Nephrology Hypertension

Calcium Metabolism Disorders

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What is the cause of this patient's calcium metabolism disorder?

Hypercalcemia

Hypercalcemia occurs when the serum level of ionized (free), not total, calcium increases. It occurs when the total serum calcium level is >10.5 mg/dL or the ionized calcium level is > 5.6 mg/dL (1.4 mmol/L). Hypercalcemia is a common disorder that can be a challenge to clinicians.

The two most common causes of hypercalcemia are primary hyperparathyroidism and malignancy. Together, they account for over 90% of all cases. The clinical history can help distinguish between the two disorders and can identify other less common causes of hypercalcemia (Table 1). It is important to identify the cause as treatment and prognosis vary according to the underlying disorder. A careful history and physical should be performed focusing on the following key elements.

Table 1.

Causes of Hypercalcemia
Parathyroid Hormone Related     Primary hyperparathyroidism     Tertiary hyperparathyroidism
Malignancy Related     Humoral hypercalcemia of malignancy (PTHrp)     Solid tumors (e.g. breast, ovary, lung, kidney)     Local osteolysis (e.g. multiple myeloma)
Vitamin D Related     Vitamin D intoxication     Granulomatous diseases (e.g. sarcoidosis)     Lymphoma
Genetic Disorders     Familial hypocalciuric hypercalcemia
Medication Related     Vitamin D supplements     Thiazide diuretics     Calcium carbonate     Vitamin A intoxication     Lithium     Theophylline     Estrogen     Anti-estrogen (e.g. tamoxifen)
Endocrine Disorders     Hyperthyroidism     Adrenal insufficiency     Pheochromocytoma     Acromegaly
Other     Chronic kidney disease     Immobilization     Total parental nutrition

Risk factors for malignancy should be evaluated in the history. Hypercalcemia is most common with hematologic malignancies and solid tumors of the breast, ovary, lung and kidney. Malignancy is usually evident clinically by the time hypercalcemia develops. Symptoms of hypercalcemia are often more severe in patients with malignancy whereas asymptomatic hypercalcemia is common in patients with primary hyperparathyroidism. The clinical manifestations of hypercalcemia are discussed below.

The timing of hypercalcemia is important. Chronic hypercalcemia suggests primary hyperparathyroidism whereas rapid increases in serum calcium suggest malignancy. Patients with hypercalcemia from malignancy may have higher serum calcium concentrations than patients with hypercalcemia from other causes. Serum calcium levels >13 mg/dL are more common in malignancy than in primary hyperparathyroidism.

The age and sex of the patient is helpful in the diagnosis of hypercalcemia. Primary hyperparathyroidism is more common in women than in men and the incidence increases in women after menopause. Hypercalcemia is less common in children than adults, but is more likely to be clinically significant in children. Idiopathic infantile hypercalcemia is a disorder characterized by transiently high serum calcium levels in infancy. It is usually a benign disorder but there is a severe form associated with somatic deformations called Williams syndrome which is characterized by mental deficiency, "elfin face," epicanthal folds, renal disease, heart defects, and bladder diverticuli.

Hypercalcemia is found in 17% of patients with sarcoidosis. It is more common in males than females and results from increases in serum 1,25-dihydroxyvitamin D (calcitriol) levels. The hypercalcemia is usually corrected with glucocorticoids in the majority of patients.

A careful family history must be performed. Patients with a family history are more likely to have primary hyperparathyroidism or familial hypocalciuric hypercalcemia (FHH). FHH is an autosomal dominant disorder in which patients have hypocalciuria and hypercalcemia. It is a mild disease that usually does not require treatment. Patients may also have a family history or personal history of multiple endocrine neoplasia type 1 (MEN 1) or type 2A (MEN 2A). A family history of recurrent kidney stones is also suggestive of a familial cause of hypercalcemia.

Medication use must be reviewed with the patient. Specifically the use of vitamin D supplements, calcium carbonate (Tums), calcium acetate, calcium supplements, thiazide diuretics, lithium, vitamin A, estrogen or antiestrogens and theopylline, all of which can result in hypercalcemia (Table 1).

  • Thiazide diuretics rarely cause hypercalcemia in patients without any underlying disease. However, thiazide diuretic use may unmask primary hyperparathyroidism.

  • Ingestion of large amounts of calcium containing antacids (e.g. calcium carbonate) can result in the milk-alkali syndrome (hypercalcemia, hyperphosphatemia, metabolic alkalosis and renal insufficiency). The incidence of milk-alkali syndrome has increased because of recommendations for the use of calcium carbonate for prevention and treatment of osteoporosis. It is now the third most common cause of hypercalcemia.

  • Vitamin D intoxication results from ingestion of high doses of nutritional vitamin D (vitamin D2 or D3). Hypercalcemia does not usually occur unless the dose is >10,000 I.U. per day and the serum level exceeds 100 ng/mL. Active vitamin D analogs (e.g. calcitriol) can also result in hypercalcemia. Active vitamin D analogs are commonly used in patients with chronic kidney disease and in patients who have previously had a parathyroidectomy.

There are several endocrine causes of hypercalcemia and risk factors for these conditions should be reviewed in the history. Hypercalcemia develops in 10-22% of patients with hyperthyroidism through increased bone resorption. The hypercalcemia is usually mild and reverses with antithyroid therapy. Rarely, hypercalcemia results in patients with pheochromocytomas either from the pheochromocytoma itself or in combination with hyperparathyroidism (i.e. MEN 2A). Patients with adrenal insufficiency and acromegaly may also develop hypercalcemia and these disorders should be included in the differential diagnosis.

The history should focus on other rare causes of hypercalcemia including chronic kidney disease, immobility and the recovery phase of acute renal failure secondary to rhabdomyolysis.

  • Chronic kidney disease (CKD) usually results in hypocalcemia, but prolonged hyperphosphatemia and low vitamin D levels lead to enhanced parathyroid hormone (PTH) secretion which can result in hypercalcemia. This disorder is termed tertiary hyperparathyroidism and is discussed below.

  • Immobility (including prolonged bed rest) leads to loss of bone minerals and in patients with rapid bone turnover (e.g. children, adolescents, and patients with bone abnormalities such as Paget disease) hypercalcemia can occur.

  • During the recovery phase of rhabdomyolysis, the calcium deposited in the tissues mobilizes back into the circulation resulting in hypercalcemia.

What are the key signs and symptoms of hypercalcemia?

Regardless of the etiology of hypercalcemia, the signs and symptoms are similar. However, more severe symptoms may manifest in certain disease states. The severity of the symptoms depend on the level and rate of rise of serum calcium. Patients with serum calcium levels <12 mg/dL are often asymptomatic. If the hypercalcemia is chronic, patients may remain asymptomatic even with serum calcium levels of 12-14 mg/dL. However, acute rises in serum calcium to these levels may result in discernible symptoms. Levels >14 mg/dL are not well tolerated and may result in severe symptoms including coma. Elderly patients are more susceptible to the severe symptoms of hypercalcemia. The most common clinical manifestations of hypercalcemia are shown in Table 2 and are discussed below.

Table 2.

Clinical Manifestations of Hypercalcemia
Neuropsychiatric Symptoms     Fatigue     Headache     Lethargy     Cognitive dysfunction     Muscle weakness     Stupor     Coma
Gastrointestinal Symptoms     Anorexia     Constipation     Nausea     Pancreatitis     Peptic ulcer disease
Renal Symptoms     Acute and chronic renal failure     Nephrolithiasis     Nephrogenic diabetes insipidus
Cardiac Symptoms     Shortened QT interval     Arrhythmias     Vascular calcification
Skeletal Symptoms     Bone pain     Arthritis     Osteitis fibrosa cystica
Ocular Symptoms     Conjunctivitis     Band keratopathy

The first symptoms that occur are usually general and nonspecific. They include fatigue, muscle weakness, nervousness, difficulty concentrating and depression. As the hypercalcemia persists, other symptoms begin to manifest and are discussed by systems below.

  • Gastrointestinal symptoms are common in hypercalcemia. They include nausea, constipation, anorexia and rarely peptic ulcer disease or pancreatitis.

  • Neuropsychiatric manifestations include headache, mild cognitive dysfunction, lethargy and rarely stupor and coma.

  • Conjunctivitis may occur from crystal deposition. Other rare opthalmologic mainfestations include band keratopathy resulting from calcium phosphate deposition in the cornea.

  • Skeletal manifestations include bone pain, osteoarthritis, osteitis fibrosa cystica, and osteoporosis.

  • Elevated serum calcium causes shortening of the QT interval. Cardiac arrhythmias have been reported in patients with severe hypercalcemia ( levels > 14 mg/dL) but are rare and are usually not clinically relevant. Long standing hypercalcemia can result in vascular and valvular calcification.

There are several renal manifestations of hypercalcemia including acute and chronic renal dysfunction, nephrolithiasis and nephrogenic diabetes insipidus.

  • Renal dysfunction rarely occurs with mild hypercalcemia. Acute renal failure may occur with levels >12 mg/dL and is usually reversible with correction of the elevated calcium. Long standing hypercalcemia can result in tubulointersitial disease with medullary and cortical deposition of calcium (nephrocalcinosis). The nephrocalcinosis can result in a distal type 1 renal tubular acidosis which can predispose patients to the development of kidney stones.

  • Nephrolithiasis occurs in patients with chronic hypercalcemia. The chronically elevated serum calcium levels leads to increased excretion of calcium into the urine resulting in hypercalciuria and kidney stones. Kidney stones do not develop in FHH.

  • Polyuria and polydipsia occur secondary to the development of nephrogenic diabetes insipidus.

Key physical exam findings: There are no specific physical examination findings of hypercalcemia except for band keratopathy, which is rare. The physical exam may point to the underlying etiology of the hypercalcemia as there may be manifestations of malignancy, hyperthyroidism, etc.

Hypocalcemia

Hypocalcemia occurs when the level of serum ionized calcium falls below 1.16 mmol/L (true hypocalcemia). False hypocalcemia occurs from a reduction in the serum albumin which decreases the total serum calcium level but the ionized calcium level remains stable. False hypocalcemia should be considered in patients with chronic illness, malnutrition, cirrhosis and/or nephrotic syndrome as these disorders result in hypoalbuminemia.

False hypocalcemia must be excluded before a diagnosis of hypocalcemia can be made by correcting the calcium for the hypoalbuminemia or directly measuring the ionized calcium level. The most commonly used formula for correction is to add 0.8 mg/dL to the total serum calcium level for each 1 gm decrease in serum albumin below 4 g/dL. However, it is better to directly measure ionized calcium if this test is available.

There are numerous causes of hypocalcemia (Table 3). A careful history and physical examination can help identify the underlying cause of the hypocalcemia and should focus on the following key elements:

Table 3.

Causes of Hypocalcemia
HypoparathyroidismPost-surgicalAutoimmuneGenetic disorders (Calcium sensor receptor mutation, DiGeorge syndrome)IrradiationInfiltrative Diseases (hemochromatosis, thalassemia, amyloidosis, Wilson's disease)
Vitamin D DeficiencyMalabsorptionPoor nutritionDecreased 25-hydrovitamin D formationDecreased calcitriol formationResistance to calcitriol
PseudohypoparathyroidismAlbright's hereditary osteodystrophy
Renal DiseaseChronic kidney disease, usually advanced
Increased loss of calcium from the circulationHyperphosphatemiaHungry bone syndromeTumor lysis syndromeRhabdomyolysisAcute pancreatitisOsteoblastic metastasesSepsis
Magnesium DeficiencyPTH resistanceDecreased secretion of PTH
Drug RelatedCinacalcetBisphosphonatesCalcium chelators (citrate, phosphate)Gadolinium (pseudohypocalcemia)PhenytoinPhenobarbitalCisplatinum
Changes in Acid/Base statusRespiratory alkalosisInfusion of sodium bicarbonate

Hypocalcemia spans all ages and the incidence is equal in males and females. The differential diagnosis will vary depending on the patient's age and other comorbidities.

The patient should be asked about recent surgery, as acquired hypoparathyroidism is usually the result of post-surgical damage to the parathyroid glands. Hypoparathyroidism can occur after parathyroid, thyroid or radical neck surgery (e.g. head and neck cancer). Neck trauma from accidents, etc. also can result in hypoparathyroidism. The hypoparathyroidism may be permanent or transient. Transient hypoparathyroidism should resolve in days to months. Bowel surgery is also a cause of hypocalcemia secondary to malabsorption.

The patient may have a history of chronic diarrhea or intestinal disease (e.g. Crohn's, celiac sprue). These disorders may result in hypocalcemia from malabsorption of calcium and/or vitamin D. Acute gastroinestinal disease can cause acute hypocalcemia that is usually transient.

Autoimmune damage to the parathyroid glands is a cause of acquired hypoparathyroidism. Autoimmune damage is common in polyglandular autoimmune syndrome type 1 (candidiasis, hypoparathyroidism and Addison's disease) but autoimmune damage can also occur as an isolated endocrinopathy. Thus, it is important to document any autoimmune diseases such as hyperthyroidism in the history.

The timing of hypocalcemia is important. Hypocalcemia that has been present for a prolonged period of time suggests hypoparathyroidism or pseudohypoparathyroidism.

Family history is very important in the work-up of hypocalcemia as several causes of hypocalcemia are genetic. Polyglandular autoimmune syndrome type 1 is an autosomal recessive disorder in which hypocalcemia is very common. There are also inherited vitamin D disorders including vitamin D-dependent rickets. Familial isolated hypoparathyroidism is also reported with different modes of inheritance. Mutations in the calcium sensing receptor have been identified in autosomal dominant hypocalcemia.

Pseudohypoparathyroidism (parathyroid hormone resistance) is also a familial disease that causes hypocalcemia as well as short stature, hypothyroidism, hypogonadism and developmental delay.

The patient's medical history should be explored for kidney disease as this is a common cause of hypocalcemia, especially in those with advanced kidney disease (e.g. dialysis patients).

Hypocalcemia is very common in patients in the intensive care unit, with an incidence around 80%. There are multiple reasons why these patients develop hypocalcemia: acute or chronic kidney disease (CKD), medications, transfusions with citrated blood, radiology studies using contrast dyes that may contain ethlyenediaminetetra-acetic acid (EDTA), hypomagnesemia and sepsis. Hypocalcemia is a poor prognostic sign in patients with critical illness.

Pancreatitis is a frequent cause of hypocalcemia. The hypocalcemia is due to precipitation of calcium in the retroperitoneum. Hypomagnesemia may augment the problem if there is associated alcohol abuse or other history of poor nutritional intake.

The patient's nutritional status should be explored in the history. Poor nutritional status is a cause of hypocalcemia usually as a result of vitamin D deficiency and/or low calcium intake.

Vitamin D deficiency is common in the general population. Most cases of vitamin D deficiency do not result in hypocalcemia unless the deficiency is severe. Patients with CKD and the elderly are more likely to have hypocalcemia as a result of vitamin D deficiency. Vitamin D deficiency is defined as a serum 25-hydroxyvitamin D level less than 20 mg/dL. Vitamin D insufficiency is defined as a serum level of 25-hydroxvyitmain D of 21-30 ng/mL.

Medication use must be reviewed with the patient. Bisphosphonates and calcitonin are common causes of hypocalcemia. Radiocontrast dyes that use EDTA or gadolinium can result in hypocalcemia but it is usually transient. Several chemotherapy agents can cause hypocalcemia (cisplatinum, 5-flurouracil and lecovorin). Prolonged therapy with anticonvulsants such as phenytoin and phenobarbital can also lead to hypocalcemia by causing vitamin D deficiency.

Gadolinium based contrast agents cause pseudohypocalcemia as they interfere with the colorimetric assays for calcium. A marked reduction can be seen in the serum calcium level (as low as 6 mg/dL) if the test is performed soon after the gadolinium is given. The effect rapidly reverses as the gadolinium is metabolized. The effect is prolonged in patients with CKD as gadolinium is metabolized renally. Patients are asymptomatic and no treatment is required.

The history should be reviewed for recent blood or other blood product transfusions. Citrate is a calcium chelator that is used to prevent coagulation in blood products and results in hypocalcemia. The hypocalcemia resulting from transfusion of blood or plasma is usually mild and patients are asymptomatic. However, significant hypocalcemia can occur in patients receiving large quantities of blood products, such as with plasmapheresis or massive blood transfusions. Patients with liver failure may also develop symptomatic hypocalcemia as citrate metabolism is impaired.

Hungry bone syndrome can occur after thyrotoxicosis or hyperparathyroidism due to a rapid increase in bone formation. Hypocalcemia occurs if the rate of bone formation exceeds the rate of bone resorption.

Patient history should be reviewed for metastases to bone. Patients with prostate or breast cancer can have osteoblast metastases that result in hypocalcemia.

Changes in acid/base status:

  • Acute respiratory alkalosis causes hypocalcemia. The decrease in hydrogen ion concentration frees up binding sites on albumin and albumin then binds up ionized calcium causing a decrease in serum levels.

  • Infusion of sodium bicarbonate also results in hypocalcemia. The addition of sodium bicarbonate results in a decrease in hydrogen ion concentration which frees up binding sites on albumin. Albumin then binds ionized calcium and decreases the serum levels.

  • Importantly, in both the above conditions, total serum calcium levels will not change. The diagnosis of hypocalcemia can only be made by checking the ionized calcium level. Ionized calcium levels must be monitored closely during sodium bicarbonate infusions to evaluate for hypocalcemia.

  • Magnesium depletion can cause hypocalcemia. Hypocalcemia usually occurs when the serum magnesium level falls below 1.0 mg/dL. Hypomagnesemia results in decreased serum ionized calcium levels by inducing PTH resistance and decreasing PTH secretion.

  • Excessive intake of fluoride can cause hypocalcemia from excessive rates of bone mineralization from formation of calcium difluoride.

What are the key signs and symptoms of hypocalcemia?

Most patients with hypocalcemia are asymptomatic. Rapid or large changes in ionized calcium levels may lead to symptoms which can be life-threatening. The clinical manifestations depend on how severe and how long the hypocalcemia has been present. The key clinical symptoms are shown in Table 4 and are reviewed here.

Table 4.

Clinical Manifestations of Hypocalcemia
Neuromuscular irritabilityPerioral numbnessCarpopedal spasms of the hands and feetTetanyChvostek's signTrousseaus's signMuscle crampsFatigueSeizuresPolymyositisLaryngeal spasmsBronchial spasms
Neurologic symptomsIrritabilityConfusionPsychosisExtrapyramidal signsParkinsonismCalcification of cerebral cortex or cerebellum
Cardiac signs/symptomsProlonged QT intervalArrhythmiaCongestive heart failureHypotension
Ectodermal symptomsDry skinCoarse hairBrittle nailsAlopeciaAbnormal dentition
Opthalmologic manifestationsSubcapsular cataractsPapilledema

Acute clinical manifestations

The hallmark of acute hypocalcemia is neuromuscular irritability. The most specific symptoms are perioral numbness and carpodedal spasms of the hands and feet. Muscle cramps can be extremely painful and may progress to tetany. Seizures may be the only presenting symptom of hypocalcemia. Patients may also present with lethargy and altered mental status, especially if the hypocalcemia is severe.

Tetany usually only occurs when the total serum calcium level falls below 7.0 mg/dL which corresponds to an ionized calcium of 1.1 mmol/L.

  • Tetany is characterized by repetitive high frequency discharges after a single stimulus.

  • Alkalosis worsens tetany. Thus, patients with acute respiratory alkalosis and hypocalcemia are more likely to develop tetany whereas tetany is rare in patients with CKD and hypocalcemia as there is usually concomitant metabolic acidosis.

  • In extreme cases of hypocalcemia bronchial or laryngeal spasm may occur.

Neuromuscular irritability can be tested by Chvostek's sign and Trousseau's sign.

  • Chvostek's sign is tested by tapping on the facial nerve near the temporal mandibular joint. A positive test is ipsilateral contraction of the facial muscles. Chvostek's sign may be present in up to 10% of normal individuals.

  • Trousseau's sign is tested by inflating a blood pressure cuff to 20 mmHg above the patient's systolic blood pressure for 3 to 5 minutes and watching for spasm of the outstretched hand. The spasm presents as flexion of the wrist and metacarpal phalangeal joints, extension of the intraphalangeal joints and adduction of the thumb. It is more specific for hypocalcemia than Chvostek's sign.

Seizures: Grand mal, petit mal and focal seizures all can occur as a result of hypocalcemia. Patients who develop seizures usually also have tetany, but seizures can occur without tetany.

Cardiovascular manifestations may be present as a sign or symptom of hypocalcemia.

  • Prolongation of the QT interval is the classic sign of hypocalcemia on the electrocardiogram (EKG) and occurs in approximately 50% of patients. T-waves may also be abnormal. In patients with severe hypocalcemia EKG changes may mimic those of acute anteroseptal injury. If hypomagnesemia is also present the EKG abnormalities may be magnified. Dsyrthymias can be triggered by hypocalcemia. Serious dysrthymias such as ventricular tachycardia and heart block can occur but are rare.

  • Hypotension may occur as a result of low ionized calcium levels. Acute hypotension can occur following rapid transfusions of citrated blood. Hypocalcemia has also been found to be a cause of refractory hypotension in critically ill patients.

  • Heart failure is uncommon and is usually reversible with correction of the hypocalcemia.

  • Papilledema can occur in patients with hypocalcemia from increased intracranial pressure and usually improves with reversal of the hypocalcemia.

Chronic clinical manifestations

Patients with chronic hypocalcemia are often asymptomatic. However, prolonged hypocalcemia can lead to changes in the skin, bones, eyes and brain. Ectodermal changes are frequently found in patients with chronic hypocalcemia. These include dry skin, coarse hair and brittle nails. Dental abnormalities can occur if the hypocalcemia was present before the age of five. Alopecia is associated with autoimmune hypoparathyroidism and in some cases of post-surgical hypoparathyroidism. Resolution of the hypocalcemia results in improvement in these disorders.

Basal ganglia calcifications occur due to long standing hypoparathyroidism. Patients with these calcifications often develop extrapyramidal symptoms including parkinsonism and other movement disorders such as dystonic spasms and choreoathetosis. Dementia can also occur secondary to the calcifications. These symptoms may be reversible with treatment of the hypocalcemia.

Neurologic symptoms including psychoses, psychoneuroses and impaired intellectual ability have been noted with chronic hypocalcemia.Treatment of the hypocalcemia may improve intelligence but the psychiatric symptoms may not resolve.

Cataracts are common in patients with prolonged hypocalcemia and usually reverse with correction of the hypocalcemia.

Skeletal abonormalities are common in patients with chronic hypocalcemia and are related to the underlying cause. Different skeletal abnormalities are seen in hypoparathyroidism, pseudohypoparathyroidism and vitamin D deficiency.

Key physical examination findings

The physical exam may reveal findings that are specific to hypocalcemia such as Chvostek's or Trousseau's signs. Many nonspecific findings such as epidermal changes, mental status changes, etc. may be present. The physical exam may point to the underlying etiology of the hypercalcemia as there may be manifestations of pancreatitis, sepsis, renal failure, etc.

What tests to perform?

Hypercalcemia

Work-up of hypercalcemia

Hypercalcemia should be confirmed if there is only one elevated serum calcium level. It is important to remember that the serum calcium level is a poor reflection of overall total body calcium. Ionized calcium is the physiologically active form of calcium and usually comprises approximately 40% of the total serum calcium. In the presence of low serum albumin the total serum calcium usually underestimates the amount of ionized calcium.

Therefore, in the setting of hypoalbuminemia the total calcium level needs to be corrected for the albumin level. The most commonly used formula for correction is to add 0.8 mg/dL to the total serum calcium level for each 1 gm decrease in serum albumin below 4 g/dL. However, it is better to directly measure ionized calcium if this test is available.

Once hypercalcemia is confirmed, the next step is to measure the serum intact parathyroid hormone (PTH) level to differentiate between PTH-related and non-PTH related hypercalcemia (Table 1). If the serum PTH level is high this is indicative of primary hyperparathyroidism. If the level of PTH is low or high normal then further laboratory testing should be performed ) (Figure 1). A high PTH level can also be seen with tertiary hyperparathyroidism. Tertiary hyperparathyroidism develops in patients with end-stage renal disease from hyperfunctioning parathyroid tissue. Serum intact PTH levels are usually very high (> 600 pg/mL).

Figure 1.

Evaluation of hypercalcemia.

A high-normal PTH level is still highly suggestive of primary hyperparathyroidism. However, FHH must be ruled out as 15% of patients may have a mildly elevated PTH. The next step is to order a 24 hour urine to evaluate calcium excretion. Primary hyperparathyroidism has high urinary calcium excretion (> 200 mg/24 hours) whereas FHH has low urinary calcium excretion (<100 mg/24 hours). The urine calcium to creatinine ratio is usually very low (<0.01) in patients with FHH.

A low PTH level (< 20 pg/mL) indicates non-PTH related hypercalcemia (Table 1). Since malignancy is the most common cause of hypercalcemia the next laboratory test should be measurement of serum PTH-related protein (PTHrp). Most malignancies (usually solid tumors) cause hypercalcemia through secretion of PTHrp, a condition termed humoral hypercalcemia of malignancy. If the serum PTHrp is high then the patient should be evaluated for malignancy (Figure 1).

Serum 1,25-dihydroxyvitamin D should be measured if PTHrp is not elevated. Lymphoma usually results in hypercalcemia through increased production of 1,25-dihydroxyvitamin D. Sarcoidosis and other granulomatous diseases also over produce 1,25-dihydroxyvitamin D. A high serum 1,25-dihydroxyvitamin D level should prompt further testing for these disorders. Medications should also be reviewed to ensure the patient is not taking any form of active vitamin D (e.g. calcitriol).

Measurement of serum 25-hydroxyvitamin D should be performed if there is a concern for vitamin D intoxication. An elevated serum 25-hydroxyvitamin D level results from exogenous intake of compounds containing vitamin D. Thus, all medications, including herbal supplements, should be reviewed with the patient. 25-hydroxyvitamin D should also be checked in all patients diagnosed with primary hyperparathyroidism as vitamin D deficiency needs to be treated prior to any surgical treatment.

If PTHrp is negative and 1,25 and 25 vitamin D levels are normal, other non-PTH related causes of hypercalcemia should be considered. Given the large number of diseases associated with hypercalcemia, one should use patient factors and symptoms to guide further testing.

All patients should have a creatinine checked to evaluate for chronic kidney disease (CKD) as well as any acute kidney dysfunction from hypercalcemia. Serum phosphate concentration should also be measured. Serum alkaline phosphatase, a measure of bone turnover, can be measured in patients with suspected bone lysis. Serum TSH should be considered in patients with signs/symptoms of hyperthyroidism. Serum and urine protein electrophoresis should be measured in patients at risk for multiple myeloma.

Testing for other endocrinopathies (adrenal insufficiency, pheochromocytoma, and acromegaly) should be considered but not routinely performed. It is reasonable to consider referring the patient to an endocrinologist prior to performing these specialized tests.

Imaging studies are helpful for identifying malignancy or granulomatous disease. The type of imaging performed should be based on clinical suspicion of the underlying disease. Renal imaging should be performed if kidney stones are suspected as it helps guide management of primary hyperparathyroidism (discussed below). Imaging studies of the parathyroid gland have no role in the diagnosis of primary hyperparathyroidism but preoperative localization imaging studies are useful in planning the approach for surgery.

Hypocalcemia

Work-up of hypocalcemia

Hypocalcemia should be confirmed if there is only one low serum calcium value. It is important to remember that the serum calcium level is a poor reflection of overall total body calcium. Ionized calcium is the physiologically active form of calcium and usually comprises approximately 40% of the total serum calcium. In the presence of low serum albumin the total serum calcium usually underestimates the amount of ionized calcium (false hypocalcemia).

Therefore, in the setting of hypoalbuminemia the total calcium level needs to be corrected for the albumin level. The most commonly used formula for correction is to add 0.8 mg/dL to the total serum calcium level for each 1 gm decrease in serum albumin below 4 g/dL. However, it is better to directly measure ionized calcium if this test is available.

After hypocalcemia is confirmed the laboratory evaluation should be guided by the medical history and physical examination as the cause of the hypocalcemia may be obvious (Table 3). Acute pancreatitis, acute or chronic kidney disease, post-surgical hypoparathyroidism, medication related causes, rhabdomyolysis, and tumor lysis syndrome may be diagnosed or excluded based on the history, physical and routine laboratory measurements (creatinine, creatinine kinase, amylase).

The next step is to measure the serum magnesium level to determine its potential contribution to the hypocalcemia. This is especially important if the cause of the hypocalcemia is not obvious from the patient's history. If the serum magnesium is low (<1.0 mg/dL) magnesium should be repleted. Hypocalcemia should resolve quickly (within minutes to hours) if hypomagnesemia is the cause of the hypocalcemia. If the hypocalcemia does not resolve or if the magnesium level is normal or greater then 1.0 mg/dL further laboratory testing is required in order to identify the underlying cause (Figure 2).

Figure 2.

Initial evaluation of hypocalcemia.

The next step in the evaluation is to check serum intact parathyroid hormone (PTH). Low ionized calcium is the strongest stimulus of PTH secretion. In patients with hypocalcemia the PTH should be elevated unless the underlying disorder results in decreased PTH secretion (e.g. hypoparathyroidism). Thus, the PTH level gives critical information about the cause of the hypocalcemia. (Figure 3).

Figure 3.

Further laboratory evaluation of hypocalcemia.

Low or inappropriately normal PTH

If the PTH is low it is essentially diagnostic of hypoparathyroidism (hereditary or acquired) but autosomal dominant hypocalcemia (activating mutation of the calcium sensing receptor) must be ruled out with further laboratory testing. Chronic hypomagnesemia also results in low or normal PTH. Hungry bone syndrome results from an abrupt decrease in PTH levels post-surgery resulting in increased bone uptake of calcium, magnesium and phosphorus.

  • A serum phosphate level should be checked next. Serum phosphate is elevated in hypoparathyroidism and autosomal dominant hypocalcemia but is not usually elevated in hypomagnesemia. The magnesium level is low (<1.0 mg/dL) in hypomagnesemia related hypocalcemia whereas it is usually normal in hypoparathyroidism and autosomal dominant hypocalcemia. The phosphate level is usually low in hungry bone syndrome unless the patient has underlying CKD in which the serum phosphate levels are usually normal. Hungry bone syndrome should be obvious from the patient's history as it follows parathyroid or thyroid surgery.

  • It is difficult to distinguish between hypoparathyroidism and autosomal dominant hypocalcemia by laboratory testing alone as both present with hypocalcemia and hyperphosphatemia. However, urinary calcium excretion is usually normal or increased in autosomal dominant hypocalcemia whereas it is low in hypoparathyroidism. The clinical history of the patient can help to distinguish these two disorders. Previously normal calcium levels essentially rule out autosomal dominant hypocalcemia as the calcium levels are always low in these patients.

  • Patients with autosomal dominant hypocalcemia also typically develop kidney stones and nephrocalcinosis when treated with vitamin D and calcium supplementation. A history of recent neck surgery is highly suggestive of acquired hypoparathyroidism. The only way to make a definitive diagnosis is by testing for a mutation in the calcium sensing receptor.

High PTH level

A high PTH level is the normal response to hypocalcemia (secondary hyperparathyroidism). Thus, an elevated PTH levels is seen in patients with hypocalcemia from acute or chronic kidney disease, pseudohypoparathyroidism, vitamin D deficiency, rhabdomyolysis, tumor lysis syndrome, osteoblastic metastases, sepsis, etc. Most of these causes are obvious from the patient's history and physical examination. Further laboratory testing can be used to distinguish vitamin D deficiency from pseudohypoparathyroidism (Figure 3).

The serum phosphate level should be checked. If the phosphate level is high this indicates acute or chronic renal failure or pseudohypoparathyroidism. These disorders can be distinguished easily by measuring the serum creatinine as it will be elevated in patients with renal failure and normal in patients with pseudohypoparathyroidism. A low serum phosphate indicates vitamin D deficiency or osteoblastic metastases and serum 25-hydroxyvitamin D should be checked. If the patient has low 25-hydroxyvitamin D levels, then 1,25-dihydroxyvitamin D levels should be checked.

  • Low 25-hydroxyvitamin D levels (<20 ng/mL) and normal to high 1,25-dihydroxyvitamin D levels indicate inadequate intake, inadequate sunlight, low absorption of vitamin D, nephrotic syndrome, and the use of anticonvulsants which alter vitamin D metabolism. Hereditary vitamin D-resistant rickets also has low 25-hydroxyvitamin D levels and high 1,25-dihydroxyvitamin D levels but this disorder can be ruled out in adult patients without a lifelong history of hypocalcemia as it presents in early childhood.

  • Low 25-hydroxyvitamin D levels and low 1,25-dihydroxyvitamin D levels indicate vitamin D-dependent rickets type 1. These patients present in the first year of life with profound hypocalcemia and skeletal disease. This disorder is reviewed in detail in the vitamin D deficiency/rickets chapter.

  • If the patient does not have vitamin D deficiency or the diagnosis remains unclear, serum alkaline phosphatase should be measured. Patients with osteoblastic metastases will have elevated serum levels of alkaline phosphatase. Imaging studies can then be performed to confirm the presence of metastases.

  • Imaging studies are useful for identifying osteoblastic metastases which can usually be seen on plain films. In patients with idiopathic hypoparathyroidism or pseudohypoparathyroidism computed tomography (CT) scans of the head may show basal ganglia calcification.

How should patients with calcium metabolism disorders be managed?

Hypercalcemia

The main goal of therapy is to treat the underlying disorder leading to hypercalcemia (discussed below). Whether the patient requires immediate treatment of hypercalcemia depends on the presence of symptoms and the level of serum calcium.

  • Patients that are asymptomatic with calcium levels of 12-14 mg/dL do not usually require immediate treatment. They should avoid medications that can cause hypercalcemia and should increase fluid intake to at least 2 liters per day to decrease the risk of kidney stones. Further therapy should be aimed at the underlying cause of the hypercalcemia. Any offending medications must be stopped.

  • Patients with acute symptoms of hypercalcemia (even if the serum calcium level is <14 mg/dL) require immediate treatment and steps must be taken to lower the serum calcium level. Furthermore, patients with serum calcium levels >14 mg/dL require immediate treatment regardless of the presence or absence of symptoms. Patients with a hypercalcemic crisis should be managed initially in the intensive care unit.

Conservative therapies

Immediate treatment of severe hypercalcemia involves conservative therapies (saline plus loop diuretics) as well as pharmacologic management.

Intravenous volume resuscitation with saline

  • The safest and most effective immediate treatment is intravenous volume resuscitation with normal saline to euvolemia, assuming the patient has reasonable cardiac and renal function. Patients with hypercalcemia are often volume depleted and infusion of saline corrects the volume depletion and thereby reduces the reabsorption of sodium and calcium in the proximal tubule of the kidney.

  • The rate of saline infusion depends on the severity of hypercalcemia and patient factors including cardiac or renal disease. If the patient does not have significant cardiac or renal dysfunction it is reasonable to start the normal saline infusion at 200-400 mL/hour and then adjust the rate to keep urine output around 100 mL/hour.

  • The patient must be monitored carefully for signs and symptoms of volume overload. Elderly patients are more susceptible to volume overload with rapid infusions of saline. Severe cardiac or renal failure are contraindications to large volume expansion with saline.

  • Infusion of saline is only used to restore euvolemia. Use of saline after euvolemia is reached is not recommended given the risk of substantial volume overload.

Loop diuretics

Loop diuretics (e.g. furosemide) may be added as an adjunct therapy to saline once volume expansion is achieved. This helps minimize the risk of volume overload and substantially increases the urinary excretion of calcium.

  • The dose of intravenous (IV) furosemide used should be based on the estimated glomerular filtration rate (eGFR) of the patient. For patients with an eGFR >60 ml/min, 20 mg of IV furosemide is a reasonable starting dose whereas patients with an eGFR of 35-59 ml/min may require 40 mg IV. It is always better to use conservative dosing (i.e. 20 mg IV as starting dose) as the response to a given dose of furosemide is hard to predict.

  • Caution must be taken to ensure that loop diuretics are only given once volume resuscitation is complete as the diuresis will lead to loss of sodium and water. The intake and output of the patient must be monitored carefully as patients will require replacement of the lost salt and water. Serum electrolytes, especially potassium and magnesium, must be monitored closely as therapy can lead to significant hypokalemia and hypomagnesemia.

Pharmacologic therapies

If conservative therapies fail to decrease the serum calcium level or patients have contraindications to saline therapy then pharmacologic therapies should be used.

Intravenous bisphosphonates are very effective for the treatment of hypercalcemia. Bisphosphonates block osteoclast mediated bone resorption through induction of osteoclast apoptosis. Pamidronate (60-90 mg IV over 4 hours) and zoledronate (4 mg over 15 minutes) are usually the agents of choice and are approved in the United States for the treatment of malignancy related hypercalcemia. Zoledronate is more potent than pamidronate at reversing hypercalcemia.

A single dose of these medications usually results in normocalcemia. Decreases in serum calcium levels are seen within 2 to 4 days. Very rare side effects of these mediations are osteonecrosis of the jaw and acute renal failure. These medications should be used with caution in patients with significant renal impairment and the dose must be reduced. We recommend using pamidronate 30-45 mg IV over 4 hours in patients with renal impairment.

Calcitonin is another option for reducing serum calcium. It has a rapid effect and usually lowers serum calcium within four to six hours by increasing urinary calcium excretion and decreasing bone resorption. Its use in clinical practice is limited by its short duration of action and the rapid development of tachyphylaxis. It is most useful when used in combination with saline hydration for a rapid reduction in serum calcium in patients with severe hypercalcemia.

The recommended dose is 4 international units/kg of salmon calcitonin given subcutaneously or intramuscularly every 12 hours. If there is no response to the initial dose, the dose can be increased to 6-8 international units/kg. Calcitonin is usually well tolerated with few side effects.

Glucocorticoids are effective for hypercalcemia resulting from malignancy and excess vitamin D, either endogenous (e.g. sarcoid) or endogenous excess (e.g. vitamin D intoxication). The mechanism of action is unclear but may involve decreased intestinal absorption of calcium and suppression of bone resorption. Glucocorticoids are usually given orally starting at 40 to 60 mg per day. The decrease in serum calcium usually occurs within 1 to 2 days.

Plicamycin (Mithramycin) is a cytostatic drug that inhibits bone resorption. It results in a rapid decline in serum calcium levels within a few hours and its effect lasts several days. Serious side effects including bone marrow suppression liver and renal toxicity occur and have limited its use in clinical practice. The maximum daily dose is 25 micrograms (mcg) per kg.

Gallium nitrate is another agent that reduces serum calcium via inhibition of bone resorption. It must be infused continuously for four to five days. Nephrotoxicity is a major side effect of gallium nitrate. It is not favored for the treatment of hypercalcemia and has largely been replaced by the bisphosphonates.

Dialysis can be used in cases of resistant, life-threatening hypercalcemia (serum calcium levels of 18-20 mg/dL). Immediate consultation with nephrology is recommended in patients who meet this criteria. As stated earlier, the goal of therapy is to treat the underlying cause of hypercalcemia. The treatment of the most common causes of hypercalcemia is discussed here.

Primary hyperthyroidism

Parathyroidectomy is the only definitive cure at this time. Experts agree that patients with symptomatic hyperparathyroidism should undergo parathyroid surgery. The treatment of asymptomatic primary hyperparathyroidism is more controversial. Guidelines from the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism recommend surgical intervention in patients with age less than 50 years, serum calcium 1 mg/dL greater than the laboratory upper limits of normal, urine calcium excretion > 400 mg/day, creatinine clearance less than 60 mL/min, and T-score less than -2.5 at any site and/or previous low trauma fracture.

Patients who do not meet these criteria should be followed closely with yearly measurements of serum calcium and renal function and bone mineral density studies every one to two years. If their disease progresses they should be referred for surgical intervention.

  • Medical management can be used in patients who are poor surgical candidates or decline surgery. Medical management includes the use of bisphosphonates and calcimimetics (e.g. cinacalcet). Bisphosphonates are useful for treatment of osteopenia in these patients. Calcimimetics are new drugs that activate the calcium sensing receptor on the parathyroid gland and reduce PTH secretion. They are currently only approved for the treatment of secondary hyperparathyroidism but small studies suggest that they are also effective for the treatment of primary hyperparathyroidism at a starting dose of 30 mg orally twice a day.

  • Vitamin D deficiency is common in patients with primary hyperparathyroidism and might be associated with more severe disease and disease progression. The Third International Workshop on Asymptomatic Primary Hyperparathyroidism recommend repleting vitamin D in patients with 25-hydroxyvitamin D levels <20 ng/mL prior to any surgical or medical intervention. There is no standard regimen of vitamin D repletion. It can be given in the form of cholecalciferol or ergocalciferol. There is a possibility that hypercalcemia and hypercalciuria will worsen with vitamin D repletion and therefore repletion should be given cautiously.

  • Humoral hypercalcemia of malignancy: At this time there is no treatment that suppresses PTHrp. Treatment is aimed at lowering the serum calcium and preventing complications in the bones. Bisphosphonates are the most commonly used medications to treat hypercalcemia related to malignancy.

  • Vitamin D Related Hypercalcemia: Patients with granulomatous disease or lymphoma have increased 1,25-dihydroxyvitamin D production. In addition to treatment of the underlying disease patients should be placed on a low calcium diet and given glucocorticoids.

    • Hypercalcemia from exogenous intake of active vitamin D (e.g. calcitriol) can usually be managed by stopping the drug as the drug effect usually only lasts a couple of days.

    • Hypercalcemia resulting from exogenous intake of 25-hydroxyvitamin D (e.g. cholecalciferol, ergocalciferol) is managed by stopping the drug. However, the half life is longer and glucocorticoids are often needed to reduce serum calcium levels.

  • Milk-Alkali Syndrome: Hypercalcemia usually resolves with cessation of the offending agents.

  • Familial Hypocalciuric Hypercalcemia: No treatment is usually required as these patients typically have only mild hypercalcemia that is usually asymptomatic.

  • Tertiary Hyperparathyroidism: Treatment consists of trying to suppress PTH levels and serum calcium levels. Treatment with vitamin D and calcium based phosphate binders is limited in tertiary hyperparathyroidism as these treatments can lead to worsening hypercalcemia.

  • Calcimimetics are appealing because they increase the activity of the calcium sensing receptor and result in decreases in serum calcium levels. Cinacalcet is currently approved for secondary hyperparathyroidism but its effect on persistently elevated PTH levels in those with tertiary hyperparathyroidism is unclear and clinical trials are currently ongoing. Parathyroidectomy is used for symptomatic patients. The indications for surgery include severe hypercalcemia, severe bone disease, worsening extraskeletal calcifications and calciphylaxis.

Hypocalcemia

The management of hypocalcemia depends on the severity and rapidity with which the hypocalcemia develops. In chronic hypocalcemia, patients can often tolerate severe hypocalcemia and remain asymptomatic. Patients with acute hypocalcemia may have tetany, seizures or prolonged QT interval on EKG which requires aggressive treatment with intravenous calcium. Patients who are asymptomatic should be treated with oral calcium and vitamin D supplementation. Most importantly, the underlying disorder resulting in the hypocalcemia must be treated.

Calcium comes in multiple preparations both orally and intravenously. It is important to know the appropriate dosing units and conversion factors as medical errors can occur if the wrong dose is administered.

  • The amount of calcium in each form is measured in two different ways: 1) by the amount of calcium salt (mg of the cation plus the anion or the mL of a specified concentration or 2) by the amount of elemental calcium in milligrams (mg), milliequivalents (mEq) or millimoles (mmol). Since calcium has a valence of +2, the milliequivalents equals two times the number of millimoles.

  • Intravenous calcium comes in two forms: calcium gluconate or calcium chloride. Oral calcium comes in several forms, the most commonly used are calcium carbonate, calcium acetate and calcium citrate. The amount of calcium in each preparation is shown in Table 5.

  • The amount of calcium in intravenous calcium may also be given by mL of a specified concentration. Ten percent calcium gluconate refers to 93 mg of elemental calcium per 10 mL vial and ten percent calcium chloride refers to 273 mg per 10 mL vial. Calcium gluconate is the preferred form as calcium chloride often causes local irritation and tissue necrosis if extravasated. Calcium chloride should be administered through a central vein.

Table 5.

Calcium Equivalents
Salt Elemental calcium
Calcium Acetate 1 gram 253 mg 12.6 mEq 6.30 mmol
Calcium Carbonate 1 gram 400 mg 19.9 mEq 9.96 mmol
Calcium Citrate 1 gram 211 mg 10.5 mEq 5.26 mmol
Calcium Chloride 1 gram 273 mg 13.6 mEq 6.80 mmol
Calcium Gluconate 1 gram 93 mg 4.65 mEq 2.32 mmol

Acute hypocalcemia

Patients with severe acute symptomatic hypocalcemia with tetany, carpopedal spasm, seizures or EKG changes need to be treated promptly with intravenous calcium.

  • Intravenous calcium: Initially, 1 to 2 grams (93 to 186 mg elemental calcium) of intravenous calcium gluconate diluted in 50 to 100 mL of 5% dextrose should be infused over 10 to 20 minutes. Faster administration of calcium may result in cardiac dysfunction, including cardiac arrest.

  • If hypocalcemia persists a slow calcium infusion should be started at 0.5 to 1.5 mg/kg/hour. The pharmacist can make a calcium gluconate solution containing 1mg/mL of elemental calcium diluted in 5% dextrose water or normal saline. The solution must be diluted to prevent vein irritation. The calcium infusion should be started at 0.5 mg/kg/hour (usually no more then 50 mL/hour to start) and titrated based on the ionized calcium level. The goal is to raise and maintain the serum ionized calcium level in the low-normal range. The calcium infusion should be continued until patients are on an effective oral calcium regimen.

  • Problems do occur with the administration of intravenous calcium. As discussed earlier, cardiac dysfunction can occur if calcium is infused rapidly. Local vein irritation can occur if solutions contain more then 200 mg/100 mL of elemental calcium. Calcification with precipitation of calcium phosphate crystals can occur if there is extravasation into soft tissues. The solution must not contain bicarbonate or phosphate because these will combine with calcium and form an insoluble calcium salt.

  • Caution should be used in administering intravenous calcium to patients with severe hyperphosphatemia as there is a risk of precipitation of calcium with phosphate. Calcium phosphate deposition can occur in any organ. However, intravenous calcium should be given to patients with acute severe symptomatic hypocalcemia (tetany, seizures, prolonged QT) as these symptoms can be life-threatening. Dialysis may be required in patients with severe hyperphosphatemia and hypocalcemia.

  • Oral calcium supplementation should be initiated at the same time as the calcium infusion. 1 to 2 grams of elemental calcium should be given daily in the form of calcium carbonate or calcium citrate.

  • Oral 1,25-dihydroxyvitamin D (calcitriol) supplementation should also be given to patients with severe acute symptomatic hypocalcemia. Calcitriol should be started at 0.25 to 0.5 mcg twice a day.

  • The calcium infusion should be continued until patients are on an effective oral regimen of calcium plus 1,25-dihydroxyvitamin D.

Serum magnesium must be checked and if low must be repleted. Correction of hypomagnesemia must occur to overcome PTH resistance or serum calcium will not be able to return to normal.

  • An intravenous bolus of magnesium should be given (2 grams of magnesium sulfate given over 10 to 20 minutes). Magnesium infusion should then be slowed to around 1 gram per hour until the serum magnesium level is greater then 1 mg/dL.

  • Magnesium is excreted renally so caution should be used when giving magnesium to patients with renal failure as hypermagnesemia can occur.

  • Patients with milder symptoms of hypocalcemia can usually be treated with oral calcium supplementation alone. However, if the symptoms do not improve then intravenous calcium should be used.

Chronic hypocalcemia

Patients who are asymptomatic or with mild symptoms can be treated with oral calcium and vitamin D supplementation. One to three grams of elemental calcium should be given in 2 to 3 divided doses daily. Calcium carbonate is the most common formulation used as it contains 40% elemental calcium and is relatively inexpensive. Other formulations of oral calcium exist but they contain less elemental calcium so the patient would require a larger number of tablets (Table 5).

The goal of therapy is to restore and maintain the serum calcium level in the low-normal range (usually around 8.0 mg/dL). Higher targets increase the risk of hypercalciuria which can lead to nephrolithiasis and/or nephrocalcinosis. Urinary calcium excretion should be measured annually once the patient is on a stable dose. The dose should be reduced if the urinary calcium excretion is > 300mg/day.

Vitamin D may need to be added if the oral calcium administration does not correct the hypocalcemia. Vitamin D supplementation is usually needed in the treatment of hypoparathyroidism (discussed below).

Patients should see an opthalmologist annually to screen for cataracts.

Treatment of specific disorders causing hypocalcemia

Hypoparathyroidism

Most patients with hypoparathyroidism will need life-long treatment with calcium and vitamin D as the hypoparathyroidism is usually not reversible. Patients usually require vitamin D in addition to calcium as 1,25-dihydroxyvitamin D synthesis is decreased. The initial dose of oral calcium is 1 to 2 grams of elemental calcium daily given in divided doses. Calcium carbonate is the most common form used as it is inexpensive and contains the most elemental calcium.

Calcitriol (active vitamin D) is the treatment of choice for hypoparathyroidism as it does not require renal activation, has a rapid onset of action, a half-life of four to six hours and is usually well tolerated. The initial starting dose of calcitriol is 0.25 mcg twice a day. Medications should be titrated to keep the serum calcium level in the low-normal range.

Serum calcium should be monitored weekly until a stable dose is reached. Once the patient is on a stable dose the serum calcium can be monitored every three to six months.

Urinary calcium should be monitored frequently (weekly to biweekly) until a stable dose is reached as hypercalciuria can occur. Hypercalciuria can result in nephrolithiasis and nephrocalcinosis. If the urinary calcium excretion is >300 mg/day the dose of calcium and vitamin D must be reduced. Thiazide diuretics can be used to increase renal calcium absorption. Thiazides should be started at 12.5 to 25 mg daily if the urinary calcium excretion is nearing 300 mg/day and the dose of calcium and vitamin D have been decreased.

Recombinant PTH is not yet approved for use in hypoparathyroidism but results from trials look promising. In a randomized trial, subcutaneous recombinant PTH1-34 normalized serum calcium levels with less hypercalciuria than calcitriol therapy.

Hungry bone syndrome can develop in patients after parathyroidectomy. Patients who develop hungry bone syndrome require much larger doses of calcium and vitamin D to normalize serum calcium levels due to the massive amount of calcium taken up by demineralized bone after surgery. Patients who are vitamin D deficient at the time of surgery have a higher risk of developing hungry bone syndrome.

Pregnant women with hypoparathyroidism will require higher doses of calcitriol as vitamin D requirements increase gradually during pregnancy. Thus, calcitriol supplementation should be titrated during pregnancy using frequent serum calcium level measurements. Calcitriol requirements decrease after delivery and during lactation.

Vitamin D Deficiency

Vitamin D deficiency is treated with oral cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2). Treatment for vitamin D deficiency includes a repletion and a maintenance phase. A regimen that is usually used is ergocalciferol 50,000 International units (I.U.) weekly for one month (repletion phase) then 50,000 I.U. monthly for five months (maintenance phase). A regimen using cholecalciferol is 4,000 I.U. daily for one month then 1,000 to 2,000 I.U. daily for five months. 25-hydroxyvitamin D levels should be checked after three to six months with therapy to assess repletion.

Rarely, vitamin D intoxication can occur if the serum 25-hydroxyvitamin D level is > 100 ng/mL or the daily dose of vitamin D is > 10,000 I.U. Patients may become hypercalcemic and hyperphosphatemic if intoxication occurs (see section on hypercalcemia). The hypercalcemia will resolve once the vitamin D is discontinued. Glucocorticoids may need to be used to reduce serum calcium levels as vitamin D has a long half-life.

Active vitamin D (calcitriol) is used for treatment of disorders that result in low 1,25-dihydroxyvitamin D such as hypoparathyroidism and chronic kidney disease. Some of the inherited disorders of vitamin D metabolism also need active vitamin D for treatment.

Magnesium deficiency

Intravenous magnesium should be given until the serum magnesium level is greater than 1.0 mg/dL. An intravenous bolus of magnesium should be given (2 grams of magnesium sulfate given over 10 to 20 minutes). Magnesium infusion should then be slowed to around 1 gram per hour until the serum magnesium level is greater then 1 mg/dL. Magnesium is excreted renally so caution should be used when giving magnesium to patients with renal failure as hypermagnesemia can occur.

Chronic hypomagnesemia can be treated with oral magnesium tablets once the level is > 1.0 mg/dL. The underlying cause of the magnesium deficiency needs to be treated. Magnesium deficiency and treatment is discussed in detail in the chapter on magnesium abnormalities.

Autosomal dominant hypocalcemia

This rare disorder is caused by an activating mutation in the calcium sensing receptor. Most patients are asymptomatic and do not require treatment. If patients are symptomatic calcium and vitamin D supplementation should be given but only until the symptoms resolve as patients are prone to nephrolithiasis and nephrocalcinosis.

Pseudohypoparathyroidism

Treatment of hypocalcemia from pseudohypoparathyroidism is the same for other types of hypoparathyroidism. Patients should be treated with oral calcium and vitamin D supplementation to keep serum calcium levels in the low-normal range. Patients with this disorder have skeletal abnormalities that may require special orthopedic procedures.

Hungry bone syndrome

As discussed above, hungry bone syndrome can occur following parathyroidectomy or thyroidectomy. Patients develop severe hypocalcemia, hypomagnesemia, hypophosphatemia and hyperkalemia. HypocalceWmia should be treated aggressively if symptoms are present (see section on treatment of acute hypocalcemia). Magnesium deficiency must also be corrected. Hypophosphatemia should only be treated if the serum phosphate level is less than 1.0 mg/dL since phosphate can combine with calcium and precipitate resulting in worsening hypocalcemia. However, serum phosphate levels less than 1.0 mg/dL can be life-threatening and must be treated.

Chronic kidney disease

Symptoms rarely develop in patients with CKD and hypocalcemia so calcium supplementation is not usually needed. Calcium based phosphate binders are used to treat hyperphosphatemia (calcium carbonate, calcium acetate) in CKD. Caution must be used in giving calcium carbonate or calcium acetate to patients with CKD as hypercalcemia can occur. Furthermore, patients with CKD may have hyperphosphatemia and the calcium given can combine with phosphate and deposit in the bone, soft tissues and vasculature.

However, patients with CKD who have life threatening symptoms of hypocalcemia (tetany, seizures, prolonged QT) should be treated with calcium until the symptoms resolve. Dialysis may be necessary in patients with severe hyperphosphatemia and hypocalcemia. Nutritional vitamin D deficiency should be treated in patients with CKD. Calcitriol is usually needed for treatment of secondary hyperparathyroidism as patients with CKD cannot convert 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D.

What happens to patients with calcium metabolism disorders?

Hypercalcemia is a common disorder that can present a challenge to clinicians. The cause of hypercalcemia can either be easy or very difficult to identify. The pathophysiology and prognosis of hypercalcemia depends on the underlying cause.

In order to understand how hypercalcemia occurs it is important to know how calcium is regulated in the body. The majority (99%) of total body calcium is stored in bone. Only 1% of calcium is extracellular and serum calcium makes up only 0.1-0.2% of extracellular calcium. Forty percent of total serum calcium is free or ionized. The remaining serum calcium is protein bound, mainly to albumin. Serum levels of calcium are tightly regulated through the actions of PTH and 1,25-dihydroxyvitamin D (Figure 4, Figure 5).

Figure 4.

Response to hypercalcemia.

Figure 5.

Response to hypocalcemia.

PTH is a polypeptide produced by the parathyroid gland. It is stimulated through calcium sensing receptors by low ionized calcium and results in 1) increased renal absorption of calcium; 2) increased mobilization of calcium from the skeleton and soft tissues; and 3) increased production of 1,25-dihydroxyvitamin D and subsequent increased intestinal absorption of calcium. The increase in PTH from hypocalcemia restores serum calcium levels to normal. PTH secretion is lowered in hypercalcemia as increases in serum ionized calcium suppress PTH secretion.

  • PTH is also involved in phosphate homeostasis. Through its effects on bone and calcitriol synthesis it results in increased absorption of phosphate from the intestine and mobilization of phosphate from the bone. PTH also results in reduced phosphate reabsorption in the proximal tubule of the kidney and this urinary effect predimonates in patients with normal renal function. Thus, PTH lowers serum phosphate.

  • 1,25-dihydroxyvitamin D (calcitriol) is a hormone produced in the kidney from conversion of vitamin D3. 7-dehydrocholesterol is converted in the skin into vitamin D3 in response to UV light. Vitamin D3 is converted in the liver to 25-hydroxyvitamin D which then travels to the kidney and through 1-alpha-hydroxylase is converted into calcitriol. Calcitriol results in increases in intestinal absorption of calcium, renal reabsorption of calcium and bone resorption. It also inhibits PTH synthesis in the parathyroid gland to prevent an excess PTH response to hypocalcemia. Synthesis of calcitriol is primary regulated by PTH. Thus, hypercalcemia results in decreased calcitriol production and hypocalcemia stimulates calcitriol production.

  • Hypercalcemia results from an increase in intestinal calcium absorption, an increase in bone resorption or a decrease in calcium excretion. Enhanced bone resorption is responsible for most cases of hypercalcemia. The pathophysiology and natural history of the causes of hypercalcemia will be reviewed here.

Primary hyperparathyroidism

Epidemiology

Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. The prevalence in the United States is about 1 in 1000. The exact incidence of primary hyperparathyroidism is less clear but appears to be between 27 and 30 per 100,000 person-years.The incidence increases with age with those >75 years with a five-fold increased risk compared to those age <40 years. It is more common in women then men. The highest incidence is seen in postmenopausal women age 50 to 60 years.

Clinical presentation

Interestingly over the past several decades there has been a change in the clinical presentation of primary hyperparathyroidism. In the past very few patients were asymptomatic and now the majority of patients (approximately 75%) do not have any signs or symptoms of their disease besides an elevated serum calcium level. Of the patients who are symptomatic, the symptoms are usually those of hypercalcemia (see Table 2).

The most common symptom in patients with primary hyperparathyroidism is nephrolithiasis. Most stones are composed of calcium oxalate. The increased calcium excretion and increased calcitriol levels seen with primary hyperparathyroidism are responsible for the formation of kidney stones. Osteitis fibrosa cystica is the most common bone disease seen with primary hyperparathyroidism, although most patients in the United States do not have any manifestations of this disease. The diagnosis and treatment of hyperparathyroidism are discussed in the previous sections.

Pathophysiology

In the absence of a stimulus, one or more of the four parathyroid glands secrete excess PTH resulting in hypercalcemia. The serum calcium level is reset upward from its normal level likely as a result of the increased parathyroid gland mass and an increase in the set point for calcium regulated PTH release. There is reduced expression of the calcium sensing receptor making the parathyroid gland resistant to calcium. This reduced expression of the calcium sensing receptor likely contributes to the excess PTH release as the gland cannot "sense" the elevated serum calcium.

Once the PTH is elevated it results in hypercalcemia through bone resorption, increased renal reabsorption of calcium and intestinal absorption of calcium. A single adenoma is responsible in more than 80% of cases. Glandular hyperplasia is the cause in approximately 10-15% of the cases. Parathyroid carcinomas are rare and only account for 1 to 2% of the cases. Primary hyperparathyroidism can be inherited either as part of multiple endocrine disorders (e.g. MEN1 or MEN2A) or as diffuse hyperplasia of the parathyroid glands alone. However, these disorders are very rare.

Natural history

In patients treated for primary hyperparathyroidism with surgery there is a rapid fall in serum calcium and PTH levels and urinary calcium excretion also falls. There is also a decrease in bone resorption as studies have found a decline in bone resorption markers following parathyroidectomy.Surgery also leads to improvement in bone mineral density and the recurrence of kidney stones is reduced by greater than 90% following surgery.

In patients who are not treated, the disease appears to remain stable over time. In a series of 52 patients followed for 10 years, 42 did not have any disease progression over time. The progression of the disease in the other patients (development of marked hypercalcemia in two and marked hypercalciuria in eight) was not associated with any overt complications (e.g. fractures or kidney stones). There does not appear to be an increased risk of death from mild primary hyperparathyroidism.

Data regarding cardiovascular disease from primary hyperparathyroidism is scarce and is currently an area under active investigation. A small study found that patients with primary hyperparathyroidism had increased aortic and mitral valve calcifications and left ventricular hypertrophy (LVH) compared to patients without the disease and parathyroidectomy resulted in regression of the LVH. Further studies are needed to identify the effects of primary hyperparathyroidism on the cardiovascular system.

Medical therapy

As discussed in the treatment section, medical therapies are used when patients are not surgical candidates. Calcimimetics (cinacalcet) are drugs that activate the calcium sensing receptor in the parathyroid gland. It is not approved for the treatment of primary hyperparathyroidism in the United States. Cinacalcet has been shown to decrease serum calcium and PTH levels in patients with primary hyperparathyroidism. However, to date, no trials have examined the effect of cinacalcet on nephrolithiasis or bone mineral density.

If cinacalcet is used to treat primary hyperparathyroidism in nonsurgical candidates these patients may need more frequent monitoring of bone mineral density. Further studies are needed to evaluate the effect of cinacalcet on the complications of primary hyperparathyroidism.

Tertiary hyperparathyroidism

Epidemiology

Tertiary hyperparathyroidism is a disorder that occurs in patients with end-stage renal disease (ESRD). Patients with ESRD usually develop secondary hyperparathyroidism and some progress to tertiary hyperparathyroidism. The exact incidence and prevalence of this disorder are not well characterized. Almost all patients with ESRD have secondary hyperparathyroidism. The incidence of parathyroidectomy in patients with ESRD has decreased to 5.28 per 1000 patient years. This likely reflects the fact that medical therapies for the treatment of secondary and tertiary hyperparathyroidism have improved. Tertiary hyperparathyroidism is less common than secondary hyperparathyroidism.

Clinical manifestations

As with primary hyperparathyroidism, the majority of patients are asymptomatic. However, these patients develop vascular calcification which leads to significant morbidity and mortality. The pathophysiology of vascular calcification is not completely understood but hypercalcemia does appear to increase the risk. Bone disease, called renal osteodystrophy, is also highly prevalent in these patients and is frequently asymptomatic. There are several forms of renal osteodystrophy including osteitis fibrosa cystica, osteomalacia and adynamic bone disease. Renal osteodystrophy is discussed in detail in another chapter. The diagnosis and treatment of tertiary hyperparathyroidism are discussed in other sections.

Pathophysiology

Increases in PTH in patients with chronic kidney disease occur because of hypocalcemia, decreases in calcitriol levels and hyperphosphatemia. Almost all patients with CKD will develop secondary hyperparathyroidism. When the glomerular filtration rate (GFR) falls below 60 mL/min the ability of the kidneys to excrete a phosphate load is diminished, leading to elevated serum phosphate levels.

In response to the hyperphosphatemia, PTH secretion and fibroblast growth factor-23 (FGF-23) secretion is increased. FGF-23 is a hormone produced by bone whose main function is to maintain serum phosphate levels by increasing urinary excretion of phosphate and by inhibiting 1-α-hydroxylase activity resulting in decreased synthesis of calcitriol. With the decrease in calcitriol levels, intestinal absorption of calcium falls, leading to hypocalcemia and further increases in PTH levels.

As kidney function declines the kidney can no longer respond to PTH or FGF-23 and serum phosphate levels continue to increase, as do PTH and FGF-23 levels. This rise in PTH is termed secondary hyperparathyroidism. Secondary hyperparathyroidism is managed with active vitamin D analogs, calcimimetics and phosphate binders.

Despite medical therapy some patients have persistent hyperfunction of the parathyroid. which is called tertiary hyperparathyroidism. This disorder develops as a result of increased parynchemal mass and cellular differentiation of the parathyroid gland. These changes in the parathyroid gland result in decreased expression of calcium sensing receptors as well as abnormalities in vitamin D receptors both of which lead to further secretion of PTH. This autonomous production of PTH results in hypercalcemia. Patients often have serum PTH levels >800 pg/mL.

Natural history

If tertiary hyperparathyroidism is left untreated the result is severe hypercalcemia, severe bone disease and extraskeletal calcifications. Ultimately this leads to increased morbidity and mortality from fractures and cardiovascular disease. Parathyroidectomy results in increased bone mineral density and decreased risk of fracture in dialysis patients.Long-term survival is also improved after parathyroidectomy. A large cohort study compared survival in 4558 dialysis patients who underwent parathyroidectomy to 4558 control patients who did not have surgery. Patients who had surgery had higher short-term mortality but had longer long-term survival than control patients (medial survival 53.4 months vs. 46.8 months).

Hypercalcemia of malignancy

Epidemiology

Hypercalemia is very common in malignancy occurring in 10-30% of patients with cancer. Hypercalcemia is most common with hematologic malignancies and solid tumors of the breast, ovary, lung and kidney. Malignancy is usually clinically evident when hypercalcemia is present. Malignancy is the most common cause of inpatient hypercalcemia.

Pathophysiology

Hypercalcemia from malignancy occurs via three mechanisms: osteolytic metastases, production of PTH-related protein (PTHrp) and production of 1,25-dihydroxyvitamin D (calcitriol).

  • Osteolytic metastases: Hypercalcemia via this mechanism is common with solid malignancies that metastasize to bone as well as with multiple myeloma. The metastatic disease results in bone destruction through the action of osteoclasts as the tumor cells release osteoclast activating factors.

  • PTH-related protein: The most common mechanism of hypercalcemia from malignancy is through the secretion of PTHrp. This condition is termed humoral hypercalcemia of malignancy. The most common cancers that secrete PTHrp are cancers of the breast, kidney, ovary, bladder and squamous cell cancers of the head, neck and lung.

  • PTHrp is a normal gene product present in multiple tissues. PTHrp shares a common receptor with PTH and has essentially identical actions to PTH. PTHrp results in increases in serum calcium through bone resorption and decreased urinary calcium excretion. PTHrp does not usually result in the increased synthesis of calcitriol. PTHrp appears to also be produced locally in some cancers. In breast cancer, tumor cells release PTHrp locally. This locally secreted PTHrp results in activation of osteoclast precursors and bone destruction.

  • Production of 1,25-dihydroxyvitamin D: Increased production of 1,25-dihydroxyvitamin D (calcitriol) is the mechanism of hypercalcemia in most cases of Hodgkins lymphoma and in about 30% of cases of non-Hodgkin lymphoma. Malignant lymphocytes and macrophages convert 25-hydroxyvitamin D into calcitriol resulting in increased levels of calcitriol. This extrarenally synthesized calcitriol is not controlled by PTH. The excess calcitriol causes increased calcium absorption from the intestine which results in hypercalcemia.

Natural history

The development of hypercalcemia in patients with malignancy is a poor prognostic sign. Survival is dependent on the underlying cancer, age and comorbidities. Thus, prognosis is determined on a case by case basis.

Hypercalcemia in granulomatous disease

Epidemiology

Most of the data regarding hypercalcemia in granulomatous disease comes from studies of patients with sarcoidosis. Ten to twenty percent of patients with sarcoidosis develop hypercalcemia. There is no evidence that age, sex or race predispose to hypercalcemia. Hypercalciuria is three times as common as hypercalcemia in sarcoidosis. The incidence of hypercalcemia in tuberculosis is not known but it does occur. Hypercalcemia is uncommon in fungal granulomatous diseases.

Pathophysiology

Activated mononuclear cells, usually macrophages, in the lung or lymph nodes synthesize calcitriol from 25-hydroxyvitamin D independent of PTH. This unregulated synthesis results in high serum levels of calcitriol. This extrarenally produced calcitriol causes increased absorption of calcium from the intestine which results in hypercalcemia. Bone resorption also occurs in response to the excess calcitriol. The elevated serum calcium levels leads to increased filtration of calcium in the kidney and increased excretion in the urine.

Natural history

In granulomatous disease, severe hypercalcemia (>14 mg/dL) is rare. The hypercalcemia and hypercalciuria need to be corrected to prevent the development of kidney stones and renal failure. The use of glucocorticoids causes a rapid decline in serum calcitriol levels and serum calcium, usually within 3 to 5 days. Hypercalciuria begins to decrease soon after, usually within 7 to 10 days. Patients should have calcium levels monitored especially in sarcoidosis as levels can fluctuate with chronic disease. See the chapter on sarcoidosis for more details on the natural history of the disease.

Thiazide Induced hypercalcemia

Epidemiology

The incidence of hypercalcemia secondary to thiazide diuretic use is increasing. A recent study found the overall age and sex adjusted incidence to be 7.7 per 100,000. The incidence increased after 1996 with a rate of 16.3 per 100,000 in 1998.Hypercalcemia related to thiazide use is more common in women than men. Thiazide use often unmasks hyperparathyroidism. In a population based study of 72 patients with thiazide-associated hypercalcemia, underlying primary hyperparathyroidism was diagnosed in 28%.

Pathophysiology

Thiazide diuretics inhibit the sodium/chloride transporter in the distal convuluted tubule resulting in increased sodium chloride excretion in the urine. This leads to a decrease in effective arterial blood volume. leading to an increase in sodum reabsorption in the proximal tubule. Calcium gets reabsorbed passively with sodium in the proximal tubule.

In the distal tubule the blockage of the sodium/chloride transporter results in decreased cellular sodium. This fall in cellular sodium results in increased activity of the sodium/calcium exchanger on the basolateral side of the cell resulting in increased absorption of calcium as it is being exchanged for sodium. The main mechanism of hypercalcemia is decreased urinary calcium excretion. Thiazide therapy results in hypocalciuria within a couple of weeks of use.

Natural history

The hypercalcemia is usually transient and mild in normal patients as PTH will be suppressed in response to the elevated calcium. Discontiuing the thiazide should result in resolution of the hypercalcemia. If the hypercalcemia persists this suggests an underlying disorder such as primary hyperparathyroidism and further work up must be done to look for the underlying cause. Severe hypercalcemia has been reported when thiazide diuretics are given to patients with primary hyperparathyroidism.

Milk-Alkali syndrome

Epidemiology

The incidence of milk-alkali syndrome has increased over the past twenty years secondary to the use of calcium and vitamin D supplements for the treatment of osteoporosis. The incidence currently ranges from 8 to 36%.Patients who develop this disorder have a history of ingesting excessive amounts of calcium, usually calcium carbonate. They present with the classic findings of hypercalcemia, hypophosphatemia, metabolic alkalosis and renal failure. Patients at the highest risk are postmenopausal women, pregnant women, elderly patients, patients with CKD (mainly dialysis patients), transplant recipients and those with eating disorders.

Pathophysiology

High levels of ingested calcium result in passive absorption of calcium in the gut. Hypercalcemia results in decreased GFR from renal vasoconstriction which causes decreased filtration and excretion of calcium resulting in worsening hypercalcemia. The metabolic alkalosis that develops sustains the hypercalcemia through increased distal tubule reabsorption of calcium and decreased renal excretion.

Natural history

Cessation of the offending medications usually results in resolution of the symptoms and electrolyte abnormalities. Renal failure usually resolves but may be irreversible if hypercalcemia has been present for a prolonged period of time. Supportive therapy and hydration following cessation of the drug is usually all the treatment that is required.

Hypervitaminosis D and hypercalcemia

Epidemiology

Exogenous intake of vitamin D (Vitamin D2 or D3) and active vitamin D (e.g. calcitriol) both result in hypercalcemia. Vitamin D intoxication (excess 25-vitamin D) is rare. Hypercalcemia from high serum calcitriol levels is more common and is usually the result of the use of active vitamin D for the treatment of hypoparathyroidism or secondary hyperparathyroidism associated with renal failure.

Pathophysiology

Increased levels of 1,25-dihydroxyvitamin D (calcitriol) can occur via endogenous production by lymphoma and granulomatous disease (discussed above) or by exogenous intake of active vitamin D. The increased levels of calcitriol cause increased intestinal absorption of calcium and bone resorption resulting in hypercalcemia. High serum concentrations of 25-hydroxyvitamin D also result in hypercalcemia.

The mechanism behind the hypercalcemia from high 25-hydroxyvitamin D is less clear. Even when 25-vitamin D levels are extremely high from intoxication, serum calcitriol levels do not increase. Thus the hypercalcemia from 25-vitamin D toxicity does not occur as a result of elevated calcitriol levels.

Two current theories on how vitamin D intake results in hypercalcemia are: 1) High vitamin D intake leads to very high 25-vitamin D levels which overcome vitamin D binding protein capacity and "free 25-vitamin D" enters the cell where it directly effects gene transcription which leads to hypercalcemia; 2) High vitamin D intake causes increased concentrations of 25-vitamin D and other vitamin D metabolites which displace calcitriol from vitamin D binding protein and thus increase "free calcitriol" concentration. The free calcitriol then enters the cell and results in gene transcription leading to hypercalcemia. Studies in humans support the latter hypothesis. Studies have shown that 25-vitamin D levels have to be >100 ng/mL for toxicitiy to occur.

Natural history

Calcitriol induced hypercalcemia usually only lasts 1 to 2 days once the offending agent is stopped as the half-life of calcitriol is about 15 hours. Hypercalcemia from 25-vitamin D intoxication lasts longer as the half-life of 25-vitamin D is 15 days. Glucocorticoids and other treatments for hypercalcemia such as bisphosphonates may be needed in 25-vitamin D intoxication.

Lithium toxicity

Epidemiology

Long term lithium therapy is associated with hypercalcemia. Studies have found that 10 to 42% of patients taking lithium will develop hypercalcemia. Patients on lithium therapy for more then 15 years are 3 to 6 times more likely to develop hypercalcemia than the general population. Chronic lithium use is also associated with the development of hyperparathyroidism usually from adenomas but occassionally from hyperplasia.

Pathophysiology

The mechanism of hypercalcemia from lithium use is not completely known. It is thought to result from increased secretion of PTH as a result of insensitivity of the calcium sensing receptor to calcium, i.e. an increase in the set point for PTH secretion by calcium concentration.

Natural history

The hypercalcemia usually subsides when lithium is discontinued but occassionally it may persist. Chronic lithium use may also unmask primary hyperaparathyroidism. If lithium use cannot be discontinued due to severe psychiatric illness, cinacalcet may be a treatment option. A small case study of three patients found that cinacalcet ameliorated the hypercalcemia induced by lithium without any adverse effects. Larger studies are needed to confirm these results.

Familial hypocalciuric hypercalcemia

Epidemiology

Familial hypocalciuric hypercalcemia (FHH) is a rare genetic disorder resulting in mild, asymptomatic hypercalcemia. It can be detected at birth but usually is identified during the third decade. Family history is key in the diagnosis as usually one or more first degree relatives have hypercalcemia. The diagnosis and treatment is discussed in the previous sections.

Familial hypocalciuric hypercalcemia (FHH) is caused by an inactivating mutation in the calcium-sensing receptor gene. The set point for calcium homeostasis is shifted so higher than normal serum calcium concentrations are needed to suppress PTH.

Natural history

Treatment is unnecessary as these patients are asymptomatic with only mildly elevated serum calcium levels. Parathyroidectomy does not fix the hypercalcemia.

Adrenal insufficiency and hypercalcemia

Epidemiology

Hypercalcemia can occur in patients with adrenal insufficiency but severe hypercalcemia is rare. The exact incidence is unknown but it is not uncommon.

Pathophysiology

There are several mechanisms by which hypercalcemia develops: 1) increased proximal tubule reabsorption of calcium as a result of reduced GFR from volume contraction; 2) increased bone resorption that occurs despite suppressed levels of PTH and calcitriol. The increase in bone resorption appears to occur via thyroid hormone. In the setting of glucocorticoid deficiency thyroid hormone results in increased efflux of calcium from bone.

Natural history

Hypercalcemia can be reversed with hydration and the use of glucocorticoids. Serum calcium levels usually return to normal within 2-3 days.

Hyperthyroidism and hypercalcemia

Epidemiology

Mild hypercalcemia occurs in 15-20% of patients with hyperthyroidism. An even larger number of patients with hyperthyroidism have hypercalciuria.

Pathophysiology

Hypercalcemia develops secondary to bone resorption. Both bone formation and resorption are stimulated but bone resorption predominates resulting in hypercalcemia and hypercalciuria. Thyroid hormone has a direct effect on bone, causing increased bone turnover, and enhances the ability of PTH to increase bone resorption.

Natural history

Patients with hypercalcemia from hyperthyroidism usually only have mild, often asymptomatic disease. Treatment of the hyperthyroidism results in resolution of the hypercalcemia.

Immobilization and hypercalcemia

Epidemiology

Immobilization is a rare cause of hypercalcemia and should be a diagnosis of exclusion. The incidence and prevalence of hypercalcemia resulting from immobilization is not reported. Patients at risk include those with underlying bone disease, elderly patients and patients with high bone turnover, such as children and adolescents. Immobilization is a common cause of hypercalciuria in children.

Pathophysiology

Immobilization causes a change in the balance of bone turnover with an increase in bone resorption. In individuals where the homeostatic regulatory mechanisms are inadequate, such as patients with underlying bone disease with accelerated bone resorption such as Paget's, hypercalcemia occurs. However, hypercalcemia can also occur in children and adolescents who have a high rate of bone turnover even in the absence of underlying bone disease.

Natural history

Hypercalcemia can be treated successfully with bisphosphonates, e.g., pamidronate, in patients with prolonged immobilzation.

Chronic kidney disease and hypercalcemia

Epidemiology

Hypercalcemia is common in patients with CKD who are treated with calcium acetate or calcium carbonate for hyperphosphatemia and with active vitamin D (calcitriol) for secondary hyperparathyroidism. In a study of dialysis patients, 39% became hypercalcemic when calcium carbonate was used as their phosphate binder.

Pathophysiology

Even though there is a decrease in calcium excretion with renal failure, renal failure itself does not cause hypercalcemia. The hypercalemia develops as a result of increased calcium intake in the setting of decreased calcium excretion as well as increased PTH levels causing bone resorption.

Natural history

Hypercalcemia resolves when the offending agents (calcium-based phosphate binders and/or active vitamin D) are discontinued. Non-calcium based binders are available (e.g. sevelamer) and cinacalcet can be used for treating secondary hyperparathyroidism.

Idiopathic Infantile hypercalcemia

Epidemiology

Idiopathic infantile hypercalcemia is often transient during infancy. There are benign and severe forms of the disorder. The severe form, known as Williams syndrome,, is characterized by somatic abnormalities including mental deficiency, "elfin face" valvular and renal disease. Hypercalcemia develops in approximately 15% of patients with Williams syndrome.

Pathophysiology

The mechanism of hypercalcemia in this disorder is attributed to hypersensitivity to vitamin D, as serum PTH levels are low and serum calcitriol levels are usually normal. Hypersensitivity to vitamin D may occur as a result of a decreased ability of ligand bound vitamin D receptor (VDR) to induce repression of the 25-vitamin D 1-alpha hydroxylase gene.

Patients with Williams syndrome have a defect in the Williams syndrome transcription factor (WSTF). WTSF is involved in chromatin remodeling in response to DNA damage. The chromatic complex that incorporates WTSF potentiates ligand-induced VDR action in both gene activation and repression. Thus, defects in WSTF prevent repression of the 25-vitaminD 1-alpha-hydroxylase gene.

Natural history

Hypercalcemia typically occurs during infancy and resolves by the age of 4. Some patients have persistent hypercalcemia. Benign forms of the disease are associated with an excellent prognosis. Hypercalcemia associated with Williams syndrome usually is transient but the somatic abnormalities are permanent.

Hypocalcemia

Hypocalcemia is a common disorder encountered in clinical practice, especially in hospitalized patients. The pathophysiology and prognosis of hypocalcemia depend on the underlying cause. In order to understand how hypercalcemia occurs it is important to know how calcium is regulated in the body. The majority (99%) of total body calcium is stored in bone.

Only 1% of calcium is extracellular and serum calcium makes up only 0.1-0.2% of extracellular calcium. Forty percent of total serum calcium is free or ionized. The remaining serum calcium is protein bound, mainly to albumin. Serum levels of calcium are tightly regulated through the actions of PTH and 1,25-dihydroxyvitamin D (Figure 4, Figure 5).

PTH is a polypeptide produced by the parathyroid gland. It is stimulated through calcium sensing receptors by low ionized calcium and results in 1) increased renal absorption of calcium; 2) increased mobilization of calcium from the skeleton and soft tissues; and 3) increased production of 1,25-dihydroxyvitamin D and subsequent increased intestinal absorption of calcium. The increase in PTH from hypocalcemia restores serum calcium levels to normal. PTH secretion is lowered in hypercalcemia as increases in serum ionized calcium suppress PTH secretion.

  • PTH is also involved in phosphate homeostasis. Through its effects on bone and calcitriol synthesis it results in increased absorption of phosphate from the intestine and mobilization of phosphate from the bone. PTH also results in reduced phosphate reabsorption in the proximal tubule of the kidney and this urinary effect predimonates in patients with normal renal function. Thus, PTH lowers serum phosphate.

  • 1,25-dihydroxyvitamin D (calcitriol) is a hormone produced in the kidney from conversion of vitamin D3. 7-dehydrocholesterol is converted in the skin into vitamin D3 in response to UV light. Vitamin D3 is converted in the liver to 25-hydroxyvitamin D which then travels to the kidney and through 1-alpha-hydroxylase is converted into calcitriol. Calcitriol results in increases in intestinal absorption of calcium, renal reabsorption of calcium and bone resorption. It also inhibits PTH synthesis in the parathyroid gland to prevent an excess PTH response to hypocalcemia. Synthesis of calcitriol is primary regulated by PTH. Thus, hypercalcemia results in decreased calcitriol production and hypocalcemia stimulates calcitriol production.

  • Hypocalcemia is most often caused by disorders of PTH or vitamin D. However, there are numerous causes of hypocalcemia (Table 3). The pathophysiology and natural history of the causes of hypocalcemia will be reviewed here.

Hypoparathyroidism

Epidemiology:

Hypoparathyroidism is a common cause of hypocalcemia. Hypoparathyroidism may be secondary or idiopathic. Surgery is the most common cause of secondary hypoparathyroidism. Hypoparathyroidism from surgery occurs from either accidental removal or damage to the parathyroid glands or from traumatic interruption of the parathyroid glands blood supply. Hungry bone syndrome is another cause of post-surgical hypocalcemia (discussed below). Secondary hypoparathyroidism can also be caused by an autoimmune disease that results in damage to the parathyroid glands.

Autoimmune damage is common in polyglandular autoimmune syndrome type 1 (candidiasis, hypoparathyroidism and Addison's disease) but autoimmune damage can also occur as an isolated endocrinopathy. Rare causes of hypoparathyroidism are genetic disorders such as autosomal dominant hypocalcemia (discussed below), irradiation, infiltrative diseases of the parathyroid glands (Wilson's disease, hemochromatosis), and HIV infection. The diagnosis and clinical manifestations of hypoparathyroidism are discussed in previous sections.

Pathophysiology

Hypocalcemia results from decreased secretion of PTH from the parathyroid glands. The normal response to hypocalcemia is an increase in PTH production. Patients with hypoparathyroidism are unable to produce and/or secrete PTH. This results in decreased mobilization of calcium and phosphate from bone, decreased synthesis of calcitriol and decreased calcium reabsorption in the kidney and intestine. The end result is an inability to return serum calcium levels to normal.

Natural history

Hypoparathyroidism secondary to surgery may be transient or permanent. Permanent hypocalcemia is rare (<10%). The risk of permanent hypoparathyroidism is higher with more invasive surgeries. Patients must be monitored closely following surgery and calcium supplementation should be started if the ionized calcium falls or if the patient develops symptoms.

Treatment of autoimmune hypoparathyroidism is more difficult, especially when the hypoparathyroidism is associated with polyglandular autoimmune syndrome. The hypoparathyroidism may mask the symptoms of Addison's disease and glucocorticoid therapy may be withheld which can result in death. Hypoparathyroidism resulting from a genetic or developmental cause is permanent and patients require life-long calcium and vitamin D therapy to maintaint serum calcium levels in the low-normal range.

Pseudohypoparathyroidism

Epidemiology

Pseudohypoparathyroidism is a rare familial disorder characterized by hypocalcemia and hyperphosphatemia. The biochemical abnormalities are similar to hypoparathyroidism except PTH levels are high in pseudohypoparathyroidism and low in hypoparathyroidism. Patients with pseudohypoparathyroidism type IA (Albright's Hereditary Osteodystrophy) have developmental and somatic defects in addition to the hypocalcemia and hyperphosphatemia. Patients have mental retardation, short stature, obestiy, brachydactyly and subcutaneous calcifications. This disorder is inherited in an autosomal dominant fashion. Patients with pseudohypoparathyroidism type Ib do not have the development and somatic defects.

Pathophysiology

The hallmark of this disorder is PTH resistance. Patients have an inactivating mutation of the α-subunit of the G protein that stimulates adenylate cyclase. Adenylate cyclase is required for end-organ (bone and kidney) response to PTH. With this mutation, patients cannot respond to PTH. The hallmark test for diagnosis is administering exogenous PTH. In patients with pseudohypoparathyroidism, PTH does not result in increased urinary cyclic AMP and phosphaturia does not occur. Patients also have resistance to other hormones whose effects are mediated by G protein receptors such as thyroid stimulating hormone, glucagon and calcitonin.

Natural history

Patients may present in early childhood with symptoms of hypocalcemia. Other patients may remain asymptomatic and not get diagnosed until adulthood. Patients require lifelong treatment with calcium and vitamin D supplementation to maintain serum calcium levels in the low-nromal range. Patients may require specific therapies for the skeletal abnormalities such as custom made shoes and orthopedic surgery.

Vitamin D deficiency

Epidemiology

In the general population it is estimated that over 1 billion people worldwide are vitamin D deficient. In a study using data from the Third National Health and Nutrition examination survey, the prevalence of low vitamin D levels <30 ng/mL was present in > 40% of men and >50% of women. There is no consensus on the optimal level of vitamin D, but most experts define vitamin D deficiency as a 25-hydroxyvitamin D level < 20 ng/mL and insufficiency as 25-hydroxyvitamin D levels of 21-30 ng/mL.

The most common causes of vitamin D deficiency are intestinal malabsorption, poor nutritional intake, lack of sunlight and nephrotic syndrome. Vitamin D disorders can also be caused by lack of conversion of 25-hydroxyvitamin D into calcitriol which is seen in CKD and vitamin D-dependent rickets. Some anticonvulsants can interfere with the formation of 25-hydroxyvitamin D from vitamin D3. The diagnosis and treatment of vitamin D deficiency are discussed in previous sections.

Pathophysiology

Hypocalcemia is not usually seen in vitamin D deficiency as there is a compensatory rise in PTH (secondary hyperparathyroidism). Lack of vitamin D results in decreased calcium absorption in the gut. The resulting hypocalcemia increases serum PTH causing mobilization of calcium from bone to maintain serum calcium levels. Once the skeletal stores of calcium are depleted, hypocalcemia occurs.

Natural history

Nutritional vitamin D deficiency is easily treated with oral vitamin D supplements. Many patients may require lifelong supplementation. Hypocalcemia will resolve with treatment of the vitamin D deficiency. Patients with inherited vitamin D disorders can be treated with calcitriol in some cases. This is reviewed in detail in the chapter on vitamin D and rickets.

Magnesium depletion and hypocalcemia

Epidemiology

Magnesium depletion is very common in hospitalized patients and occurs in approximately 10% of the general population. Hypocalcemia is commonly seen with magnesium depletion when the magnesium level is < 1.0 mg/dL. Magnesium depletion is usually the result of malabsorption, chronic alcoholism and poor nutritional intake. Cisplatin therapy also causes hypomagnesemia.

Pathophysiology

Magnesium depletion causes hypocalcemia by producing end organ PTH resistance and by decreasing PTH secretion. Serum PTH levels are normal or low in hypomagnesemia indicating inadequate PTH secretion to hypocalcemia. The mechanism by which magnesium depletion causes PTH resistance is unclear but it may involve interference with G protein activation of adenylate cyclase.

Natural history

Hypocalcemia resolves quickly (minutes to hours) with correction of hypomagnesemia. The underlying cause of the hypomagnesemia must also be treated.

Chronic kidney disease and hypocalcemia

Epidemiology

Chronic kidney disease affects approximately 5-10% of the population worldwide. Hypocalcemia is very common in patients with kidney disease. Disruptions in calcium and phosphate homeostasis occur as kidney function declines.

Pathophysiology

Almost all patients with CKD will develop secondary hyperparathyroidism. When the glomerular filtration rate (GFR) falls below 60 mL/min the ability of the kidneys to excrete a phosphate load is diminished leading to elevated serum phosphate levels. In response to the hyperphosphatemia, PTH secretion and fibroblast growth factor-23 (FGF-23) secretion is increased. FGF-23 is a hormone produced by bone whose main function is to maintain serum phosphate levels by increasing urinary excretion of phosphate and by inhibiting 1-α-hydroxylase activity resulting in decreased synthesis of calcitriol.

With the decrease in calcitriol levels, intestinal absorption of calcium falls leading to hypocalcemia and further increases in PTH levels. As kidney function declines the kidney can no longer respond to PTH or FGF-23 and serum phosphate levels continue to increase. Furthermore, 25-hydroxyvitamin D is no longer able to be converted into calcitriol. At the tissue level there is also down regulation of vitamin D receptors and resistance to PTH which lead to hypocalcemia.

Natural history

Secondary hyperparathyroidism results in increased morbidity and mortality in patients with CKD. Patients have increased cardiovascular disease including vascular calcifcations and increased bone disease termed renal osteodystrophy. Secondary hyperparathyroidism is managed with active vitamin D analogs, calcimimetics, phosphate binders and parathyroidectomy if severe. Despite medical therapy some patients have persistent hyperfunction of the parathyroid which is called tertiary hyperparathyroidism. Patients with tertiary hyperparathyroidism develop hypercalcemia and parathyroidectomy is usually indicated.

Hyperphosphatemia and hypocalcemia

Epidemiology

Hyperphosphatemia is rare is the general population. Hyperphosphatemia is most often seen in patients with decreased renal excretion of phosphate or acute kidney injury. The most common causes of hyperphosphatemia that result in hypocalcemia are oral or intravenous administration of phosphate, laxatives containing phosphate, renal failure, rhabdomyolysis and neoplasms treated with cytotoxic agents (tumor lysis syndrome).

Pathophysiology

Hyperphosphatemia causes hypocalcemia by several mechanisms. Phosphate that is infused or released from tissues precipitates with calcium. The calcium phosphate then gets deposited in the bone, soft tissues and vasculature causing hypocalcemia. High phosphate also down regulates 1-α-hydroxlase activity in the kidney resulting in lower calcitriol levels which further aggravates the hypocalcemia through decreased intestinal absorption of calcium. Secondary hyperparathyroidism occurs in response to long-term hyperphosphatemia and hypocalcemia occurs as discussed in the CKD and hypocalcemia section.

Natural history

Treatment is directed towards the underlying cause of the hyperphosphatemia. High serum phosphate can be controlled with phosphate binders. Long-term consequences of high serum phosphate and hypocalcemia are ectopic calcifications in blood vessels, skin, heart and cornea. Consequences of hyperphosphatemia are discussed in more detail in the chapter on disorders of phosphate metabolism.

Pancreatitis and hypocalcemia

Epidemiology:

Hypocalcemia is very common in patients with acute pancreatitis. If there is associated alcohol abuse or poor nutritional status patients may also have hypomagnesemia, which magnifies the hypocalcemia.

Pathophysiology

The mechanism by which hypocalcemia occurs is not well understood. One potential mecanism involves free fatty acids that are generated when the pancreas is damaged. These free fatty acids chelate insoluble calcium sats that are present in the pancrease resulting in calcium deposition in the retroperitoneum. PTH levels can be normal, decreased or elevated. If PTH is normal or low, hypomagnesemia is likely also present. High PTH levels indicate the normal reponse to hypocalcemia.

Natural history

Patients with acute pancreatitis and hypocalcemia should be treated with calcium and magnesium. The serum calcium level should return to normal once the pancreatitis resolves and hypomagnesemia is treated.

Sepsis and hypocalcemia

Epidemiology

Hypocalcemia is present in more then 80% of critically ill patients. Sepsis and severe burns are a common source of hypocalcemia. In a study of septic patients, only those with gram negative sepsis became hypocalcemic.

Pathophysiology

The etiology of hypocalcemia from sepsis is multifactorial. During sepsis there is decreased PTH and calcitriol synthesis as well as end-organ resistance to PTH and calcitriol. How this occurs remains unknown but may be due to inflammatory cytokines such as IL-6 and TNF-α.

Natural history

Hypocalcemia in critically ill patients is a poor prognostic sign. Mortality is higher in septic patients with hypocalcemia than with normocalcemia.

Bisphosphonates and hypocalcemia

Epidemiology

Hypocalcemia is a common complication of bisphosphonate therapy and is the most well recognized electrolyte complication of bisphosphonates. Patients at highest risk for hypocalcemia from these agents are those with underlying vitamin D deficiency, hypoparathyroidism and hypomagnesemia. The more potent the bisphosphonate the higher the risk of hypocalcemia.

Pathophysiology

Bisphosphonates reduce osteoclastic bone resorption and thus slow the efflux of calcium from the skeleton.

Natural history

Hypocalcemia is usually mild and usually resolves quickly with discontinuiation of the bisphosphonate. Calcium supplementation can be used if patients are symptomatic. In some cases, the hypocalcemia can last for several months requiring long-term therapy of calcium supplementation.

Osteoblastic metastases and hypocalcemia

Epidemiology

Hypocalcemia usually develops in patients with osteoblastic metastases from breast or prostate cancer. The exact incidence and prevalence is not reported.

Pathophysiology

Hypocalcemia results from mineralization of large amounts of unmineralized osteoid.

Natural history

The prognosis depends on the treatment of the underlying cancer and hypocalcemia is often a poor prognostic sign.

How to utilize team care in the treatment of calcium matabolism disorders?

Hypercalcemia

  • Specialty consultations: A nephrologist should be consulted for severe life threatening hypercalcemia (>18mg/dL) as hemodialysis may be necessary. Nephrology should also be consulted for any patient with hypercalcemia and renal dysfunction. Endocrinology should be consulted if there is concern for an endocrine related etiology of the hypercalcemia. Of course, hematology/oncology should be consulted if there is a concern for malignancy related hypercalcemia.

  • Dietitians: A dietician should be consulted for patients with hypercalcemia related to excess calcium or vitamin A or D intake. Dieticians can educate patients about low calcium diets and dietary supplements.

  • Pharmacists: Pharmacists are a great resource for information on dosing and administering medications used in the treatment for hypercalcemia, especially in patients with renal failure. Pharmacists can also assist in identifying medications that result in hypercalcemia.

  • Nurses: Nurses are key in the management of acute symptomatic hypercalcemia. When saline hydration is used, urine output and vital signs must be monitored frequently. Nurses should monitor and report urine output and vital signs hourly. With close monitoring by nurses, volume overload should be prevented. Nurses should also monitor changes in symptoms, including EKG changes as more aggressive therapy may be needed if symptoms persist or worsen.

Hypocalcemia

  • Specialty consultations: Endocrinology should be consulted if the patient has hypoparathyroidism or pseudohypoparathyroidism. Nephrology should be consulted for severe hyperphosphatemia resulting in hypocalcemia as these patients often have acute or chronic renal failure and dialysis may be necessary. Oncology should be consulted for any patient with tumor related hypocalcemia.

  • Dietitians: A dietician should be consulted for patients with hypocalcemia from chronic malnutrition, alcohol abuse or chronic illness. Dieticians can educate patients about calcium and vitamin D intake and the use of supplementation.

  • Pharmacists: Pharmacists are a great resource for information on dosing and administering medications used in the treatment for hypocalcemia. Pharmacists can make sure the proper dose of calcium is given. Pharmacists can also assist in identifying medications that result in hypocalcemia.

  • Nurses: Nurses are key in the management of acute symptomatic hypocalcemia as patients must be monitored closely. Nurses should monitor changes in symptoms, including EKG changes as more aggressive therapy may be needed if symptoms persist or worsen.

Other considerations for hypercalcemia/hypocalcemia

  • DRG codes

    • Nutritional and Miscellaneous Metabolic Disorders 640-641

What is the evidence?

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