- Clinical science
The maintenance of calcium homeostasis in the body is complex and influenced by several variables. Calcium is absorbed in the gastrointestinal (GI) tract, integrated into and resorbed from the calcified bone matrix, and renally excreted. Parathyroid hormone (PTH) regulates all of these processes, which are also dependent on the balance of vitamin D (specifically vitamin D3, or calcitriol), calcitonin, and phosphate in the body. Therefore, disorders of the parathyroid glands as well as the bone, kidney, and GI tract may lead to disruptions in calcium homeostasis. Hypocalcemia, for example, is most often caused by hypoparathyroidism (e.g., autoimmune, surgical) or vitamin D deficiency (e.g., malabsorption, chronic kidney disease). Hypercalcemia is often the result of either primary hyperparathyroidism or malignancy. In cases of malignancy, PTH-related protein (PTHrP) produced by tumor cells is often responsible; osteolytic bone metastases (e.g., multiple myeloma) must also be considered.
The concentration of calcium in the serum affects multiple processes in the body, including coagulation, cell signaling, and hormone release. In addition to hormonal control by PTH and calcitriol, calcium homeostasis is influenced by serum protein levels and acid-base status, both of which impact the ratio of protein bound to ionized calcium in the serum. If serum ionized calcium concentrations are not maintained within a narrow range, signs and symptoms appear in a variety of systems. Symptoms of hypocalcemia include signs of tetany (typically carpopedal spasm) and a “pins and needles” sensation or other paresthesia, which indicates neuromuscular excitation due to a lessening of the membrane-stabilizing effect normally exerted by calcium. The presentation of hypercalcemia, in contrast, classically includes stones (nephrolithiasis), bones (bone pain, arthralgias), abdominal groans (abdominal pain, nausea, constipation), and psychiatric overtones (anxiety, depression). Management of calcium imbalance consists primarily of treating the underlying disorder and, if necessary, supplementing or eliminating calcium.
- Hypocalcemia = total serum calcium concentration < 8.5 mg/dL (< 2.12 mmol/L), or ionized (or free) calcium concentration < 4.65 mg/dL (< 1.16 mmol/L)
- 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)
Role of calcium in the cell
- Ionized calcium is responsible for stabilizing the resting membrane potential of cells.
Total and ionized calcium concentrations
- It is important to distinguish between total calcium and ionized (free, or active) calcium, as only the latter is biologically active and can cause symptoms in excess or deficiency.
In order to differentiate between factitious and true hypo/hypercalcemia, the measured total calcium can be corrected for a lower or higher serum albumin
- Corrected Ca2+ (mg/dL) = measured total Ca2+ (mg/dL) + [0.8 x (4.0 - albumin concentration in g/dL)]
- Decreased or increased total calcium with normal ionized (active) calcium → pseudohypocalcemia (factitious hypocalcemia) or pseudohypercalcemia (factitious hypercalcemia) → asymptomatic
- Decreased or increased ionized (active) calcium, regardless of total calcium levels → true hypocalcemia/hypercalcemia → potentially symptomatic
- pH influences the binding of calcium to serum proteins. This is because Ca2+ ions compete with H+ ions for binding sites on serum proteins. Acidosis reduces calcium binding, while alkalosis enhances it.
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!
Serum calcium concentration is primarily regulated by PTH.
- Decreases in serum calcium (ionized calcium < 1.25 mmol/L) stimulate the release of PTH; increases in serum calcium inhibit it.
- Further stimulatory factors for PTH secretion are: low levels of calcitriol, hyperphosphatemia; , and mild hypomagnesemia(e.g., due to chronic diarrhea, inflammatory bowel disease, loop diuretics, or alcohol dependence)
- Promotion of calcium reabsorption in the distal tubule of the kidney (as well as phosphate excretion)
- Increased active vitamin D production via stimulation of synthesis in the kidneys: 25-hydroxyvitamin D (calcidiol) → 1,25-dihydroxyvitamin D (calcitriol, the most active form of vitamin D)
- Release of calcium and phosphate from the bones, activation of osteoclasts indirectly via PTH's effect on osteoblasts (PTH increases RANKL receptor expression on osteoblasts. RANKL binds to RANK receptors on osteoclasts, stimulating osteoclasts, bone resorption, and calcium release.) → relevant effect only when PTH levels are pathologically high
- PTH secretion
Vitamin D increases serum Ca2+ via its effect on the kidneys and gastrointestinal tract.
- For more information see and .
- Calcitonin opposes the effects of PTH.
|Types of hypocalcemia||Etiology||Pathophysiology|
|Low PTH||Hypoparathyroidism|| |
|High PTH (secondary hyperparathyroidism)||Vitamin D deficiency|
|Pseudohypoparathyroidism (Albright hereditary osteodystrophy)|| |
Hyperphosphatemia (see )
|Acute necrotizing pancreatitis (see )|| |
|Multiple blood transfusions|| |
|Hypomagnesemia (see )|
|Types of hypercalcemia||Etiology||Pathophysiology|
|Non-PTH-mediated||Hypercalcemia of malignancy|| |
|Granulomatous disorders (e.g., )|
|Other||Intake of medications|| |
|Long periods of immobilization|
|Milk-alkali syndrome|| |
|of the bone|| |
Primary hyperparathyroidism and hypercalcemia of malignancy account for > 90% of cases of hypercalcemia. Compared with 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!
Increased neuromuscular excitability → tetany (when caused by respiratory alkalosis = hyperventilation-induced tetany)
- Paresthesias (typically acral and/or perioral tingling or "pins and needles" sensation)
- Muscle spasms, such as carpopedal spasm; (possible in any muscle) and cramps
- Additional tests for tetany in physical exam (see the video in “Tips and links”)
- Chvostek's sign = contraction of the facial muscles elicited by tapping the facial nerve in the area of the cheek (approx. 2 cm ventral to the ear lobe)
- Trousseau's sign = ipsilateral carpopedal spasm occurring several minutes after inflation of a blood pressure cuff to pressures above the systolic blood pressure
- Cardiac arrhythmias
- Abdominal cramping and diarrhea
Hypercalcemia (variable presentation, may be asymptomatic)
- Nephrolithiasis, nephrocalcinosis (calcium oxalate > calcium phosphate stones)
- Bone pain, arthralgias, myalgias, fractures
- Abdominal pain, nausea and vomiting, peptic ulcer disease, constipation, pancreatitis
- Neuropsychiatric symptoms such as anxiety, depression, fatigue; , and cognitive dysfunction
- Diminished muscle excitability
- Cardiac arrhythmias
- Muscle weakness, paresis
- Polyuria and dehydration
The presentation of hypercalcemia includes stones (nephrolithiasis), bones (bone pain, arthralgias), abdominal groans (abdominal pain, nausea, vomiting), and psychiatric overtones (anxiety, depression, fatigue). Note that these are also the findings of vitamin D overdose!
- Evaluate calcium imbalance
- Differentiate between low PTH and high PTH: to determine the underlying cause of calcium imbalance (see Differential diagnosis of hypocalcemia and Differential diagnosis of hypercalcemia below)
- Further tests
PTH in hypocalcemia
|PTH level||Conditions||Laboratory findings|
|Low PTH||Hypoparathyroidism (e.g., postsurgical)|
|High PTH||Vitamin D deficiency|
|Chronic kidney disease|
|Malabsorption or alcoholism|
PTH in hypercalcemia
|PTH level||Conditions||Laboratory findings|
|Low PTH||Hypercalcemia of malignancy|| |
|Vitamin D intoxication|
Sarcoidosis or other granulomatous disease, lymphoma
|High to normal PTH||Primary hyperparathyroidism|
|Familial hypocalciuric hypercalcemia (FHH)|| |
|Vitamin D deficiency|
|Calcium citrate complex formation|
- Etiology: autosomal dominant inactivating mutation in the CaSR gene → decreased sensitivity of calcium-sensing receptors in the kidneys and parathyroid glands
- Clinical features
- Therapy: no treatment necessary
The differential diagnoses listed here are not exhaustive.
- Treat any underlying disorders.
- IV calcium (1–2 g calcium gluconate; in 50 mL of 5% dextrose infused over 10–20 mins): indicated in severely symptomatic patients (e.g., tetany, seizures), those with a prolonged QT interval, and asymptomatic patients with an acute decrease in serum corrected calcium to ≤ 7.5 mg/dL (≤ 1.9 mmol/L)
- Oral calcium: indicated in patients with mild neuromuscular irritability (e.g., paresthesias), and those with serum corrected calcium > 7.5 mg/dL (> 1.9 mmol/L)
- Vitamin D supplementation: indicated in hypocalcemia caused by hypoparathyroidism or vitamin D deficiency
- For patients taking loop diuretics, medication change to thiazides
- Magnesium supplementation: indicated in hypocalcemia caused by hypomagnesemia
- Patient reassurance and possibly rebreathing into a paper bag: indicated in hyperventilation
- 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)
- Moderate hypercalcemia: total calcium between 12–14 mg/dl (3–3.5 mmol/L)
Severe or symptomatic hypercalcemia: total calcium > 14 mg/dL (> 3.5 mmol/L) or ionized calcium > 12 mg/dL (> 3 mmol/L)
- IV hydration with isotonic saline
- Loop diuretics (with monitoring of serum potassium!) in patients with renal insufficiency or heart failure to avoid volume overload (Loop diuretics increase the renal excretion of calcium but also prevent volume overload in at-risk patients.)
- Bisphosphonates; (e.g., zoledronic acid, pamidronate), in cases of excessive bone resorption (e.g., hypercalcemia of malignancy, immobilization)
- Dialysis in severe cases or renal failure: > 18 mg/dL (> 4.5 mmol/L)
- Brief description: life-threatening condition that should be suspected at total calcium levels > 14 mg/dL (3.5 mmol/L) or ionized calcium > 12 mg/dL (3 mmol/L)
- Symptoms: dehydration; (ADH resistance, nausea, and vomiting), fever, psychosis, and ultimately coma
- Treatment: immediate forced diuresis (following volume replacement!) → For additional options, see “Treatment” above.
We list the most important complications. The selection is not exhaustive.