DESCRIPTION

Hypercalcemia represents 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 depending on age of presentation

ETIOLOGY

The first step in the determination of an etiology for hypercalcemia is measurement of the 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 usually normal (slightly elevated in 15–20%)
    • Fractional calcium excretion <1%
• Hypercalcemia with low PTH
  • Williams syndrome
    • 15% with (usually 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 delays, “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, vitamins A and D excess, theophylline, teriparatide, abaloparatide
  • Malignancy
    • Local osteolysis (PTHrP, cytokine production, chemotherapy)
    • Humoral hypercalcemia of malignancy (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 observe 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), inflammatory bowel disease, parenteral nutrition, phosphate depletion in severe prematurity

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 into the circulation
• Increased renal tubule calcium reabsorption
• Calcium entry in the circulation greater than urinary calcium excretion and deposition of calcium in bone