Hypercalcemia

Hypercalcemia is a topic covered in the 5-Minute Pediatric Consult.

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Basics

Description

Hypercalcemia represents an elevation in ionized and total calcium concentrations.

Epidemiology

  • Less common than hypocalcemia
  • Less common in children than in adults
  • Adults: >90% caused by hyperparathyroidism (HPT) or malignancy
  • Children: more diverse etiologies dependent on age of presentation

Risk Factors

  • Family history of hypercalcemia
  • Family history of renal stones
  • Chronic renal failure
  • Immobilization
  • Certain genetic syndromes
  • Certain malignancies
  • History of neck irradiation
  • Gestational maternal hypocalcemia

Pathophysiology

  • Increased calcium influx from the intestinal tract or the skeleton
  • Increased renal tubule calcium reabsorption

Etiology

ALERT
The first step in the determination of an etiology of hypercalcemia is measurement of an intact serum parathyroid hormone (intact PTH) concentration.
  • Hypercalcemia with increased PTH
    • Familial isolated primary HPT
      • Autosomal dominant (AD)
      • Parathyroid hyperplasia or adenoma(s)
      • MEN1, HRPT2, HRPT3 mutations
    • Multiple endocrine neoplasia (MEN)
      • MEN1 (AD)
        • MEN1-inactivating mutation
        • Parathyroid tumors in 90%
        • Pancreatic and pituitary tumors
      • MEN2A (AD)
        • RET proto-oncogene mutations
        • Parathyroid tumors in 20%
        • Medullary thyroid carcinoma and pheochromocytoma
    • Sporadic parathyroid adenoma
      • Cyclin D1/PRAD1
      • MEN1 mutations
    • Parathyroid carcinoma (rare)
    • Hyperparathyroidism-jaw tumor syndrome (HPT-JT)
      • HRPT2 inactivating mutations
      • Parathyroid tumors may present in adolescence.
      • Mandibular, maxillary, and renal tumors may occur.
    • Neonatal severe HPT (NSHPT)
      • Homozygous inactivating calcium-sensing receptor (CaSR) mutations (AR)
    • Neonatal HPT (NHPT)
      • Heterozygous inactivating CaSR mutations or dominant/negative (less severe presentation)
  • Hypercalcemia with normal PTH
    • Familial benign hypercalcemia or familial hypocalciuric hypercalcemia (FHH)
      • Heterozygous inactivating CaSR mutations (AD)
      • Typically asymptomatic
      • Mild hypercalcemia
      • PTH is usually normal (slightly elevated in 15–20%).
      • Fractional calcium excretion <1%
  • Hypercalcemia with low PTH
    • Williams syndrome
      • 15% with (neonatal, transient) hypercalcemia
      • Hypercalcemia usually resolves after infancy.
      • Caused by a hemizygous microdeletion of up to 28 genes in chromosome 7q11.23, involving the gene encoding the transcription factor TFII-I. TFII-I negatively regulates cellular calcium entry. Without TFII-I, transient receptor potential C3 (TRPC3) channels are overexpressed in kidneys and intestine, leading to hypercalcemia.
      • Associated features: supravalvular aortic stenosis, cognitive impairment, “elfin facies,” poor growth
    • Jansen metaphyseal chondrodysplasia
      • Heterozygous mutations in PTHR1 lead to constitutive activation of PTH/PTHrP receptor.
      • Short-limbed short stature
    • Idiopathic hypercalcemia of infancy
      • Some cases due to loss of function mutations in CYP24A1, resulting in impaired inactivation of 1,25(OH)2-vitamin D
      • Some patients with a mutation in SLC34A1, encoding the renal sodium-phosphate cotransporter 2A (NaPi-IIa), leading to renal phosphate wasting
      • Infants have failure to thrive, vomiting, dehydration, and nephrocalcinosis.
  • Other causes of hypercalcemia (mostly PTH-independent):
    • Medications:
      • Thiazides, antifungals, lithium, vitamin A and D
    • Malignancy
      • Local osteolysis (PTHrP, cytokine production, chemotherapy)
      • Humoral hypercalcemia of malignancy (HHM) (PTHrP)
      • Ectopic 1,25(OH)2-vitamin D production (lymphomas)
      • Ectopic PTH production
    • Granulomatous disease
      • Sarcoidosis, tuberculosis, cat-scratch disease
      • Increased 1,25(OH)2-vitamin D production due to dysregulated 1-α hydroxylase expression in monocytes/macrophages
    • Renal disease
      • Chronic renal failure may lead to secondary and tertiary HPT.
    • Endocrine disorders:
      • Thyrotoxicosis, acute adrenal insufficiency
    • Inborn errors of metabolism:
      • Blue diaper syndrome (defect in tryptophan metabolism)
      • Congenital lactase deficiency
      • Infantile hypophosphatasia (deficiency of tissue nonspecific alkaline phosphatase)
    • Immobilization
      • More common in adolescence
      • Spinal cord injury, quadriplegia
      • May see low serum alkaline phosphatase, hypercalciuria
    • Subcutaneous fat necrosis (SCFN)
      • After complicated delivery
      • Often a history of birth asphyxia
      • Excessive 1,25(OH)2-vitamin D production
    • Other
      • Trisomy 21, SHORT syndrome (short stature, hyperextensibility of joints/[inguinal] hernia, ocular depression, Rieger anomaly, tooth eruption delay), and inflammatory bowel disease, phosphate depletion in severe prematurity

History

  • Clinical presentation is dependent on age of child, degree of hypercalcemia, and the underlying disorder.
  • Mild hypercalcemia (10 to 12 mg/dL)
    • Patients often asymptomatic
    • Failure to thrive
    • Hematuria
    • Nephrolithiasis
    • Nephrocalcinosis
  • Moderate hypercalcemia (12 to 14 mg/dL)
    • Constipation
    • Anorexia
    • Abdominal pain
    • Weakness
    • Hematuria
    • Polyuria
    • Dehydration (in infants)
  • Severe hypercalcemia (>14 mg/dL)
    • Nausea, vomiting
    • Dehydration
    • Encephalopathy
    • Psychological changes,
    • Poor feeding, hypotonia, and apnea (in newborns)

Physical Exam

  • Usually normal—unless syndromic
  • Parathyroid mass usually not palpable
  • Hypertension
  • Dehydration
  • Soft tissue calcifications uncommon

Diagnostic Tests and Interpretation

Initial Tests

  • Confirm hypercalcemia and obtain intact PTH, serum phosphate, and magnesium, plus electrolyte panel.
  • Collect urine to measure calcium excretion and evaluate calcium-to-creatinine ratio:
    • Normal spot urine calcium to creatinine varies by age (<7 months of age, <0.86 mg/mg; 7 to 18 months of age, <0.60 mg/mg; 19 months to 6 years, <0.45 mg/mg; >6 years to adults, <0.22 mg/mg).
    • In children with low muscle mass, can use urine calcium-to-osmolality ratio instead
  • Hypercalcemia + low or inappropriately normal urinary calcium indicate FHH (or NSHPT).
  • Hypercalcemia, hypophosphatemia, and hyperphosphaturia, plus increased PTH, indicate primary HPT.
  • Hypercalcemia, hypophosphatemia, and hyperphosphaturia, with a decreased PTH, indicate HHM if PTHrP is elevated.
  • Hypercalcemia/hypercalciuria with normal or increased phosphate points toward other causes (vitamin D or A excess, endocrine disorders, drugs).
  • Radiography may show soft tissue calcifications in skin, subcutaneous soft tissues, and gastric mucosa.
  • Radiography may show subperiosteal resorption (distal phalanges), tapering of the distal clavicles, “salt and pepper” appearance of the skull, bone cysts and “brown tumors,” called osteitis fibrosa cystica (in prolonged hypercalcemia due to HPT).
  • Renal ultrasound may show nephrocalcinosis/nephrolithiasis.
  • Doppler ultrasound or sestamibi scintigraphy for preoperative assessment of parathyroid adenomas

Diagnostic Procedures/Other

Electrocardiogram may show shortened QTc interval.

ALERT
  • In hypoalbuminemia, measured calcium should be corrected for the abnormality in albumin.
  • Corrected calcium = measured calcium (in mg/dL) + 0.8 (4.0 − albumin [in g/dL])
  • Some prefer to measure ionized calcium in such situations.

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