Hypercalcemia

Hypercalcemia is a condition of high calcium levels (total Ca²⁺> 10.5 mg/dL or ionized Ca²⁺> 5.25 mg/dL) in the blood serum. For information regarding the physiology and homeostasis of calcium, please see the hypocalcemia article. The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy with paraneoplastic production of parathyroid hormone-related protein (PTHrP). Symptoms of hypercalcemia include nephrolithiasis, bone pain, abdominal pain, and polyuria. Management depends on the severity of calcium imbalance. Mild and asymptomatic moderate hypercalcemia is treated with oral rehydration and low calcium intake, while symptomatic moderate cases and severe cases require IV rehydration and calcitonin administration. Hypercalcemic crisis is a life-threatening complication that manifests with dehydration, oliguria, and altered consciousness and requires immediate forced diuresis.

Hypercalcemia = total serum calcium concentration > 10.5 mg/dL (> 2.62 mmol/L), or ionized (free) calcium concentration > 5.25 mg/dL (> 1.31 mmol/L) ^[1]

Types of hypercalcemia	Etiology	Pathophysiology
PTH-mediated	Primary hyperparathyroidism	Adenoma (sporadic or in multiple endocrine neoplasia) Excess PTH → increased active vitamin D (calcitriol) production via stimulation of 1-alpha-hydroxylase synthesis in the kidneys
	Secondary hyperparathyroidism	Renal insufficiency → ↓ production of 1,25-dihydroxyvitamin D → ↑ PTH May also be caused by vitamin D deficiency or hypocalcemia
	Tertiary hyperparathyroidism	Renal failure → chronic secondary hyperparathyroidism → autonomous activation of one or more parathyroid glands
	Familial hypocalciuric hypercalcemia (FFH)	See FHH in subtypes and variants section below.
Non-PTH-mediated	Hypercalcemia of malignancy	Most common cause: paraneoplastic production of PTHrP (e.g., squamous cell carcinomas of the lung, head, and neck; breast, ovarian, bladder, and renal cancer; lymphoma and leukemia) Osteolytic metastases (e.g., multiple myeloma, breast cancer, lymphoma and leukemia, renal and prostate cancer) Paraneoplastic production of 1,25-dihydroxyvitamin D (calcitriol): e.g., lymphoma, ovarian dysgerminoma
	Granulomatous disorders (e.g., sarcoidosis)	Hydroxylase activity in activated mononuclear cells produces 1,25-dihydroxyvitamin D (calcitriol) outside of the kidneys.
Other	Medications	Thiazide diuretics: reduce renal calcium excretion Excess vitamin D: increases intestinal calcium absorption Calcium supplements
	Hyperthyroidism	↑ Thyroid hormone → increased osteoclastic activity → increased bone resorption
	Long periods of immobilization	Lack of weight-bearing activities → osteoclast activation → bone demineralization → hypercalcemia
	Milk-alkali syndrome	Excessive consumption of calcium carbonate Presents with hypercalcemia, metabolic alkalosis, and acute kidney injury
	Paget disease of the bone	Increased rate of bone remodeling
	Adrenal insufficiency	The exact pathophysiology is unknown; several mechanisms are proposed. [2] Hypovolemia → ↓ GFR → ↓ Ca2+ excretion → ↑ blood concentration of Ca2+ ↑ 1α-hydroxylase → ↑ calcitriol → ↑ Ca2+ intestinal absorption ↓ Stanniocalcin

Primary hyperparathyroidism and hypercalcemia of malignancy account for > 90% of cases of hypercalcemia. Compared to primary hyperparathyroidism, serum calcium is typically higher in hypercalcemia of malignancy (> 13 mg/dL, or > 3.25 mmol/L), and patients, therefore, exhibit more severe symptoms.
References:^[3][4]

The clinical presentation is variable and may be asymptomatic.

• Nephrolithiasis, nephrocalcinosis (calcium oxalate > calcium phosphate stones)
• Bone pain; , arthralgias, myalgias, fractures
• Constipation
• Abdominal pain
• Nausea and vomiting
• Anorexia
• Peptic ulcer disease ^[5]
• 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
• Hypercalcemic crisis: life-threatening condition that should be suspected at total calcium levels > 14 mg/dL (3.5 mmol/L) or ionized calcium > 10 mg/dL (2.5 mmol/L); patients present with
  • Dehydration (due to ADH resistance and vomiting)
  • Oliguria/anuria
  • Altered consciousness
  • Psychosis

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:^[1]

Familial hypocalciuric hypercalcemia (FHH) ^[6]

• Etiology: autosomal dominant inactivating mutation in the CaSR gene → decreased sensitivity of G-coupled Ca²⁺-sensing receptors in the kidneys and parathyroid glands →; higher levels of Ca²⁺ required to suppress PTH → 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)
    • ↓ Calcium/creatinine clearance ratio (< 0.01 )
• Therapy: no treatment necessary

Approach ^[7]

1. Evaluate calcium imbalance
   • Initial test: serum calcium concentration
   • Confirm true hypercalcemia: measure ionized calcium or use serum albumin to calculate corrected calcium.
     • Corrected calcium (mg/dL) = measured total Ca²⁺ (mg/dL) + [0.8 x (4.0 - albumin concentration in g/dL)]
       • Increased ionized calcium, regardless of total calcium levels → true hypercalcemia (potentially symptomatic)
       • Increased total calcium with normal ionized (active) calcium → factitious hypercalcemia (asymptomatic finding)
2. Differentiate between low PTH and high PTH: to determine the underlying cause of hypercalcemia
   • PTH: the most important test for patients with disorders of calcium balance
   • Further laboratory tests to confirm the diagnosis (e.g., creatinine in suspected CKD)
3. Further tests
   • ECG
     • QT interval shortening
     • In severe hypercalcemia: J wave
   • Further evaluation of bone disorders: See laboratory evaluation of bone diseases.

The corrected calcium concentration calculated using serum albumin may not be accurate when major pH changes have taken place in the body (e.g., following surgery). In these cases, it is better to measure ionized calcium directly.

PTH levels in hypercalcemia

PTH level	Conditions	Laboratory findings
Low PTH	Hypercalcemia of malignancy	↑ PTHrP
	Vitamin D intoxication	↑ Calcidiol (25-hydroxyvitamin D)
	Sarcoidosis or other granulomatous disease, lymphoma	↑ Calcitriol (1,25-dihydroxyvitamin D)
	Milk-alkali syndrome	Metabolic alkalosis
High to normal PTH	Primary hyperparathyroidism	↓ Phosphate ↔︎/↑ Urine calcium
	Familial hypocalciuric hypercalcemia (FHH)	↓ Urine calcium

• Treatment of any underlying disorder (e.g., glucocorticoids in sarcoidosis or any other granulomatous disease → reduction in activity of mononuclear cells producing calcitriol)
• Mild or asymptomatic hypercalcemia: total calcium < 12 mg/dL (< 3 mmol/L) or ionized calcium < 8 mg/dL (< 2 mmol/L)
  • Encourage adequate oral hydration
  • Reduce dietary intake of calcium
  • Avoid thiazide diuretics, lithium, high-calcium diet
• Moderate hypercalcemia: total calcium 12–14 mg/dl (3–3.5 mmol/L)
  • Asymptomatic: same treatment as for mild hypercalcemia (see above)
  • Symptomatic: same treatment as described for severe hypercalcemia (see below)
• Severe or symptomatic hypercalcemia: total calcium > 14 mg/dL (> 3.5 mmol/L) or ionized calcium > 10 mg/dL (> 2.5 mmol/L)
  • Immediate therapy ^[8]
    • IV hydration with isotonic saline
    • Calcitonin ^[9]
    • In hypercalcemic crisis: immediate forced diuresis (following volume replacement!)
  • Cause-based therapy
    • Excessive bone resorption (e.g., hypercalcemia of malignancy, immobilization): bisphosphonates (zoledronic acid, pamidronate)
    • Renal insufficiency or heart failure: loop diuretics (with monitoring of serum potassium) to avoid volume overload
    • Dialysis in very severe cases (total calcium > 18 mg/dL; ionized calcium > 4.5 mmol/L) or concomitant renal failure

Thiazide diuretics enhance Tubular calcium resorption → Discontinue them in hypercalcemia. Loop diuretics Lose calcium → Administer them in hypercalcemia.

References:^[10][1][9]