• Clinical science

Disorders of calcium balance

Abstract

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.

Definition

  • 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)

References:[1]

Calcium homeostasis and calcium physiology

Role of calcium in the cell

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.
    • Approx. half of the total serum calcium is transported bound to proteins such as albumin. Decreases in serum protein concentrations (e.g., in nephrotic syndrome) are mirrored by decreases in total calcium levels. However, these decreases are typically asymptomatic, as ionized calcium is hormonally regulated and independent from serum protein.
    • Laboratories often only calculate total calcium, and not ionized calcium. In hypoproteinemia or hyperproteinemia, total calcium is low or high respectively, but true hypocalcemia or hypercalcemia (i.e. that of ionized calcium) is not present.
  • In order to differentiate between factitious and true hypo/hypercalcemia, the measured total calcium can be corrected for a lower or higher serum albumin
  • 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.
    • ↓ pHH+ in serum binding to proteins↓ Ca2+ binding to proteins↑ ionized Ca2+ concentration
    • ↑ pH↓ H+ in serum binding to proteins↑ Ca2+ binding to proteins↓ ionized Ca2+ concentration

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!

Calcium homeostasis

Calcium homeostasis is a complex process, influenced by many organs and hormones (kidneys, gastrointestinal tract, bones, parathyroid gland, liver, skin, PTH, calcitonin, vitamin D).

  1. Serum calcium concentration is primarily regulated by PTH.
  2. Vitamin D: increases serum Ca2+ via its effect on the kidneys and gastrointestinal tract.
  3. Calcitonin opposes the effects of PTH.

PTH = Phosphate Trashing Hormone

References:[2][1][3][4][5][6]

Etiology

Hypocalcemia

Types of hypocalcemia Etiology Pathophysiology
Low PTH Hypoparathyroidism
  • Destruction of the parathyroid glands
    • Surgical
    • Autoimmune
High PTH (secondary hyperparathyroidism) Vitamin D deficiency
Pseudohypoparathyroidism (Albright hereditary osteodystrophy)
  • PTH resistance

Hyperphosphatemia (see phosphate)

Acute necrotizing pancreatitis (see acute pancreatitis)
  • Calcium soap precipitation in the abdomen

Other Medications
Multiple blood transfusions
  • Citrate in blood products chelates serum calcium
Hypomagnesemia (see magnesium)
  • Hypomagnesemia → reduction of PTH secretion or PTH resistance hypocalcemia
    • Another cause of hypocalcemia in alcoholics in addition to vitamin D deficiency from malnutrition.
    • This type of hypocalcemia is unresponsive to calcium supplementation and is treatable only with magnesium.
Hyperventilation
  • Redistribution of calcium

Hypocalcemia is most often due to hypoparathyroidism or vitamin D deficiency (e.g., malabsorption, chronic kidney disease)

Hypercalcemia

Types of hypercalcemia Etiology Pathophysiology
PTH-mediated Primary hyperparathyroidism
Familial hypocalciuric hypercalcemia
  • See “Differential diagnosis” below.

Tertiary hyperparathyroidism
Non-PTH-mediated Hypercalcemia of malignancy
Granulomatous disorders (e.g., sarcoidosis)
Other Intake of medications
  • Thiazide diuretics → reduced renal calcium excretion
  • Excess vitamin D → increased intestinal calcium absorption
  • Calcium supplements
Hyperthyroidism
Long periods of immobilization
Milk-alkali syndrome
  • Consumption of calcium carbonate
Paget's disease of the bone
Adrenal insufficiency
  • Multifactorial

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!
References:[7][1][8]

Clinical features

Hypocalcemia

  • 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
    • Seizures
    • Cardiac arrhythmias
    • Abdominal cramping and diarrhea

Suspect hypocalcemia in the postoperative thyroidectomy patient with new onset paresthesias and muscle spasms or cramping!

Hypercalcemia (variable presentation, may be asymptomatic)

Calcium and pancreatitishypercalcemia can cause pancreatitis. Hypocalcemia in patients with pancreatitis suggests pancreatic necrosis!

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!
References:[9][10]

Subtypes and variants

Paradoxical intracerebral calcifications in hypocalcemia

  • Brief description
    • Non-arteriosclerotic calcification of the basal ganglia caused by hypocalcemia (rather than hypercalcemia) secondary to hypoparathyroidism.
    • Similar calcifications occur in a condition known as Fahr syndrome, which may have genetic or idiopathic causes, but is not associated with parathyroid disorders.
  • Pathophysiology
    • Hypoparathyroidismkidneys respond to low PTH with less phosphate excretion → hyperphosphatemia → solubility product of calcium phosphate exceeded (e.g., following the intake of foods rich in phosphorus) → precipitation of calcium phosphate crystals in the basal ganglia and other predisposed locations (e.g., the lens of the eye)
    • Calcifications that occur despite low serum calcium levels are known as paradoxical calcifications.

Diagnostics

Approach

  1. Evaluate calcium imbalance
    • Initial test: serum calcium concentration
    • Confirm true hypocalcemia/hypercalcemia: Order an ionized calcium or use serum albumin to calculate corrected calcium.
  2. 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)
    • 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

Differential diagnosis of hypocalcemia

PTH level Conditions Laboratory findings
Low PTH Hypoparathyroidism (e.g., postsurgical)
High PTH Vitamin D deficiency
Chronic kidney disease
Pseudohypoparathyroidism
Malabsorption or alcoholism

The typical laboratory findings of vitamin D deficiency are: ↓ calcium, ↓/↔ phosphate, PTH!

Differential diagnosis of 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)

* Not all cases of hypercalcemia caused by malignancy have an elevated PTHrP (e.g., multiple myeloma and lymphoma).


References:[11][12]

Differential diagnoses

Familial hypocalciuric hypercalcemia (FHH)

References:[13]

The differential diagnoses listed here are not exhaustive.

Treatment

Hypocalcemia

  • Treat any underlying disorders.
  • Calcium supplementation
    • 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

Patients receiving cardiac glycosides (digoxin and digitoxin) should never be given IV calcium, which can provoke ventricular fibrillation!

Hypercalcemia

Loop diuretics Lose calcium → Discontinue them in hypocalcemia!

Thiazide diuretics are calcium sparing → Discontinue them in hypercalcemia!
References:[14][15][9]

Complications

Hypercalcemic crisis

  • 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.

Prevention

Recommended daily allowances

  • Adults: ages 19–50
    • 1000 mg of calcium (dietary sources + supplements)
    • 600 international units of vitamin D
  • Women: ages 51–70
    • 1200 mg of calcium (dietary sources + supplements)
    • 600 international units of vitamin D
  • Men: ages 51–70
    • 1000 mg of calcium (dietary sources + supplements)
    • 600 international units of vitamin D
  • Seniors: ages 70+
    • 1200 mg of calcium (dietary sources + supplements)
    • 800 international units of vitamin D