Basics
Description
Hypercalcemia represents an elevation in ionized and total calcium concentrations.
Epidemiology
- Less common than hypocalcemia
- Less common in children than adults
- Adults: >90% caused by a tumor or hyperparathyroidism (HPT)
- 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
- 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
- CyclinD1/PRAD1, MEN1 mutations
- Parathyroid carcinoma (rare)
- Neonatal severe HPT (NSHPT)
- Homozygous inactivating calcium-sensing receptor (CaSR) mutations
Hypercalcemia with NORMAL PTH
- Familial benign hypercalcemia or familial hypocalciuric hypercalcemia (FHH)
- Heterozygous inactivating CaSR mutations (AD)
- Typically asymptomatic
- Mild hypercalcemia
- PTH usually normal (may be slightly elevated)
- Fractional calcium excretion <1%
Hypercalcemia with LOW PTH
- Williams syndrome
- 15% with (transient) hypercalcemia
- Contiguous gene deletion syndrome 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 "
- Jansen metaphyseal chondrodysplasia
- Heterozygous mutations in PTHR1 lead to constitutive activation of PTH/PTHrP receptor.
- Short-limbed short stature
- Idiopathic hypercalcemia of infancy (Lightwood syndrome)
- Some cases due to loss of function mutations in CYP24A1
Other causes of hypercalcemia (mostly PTH-independent):
- Medications:
- Thiazides, 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
- 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, hypophosphatasia
- 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
Alert
The first step in the determination of an etiology of hypercalcemia is measurement of an intact serum parathyroid hormone (intact PTH) concentration.
History
- Clinical presentation is dependent on age of child, degree of hypercalcemia and the underlying disorder.
- Mild hypercalcemia (10 " 12 mg/dL)
- Patients often asymptomatic
- Failure to thrive
- Hematuria
- Nephrolithiasis
- Nephrocalcinosis
- Moderate hypercalcemia (12 " 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 & Interpretation
Lab
- Confirm hypercalcemia and obtain intact PTH, serum phosphate, and magnesium, plus electrolyte panel.
- Collect urine to measure calcium excretion and examine calcium/creatinine ratio:
- Normal spot urine calcium creatinine varies by age (<7 months of age, <0.86 mg/mg; 7 " 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 point toward other causes (vitamin D or A excess, endocrine disorders, drugs).
Imaging
- 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 (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.
Treatment
General Measures
- Management depends on the etiology and the severity of hypercalcemia.
- Prompt therapy is needed for severe hypercalcemia (calcium >14 mg/dL).
- In mild/asymptomatic hypercalcemia, no treatment may be needed (FHH).
Alert
Important to diagnose FHH and distinguish it from other forms of hypercalcemia to avoid unnecessary drug therapy and parathyroid surgeries
General Principles
- Rehydration
- Increase urinary calcium excretion.
- Inhibit bone resorption.
- Decrease intestinal absorption:
- Depending on cause of hypercalcemia, consider low-calcium diet.
Medication (Drugs)
- Hydration therapy (saluresis)
- Isotonic saline 3,000 mL/m2 over 24 " 48 hours intravenously
- Promote calciuresis (after hydration):
- Furosemide 1 mg/kg every 6 hours intravenously
- Decrease bone resorption:
- For persistent moderate to severe hypercalcemia
- Acutely: calcitonin 4 units/kg subcutaneously every 12 hours
- Bisphosphonate therapy (pamidronate 0.5 " 1 mg/kg intravenously over 4 " 6 hours)
- Glucocorticoids
- Inhibit 1-α hydroxylase and reduce intestinal absorption
- Prednisone 1 " 2 mg/kg/24 h
- Calcimimetics (cinacalcet) bind the CaSR and suppress PTH secretion:
- At this time, caution in using cinacalcet in children given pediatric death in a research study using this drug.
Surgery/Other Procedures
- Dialysis: last resort
- Surgery (for primary HPT)
Ongoing Care
Follow-up Recommendations
Postsurgical hypocalcemia is common after parathyroidectomy " especially after severe HPT ( "hungry bone syndrome " ), and requires calcium and phosphate supplementation, and sometimes calcitriol treatment.
Prognosis
- Depends on cause
- Permanent hypoparathyroidism may result from total parathyroidectomy.
Additional Reading
- Hendy GN, D 'Souza-Li L, Yang B, et al. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat. 2000;16(4):281 " 296. [View Abstract]
- Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Miner Res. 1991;6(Suppl 2):S51 " S59. [View Abstract]
- Letavernier E, Rodenas A, Guerrot D, et al. Williams-Beuren syndrome hypercalcemia: is TRPC3 a novel mediator in calcium homeostasis? Pediatrics. 2012;129(6):e1626 " e1630. [View Abstract]
- Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011;365(5):410 " 421. [View Abstract]
- Sebestyen JF, Srivastava T, Alon US. Bisphosphonates use in children. Clin Pediatr. 2012;51(11):1011 " 1024. [View Abstract]
- Trehan A, Cheetham T, Bailey S. Hypercalcemia in acute lymphoblastic leukemia: an overview. J Pediatr Hematol Oncol. 2009;31(6):424 " 427. [View Abstract]
- Wesseling K, Bakkaloglu S, Salusky I. Chronic kidney disease mineral and bone disorder in children. Pediatr Nephrol. 2008;23(2):195 " 207. [View Abstract]
Codes
ICD09
- 275.42 Hypercalcemia
- 252.00 Hyperparathyroidism, unspecified
ICD10
- E83.52 Hypercalcemia
- P71.8 Other transitory neonatal disord of calcium & magnesium metab
- E21.3 Hyperparathyroidism, unspecified
SNOMED
- 66931009 Hypercalcemia (disorder)
- 276645004 Infantile hypercalcemia (disorder)
- 66999008 hyperparathyroidism (disorder)
FAQ
- Q: When should vitamin D or vitamin A levels be measured?
- A: If there is a history of alternative medicine, over-the-counter drugs, or supplements
- Q: When should one consider bisphosphonate therapy?
- A: In hypercalcemia mainly due to mobilization of calcium from bone (e.g. severe HPT, immobilization, tumor)
- Q: When should one consider glucocorticoids?
- A: In hypervitaminosis D or A and in excessive 1,25(OH)2-vitamin D production