History

Hypercalcemia can cause symptoms at levels as low as 12 mg/dL and consistently causes symptoms at 15 mg/dL. Hypercalcemia initially and predominantly affects the GI and nervous systems. Symptoms include the following:

Nervous system
- Personality changes
- Malaise
- Headache
- Hallucinations
- Unsteady gait
- Proximal muscle weakness
- CNS depression
- Irritability
- Confusion
GI system
- Hypercalcemia can cause a paralytic ileus, with resultant abdominal cramping, constipation, anorexia, nausea, and vomiting.
- Ectopic calcification can lead to symptoms of pancreatitis, with epigastric pain and vomiting.
- Increased gastric acid secretion may produce symptoms consistent with gastritis.
Renal symptoms
- Renal stones
- Nephrogenic diabetes insipidus (DI) with polyuria and polydipsia
- Renal failure
Musculoskeletal system - Bone pain
Ectopic calcification
- Pruritus
- Conjunctivitis
Miscellaneous symptoms
- Congenital deformity
- Other symptoms of malignancy
- Symptoms of other underlying causes of hypercalcemia
- Hypercalcemia-associated acute respiratory distress syndrome (rare)^[11]

Physical Examination

Vital signs include the following:

Bradycardia
Possible hypertension

Neurologic examination findings include the following:

Depressed sensorium
Confusion
Gait disturbances
Hyporeflexia
Proximal muscle weakness

Even at lower levels, patients can have renal failure and ectopic calcification, including renal stones and pancreatitis.

Ectopic calcification can also manifest as conjunctivitis or band keratopathy on eye examinations.

Neonates may be asymptomatic or may have vomiting, hypotonia, hypertension, or seizures.

At levels of 17 mg/dL, calcium phosphate precipitation through the blood and soft tissues can lead to coma or lethal cardiac arrest.

Hypercalcemia is often asymptomatic. If hypercalcemia is symptomatic, the differential diagnosis rests heavily on the predominating symptom.

Weakness and altered sensorium may be symptomatic of a myriad of neurologic disorders, as well as toxins (eg, organophosphate poisoning), lupus, or thyroid dysregulation.

Weakness alone may be confused with hypokalemia, whereas ataxia is found in phenytoin overdoses, mass lesions, stroke syndromes, and encephalitides.

Hypertension may indicate a cardiac or renal problem.

Many manifestations of hypercalcemia (eg, pancreatitis, renal stones, gastritis, conjunctivitis) may be caused by etiologies different from hypercalcemia.

Differential Diagnoses

[Guideline] Hawley C, Elder G. Calcium. Westmead NSW (Australia): CARI - Caring for Australasians with Renal Impairment; 2005 Oct. [Full Text].
Vezzoli G, Soldati L, Gambaro G. Roles of calcium-sensing receptor (CaSR) in renal mineral ion transport. Curr Pharm Biotechnol. Apr 2009. 10(3):302-10. [QxMD MEDLINE Link].
Sangun O, Dundar BN, Erdogan E. Severe hypercalcemia associated with Williams syndrome successfully treated with pamidronate infusion therapy. J Pediatr Endocrinol Metab. 2011. 24(1-2):69-70. [QxMD MEDLINE Link].
Lenherr-Taube N, Furman M, Assor E, et al. Mild idiopathic infantile hypercalcemia-part 2: a longitudinal observational study. J Clin Endocrinol Metab. 2021 Sep 27. 106 (10):2938-48. [QxMD MEDLINE Link].
Roizen J, Levine MA. A meta-analysis comparing the Biochemistry of Primary Hyperparathyroidism in Youths to the Biochemistry of Primary Hyperparathyroidism in Adults. J Clin Endocrinol Metab. 2014 Sep 2. jc20142268. [QxMD MEDLINE Link].
Arico M, Egeler RM. Clinical aspects of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998 Apr. 12(2):247-58. [QxMD MEDLINE Link].
De Sanctis V, Fiscina B, Ciccone S. Severe hypercalcemia in a patient treated for hypoparathyroidism with calcitriol. Pediatr Endocrinol Rev. 2010 Jun. 7(4):363-5. [QxMD MEDLINE Link].
Bennett MT, Sirrs S, Yeung JK, Smith CA. Hypercalcemia due to all trans retinoic acid in the treatment of acute promyelocytic leukemia potentiated by voriconazole. Leuk Lymphoma. 2005 Dec. 46(12):1829-31. [QxMD MEDLINE Link].
Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clin Endocrinol (Oxf). 2005 Nov. 63(5):566-76. [QxMD MEDLINE Link].
Guise TA, Wysolmerski JJ. Cancer-associated hypercalcemia. N Engl J Med. 2022 Apr 14. 386 (15):1443-51. [QxMD MEDLINE Link].
Hsu YH, Chen HI. Acute respiratory distress syndrome associated with hypercalcemia without parathyroid disorders. Chin J Physiol. Dec 2008. 51(6):414-8. [QxMD MEDLINE Link].
Balentine CJ, Xie R, Kirklin JK, Chen H. Failure to Diagnose Hyperparathyroidism in 10,432 Patients With Hypercalcemia: Opportunities for System-level Intervention to Increase Surgical Referrals and Cure. Ann Surg. 2017 Jul 3. [QxMD MEDLINE Link].
Baroncelli GI, Bertelloni S. The Use of Bisphosphonates in Pediatrics. Horm Res Paediatr. 2014 Nov 6. 290-302. [QxMD MEDLINE Link].
Gatti D, Viapiana O, Idolazzi L, Fracassi E, Adami S. Neridronic acid for the treatment of bone metabolic diseases. Expert Opin Drug Metab Toxicol. Oct 2009. 5(10):1305-11. [QxMD MEDLINE Link].
Faggiano A, Tavares LB, Tauchmanova L, Milone F, Mansueto G, Ramundo V et al. Effect of treatment with depot somatostatin analogue octreotide on primary hyperparathyroidism in MEN1 patients. Clin Endocrinol. May 2008. Epub:[QxMD MEDLINE Link].
Landesberg R, Cozin M, Cremers S, Woo V, Kousteni S, Sinha S, et al. Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg. May 2008. 66(5):839-47. [QxMD MEDLINE Link].
Oski F, DeAngelis CD, Feigin RD. Principles and Practice of Pediatrics. 2nd ed. 1994.

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Investigations flowchart.

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Table.

Laboratory Test	Reference Range	Normal Response to Increased Calcium
Serum calcium	8.5-10.2 mg/dL	NA
Ionized calcium	1-1.3 mmol/L	NA
PTH (intact)	10-55 pg/mL*	Decrease
Serum phosphate	Age-dependent	Increase
1,25-dihydroxyvitamin D	36-108 pmol/L	Decrease
Alkaline phosphatase	68-217 U/L	Normal
Urine calcium	4 mg/kg/d	Increase
Urine Ca/Cr ratio	See note†	Increase
Urine cAMP‡	< 5 mol	Decrease
*Note that 1 mmol/L equals 4 mg/dL. †In infants younger than 7 months, the reference range is less than 0.86; in infants aged 7-18 months, the reference range is less than 0.6. By age 6-7 years, the adult reference range of less than 0.21 is reached.‡The urine cAMP level generally parallels the PTH level.

Table.

Condition	Serum Phosphorus	Serum Alkaline Phosphatase	Urine Calcium	Urine Phosphate	PTH
Hyperparathyroidism	Low	Normal-high	High*	High	High
Vitamin D excess	Normal-high	Low	High	High
Malignancy	Often low	High †	Variable	High
Granulomatous disease	Normal-high	Normal-high	High	Normal
Milk alkali syndrome	Normal-high	Normal	Normal	Normal
FHH	Normal or low	Normal	Low (< 200mg/d)	Normal	Low
*67% of the time † Except hematologic malignancies, in which alkaline phosphatase is normal

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Author

Pisit (Duke) Pitukcheewanont, MD Associate Professor of Clinical Pediatrics, University of Southern California, Keck School of Medicine, Childrens Hospital Los Angeles

Pisit (Duke) Pitukcheewanont, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, American Society for Bone and Mineral Research, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Chief Editor

Sasigarn A Bowden, MD, FAAP Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital

Sasigarn A Bowden, MD, FAAP is a member of the following medical societies: American Society for Bone and Mineral Research, Central Ohio Pediatric Society, Endocrine Society, International Society for Pediatric and Adolescent Diabetes, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Ilene A Claudius, MD Assistant Professor of Pediatrics, Division of Emergency Medicine, Children's Hospital, Los Angeles

Ilene A Claudius, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

Jon Nakamoto, MD Consulting Staff, Department of Pediatric Endocrinology, Quest Diagnostics

Jon Nakamoto, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

Acknowledgements

Oved Fattal, MD Staff Physician, Department of Pediatrics, Kaiser Permanente Medical Group

Oved Fattal, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.