General Neurology

Updated 08.17.2022
Released 11.03.1993
Expires For CME 08.17.2025

Hypercalcemia

Author: Douglas J Lanska MD FAAN MS MSPH

Introduction

Overview

Hypercalcemia is associated with a broad range of neurologic manifestations that have been ascribed to both central nervous system and peripheral nervous system dysfunction. Reported neurologic manifestations can include weakness, fatigue, confusion, posterior reversible leukoencephalopathy syndrome, a Creutzfeldt-Jakob–like syndrome due to hypercalcemic encephalopathy, stupor, and coma. It remains unclear if the weakness associated with hypercalcemia is primarily due to both central nervous system and peripheral nervous system effects of hypercalcemia. In this article, the author reviews the clinical spectrum of neurologic dysfunction associated with hypercalcemia, as well as the evaluation and management of hypercalcemia.

Key points

	• Depending on the severity and rate of development, hypercalcemia can produce varying degrees of a generalized encephalopathy ranging from mild impairment of attention to coma.
	• Primary hyperparathyroidism and malignancy-associated hypercalcemia are the most common causes of hypercalcemia, together accounting for more than 90% of cases.
	• Hypercalcemia in the setting of malignancy is a common oncologic emergency and develops in 20% to 30% of patients with cancer.
	• For patients with severe hypercalcemia (greater than 13.5 mg/dL) or moderate hypercalcemia and significant clinical manifestations, the initial management entails strategies that directly lower the calcium concentration, independent of the underlying cause.

Historical note and terminology

The parathyroid glands were discovered (but not named) in 1852 by comparative anatomist and paleontologist (later Sir) Richard Owen (1804-1892) in the necropsy of an Indian rhinoceros that died at the London Zoo (206; 59; 42; 118; 91). In his description, Owen referred to the glands as "a small compact yellow glandular body attached to the thyroid at the point where the veins emerged" (206; 59). The significance of this report was only evident in retrospect, and Owen was much more famously recognized for naming the Dinosauria (ie, dinosaurs) in the 1830s and infamously as an antievolutionist opposed to Charles Darwin and his proponent Thomas Huxley after publication of Darwin’s The Origin of Species by Means of Natural Selection (1859) (174; 105; 106; 94; 215). Although Owen was notorious for usurping the work of others and passing it off as his own, in this case Owen was apparently responsible for the observation, although he had no idea of its significance.

British surgeon and anatomist Richard Owen

British surgeon and anatomist Richard Owen (1804-1892) c1856 with the skull of a crocodile. In 1852, Owen discovered the parathyroid glands in the necropsy of an Indian rhinoceros. However, he neither named the glands, nor underst...

Unaware of Owen’s earlier work, published as it was in what was then a relatively obscure society proceeding, the parathyroid glands were identified decades later in humans in 1880 by Ivar Sandstrom (1852-1889), a 25-year-old medical student working as a praelector (lecturer) in anatomy at the University of Uppsala, Sweden (222; 223; 47; 56; 136; 137). In his classic paper, On a New Gland in Man and Fellow Animals (in translation), he described what he called the “glandulae parathyroidae” (parathyroid glands) in dogs, cats, rabbits, oxen, horses, and man (gross and micro). Sandstrom’s principal interest was the organ in man, and he examined 50 individuals and found in most of them two parathyroid glands on each side. Unfortunately, Sandstrom's report was not well received and he later committed suicide at age 37 years.

Swedish physician and anatomist Ivar Sandstrom (1852-1889)

In 1880, Sandstrom identified the parathyroid glands in man and various other mammals. (Courtesy of Wikipedia and Wellcome Library. Public domain.)
Parathyroid glands (gross appearance)

Gross appearance of the parathyroid glands (marked as “gl. pth.” in the Figure) in man as illustrated by Swedish physician and anatomist Ivar Sandstrom in 1880. (Public domain.)
Parathyroid glands (microscopic appearance)

Microscopic appearance of the parathyroid glands in man as illustrated by Swedish physician and anatomist Ivar Sandstrom in 1880. (Public domain.)

The clinical importance of the parathyroid glands was not appreciated until 1891, when French physiologist Eugène Émile Gley (1857-1930) observed that tetany and death following experimental thyroidectomy in dogs occurred only if the excised material included the glandulae parathyroidae described by Sandström (99). To this point, tetany in association with thyroidectomy had been misattributed to removal of the thyroid gland. Because of Gley’s discovery, parathyroid glands have sometimes been referred to as "Gley's glands."

French physiologist Eugène Émile Gley (1857-1930)

Gley observed that tetany and death following experimental thyroidectomy in dogs occurred only if the excised material included the glandulae parathyroidae (parathyroid glands) described by Ivar Sandstrom in 1880. (Courtesy of the...

From 1903 to 1908, American pathologist William G MacCallum (1874-1944) and Swiss-U.S. pharmacologist (and later the first head of the U.S. National Cancer Institute from 1938-1943) Carl Voegtlin (1879-1960), both working at Johns Hopkins, demonstrated that tetany following parathyroidectomy was the result of the hypocalcemia (173; 172; 134; 177; 83). Not only was there a “marked reduction in the calcium content of the tissues especially of the blood and brain, during tetany” following parathyroidectomy, but the “injection of a solution of a salt of calcium into the circulation of an animal in tetany promptly checks all the symptoms and restores the animal to an apparently normal condition.” MacCallum and Voegtlin also showed that variable production of tetany following parathyroidectomy in animal experiments depended on the presence of residual parathyroid tissue, a result that was not infrequent because of the variable number and location of the parathyroid glands. In 1909, William B Berkeley and S P Beebe, at Cornell University Medical College in New York, described correction of hypocalcemic tetany with parathyroid extract in man (37).

American pathologist William G MacCallum (1874-1944)

From 1903 to 1908, MacCallum studied the effects of parathyroidectomy. In 1908, MacCallum and colleague Carl Voegtlin, both working at Johns Hopkins, demonstrated that tetany following parathyroidectomy was the result of the hypoc...
Swiss-American pharmacologist Carl Voegtlin

Swiss-American pharmacologist (and later the first head of the U.S. National Cancer Institute) Carl Voegtlin (1879–1960). In 1908, Voegtlin and colleague William G MacCallum, both working at Johns Hopkins, demonstrated that tetany...

In 1891, German pathologist Friedrich Daniel von Recklinghausen (1833-1910) described osteitis fibrosa cystica, which is characterized by a loss of bone mass, a weakening of the bones as their calcified supporting structures are replaced with fibrous tissue (peritrabecular fibrosis), and the formation of cyst-like brown tumors in and around the bone. This is also known as osteitis fibrosa, osteodystrophia fibrosa, and Recklinghausen disease of bone (which should not be confused with Recklinghausen disease, neurofibromatosis type I). By 1914 Austrian pathologist Jacob Erdheim (1874-1937), working in Vienna, suggested that parathyroid pathology may cause skeletal abnormalities, and this was documented the following year by Z Schlagenhaufer from the observation that in patients with osteitis fibrosa cystica, only one parathyroid gland is typically enlarged (ie, a parathyroid adenoma). If the parathyroid enlargement had been somehow due to or in response to the bony changes, then all of the parathyroid glands routinely should have been similarly enlarged. This ultimately led to the use of parathyroidectomy as a treatment for osteitis fibrosa cystica beginning in 1925.

German pathologist Friedrich Daniel von Recklinghausen

German pathologist Friedrich Daniel von Recklinghausen (1833-1910) is most known for his monograph in 1882 (Über die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen) in which he reviewed previous literature...
Osteitis fibrosa cystica (x-ray)

Osteitis fibrosa cystica is characterized by a loss of bone mass, a weakening of the bones as their calcified supporting structures are replaced with fibrous tissue (peritrabecular fibrosis), and formation of cyst-like brown tumor...
Austrian pathologist Jacob Erdheim (1874-1937)

By 1914 Erdheim, working in Vienna, suggested that parathyroid pathology may cause skeletal abnormalities. Photograph reproduced with permission from Erdheim’s great niece, Claudia Erdheim. The image is the private property of Cla...

Parathyroid surgery began before that, though. British surgeon Sir John Bland-Sutton (1855-1936) had described a postmortem specimen of a parathyroid tumor in 1886, had surgically removed a parathyroid cyst in 1909, and had performed a parathyroidectomy for a parathyroid tumor some time before 1917 (77). In 1907, Herbert M Evans, working with American surgeon William Stewart Halsted (1852-1922) at Johns Hopkins in Baltimore, described the vascular supply of the parathyroid glands in man, and in the same paper Halsted discussed preservation of the parathyroid glands with thyroid surgery (111). Evans careful drawing of the parathyroid glands was later used by anatomist Henry Gray in his Anatomy of the Human Body (1918). In 1909, Halsted attempted both iso- and auto- transplantation of parathyroid tissue by transplanting canine parathyroid glands into thyroid tissue and under the skin (110). In 1925, Viennese surgeon Felix Mandl (1892-1957), at the Hochenegg Clinic, performed a successful parathyroidectomy as a means of alleviating the bone disease of hyperparathyroidism; his patient was a 34-year-old tram-car conductor with severe osteitis fibrosa cystica (178).

British surgeon Sir John Bland-Sutton (1855-1936)

Bland-Sutton had described a postmortem specimen of a parathyroid tumor in 1886, had surgically removed a parathyroid cyst in 1909, and had performed a parathyroidectomy for a parathyroid tumor some time before 1917. (Courtesy of ...
American surgeon William Stewart Halsted (1852-1922)

In 1909, Halstead, working at Johns Hopkins in Baltimore, attempted both iso- and auto-transplantation of parathyroid tissue, by transplanting canine parathyroid glands into thyroid tissue and under the skin. (Courtesy of the U.S....
Parathyroid glands (drawing)

Drawing of the parathyroid glands by Herbert M Evans, working with American surgeon William Stewart Halsted (1852-1922). Evans careful drawing of the parathyroid glands was subsequently used in a later edition (1918) of Anatomy of...

In 1923 Adolph M Hanson (1880-1959), and 2 years later Canadian biochemist James B Collip (1892-1965) independently isolated parathyroid hormone from crude glandular extracts (117; 88; 113; 114; 115; 116; 68; 68; 200; 254; 48; 29; 167; 168; 140). The purification of parathyroid hormone greatly accelerated experimental studies to determine the effect of the hormone on bone and kidneys. In addition, American medical physicist Rosalyn Sussman Yalow (1921-2011) successfully developed radioimmunoassays for peptide hormones, including parathyroid hormone (41; 38; 38; 39; 40; 234; 256). Yalow was awarded a Nobel Prize for Physiology or Medicine in 1977.

Canadian biochemist James B Collip (1892-1965)

In 1923, following the earlier work of Adolph M Hanson, Collip isolated parathyroid hormone from crude glandular extracts. (Courtesy of Wikipedia. Public domain.)
American medical physicist and Nobel laureate Rosalyn Sussman Yalow (1921-2011)

Yalow successfully developed radioimmunoassays for peptide hormones, including parathyroid hormone. (Courtesy of Wikipedia. Public domain.)

From the late 1920s until 1956 (when he suffered a career-ending postoperative complication of chemopallidectomy for early-onset Parkinson disease (ie, intracranial hemorrhage with resulting akinetic mutism), American endocrinologist Fuller Albright (1900-1969) and associates at the Massachusetts General Hospital in Boston studied numerous aspects of disordered parathyroid gland function and conducted landmark metabolic balance studies that clearly defined several of the diseases associated with parathyroid dysfunction, as well as related disorders of calcium and phosphorus metabolism (33; 06; 04; 05; 07; 09; 15; 14; 16; 02; 18; 128; 03; 03; 66; 49; 11; 12; 184; 70; 21; 25; 31; 32; 121; 125; 158; 242; 126; 86; 208; 147; 146; 92; 179). In 1929 Albright colleague Read McLane Ellsworth (1899-1970) diagnosed a first case of idiopathic hypoparathyroidism (10). Albright and colleagues noted that most patients treated with parathyroidectomy for primary hyperparathyroidism and osteitis fibrosa cystica also had nephrolithiasis or nephrocalcinosis (06), established the concept of secondary hyperparathyroidism (06), described hyperparathyroidism due to adrenal hyperplasia (06), described vitamin D-resistant rickets and effective treatment with high doses of vitamin D (08), established a primary effect of vitamin D is to increase intestinal absorption of calcium (16), and described postmenopausal osteoporosis (02), hypercalcemia with disuse osteoporosis (02), pseudohypoparathyroidism (18), the milk-alkali syndrome (17), pseudo-pseudohypoparathyroidism (11), and idiopathic hypercalciuria (12).

The subsequent assay, sequencing, and cloning of parathyroid hormone led to the further elaboration of the multiple actions of the hormone and of the abnormalities associated with dysfunction of the parathyroid glands.

In 1957, Walter T St Goar, at the College of Physicians and Surgeons of Columbia University in New York, emphasized the abdominal manifestations of hyperparathyroidism and proposed a mnemonic triad for recognizing the disorder as a “disease of stones, bones and abdominal groans” (237). St Goar had been influenced to pursue studies in this area by Fuller Albright while St Goar and his wife were interns and residents at Massachusetts General Hospital. As St Goar elaborated (237):

Gastrointestinal symptoms appear to represent a clue to the earlier recognition of some cases of hyperparathyroidism…Unexplained episodes of nausea and vomiting, unexplained anorexia and weight loss, peptic ulcers which do not respond in the usual way to therapy, [marked constipation,] and a variety of unexplained abdominal pains should all lead to a consideration of hyperparathyroidism as a possible diagnosis. Hyperparathyroidism, which has been popularly thought of by medical men as a ‘disease of stones and bones,’ might be recognized both earlier and more frequently if it were widely regarded as a ‘disease of stones, bones and abdominal groans.

St Goar recognized that the abdominal manifestations of hyperparathyroidism are nonspecific, but he hoped that greater recognition of their prominence in this disorder might speed clinical recognition and treatment (237):

These gastrointestinal symptoms are meaningless in themselves. An awareness of their occurrence in hyperparathyroidism, however, may prove helpful in recognizing other nonspecific manifestations of a potentially reversible disease and thus lead to its earlier diagnosis.

In 1961, William C Mieher Jr., Yvan Thibaudeau, and Boy Frame, at Henry Ford Hospital in Detroit, emphasized the neuropsychiatric features of hyperparathyroidism, which can include apathy, agitated depression, psychosis with hallucinations or delusions, paranoia, and dementia. They modified St Goar’s mnemonic triad into a mnemonic quadrad by adding “psychic moans” to reflect the neuropsychiatric manifestations: “we wish to add a postscript to St Goar's description and emphasize that hyperparathyroidism is a disease of stones, bones, abdominal groans, and psychic moans” (188).

In 1965 Charles E Boonstra and Charles E Jackson, at the Caylor-Nickel Clinic in Bluffton, Indiana, emphasized the chronic fatigue and nonspecific irritability seen in many patients with hyperparathyroidism (45). Boonstra further modified the existing mnemonic for hyperparathyroidism from a quadrad into a pentad by adding “fatigue overtones” to reflect the fatigue and “nervous irritability” often seen in patients with hyperparathyroidism even when more specific findings are either absent or not clinically manifest (45):

The majority of patients with hyperparathyroidism manifested nonspecific fatigue and nervous irritability that were alleviated by excision of the parathyroid adenoma. The tiredness noted by many patients…was often present in our patients on arising even though it became worse with activity and was partially relieved by resting. St. Goar (1957) proposed that hyperparathyroidism be thought of as a disease of ‘stones, bones and abdominal groans’ to which Mieher, Thibaudeau, and Frame (1961) added ‘and psychic moans.’ Perhaps this statement should be amplified to ‘stones, bones, abdominal groans, and psychic moans with fatigue overtones.

Clinical manifestations

Presentation and course

	• Hypercalcemia is often asymptomatic, and more than half of cases are identified by an unanticipated elevation in serum calcium on biochemical screening studies, whereas other cases present with symptoms and signs of their underlying diseases (eg, bone pain from osseous metastases or kidney stones in hyperparathyroidism).
	• Symptoms and signs of hypercalcemia per se depend on the severity and rate of development of the hypercalcemia.
	• Patients with serum calcium levels less than 11 mg/dl are rarely symptomatic from hypercalcemia, whereas those with levels between 11 mg/dl and 14 mg/dl may be symptomatic, and those with levels above 14 mg/dl are uniformly symptomatic and at risk of severe organ damage.
	• Ectopic soft-tissue calcification is increasingly likely as serum calcium levels rise above 13 mg/dl.
	• Symptoms tend to be more likely and more severe if hypercalcemia develops rapidly.
	• Hypercalcemia can cause a broad range of nonspecific systemic manifestations, including dehydration, fatigue, weight loss, anorexia, constipation, nausea, vomiting, abdominal pain, and pruritus.
	• The most specific sign of chronic hypercalcemia is band keratopathy, a condition in which metastatic calcification occurs in the medial and lateral margins of the cornea adjacent to the scleral limbus.
	• Depending on the severity and rate of development, hypercalcemia can produce varying degrees of a generalized encephalopathy, ranging from mild impairment of attention to coma.
	• Patients with hypercalcemic encephalopathy can also present with a posterior reversible leukoencephalopathy syndrome, or a subacute Creutzfeldt-Jakob-like syndrome of progressive dementia.
	• Weakness is a common symptom of hypercalcemia.
	• Hypercalcemia in the setting of malignancy is a common oncologic emergency and ultimately develops in 10% to 30% of patients with cancer.

Hypercalcemia is often asymptomatic, and more than half of cases are identified by an unanticipated elevation in serum calcium on biochemical screening studies. Other cases present with symptoms and signs of their underlying diseases (eg, bone pain from osseous metastases or kidney stones in hyperparathyroidism). Symptoms and signs of hypercalcemia per se depend on the severity and rate of development of the hypercalcemia. Patients with serum calcium levels less than 11 mg/dl are rarely symptomatic from hypercalcemia, whereas those with levels between 11 mg/dl and 14 mg/dl may be symptomatic, and those with levels above 14 mg/dl are uniformly symptomatic and at risk of severe organ damage. Ectopic soft-tissue calcification is increasingly likely as serum calcium levels rise above 13 mg/dl. Symptoms tend to be more likely and more severe if hypercalcemia develops rapidly.

Hypercalcemia can cause a broad range of nonspecific systemic manifestations, including dehydration, fatigue, weight loss, anorexia, constipation, nausea, vomiting, abdominal pain, and pruritus. Most of these can be traced to dysfunction of the renal, cardiovascular, and gastrointestinal systems (85; 61; 129; 43), and in the setting of malignancy-associated hypercalcemia may be difficult to differentiate from tumor- or treatment-related symptoms (162). Hypercalcemia impairs the ability of the renal tubules to respond to antidiuretic hormone (vasopressin), causing a form of nephrogenic diabetes insipidus that decreases the ability of the kidneys to concentrate the urine by removing free water, which in turn produces polyuria and contributes to dehydration (as do nausea and vomiting). Other renal effects include azotemia, renal stones, and nephrocalcinosis (ie, deposition of calcium salts in the renal parenchyma). Cardiovascular manifestations include atrial or ventricular arrhythmias, and the arrhythmogenic effects of hypercalcemia may be potentiated by concomitant therapy with digitalis or by underlying cardiac disease (253). Anorexia, nausea, vomiting, constipation, and ileus are common gastrointestinal symptoms; pancreatitis and peptic ulcer disease are less common associated conditions involving the gastrointestinal system.

Regarding skeletal manifestations of hypercalcemia in hyperparathyroidism, evidence of loss of bone mineral density can be detected and monitored with central dual-energy x-ray absorptiometry studies. Advanced forms of bone disease, such as osteitis fibrosa cystica, are infrequently seen now. In osteitis fibrosa cystica, osteoclastic bone resorption in hyperparathyroidism results in a loss of bone mineral density, peritrabecular fibrosis, and formation of cyst-like brown tumors in and around the bone. These changes produce a general softening of the bones, fragility-related bone fractures, and a moth-eaten appearance of the bones on x-ray studies. Osteitis fibrosa cystica was first described by Gerhard Engel in 1864 and Friedrich Daniel von Recklinghausen in 1890.

Hand x-rays in hyperparathyroidism

X-ray of the hands showing brown tumors in a patient with hyperparathyroidism. (Contributed by Ahmed Haroud. Courtesy of Radiopaedia.org and Wikipedia.)
German pathologist Friedrich Daniel von Recklinghausen

German pathologist Friedrich Daniel von Recklinghausen (1833-1910) is most known for his monograph in 1882 (Über die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen) in which he reviewed previous literature...

The most specific sign of chronic hypercalcemia is band keratopathy, a condition in which metastatic calcification occurs in the medial and lateral margins of the cornea adjacent to the scleral limbus. Band keratopathy differs in appearance from arcus senilis, which begins superiorly and inferiorly and eventually extends around the margins of the cornea (annulus senilis) (260).

Band keratopathy

Band keratopathy in a patient with aphakia (due to congenital cataracts) and a history of partial iridectomy. Note the white calcium deposits along the medial and lateral margins of the cornea adjacent to the scleral limbus. (Phot...
Arcus senilis

Arcus senilis (for comparison with band keratopathy). (Source Loren A Zech Jr and Jeffery M Hoeg 2008.)

Depending on the severity and rate of development, hypercalcemia can produce varying degrees of a generalized encephalopathy, ranging from mild impairment of attention to coma. Between these two extremes, patients commonly manifest an acute confusional state associated with apathy, depression, or lethargy (207). Personality changes and psychosis have also been described (246; 61; 262; 205), although primary hyperparathyroidism may present with various severe psychiatric symptoms, even in mild hypercalcemia (205). Rarely, other neurologic manifestations may occur, including seizures (58) and parkinsonism (203).

Several case reports have highlighted patients with hypercalcemia who presented with a posterior reversible leukoencephalopathy syndrome (143; 63; 199). Hypercalcemia associated with posterior reversible leukoencephalopathy syndrome was due to a variety of causes, including excessive oral intake of calcium, plasmacytoma, carcinoma, and AIDS-associated mycobacterial infection. Although immune suppression and arterial hypertension are well known to predispose patients to the development of posterior reversible leukoencephalopathy syndrome, isolated hypercalcemia in normotensive immunocompetent patients is a relatively recently described etiology (143; 63; 199).

Patients with hypercalcemic encephalopathy can also present with a subacute Creutzfeldt-Jakob-like syndrome of progressive dementia (217). EEG may show bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on low-voltage background activity. Unlike in Creutzfeldt-Jakob disease, myoclonic jerks and periodic discharges are rare in hypercalcemic encephalopathy. Clinical and EEG abnormalities may resolve after normalization of serum calcium levels.

Weakness is a common symptom of hypercalcemia, and one that may have multiple etiologies. Although the pathophysiology of objective weakness due to hypercalcemia is not always clear, it is thought to be primarily a manifestation of CNS dysfunction, based on the presence of hyperreflexia and extensor plantar responses in some well-detailed case reports, and the lack of convincing evidence of dysfunction within the motor unit (157). At times, weakness and muscle wasting occur in combination with brisk muscle stretch reflexes, and the clinical picture can mimic amyotrophic lateral sclerosis. Some have postulated a neurogenic source of weakness in such cases. However, the proposal that hyperparathyroidism can cause a form of motor neuron disease remains highly contentious (209; 157; 131). The presence of paraparesis or quadriparesis and upper motor neuron signs, with or without a sensory level, should also prompt consideration of spinal cord compression due to a brown tumor arising in a vertebral body, a rare complication of primary or secondary hyperparathyroidism (246). In addition, in the setting of primary hyperparathyroidism, instances of true myopathy have been documented with support from electrophysiologic and histologic studies, but such cases appear to be uncommon (249; 156; 141).

Hypercalcemia in the setting of malignancy is a common oncologic emergency and ultimately develops in 10% to 30% of patients with cancer (238; 162; 218; 100). The point prevalence of hypercalcemia among cancer patients is only about 2% to 3% (97). The point prevalence of hypercalcemia of malignancy varies by tumor type and is highest for patients with multiple myeloma (8% to 10%) and lowest among colorectal and prostate cancer patients (97). Patients with malignancy-related hypercalcemia can present with a prominent encephalopathy, dehydration, and generalized weakness. Hypercalcemia is the most common life-threatening metabolic disorder in patients with advanced-stage cancers and is a poor prognostic indicator (23).

Prognosis and complications

Malignancy-associated hypercalcemia has a dire prognosis: the mean survival in patients with cancer once hypercalcemia supervenes is approximately 30 days. The prognosis of hypercalcemia is otherwise excellent, provided that the underlying disease is identified and appropriately treated.

Severe hypercalcemia itself is not generally immediately life-threatening (108). A retrospective observational study over a 5-year period of patients admitted to the adult emergency department of a large tertiary hospital found no cases of immediately life-threatening cardiac arrhythmias or neurologic complications associated with hypercalcemia above 4 mmol/l (16 mg/dl) (108).

Clinical vignette

A 55-year-old woman was brought to the emergency room by her family because of increasing confusion. Her family reported that she had been depressed and withdrawn for many months, but she had recently become less responsive and more somnolent. She was diagnosed with breast cancer 6 months earlier and was treated with modified radical mastectomy and radiation. Review of systems was remarkable for complaints of headache, polyuria, and lightheadedness on standing. Neurologic examination showed a decreased level of arousal, poor attention, and an inability to follow complex commands. Cranial nerve, motor, sensory, coordination, and muscle stretch reflex examinations were unremarkable. Plantar responses were downgoing. Serum calcium was 14 mg/dL (3.5 mmol/L). A bone survey revealed multiple osteolytic metastatic lesions. Initial treatment included volume expansion with normal saline, calcitonin, and zoledronic acid.

Biological basis

	• Calcium is transported through the bloodstream as dissolved divalent cations (Ca2+) or bound to proteins (eg, serum albumin).
	• Parathyroid hormone, secreted by the parathyroid gland, regulates (1) the resorption of calcium from bone (the major calcium storage site in the body); (2) reabsorption in the kidney back into circulation; and (3) increases in the activation of vitamin D3 to calcitriol.
	• Calcitriol, the active form of vitamin D3, promotes absorption of calcium from the intestines and the mobilization of calcium ions from bone matrix.
	• Hyperparathyroidism and malignancy-associated hypercalcemia are by far the most common causes of hypercalcemia, together accounting for more than 90% of cases.
	• Primary hyperparathyroidism is most often caused by a parathyroid adenoma.
	• Homeostasis of calcium concentration depends primarily on the parathyroid’s capacity to regulate calcium fluxes between the extracellular fluid space, the intestine, the kidneys, and the other bones.

Etiology and pathogenesis

Calcium regulation and balance in the human body. Calcium is transported through the bloodstream as dissolved divalent cations (Ca2+) or bound to proteins (eg, serum albumin). Calcium levels are tightly regulated.

Calcium regulation

Calcium is transported through the bloodstream as dissolved divalent cations (Ca2+) or bound to proteins (eg, serum albumin). Calcium levels are tightly regulated. Parathyroid hormone, secreted by the parathyroid gland, regulates ...
Calcium balance in the human body

The movement of calcium ions from the plasma (central square) to and from various body compartments. The sizes of the red arrows are roughly in proportion to the quantities moved in and out of the plasma per day. The influence of ...

The parathyroid gland. Although the number varies, there are usually four parathyroid glands, two on each side. The parathyroid glands are usually located on the posterior surface of the thyroid gland. The position of the parathyroid glands varies considerably. Most (71%) are located at the level of the middle or lower third of the thyroid gland, some (6%) are located at the level of the upper third of the thyroid gland, and the rest are located away from the thyroid gland, even into the mediastinum (119).

Parathyroid glands typical location (anterior-posterior view)

The parathyroid glands are located usually on the posterior surface of the thyroid gland. Although the number varies, there are usually 4 parathyroid glands, 2 on each side. (Courtesy of Wikimedia Commons. Creative Commons Attribu...
Parathyroid glands typical location (lateral view)

The parathyroid glands are located usually on the posterior surface of the thyroid gland. Although the number varies, there are usually 4 parathyroid glands, 2 on each side. (Courtesy of Wikimedia Commons. Creative Commons Attribu...
Parathyroid glands to thyroid gland relationship

The parathyroid glands, and their relationship to the thyroid gland, the three laryngeal nerves, and the inferior thyroid artery (from behind). The original image has been modified by coloring the parathyroid glands purple for eas...
Parathyroid glands (range in position)

This shows a composite of the positions of the parathyroid glands found in 25 cadavers in relation to the thyroid gland and trachea. The thyroid gland is illustrated as transparent so the parathyroid gland positions can be seen. T...

Like all endocrine glands, the parathyroid gland has a capsule and is well vascularized. There are two main cell types: principal (chief) cells and oxyphil cells. Principal (chief) cells are the predominant cell type. Principal cells have clear-cut cell outlines, and an eosinophilic cytoplasm containing lipofuscin pigment granules and moderate amounts of glycogen. Principal cells produce parathyroid hormone. Less common are oxyphil cells, which are larger than principal cells, and have light hyperchromatic to eosinophilic cytoplasmic staining and an abundant amount of cytoplasm. Oxyphil cells also secrete parathyroid hormone. Adipose tissue is frequently found in this gland in older individuals.

Parathyroid gland histology (low magnification)

Low-magnification micrograph of the parathyroid gland. Hematoxylin and eosin stain. The predominant cell type is the chief cell, with its intense hyperchromatic to eosinophilic cytoplasmic staining; chief cells manufacture parathy...
Parathyroid gland histology (intermediate magnification)

Intermediate-magnification micrograph of the parathyroid gland. Hematoxylin and eosin stain. (Courtesy of Wikimedia Commons. Creative Commons Attribution-Share Alike 3.0 Unported.)
Parathyroid gland histology (high magnification)

High-magnification micrograph of the parathyroid gland. Hematoxylin and eosin stain. (Courtesy of Wikimedia Commons. Creative Commons Attribution-Share Alike 3.0 Unported.)

Disorders associated with hypercalcemia. A broad range of disorders may lead to hypercalcemia (227; 61; 132; 193; 224). Hyperparathyroidism and malignancy-associated hypercalcemia are by far the most common causes of hypercalcemia, together accounting for more than 90% of cases (193; 235).

Parathyroid adenoma (low magnification)

Low-magnification micrograph of the parathyroid adenoma (left side). Hematoxylin and eosin stain. Parathyroid adenomas as small, solitary, clearly demarcated nodules within the parathyroid gland. They consist of a single cell popu...
Parathyroid adenoma (intermediate magnification)

Intermediate-magnification micrograph of the parathyroid adenoma (left side). Hematoxylin and eosin stain. In this case, normal parathyroid gland with prominent adipose tissue is seen on the right side of the image. (Courtesy of W...
Parathyroid adenoma (high magnification)

High-magnification micrograph of the parathyroid adenoma (left side). Hematoxylin and eosin stain. In this case, normal parathyroid gland with prominent adipose tissue is seen on the right side of the image. (Courtesy of Wikimedia...
Parathyroid hyperplasia (low magnification)

(Courtesy of Wikimedia Commons. Creative Commons Attribution-Share Alike 3.0 Unported.)
Parathyroid hyperplasia (intermediate magnification)

(Courtesy of Wikimedia Commons. Creative Commons Attribution-Share Alike 3.0 Unported.)
Parathyroid hyperplasia (high magnification)

(Courtesy of Wikimedia Commons. Creative Commons Attribution-Share Alike 3.0 Unported.)

Primary hyperparathyroidism (61; 181; 43)
	• Primary hyperparathyroidism is most common in patients older than 40 years, with an average age of about 55 years, and women are 2 to 3 times more likely to be affected than men. Primary hyperparathyroidism is rare in childhood.
	• Primary hyperparathyroidism is most often caused by a parathyroid adenoma, a benign tumor in a single parathyroid gland (80% to 85% of cases), or parathyroid hyperplasia, an enlargement of all four parathyroid glands (15% to 20% of cases), and rarely by parathyroid carcinoma (less than 0.1% of cases).
	• Parathyroid hyperplasia may be sporadic or occur in the multiple endocrine neoplasia syndromes with pheochromocytoma, islet cell tumors, pituitary tumors, or medullary carcinoma of the thyroid.
	• A significant proportion of patients with hyperparathyroidism do not undergo appropriate evaluation and surgical referral. In a large series of 10,432 patients with hypercalcemia, only 31% had parathyroid hormone levels measured and 28% had a documented diagnosis of hypercalcemia in the medical record; of those with classic hyperparathyroidism only 22% had a surgical referral (26).
	• End-organ damage develops before or within 5 years of diagnosis for about two thirds (62% in one study) of patients (24).
	• Hyperparathyroidism-induced hypercalcemic crisis is a rare presentation of primary hyperparathyroidism (169).
Malignancy-associated hypercalcemia (196; 238; 65; 162; 218; 198; 229; 149; 97; 100; 154; 189; 192; 20).
	• Malignancy-associated hypercalcemia is the most common cause of non-parathyroid hypercalcemia (101).
	• Malignancy-associated hypercalcemia is a common complication, occurring in 10% to 30% of patients with cancer (238; 162; 218; 100).
	• Patients with malignancy-associated hypercalcemia almost always have advanced clinically evident disease.
	• Production of humoral factors by the primary tumor is collectively known as humoral hypercalcemia of malignancy and is the mechanism responsible for 80% of cases of malignancy-associated hypercalcemia (65).
	• The malignancies that are most frequently associated with humoral hypercalcemia of malignancy are hematological malignancies (eg, multiple myeloma, non-Hodgkin lymphoma, leukemias) and solid cancers (particularly renal, breast, ovarian, and endometrial carcinomas as well as squamous cell carcinomas of the lung, head and neck, or esophagus) (238; 23). In rare cases, lymphoma may present with hypercalcemia, and CT is less sensitive for lymphoma than for most solid tumors, so the diagnosis may be missed or delayed (20).
	• Humoral hypercalcemia of malignancy is usually due to secretion of parathyroid hormone-related protein by malignant tumors, but other humoral factors may be involved in rare cases (eg, tumor production of 1,25(OH)2D or parathyroid hormone) (241; 65; 198; 229; 100; 154; 192; 102). Parathyroid hormone-related protein is encoded by a separate gene (cytogenetic location: 12p11.22), but it shares sequence homology with the amino-terminal domain of parathyroid hormone (cytogenetic location: 11p15.3); this allows parathyroid hormone-related protein to cross-react at a common G protein receptor, the type 1 PTH/PTHrP receptor (PTHR1), resulting in similar skeletal effects and effects on calcium and phosphorus metabolism to that produced by parathyroid hormone (101). Hypercalcemia with concomitant elevation of both serum parathyroid hormone and parathyroid-related protein levels has been reported in a patient with advanced gastric carcinoma and multiple liver metastases (198). Severe hypercalcemia with concomitant elevation of both PTHrP and 1,25(OH)2D has been reported in a patient with non-Hodgkin lymphoma that expressed both PTHrP and CYP27B1 (this enzyme carries out the second of two reactions to convert vitamin D to its active form, 1,25-dihydroxyvitamin D3, which is also known as calcitriol (102).
	• Local osteolytic hypercalcemia is due to skeletal invasion by malignant cells, as in multiple myeloma (which makes osteoclast activating factor that stimulates osteoclasts to resorb bone), breast or lung cancer metastatic to bone, lymphoma, and occasionally other malignancies (eg, acute lymphoblastic leukemia) (149). This is the mechanism responsible for 20% of cases of malignancy-associated hypercalcemia (65).
	• Absorptive hypercalcemia is due to excess 1,25(OH)2D production by malignancies (eg, lymphoma) (218; 189).
	• Hypercalcemia in patients with malignancies can also occur to nonmalignancy-related causes (100).
Granulomatous disorders (231; 145; 55; 225; 79)
	• A wide variety of granulomatous diseases cause hypercalcemia (233) due to enhanced extra-renal conversion of 25-hydroxy vitamin D to 1,25(OH)2D by activated macrophages within the granulomas.
	• Sarcoidosis is the granulomatous disorder most commonly associated with hypercalcemia. The incidence of hypercalcemia in sarcoidosis ranges from 10% to 20%, but over 40% have hypercalciuria, often with nephrolithiasis. It may present as hypercalcemia without evident systemic manifestations (194; 22; 123).
	• Other granulomatous causes of hypercalcemia include berylliosis, mycobacteria infections (tuberculosis and granulomatous leprosy), fungal infections (histoplasmosis, blastomycosis, and coccidiomycosis), Wegener granulomatosis, foreign body granulomas, and eosinophilic granuloma.
	• Rare cases of hypercalcemia in granulomatous disorders are not explained by elevated levels of vitamin D or its metabolites (233).
Endocrine disorders (other than hyperparathyroidism)
	• Hyperthyroidism, which is associated with both increased bone resorption and increased bone turnover.
	• Addisonian crisis due to primary adrenal insufficiency is a rare cause of hypercalcemia that resolves with glucocorticoid treatment (195; 235)
	• Pheochromocytoma may be part of a multiple endocrine neoplasia syndrome, or hypercalcemia may result from production of parathyroid hormone-related protein by the pheochromocytoma (240; 235).
	• Pancreatic islet tumors that secrete vasoactive intestinal polypeptide (235). These tumors are associated with the watery diarrhea hypokalemia achlorhydria syndrome, also called pancreatic cholera (50).
	• Acromegaly may be a cause of 1,25(OH)2D-dependent hypercalcemia (228).
	• Familial hypocalciuric hypercalcemia ("familial benign hypocalciuric hypercalcemia") resembles primary hyperparathyroidism but is relatively benign in comparison: the hypercalcemia is usually asymptomatic (181; 170; 252; 87; 232; 191; 180; 243). Familial hypocalciuric hypercalcemia is generally transmitted as an autosomal dominant disorder (170; 191). Most cases are caused by a loss of function mutations in the CaSR gene, which encodes a calcium-sensing receptor that is expressed in parathyroid and kidney tissue. The perceived lack of calcium levels by the parathyroid glands results in high levels of parathyroid hormone secretion and, therefore, hypercalcemia. The diagnosis can be confirmed by genetic testing for a mutation in the gene encoding the calcium-sensing receptor (87). Homozygous mutations in CaSR may lead to life-threatening forms of neonatal severe hyperparathyroidism. Transient neonatal hyperparathyroidism may occur in affected neonates if the mutation is paternally inherited (124).
	• The mitochondrial enzyme 1,25-dihydroxyvitamin D3 24-hydroxylase, a member of the cytochrome P450 superfamily of enzymes, is encoded by the CYP24A1 gene. Mutations in CYP24A1 may cause failure to metabolize 1,25-dihydroxyvitamin D, with resultant chronic hypercalcemia, hypercalciuria, or nephrolithiasis (133; 53; 216; 213). Pregnant women with a CYP24A1 gene mutation are at increased risk of hypercalcemia (due to upregulation of calcitriol) and fetal demise (53; 216; 213). Pathogenic mutations of CYP24A1 should be considered in the differential diagnosis of hypercalcemia with low parathyroid hormone concentrations, particularly if there is a reduced ratio of 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D (213). Diagnosis is confirmed by genetic analyses (213). Monoallelic carriers have significant rates of nephrolithiasis (19%), nephrocalcinosis (5%), and symptomatic hypercalcemia (6%) (53). Strictly avoiding vitamin D supplementation may be effective in preventing or reducing the degree of hypercalcemia in affected individuals (216; 213).
	• Malignancies and systemic lupus erythematosus can be associated with elevated parathyroid hormone-related protein (241; 65; 198; 229; 100; 154; 261; 192).
Medications
		Recombinant human PTH (159). Transient hypercalcemia can occur in patients with hypoparathyroidism receiving recombinant human PTH because of overtreatment, usually during acute illness (159).
	• Vitamin A intoxication (251; 220; 46), usually with doses over 50,000 units daily. Vitamin A is provided in supplements and animal sources (animal liver, fish liver oil, dairy, and eggs).
	• Vitamin D intoxication in health faddists or as a complication of treatment, usually with high-dose ergocalciferol that is stored in fat depots for months (50; 107; 175; 211; 245; 71; 144; 95; 159; 225). Vitamin-D toxicity is the second most common cause of hypercalcemia after primary hyperparathyroidism (144). In a systematic review of vitamin D toxicity from overcorrection of vitamin D deficiency, patients presented with serum 25-hydroxy vitamin D concentrations ranging between 150 and 1220 ng/mL and serum calcium concentrations between 11.1 and 23.1 mg/dL (95). Most of the reported patients showed symptoms of vitamin D toxicity including vomiting, dehydration, pain, and loss of appetite (95). The underlying causes of overcorrection of vitamin D deficiency included manufacturing errors and overdosing by patients or prescribers (95).
	• Thiazide diuretics (51; 78; 159). Thiazide-induced hypercalcemia is usually attributed to enhanced renal calcium reabsorption by increasing Na/Ca exchange in the distal convoluted tubule (eg, changing preexistent asymptomatic normocalcemic or intermittently hypercalcemic hyperparathyroidism into the classic hypercalcemic hyperparathyroidism) (159). The hypercalcemic effect of thiazides also occurs in anephric patients, so nonrenal mechanisms contribute to the development of thiazide-associated hypercalcemia (150).
	• Lithium carbonate (163; 185). Lithium causes hypercalcemia mainly by drug-induced hyperparathyroidism (159).
	• Theophylline preparations (usually seen following "bolus" administration of aminophylline in emergency room settings) (182)
	• Estrogen and antiestrogen use in women with breast cancer and skeletal metastases (161)
	• Corticosteroid therapy (203)
	• Foscarnet (98; 27; 214; 101)
	• Milk-alkali syndrome is characterized by the triad of hypercalcemia, renal insufficiency, and metabolic alkalosis that results from overconsumption of calcium-containing products (34; 148; 122; 197). During pregnancy there is a physiological increase in calcium absorption, and in this setting milk-alkali syndrome can be life-threatening (148).
Acute and chronic renal failure
	• Causes of hypercalcemia in acute and chronic renal failure include vitamin D therapy, calcium carbonate use, aluminum intoxication, and severe secondary hyperparathyroidism (51; 181; 89). Hypercalcemia may occur rarely during the recovery phase of acute renal failure (224).
	• In patients with end-stage renal disease, neither uncorrected nor albumin corrected total serum calcium levels are reliable indicators or ionized calcium levels (202). Most patients with end-stage renal disease and elevated ionized calcium levels are falsely categorized as normocalcemic using conventional total serum calcium assays (202). Such “hidden hypercalcemia” in patients with end-stage renal disease is associated with a significantly higher risk of death (202).
Advanced chronic liver disease (153)
	• This may be transient and may not require treatment (153).
Immobilization (239; 62; 160; 52; 122; 187)
	• Severe hypercalcemia may result from immobilization in the setting of paraplegia, quadriplegia, extensive skeletal fractures, or prolonged enforced bedrest.
	• Immobilization hypercalcemia usually occurs with immobilization in the setting of increased skeletal turnover (eg, children or adolescents, Paget disease of the bone, primary or secondary hyperparathyroidism, cancer) (239; 62; 160; 122).
Protein abnormalities
	• Hyperalbuminemia. Approximately 50% of circulating calcium is bound to albumin. Disorders that raise or lower albumin concentrations cause corresponding alterations in total but not ionized serum calcium. This is a formula to correct for changes in albumin concentration: corrected calcium = serum calcium + 0.8* (normal albumin – patient albumin).
	• Calcium binding immunoglobulins in patients with multiple myeloma. Rarely, immunoglobulins are produced that specifically bind calcium and lead to asymptomatic elevation in total but not ionized serum calcium (186).
Infantile hypercalcemia
	• Williams syndrome (or Williams-Beuren syndrome, OMIM #194050). Infantile hypercalcemia, usually mild and transient, is associated with multiple congenital developmental defects, including mental retardation, gregariousness, profound visuo-spatial impairment, “elfin” facies, a low nasal bridge, and supravalvular aortic stenosis (227; 224). Other findings can include chronic serous otitis media, hyperacusis, and obstructive sleep apnea (190). It is caused by a deletion of about 26 genes from the long arm of chromosome 7 (7q11.23). The syndrome was described in 1961 by New Zealand cardiologist John C P Williams (b 1922). The hypercalcemia associated with Williams syndrome typically, but not invariably, resolves by the first year (120). The cause of the hypercalcemia in Williams syndrome is still unclear (72; 96; 219; 151; 212; 166).
	• Idiopathic infantile hypercalcemia (OMIM #143880). Idiopathic infantile hypercalcemia (oddly, the "idiopathic" persists even though responsible mutations in several genes have been identified) is a rare inborn form of severe hypersensitivity to vitamin D, which tends to abate by 1 year of age (183; 259; 221; 226; 225; 76; 57; 81; 93; 236; 138; 82; 248; 64; 165; 164). Infantile hypercalcemia1 (HCINF1) is caused by a CYP24A1 mutation (cytochrome p450, family 24, subfamily a, polypeptide 1) on chromosome 20q13.2, resulting in slow inactivation of 1,25-dihydroxy-vitamin D3 with subsequent hypercalcemia. Common signs include lethargy, psychomotor retardation, failure to thrive, muscle hypotonia, dehydration, constipation, and nephrocalcinosis. Infantile hypercalcemia-2 (HCINF2) is caused by a homozygous or compound heterozygous mutation in the SLC34A1 gene (solute carrier family 34; type II sodium/phosphate cotransporter; OMIM 182309) on chromosome 5q35. Infantile hypercalcemia with nephrocalcinosis can also be caused by a heterozygous mutation in the SLC34A3 gene (solute carrier family 34; sodium/phosphate cotransporter) on chromosome 9q34.3 (165). Biallelic mutations in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria and also, rarely, with intermittent hypercalcemia (75; 244). The clinical presentation of mild so-called "idiopathic" infantile hypercalcemia is variable as is the underlying genetic cause (165; 164). Dietary calcium and vitamin D restriction does not consistently normalize elevated 1,25(OH)2D concentrations or uniformly prevent worsening of renal calcification (164). The milder form of idiopathic infantile hypercalcemia has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants, whereas biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe idiopathic infantile hypercalcemia (165).
	• Benign familial hypercalciuric hypercalcemia (236). At least three types of benign familial hypercalciuric hypercalcemia have been identified: type I with autosomal dominant inheritance due to heterozygous loss-of-function mutations in the CASR gene (601199), which encodes the calcium-sensing receptor, on chromosome 3q13.3-q21.1, OMIM #145980; type II with autosomal dominant inheritance due to heterozygous mutations in the GNA11 gene (139313) on chromosome 19p13.3, OMIM #145981; and type III with autosomal dominant inheritance due to heterozygous mutations in the AP2S1 gene (602242) on chromosome 19p13.32, OMIM # 600740.
	• Iatrogenic hypervitaminosis D (139; 236).
	• Subcutaneous fat necrosis (28; 255; 258; 19; 80; 44; 171; 263; 01; 236).

Primary hyperparathyroidism is most often caused by a parathyroid adenoma.

Parathyroid adenoma

Parathyroid glands in a patient with hyperparathyroidism caused by a parathyroid adenoma. (Source Bruce Blaum.)

Homeostasis of calcium concentration depends primarily on the parathyroid’s capacity to regulate calcium fluxes between the extracellular fluid space, the intestine, the kidneys, and the other bones (129). Parathyroid hormone induces renal calcium reabsorption in the distal tubule, activates osteoclastic bone resorption, and stimulates the conversion of vitamin D precursors to the active form of vitamin D [1,25(OH)2D], which in turn increases intestinal calcium absorption. In hypercalcemia due to hyperparathyroidism, the problem is an excess secretion of parathyroid hormone with otherwise intact homeostatic control, resulting in an elevated but relatively stable concentration of calcium (so-called equilibrium hypercalcemia) (85). In hypercalcemia due to other causes, compensatory mechanisms ultimately fail, despite appropriate suppression of parathyroid hormone. Typically, one of the central features of this decompensation, occurring in the more advanced stages of primary hyperparathyroidism as well, relates to the hypercalciuria-induced diuresis that leads to volume depletion and decreased glomerular filtration rate. The resulting decreased delivery of calcium and increased tubular reabsorption (which may already be increased if the parathyroid hormone or parathyroid-related protein is elevated) diminishes the kidney’s capacity to counteract the underlying problem (85; 51).

Calcium ions from the serum diffuse easily across the blood-brain barrier, and levels can directly correlate with calcium levels in both cerebrospinal fluid and brain parenchyma (135). Nevertheless, the precise mechanisms by which hypercalcemia causes neurologic symptoms remain unclear.

Differential diagnosis

Confusing conditions

The symptoms of hypercalcemia are nonspecific, and especially in the setting of malignancy-associated hypercalcemia the symptoms caused by hypercalcemia may be difficult to differentiate from tumor- or treatment-related symptoms (162).

Hypercalcemia should be considered in the differential diagnosis of encephalopathy, generalized weakness, and posterior reversible leukoencephalopathy syndrome. The likelihood of hypercalcemia being present increase if commonly associated symptoms are present, such as dehydration, fatigue, weight loss, anorexia, constipation, nausea, vomiting, or abdominal pain. Note that hypermagnesemia may closely mimic the effects of hypercalcemia.

An important consideration in the differential diagnosis of patients with a malignancy and a clinical picture of encephalopathy is tumor lysis syndrome. This oncologic emergency occurs most commonly after the initiation of cytotoxic chemotherapy in patients with high-grade lymphomas or other hematologic malignancies and rarely with solid tumors. Massive cell lysis results in multiple metabolic derangements, including elevated serum uric acid 8.0 mg/dL or greater, hyperkalemia 6.0 mmol/L or greater, hyperphosphatemia 6.5 mg/dL or greater, and hypocalcemia 7.0 mg/dL or less. Clinical presentation can include encephalopathy, nausea, vomiting, anorexia, heart failure, cardiac dysrhythmias, seizures, tetany, and death (67). In contrast to malignancy-associated hypercalcemia, patients with tumor lysis syndrome are more likely to suffer diarrhea than constipation.

Associated or underlying disorders

The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy, with primary hyperparathyroidism being the most common cause in ambulatory patients, and malignancy-related hypercalcemia being the most common cause among hospitalized patients. A history of hypercalcemia for over a year, in the absence of known malignancy, weight loss, and other systemic signs and symptoms, generally excludes malignancy-associated hypercalcemia. Less common causes of hypercalcemia include, for example, endocrine disorders (the most common cause in this group being hyperthyroidism), granulomatous disorders (the most common cause in this group being sarcoidosis), medications (especially thiazine diuretics, vitamin D, vitamin A, calcium carbonate, and lithium), acute and chronic renal failure, and immobilization (227).

The differential diagnosis of infantile hypercalcemia includes idiopathic infantile hypercalcemia (OMIM #143880), benign familial hypercalciuric hypercalcemia (types I-III), Williams syndrome (or Williams-Beuren syndrome, OMIM #194050), iatrogenic hypervitaminosis D, neonatal hyperparathyroidism, primary hyperparathyroidism, malignancy, granulomatous disease, Jansen metaphyseal dysplasia, and subcutaneous fat necrosis (236).

Diagnostic workup

	• In most clinical circumstances, total serum calcium levels accurately reflect ionized calcium levels.
	• Hypoalbuminemia and end-stage renal disease are two common situations where total serum calcium levels may be misleading.
	• Recognizing that all calcium in the body is ionized, the term “ionized calcium” refers to the free ionic fraction that is physiologically active in blood.
	• About half of the calcium circulating in the blood is protein bound. Ninety percent of protein-bound calcium is linked to albumin, whereas the remaining 10% is bound to a variety of globulins.
	• In patients with end-stage renal disease, neither uncorrected nor albumin-corrected total serum calcium levels are reliable indicators of ionized calcium levels.
	• When the cause of hypercalcemia is not immediately obvious, careful history taking, with particular attention to medication use, will sometimes suggest the underlying problem.
	• Appropriate initial laboratory testing for hypercalcemia in adults generally includes serum total and ionized calcium, magnesium, albumin, phosphate, alkaline phosphatase, creatinine, and parathyroid hormone.
	• The principal ECG finding in hypercalcemia is a short QT interval, but EKG changes may mimic an acute myocardial infarction, and in severe hypercalcemia an Osborn wave (or J wave, ie, notching of the terminal QRS complex) may be present, mimicking the EKG findings in hypothermia.
	• In hyperparathyroidism, x-rays may show evidence of a moth-eaten appearance to the bones, so-called brown tumors, and fragility fractures.
	• EEG abnormalities associated with hypercalcemic encephalopathy include excess theta activity, delta and theta slowing, bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on low-voltage background activity, and diffuse but predominantly occipital spike-slow-wave complexes.

In most clinical circumstances, total serum calcium levels accurately reflect ionized calcium levels. However, hypoalbuminemia and end-stage renal disease are two common situations where total serum calcium levels may be misleading (202).

Recognizing that all calcium in the body is ionized, the term “ionized calcium” refers to the free ionic fraction that is physiologically active in blood. Ionized calcium competes with hydrogen ions to bind to negatively charged sites on albumin and other calcium-binding proteins. About half of the calcium circulating in the blood is protein bound. Ninety percent of protein-bound calcium is linked to albumin, whereas the remaining 10% is bound to a variety of globulins. There are 12 potential binding sites on each albumin molecule, but only about 10% to 15% are utilized under normal conditions. Therefore, each 1 g/dL reduction in the serum albumin concentration lowers total calcium concentration by approximately 0.8 mg/dL (0.2 mmol/L) without affecting the ionized calcium concentration and, consequently, without producing any symptoms or signs of hypocalcemia.

In patients with end-stage renal disease, neither uncorrected nor albumin-corrected total serum calcium levels are reliable indicators or ionized calcium levels (202). Most patients with end-stage renal disease and elevated ionized calcium levels are falsely categorized as normocalcemic using conventional total serum calcium assays (202). Such “hidden hypercalcemia” in patients with end-stage renal disease is associated with a significantly higher risk of death (202).

Rarely, endogenous antibodies can interfere with 25-hydroxy vitamin D immunoassays (35). In one case with a myeloma-related IgG monoclonal gammopathy, hypercalcemia with low parathyroid hormone levels and apparently very high 25-hydroxyvitamin D levels mimicked vitamin D intoxication (35). Alternative vitamin D assays are available, which can give correct results in these rare circumstances.

The clinical setting often dictates the extent of the diagnostic workup for hypercalcemia, as the likely etiology may be evident at the time of presentation (eg, malignancy or renal failure). When the cause is not immediately obvious, careful history taking, with particular attention to medication use, will sometimes suggest the underlying problem. Appropriate initial laboratory testing in adults generally includes serum total and ionized calcium, magnesium, albumin, phosphate, alkaline phosphatase, creatinine, and parathyroid hormone (89). The highly sensitive and specific immunoassay for parathyroid hormone offers a straightforward approach to the diagnosis of hyperparathyroidism. Assays measuring intact parathyroid hormone should be used because the results of these assays are independent of renal function. The finding of an elevated parathyroid hormone-related peptide is helpful in confirming a diagnosis of humoral malignancy-associated hypercalcemia: parathyroid hormone-related peptide acts via parathyroid hormone receptors but is not detected by parathyroid hormone assays. When these latter two tests fail to provide a diagnosis, measurement of plasma 1,25(OH)2D may be useful; an elevated level in this setting would raise the possibility, for example, of a granulomatous disorder. Diagnosis of one of the less frequent causes of hypercalcemia (eg, sarcoidosis) may require a more focused and intensive search (227).

Different causes of infantile hypercalcemia can be distinguished by blood and urine studies, and then targeted genetic studies in appropriate circumstances (236). The following blood studies are recommended: calcium, phosphate, parathyroid hormone, 25(OH)D, and 1,25(OH)2D. Urine calcium and phosphate are also recommended.

The principal ECG finding in hypercalcemia is a short QT interval, but EKG changes may mimic an acute myocardial infarction, and in severe hypercalcemia an Osborn wave (or J wave, ie, notching of the terminal QRS complex) may be present, mimicking the EKG findings in hypothermia (204).

Osborn wave

Osborn wave (J wave, ie, notching of the terminal QRS complex) on EKG, which may be seen in hypothermia and severe hypercalcemia. (Source J E Roediger. Courtesy of Wikipedia.)

In hyperparathyroidism, x-rays may show evidence of a moth-eaten appearance to the bones, so-called brown tumors, and fragility fractures.

Hand x-rays in hyperparathyroidism

X-ray of the hands showing brown tumors in a patient with hyperparathyroidism. (Contributed by Ahmed Haroud. Courtesy of Radiopaedia.org and Wikipedia.)

EEG abnormalities associated with hypercalcemic encephalopathy include excess theta activity, delta and theta slowing, bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on low-voltage background activity, and diffuse but predominantly occipital spike-slow-wave complexes (142; 217). Periodic discharges are rare in hypercalcemic encephalopathy (217). EEG abnormalities may resolve after normalization of serum calcium levels (217).

Management

	• The management of hypercalcemia depends on its severity and the nature of the underlying disorder.
	• In cases of primary hyperparathyroidism, surgery is generally indicated for all symptomatic patients and for patients with asymptomatic, mild hypercalcemia who meet certain clinical or laboratory criteria.
	• In patients with advanced incurable cancer, withholding treatment of hypercalcemia may be the most appropriate course of action.
	• Patients with mild hypercalcemia (less than 12 mg/dl) do not require emergent intervention.
	• Treatment of patients with moderate hypercalcemia (12 to 13.5 mg/dl) is guided by the clinical status of the patient.
	• In the setting of severe hypercalcemia, treatment with intravenous bisphosphonates is recommended because bisphosphonates are well tolerated and have a more prolonged effect than most other agents.
	• Calcitonin can be a useful initial adjunct for severe hypercalcemia because of its rapid onset of action.
	• Dietary calcium restriction (less than 400 mg/day) is indicated in patients with vitamin D intoxication, granulomatous disorders, milk-alkali syndrome, severe hyperparathyroidism, and in patients with lymphomas that produce 1,25(OH)2D.
	• Dialysis using a low-calcium dialysate is an effective means of lowering the serum calcium and is indicated particularly in selected patients with congestive heart failure or acute reversible renal failure.

The management of hypercalcemia depends on its severity and the nature of the underlying disorder (85; 61; 51; 130; 238; 247).

Treatment or correction of the underlying cause. Treatment or correction of the underlying cause, when possible, may be the only necessary intervention when hypercalcemia is mild. In cases of primary hyperparathyroidism, surgery is generally indicated for all symptomatic patients and for patients with asymptomatic, mild hypercalcemia who meet certain clinical or laboratory criteria (51; 250; 43; 90). In patients with advanced incurable cancer, withholding treatment of hypercalcemia may be the most appropriate course of action.

Mild hypercalcemia (less than 12 mg/dl). Patients with mild hypercalcemia (less than 12 mg/dl) do not require emergent intervention. Instead, they should be counseled to avoid possible exacerbating factors, including excess calcium intake (more than 1000 mg/day), and alternative medications should be prescribed in place of those that can lead to hypercalcemia (ie, lithium carbonate and thiazide diuretics). Patients should also be instructed to avoid immobilization, avoid salt restriction, and maintain adequate fluid intake.

Moderate hypercalcemia (12 to 13.5 mg/dl). Treatment of patients with moderate hypercalcemia (12 to 13.5 mg/dl) is guided by the clinical status of the patient. If the patient is asymptomatic, a conservative approach may be sufficient. However, if the patient is symptomatic, especially with signs of encephalopathy, then a more aggressive approach is required. The goal of therapy is alleviation of symptoms rather than rapid normalization of serum calcium.

Severe hypercalcemia (greater than 13.5 mg/dL). For patients with severe hypercalcemia (greater than 13.5 mg/dL) or moderate hypercalcemia and significant clinical manifestations, the initial management entails strategies that directly lower the calcium concentration independent of the underlying cause, including measures that either restore extracellular fluid volume or increase renal calcium excretion of inhibit bone resorption.

Restore extracellular fluid volume. Because almost all patients in this setting are dehydrated, volume repletion is the essential first step toward reestablishing calcium homeostasis. Volume repletion requires careful monitoring for fluid overload, especially in this patient population that is at risk for renal and cardiac dysfunction. Hydration alone is rarely sufficient to normalize calcium levels, and additional pharmacotherapy is typically required.

Enhancing renal calcium excretion. Once extracellular fund volume has been restored, saline diuresis with normal saline infusion facilitates calcium excretion. Furosemide adds little to the effect of saline diuresis and may interfere with restoration and maintenance of adequate extracellular fluid volume.

Antiresorptive therapies. Agents that inhibit bone resorption include bisphosphonates (eg, zoledronate and pamidronate), denosumab, calcitonin, plicamycin, and gallium nitrate. Of these, bisphosphonates are the most widely used because of their relative safety and efficacy profiles (264).

In the setting of severe hypercalcemia, treatment with intravenous bisphosphonates is recommended because bisphosphonates are well tolerated and have a more prolonged effect than most other agents. An intravenous infusion of bisphosphonate pamidronate disodium (60 to 90 mg) will become effective within 48 hours, and the hypocalcemic effect peaks in 1 week and can last up to 2 weeks (201). Pamidronate is less effective in patients with humoral-related hypercalcemia (109). For this reason, zoledronic acid is often used as a first-line bisphosphonate in malignancy-associated hypercalcemia (60). It has a higher response rate in normalizing serum calcium and a more prolonged effect of up to 32 days (176). Side effects can include fever, hypocalcemia, hypophosphatemia, nausea, pruritus, and acute renal failure. Osteonecrosis, particularly of the jaw, is an infrequent but important side effect of bisphosphonate therapy that is most common in patients with malignancy-associated hypercalcemia (84). Although there may be an increased risk of atypical femoral neck fractures with prolonged use of bisphosphonates in patients with osteoporosis, this is of little relevance in the setting of malignancy-associated hypercalcemia, and the overall benefit in these patients far outweighs the minimal risk of atypical fracture (230). Available data are conflicting regarding whether chronic use of bisphosphonates is associated with increased risk of esophageal cancer, but again with the time course involved in the treatment of malignancy-associated hypercalcemia, there is little relevance in this setting (54; 104).

Subcutaneous denosumab is used for bisphosphonate-refractory hypercalcemia (eg, as a second-line therapy for hypercalcemia of malignancy) and in patients with renal failure (60; 152; 30; 247). Denosumab is a human monoclonal antibody that acts as a RANKL inhibitor, a critical mediator of bone resorption and overall bone density through its ability to stimulate osteoclast formation and activity. Denosumab binds RANKL, preventing RANKL from activating RANK, its receptor on the osteoclast surface. Osteoclast formation, function, and survival are inhibited with reduced RANK–RANKL binding, and consequently, bone resorption decreases and bone mass increases (112).

Calcitonin can be a useful initial adjunct for severe hypercalcemia because of its rapid onset of action. The addition of calcitonin will produce a rapid but mild reduction in serum calcium levels (1 to 2 mg/dl) (155); calcitonin acts primarily by decreasing bone reabsorption, but it also increases renal excretion of calcium. It is effective for up to 48 hours, but tachyphylaxis eventually develops.

Gallium nitrate and plicamycin are additional therapeutic options, though both have significant side effects (264; 73).

Treatments with restricted indications

Dietary calcium restriction. Dietary calcium restriction (less than 400 mg/day) is indicated in patients with vitamin D intoxication, granulomatous disorders, milk-alkali syndrome, severe hyperparathyroidism, and in patients with lymphomas that produce 1,25(OH)2D.

Glucocorticoids. Glucocorticoids may be useful in a select group of patients, namely those with myeloma, other hematologic malignancies, sarcoidosis, and vitamin D intoxication. Glucocorticoids act to lower serum calcium by several mechanisms, including inhibiting cytokine release, producing direct cytotoxic effects on some tumor cells, decreasing intestinal calcium absorption, and increasing urinary calcium excretion.

Dialysis. Dialysis using a low-calcium dialysate is an effective means of lowering the serum calcium and is indicated in selected patients (36). It is particularly effective in patients with congestive heart failure or acute reversible renal failure.

Special circumstances

Hypercalcemia of malignancy. As indicated earlier with general considerations on the management of hypercalcemia, the treatment of hypercalcemia of malignancy consists of enhancing renal calcium excretion (mostly through hydration with isotonic fluids) and the use of antiresorptive therapies. Intravenous zoledronic acid is the first-line treatment, with subcutaneous denosumab used for bisphosphonate-refractory hypercalcemia and in patients with renal failure (60; 127). Dialysis may be needed in some cases (36).

Hypophosphatemia. Oral phosphorus replacement should be used only in patients with phosphorus values less than 3.0 mg/dL and normal renal function to minimize the risk of ectopic soft-tissue calcification.

Immobilized patients. Mobilization is critical in reversing hypercalcemia in immobilized patients. This must include weight bearing. Passive range-of-motion exercises are inadequate.

Special considerations

Pregnancy

Although none of the common forms of hypercalcemia are epidemiologically linked with pregnancy, hypercalcemia due to any of the possible underlying disorders may first come to light during pregnancy.

Primary hyperparathyroidism. Hypercalcemic disorders in pregnant women are usually due to primary hyperparathyroidism (74). In general, in patients with primary hyperparathyroidism, parathyroidectomy is delayed until after parturition, but severe cases may warrant second trimester parathyroidectomy.

Loss-of-function mutations of the CYP24A1 gene. Loss-of-function mutations of the CYP24A1 gene cause a deficiency of the CYP24A1 enzyme, which is involved in the catabolism of 1,25-dihydroxyvitamin D₃ (calcitriol). Because pregnancy is associated with an upregulation of the active vitamin D hormone calcitriol, loss-of-function mutations of the CYP24A1 gene are likely to trigger symptomatic hypercalcemia in affected women during pregnancy (53; 213). Pathogenic mutations of CYP24A1 should be considered in the differential diagnosis of hypercalcemia with low parathyroid hormone concentrations, particularly if there is a reduced ratio of 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D, or if the 1,25-dihydroxyvitamin D₃ level is elevated while the 25-hydroxyvitamin D level is still within the reference range (216; 213). Diagnosis is confirmed by genetic analyses (213). In affected women, pregnancy is associated with high rates of obstetric complications (53). Strictly avoiding vitamin D supplementation may be effective in preventing or reducing the degree of hypercalcemia (216; 213). Calcium and 25-hydroxyvitamin D levels should be monitored in routine blood tests during pregnancy (216). Hypercalcemia in a newborn should be carefully evaluated and treated as hypercalciuria can lead to nephrocalcinosis (216).

Anesthesia

General anesthesia is best avoided in patients with hypercalcemia except in emergencies because of the risk of cardiac arrhythmias.

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Hypercalcemia

Associated Disorders

Acute and chronic renal failure
Endocrine disorders
Familial hypocalciuric hypercalcemia
Granulomatous disorders
Infantile hypercalcemia (Williams syndrome)
- Malignancy
- Milk-alkali syndrome
- Primary hyperparathyroidism

Differential Diagnosis

primary hyperparathyroidism
malignancy
endocrine disorders
hyperthyroidism
granulomatous disorders
- sarcoidosis
- acute and chronic renal failure
- immobilization
- tumor- or treatment-related symptoms
- metabolic encephalopathy
- hyponatremia
- encephalopathy
- generalized weakness
- posterior reversible leukoencephalopathy syndrome
- hypermagnesemia
- tumor lysis syndrome
- idiopathic infantile hypercalcemia
- benign familial hypercalciuric hypercalcemia (types I-III)
- Williams syndrome (or Williams–Beuren syndrome)
- iatrogenic hypervitaminosis D
- neonatal hyperparathyroidism
- Jansen metaphyseal dysplasia
- subcutaneous fat necrosis

Also Relevant

Catatonia
Chemotherapy: Neurologic complications
Hypoparathyroidism
Leukemia: neurologic complications
Metabolic encephalopathy and metabolic coma
- Myopathies associated with parathyroid disorders
- Neuropathies associated with monoclonal gammopathies
- Nutrition and the brain
- Thyrotoxicosis

Content Categories

General Neurology

Web References

Clinical Trials

NIH: Hypercalcemia

	• The methods for prevention of hypercalcemia depend on the underlying disorder.
	• Only some causes of hypercalcemia are preventable (eg, vitamin D and A intoxication).
	• Intravenous bisphosphonates are effective in reducing the incidence of hypercalcemia in patients with breast cancer and known skeletal metastases.

Hypercalcemia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Treatments with restricted indications

Special circumstances

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

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