Hypercalcemia

Etiology

Parathyroid-Related

  • Benign Familial Hypercalcemia
  • Primary Hyperparathyroidism (see Hyperparathyroidism, [[Hyperparathyroidism]])
  • Tertiary Hyperparathyroidism (see Hyperparathyroidism, [[Hyperparathyroidism]])

Non-Parathyroid-Related

Drugs

Endocrine Disease

Granulomatous Disease

Malignancy

  • Breast Cancer (see Breast Cancer, [[Breast Cancer]])
  • Non-Hodgkin’s Lymphoma (see Lymphoma, [[Lymphoma]])
  • Prostate Cancer (see Prostate Cancer, [[Prostate Cancer]])
  • Renal Cell Carcinoma (see Renal Cancer, [[Renal Cancer]]): hypercalcemia occurs in 15% of cases
    • Mechanisms: lytic bone metastases, parathyroid hormone-related protein (PTHrp) production, increased IL-6 (which enhances effect of PTHrp), and prostaglandin-induced enhancement of bone resorption
  • Squamous Cell Lung Cancer (see Lung Cancer, [[Lung Cancer]])
  • Other Squamous Cell Cancers

Other

  • Immobilization
  • Rhabdomyolysis (see Rhabdomyolysis, [[Rhabdomyolysis]]): approximately 30% of patients with rhabdomyolysis are hypercalcemic during the recovery/diuretic phase of AKI (ATN), this is due to increased 1,25(OH)2D occurring during this phase

Physiology

Effects on Cardiac Physiology

  • Hypercalcemia Shortens the Duration of Plateau of the Cardiac Fiber Action Potential

Diagnosis

Diagnosis Based on Parathyroid Hormone (PTH) Level

Normal-High PTH Level

  • Parathyroid-Related Etiology
    • Normal-High 24 hr Urinary Calcium: suggests primary hyperparathyroidism
    • Low 24 hr Urinary Calcium: suggests benign familial hypercalcemia

Low PTH Level

  • Drug-Induced Hypercalcemia
  • Endocrine Disease
    • Adrenal Insufficiency
    • Hyperthyroidism
  • Granulomatous Disease
    • Sarcoidosis
    • Tuberculosis
  • Malignancy

Clinical Manifestations

General Comments

  • Relationship of Symptoms to Calcium Level: symptoms are related to the calcium level and rapidity of increase in the calcium level

Cardiovascular Manifestations

Arrhythmias

  • Clinical: arrhythmias can occur at calcium levels 14-15

Atrioventricular Heart Blocks

Bradycardia (see Bradycardia, [[Bradycardia]])

  • Epidemiology: predominantly occurs in severe hypercalcemia

Increased Sensitivity to Digoxin (see Digoxin, [[Digoxin]])

  • Clinical: enhanced digoxin toxicity

Shortened Q-T Interval (see Shortened Q-T Interval, [[Shortened Q-T Interval]])

  • Physiology: serum calcium is negatively correlated with the QT (and QTc) interval duration

Lengthened T-Wave Duration

  • Physiology: serum calcium is positively correlated with the T-wave duration

Gastrointestinal Manifestations

Neurologic Manifestations

Renal Manifestations


Treatment

Normal Saline (see Normal Saline, [[Normal Saline]])

  • Mechanism: increases glomerular filtration rate and decreases distal tubular sodium and calcium absorption -> lowers calcium 1.5-2.5 mg/dL
  • Dose: 3-4 L of normal saline per 24-48 hrs
  • Onset of Action: hours
  • Duration of Action: hours

Furosemide (Lasix) (see Furosemide, [[Furosemide]])

  • Mechanism: inhibits sodium and calcium absorption in thick ascending Loop of Henle
  • Dose: give only after intravenous fluid repletion
  • Onset of Action: hours
  • Duration of Action: hours

Calcitonin (see Calcitonin, [[Calcitonin]])

  • Mechanism: decreases bone calcium release/increases renal excretion (useful for increased bone turnover) -> lowers calcium about 1-2 mg/dL
  • Dose: 4-8 ug/ kg IM/SQ q6-8 hours
  • Onset of Action: hours
  • Duration of Action: transient (may be <24 hrs)

Pamidronate (see Pamidronate, [[Pamidronate]])

  • Mechanism: bisphosphonate -> binds to hydroxyapatite
  • Dose: 60 mg IV over 4 hours
  • Onset of Action: 1-2 days (peak in 7 days)
  • Duration of Action : days-4 weeks
  • Adverse Effects

Prednisone (see Corticosteroids, [[Corticosteroids]])

  • Indications: tumors that have 1,25-Vitamin D3 as part of their mechanism
    • Non-Hodgkin’s Lymphoma (see Lymphoma, [[Lymphoma]])
    • Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]])
    • Breast Cancer (see Breast Cancer, [[Breast Cancer]])
    • Vitamin D Toxicity (see Vitamin D, [[Vitamin D]])
    • Granulomatous Disease
  • Mechanism: increases calcium excretion
  • Dose
    • Prednisone: 40-100 mg/day in 4 divided doses x 3-5 days
    • Hydrocortisone: 100 q8hrs X 3-5 days
  • Onset of Action: hours
  • Duration of Action: days

Gallium Nitrate (see Gallium Nitrate, [[Gallium Nitrate]])

  • Mechanism: lowers calcium 1-5 mg/dL
  • Dose: 200 mg/m2 per day IV for 5 days (continuous)
  • Onset of Action: peaks at 8 days
  • Duration of Action: days-weeks
  • Adverse Effects: renal

Mithramycin (Plicamycin) (see Mithramycin, [[Mithramycin]])

  • Mechanism: inhibits osteoclasts -> lowers calcium 1-5 mg/dl
  • Dose: 15-25 ug/kg IV over 4-6 hours q24-48 hours
  • Onset of Action: 12 hours
  • Duration of Action: days-weeks
  • Adverse Effects
    • Bone Marrow Toxicity
    • Renal
    • Hepatic
    • Hypokalemia (see Hypokalemia, [[Hypokalemia]])
    • Stomatitis
    • Nausea (see Nausea and Vomiting, [[Nausea and Vomiting]])

Hemodialysis with Low Calcium Dialysate (see Hemodialysis, [[Hemodialysis]])

  • Indications: for emergent severe hypercalcemia

Indomethacin/Aspirin (see Indomethacin, [[Indomethacin]] and Acetylsalicylic Acid, [[Acetylsalicylic Acid]]))

  • Indications
    • Malignancy-Associated Hypercalcemia
    • Humoral Hypercalcemia
    • Hypercalcemia with Osteolytic Lesions
  • Mechanism: inhibits prostaglandin E synthesis

References

  • Cardiac conduction in patients with hypercalcaemia due to primary hyperparathyroidism. Clin Endocrinol (Oxf) 1992;37:29-33 [MEDLINE]
  • Acute hypercalcemia and severe bradycardia in a patient with breast cancer. CMAJ. 1993 May 1;148(9):1506-8 [MEDLINE]
  • Sinus node dysfunction secondary to hyperparathyroidism. J Cardiovasc Pharmacol Ther. 2004 Jun;9(2):145-7 [MEDLINE]
  • Endocrine and metabolic emergencies: hypercalcaemia. Ther Adv Endocrinol Metab. 2010 Oct; 1(5): 225–234 [MEDLINE]
  • Atrioventricular nodal dysfunction secondary to hyperparathyroidism. J Thorac Dis. 2013 Jun; 5(3): E90–E92 [MEDLINE]
  • Heart Block and Acute Kidney Injury Due to Hyperparathyroidism-Induced Hypercalcemic Crisis Yale J Biol Med. 2014 Dec; 87(4): 563–567 [MEDLINE]