Hypercalcemia

Aka: Hypercalcemia, High Serum Calcium, Serum Calcium Elevation, Hypercalcemic Crisis

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II. Causes: General

  1. Most common causes of Hypercalcemia
    1. Malignancy
    2. Primary Hyperparathyroidism
  2. Malignancy
    1. See Hypercalcemia of Malignancy (mediated by PTH-Related peptide)
    2. Presents with rapid onset, low PTH Levels and weight loss, Night Sweats
    3. Breast Cancer with bone metastases
    4. Squamous Cell Lung Cancer
    5. Head and Neck squamous cell cancer
    6. Renal Cell Cancer
    7. Esophageal Cancer
    8. Skin Cancer
    9. Hematologic
      1. Multiple Myeloma
      2. Hodgkin's Lymphoma
  3. Paget's Disease of Bone
  4. Medications
    1. Thiazide Diuretics
    2. Lithium
    3. Vitamin A Toxicity
    4. Vitamin D Toxicity (e.g. 25-Hydroxyvitamin D2)
    5. Milk Alkali Syndrome
    6. Theophylline
    7. Synthetic PTH (Teriparatide, Abaloparatide)
  5. Hyperparathyroidism (PTH Dependent Hyperparathyroidism)
    1. Primary Hyperparathyroidism (most common cause)
    2. Multiple Endocrine Neoplasia (type 1 or 2A)
    3. Familial Hypocalciuric Hypercalcemia
    4. Lithium treatment
    5. Chronic Kidney Disease (Renal Osteodystrophy)
    6. Hyperparathyroidism - Jaw Tumor Syndrome
  6. Endocrine
    1. Vitamin D Deficiency (Secondary Hyperparathyroidism)
    2. Adrenal Insufficiency
    3. Thyrotoxicosis (Hyperthyroidism)
    4. Pheochromocytoma
    5. Acromegaly
  7. Other causes
    1. Familial Hypocalciuric Hypercalcemia
    2. Prolonged immobilization
    3. Granulomatous disease (Sarcoidosis, Tuberculosis, Histoplasmosis, Coccidioidomycosis)
    4. Williams Syndrome
    5. Jansen Disease (metaphyseal chondrodysplasia)

III. Findings: 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. Calcium >14 mg/dl (3.5 mmol/L)
      1. Severe Hypercalcemia (or Parathyroid crisis)
  3. Cardiovascular
    1. Chest Pain
    2. Dyspnea
    3. Palpitations
    4. Syncope
    5. Hypertension
    6. Bradycardia
  4. Gastrointestinal
    1. Anorexia
    2. Constipation
    3. Epigastric Pain or other Abdominal Pain
    4. Dyspepsia
    5. Nausea
    6. Vomiting
    7. Pancreatitis
  5. Renal
    1. Polydipsia
    2. Polyuria
    3. Renal Colic or Flank Pain
    4. Renal Failure
  6. Neurologic
    1. Anxiety
    2. Confusion, Delirium
    3. Decreased Concentration
    4. Memory Loss
    5. Headache
    6. Fatigue
    7. Lethargy
    8. Weakness
  7. Psychiatric
    1. Anxiety
    2. Depressed Mood
    3. Emotional lability
  8. Musculoskeletal
    1. Bone pain
    2. Arthralgias
    3. Myalgias
    4. Pathologic Fractures
  9. Skin
    1. Pruritus (Metastatic calcification of skin)

IV. 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 or Delirium
    2. Decreased concentration and memory
    3. Personality change
    4. Psychosis
    5. Major Depression
  5. Eye
    1. Band Keratopathy (Corneal calcification)
      1. Metastatic calcification in eye limbus
  6. Cardiovascular
    1. Cardiac Arrhythmia
    2. Diastolic Dysfunction
    3. Hypertension
      1. Hypercalcemia Vasoconstricts vessels

V. Imaging

  1. Calcified soft tissues

VI. Labs: Serum Calcium

  1. Total Serum Calcium increased
    1. Hypercalcemia: Total Serum Calcium > 10.5 mg/dl
    2. Severe Hypercalcemia (Hypercalcemic Crisis): Serum Calcium >14 mg/dl (>3.50 mmol/L)
  2. Confirmatory
    1. Ionized Calcium >5.6 mg/dl or
    2. Corrected Serum Calcium increased (corrected for Serum Albumin)

VII. Labs: Hypercalcemia Evaluation

  1. First-line
    1. Parathyroid Hormone
    2. 25-Hydroxyvitamin D
    3. Serum Magnesium
    4. Serum Creatinine
  2. Second-line: PTH level normal or high (PTH-dependent Hypercalcemia)
    1. Urine Calcium to Creatinine Ratio
      1. Decreased <0.01 in Familial Hypocalciuric Hypercalcemia
      2. Increased >0.01 in Primary Hyperparathyroidism, Hypercalcemia or Malignancy, MEN I
  3. Second-line: PTH level <20 pg/ml (PTH-independent Hypercalcemia)
    1. Parathyroid Hormone-related Peptide (PTHrp) increased
      1. Hypercalcemia of Malignancy
      2. Consider broad evaluation for malignancy
        1. Complete Blood Count
        2. Liver Function Tests
        3. Chest XRay
        4. Chest CT and Abdominal CT
        5. Protein electrophoresis (SPEP and UPEP)
        6. Bone Scan
        7. Mammogram
    2. 1,25 Dihydroxyvitamin D increased
      1. Lymphoma
      2. Granuloma (e.g. Sarcoidosis)
    3. 25-Hydroxyvitamin D (Calcitriol) increased
      1. Vitamin D Toxicity

VIII. Diagnostics: Electrocardiogram

  1. Short QT Interval
  2. Prolonged PR Interval
  3. Wide QRS Complex
  4. Bradycardia

IX. Evaluation

  1. General
    1. Primary Hyperparathyroidism and Hypercalcemia of Malignancy: 90% of cases
  2. Step 1: Confirm Hypercalcemia present (see labs above)
    1. Confirm Hypercalcemia with Ionized Calcium >5.6 mg/dl or Corrected Serum Calcium >10.5 mg/dl
    2. Immediate management for symptomatic or severe Hypercalcemia (Serum Calcium >14 mg/dl)
      1. See protocol below
  3. Step 2: Obtain history for potential causes
    1. See causes above
    2. Perform history (including diet, medications) and exam
    3. Consider Renal Osteodystrophy
    4. Eliminate potential causative medications (Thiazide Diuretics, Lithium)
  4. Step 3: Obtain intact Parathyroid Hormone (PTH) Level
    1. PTH low: Go to Step 4
    2. PTH normal or high (PTH-Dependent Hypercalcemia)
      1. Labs
        1. Urine Calcium to Creatinine Ratio (24 hour Urine Calcium and Urine Creatinine)
        2. Serum Creatinine
        3. Bone Mineral Density
        4. 25-Hydroxyvitamin D
      2. Urine Calcium to Creatinine Ratio <0.01
        1. Familial Benign Hypocalciuric Hypercalcemia (FBHH)
      3. Urine Calcium to Creatinine Ratio normal or high
        1. Causes
          1. Primary Hyperparathyroidism
          2. Recovery from Acute Tubular Necrosis
          3. Lithium
          4. Multiple Endocrine Neoplasia Type I (MEN I)
          5. Parathyroid carcinoma (severe Hypercalcemia and very high PTH)
        2. Approach
          1. Consult Endocrinology
          2. Exclude Multiple Endocrine Neoplasia Type I (MEN I)
          3. Manage Primary Hyperparathyroidism
            1. Medical management of Primary Hyperparathyroidism
            2. Parathyroidectomy if symptomatic, age <50, complications (e.g. renal)
  5. Step 4: PTH-Independent Hypercalcemia
    1. Assess for malignancy and endocrinopathy
    2. Careful history and examination for tumor
    3. Initial Labs
      1. Parathyroid Hormone-related Peptide (PTHrp)
        1. Increased in solid tumors (see Hypercalcemia of Malignancy)
        2. Consider broad evaluation for malignancy
          1. Complete Blood Count
          2. Liver Function Tests
          3. Chest XRay
          4. Chest CT and Abdominal CT
          5. Protein electrophoresis (SPEP and UPEP)
          6. Bone Scan
          7. Mammogram
      2. 1,25-dihydroxyvitamin D (Calcitriol) increased
        1. Obtain chest imaging (Chest XRay or Chest CT)
        2. Causes
          1. Lymphoma
          2. Granulomatous Disease (Sarcoidosis, Tuberculosis, Histoplasmosis, Coccidioidomycosis)
      3. 25-Hydroxyvitamin D Level increased
        1. Vitamin D Toxicity
    4. Other Labs to consider
      1. Alkaline Phosphatase: Increased with bone lysis
        1. Consider bone scan
      2. Protein electrophoresis (SPEP and UPEP)
        1. Monoclonal peak in Multiple Myeloma
      3. Endocrine Labs
        1. Thyroid Stimulating Hormone (Hyperthyroidism)
        2. Corticotropin Stimulation Test (Addison's Disease)
        3. Insulin-like Growth Factor 1 (Acromegaly)
    5. Reconsider medication causes of low PTH
      1. Thiazide Diuretics
      2. Vitamin D Toxicity
      3. Vitamin A Toxicity
      4. Milk-Alkali Syndrome
      5. Aluminum Intoxication

X. 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 or Hypercalcemic Crisis (Serum Calcium >14 mg/dl, >3.50 mmol/L)
    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. Furosemide (Lasix) 10-20 mg every 1-2 hours as needed
        1. Most effective agent in Calcium elimination
      2. Calcitonin 4-8 IU/kg IM or SQ every 6 hours for 24 hours (up to 48 hours)
        1. Rapid onset, but weakest of the agents (do not use as monotherapy)
    4. Agents with specific indications
      1. Malignancy: Bisphosphonates
        1. Zoledronic acid (Zometa) 4 mg IV over 15 minutes
        2. Pamidronate (Aredia) 60-90 mg IV over 4 hours
      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
      2. Denosumab
        1. Hu (2014) J Clin Endocrinol Metab 99(9):3144-52 +PMID: 24915117 [PubMed]
        2. Eremkina (2020) Endocr Connect 9(10):1019-27 +PMID: 33112830 [PubMed]
    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
    7. Refractory Cases
      1. Hemodialysis
        1. Loh (2014) Case Rep Crit Care +PMID: 24829837 [PubMed]

XI. Prognosis

  1. Hypercalcemia of Malignancy suggests terminal stages
    1. Implies Life Expectancy of days to weeks

XII. 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 [PubMed]
  4. Michels (2013) in Am Fam Physician 88(4): 249-57 [PubMed]
  5. Minisola (2015) BMJ 350: h2723 [PubMed]
  6. Sell (2022) Am Fam Physician 105(3): 289-98 [PubMed]
  7. Suliburk (2007) Oncologist 12(6): 644-53 [PubMed]
  8. Ziegler (2001) J Am Soc Nephrol 12 Suppl 17:S3-9 [PubMed]

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Related Studies

Ontology: Hypercalcemia (C0020437)

Definition (CHV) high level of calcium in the blood
Definition (CHV) high level of calcium in the blood
Definition (MSHCZE) Abnormálně vysoká úroveň vápníku v krvi.
Definition (NCI_NCI-GLOSS) Higher than normal levels of calcium in the blood. Some types of cancer increase the risk of hypercalcemia.
Definition (NCI) Abnormally high concentration of calcium in the peripheral blood.
Definition (NCI_CTCAE) A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium in blood.
Definition (MSH) Abnormally high level of calcium in the blood.
Definition (CSP) abnormally high level of calcium in the blood; manifestations include fatigability, muscle weakness, depression, anorexia, nausea, and constipation.
Concepts Disease or Syndrome (T047)
MSH D006934
ICD9 275.42
ICD10 E83.52
SnomedCT 154752005, 267505006, 166702002, 66931009
English Hypercalcemia, Hypercalcemias, HYPERCALCAEMIA, HYPERCALCEMIA, hypercalcemia, hypercalcemia (diagnosis), Blood calcium increased, Calcium blood increased, Hypercalcemia [Disease/Finding], Serum calcium concentration above normal, Hypercalcemic disorder, Hypercalcemia syndrome, Hypercalcaemia, Hypercalcaemia syndrome, Raised serum calcium level, Hypercalcemia (disorder), Raised serum calcium level (finding), hypercalcinemia, hypercalcaemia
French HYPERCALCEMIE, Calcium sanguin augmenté, Hypercalcémie
Portuguese HIPERCALCEMIA, Cálcio no sangue aumentado, Síndrome Leite-Álcalis, Síndrome do Leite e Alcalino, Calcemia aumentada, Hipercalcemia
Spanish HIPERCALCEMIA, hipercalcemia (trastorno), hipercalcemia, nivel elevado de calcio sérico (hallazgo), nivel elevado de calcio sérico, síndrome de hipercalcemia, síndrome hipercalcémico, Calcio elevado en sangre, Hipercalcemia
German HYPERKALZAEMIE, Hyperkalzaemie, Hyperkalziaemie, Kalzium im Blut erhoeht, Hyperkalzämie
Dutch calcium bloed verhoogd, bloed calcium verhoogd, hypercalciëmie, Burnett, syndroom van, Calciëmie, hyper-, Hypercalciëmie
Japanese 血中カルシウム増加, 高カルシウム血症, ｹｯﾁｭｳｶﾙｼｳﾑｿﾞｳｶ, ｺｳｶﾙｼｳﾑｹﾂｼｮｳ, ｺｳｶﾙｼｳﾑｹｯｼｮｳ
Swedish Hyperkalcemi
Finnish Hyperkalsemia
Russian GIPERKAL'TSIEMIIA PISHCHEVAIA, SINDROM, MOLOCHNOGO ALKOGOLIKA SINDROM, BERNETTA SINDROM, GIPERKAL'TSIEMIIA, MOLOCHNO-SHCHELOCHNOI SINDROM, БЕРНЕТТА СИНДРОМ, ГИПЕРКАЛЬЦИЕМИЯ, ГИПЕРКАЛЬЦИЕМИЯ ПИЩЕВАЯ, СИНДРОМ, МОЛОЧНОГО АЛКОГОЛИКА СИНДРОМ, МОЛОЧНО-ЩЕЛОЧНОЙ СИНДРОМ
Czech Hyperkalcemie, Zvýšený vápník v krvi, Kalcium v krvi zvýšené, hyperkalcémie, hyperkalcemie
Croatian HIPERKALCEMIJA
Italian Calcio ematico aumentato, Ipercalcemia
Polish Hiperkalcemia, Zespół mleczno-alkaliczny
Hungarian Kalcium vérszint emelkedett, Hypercalcaemia
Norwegian Hyperkalcemi, Hyperkalsemi
Derived from the NIH UMLS (Unified Medical Language System)

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