In Brief: Hypocalcemia and Hypercalcemia in Children

Case presentation:

A 3-year-old male presents to his pediatrician for difficulty walking. His parents recently noted that he tires easily, prefers to sit inside rather than play outside with his siblings and that his legs seem bowed. He has not had any fractures. He was exclusively breastfed until 1 year of age and transitioned to cow’s milk around 18 months. He did not take vitamin D supplementation in infancy, nor does he currently take a multi-vitamin. On presentation, his serum calcium level was 7.8 mg/dL.

Calcium is a mineral that is essential to all living organisms. Neuromuscular conduction, bone mineralization and enzyme secretion are all dependent on adequate serum calcium levels.

Calcium is measured as serum or ionized. Of the body’s total calcium stores, 99% can be found in the skeleton, and 1% in the serum. About half of total serum calcium is comprised of ionized calcium, while 80% of the remainder is bound to albumin. Hypoalbuminemia leads to a decrease in measured total calcium. Consequently, measured calcium must be corrected for hypoalbuminemia. (Corrected Ca= Ca(mg/dL)+0.8* [4.0-albumin(g/dL)]). Similarly, ionized calcium is affected by changes in pH: alkalosis increases protein binding and decreases measured ionized calcium.

Parathyroid hormone (PTH), produced in the chief cells of the parathyroid gland, is secreted when the calcium-sensing receptor (CaSR) senses low calcium or high phosphate levels. At the kidneys, PTH inhibits renal absorption of phosphate in the proximal tubule, increases reabsorption of calcium from the distal tubule, and increases renal 1α-hydroxylation of 25(OH)D into 1,25(OH)₂D. PTH increases intestinal absorption of calcium. PTH also mobilizes both calcium and phosphorous from the skeleton by stimulation of osteoclasts. The net effect of PTH action is an increase in serum calcium and decrease in serum phosphorous. 1,25(OH)₂D actively transports calcium across gastrointestinal cells.

Initial screening labs to evaluate hypo- or hypercalcemia should include serum calcium, phosphorous, albumin, 25(OH)D, alkaline phosphatase, PTH, and urine calcium/creatinine ratio. Ionized calcium may provide additional information if the specimen is collected and processed appropriately; however, serum calcium remains first line. Additionally, if there is a concern for persistent hypocalcemia, then magnesium should be checked.

Hypocalcemia in children:

Symptoms of hypocalcemia (serum calcium <8.5 mg/dL, or ionized calcium <1.0 mmol/L) include perioral or peripheral numbness or tingling, muscle spasm or tetany, laryngospasm, and in severe cases, syncope, seizures or congestive heart failure. Exam findings may include neural hyperexcitability, cardiac arrythmia (prolonged QT), Trousseau sign (carpopedal spasm induced by ischemia through inflation of a sphygmomanometer) and Chovstek sign (twitching of facial muscles in response to tapping on the facial nerve). Chovstek sign has a low sensitivity for and may not always be present with hypocalcemia. Table 1 summarizes the differential diagnoses for hypocalcemia in both the neonatal period and throughout childhood.

Table 1:

Differential diagnosis of hypocalcemia in children and neonates

Etiology	Notes
Rickets	See table 2 for more details
Severe vitamin D deficiency	Hypocalcemia with high PTH
Hypomagnesemia	Needed for PTH secretion and action
Hypoparathyroidism	See text
Hyperphosphatemia	Commonly associated with chronic kidney disease
Liver disease	Impaired hydroxylation of vitamin D to 25(OH)D
Sepsis	Impaired PTH secretion, PTH resistance, decreased calcitriol production
Medication-induced	Anti-epileptic drugs, loop diuretics
Chronic kidney disease	Impaired hydroxylation of 25(OH)D to 1,25(OH)2D
Pancreatitis	Calcium soap precipitation in abdomen
Neonatal
Prematurity	Hypoalbuminemia, low milk intake, impaired response to PTH
Perinatal asphyxia	Increased phosphate load from tissue catabolism, delayed initiation of feeding, renal insufficiency
Sepsis
Maternal diabetes	Lower PTH concentration
Maternal hypoparathyroidism	Fetal hypercalcemia leads to fetal and neonatal PTH suppression
DiGeorge Syndrome	Due to hypoparathyroidism
Metabolic or mitochondrial disorder	Kearns-Sayre, Kenny-Caffey syndromes

If inadequate amounts of PTH are secreted in response to hypocalcemia (hypoparathyroidism) or there is end-organ resistance to PTH (pseudohypoparathyroidism), then PTH-mediated renal and intestinal calcium absorption, renal inhibition of phosphate reabsorption, conversion of 25(OH)D into 1,25(OH)₂D, and calcium and phosphate release from the bone do not occur. Both hypoparathyroidism and pseudohypoparathyroidism lead to hypocalcemia and hyperphosphatemia.

Hyperphosphatemia, as seen in renal disease, results in calcium-phosphate deposition leading to decreased plasma calcium concentration. It also leads to a decrease in 1,25(OH)₂D, and subsequently a decrease in calcium absorption through the gut.

Calcipenic forms of rickets include 1α-hydroxylase deficiency, vitamin D resistance and severe vitamin D deficiency. Common risk factors for vitamin D deficiency include nutritional (maternal vitamin D deficiency, exclusive breastfeeding without supplementation for infants, poor diet in older children), malabsorption (celiac disease, inflammatory bowel disease, cystic fibrosis), 25-hydroxylase deficiency (liver or genetic disease) and obesity. UVB radiation from sunlight stimulates vitamin D production in the skin; however, production is mitigated by sunscreen use, skin pigmentation, and geographic latitude. Genetic causes of hypocalcemia include DiGeorge syndrome (due to hypoparathyroidism) and mutations of CaSR.

Neonatal hypocalcemia is defined as a low calcium noted in the first 2-3 days after birth. For term or preterm infants with birthweight ≥1,500 g, hypocalcemia is defined as serum calcium <8 mg/dl or ionized calcium <4.4 mg/dl. For very low birth weight preterm infants (birth weight <1,500 g), hypocalcemia is defined as serum calcium <7mg/dL or ionized calcium <4mg/dl. Neonatal hypocalcemia has distinct etiologies when compared to hypocalcemia in older children (Table 1). Transient causes of neonatal hypocalcemia often resolve with oral treatment.

Treatment for hypocalcemia varies depending on the severity of symptoms. In the setting of EKG changes, laryngospasm, or seizure, IV calcium gluconate is preferred followed by transition to oral calcium carbonate. Calcitriol may be added in conjunction with an endocrinologist depending on the degree and etiology of hypocalcemia, such as conditions in which 1,25(OH)₂D is not produced, or transiently for management of acute hypocalcemia. Long-term adverse effects of chronic untreated hypocalcemia include cataracts, cerebral calcifications (most commonly in untreated hypoparathyroidism), dermatitis, dystonia, ataxia, and osteoporosis.

For infants aged 0-1 years, the recommended dietary intake (RDI) of vitamin D is 400 international units (IU) (1mcg), and 200-260 mg of calcium per day. For children aged 1-3 years, RDI increases to 600 IU (1.5 mcg) of Vitamin D and 700 mg of calcium. From age 4 to adulthood, RDI of vitamin D remains at 600 IU (1.5 mcg), and calcium increases to 1,000-1,300 mg.

Hypercalcemia:

Hypercalcemia (mild 10.5-12 mg/dL, moderate 12-14 mg/dL, severe >14 mg/dL) often manifests with the well-known phrase “moans, bones, stones, groans and psychiatric overtones.” However, these symptoms may be difficult to elicit in children: vomiting, abdominal pain, constipation, polyuria/polydipsia, poor oral intake and poor weight gain may be more relevant. Exam findings may include hypertension, bradycardia, hyperreflexia, and fasciculations. Etiologies may be broadly divided into PTH or non-PTH mediated (Table 2). Important non-PTH mediated etiologies to consider include vitamin D toxicity, subcutaneous fat necrosis (often seen in neonates after traumatic birth), immobility, and medication induced. Genetic causes of hypercalcemia are more common in younger children compared to adolescents and include MEN syndromes 1 and 2A due to hyperparathyroidism and Williams syndrome, thought to be due to increased vitamin D sensitivity.

Table 2:

Differential diagnosis of hypercalcemia

Etiology	Notes
PTH-mediated
Primary hyperparathyroidism	Most commonly due to parathyroid adenoma
Tertiary hyperparathyroidism	Persistent hyperparathyroidism after an initially physiologic response, common in chronic kidney disease
Familial hypocalciuric hypercalcemia	Low urine calcium
Non-PTH mediated
Malignancy	PTHrP mediated
Granulomatous disease	1,25(OH)2 mediated
Thyrotoxicosis	Increased bone resorption
Immobility	Increased bone resorption
Hypervitaminosis A	Increased bone resorption and decreased bone formation
Hypervitaminosis D	Increase in bone resorption and calcium absorption
Medication-induced	Lithium, thiazide diuretics
Subcutaneous fat necrosis	Increased bone turnover

First-line treatment for hypercalcemia is hyperhydration with normal saline. If treatment beyond hyperhydration and reducing dietary calcium is needed, consider consulting endocrinology. Calcitonin may be used as a bridge to bisphosphonate therapy. In cases where bisphosphonates are contraindicated (chronic renal disease), denosumab has been used. Calcitonin, bisphosphonates and denosumab inhibit osteoclast-mediated bone resorption, leading to a decrease in serum calcium levels. For similar reasons, glucocorticoids may also be used to treat hypercalcemia. In rare cases, hemodialysis may be needed for treatment of severe hypercalcemia in an acutely ill patient. Although loop diuretics lead calciuria, they are not commonly used or recommended in the treatment of acute hypercalcemia due to the need for close monitoring and secondary electrolyte imbalances. Chronic untreated hypercalcemia may lead to nephrocalcinosis with reversible or irreversible kidney damage.

Back to the Case presentation:

In addition to calcium of 7.8 mg/dL, this patient’s laboratory evaluation revealed: 25(OH)D level <5 ng/mL, normal phosphorous, and alkaline phosphatase elevated to 800 IU/L. He has multiple risk factors for hypocalcemia: exclusive breastfeeding without vitamin D supplementation, late transition to cow’s milk (at which time calcium and vitamin D requirements have increased), and little time outdoors. On physical exam he was noted to have bowed legs and discomfort with normal physical activity, consistent with vitamin D deficiency rickets. Laboratory evaluation should include 25(OH)D, electrolyte panel, alkaline phosphatase, magnesium and PTH levels, and dietary intake of calcium and vitamin D should be reviewed. Treatment includes initiating high dose vitamin D therapy as outlined in the 2016 global consensus guidelines, and ensuring adequate intake of calcium through diet and/or supplements. Improvement in bone discomfort and normalization of biochemical parameters is usually seen after a few months of therapy. It is important that patients continue meeting vitamin D and calcium requirements to avoid recurrence of symptoms.

Hypocalcemia in older children has distinct etiologies compared to neonates and should be treated first through increased dietary sources and supplementation. The prevalence of vitamin D deficiency has increased globally, and pediatricians are frontline in preventing and treating vitamin D deficiency to protect children from adverse sequelae including hypocalcemia. Hypercalcemia is less common in the pediatric population but can have devastating long-term consequences if not recognized and treated appropriately.

4 tables is a lot

Comments: This In Brief reminded me of several patients for whom I cared who presented with hypo or hypercalcemia. A young infant presented with a seizure found to be secondary to hypocalcemia in an exclusively breastfed infant without vitamin D supplementation. Several others were children 10 months to 3 years of age who were exclusively breastfed and presented with nutritional rickets, again reinforcing the AAP recommendation of vitamin D supplementation in breastfed infants. Another was a 9 year old with cognitive delay, who never went outside and his diet was almost exclusively noodleos. He had not walked in more than a year and on exam you could appreciate the thickened wrists and ricketsial rosary and who was vitamin D deficient and had hypocalcemia on laboratory exam. While I have seen fewer patients with hypercalcemia I remember a patient who was 15 days old who had significant subcutaneous fat necrosis following delivery and presented with a calcium level of 14. Taking care of each of these patients taught me a great deal. The importance of reinforcing the vitamin D supplementation for solely breastfed infants, which has always been a recommendation but I have found some parents and pediatricians disregard, the importance of dietary and sunlight exposure history and also the need to check calcium levels in infants with significant subcutaneous fat necrosis. What a privilege to be a pediatrician and have opportunities to learn so much from our patients and their families.