Hypercalcemia

1. Causes
   1. Malignancy
      1. See Hypercalcemia of Malignancy
      2. Breast Cancer with bone metastases
      3. Lung Cancer
      4. Head and Neck squamous cell cancer
      5. Renal Cell Cancer
      6. Hematologic
         1. Multiple Myeloma
         2. Hodgkin's Lymphoma
   2. Paget's Disease of Bone
   3. Hyperparathyroidism
      1. Primary Hyperparathyroidism (most common cause)
         1. May be associated with multiple endocrine neoplasia
      2. Secondary Hyperparathyroidism
         1. Vitamin D Deficiency
         2. Chronic Renal Failure (CRF)
            1. Initially CRF results in Hypocalcemia
            2. PTH increases as response to low Vitamin D
            3. Known as tertiary Hyperparathyroidism
   4. Medications
      1. Thiazide Diuretics
      2. Lithium
      3. Vitamin A toxicity
      4. Vitamin D Toxicity (e.g. 25-Hydroxyvitamin D2)
      5. Milk alkali syndrome
   5. Endocrine
      1. Adrenal Insufficiency
      2. Thyrotoxicosis (Hyperthyroidism)
      3. Pheochromocytoma
      4. Acromegaly
   6. Other causes
      1. Familial hypocalciuric Hypercalcemia
      2. Prolonged immobilization
      3. Granulomatous disease (Sarcoidosis, Tuberculosis)
2. Symptoms and Signs
   1. Often asymptomatic
   2. Symptoms and Signs are related to Serum Calcium Levels
      1. Calcium > 11.5 mg/dl (2.9 mmol/L)
         1. Symptom onset
      2. Calcium > 13 mg/dl (3.2 mmol/L)
         1. Nephrocalcinosis
         2. Acute Renal Failure
   3. General Symptoms
      1. See complication-specific symptoms below
      2. Nausea
      3. Headache
      4. Diarrhea
      5. Anorexia
      6. Lethargy
      7. Pruritus (Metastatic calcification of skin)
3. Complications: Stones, Bones, Moans, Psychic Groans
   1. Renal ("Stones")
      1. Nephrolithiasis (Calcium Oxalate)
      2. Nephrocalcinosis
         1. Metastatic calcification renal tubules
         2. Polyuria from loss of urine concentrating function
   2. Musculoskeletal ("Bones")
      1. Osteitis fibrosa cystica (Late finding)
         1. Bone cysts from subperiosteal bone resorption
         2. "Brown tumor" in jaw
      2. Pseudogout
         1. Calcium pyrophosphate - Positively birefringent
      3. Osteoporosis
   3. Gastrointestinal ("Abdominal Moans")
      1. Peptic Ulcer Disease
         1. Calcium stimulates gastrin release
      2. Acute Pancreatitis
         1. Calcium activates phospholipases
      3. Constipation
         1. Most common gastrointestinal symptom
   4. Neuropsychiatric ("Psychic groans")
      1. Altered Level of Consciousness
      2. Decreased concentration and memory
      3. Personality change
      4. Psychosis
      5. Depression
   5. Eye
      1. Band Keratopathy (Corneal calcification)
         1. Metastatic calcification in eye limbus
   6. Cardiovascular
      1. Cardiac arrhythmia
      2. Hypertension
         1. Hypercalcemia Vasoconstricts vessels
4. Imaging
   1. Calcified soft tissues
5. Labs and Diagnostics
   1. Serum Calcium increased
      1. Total Serum Calcium > 10.5 mg/dl
      2. Ionized Calcium >5.6 mg/dl
   2. Electrocardiogram
      1. Shortened QT Interval
      2. Tall U Wave
      3. Bradycardia
6. Evaluation
   1. General
      1. Primary Hyperparathyroidism and cancer: 90% of cases
   2. Step 1: Confirm Hypercalcemia present (see labs above)
   3. Step 2: Obtain history for potential causes
      1. See causes above
      2. Eliminate potential causative medications
   4. Step 3: Obtain intact Parathyroid Hormone (PTH) Level
      1. PTH low: Go to Step 4
      2. PTH normal or high: Obtain 24 hour Urine Calcium
         1. 24 hour Urine Calcium normal or high
            1. Primary Hyperparathyroidism
            2. Recovery from Acute Tubular Necrosis
            3. Lithium therapy
         2. 24 hour Urine Calcium low
            1. Familial hypocalciuric Hypercalcemia
               1. Calcium to Creatinine ratio <0.01
   5. Step 4: Assess for malignancy and endocrinopathy
      1. Careful history and examination for tumor
      2. Tumor specific labs
         1. PTHrP: Increased in solid tumors
            1. Chest XRay
            2. Renal imaging
            3. Clinical Breast Exam and Mammogram
         2. Alkaline Phosphatase: Increased with bone lysis
            1. Consider bone scan
         3. Serum Protein Electrophoresis (SPEP)
            1. Monoclonal peak in Multiple Myeloma
         4. Calcitriol: Increased in Lymphoma and Granulomas
      3. Endocrine Labs
         1. Thyroid Stimulating Hormone (Hyperthyroidism)
         2. Corticotropin stimulation test (Addison's Disease)
         3. Insulin-like Growth Factor 1 (Acromegaly)
      4. Reconsider medication causes of low PTH
         1. Thiazide Diuretics
         2. Excessive Vitamin D Intake
         3. Excessive Vitamin A Intake
         4. Milk-Alkali Syndrome
         5. Aluminum Intoxication
7. Management
   1. Identify and treat underlying cause
   2. Mild Hypercalcemia (Serum Calcium <12 mg/dl)
      1. Adequate Hydration (>2 Liters per day)
      2. Maximize mobility
      3. Diuretics if symptomatic
         1. Furosemide (Lasix) 40-160 mg/day
   3. Severe Hypercalcemia (Serum Calcium >14 mg/dl)
      1. Consider also in moderate symptomatic Hypercalcemia
      2. Normal Saline 2 to 4 Liters/day for 1-3 days
         1. Adjust to obtain 200 ml urine output per hour
         2. Exercise caution in Congestive Heart Failure
         3. Anticipate 1-3 mg/dl drop in Serum Calcium
      3. Additional measures if refractory after hydration
         1. Lasix 10-20 mg q1-2 hours as needed
         2. Calcitonin 4-8 IU/kg IM or SQ q6 hours for 24 hours
      4. Agents with specific indications
         1. Malignancy: Bisphosphonates
            1. Pamidronate (Aredia) 60-90 mg IV over 4 hours
            2. Zoledronic acid (Zometa) 4 mg IV over 15 minutes
         2. Vitamin D Toxicity, Lymphoma, Myeloma or Granuloma
            1. Hydrocortisone 200 mg IV qd for 3 days
      5. Other measures
         1. Oral Phosphate (Neutra-Phos) 250 mg PO q6 hours
      6. Third line agents due to toxicity (avoid if possible)
         1. Plicamycin 10-25 mcg/kg/day IV over 6 hours x3 dose
            1. Cumulative liver, Kidney and platelet toxicity
            2. Bisphosphonates are preferred over Plicamycin
         2. Gallium Nitrate (Ganite)
            1. Dose: 100-200 mg/m2 IV over 24 hours for 5 days
            2. Significant renal and Bone Marrow toxicity
8. Prognosis
   1. Hypercalcemia of Malignancy suggests terminal stages
      1. Implies life expectancy of days to weeks
9. References
   1. Gibbs in Marx (2002) Rosen's Emergency Med, p. 1734-6
   2. Spiegel in Goldman (2000) Cecil Medicine, p. 1400-2
   3. Carroll (2003) Am Fam Physician 67(9):1959-66
   4. Ziegler (2001) J Am Soc Nephrol 12 Suppl 17:S3-9