Parathyroid-Related

• Benign Familial Hypercalcemia
• Primary Hyperparathyroidism (see Hyperparathyroidism)
• Tertiary Hyperparathyroidism (see Hyperparathyroidism)

Non-Parathyroid-Related

Drugs

• Lithium (see Lithium)
• Milk Alkali Syndrome (see Milk Alkali Syndrome)
• Thiazides (see Thiazides)
• Vitamin D Intoxication (see Vitamin D)
• Vitamin A Intoxication (see Vitamin A)

Endocrine Disease

• Adrenal Insufficiency (see Adrenal Insufficiency)
• Hyperthyroidism (see Hyperthyroidism)

Granulomatous Disease

• Chronic Berylliosis (see Beryllium)
• Sarcoidosis (Sarcoidosis)
• Tuberculosis (TB) (see Tuberculosis)

Malignancy

• Breast Cancer (see Breast Cancer)
• Multiple Myeloma (see Multiple Myeloma)
• Non-Hodgkin’s Lymphoma (see Lymphoma)
• Prostate Cancer (see Prostate Cancer)
• Renal Cell Carcinoma (see Renal Cancer)
  • Epidemiology
    • Hypercalcemia Occurs in 15% of Renal Cell Carcinoma Cases
  • Mechanisms
    • Osteolytic Bone Metastases
    • Parathyroid Hormone-Related Protein (PTHrp) Production
    • Increased Interleukin-6 (IL-6): which enhances the effect of PTHrp
    • Prostaglandin-Induced Enhancement of Bone Resorption
• Squamous Cell Lung Cancer (see Lung Cancer)
  • Epidemiology
    • Squamous Cell Histology: accounts for 51% of paraneoplastic hypercalcemia cases in lung cancer
    • Adenocarcinoma Histology: accounts for 22% of paraneoplastic hypercalcemia cases in lung cancer
    • Small Cell Histology: accounts for 15% of paraneoplastic hypercalcemia cases in lung cancer
  • Mechanisms
    • Osteolytic Bone Metastases
    • Tumor Production of PTH-Related Protein (PTHrP), Calcitriol, or Osteoclast-Activating Factors
• Other Squamous Cell Cancers

Other

• Immobilization
  • Epidemiology
    • Immobilization is a Common Etiology of Mild Hypercalcemia in Patients with Critical Illness
• Rhabdomyolysis (see Rhabdomyolysis)
  • Approximately 30% of Patients with Rhabdomyolysis are Hypercalcemic During the Recovery/Diuretic Phase of Acute Kidney Injury Due to Acute Tubular Necrosis
    • Due to Increased 1,25(OH)2D Occurring During this Phase

Effects of Hypercalcemia on Cardiac Physiology

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

Diagnosis Based on Parathyroid Hormone (PTH) Level

Normal-High Parathyroid Hormone (PTH) Level

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

Low Parathyroid Hormone (PTH) Level

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

General Comments

• Relationship of Symptoms to Calcium Level
  • Clinical Symptoms in Hypercalcemia are Related to the Calcium Level and the Rapidity of Increase in the Calcium Level

Cardiovascular Manifestations

• Arrhythmias
  • Clinical
    • Arrhythmias Can Occur at Calcium Levels 14-15
• Atrioventricular Heart Blocks
  • Epidemiology
    • Heart Blocks Predominantly Occur in the Setting of Severe Hypercalcemia
  • Clinical
    • First Degree Atrioventricular Block (see First Degree Atrioventricular Block)
    • Second Degree Atrioventricular Block-Mobitz Type I (Wenckebach) (see Second Degree Atrioventricular Block-Mobitz Type I)
    • Second Degree Atrioventricular Block-Mobitz Type II (see Second Degree Atrioventricular Block-Mobitz Type II)
    • Third Degree Atrioventricular Block (see Third Degree Atrioventricular Block)
• Increased Sensitivity to Digoxin(see Digoxin)
  • Clinical: enhanced digoxin toxicity
• Lengthened T-Wave Duration
  • Physiology
    • Serum Calcium is Positively Correlated with the T-Wave Duration
• Shortened Q-T Interval (see Shortened Q-T Interval)
  • Physiology
    • Serum Calcium is Negatively Correlated with the QT (and QTc) Interval Duration
• Sinus Bradycardia (see Sinus Bradycardia)
  • Epidemiology
    • Sinus Bradycardia Predominantly Occurs in the Setting of Severe Hypercalcemia

Gastrointestinal Manifestations

• Abdominal Pain (see Abdominal Pain)
• Acute Pancreatitis (see Acute Pancreatitis)
• Anorexia (see Anorexia)
• Constipation (see Nausea and Vomiting)
• Peptic Ulcer Disease (PUD) (see Peptic Ulcer Disease)

Neurologic Manifestations

• Fatigue (see Fatigue)
• Confusion/Delirium (see Delirium)
• Depression (see Depression)
• Increased Sleep Requirement/Coma (see Obtundation-Coma)
• Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome)
• Generalized Weakness (see Weakness)

Renal Manifestations

• Decreased Concentrating Ability/Polyuria (see Polyuria)
• Metastatic Calcification (see Metastatic Calcification)
• Nephrocalcinosis
• Nephrolithiasis (see Nephrolithiasis)

Normal Saline (see Normal Saline)

• Mechanism
  • Normal Saline Increases the Glomerular Filtration Rate and Decreases Distal Tubular Sodium and Calcium Absorption
    • Normal Saline Typically Lowers the Serum 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)

• Mechanism
  • Furosemide 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)

• Mechanism
  • Calcitonin Decreases Bone Calcium Release/increases Renal Excretion (Useful for Diseases Characterized by Increased Bone Turnover)
    • Calcitonin Typically Lowers the Serum Calcium About 1-2 mg/dL
• Dose: 4-8 μg/kg IM/SQ q6-8 hours
• Onset of Action: hours
• Duration of Action: transient (may be <24 hrs)

Pamidronate (see Pamidronate)

• Mechanism
  • Bisphosphonates Bind 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
  • Fever (see Fever)
  • Leukopenia (see Leukopenia)
  • Myalgias (see Myalgias)

Prednisone (see Corticosteroids)

• Indications Useful for Tumors/conditions Which Have 1,25-Vitamin D3 as Part of Their Mechanism)
  • Non-Hodgkin’s Lymphoma (see Lymphoma)
  • Multiple Myeloma (see Multiple Myeloma)
  • Breast Cancer (see Breast Cancer)
  • Vitamin D Toxicity (see Vitamin D)
  • Granulomatous Disease
• Mechanism
  • Prednisone 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)

• Mechanism
  • Gallium Nitrate Typically Lowers the Serum 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)

• Mechanism
  • Mithramycin Inhibits Osteoclasts
    • Mithramycin Lowers the Serum 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)
  • Stomatitis
  • Nausea (see Nausea and Vomiting)

Hemodialysis with Low Calcium Dialysate (see Hemodialysis)

• Indications
  • Emergent Severe Hypercalcemia

Indomethacin/Aspirin (see Indomethacin and Acetylsalicylic Acid)

• Indications
  • Malignancy-Associated Hypercalcemia
    • Renal Cell Carcinoma (see Renal Cancer)
  • Humoral Hypercalcemia
  • Hypercalcemia with Osteolytic Lesions
• Mechanism
  • Indomethacin/Aspirin Inhibit Prostaglandin E Synthesis

Denosumab (Xgeva, Prolia) (see Denosumab)

• Indications
  • Hypercalcemia of Malignancy: Xgeva is FDA-approved for this indication