

• Early Neonatal Hypocalcemia (<72 hours of life): Typically occurs in prematurely delivered infants, small-for-gestational-age neonates, or those subjected to birth asphyxia.
• Infants of diabetic mothers are at high risk due to maternal hypomagnesemia and hypercalcitoninemia.
• Unsuspected maternal hyperparathyroidism can cause fetal hypercalcemia, which profoundly suppresses the fetal parathyroid glands, leading to neonatal hypocalcemia.
• Late Neonatal Hypocalcemia (>72 hours of life): Commonly caused by the ingestion of modified cow's milk formulas with high phosphate loads, which complex with calcium and impair its intestinal absorption.
• Other late causes include transient or congenital hypoparathyroidism, hypomagnesemia, and profound maternal vitamin D deficiency.

Parathyroid Hormone (PTH) Related Disorders

• Congenital Hypoparathyroidism: Can result from abnormal embryogenesis of the parathyroid glands, most notably DiGeorge syndrome (deletion 22q11.2), which presents with conotruncal cardiac defects, thymic aplasia, and hypocalcemia.
• Other syndromic forms include Sanjad-Sakati syndrome (hypoparathyroidism, retardation, and dysmorphism) and Barakat syndrome (HDR syndrome: hypoparathyroidism, deafness, and renal dysplasia).
• Activating Mutations of the Calcium-Sensing Receptor (CaSR): Gain-of-function mutations in the CASR gene (Autosomal Dominant Hypocalcemia) lead to an abnormally sensitive CaSR that suppresses PTH secretion and increases renal calcium excretion even at low serum calcium levels, causing hypercalciuric hypocalcemia.
• Acquired Hypoparathyroidism: Autoimmune destruction of the parathyroid glands is the most common acquired cause in older children, frequently presenting as part of Autoimmune Polyendocrinopathy Syndrome type 1 (APS-1), associated with chronic mucocutaneous candidiasis and adrenal insufficiency.
• Pseudohypoparathyroidism (PTH Resistance): Caused by an inactivating mutation in the GNAS gene encoding the stimulatory G protein alpha subunit. Patients present with hypocalcemia, hyperphosphatemia, and elevated PTH, often accompanied by Albright Hereditary Osteodystrophy (AHO) phenotype (round facies, short stature, obesity, and brachydactyly).

Vitamin D Related Disorders

• Nutritional Vitamin D Deficiency: The most common global cause of pediatric hypocalcemia, associated with inadequate dietary intake or sunlight exposure, leading to secondary hyperparathyroidism, hypophosphatemia, and rickets.
• Vitamin D-Dependent Rickets Type I: Caused by a genetic deficiency of the 1-alpha-hydroxylase enzyme, impairing the conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D (calcitriol).
• Vitamin D-Dependent Rickets Type II: Caused by an inactivating mutation in the Vitamin D Receptor (VDR), leading to severe end-organ resistance to calcitriol, often presenting with early-onset hypocalcemia, severe rickets, and alopecia.

Increased Calcium Chelation and Other Causes

• Hyperphosphatemia: Excessive phosphate loads bind serum calcium, causing extracellular deposition. This can result from acute or chronic renal failure, tumor lysis syndrome, rhabdomyolysis, or the administration of phosphate-containing enemas/laxatives.
• Acute Illness and Transfusions: Large volume transfusions of citrated blood rapidly chelate ionized calcium. Hypocalcemia is also prevalent in critically ill patients, acute pancreatitis (calcium saponification with free fatty acids), and severe sepsis.
• Hypomagnesemia: Magnesium deficiency (serum Mg <1.5 mg/dL) profoundly impairs the release of PTH from the parathyroid glands and induces peripheral resistance to PTH action, causing refractory hypocalcemia.
• Alkalosis: Both respiratory and metabolic alkalosis increase the binding of calcium to serum albumin, leading to a sudden drop in the biologically active ionized calcium fraction and precipitating tetany.

Diagnostic Evaluation

Clinical and Initial Laboratory Assessment

• A detailed dietary, developmental, and family history must be obtained, alongside a careful physical examination looking for dysmorphic features (e.g., DiGeorge phenotype, AHO phenotype) and signs of rickets.
• Initial biochemical evaluation requires simultaneous measurement of serum total and ionized calcium, phosphate, magnesium, alkaline phosphatase, creatinine, and intact PTH.
• A spot urine calcium-to-creatinine ratio is essential to evaluate for hypercalciuria, particularly if an activating CaSR mutation is suspected.
• An electrocardiogram should be obtained to assess for a prolonged QTc interval, which confirms the physiologic severity of the hypocalcemia.

Interpretation of Biochemical Profiles

• High Phosphate + Low/Normal PTH: Strongly indicates hypoparathyroidism, either congenital (e.g., DiGeorge) or acquired (e.g., autoimmune).
• High Phosphate + High PTH: Indicates PTH resistance (Pseudohypoparathyroidism) or impaired renal phosphate excretion (renal failure).
• Low/Normal Phosphate + High PTH: Points toward a Vitamin D-related disorder (deficiency or resistance) leading to secondary hyperparathyroidism, which increases renal phosphate wasting.
• Low Magnesium + Low/Normal PTH: Confirms hypomagnesemia-induced impaired PTH secretion.

Management of Hypocalcemia

Acute and Emergency Management

• Symptomatic hypocalcemia (tetany, seizures, laryngospasm) is a medical emergency requiring immediate intravenous calcium therapy.
• Intravenous 10% calcium gluconate (containing 9.3 mg of elemental calcium per mL) is administered at a dose of 1 to 3 mL/kg (or 9-20 mg of elemental calcium/kg) via slow infusion over 5 to 15 minutes.
• Administration must be performed under continuous cardiac monitoring to detect bradycardia or arrhythmias.
• Extravasation of intravenous calcium must be strictly avoided, as it can cause severe tissue necrosis and calcinosis cutis.
• If hypocalcemia recurs or persists after the initial bolus, a continuous intravenous infusion of calcium gluconate (e.g., 500 mg/kg/24 hours) may be established.
• If hypomagnesemia is present, it must be corrected first, as calcium replacement alone will be ineffective. Administer 50% magnesium sulfate (0.1 to 0.2 mL/kg) intravenously or intramuscularly.

Maintenance and Specific Therapy

• Hypoparathyroidism and Pseudohypoparathyroidism: Management relies on the administration of active vitamin D, specifically calcitriol (1,25-dihydroxyvitamin D), at an initial dose of 0.25 mcg/day or 20-60 ng/kg/day, divided twice daily.
• Supplemental oral elemental calcium (30 to 75 mg/kg/day in divided doses with meals) is given concurrently as calcium carbonate, glubionate, or citrate.
• The therapeutic goal in hypoparathyroidism is not to completely normalize the serum calcium, but to maintain it in the asymptomatic low-normal range to prevent hypercalciuria, nephrocalcinosis, and renal impairment.
• Frequent monitoring of serum calcium, phosphate, and the urinary calcium-to-creatinine ratio is mandatory; thiazide diuretics (e.g., hydrochlorothiazide) may be added if hypercalciuria develops, especially in patients with activating CaSR mutations.
• Vitamin D Deficiency: Nutritional rickets is treated with high-dose oral Vitamin D (cholecalciferol or ergocalciferol) at 2000 IU/day for 6 to 8 weeks, followed by a maintenance dose of 400 to 1000 IU/day.
• Oral elemental calcium (30–75 mg/kg/day) must be co-administered during the initial phase of Vitamin D therapy to prevent the "hungry bone syndrome," an abrupt worsening of hypocalcemia caused by rapid skeletal remineralization.