Hypercalcemia

Hypercalcemia Causes & Presentation

Hypercalcemia is a condition in which the calcium level in your blood is above normal. The normal range of calcium is 8.5 to 10.5 mg/dl (4.3 to 5.3 mEq/L or 2.2 to 2.7 mmol/L).1 This reference range may differ by 0.5 mg/dl depending on the laboratory or hypercalcemia workup. Patients typically present with symptoms of hypercalcemia when the serum calcium level is more than 12 mg/dl.

Hypercalcemia symptoms may include2:

  • Digestive symptoms, such as stomach pain, nausea, and vomiting
  • Fatigue
  • Constipation
  • Increased urination
  • Increased thirst
  • Confusion and memory loss
  • Depression
  • Muscle weakness

Chronic hypercalcemia symptoms may include2:

  • Kidney stones
  • Bone pain
  • Osteoporosis
  • Osteomalacia
  • Arthritis
  • Fractures
  • Pancreatitis
  • Peptic ulcer disease

Causes include2:

  • Excess parathyroid hormone due to:
    • Hyperplasia or adenoma of the parathyroid gland
    • Familial hypocalciuric hypercalcemia (FHH). This is an inherited disorder that causes high blood levels of calcium and low to moderate levels of urine calcium. A diagnosis is typically made after routine blood work as symptoms are not common.3
    • Endocrine neoplasia syndrome. People with this inherited disorder are at increased risk of developing medullary carcinoma of the thyroid and overgrowth of the parathyroid gland.4
  • Malignancies, including5:
    • Leukemia
    • Lymphoma
    • Rhabdomyosarcoma
    • Kidney
    • Breast
    • Gastrointestinal
    • Head and neck
    • Lung
    • Multiple myeloma
  • Excessive intake of milk
  • Sarcoidosis
  • Tuberculosis
  • Fungal infections
  • Thyrotoxicosis
  • Hypoadrenalism
  • Pheochromocytoma
  • Other causes, such as2:
    • Murk Jansen syndrome
    • Williams syndrome
    • Acute or chronic renal failure
    • Being immobilized for long periods of time
    • Hypophosphatasia
    • Hypervitaminosis A
    • Treatment with lithium or thiazide diuretics
    • Milk-alkali syndrome (too much calcium in the diet)
    • Subcutaneous fat necrosis
    • Severe dehydration

Diagnostic Hypercalcemia Workup

Patients presenting with signs of hypercalcemia should have the following labs drawn2:

  • Serum parathyroid hormone
  • Vitamin D
  • Calcitonin
  • Ionized calcium
  • Phosphorous
  • Magnesium
  • Alkaline phosphatase
  • Urinary calcium-creatinine ratio
  • Renal function

Laboratory values and presentation of symptoms aid in determining a diagnosis of hypocalcemia vs hypercalcemia. Hypocalcemia is defined as total serum calcium concentration below the normal range of 8.5 to 10.5 mg/dL.6

Hypercalcemia may be described as2:

  • Mild (serum calcium level 10.5 to 11.9 mg/dL)
  • Moderate (serum calcium level 12.0 to 13.9 mg/dL)
  • Crisis (serum calcium level 14.0 to 16.0 mg/dL)

Imaging, including X-ray, MRI, and ultrasound should be done to rule out2:

  • Kidney stones
  • Sarcoidosis
  • Malignancies

Arrhythmias can occur and hypercalcemia ECG changes seen include2:

  • Mildly prolonged QRS and PR intervals
  • Elevated ST segment
  • Flattened or inverted T wave
  • J wave after QRS complex

Differential Diagnosis

Other diagnoses to consider during the hypercalcemia workup include2:

  • Hypermagnesemia
  • Hyperparathyroidism
  • Hyperphosphatemia
  • Familial hypocalciuric hypercalcemia
  • Williams or Murk Jansen syndrome

Patients with hyperparathyroidism will have high calcium and parathyroid hormone levels with low phosphorus. Patients with familial hypocalciuric hypercalcemia will have normal parathyroid hormone levels, high magnesium, and low calcium creatinine clearance.2

Parathyroid hormone related peptide levels are high in patients with hypercalcemia due to malignancy.

Infants with high calcium levels and dysmorphic features should be evaluated for Williams or Murk Jansen syndrome.2

Hypercalcemia Management (Nonpharmacotherapy & Pharmacotherapy)

Hypercalcemia treatment should be started in patients who present with hypercalcemia symptoms or have a serum calcium level of more than 14 mg/dl. Hypercalcemia treatment goals include eliminating excess calcium from the extracellular fluid, decreasing absorption of calcium in the digestive tract, and decreasing resorption of calcium in the bones.2

An infusion of 0.9% saline should be started at twice the maintenance rate. This is continued until urine output is greater than or equal to 200 mL/h to 300 mL/h. Patients with heart failure or insufficient renal function should receive hemodialysis to quickly lower the serum calcium level.2

Furosemide may be given to increase excretion of calcium.2

Patients with high parathyroid hormone levels should be evaluated for possible surgery to remove the source of increased parathyroid hormone secretion.

Hypercalcemia of malignancy is treated with bisphosphonates, such as etidronate, pamidronate, and alendronate. If further drug treatment for hypercalcemia is needed, mithramycin may be given. Mithramycin inhibits osteoclast function, but it can cause toxicity of the bone marrow, kidneys, and liver. 2

Hypercalcemia due to excess vitamin D is treated with corticosteroids or ketoconazole. These drugs inhibit 1-alpha-hydroxylase activity, the enzyme that catalyzes the synthesis of the active form of vitamin D.2

Calcitonin is used as an emergency treatment for hypercalcemia. It may be combined with other treatments, including intravenous saline, furosemide, oral phosphate, corticosteroids, and other treatments.7

The typical starting dosage of calcitonin injection is 4 IU/kg body weight given every 12 hours by subcutaneous or intramuscular injection. After one or two days, the dose may be doubled to 8 IU/kg body weight every 12 hours if necessary. After two more days, the dose may be increased to 8 IU/kg every 6 hours if needed.8

Hypercalcemia Complications

Complications may include2:

  • Mental status changes
  • Depression
  • Ulcers
  • Tingling and numbness of extremities
  • Dizziness
  • Heart arrhythmias
  • Kidney stones and renal failure
  • Constipation
  • Bone pain
  • Pancreatitis

Prognosis following a diagnosis of hypercalcemia typically depends on the cause. Hospitalization often results due to a hypercalcemia of malignancy. Hypercalcemia due to hyperparathyroidism may have a better prognosis but may have mild symptoms that last a long time.2

Monitoring

Patients’ vital signs should be monitored while hospitalized. Maintaining proper hydration should be stressed. Patients’ receiving hypercalcemia treatment with bisphosphonates should be educated to take these drugs while seated upright on an empty stomach with a full glass of water and to wait 30 minutes before eating food or drinking other beverages.2

Patients and family members should be instructed to watch for hypercalcemia symptoms and signs. Dieticians may provide diet plans to help patients avoid certain foods that may increase calcium levels. A team approach is helpful to educate patients and their families about this condition.2

References

1. Goldstein DA. Serum calcium. In: Walker HK, Hall WD, Hurst JW, ed. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Butterworths; 1990: chapter 143. 

2. Sadiq NM, Naganathan S, Badireddy M. Hypercalcemia. In: StatPearls. NCBI Bookshelf version. StatPearls Publishing: 2021. Accessed July 19, 2022.

3. Familial hypocalciuric hypercalcemia. National Center for Advancing Translational Sciences: Genetic and Rare Diseases Information Center. Updated Nov. 8, 2021. Accessed July 19, 2022.

4. Multiple endocrine neoplasia type 2A. National Center for Advancing Translational Sciences: Genetic and Rare Diseases Information Center. Updated Nov 8, 2021. Accessed July 19, 2022.

5. High calcium levels or hypercalcemia. American Society of Clinical Oncology. Published January 2020. Accessed July 19, 2022.

6. Goyal A, Anastasopoulou C, Ngu M, et al. Hypocalcemia. In: StatPearls. NCBI Bookshelf version: 2022. Accessed July 19, 2022.

7. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylaseJ Clin Endocrinol Metab. 2001;86(2):888-894. doi:10.1210/jcem.86.2.7220

8. Highlights of prescribing information: Miacalcin (calcitonin-salmon) injection, synthetic, for subcutaneous or intramuscular use. Food & Drug Administration. Revised September 2017. Accessed July 19, 2022.

Author Bio

Jen Seabright, PharmD, is a freelance medical writer based in Pittsburgh, PA.