Hypercalcemia

Hypercalcemia refers to high serum calcium levels (total Ca > 10.5 mg/dL or ionized Ca²⁺ > 5.25 mg/dL). The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy involving paraneoplastic production of parathyroid hormone-related protein (PTHrP). Manifestations of hypercalcemia include nephrolithiasis, bone pain, abdominal pain, polyuria, muscle weakness, and neuropsychiatric symptoms. The most important initial diagnostic steps are ruling out factitious hypercalcemia (by measuring ionized calcium or calculating the corrected calcium) and measuring intact PTH levels (to differentiate between PTH-mediated hypercalcemia and non-PTH-mediated hypercalcemia). Management depends on the severity of the calcium imbalance. Mild and asymptomatic moderate hypercalcemia is treated with oral rehydration and low calcium intake, while symptomatic or severe hypercalcemia is a potentially life-threatening medical emergency requiring hospitalization and immediate treatment with IV fluid repletion and medications that inhibit bone resorption (e.g., calcitonin, bisphosphonates). In addition, identification and treatment of the underlying cause of hypercalcemia are essential.

See “Hypocalcemia” for details on calcium physiology and homeostasis.

• Hypercalcemia is a total serum calcium concentration of > 10.5 mg/dL (> 2.62 mmol/L) or ionized (free) calcium concentration of > 5.25 mg/dL (> 1.31 mmol/L). ^[1]
  • True hypercalcemia: ↑ ionized calcium or ↑ corrected calcium (regardless of total calcium level); can be symptomatic.
  • Factitious hypercalcemia: ↑ total calcium with normal ionized (non-protein bound, physiologically active) calcium or normal corrected calcium level; asymptomatic.
    • The increase in total serum calcium levels is caused by increased protein levels, for example:
      • Hyperalbuminemia in dehydrated patients
      • Paraproteinemia in patients with multiple myeloma.

Hypercalcemia may be due to PTH-mediated or non-PTH-mediated causes. Primary hyperparathyroidism and malignancy are the most common causes, accounting for ∼ 90% of all cases. ^[2]

Severe/symptomatic hypercalcemia usually develops acutely and is typically caused by excessive osteoclast-mediated bone resorption, most commonly in association with malignancy.In primary hyperparathyroidism, serum calcium is typically lower and rises more slowly than in hypercalcemia of malignancy. Patients are, therefore, less symptomatic.

For causes of hypercalcemia, remember “Thinking Chimpanzees!”
Thinking: Thiazides, thyroid
Calcium supplementation
Hyperparathyroidism
Immobilization, inherited (FHH)
Milk-alkali synd., meds (thiazides, lithium)
Paraneoplastic PTHrP
Adrenal insufficiency
Neoplasm (multiple myeloma, breast, lung)
Zollinger-Ellison syndrome
Excessive vitamin D
Excessive vitamin A
Sarcoidosis & granulomatous diseases

The clinical presentation is variable and ranges from asymptomatic presentation in mild hypercalcemia to life-threatening clinical features in severe hypercalcemia. See “Classification of hypercalcemia.”

• Nephrolithiasis, nephrocalcinosis (calcium oxalate > calcium phosphate stones)
• Bone pain, arthralgias, myalgias, fractures
• Constipation
• Abdominal pain
• Nausea and vomiting
• Anorexia
• Peptic ulcer disease ^[10]
• Pancreatitis
• Neuropsychiatric symptoms such as anxiety, depression, fatigue, and cognitive dysfunction
  • Somnolence
  • Obtundation and coma indicate progression to hypercalcemic crisis
• Diminished muscle excitability
  • Cardiac arrhythmias
  • Muscle weakness, paresis
• Polyuria and dehydration

Hypercalcemia can cause pancreatitis. Hypocalcemia in patients with pancreatitis suggests pancreatic necrosis.

The presentation of hypercalcemia includes stones (nephrolithiasis), bones (bone pain, arthralgias), thrones (increased urinary frequency), groans (abdominal pain, nausea, vomiting), and psychiatric overtones (anxiety, depression, fatigue). Note that these are also the findings of vitamin D overdose!

References:^[11]

Laboratory values and the presence of symptoms should be used in conjunction to determine the need for treatment. Acutely symptomatic moderate hypercalcemia and severe hypercalcemia are medical emergencies and require hospital admission and immediate initiation of treatment.

• Mild hypercalcemia
  • Total calcium 10.5–12 mg/dL (2.62–3 mmol/L)
  • OR ionized calcium 5.25–8 mg/dL (1.31–2 mmol/L)
  • Typically asymptomatic
• Moderate hypercalcemia
  • Total calcium 12–14 mg/dL (3–3.5 mmol/L)
  • OR ionized calcium 8–10 mg/dL (2–2.5 mmol/L)
  • Can be asymptomatic or symptomatic (especially if it develops acutely)
• Severe hypercalcemia, also known as hypercalcemic crisis
  • Total calcium > 14 mg/dL (> 3.5 mmol/L)
  • OR ionized calcium > 10 mg/dL (> 2.5 mmol/L)
  • A life-threatening condition that can be associated with:
    • Dehydration (due to ADH resistance and vomiting)
    • Oliguria/anuria
    • Altered consciousness
    • Psychosis

Familial hypocalciuric hypercalcemia (FHH) ^[12]

• Etiology: : autosomal dominant inactivating mutation in the CaSR gene → decreased sensitivity of G-coupled calcium-sensing receptors in parathyroid glands and kidneys →; higher levels of Ca²⁺ required to suppress PTH and higher reabsorption of Ca²⁺ in the kidney → hypocalciuria with mild hypercalcemia and normal or increased PTH levels
• Clinical features
  • Usually asymptomatic (incidental finding)
  • Neonatal hypocalcemia in children of mothers with FHH (e.g., paresthesias, muscle spasms, seizures)
• Diagnosis
  • Hypercalcemia and inappropriately normal or increased PTH
  • Hypocalciuria
    • ↓ 24-hour urinary calcium excretion (< 200 mg/ day)
    • ↓ Urine Ca/Cr clearance ratio (< 0.02)
    • See also “Assessment of urinary calcium excretion.”
  • Confirmatory genetic testing for CaSR gene mutations
• Therapy:
  • No treatment necessary
  • Cinacalcet may be considered in patients with symptomatic FHH ^[13]

Approach ^[1][2][3][8]

• Confirm true hypercalcemia: measure ionized calcium OR calculate corrected calcium using total calcium and serum albumin.
• Risk assessment and global evaluation
  • Determine severity: see “Classification of hypercalcemia”
  • Begin treatment immediately for patients with severe hypercalcemia or symptomatic patients while pursuing further diagnostic workup.
  • Perform volume status assessment.
  • Obtain ECG
  • Identify concurrent electrolyte abnormalities.
• Initial investigations of underlying etiology
  • Measure serum intact PTH: initial study to determine the etiology of hypercalcemia and to differentiate PTH-mediated hypercalcemia from non-PTH-mediated hypercalcemia
  • Order other routine tests as guided by clinician suspicion : e.g. alkaline phosphatase, TSH
• Intermediate investigations of underlying etiology: Consider these based on the results of initial investigations.
  • Normal or ↑ PTH: urine calcium excretion
  • ↓ PTH: PTHrP and vitamin D levels ^[2][14]
• Advanced investigations of underlying etiology: Consider these based on combined results of the initial and intermediate investigations (see “Other investigations to consider” for details).^[1][8]
  • ↑ PTHrP or ↑ 1,25-dihydroxyvitamin D: investigations for tumors, lymphoma, or granulomatous diseases
  • Normal or ↓ PTHrP, and normal or ↓ vitamin D levels: investigations for multiple myeloma, thyrotoxicosis, Paget disease, vitamin A toxicity, or adrenal insufficiency
  • ↓ Urine calcium excretion: investigations for FHH (e.g., genetic testing, see FHH)
  • Adjunctive studies: consider on an individual basis (e.g., bone densitometry or detailed laboratory evaluation of bone disease)

Severe or symptomatic hypercalcemia is a medical emergency. Treatment should be initiated immediately, in parallel with diagnostic workup.

Routine investigations ^[2][8]

• Serum calcium
  • Total calcium
  • Ionized calcium
  • Corrected calcium (mg/dL) = measured total Ca²⁺ (mg/dL) + [0.8 x (4.0 - albumin concentration in g/dL)]
• Other laboratory studies
  • Albumin
  • Phosphate: typically low in primary hyperparathyroidism and PTHrP-mediated hypercalcemia ^[8]
  • BMP
  • Alkaline phosphatase
  • ABG/VBG
  • CBC
• ECG findings may include:
  • QT interval shortening and in severe hypercalcemia J wave
  • Bradycardia
  • Arrhythmias

The corrected calcium concentration, calculated using serum albumin, may not be accurate in the setting of major acid-base imbalances. In patients with significant alkalemia or acidemia, it is recommended to measure ionized calcium directly.

Investigations to determine underlying etiology

• Serum intact PTH
  • Normal or ↑ PTH: PTH-mediated hypercalcemia
  • ↓ PTH: non-PTH-mediated hypercalcemia
• PTHrP
  • A protein produced by malignant cells that has the same function as parathyroid hormone.
  • Production of PTHrP is the most common cause of hypercalcemia of malignancy.
  • ↑ PTHrP: solid malignancy or neuroendocrine tumors
  • Normal or ↓ PTHrP: Consider other causes of non-PTH-mediated hypercalcemia (see “Etiology of hypercalcemia”).
• Vitamin D levels
  • ↑ 1,25-dihydroxyvitamin D: lymphoma, granulomatous disease, or calcitriol ingestion
  • ↑ 25-hydroxyvitamin D: vitamin D intoxication (i.e., due to ingestion of ergocalciferol, cholecalciferol, or calcidiol)
• Assessment of urinary calcium excretion ^{[2][8][15][16]}
  • Studies
    • 24-hour urinary excretion of calcium
    • AND/OR urine Ca/Cr clearance ratio (an index of renal calcium excretion; determined by measuring the concentrations of calcium and creatinine in the serum and in a 24-hour urine collection sample) ^[17]
  • Interpretation ^[8][16]
    • Normal or ↑ urine calcium (urine Ca/Cr clearance ratio > 0.02 or 24-hour urine calcium > 200 mg): primary hyperparathyroidism ^[15]
    • ↓ Urine calcium (urine Ca/Cr clearance ratio < 0.02 or 24-hour urine calcium < 200 mg): FHH or primary hyperparathyroidism; consider genetic testing for FHH. ^[18]

Measurement of serum intact PTH level is the key initial study for confirmed hypercalcemia with no immediately evident etiology.

Other investigations to consider ^[1][8]

• Laboratory studies
  • TSH, T4, T3: assess for thyrotoxicosis
  • Cortisol and ACTH stimulation test: assess for adrenal insufficiency
  • Vitamin A levels: assess for vitamin A toxicity
  • Serum protein electrophoresis and urine Bence Jones protein: assess for multiple myeloma
  • Detailed laboratory evaluation of bone disease: further evaluation of bone disorders
  • Genetic testing: See FHH.
• Imaging
  • CT chest, abdomen, pelvis: assess for tumors, lymphoma, or granulomatous diseases
  • Skeletal survey: assess for lytic bone lesions and Paget disease
  • Bone densitometry: further evaluation of patients with primary hyperparathyroidism ^[14]

Approach ^[2][8]

• All patients
  • Ensure adequate supportive care.
  • Identify and treat the underlying cause (see “Etiology of hypercalcemia”).
  • Consider consulting endocrinology, nephrology, oncology, and/or surgery services as needed.
• Severe hypercalcemia and symptomatic moderate hypercalcemia: Admit to hospital and treat as a medical emergency.
  • Rapidly lower calcium levels.
    • Start IV fluid therapy with 0.9% NaCl.
    • Consider adding diuretics if there is volume overload.
    • Initiate pharmacotherapy: e.g., calcitonin, bisphosphonates, denosumab.
  • Consider targeted therapy based on suspected etiology: e.g., surgery, calcimimetics, corticosteroids.
  • Treat any complications: e.g., arrhythmias, nephrolithiasis.
  • Consider hemodialysis for refractory life-threatening hypercalcemia or if other therapies are contraindicated (e.g., bisphosphonates in severe renal failure).
• Mild hypercalcemia or asymptomatic moderate hypercalcemia: Consider inpatient vs. outpatient therapy on an individual basis.
  • Acute treatment other than supportive care and treatment of the underlying cause is usually not necessary.
  • Follow calcium levels and monitor for the development of symptoms. ^[2]

Supportive care

• Ensure adequate hydration.
• Reduce dietary intake of calcium.
• Avoid; potentially aggravating medications (e.g., thiazides, lithium, vitamin D, calcidiol, calcitriol).
• Encourage mobility and avoid prolonged bed rest/inactivity. ^[8]

Fluid therapy and volume status management

• IV fluid repletion with 0.9% NaCl : typically 4–6 L in 24 hours
• Obtain serial calcium checks and monitor urine output and volume status.
• Consider IV loop diuretic (e.g. IV furosemide ) ONLY if there are signs of volume overload (e.g., pulmonary congestion, significant peripheral edema). ^[19]

Thiazide diuretics enhance Tubular calcium upTake: Discontinue them in hypercalcemia. Loop diuretics Lose calcium: They may be used to treat fluid overload in patients with hypercalcemia.

Standard pharmacotherapy

Pharmacotherapy is aimed at inhibiting bone resorption.

• Consider calcitonin for rapid-onset, short-term control of hypercalcemia.
  • Reduces serum calcium within 2–6 hours, with maximal effect within 12–24 hours
  • Often limited by tachyphylaxis after 48 hours of use
• Bisphosphonates for slow-onset, long-term control of hypercalcemia
  • Options
    • Zoledronic acid ^[3]
    • Pamidronate
  • Typically lead to normalization of serum calcium within 2–4 days, with effect duration of days to weeks following a single dose
  • The dose may be repeated, if needed, after a minimum of 7 days.
  • Contraindicated in severe CKD (CrCl < 30 mL/min)

Targeted therapies

• Hypercalcemia due to primary or tertiary hyperparathyroidism ^[4][14]
  • Surgical management preferred: partial or total parathyroidectomy
  • Calcimimetics (e.g., cinacalcet ) for patients unable to undergo surgery
  • See “Treatment” in “Hyperparathyroidism.”
• Hypercalcemia due to lymphoma, granulomatous diseases, or vitamin D intoxication: systemic glucocorticoids (e.g., prednisone ) ^[3]

Alternative therapeutic options

These treatment options may be considered if hypercalcemia is resistant to other measures or the use of bisphosphonates is contraindicated due to severe renal failure.

• Denosumab ^[2][8][20]
• Hemodialysis may additionally be considered in the following circumstances:
  • Aggressive fluid repletion is contraindicated (e.g., patients with fluid overload due to severe heart failure or oliguric AKI).
  • Immediate reduction of calcium levels is necessary due to life-threatening symptomatic hypercalcemia. ^[21]

• Confirm hypercalcemia (i.e., check ionized calcium and/or correct serum calcium for albumin).
• Initial diagnostic work-up: serum PTH, CBC, BMP, phosphate, alkaline phosphatase, and VBG
• Initiate immediate treatment in parallel with the diagnostic workup for severe or symptomatic hypercalcemia.
• Obtain IV access.
• Provide aggressive IV fluid repletion with isotonic saline.
• Give IV bisphosphonate.
• Consider SQ or IM calcitonin.
• Consider an IV loop diuretic (e.g. furosemide) ONLY if there are signs of fluid overload.
• Consider dialysis in severe, life-threatening hypercalcemia or if IV fluid repletion is contraindicated due to severe heart failure or oliguric AKI.
• Give glucocorticoids for hypercalcemia due to lymphoma, granulomatous diseases, or vitamin D intoxication.
• Consider surgical consult for hypercalcemia due to primary or tertiary hyperparathyroidism
• Monitor serum calcium levels, hydration status, and urine output.
• Discontinue potentially aggravating medications (e.g., thiazides, lithium, vitamin D, calcium supplements).
• Reduce dietary intake of calcium.
• Encourage mobility.
• Identify and treat other underlying causes of hypercalcemia (see “Etiology of hypercalcemia”).
• Consider consulting endocrinology, nephrology, and/or oncology as needed.