• Clinical science

Disorders of calcium balance

Summary

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.
    • 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
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)
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

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]

Diagnostics

Approach

  1. Evaluate calcium imbalance
    • Initial test: serum calcium concentration
    • Confirm true hypocalcemia/hypercalcemia: measure 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

PTH in 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!

PTH in hypercalcemia

PTH level Conditions Laboratory findings
Low PTH Hypercalcemia of malignancy
Vitamin D intoxication

Sarcoidosis or other granulomatous disease, lymphoma

Milk-alkali syndrome
High to normal PTH Primary hyperparathyroidism
Familial hypocalciuric hypercalcemia (FHH)


References:[11][12]

Differential diagnoses

Differential diagnoses of hypocalcemia

Causes [13]
Vitamin D deficiency
Hypoparathyroidism
Medications
Hyperphosphatemia
Calcium citrate complex formation
Other

Familial hypocalciuric hypercalcemia (FHH)

  • Etiology: autosomal dominant inactivating mutation in the CaSR gene → decreased sensitivity of calcium-sensing receptors in the kidneys and parathyroid glands
  • Clinical features
    • Usually asymptomatic (incidental finding)
    • Neonatal hypocalcemia in children of mothers with FHH
  • Diagnosis
    • Hypercalcemia and inappropriately normal or increased PTH
    • Hypocalciuria
      • ↓ 24-hour urinary calcium excretion (< 200 mg/ day)
      • ↓ Ca/Cr clearance ratio (< 0.01 )
  • Therapy: no treatment necessary

References:[14]

The differential diagnoses listed here are not exhaustive.

Treatment

Hypocalcemia

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

Hypercalcemia

  • 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
    • Reduced dietary intake of calcium
    • Avoidance of thiazide diuretics, lithium, high-calcium diet
  • Moderate hypercalcemia: total calcium between 12–14 mg/dl (3–3.5 mmol/L)
    • Asymptomatic: same treatment as for mild hypercalcemia (see above)
    • Symptomatic: same treatment as described above for severe hypercalcemia (see below)
  • Severe or symptomatic hypercalcemia: total calcium > 14 mg/dL (> 3.5 mmol/L) or ionized calcium > 12 mg/dL (> 3 mmol/L)

Loop diuretics Lose calcium → Discontinue them in hypocalcemia!

Thiazide diuretics are calcium sparing → Discontinue them in hypercalcemia!
References:[15][16][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.