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CLINICAL SCIENCE

 Disorders of calcium balance


Library 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,
Qbank 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
Analysis
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
Shop
(anxiety, depression). Management of calcium imbalance consists primarily of treating the underlying disorder and, if necessary, supplementing or eliminating
calcium.
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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]

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Calcium homeostasis and calcium physiology


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.
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
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.
↓ pH → ↑ H+ 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.
PTH secretion
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)
PTH effects
Promotion of calcium reabsorption in the distal tubule of the kidney (as well as phosphate excretion)
Increased active vitamin D production via stimulation of 1-alpha-hydroxylase 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
2. Vitamin D increases serum Ca2+ via its effect on the kidneys and gastrointestinal tract.
For more information see vitamin D synthesis and vitamin D deficiency.
3. Calcitonin opposes the effects of PTH.
Inhibits bone resorption, decreasing serum calcium
Significant in medullary thyroid cancer (as a tumor marker)

PTH = Phosphate Trashing Hormone

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

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Etiology
Hypocalcemia
Types of hypocalcemia Etiology Pathophysiology
Low PTH Hypoparathyroidism Destruction of the parathyroid glands
Surgical
Autoimmune
High PTH (secondary Vitamin D deficiency Poor dietary intake of Vitamin D due to malnutrition or malabsorption (e.g.,
hyperparathyroidism) alcoholism, chronic GI disease)
Inadequate sun exposure
Decreased enzymatic hydroxylation to active form (e.g., liver failure, chronic
kidney disease)

Pseudohypoparathyroidism (Albright PTH resistance


hereditary osteodystrophy)
Hyperphosphatemia (see phosphate) In patients with:
Impaired renal function (e.g., ↓ renal excretion)
Increased phosphate intake
Increased tissue breakdown (e.g., tumor lysis syndrome, rhabdomyolysis)
Phosphate deposition together with calcium in the bones

Acute necrotizing pancreatitis (see acute Calcium soap precipitation in the abdomen
pancreatitis)
Other Medications Loop diuretics (increase renal calcium excretion)
Glucocorticoids
Calcitonin

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 Etiology Pathophysiology
hypercalcemia
PTH-mediated Primary Adenoma (sporadic) or multiple endocrine neoplasia
hyperparathyroidism
Familial hypocalciuric See “Differential diagnosis” below.
hypercalcemia
Tertiary Renal failure → chronic secondary hyperparathyroidism → hyperplasia of the parathyroid glands → one or more
hyperparathyroidism glands becomes autonomous
Non-PTH-mediated Hypercalcemia of Most common cause: paraneoplastic production of PTHrP (e.g., squamous cell carcinomas of the lung, head,
malignancy and neck; renal, bladder, breast, and ovarian 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 Hydroxylase activity in activated mononuclear cells produces 1,25-dihydroxyvitamin D (calcitriol) outside of the
(e.g., sarcoidosis) kidneys

Other Intake of medications Thiazide diuretics → reduced renal calcium excretion


Excess vitamin D → increased intestinal calcium absorption
Calcium supplements
Hyperthyroidism Thyroid hormones have osteoclastic activity.

Long periods of Lack of weight-bearing activities → osteoclast activation → bone demineralization → hypercalcemia
immobilization
Milk-alkali syndrome Consumption of calcium carbonate

Paget's disease of the Increased rate of bone remodeling


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]

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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)


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
Somnolence progressing to obtundation and coma (hypercalcemic crisis!)
Diminished muscle excitability
Cardiac arrhythmias
Muscle weakness, paresis
Polyuria and dehydration
Calcium and pancreatitis → hypercalcemia 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]

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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
ECG
Hypocalcemia: QT interval prolonged
Hypercalcemia: QT interval shortened
Further evaluation of bone disorders: See laboratory evaluation of bone diseases.

Differential diagnosis of hypocalcemia


PTH level Conditions Laboratory findings
Low PTH Hypoparathyroidism (e.g., postsurgical) ↑ Phosphate
High PTH Vitamin D deficiency ↓/↔ Phosphate
↓ Calcidiol (25-hydroxyvitamin D)
↔/↑ Calcitriol (1,25-dihydroxyvitamin D)
Chronic kidney disease ↑ Phosphate
(↑ Creatinine)
Pseudohypoparathyroidism ↑ Phosphate
Malabsorption or alcoholism ↓ Magnesium

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* ↑ PTHrP
Vitamin D intoxication ↑ Calcidiol (25-hydroxyvitamin D)

Sarcoidosis or other granulomatous disease, lymphoma ↑ Calcitriol (1,25-dihydroxyvitamin D)


High to normal PTH Primary hyperparathyroidism ↓ Phosphate
↔/↑ Urine calcium
Familial hypocalciuric hypercalcemia (FHH) ↓ Urine calcium

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

References:[11][12]

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Differential diagnoses
Familial hypocalciuric hypercalcemia (FHH)
Etiology: autosomal dominant inactivating mutation in the CaSR gene → decreased sensitivity of calcium-sensing receptors in the kidneys and parathyroid gland
Clinical features
Usually asymptomatic (incidental finding)
Neonatal hypocalcemia in children of mothers with FHH
Diagnosis
Hypercalcemia and normal or increased PTH
Hypocalciuria
↓ 24-hour urinary calcium excretion (< 200 mg/ day)
↓ Ca/Cr clearance ratio (< 0.01 )
Therapy: no treatment necessary
References:[13]

The differential diagnoses listed here are not exhaustive.

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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
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)
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)
Calcitonin
Dialysis in severe cases or renal failure: > 18 mg/dL (> 4.5 mmol/L)

Loop diuretics Lose calcium → Discontinue them in hypocalcemia!

Thiazide diuretics are calcium sparing → Discontinue them in hypercalcemia!

References:[14][15][9]

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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.

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Sources last updated 10/06/2019 Tips & Links

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