Brenner and Rector's The Kidney, 8th ed.

CHAPTER 16. Disorders of Calcium, Magnesium, and Phosphate Balance

Martin R. Pollak   Alan S.L. Yu   Eric N. Taylor



Disorders of Calcium Homeostasis, 588



Hypercalcemia, 588



Hypocalcemia, 592



Disorders of Magnesium Homeostasis, 596



Hypomagnesemia and Magnesium Deficiency, 596



Hypermagnesemia, 601



Disorders of Phosphate Homeostasis, 602



Hyperphosphatemia, 602



Hypophosphatemia, 603


The extracellular calcium concentration is tightly maintained and reflects the actions of multiple hormones (including parathyroid hormone [PTH], calcitonin, and vitamin D) on multiple tissues (including bone, intestine, kidney, and parathyroid). This homeostatic system is modulated by dietary and environmental factors (including vitamins, hormones, medications, and mobility). Disorders of extracellular calcium homeostasis may be regarded as perturbations of this homeostatic system, either at the level of the genes controlling this system (as in, for example, familial hypocalciuric hypercalcemia, pseudohypoparathyroidism, or vitamin D-dependent rickets) or perturbations of this system induced by nongenetic means (as in lithium toxicity or postsurgical hypoparathyroidism).

The normal total extracellular calcium concentration is 9 mg/dL to 10.5 mg/dL. Approximately 50% of serum calcium is bound to serum proteins, a small amount is complexed to anions, and the remainder exists as free ionized calcium. It is the ionized calcium concentration that is pathophysiologically relevant. Alterations in blood pH can alter ionized calcium: acidosis decreases Ca2+/albumin binding; alkalosis increases it. Although in most instances an alteration in ionized calcium is reflected by altered total calcium, such may not be the case when an abnormality in serum protein concentrations is present.[1] A useful rule is to add 0.8 mg/dL for every 1 mg depression in serum albumin below 4 mg/dL to “correct” for hypoalbuminemia.


Hypercalcemia results from an alteration in the net fluxes of extracellular calcium at the organs responsible for calcium homeostasis: bone, gut, and kidney. Most commonly, increased osteoclastic bone resorption is responsible, as in hyperparathyroidism (HPT) or excess parathyroid hormone-related protein (PTHrP) production in malignancy. Excess circulating 1,25-dihydroxyvitamin D (1,25[OH]2D) from various causes also may contribute to excess bone resorption. Increased intestinal calcium absorption may lead to the development of hypercalcemia, as in vitamin D overdose or milk-alkali syndrome. In general, the kidney does not contribute to hypercalcemia; rather, it defends against the development of hypercalcemia. Typically, hypercalciuria precedes hypercalcemia. Extracellular calcium itself in fact appears to have a calciuric effect on the renal tubule by its direct action on the calcium-sensing receptor (CaR) of the thick ascending limb (TAL). Thus, in most hypercalcemic states, renal calcium handling is subject to competing influences: excess PTH or PTHrP acts on the PTH/PTHrP receptor to promote renal calcium reabsorption; excess calcium acts on the calcium receptor to promote calcium excretion.[2]

In rare cases, the kidney can actively contribute to the development of hypercalcemia. As opposed to primary HPT and humoral hypercalcemia of malignancy, where increases in renal calcium excretion are observed, renal calcium excretion is not elevated in familial hypocalciuric hypercalcemia because of a defective renal response to calcium itself. The hypercalcemia associated with thiazide use is also mediated by the kidney: in both thiazide use and its genetic counterpart Gitelman syndrome,[3] renal calcium excretion is decreased. Hypercalcemia is common, with an annual incidence in the population estimated to be on the order of 0.1% to 0.2% and a prevalence of about 1%. [4] [5] [6]

Signs and Symptoms

The clinical manifestations of hypercalcemia relate more to the degree of hypercalcemia and rate of increase than the underlying cause. Neuromuscular sequelae are common, as are altered mental status, depression, fatigue, and muscle weakness. Frequently observed gastrointestinal complications include constipation, nausea, and vomiting. Peptic ulcer disease is a rare complication; pancreatitis is exceedingly rare. Even very mild hypercalcemia may be of clinical significance inasmuch as some studies have suggested an increased cardiovascular risk from quite mild, but prolonged calcium elevations.[7]

Hypercalcemia causes polyuria and polydipsia, and significant hypercalcemia can lead to severe dehydration. Nephrolithiasis and nephrocalcinosis are common complications of hypercalcemia seen in 15% to 20% of cases of primary HPT. Hypercalcemia causes a shortened QT interval on electrocardiograms as a result of an incre-ased rate of cardiac repolarization. Heart block and other arrhythmias also may be observed.


Primary HPT and malignancy-associated hypercalcemia are responsible for the vast majority of cases of hypercalcemia, each contributing roughly an equal number. It is generally easy to differentiate these two entities. Hypercalcemia is only rarely an early finding in occult malignancy. PTH levels are essential in the diagnosis of hypercalcemia. In primary HPT, serum PTH is usually frankly elevated; in malignancy-associated hypercalcemia and in most other causes, PTH levels are low. In addition, PTHrP can now be assayed by commercial clinical laboratories; an elevated PTHrP level indicates humoral hypercalcemia of malignancy (although some forms of malignancy-associated hypercalcemia are not mediated by this circulating hormone).

Approximately 10% of cases of hypercalcemia are due to other causes. Of particular importance in the evaluation of a hypercalcemic patient are the family history (because of familial syndromes, including multiple endocrine neoplasia type I [MEN-I], MEN-II, and familial hypocalciuric hypercalcemia), medication history (because of the several medication-induced forms of hypercalcemia), and the presence of other disease (such as granulomatous or malignant disease).


Primary Hyperparathyroidism

Primary HPT is caused by excess PTH secretion and consequent hypercalcemia and hypophosphatemia ( Table 16-1 ). It is the underlying cause of approximately 50% of hypercalcemic cases. Its manifestation has shifted markedly over the past half century as measurement of serum calcium has become routine. Thus, the diagnosis is now usually suggested by the incidental finding of hypercalcemia rather than any of the sequelae of PTH excess or marked hypercalcemia. Hypercalcemia may be quite mild and intermittent. The estimated prevalence of HPT is on the order of 1%, but may be as high as 2% in postmenopausal women. [6] [8] The annual incidence is approximately 0.03% to 0.04%. [8] [9] [10] Most individuals (95%) have four parathyroid glands located adjacent to the thyroid. A single enlarged parathyroid gland is the cause of primary HPT in 80% to 90% of cases.

TABLE 16-1   -- Causes of Hypercalcemia






Primary hyperparathyroidism















Humoral hypercalcemia



Lytic bone disease



Ectopic 1,25(OH)2vitamin D production



Less common



Inherited disease



Multiple endocrine neoplasia type I, II



Familial hypocalciuric hypercalcemia






Granulomatous disease



Drug induced






Vitamin D












Vitamin A



Milk-alkali syndrome



Non-parathyroid endocrinopathies






Renal failure



Neonatal hypercalcemia




Most cases of primary HPT are due to a single benign adenoma, whereas in about 15% of cases, four-gland hyperplasia is responsible. The disease is about three times more common in women than men. The genetic alterations underlying parathyroid adenomas are being elucidated. Rearrangements and overexpression of the PRAD-1/cyclin D1 oncogene have been observed in about one fifth of parathyroid adenomas. [11] [12] The MEN-I gene menin is inactivated in about 15% of adenomas. [13] [14] Other chromosomal regions may also harbor parathyroid tumor suppressor genes.[15]

Substantial controversy surrounds the potential relation between primary HPT and increased mortality. Some data suggest that primary HPT may be associated with hypertension, [16] [17] dyslipidemia,[18] diabetes,[19] increased thickness of the carotid artery,[20] and increased mortality, [21] [22] [23] [24] primarily from cardiovascular disease. [25] [26] The morbidity from primary HPT can be substantial. Although the usual manifestation is the incidental finding of hypercalcemia, primary HPT may be associated with altered mental status, depression, joint pain, or constipation.

The classic bone lesion in primary HPT, osteitis fibrosa cystica, is now rarely seen. Diffuse osteopenia is more common.[27] Even in asymptomatic patients, increased rates of bone turnover are always present.[28]

Standard therapy for primary HPT remains surgery.[29] It is generally agreed that parathyroidectomy is indicated in patients with severe hypercalcemia, bone disease, or symptoms. In 2002, a National Institutes of Health consensus conference updated guidelines for the management of asymptomatic HPT.[29] Surgery was suggested for individuals with serum calcium levels greater than 1 mg/dL above normal, a history of life-threatening hypercalcemia, renal insufficiency, kidney stones, reduced bone mass, or hypercalciuria (∼400 mg calcium per 24 hours). Medical surveillance was considered a reasonable alternative for individuals older than 50 years with no obvious symptoms. Such patients should receive close follow-up, including periodic measurements of bone density, renal function, and serum calcium. Although surgery remains the definitive treatment, calcimimetic agents hold promise as a potential treatment. [30] [31] [32] Modern surgical techniques make parathyroidectomy safe even in elderly individuals.[32a]

Preoperative localization of the parathyroid glands has generally been considered unnecessary in uncomplicated patients undergoing surgery for the first time. However, there is increasing enthusiasm for the use of technetium 99m scintigraphy for preoperative localization of parathyroid adenomas.[29] If a single adenoma is visualized, minimally invasive parathyroidectomy may be an option: this procedure requires the surgeon to visualize only one gland as long as resection results in a substantial intra-operative decline in PTH. Otherwise, all four parathyroid glands should be surgically identified. Although excision of a single enlarged gland is curative, the finding of more than one enlarged gland raises the possibility of diffuse parathyroid hyperplasia and MEN. When all glands are enlarged, removal of 3½ glands or all 4 glands with forearm autotransplantation of a portion of the gland is advocated.[33]Recurrence of HPT is rare after identification and removal of one enlarged gland.[34]

If the initial exploration failed and hypercalcemia persists or recurs, preoperative parathyroid localization should be performed.[29] Techniques used include ultrasound, arteriography, magnetic resonance imaging, venous sampling, intraoperative PTH monitoring, and technetium sestamibi scanning. Complications are greater with re-exploration of the neck than after the initial operation.


Although estimates vary, parathyroid carcinoma probably accounts for less than 1% of primary HPT.[35] The diagnosis of parathyroid carcinoma may be difficult to make in the absence of metastases because the histologic appearance may be similar to that of atypical adenomas.[36] In general, parathyroid carcinoma is not aggressive, and survival is common if the entire gland can be removed.[37] Mutations of the HRPT2 tumor suppressor gene likely play an important role in the pathogenesis of parathyroid carcinoma.[38]


Humoral hypercalcemia of malignancy (HHM) generally refers to the syndrome of malignancy-associated hypercalcemia caused by secretion of PTHrP. HHM accounts for approximately 80% of cases of hypercalcemia-associated malignancy. Numerous types of malignancies are associated with HHM and secretion of PTHrP, including squamous, renal cell, breast, and ovarian carcinomas. Lymphomas associated with human T-lymphotropic virus type I (HTLV-I) infection may cause PTHrP-mediated HHM, and other non-Hodgkin lymphomas may be associated with PTHrP-mediated hypercalcemia as well.[39] Patients are hypercalcemic and hypophosphatemic and demonstrate increased osteoclastic bone resorption, increased urinary cyclic adenosine monophosphate (cAMP), and hypercalciuria. Malignancy is generally advanced at the time of diagnosis of HHM. HHM is not typically a manifestation of occult malignancy.

PTHrP is a large protein encoded by a gene on chromosome 12; it is similar to PTH only at the NH2 terminus, where the initial eight amino acids are identical.[40] PTHrP is widely expressed in a variety of tissues, including keratinocytes, mammary gland, placenta, cartilage, nervous system, vascular smooth muscle, and various endocrine sites.[41] PTH and PTHrP interact with the PTH receptor with equal affinity. Injection of PTHrP produces hypercalcemia in rats[42] and essentially reproduces the entire clinical syndrome of HHM, but other circulating factors such as cytokines may also be important. Normal circulating levels of PTHrP are negligible; it is probably unimportant in normal calcium homeostasis. However, mice with a targeted disruption in the PTHrP gene show a lethal defect in bone development,[43] thus demonstrating its importance in normal physiology.

Other forms of malignancy-associated hypercalcemia may be humoral in nature. Malignant lymphomas have been reported to produce 1,25(OH)2D [45] [46] [47] in sufficient quantity to lead to elevated levels and hypercalcemia secondary to bone resorption and increased intestinal calcium absorption. Ectopic production of PTH itself by a nonparathyroid tumor may occur, but it is rare.[47]

Bone is a frequent site of metastatic disease. Osteolytic metastases may produce severe pain, pathologic fractures, and hypercalcemia. Advanced breast and prostate cancer almost invariably spreads to bone. Hypercalcemia in breast cancer is associated with the presence of both extensive osteolytic metastases and HHM. Bisphosphonate administration is effective therapy for this form of hypercalcemia. In many cancers, bisphosphonates delay the appearance of skeletal complications of metastatic disease,[48] but research on the possible antitumor activity of this class of medication has produced conflicting results.[49]

Extensive bone destruction is seen in multiple myeloma.[50] Although bone lesions develop in all patients with myeloma, hypercalcemia does not develop in every patient, and the degree of hypercalcemia and bone destruction do not correlate well.[51] Some degree of renal impairment is common in multiple myeloma, and hypercalcemia rarely develops in the absence of any renal insufficiency. Conversely, hypercalcemia is a common cause of renal insufficiency in myeloma patients. Treatment with bisphosphonates appears to protect against the development of skeletal complications (including hypercalcemia) in patients with myeloma and lytic bone lesions.[52]

Inherited Disease

Familial Hyperparathyroid Syndromes

Familial isolated hyperparathyroidism (FIHP) and familial hypocalciuric hypercalcemia (FHH) (see later) are the major nonsyndromic familial hypercalcemic disorders. Both can cause mild hypercalcemia, and both follow autosomal dominant transmission. Because their treatment is different, correct diagnosis is important. FIHP is characterized by hypercalcemia, elevated levels of PTH, and parathyroid tumors in one or more glands. More than 70 families with FIHP have been reported.[53]

The genes involved in syndromic forms of hyperparathyroid disease (see later) also appear to be responsible for some cases of parathyroid-limited familial disease.[54] Some patients with FIHP have a defect on chromosome 1 similar to that in the familial hyperparathyroidism-jaw tumor syn-drome (HRPT2 gene),[55] but the majority do not.[56] In addition, mutations in the MEN1 gene may explain some cases of FIHP. [58] [59]

Jansen-type metaphyseal chondrodysplasia is a rare disorder characterized by bone deformity (chondrodysplasia), dwarfism, and severe hypercalcemia. PTH and PTHrP levels are undetectable. The cause of this disease has been shown to be constitutive activation of the PTH/PTHrP receptor. [60] [61]

Multiple Endocrine Neoplasias

MEN-I is the most common form of familial HPT.[61] It is an autosomal dominant disorder characterized by tumors of the parathyroid gland, pituitary, and pancreas. Primary HPT is almost always present, whereas pancreatic and pituitary tumors are more likely to be absent. Primary HPT is caused by diffuse hyperplasia of all four glands in most cases. Treatment of the HPT is surgical: subtotal parathyroidectomy or total parathyroidectomy with autotransplantation of a portion of the excised parathyroid gland in the forearm.

The gene defect in MEN-I was mapped by linkage analysis to chromosome 11q13.[62] The responsible gene has been identified[63] and is termed menin; it encodes a 610 amino acid nuclear protein peptide without obvious similarity to known proteins.[64] Genetic evidence suggests that menin is a tumor suppressor gene.[65] A large number of distinct mutations have been described.[66]

MEN-IIA is also characterized by parathyroid hyper-plasia and autosomal dominant inheritance. Associated findings are medullary thyroid carcinoma in all cases and pheochromocytoma in many, either of which may be lethal. Linkage analysis localized the gene defect to chromosome 10, and the RET proto-oncogene, which encodes a tyrosine kinase, has been identified as the MEN-IIA gene.[67] Within affected kindreds, genetic testing is supplanting calcitonin assays to aid in presymptomatic diagnosis and early treatment.[68] Diagnosis and management of MEN-I and MEN-II differ; these differences are summarized in an international consensus report.[69]

Hyperparathyroidism-jaw tumor syndrome is a rare autosomal dominant disorder characterized by severe hypercalcemia, parathyroid adenoma, and fibro-osseous jaw tumors.[70] The responsible gene, HRPT2, is a tumor suppressor gene located on chromosome 1q25-32.[71]

Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism

Familial benign hypercalcemia (FHH) is a rare inherited condition with autosomal dominant inheritance.[72] The hypercalcemia is typically mild to moderate (10.5 mg/dL to 12 mg/dL), and affected patients do not exhibit the typical complications associated with elevated serum calcium concentrations. Both total and ionized calcium concentrations are elevated, but the PTH level is generally “inappropriately normal,” although mild elevations have also been reported. Urinary calcium excretion is not elevated, as would be expected in hypercalcemia of other causes. The renal calcium-to-creatinine clearance ratio is usually less than 0.01. Bone mineral density is normal, as are vitamin D levels.

In most families with FHH, the disease is due to inactivating defects in the extracellular calcium receptor (CaR) located on chromosome 3q. CaR is widely expressed in mammalian tissues. In the kidney, CaR is expressed throughout the nephron, but particularly strongly in the TAL. The fact that relative hypocalciuria persists even after parathyroidectomy in FHH patients confirms the role of CaR in regulating renal calcium handling.[73] Inactivating mutations, most of which are missense, have been found throughout the large predicted structure of the CaR protein. [75] [76] Expression studies of mutant CaRs have shown great variability in their effect on calcium responsiveness . In some cases, CaR mutations only slightly shift the set-point of half-maximal response to calcium; other mutations appear to render the receptor largely inactive. [77] [78] [79] In about 15% of cases, CaR mutations have not been found in patients with typical features of FHH. In some of these cases, CaR mutations may be in noncoding sequence; in others, different gene defects may be responsible. Thus, mutational analysis is not yet a tool for clinical diagnosis of FHH. Differentiating primary HPT from FHH is critically important because the hypercalcemia in FHH is benign and does not respond to subtotal parathyroidectomy.

Two copies of CaR alleles bearing inactivating mutations cause neonatal severe hyperparathyroidism (NSHPT). This rare disorder, most often reported in the offspring of consanguineous FHH parents, is characterized by severe hyperparathyroid hyperplasia, PTH elevation, and elevated extracellular calcium. [80] [81] [82] In a few affected infants, only one defective allele has been found, but it is unclear whether the finding of only one defective allele is due to the presence of an undetected defect in the other CaR allele. Treatment is total parathyroidectomy followed by vitamin D and calcium supplementation. This disease is usually lethal without surgical intervention.


Hypercalcemia is a long-recognized and well-described consequence of lithium therapy.[82] Series of lithium-treated patients report about 5% to 10% with hypercalcemia, often with elevated PTH levels. Lithium probably acts through an interaction with the extracellular CaR to alter the set-point for PTH secretion in relation to extracellular calcium. [84] [85] The effect of lithium on PTH function occurs immediately. Hypercalcemia is reversible in most patients after discontinuing lithium, although lithium-independent hyperparathyroidism may develop after prolonged treatment.[85]

Vitamin A intoxication, on the order of 100,000 U/day, may cause hypercalcemia, presumably from increased osteoclast-mediated bone resorption. [87] [88] Vitamin A analogs, used in the management of dermatologic and hematologic malignant disease, have also been reported to cause hypercalcemia. [89] [90] Estrogens (and antiestrogens) used in the management of breast cancer may rarely cause hypercalcemia.[90]

Hypercalcemia is a well-recognized complication of thiazide diuretics. [92] [93] Although these agents clearly have a hypocalciuric effect, it is not clear whether the renal action alone is responsible for the hypercalcemia observed. [94] [95] Because thiazides may exacerbate borderline hypercalcemia of other causes, severe hypercalcemia in a thiazide-treated patient should prompt further investigation. Theophylline has been reported to cause mild hypercalcemia,[95] but the cause is not known.

Milk-Alkali Syndrome

The syndrome of hypercalcemia, alkalosis, and renal insufficiency caused by the ingestion of large amounts of calcium and antacids is known as the milk-alkali syndrome.[96] As calcium supplementation in the form of calcium carbonate has become popular, the incidence of milk-alkali syndrome has increased: in some reports it is now the third leading cause of hypercalcemia after primary hyperparathyroidism and malignancy, accounting for up to 12% of cases. [98] [99] The pathogenesis of the milk-alkali syndrome is unclear, and requires the ingestion of much more calcium than contained in a normal calcium-supplemented diet, on the order of 5 g/day. In susceptible individuals, increased alkali intake, hypercalcemia, and a concomitant reduction in GFR engender a metabolic alkalosis that inhibits renal calcium excretion[99] and further perpetuates the syndrome. The diagnosis is made largely by the history and may not be obvious because of atypical dietary sources of calcium and alkali.

Vitamin D Intoxication

Hypercalcemia may develop in individuals ingesting vitamin D or vitamin D analogs, including 1,25(OH)2D.[100] Hypercalcemia has been caused by accidental overdose of vitamin D from fortified cow's milk,[101] and an outbreak of hypercalcemia and hypervitaminosis D from fortified milk has been reported.[102] Serum 25(OH)D is elevated and immunoreactive parathyroid hormone (iPTH) is depressed in this setting. However, vitamin D well in excess of the normal recommended daily allowance is required for this form of hypercalcemia to develop. The diagnosis is made by the history and detection of elevated 25(OH)D levels. Treatment consists of calciuresis, volume expansion, and if necessary, glucocorticoids.


Although the mechanism is not well understood, immobilization can produce increased rates of bone resorption, decreased rates of bone formation, and hypercalcemia.[103] Typically, this entity is seen days to weeks after start of complete bed rest. The hypercalcemia is reversible with resumption of activity. Biochemically, this form of hypercalcemia is characterized by low PTH and 1,25(OH)2D levels. Bisphosphonates may help decrease the hypercalcemia and osteopenia in this setting.[104]

Granulomatous Disease

Hypercalcemia is a frequent complication of sarcoidosis and occurs in 10% of patients; hypercalciuria is more common and is seen in up to 50% of patients during the course of their disease.[105] Patients with sarcoidosis often have increased sensitivity to vitamin D, and hypercalcemia may develop in normocalcemic patients after minimally increased intake of vitamin D or sunlight exposure. The cause of hypercalcemia is increased production of 1,25(OH)2D from nonrenal sites.[106] Macrophages from sarcoid granulomas may 1-hydroxylate 25(OH)D to produce calcitriol.[107] Bone mineral content tends to be reduced in these patients. Serum calcium should be measured, but hypercalciuria may precede hypercalcemia and may be an earlier indicator of this complication. Standard treatment consists of administration of glucocorticoids, which decreases the abnormal 1,25(OH)2D production.[108]Chloroquine and ketoconazole, which also decrease 1,25(OH)2D production, have likewise been shown to be efficacious. [110] [111]

Other granulomatous disorders are also associated with altered vitamin D metabolism and hypercalcemia.[111] Leprosy, silicone-induced granulomas, disseminated candidiasis, disseminated coccidioidomycosis, acquired immune deficiency syndrome (AIDS) with pulmonary Pneumocystis carinii infection, and Wegener granulomatosis have all been reported to cause this syndrome. The development of hypercalcemia in patients with pulmonary tuberculosis is frequently mentioned, but most studies of infected patients in fact suggest it to be a rare problem.[112]

Nonparathyroid Enodcrinopathies

Mild hypercalcemia is common in thyrotoxicosis.[113] Bone turnover is increased and PTH and 1,25(OH)2D levels are decreased.[114] Pheochromocytoma may be associated with hypercalcemia[115]; most commonly, it is due to coincident PTH and MEN-IIA. Adrenal insufficiency,[116] pancreatic islet cell tumors,[117] growth hormone administration,[118] and acromegaly[119] have all been associated with hypercalcemia.

Childhood Hypercalcemia

Williams syndrome is an inherited disorder with a frequency of 1 in 10,000 that is manifested in infancy as supravalvular aortic stenosis, elfin facial features, and hypercalcemia.[120] The hypercalcemia is generally self-limited. Deletions at the elastin locus on chromosome 7 seem to be responsible for this disease,[121] but the cause of the hypercalcemia is unknown. Childhood HPT is rare; a severe recessive form of HPT results from mutations in CaR (see earlier). Infantile subcutaneous fat necrosis, caused by perinatal problems, may be associated with hypercalcemia mediated by abnormal vitamin D metabolism.[122]

Management of Hypercalcemia

Whereas treatment of chronic hypercalcemia ultimately depends on therapy specific to the underlying cause, immediate therapy is required for patients with acute severe hypercalcemia (or an acute worsening of chronic hypercalcemia). Immediate measures are generally not called for with asymptomatic mild or moderate calcium elevations.[123] Other considerations may be relevant to the decision to initiate aggressive therapy (is the cause of the hypercalcemia reversible, or is it a result of a terminal condition such as widely metastatic cancer?).

Some degree of volume depletion is almost always present with severe hypercalcemia (∼14 mg/dL). Volume repletion and induction of saline diuresis are central to successful therapy ( Table 16-2 ). Generally, large volumes of 0.9% sodium chloride are administered intravenously to increase urine calcium excretion. Loop diuretics given concurrently can increase the calciuresis by inhibiting calcium reabsorption in the TAL. Thiazide diuretics, which have a hypocalciuric effect, are not appropriate. Care must be taken to monitor the patient's volume status closely during the administration of large amounts of saline and diuretic, particularly in hospitalized patients with cardiac or pulmonary disease.

TABLE 16-2   -- Management of Hypercalcemia


Saline diuresis



Gallium nitrate






Correction of underlying cause(s)









Discontinue contributing medications







Bisphosphonates are pyrophosphate analogs with a high affinity for hydroxyapatite. These compounds inhibit osteoclast function in areas of high bone turnover.[124] Newer-generation bisphosphonates such as pamidronate and clodronate are more potent than etidronate at blocking osteoclastic bone resorption and do not cause significant demineralization as etidronate does at high doses.[104] A single intravenous dose of 30 mg to 90 mg may be effective in normalizing the serum calcium level for many weeks. These drugs appear to be particularly efficacious in patients with breast cancer. Fever is observed in about one fifth of patients. Zoledronic acid may be more effective than pamidronate as treatment of hypercalcemia.[125]

The thyroid C cell-derived polypeptide calcitonin is an effective inhibitor of osteoclast bone resorption. It has a rapid onset, but its effect is transient. Given as 4 to 8 U salmon calcitonin per kilogram subcutaneously, this drug has minimal toxicity but is of limited use as sole therapy for hypercalcemia.[126]

Gallium nitrate inhibits bone resorption by increasing the solubility of hydroxyapatite crystals. It is given as a 5-day infusion, and the hypocalcemic effect is not generally observed until the end of this period. Gallium nitrate is effective, but can be nephrotoxic. [128] [129] Other therapies for hypercalcemia, such as Plicamycin, chelation with EDTA, and intravenous phosphate, have adverse side effect profiles and are no longer recommended.

Glucocorticoids are useful therapy for hypercalcemia of a specific subset of causes. It is most effective in hematologic malignancies (multiple myeloma, Hodgkin disease) and disorders of vitamin D metabolism (granulomatous disease, vitamin D toxicity). [109] [130]

In severely hypercalcemic patients, hemodialysis or peritoneal dialysis with a low- or no-calcium dialysate is an effective treatment and should be regarded as a first-line therapy for chronic dialysis patients. [131] [132] Therapies for the management of hypercalcemia continue to evolve. Noncalcemic analogs of calcitriol, such as 22-oxacalcitriol, may reduce the release of PTHrP in patients with HHM.[132] Manipulation of the Ca2+/PTH response with calcimimetic agents such as cinacalcet holds promise as a treatment for primary and secondary HPT. [30] [31] [32] [133] [133]


At any given subnormal extracellular calcium level, the clinical manifestations may vary greatly ( Table 16-3 ). The marked chronic hypocalcemia commonly seen in chronic dialysis patients, for example, is frequently asymptomatic. When present, symptoms of chronic hypocalcemia are predominantly neurologic and neuromuscular. The most common clinical manifestations are muscle cramps and numbness in the digits. Severe hypocalcemia can cause laryngeal spasm, carpopedal spasm, bronchospasm, seizures, and even respiratory arrest. Mental changes include irritability, depression, and decreased cognitive capacity. The electrocardiogram may show shortening of the QT interval and arrhythmias. Overt heart failure is seen rarely.[133] Bedside signs of hypocalcemia include ipsilateral facial muscle twitching in response to tapping the facial nerve (Chvostek sign) and carpal spasm induced by brachial artery occlusion (Trousseau sign). The Chvostek sign is often present in the absence of hypercalcemia; both these well-known signs are often negative in hypocalcemic patients. Long-standing hypocalcemia may result in dry skin, coarse hair, alopecia, and brittle nails. Teeth can be absent or hypoplastic. Calcifications of the basal ganglia and cerebral cortex may be detected by computed tomography in chronic hypocalcemia.[134] Bone disease may be observed, but its findings differ in the various causes of hypocalcemia (see later).

TABLE 16-3   -- Major Inherited or Genetic Disorders Affecting Parathyroid Hormone Secretion or Responsiveness

Isolated hypercalcemia


MIM 145980, 601199


MIM 239200


MIM 145000

Syndromic hypercalcemia


MIM 13100


MIM 171400


MIM 145001


MIM 168468

Isolated hypocalcemia


MIM 146200, 601199

 PTH gene

MIM 168450

 PsHP Ib

MIM 603233

 X-linked (HYPX)

MIM 307700

Syndromic hypocalcemia

 PsHP Ia (AHO)

MIM 103580

 Autoimmune polyglandular syndrome I

MIM 240300

 DiGeorge (DGS)

MIM 188400

 Barakat syndrome

MIM 146255

 Kenny-Caffey syndrome

MIM 127000

 Kearns-Sayre syndrome

MIM 530000

 Hypoparathyroidism with short stature, mental retardation

MIM 241410


ADH, antidiuretic hormone; AHO, Albright hereditary osteodystrophy; FHH, familial hypocalciuric hyper-calcemia; FIHP, familial isolated hyperparathyroidism; HPT-JT, hyperparathyroidism-jaw tumor syndrome; MEN, multiple endocrine neoplasia; MIM, mendelian inheritance in man number; NSHPT, neonatal severe hyperparathyroidism; PsHP, pseudohypoparathyroidism; PTH, parathyroid hormone.




Ionized calcium is the pathophysiologically relevant biochemical measurement. Although total calcium generally reflects the ionized level, this measurement may be altered in chronic illness, where hypoalbuminemia may lead to decreased total calcium but normal ionized calcium measurements. Clinicians also should be aware of pseudohypocalcemia: some gadolinium-based contrast agents used in magnetic resonance angiography interfere with colorimetric assays for calcium, resulting in a marked reduction in the measured calcium concentration.[135]

The most common causes of hypocalcemia in the nonacute setting are hypoparathyroidism, hypomagnesemia, renal failure, and vitamin D deficiencies ( Table 16-4 ). These entities should be considered early in the diagnosis of hypocalcemic individuals. It is conceptually and clinically useful to subclassify hypocalcemic individuals into those with elevated PTH levels and those with either subnormal or “inappropriately normal” PTH concentrations, as in primary hypoparathyroidism. A thorough medical history and physical examination are diagnostically important because hypocalcemia can be caused by postsurgical, pharmacologic, inherited, developmental, and nutritional problems, in addition to being part of complex syndromes.

TABLE 16-4   -- Major Clinical Features of Hypocalcemia

Neuromuscular irritability







Prolonged QT interval on ECG




Genetic Disorders of Parathyroid Hormone Dysfunction or Altered Responsiveness

Calcium Receptor Mutations

The most proximal component of the PTH axis is extracellular calcium itself, which regulates PTH activity by interaction with the extracellular CaR on the surface of parathyroid cells ( Table 16-5 ). Just as defects in this receptor at the gene level can make the parathyroid gland hyporesponsive to calcium (as in FHH and NSHPT, discussed earlier), mutations in CaR can also activate CaR or cause CaR to be hyperresponsive to extracellular calcium.[136] The phenotype seen is essentially the opposite of FHH and has been termed both autosomal dominant hypoparathyroidism and autosomal hypocalcemia. CaR mutations associated with this phenotype continue to be reported both in familial cases and in isolated individuals presumed to have de novo mutations.[75]

TABLE 16-5   -- Causes of Chronic Hypocalcemia






Altered Ca2+/PTH set-point (CaR mutations)



PTH gene defects






Neck irradiation



Infiltrative disease






Autoimmune disease



Parathyroid hormone resistance















Vitamin D deficiency



Altered vitamin D metabolism



Drug induced




Individuals with this condition typically have mildly or moderately depressed serum calcium concentrations, low or “inappropriately normal” PTH levels, and occasionally, hypomagnesemia. Urine calcium concentrations are greater than in hypoparathyroidism of other causes, almost certainly because of the effect of an activated renal CaR. Management of the hypocalcemia with vitamin D and calcium supplementation in these patients can result in frank hypercalciuria and nephrocalcinosis.[137] Thus, medical intervention is warranted only for patients with severe symptomatic hypocalcemia. CaR mutations probably represent the most common cause of genetic hypoparathyroidism.[138]

Parathyroid Hormone Gene Abnormalities

Although most patients with familial hypoparathyroidism do not appear to have defects in the pre-pro-PTH gene,[139] both autosomal dominant and recessive inheritance of hypoparathyroidism has been reported in families with PTH gene mutations. [144] [145]

X-Linked Hypoparathyroidism

An X-linked form of hypoparathyroidism has been described. The apparent absence of parathyroid tissue in affected patients suggests a role for the responsible gene in parathyroid development: the SOX3 gene recently has been implicated.[142]

Syndromic Hypoparathyroidism

Patients with DiGeorge syndrome exhibit heart defects, thymic aplasia, facial anomalies, and neonatal hypoparathyroidism[143] resulting from defective third and fourth branchial pouch development. Most cases are sporadic, but autosomal dominant families have been observed.[144] Chromosome 22q11 mutations are the most common cause, but several other chromosomal abnormalities have also been associated with DiGeorge syndrome. The phrase CATCH22 has been introduced to describe the syndrome of cardiac anomalies, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia associated with chromosome 22 deletions. These deletions generally contain several genes, and although the precise genetic etiology of the DiGeorge syndrome and CATCH22 remains the subject of active investigation, the Tbx1 gene appears to play a major role.[145] Symptomatic hypocalcemia may be the major clinical feature of chromosome 22 deletions.[146] Hypoparathyroidism also occurs in several disorders of mitochondrial dysfunction[147] and in the autoimmune polyendocrinopathy known as APECED[148] (see later). Kenny-Caffey syndrome, a recessive disorder in which hypoparathyroidism is associated with osteosclerosis, mental retardation, and growth failure, has been shown to result from mutations in the TBCE gene encoding a chaperone protein important in tubulin folding.[149]

Inherited Disorders of Parathyroid Hormone Resistance

Individuals with pseudohypoparathyroidism (PsHP) are hypocalcemic because of resistance to the effects of PTH. Typically, PsHP patients have elevated PTH levels. PsHP is now recognized as a heterogeneous group of related disorders.[150] The patients first described by Albright exhibited a pattern of features that included short stature, round face, mental retardation, brachydactyly, and the lack of a phosphaturic response to parathyroid extract.

PsHP type I refers to complete resistance to the effects of PTH, as demonstrated by the failure of patients to increase serum calcium, urinary cAMP, and phosphate in response to PTH infusion.[151] The somatic features originally described (termed Albright hereditary osteodystrophy [AHO]) together with the biochemical features are referred to as PsHP type Ia. The presence of the biochemical features of PTH resistance without the somatic features (AHO) is referred to as PsHP type Ib. Patients with pseudo-pseudohypoparathyroidism (PPsHP) are not hypocalcemic, nor do they demonstrate the other biochemical feature seen in PsHP, but they do have the somatic features of AHO.

PsHP-Ia results from a loss-of-function mutation of the GNAS1 gene, which encodes the stimulatory G protein α-subunit Gsa (the PTH receptor utilizes the adenylyl cyclase pathway).[152] Promoter specific genomic imprinting of GNAS1 has been established and provides the probable explanation for the complex phenotypic expression of the dominantly inherited genetic defect. Maternal transmission of the mutation causes PsHP-Ia; paternal transmission leads to PPsHP.[153]

Like PsHP-Ia, PsHP-Ib follows autosomal dominant inheritance. The biochemical features of hypocalcemia and a defective urine cAMP and phosphaturic response to PTH are present, but the somatic features (AHO) are absent. Disease expression appears to be due to mutations that affect the regulatory elements of GNAS1. [158] [159] PsHP-Ib is maternally transmitted.

Of particular note, these three disorders are not the only clinical manifestations of GNAS gene defects. In McCune-Albright syndrome, which is characterized by endocrine hyperfunction and fibrous dysplasia, somatic mutations in GNAS lead to constitutive Gsa activity.[156] Temperature-sensitive mutations in GNAS were found in two hypocalcemic patients exhibiting resistance to some hormones (PTH, thyroid-stimulating hormone) and independence from the effects of others (luteinizing hormone) that lead to precocious puberty.[157]

Patients with PsHP type Ic exhibit the features of PsHP type I, but without defective Gsa activity or GNAS mutations. Presumably, some other component of the PTH/PTHrP receptor signaling pathway is defective.[158] PsHP type II is a heterogeneous group of disorders characterized by a reduced phosphaturic response to PTH but a normal increase in urinary cAMP.[159] The cause is unclear but may be a defect in the intracellular response to cAMP or some other component of the PTH signaling pathway. PsHP type II does not appear to follow a clear familial pattern.

Acquired Hypoparathyroidism

Surgical hypoparathyroidism is the most common cause of acquired hypoparathyroidism. It is observed after total thyroidectomy for cancer or thyrotoxicosis, radical neck dissection, and repeated operations for parathyroid adenoma removal. Hypoparathyroidism may result from inadvertent removal of the parathyroids, damage from bleeding, or devascularization. Transient hypoparathyroidism and hypocalcemia are quite common after total thyroidectomy. [164] [165] [166] They may result from a rapid reduction in thyroid hormone-mediated bone resorption or from temporary damage to the parathyroids. Removal of a single hyperfunctioning parathyroid adenoma can result in transient hypocalcemia because of hypercalcemia-induced suppression of PTH secretion from the normal glands.

Acquired hypoparathyroidism from nonsurgical causes is rare, with the exception of magnesium deficiency (see the next section). Although metal overload diseases (hemochromatosis, Wilson disease) and granulomatous or neoplastic invasion of the parathyroid are often mentioned as causes of hypoparathyroidism, these entities are quite rare. Miliary tuberculosis and amyloidosis are exceedingly rare causes of infiltrative hypoparathyroidism. Alcohol consumption has been reported to cause transient hypocalcemia.[163]

Magnesium-Related Disorders

Interestingly, both hypomagnesemia and hypermagnesemia are associated with hypocalcemia. Mg2+ is an extracellular CaR agonist, though less potent than calcium. Acute infusion of Mg or hypermagnesemia inhibits PTH secretion.[164] Chronic severe hypomagnesemia results in hypocalcemia, not from an effect on CaR but from intracellular Mg2+ depletion and its effect on PTH gland function.[165] In addition, hypomagnesemia also alters end-organ responsiveness to PTH.[166] Typically, these patients have low or inappropriately normal PTH levels for the degree of hypocalcemia observed.[167] Severe hypocalcemia is seen as a consequence of hypomagnesemia only when the Mg2+ deficiency is severe. The appropriate therapy is Mg repletion; in the absence of adequate Mg repletion, the hypocalcemia is resistant to PTH or to vitamin D therapy.

Mg2+ excess can also cause hypoparathyroidism. Clinically, this condition occurs in the acute setting. High doses of intravenous magnesium sulfate are used in obstetrics. The effect of acute hypermagnesemia may be a result of CaR-mediated inhibition of PTH secretion.[168]

Autoimmune Disease

Autoimmune disease may cause hypoparathyroidism as an isolated finding or as a component of a syndrome of multiple endocrinopathies. Type I polyglandular autoimmune syndromye , also referred to as APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome), is a recessive disorder.[169] Its cardinal features are childhood onset of hypoparathyroidism in association with adrenal insufficiency and mucocutaneous candidiasis (thus the older acronym HAM), although a great deal of clinical variability is seen. The gene for APECED, mapped to chromosome 21q in multiple families, has been identified. This gene, termed AIRE for autoimmune regulator, appears to be a transcription factor.[170]

Autoantibodies against parathyroid tissue have been reported in a significant percentage of cases of hypoparathyroidism, but the causative role of these antibodies is unclear. CaR has been identified as a possible autoantigen in some cases of autoimmune hypoparathyroidism (either isolated or polyglandular).[171]

Vitamin D-Related Disorders

Several inherited and acquired disorders of vitamin D metabolism or deficiency can lead to hypocalcemia, though usually not as an isolated finding. Because vitamin D3 is normally produced by the skin from 7-dehydrocholesterol in the presence of sunlight, vitamin D deficiency requires both dietary deficiency and lack of exposure to the sun. Prolonged vitamin D deficiency causes rickets (a disorder of mineralization of growing bone) and osteomalacia (a disorder of mineralization of formed bone). Elevation of PTH levels is generally observed.[172] The diagnosis is confirmed by measurement of serum 25(OH)D levels.

Despite routine dietary supplementation in milk and other foods, vitamin D deficiency appears to be relatively common in certain populations. A study of hospitalized patients found a high prevalence of vitamin D deficiency, even in younger patients without risk factors who were consuming the recommended daily allowance of vitamin D3.[173] Similarly, in nursing home residents with vitamin D-supplemented diets, hypovitaminosis D is common. Breast-feeding infants of mothers with diets low in vitamin D are also susceptible. In urban populations with low exposure to sunlight, vitamin D deficiency is common.

Vitamin D deficiency is a frequent complication of gastrointestinal disease.[174] Hypovitaminosis D and osteomalacia are commonly seen after gastrectomy, often occurring many years after surgery.[175] The cause of osteomalacia and hypocalcemia involves impaired absorption of vitamin D, impaired calcium absorption, increased vitamin D catabolism, and patient avoidance of milk products.

Vitamin D deficiency is seen in diseases of the intestine, including Crohn disease, celiac sprue, and intestinal resection, [180] [181] and is not uncommon. Causes may include altered enterohepatic circulation of 25(OH)D and 1,25(OH)2D. Treatment of celiac disease with appropriate dietary changes reverses the osteopenia and biochemical abnormalities.

Hepatobiliary disease is a relatively rare cause of vitamin D deficiency and osteopenia. More commonly, the hypocalcemia in this group of patients results from hypoalbuminemia. Causes of vitamin D deficiency include impaired hepatic 25-hydroxylation of vitamin D, malabsorption of vitamin D (possibly resulting from impaired bile salt synthesis), and poor nutritional status. Therapy with vitamin D and calcium is not fully effective.[178]

Vitamin D deficiency with hypocalcemia is commonly seen in patients with renal insufficiency (see Chapter 52 ) and is due in part to impaired 1a-hydroxylation of vitamin D. Patients with nephrotic syndrome may have decreased 25(OH)D levels as a result of urinary loss, hypocalcemia, and secondary HPT.[179]

Disorders of altered vitamin D metabolism represent a second group of vitamin D-related hypocalcemias. They may be acquired or inherited. Medications, most notably anticonvulsants, may interfere with the metabolism of vitamin D.[180] Phenytoin and phenobarbital appear to stimulate the conversion of 25(OH)D to inactive metabolites.[181]

The vitamin D-dependent rickets (VDDR type I and II) are hypocalcemic disorders of vitamin D metabolism. In VDDR-I, which is characterized by autosomal recessive, childhood-onset rickets, secondary HPT, and aminoaciduria, the biochemical abnormality is defective 1a-hydroxylation of 25(OH)D. The gene for 25(OH)D–1a-hydroxylase has been cloned and found to be defective in VDDR-I patients.[182]

VDDR-II (also called hereditary vitamin D-resistant rickets), like type I, is an autosomal recessive disorder. Affected patients have extreme elevations in 1,25(OH)2D levels, in addition to alopecia and the abnormalities seen in VDDR-I.[183] Biochemically, the disorder results from end-organ resistance to 1,25(OH)2D. A number of different mutations have been found in the vitamin D receptor gene of affected individuals.[184]


Medication-induced hypocalcemia is a relatively rare cause of hypocalcemia. Bisphosphonates, calcimimetics, mithramycin, and calcitonin, all of which may be used in the management of hypercalcemia or to inhibit bone resorption, may depress serum calcium to subnormal levels.

Citrate administration during transfusion of citrated blood or plasmapheresis may cause hypocalcemia. Transfusions of citrated blood rarely cause significant hypocalcemia, but it may occur in the course of massive transfusion.[185]Similarly, significant hypocalcemia occurs but is rare after plasmapheresis.[186]

Foscarnet (trisodium phosphoformate), which is used in the management of viral opportunistic infections, can cause hypocalcemia through the chelation of extracellular calcium ions, and normal total calcium measurements may not reflect ionized hypocalcemia.[187] As stated previously, anticonvulsants, particularly phenytoin and phenobarbital, appear to interfere with vitamin D metabolism.[181] Fluoride overdose is an exceedingly rare cause of hypocalcemia.

Other drugs associated with hypocalcemia include anti-infectious agents (pentamidine, ketoconazole) and chemotherapeutic agents (asparaginase, cisplatin, WR-2721, doxorubicin).

Miscellaneous Causes

Hypocalcemia is common in acute pancreatitis and is a poor prognostic indicator.[188] It is probably due to calcium chelation by free fatty acids generated by the action of pancreatic lipase. Severe hyperphosphatemia may cause hypocalcemia, particularly in patients with renal failure. This association is observed in several clinical settings. Soft tissue calcification and hypocalcemia have been reported in the management of hypophosphatemia.[189] Enemas containing phosphate and infant formulas supplemented with phosphate have been reported to cause hypocalcemia. Massive tumor lysis, particularly from rapidly growing hematologic malignancies, may cause hyperphosphatemia, hyperuricemia, and hypocalcemia.[190] The early phase of rhabdomyolysis may include severe hyperphosphatemia and associated hypocalcemia, in contrast to the recovery phase, when hypercalcemia is common. In hemodialysis patients, hypocalcemia is common and may result at least in part from reduced renal phosphate clearance and consequent hyperphosphatemia and reduced 1,25(OH)2D production (see Chapter 52 ).

Critical Illness

In complicated, critically ill patients, total calcium measurements may be poor indicators of the ionized calcium concentration because a large number of factors that may interfere with or alter calcium/protein binding may be present (albumin infusion, citrate, intravenous fluids, acid/base disturbances, dialysis therapy). Thus, it is particularly important to measure ionized calcium in this setting. In fact, hypocalcemia has been reported to be present in over 70% of intensive care unit patients.[191] Hypocalcemia is frequently noted in both gram-negative sepsis and toxic shock syndrome.[192] The cause in unknown, but a direct effect of interleukin-1 on parathyroid function may be partly responsible.[193]

Neonatal Hypocalcemia

In the first few days of life, infants normally have serum calcium levels significantly lower than normal adult levels. More severe hypocalcemia is referred to as neonatal hypocalcemia and is generally divided into early neonatal and late neonatal hypocalcemia by pediatricians.[194] Early-onset hypocalcemia, which appears in the first 3 to 4 days of life, is often associated with maternal gestational diabetes, prematurity, or other perinatal problems. The hypocalcemia may be severe enough to cause neuromuscular dysfunction, including seizures, but it is self-limited.

Late neonatal hypocalcemia, which occurs within the first 5 to 10 days of life, is rarer. It is observed in infants receiving cow's milk or infant formula with a high phosphate concentration[195]; hypomagnesemia may be responsible in some cases. Other forms of late-onset hypocalcemia may be ob-served in infants of hypercalcemic mothers, presumably as a result of secondary hypoparathyroidism in the fetus.[196]

Management of Hypocalcemia

Treatment of acute hypocalcemia depends on the severity of the depression in serum calcium and the presence of clinical manifestations. Oral calcium supplementation may be sufficient treatment for mild hypocalcemia; severe hypocalcemia with evidence of neuromuscular effects or tetany is treated with intravenous calcium. Typically, 1 g to 3 g of intravenous calcium gluconate is given over a period of 10 to 20 minutes, followed by slow intravenous infusion. Dialysis may be appropriate if hyperphosphatemia is also present. Correction of hypomagnesemia and hyperphosphatemia should also be undertaken when present.

Treatment of chronic hypocalcemia depends on the underlying cause, for instance, correction of hypomagnesemia or vitamin D deficiency. The principal therapy for primary disorders of parathyroid dysfunction or PTH resistance is dietary calcium supplementation and vitamin D therapy. Correction of serum calcium to the low-normal range is generally advised; correction to normal levels may lead to frank hypercalciuria.


Hypomagnesemia and Magnesium Deficiency

The terms “hypomagnesemia” and “Mg2+ deficiency” tend to be used interchangeably. However, there is a complex relationship between total body Mg2+ stores, serum Mg2+ concentrations, and the Mg2+ level in different intracellular compartments. Because extracellular fluid Mg2+ accounts for only 1% of total body Mg2+, it is hardly surprising that serum Mg2+ concentrations have been found to correlate poorly with overall Mg2+ status. Indeed, in patients with Mg2+ deficiency, serum Mg2+ concentrations may be normal or may seriously underestimate the severity of the Mg2+ deficit.[197] However, no satisfactory clinical test to assay body Mg2+ stores is available.

The Mg2+ tolerance test is generally thought to be the best test of overall Mg2+ status. It is based on the observation that Mg2+-deficient patients tend to retain a greater proportion of a parenterally administered Mg2+ load and excrete less in the urine than normal individuals do.[198] Studies in Mg2+-deficient rats indicate that the administered Mg2+ is rapidly diverted to non-extracellular fluid stores, so the low urinary excretion is due to a small filtered load of Mg2+ delivered to the nephron.[199] By contrast, in normal rats given intravenous Mg2+, the serum concentration and therefore the filtered load rise dramatically, and Mg2+ spills into the urine because of the “threshold” effect. Clinical studies indicate that the results of an Mg2+ tolerance test correlate well with Mg2+ status as assessed by skeletal muscle Mg2+ content and exchangeable Mg2+ pools. However, the test is invalid in patients who have impaired renal function or a renal Mg2+-wasting syndrome or in patients who are taking diuretics or other medications that induce renal Mg2+ wasting. For this reason and also because of the time and effort required to perform the Mg2+ tolerance test, it is used infrequently in clinical practice.

The serum Mg2+ concentration, though an insensitive measure of Mg2+ deficit, remains the only practical test of Mg2+ status in widespread use. Surveys of serum Mg2+ levels in hospitalized patients indicate a high incidence of hypomagnesemia (presumably an underestimate of the true incidence of Mg2+ deficiency), ranging from 11% in general inpatients[200] to 60% in patients admitted to intensive care units.[201] Furthermore, among intensive care unit patients, hypomagnesemia was associated with increased mortality when compared with patients who have normomagnesemia.[201]

Etiology and Diagnosis

Mg2+ deficiency may be caused by decreased intake or intestinal absorption; increased losses via the gastrointestinal tract, kidneys, or skin; or rarely, sequestration in the bone compartment. The first step in determining the etiology is to distinguish between renal Mg2+ wasting and extrarenal causes of Mg2+ loss by performing a quantitative assessment of urinary Mg2+ excretion. The fractional excretion of magnesium (FeMg2+) from a random urine specimen can be calculated in the standard fashion after multiplying the plasma magnesium concentration by 0.7 (because about 30% of circulating magnesium is bound to plasma protein and remains unfiltered). In general, a FeMg2+ of more than 3% in an individual with normal GFR is indicative of inappropriate urinary magnesium loss.[202] The FeMg2+ is likely superior to the urinary magnesium to creatinine molar ratio for this purpose. Alternatively, a 24-hour urine collection can be obtained: the kidneys can normally reduce the 24-hour urinary magnesium excretion to less than 24 mg in states of magnesium deficiency.[203] If renal Mg2+ wasting has been excluded, the losses must be extrarenal in origin and the underlying cause can usually be identified from the case history.

Extrarenal Causes

Nutritional Deficiency

Human Mg2+ deprivation studies have demonstrated that induction of Mg2+ deficiency by dietary means in normal individuals is surprisingly difficult because nearly all foods contain significant amounts of Mg2+ and renal adaptation to conserve Mg2+ is very efficient. Nevertheless, Mg2+ deficiency of nutritional origin can be observed, particularly in two clinical settings: alcoholism and parenteral feeding.

In chronic alcoholics, the intake of ethanol substitutes for the intake of important nutrients. Approximately 20% to 25% of alcoholics are frankly hypomagnesemic, and most can be shown to be Mg2+ deficient with the Mg2+tolerance test.[198] Of note, some evidence suggests that alcohol also may impair renal magnesium conservation.[204]

Patients receiving parenteral nutrition have a particularly high incidence of hypomagnesemia.[205] In general, these patients are sicker than the average inpatient and are more likely to have other conditions associated with an Mg2+deficit and ongoing Mg2+ losses. However, even for nutritionally replete subjects, the daily Mg2+ requirement to maintain Mg2+ balance is increased during parenteral feeding, for unclear reasons. Furthermore, hypomagnesemia may also be a consequence of the refeeding syndrome.[206] In this condition, overzealous parenteral feeding of severely malnourished patients causes hyperinsulinemia, as well as rapid cellular uptake of glucose and water, together with phosphorus, potassium, and Mg2+.

Intestinal Malabsorption

Generalized malabsorption syndromes caused by conditions such as celiac disease, Whipple disease, and inflammatory bowel disease are frequently associated with intestinal Mg2+ wasting and Mg2+ deficiency.[207] In fat malabsorption with concomitant steatorrhea, free fatty acids in the intestinal lumen may combine with Mg2+ to form nonabsorbable soaps, a process known as saponification, thus contributing to impaired Mg2+ absorption. Indeed, the severity of hypomagnesemia in patients with malabsorption syndrome correlates with the fecal fat excretion rate, and in rare patients, reduction of dietary fat intake alone, which reduces steatorrhea, can correct the hypomagnesemia. Previous intestinal resection, particularly of the distal part of the small intestine, is also an important cause of Mg2+ malabsorption[208] and a confounding factor in many studies of patients with Crohn disease. Similarly, Mg2+ deficiency can be a late complication of jejunoileal bypass surgery performed for the management of obesity.

Diarrhea and Gastrointestinal Fistula

The Mg2+ concentration of diarrheal fluid is high and ranges from 1 mg/dL to 16 mg/dL,[208] so Mg2+ deficiency may occur in patients with chronic diarrhea of any cause, even in the absence of concomitant malabsorption,[197]and in patients who abuse laxatives. By contrast, secretions from the upper gastrointestinal tract are low in Mg2+ content, and significant Mg2+ deficiency is therefore rarely observed in patients with an intestinal, biliary, or pancreatic fistula, ileostomy, or prolonged gastric drainage (except as a consequence of malnutrition).[208]

Cutaneous Losses

Hypomagnesemia may be observed after prolonged intense exertion. For example, serum Mg2+ concentrations fall 20% on average after a marathon run.[209] About a quarter of the decrement in serum Mg2+ can be accounted for by losses in sweat, which can contain up to 0.5 mg/dL of Mg2+, with the remainder most likely being due to transient redistribution into the intracellular space. Hypomagnesemia occurs in 40% of patients with severe burn injuries during the early period of recovery. The major cause is loss of Mg2+ in the cutaneous exudate, which can exceed 1 g/day.[210]

Redistribution to Bone Compartment

Hypomagnesemia may occasionally accompany the profound hypocalcemia of hungry bone syndrome observed in some patients with HPT and severe bone disease immediately after parathyroidectomy.[211] In such cases, a high bone turnover state exists, and sudden removal of excess PTH is believed to result in virtual cessation of bone resorption, with a continued high rate of bone formation and consequent sequestration of both Ca2+ and Mg2+ into bone mineral.

Renal Magnesium Wasting

The diagnosis of renal Mg2+ wasting is made by demonstrating an inappropriately high rate of renal Mg2+ excretion in the face of hypomagnesemia, as detailed previously.


Renal Mg2+ wasting occurs with osmotic diuresis, as in the severe hyperglycemic state of diabetic ketoacidosis. [216] [217] Indeed, the estimated average Mg2+ deficit at initial evaluation varies from 200 mg to 500 mg. [216] [217]Hypermagnesuria also occurs during the polyuric phase of recovery from acute renal failure in a native kidney, during recovery from ischemic injury in a transplanted kidney, and in postobstructive diuresis. In such cases, it is likely that residual tubule reabsorptive defects persisting from the primary renal injury play as important a role as polyuria itself in inducing renal Mg2+ wasting.

Extracellular Fluid Volume Expansion

Chronic therapy with Mg2+-free parenteral fluids, either crystalloid or hyperalimentation,[205] can cause renal Mg2+ wasting, in part because of expansion of extracellular fluid volume. Renal Mg2+ wasting is also characteristic of hyperaldosteronism.[214]

Defective Na Reabsorption in Distal Nephron

Loop diuretics inhibit the apical membrane Na+/K+/2Cl- cotransporter of the TAL and abolish the transepithelial potential difference, thereby inhibiting paracellular Mg2+ reabsorption. Hypomagnesemia is therefore a frequent finding in patients receiving chronic loop diuretic therapy.[215] Thiazides inhibit renal Mg2+ reabsorption by an incompletely understood mechanism. Thiazide-induced hypomagnesemia has been suggested to increase the risk of arrhythmias in hypertensive patients. However, in a cohort of participants from the Multiple Risk Factor Intervention Trial treated chronically with chlorthalidone, the degree of hypomagnesemia was clinically and statistically insignificant.[216]


Elevated serum ionized Ca2+ levels directly induce renal Mg2+ wasting and hypomagnesemia,[217] a phenomenon that is most clearly observable in the setting of hypercalcemia caused by malignant bone metastases. In HPT, the situation is more complicated because the hypercalcemia-induced tendency to Mg2+ wasting is counteracted by the action of PTH, which stimulates Mg2+ reabsorption, so renal Mg2+ handling is usually normal and Mg2+deficiency is rare.[218]

Tubule Nephrotoxins

Cisplatin, a widely used chemotherapeutic agent for solid tumors, frequently causes renal Mg2+ wasting. All patients receiving monthly cycles of cisplatin at a dose of 50 mg/m2 become hypomagnesemic during treatment.[219] The occurrence of Mg2+ wasting does not appear to correlate with the incidence of cisplatin-induced acute renal failure.[220] Renal magnesuria continues after cessation of the drug for a mean of 4 to 5 months, but it can persist for years.[220] Although the nephrotoxic effects of cisplatin are manifested histologically as acute tubular necrosis confined to the S3 segment of proximal tubule, the magnesuria does not correlate temporally with the clinical development of acute renal failure secondary to acute tubular necrosis. Furthermore, patients who become hypomagnesemic are also subject to the development of hypocalciuria, thus suggesting that the reabsorption defect may actually be in the distal convoluted tubule (DCT), as with Gitelman syndrome. Carboplatin, an analog of cisplatin, appears to be considerably less nephrotoxic and rarely causes either acute renal failure or hypomagnesemia.[221] Of interest, recent data suggest that cisplatin also may impair intestinal absorption of magnesium.[222]

Amphotericin B is a well-recognized tubule nephrotoxin that can cause renal K+ wasting, distal renal tubular acidosis, and acute renal failure, with tubule necrosis and Ca2+ deposition noted in the DCT and TAL on renal biopsy. Amphotericin B causes renal Mg2+ wasting and hypomagnesemia that is related to the cumulative dose administered, but these effects may be observed after as little as a 200 mg total dose.[223] Interestingly, the amphotericin-induced magnesuria is accompanied by the reciprocal development of hypocalciuria, so as with cisplatin, the serum Ca2+ concentration is usually preserved, again suggesting that the functional tubule defect resides in the DCT.

Aminoglycosides cause a syndrome of renal Mg2+ and K+ wasting with hypomagnesemia, hypokalemia, hypocalcemia, and tetany. Hypomagnesemia may occur despite levels in the appropriate therapeutic range.[224] Most patients reported had delayed onset of hypomagnesemia occurring after at least 2 weeks of therapy, and they received total doses in excess of 8 g, thus suggesting that it is the cumulative dose of aminoglycoside that is the key predictor of toxicity. In addition, no correlation has been found between the occurrence of aminoglycoside-induced acute tubular necrosis and hypomagnesemia. Mg2+ wasting persists after cessation of the aminoglycoside, often for several months. All aminoglycosides in clinical use have been implicated, including gentamicin, tobramycin, and amikacin, as well as neomycin when administered topically for extensive burn injuries. This form of symptomatic aminoglycoside-induced renal Mg2+ wasting is now relatively uncommon because of heightened general awareness of its toxicity. However, asymptomatic hypomagnesemia can be observed in one third of individuals treated with a single course of an aminoglycoside at standard doses (3 to 5 mg/kg/day for a mean of 10 days). In these cases, the hypomagnesemia occurs on average 3 to 4 days after the start of therapy and readily reverses after cessation of therapy.[225]

Intravenous pentamidine causes hypomagnesemia as a result of renal Mg2+ wasting in most patients, typically in association with hypocalcemia.[226] The average onset of symptomatic hypomagnesemia occurs after 9 days of therapy, and the defect persists for at least 1 to 2 months after discontinuation of pentamidine. Hypomagnesemia is also observed in two thirds of AIDS patients with cytomegalovirus retinitis treated intravenously with the pyrophosphate analog foscarnet.[227] As with aminoglycosides and pentamidine, foscarnet-induced hypomagnesemia is often associated with significant hypocalcemia.

Cyclosporine causes renal Mg2+ wasting and hypo-magnesemia in patients after renal and bone marrow transplantation. [232] [233] Mg2+ loss does not correlate either with serum trough cyclosporine levels or with the development of cyclosporin-induced renal failure. Interestingly, the development of hypomagnesemia correlates temporally with the onset and severity of neurologic symptoms such as ataxia, tremor, depression, and transient dysphasia. These symptoms had previously been attributed to direct cyclosporine neurotoxicity, but they may well be a secondary consequence of cyclosporine-induced Mg2+ deficiency. Interestingly, some studies have shown that Mg2+supplementation may help prevent cyclosporine nephrotoxicity.[230]

Tubulointestinal Nephropathies

Renal Mg2+ wasting has occasionally been reported in patients with acute or chronic tubulointerstitial nephritis not caused by nephrotoxic drugs, for example, in chronic pyelonephritis and acute renal allograft rejection. Other manifestations of tubule dysfunction, such as salt wasting, hypokalemia, renal tubular acidosis, and Fanconi syndrome, also may be present and provide clues to the diagnosis.

Inherited Renal Magnesium Wasting Disorders

Primary magnesium-wasting disorders are rare.[231] Though fairly heterogeneous, these patients can be broadly classified into distinct clinical syndromes by their genetic and phenotypic patterns ( Table 16-6 ). Genetic studies are helping to clarify the genetic and molecular etiologies and, in turn, elucidate the mechanism of renal and intestinal magnesium handling (see Chapter 5 ).

TABLE 16-6   -- Classification and Clinical Features of Inherited Renal Mg2+ Wasting Disorders


Isolated Familial Hypomagnesemia (Recessive)

Isolated Familial Hypomagnesemia (Dominant)

Hypomagnesemia with Hypocalcemia

Familial Hypomagnesemia with Hypercalciuria

MIM number





Fluid and electrolyte abnormalities


Hypocalcemia, hypercalciuria






Distal renal tubular acidosis



Nephrogenic diabetes insipidus



FXYD2, other(s)








Structural renal abnormalities


Chronic renal failure





Extrarenal manifestations

Ocular abnormalities

Pattern of inheritance






AD, autosomal dominant; AR, autosomal recessive. Urinary magnesium wasting can be observed in Gitelman and Bartter syndromes. These entities are discussed in Chapter 21 .




Isolated Familial Hypomagnesemia

Isolated familial hypomagnesemia is most commonly manifested in childhood as tetany or seizures. [236] [237] Laboratory investigation reveals hypomagnesemia with inappropriate magnesuria, but usually no other electrolyte or renal disturbances, and renal biopsy findings are normal by light and electron microscopy, as well as by standard immunofluorescence studies. Both autosomal dominant and recessive forms exist. [236] [237]

A locus for autosomal dominant hypomagnesemia was mapped to chromosome 11q23 by a genome-wide linkage scan in two large families with this condition. Subsequently, the gene responsible was identified as FXYD2, which encodes the sodium-potassium-adenosinetriphosphatase (Na+,K+-ATPase) α-subunit.[234] The absence of hypomagnesemia in individuals with large deletions at this locus suggested a gain-of-function rather than loss-of-function disease mechanism. Expression studies indicated that the identified Gly41Arg mutation may lead to defective posttranslational processing of the protein, which is expressed in the distal convoluted tubule. [238] [239] The dominant form of isolated hypomagnesemia is genetically heterogeneous: FXYD2 has been excluded as the responsible locus in a large family with dominant hypomagnesemia, low bone mass, relatively low PTH levels, and hypermagnesuria.[236] The gene responsible for the autosomal recessive form is unknown.[231]

Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesemia with hypercalciuria is characterized by renal Mg2+ wasting in association with significant hypercalciuria.[231] The major cause of morbidity in this disorder is probably the hypercalciuria, which leads to hypocalcemia and renal calculi in some cases and to nephrocalcinosis in all. In turn, nephrocalcinosis and renal stone disease are thought to be the cause of recurrent urinary tract infections, distal renal tubular acidosis (usually incomplete), nephrogenic diabetes insipidus, and progressive renal impairment, which may lead to end-stage renal failure. The tendency to tissue calcium deposition may also be manifested as calcification of the basal ganglia and chondrocalcinosis with crystal arthropathy. In addition, the condition is associated with several ocular abnormalities, including corneal calcification, chorioretinitis, keratoconus, macular colobomas, nystagmus, and myopia.

By means of a genome-wide scan in 12 families with recessive hypomagnesemia and hypercalciuria, Simon and co-workers[237] identified a locus on chromosome 3q and determined that the gene responsible was a member of the claudin family of cell junction proteins, claudin-16 (CLDNN16), also known as paracellin (PCLN1). PCLN1 is a tight-junction protein expressed only in the TAL and DCT and facilitates the passive, paracellular reabsorption of both magnesium and calcium.[238]

Affected patients show marked hypomagnesemia and hypercalciuria with associated nephrocalcinosis and progressive renal insufficiency. In studies of phenotype and genotype, affected patients were often initially evaluated in childhood for hematuria and urinary tract infections. Treatment with thiazides and magnesium supplementation did not prevent the progression of renal failure, which occurred in 11 of 33 patients at a median age of 14.5 years.[239]In these patients, a large fraction of mutant alleles shared a Leu151Phe mutation, thus suggesting a founder effect. Studies have suggested an increase in urine calcium and magnesium excretion in heterozygotes for CLDN16 mutations.

Hypomagnesemia with Hypocalcemia

Primary hypomagnesemia with hypocalcemia is inherited as an autosomal recessive trait. A locus was identified on chromosome 9q22 by genetic mapping in inbred Bedouin kindreds.[240] Subsequently, the gene responsible was identified as TRPM6, a member of the TRP family of ion channels.[241] TRPM6 is expressed in renal tubules and throughout the intestine, although the major problem appears to stem from altered intestinal magnesium absorption. TRPM6 is regulated by dietary magnesium and by estrogens.[241a]

The hypomagnesemia in this condition is severe, with seizures being a frequent finding in infants. High doses of enteral magnesium can help keep the serum calcium level near the normal range (presumably via paracellular absorption) and decrease complications.

Bartter/Gitelman Syndromes

Classic Bartter syndrome (see Chapter 15 ) is an autosomal recessive disorder characterized by Na+ wasting, hypokalemic metabolic alkalosis, and hypercalciuria, and it usually occurs in infancy or early childhood. Most Bartter syndrome kindreds result from inactivating mutations in one of the three transport proteins that mediate the TAL NaCl reabsorption/apical K+ recycling pathway, namely, the apical Na+/K+/2Cl- cotransporter (BSC1), the apical inwardly rectifying K+ channel (ROMK1), or the basolateral Cl- channel (CLC-Kb). All Bartter syndrome patients are by definition hypercalciuric, and in addition, one third has hypomagnesemia with inappropriate magnesuria, consistent with loss of the TAL transepithelial potential difference that drives paracellular divalent cation reabsorption. Thus, the physiology of Bartter syndrome is essentially identical to that of chronic loop diuretic therapy.

Gitelman syndrome (see Chapter 15 ) is a variant of Bartter syndrome that is distinguished primarily by hypocalciuria (urinary calcium-to-creatinine ratio, 0.07 mg/mg). Patients with Gitelman syndrome are identified later in life, usually after the age of 6 years, have milder symptoms, and generally have preserved urinary concentrating ability. The genetic defect in these families is caused by inactivating mutations in the DCT electroneutral thiazide-sensitive NaCl cotransporter TSC. The difference in the nephron segment site of the NaCl reabsorption defect can explain the difference between classic Bartter and Gitelman syndromes in urinary concentrating ability (NaCl reabsorption in the medullary TAL, but not the DCT, contributes to the medullary interstitium concentrating gradient) and Ca2+ excretion (NaCl reabsorption is required for generation of the driving force for Ca2+ reabsorption in the TAL, but not the DCT), and these in turn mirror the differences observed with chronic loop and thiazide diuretic therapy. Interestingly however, renal Mg2+ wasting and hypomagnesemia are universally found in patients with Gitelman syndrome.

Ca2+-Sensing Disorders

In FHH, the hypercalcemia is due to inactivating mutations in CaR (discussed earlier). As a consequence of the inactivated CaR, the normal magnesuric response to hypercalcemia is impaired,[242] and thus these patients are paradoxically mildly hypermagnesemic. Activating mutations in CaR cause the opposite syndrome, autosomal dominant hypoparathyroidism. As might be expected, most such patients are mildly hypomagnesemic, presumably because of TAL Mg2+ wasting.[137]

Clinical Manifestations

Hypomagnesemia may cause symptoms and signs of disordered cardiac, neuromuscular, and central nervous system function ( Table 16-7 ). It is also associated with an imbalance of other electrolytes such as K+ and Ca2+. However, many pa-tients with hypomagnesemia are completely asymptomatic.[243] ,Thus the clinical importance of hypomagnesemia remains controversial. Furthermore, many of the cardiac and neurologic manifestations attributed to Mg2+deficiency may also be explained by the frequent coexistence of hypokalemia and hypocalcemia in the same patient.

TABLE 16-7   -- Clinical Manifestations of Mg2+ Deficiency






Electrocardiographic abnormalities



Non-specific T wave changes



U waves



Prolonged QT and QU interval



Repolarization alternans






Ventricular ectopy



Monomorphic ventricular tachycardia



Torsades de pointes



Ventricular fibrillation



Enhanced digitalis toxicity






Muscle weakness



Muscle tremor and twitching



Positive Trousseau and Chvostek signs






Vertical and horizontal nystagmus






Generalized seizures



Multifocal motor seizures













Cardiovascular System

Mg2+ has protean and complex effects on myocardial ion fluxes, among which its effect on the sodium pump (Na+,K+-ATPase) is probably the most important. Because Mg2+ is an obligate cofactor in all reactions that require adenosine triphosphate (ATP), it is essential for the activity of Na+,K+-ATPase.[244] During Mg2+ deficiency, Na+,K+-ATPase function is impaired. The intracellular K+ concentration falls, which may potentially result in a relatively depolarized resting membrane potential, so the excitation threshold for activation of an action potential is more easily attainable and thus predisposes to ectopic excitation and tachyarrhythmias.[245] Furthermore, the magnitude of the outward K+ gradient is decreased, thereby reducing the driving force for the K+ efflux needed to terminate the cardiac action potential, and as a result, repolarization is delayed.

Electrocardiographic changes may be observed with isolated hypomagnesemia and usually reflect abnormal cardiac repolarization, including bifid T waves and other nonspecific abnormalities in T wave morphology, U waves, prolongation of the QT or QU interval, and rarely, electrical alternation of the T or U wave.[246]

Numerous anecdotal reports indicate that hypomagnesemia alone can predispose to cardiac tachyarrhythmias, particularly of ventricular origin, including torsades de pointes, monomorphic ventricular tachycardia, and ventricular fibrillation, which may be resistant to standard therapy and respond only to Mg2+ repletion.[246] Many of the reported patients also had a prolonged QT interval, an abnormality that is known to predispose to torsades de pointes and may also increase the period of vulnerability to R-on-T phenomena. In the setting of exaggerated cardiac excitability, hypomagnesemia may be the trigger for other types of ventricular tachyarrhythmias.[246] In addition, hypomagnesemia facilitates the development of digoxin cardiotoxicity.[247] Because both cardiac glycosides and Mg2+ depletion inhibit Na+,K+-ATPase, their additive effects on intracellular K+ depletion may account for their enhanced toxicity in combination.

The existence of occasional patients with clear hypomagnesemia-induced arrhythmias is undisputed. However, the magnitude of the risk for arrhythmias in patients with hypomagnesemia in general, the issue of whether mild hypomagnesemia carries the same risk as severe hypomagnesemia does, and the relative importance of Mg2+ deficiency versus coexistent hypokalemia or intrinsic cardiac disease in the pathogenesis of the arrhythmia remain highly controversial. In a frequently cited study by Dyckner[248] of 342 patients with acute myocardial infarction admitted to a coronary care unit, complex ventricular ectopy, ventricular tachycardia, and ventricular fibrillation were three times more frequent during the first 24 hours in hypomagnesemic than in patients with normomagnesemia. In a control group of patients without myocardial infarction, ventricular ectopy and arrhythmias were not associated with hypomagnesemia. The major difficulty in interpreting this study stems from the failure to control for hypokalemia, a well-established risk factor for ventricular arrhythmias. Indeed, the prevalence of hypokalemia was high (30%) in the hypomagnesemic patients with ventricular arrhythmias and exceeded its prevalence in those without arrhythmias (10%), so the serum K+ concentration was almost certainly an important confounder. The value of magnesium administration after cardiac surgery is also controversial. [254] [255]

Data on magnesium deficiency and arrhythmia in individuals without overt heart disease is provocative. In one small prospective study, low dietary magnesium appeared to increase the risk for supraventricular and ventricular ectopy despite the absence of frank hypomagnesemia, hypokalemia, and hypocalcemia.[251] In the Framingham Offspring Study, lower levels of serum magnesium were associated with higher prevalence of ventricular premature complexes.[252]

Neuromuscular System

Symptoms and signs of neuromuscular irritability, including tremor, muscle twitching, the Trousseau and Chvostek signs, and frank tetany, may develop in patients with isolated hypomagnesemia.[253] Hypomagnesemia is also frequently manifested as seizures, which may be generalized and tonic-clonic in nature or multifocal motor seizures, and they are sometimes triggered by loud noises.[253] Interestingly, noise-induced seizures and sudden death are also characteristic of mice made hypomagnesemic by dietary Mg2+ deprivation. The effects of Mg2+ deficiency on brain neuronal excitability are thought to be mediated by N-methyl-d-aspartate (NMDA)-type glutamate receptors. Glutamate is the principal excitatory neurotransmitter in the brain; it acts as an agonist at NMDA receptors and opens a cation conductance channel that depolarizes the postsynaptic membrane. Extracellular Mg2+ normally blocks NMDA receptors, so hypomagnesemia may release the inhibition of glutamate-activated depolarization of the postsynaptic membrane and thereby trigger epileptiform electrical activity.[254] Vertical nystagmus is a rare, but diagnostically useful neurologic sign of severe hypomagnesemia.[255] In the absence of a structural lesion of the cerebellar or vestibular pathways, the only recognized meta-bolic causes are Wernicke encephalopathy and severe Mg2+ deficiency.[255]

Electrolyte Homeostasis

Patients with hypomagnesemia are frequently also hypokalemic. Many of the conditions associated with hypomagnesemia that have been outlined earlier can cause simultaneous Mg2+ and K+ loss. However, hypomagnesemia by itself can induce hypokalemia in both humans and experimental animals, and such patients are often refractory to K+ repletion until their Mg2+ deficit is corrected.[256] The cause of the hypokalemia appears to be depletion of intracellular K+ as a result of impaired Na+,K+-ATPase function, together with renal K+ wasting; the K+ leaked from cells is lost in the urine.[245] The physiologic mechanism for renal K+ wasting in hypomagnesemia is unknown.

Hypocalcemia is present in approximately half of patients with hypomagnesemia.[243] The major cause is impairment of PTH secretion by Mg2+ deficiency, which is reversed within 24 hours by Mg2+ repletion.[166] In addition, hypomagnesemic patients also have low circulating 1,25(OH)2D levels and end-organ resistance to both PTH and vitamin D.[166]


Mg2+ deficiency may sometimes be prevented. Individuals whose dietary intake has been reduced or who are being maintained by parenteral nutrition should receive Mg2+ supplementation. The recommended daily allowance of Mg2+ in adults is 420 mg (35 mEq) for men and 320 mg (27 mEq) for women.[257] Thus, in the absence of dietary Mg2+ intake, an appropriate supplement would therefore be one 140 mg tablet of Mg oxide four to five times daily or the equivalent dose of an alternative oral Mg2+-containing salt. Because the oral bioavailability of Mg2+ is approximately 33% in patients with normal intestinal function, the equivalent parenteral maintenance requirement of Mg2+ would be 10 mEq daily.

Once symptomatic Mg2+ deficiency develops, patients should clearly be repleted with Mg2+. However, the importance of treating asymptomatic Mg2+ deficiency remains controversial. Given the clinical manifestations outlined earlier, it seems prudent to replete all Mg2+-deficient patients with a significant underlying cardiac or seizure disorder, patients with concurrent severe hypocalcemia or hypokalemia, and patients with isolated asymptomatic hypomagnesemia if it is severe (∼1.4 mg/dL).

Intravenous Replacement

In the inpatient setting, the intravenous route of administration of Mg2+ is favored because it is highly effective, inexpensive, and usually well tolerated. The standard preparation is MgSO4.7H2O. The initial rate of repletion depends on the urgency of the clinical situation. In a patient who is actively seizing or who has a cardiac arrhythmia, 8 mEq to 16 mEq (1 g to 2 g) may be administered intravenously over a 2- to 4-minute period; otherwise, a slower rate of repletion is safer. Because the added extracellular Mg2+ equilibrates slowly with the intracellular compartment and because renal excretion of extracellular Mg2+ exhibits a threshold effect, approximately 50% of parenterally administered Mg2+ is excreted into urine.[258] A slower rate and prolonged course of repletion would be expected to decrease these urinary losses and therefore be much more efficient and effective at repleting body Mg2+ stores. The magnitude of the Mg2+ deficit is difficult to gauge clinically and cannot be readily deduced from the serum Mg2+ concentration. In general, though, the average deficit can be assumed to be 1 to 2 mEq/kg body weight.[258] A simple regimen for nonemergency Mg2+ repletion is to administer 64 mEq (8 g) of MgSO4 over the first 24 hours and then 32 mEq (4 g) daily for the next 2 to 6 days. It is important to remember that serum Mg2+ levels rise early whereas intracellular stores take longer to replete, so Mg2+ repletion should continue for at least 1 to 2 days after the serum Mg2+ level normalizes. In patients with renal Mg2+ wasting, additional Mg2+ may be needed to replace ongoing losses. In patients with a reduced glomerular filtration rate (GFR), the rate of repletion should be reduced by 25% to 50%,[258] the patient should be carefully monitored for signs of hypermagnesemia, and the serum Mg2+level should be checked frequently.

The main adverse effects of Mg2+ repletion are due to hypermagnesemia as a consequence of an excessive rate or amount of Mg2+ administered. These effects include facial flushing, loss of deep tendon reflexes, hypotension, and atrioventricular block. Monitoring of tendon reflexes is a useful bedside test to detect Mg2+ overdose. In addition, intravenous administration of large amounts of MgSO4 results in an acute decrease in the serum ionized Ca2+level[259] related to increased urinary Ca2+ excretion and complexing of Ca2+ by sulfate. Thus, in an asymptomatic patient who is already hypocalcemic, administration of MgSO4 may further lower the ionized Ca2+ level and thereby precipitate tetany.[260] Administration of Mg2+ with sulfate as the anion may have an additional theoretical disadvantage. Because sulfate cannot be reabsorbed in the distal tubule, it favors the development of a negative luminal electrical potential, thereby increasing K+ secretion. In Mg2+-depleted rats with hypokalemia, repletion with Mg2+ in the form of a nonsulfate salt was associated with correction of the hypokalemia, whereas repletion with MgSO4 resulted in persistent hypokalemia and kaliuresis.[261]

Oral Replacement

Oral Mg2+ administration is used either initially for repletion of mild cases of hypomagnesemia or for continued replacement of ongoing losses in the outpatient setting after an initial course of intravenous repletion. A number of oral Mg2+ salts are available, but little is known about their relative oral bioavailability or efficacy, and all of them cause diarrhea in high doses. Mg hydroxide and Mg oxide are alkalinizing salts with the potential to cause systemic alkalosis, whereas the sulfate and gluconate salts may potentially exacerbate K+ wasting, as discussed earlier. The appropriate dose of each salt can be estimated, if ongoing losses are known, by determining its content of elemental Mg2+ and assuming a bioavailability of approximately 33% for normal intestinal function. In patients with intestinal Mg2+ malabsorption, this dose may need to be increased twofold to fourfold.

Potassium-Sparing Diuretics

In patients with inappropriate renal Mg2+ wasting, potassium-sparing diuretics that block the distal tubule epithelial Na+ channel, such as amiloride and triamterene, may reduce renal Mg2+ losses.[262] These drugs may be particularly useful in patients who are refractory to oral repletion or require such high doses of oral Mg2+ that diarrhea develops. In rats, amiloride and triamterene can be demonstrated to reduce renal Mg2+ clearance at baseline and after induction of Mg2+ diuresis by furosemide, but the mechanism is unknown. One possibility is that these drugs, by reducing luminal Na+ uptake and inhibiting the development of a negative luminal transepithelial potential difference, may favor passive reabsorption of Mg2+ in the late distal tubule or collecting duct.



In states of body Mg2+ excess, the kidney has a very large capacity for Mg2+ excretion. Once the apparent renal threshold is exceeded, most of the excess filtered Mg2+ is excreted unchanged into the final urine; the serum Mg2+concentration is then determined by the GFR. Thus, hypermagnesemia generally occurs in two clinical settings: compromised renal function and excessive Mg2+ intake.

Renal Insufficiency

In chronic renal failure, the remaining nephrons adapt to the decreased filtered load of Mg2+ by markedly increasing their fractional excretion of Mg2+.[263] As a consequence, serum Mg2+ levels are usually well maintained until the creatinine clearance falls below about 20 mL/min.[263] Even in advanced renal insufficiency, significant hypermagnesemia is rare unless the patient has received exogenous Mg2+ in the form of antacids, cathartics, or enemas. Increasing age is an important risk factor for hypermagnesemia in individuals with apparently normal renal function; it presumably reflects the decline in GFR that normally accompanies old age.[264]

Excessive Mg2+ Intake

Hypermagnesemia can occur in individuals with a normal GFR when the rate of Mg2+ intake exceeds the renal excretory capacity. It has been reported with excessive oral ingestion of Mg2+-containing antacids and cathartics and with the use of rectal Mg sulfate enemas and is common with large parenteral doses of Mg2+, such as those given for preeclampsia. Toxicity from enterally administered Mg2+ salts is particularly common in patients with inflammatory disease, obstruction, or perforation of the gastrointestinal tract, presumably because Mg2+ absorption is enhanced.


Modest elevations in serum Mg2+ (less than 4 mEq/L) have occasionally been described in patients receiving lithium therapy, as well as in postoperative and in those with bone metastases, milk-alkali syndrome, FHH,[242]hypothyroidism, pituitary dwarfism, and Addison disease. In most patients cases, the mechanism is unknown.

Clinical Manifestations

Mg2+ toxicity is a serious and potentially fatal condition. Progressive hypermagnesemia is usually associated with a predictable sequence of symptoms and signs.[265] Initial manifestations, observed once the serum Mg2+ level exceeds 4 mg/dL to 6 mg/dL, are hypotension, nausea, vomiting, facial flushing, urinary retention, and ileus. If untreated, it may progress to flaccid skeletal muscular paralysis and hyporeflexia, bradycardia and bradyarrhythmias, respiratory depression, coma, and cardiac arrest. An abnormally low (or even negative) serum anion gap may be a clue to hypermagnesemia,[264] but it is not consistently observed and probably depends on the nature of the anion that accompanies the excess body Mg2+.

Cardiovascular System

Hypotension is one of the earliest manifestations of hypermagnesemia,[266] is often accompanied by cutaneous flushing, and is thought to be due to vasodilatation of vascular smooth muscle and inhibition of norepinephrine release by sympathetic postganglionic nerves. Electrocardiographic changes are common but nonspecific.[266] Sinus or junctional bradycardia may develop, as well as varying degrees of sinoatrial, atrioventricular, and His bundle conduction block. Cardiac arrest as a result of asystole is often the terminal event.

Nervous System

High levels of extracellular Mg2+ inhibit acetylcholine release from the neuromuscular end-plate,[267] leading to the development of flaccid skeletal muscle paralysis and hyporeflexia when serum Mg2+ exceeds 8 mg/dL to 12 mg/dL. Respiratory depression is a serious complication of advanced Mg2+ toxicity.[266] Smooth muscle paralysis also occurs and is manifested as urinary retention, intestinal ileus, and pupillary dilatation. Signs of central nervous system depression, including lethargy, drowsiness, and eventually coma, are well described in severe hypermagnesemia, but they may also be entirely absent.


Mild cases of Mg2+ toxicity in individuals with good renal function may require no treatment other than cessation of Mg2+ supplements because renal Mg2+ clearance is usually quite rapid. The normal half-life of serum Mg2+ is approximately 28 hours. In the event of serious toxicity, particularly cardiac toxicity, temporary antagonism of the effect of Mg2+ may be achieved by the administration of intravenous Ca2+ (1 g of calcium chloride infused into a central vein over a period of 2 to 5 minutes or calcium gluconate infused through a peripheral vein, repeated after 5 minutes if necessary).[265] Renal excretion of Mg2+ can be enhanced by saline diuresis and by the administration of furosemide, which inhibits tubule reabsorption of Mg2+ in the medullary TAL.

In patients with renal failure, the only way to clear the excess Mg2+ may be by dialysis. The typical dialysate for hemodialysis contains 0.6 mg/dL to 1.2 mg/dL of Mg2+, but Mg2+-free dialysate can also be used and is generally well tolerated except for muscle cramps.[268] Hemodialysis is extremely effective at removing excess Mg2+ and can achieve clearances of up to 100 mL/min.[268] As a rough rule of thumb, the expected change in serum Mg2+ after a 3- to 4-hour dialysis session with a high-efficiency membrane is approximately one third to one half the difference between the dialysate Mg2+ concentration and predialysis serum ultra-filterable Mg2+ (estimated at 70% of total serum Mg2+).[268] Note that when hemodialysis is performed against a bath with the same total concentration of Mg2+ as in serum, net transfer of Mg2+ into the patient occurs because the ultra-filterable (and therefore free) Mg2+concentration in serum is less than the total concentration and thus the gradient of free Mg2+ is directed from dialysate to blood. Peritoneal dialysis is also effective at Mg2+ removal.[269]



Hyperphosphatemia is generally defined as serum phosphate levels elevated above 5 mg/dL. The threshold for labeling a child as hyperphosphatemic is higher because children tend to have higher phosphate levels than adults do. Whereas the normal range of blood phosphorus for adult men and women is 4.5 mg/dL to 5.2 mg/dL, for children, the upper range of normal is 6 mg/dL. In infants, phosphorus levels as high as 7.4 mg/dL are considered normal.[270]The serum phosphorus level usually exhibits diurnal variation. Typically, phosphorus levels are lowest in the late morning and peak in the first morning hours.[271] Hemolysis in the blood specimen can lead to spuriously elevated measurements of phosphorus.


The clinical causes of hyperphosphatemia can be broadly classified into one of three groups: reduced phosphate excretion, excess intake of phosphorus, and redistribution of cellular phosphorus ( Table 16-8 ).

TABLE 16-8   -- Causes of Hyperphosphatemia



Decreased renal excretion of phosphorus



Renal insufficiency



Hypoparathyroidism, pseudohypoparathyroidism






Tumoral calcinosis



Redistribution of phosphorus



Tumor lysis syndrome



Respiratory acidosis



Exogenous phosphorus administration



Ingestion of phosphate containing enemas



IV phosphate




Decreased Renal Phosphate Excretion

Renal Insufficiency

Decreased renal function is by far the most common cause of hyperphosphatemia. Increased fractional excretion of PO4 is able to compensate until GFR falls and normal PO4 excretion can no longer be maintained. Increases in serum phosphorus levels are observed even among individuals with mild to moderate chronic kidney disease.[272] Hyperphosphatemia is observed in acute kidney injury as well as chronic disease. Hyperphosphatemia caused by decreased renal function is not discussed in detail here because it is reviewed extensively in Chapter 52 in the context of renal osteodystrophies.

Hypoparathyroidism and Pseudohypoparathyroidism

Decreased renal excretion of phosphate may also occur in the setting of reduced PTH (hypoparathyroidism) or an altered renal response to PTH (PsHP). These entities are discussed earlier in this chapter. In primary hypoparathyroidism, circulating phosphorus generally reaches a higher than normal steady-state level (6 mg/dL to 7 mg/dL), with a low serum calcium level. Patients with PsHP typically have increased PTH levels, but serum chemistries are similar to those seen in hypoparathyroidism.


Some patients with acromegaly demonstrate hyperphosphatemia. Parathyroid function is usually normal or slightly increased in acromegaly.[119] The hyperphosphatemia observed appears to result from increased proximal tubule phosphate reabsorption. Growth hormone directly stimulates proximal tubule phosphorus reabsorption and increases the Tm for phosphorus.[273]

Familial Tumoral Calcinosis

Familial tumoral calcinosis is a rare autosomal recessive disorder. The hyperphosphatemia that characterizes the disease is a result of increased proximal tubular reabsorption of phosphorus. Often, increased serum 1,25-(OH)2D levels are observed.[274] The disease is genetically heterogeneous: defects have been described in the GALNT3 gene,[275] which encodes a glycosyltransferase, and in the FGF-23 gene. [281] [282] Mutations in the GALNT3 or FGF23 genes may lead to deficiency of FGF-23, an important promoter of urinary phosphate excretion. If so, familial tumoral calcinosis may be the phenotypic opposite of X-linked and autosomal dominant hypophosphatemic rickets (see later discussion).

Together, a normal serum calcium concentration and elevated serum phosphorus lead to an elevated calcium phosphate product and soft tissue calcium phosphate deposition. Though usually periarticular, the calcifications can occur as paraspinal or extradural masses. Decreasing phosphorus intake by ingestion of a low-phosphate diet or the addition of phosphate binders, as well as the use of acetazolamide, has been reported to be effective treatment.[278]


Bisphosphonates can cause hyperphosphatemia. In a study by Walton and colleagues,[279] altered renal phosphate handling with bisphosphonate treatment was suggested by the absence of altered urine phosphate excretion despite increased plasma phosphate. Studies in humans have shown that various members of this class of medication cause a similar increase in tubule reabsorption of phosphate.[280]

Increased Phosphorus Intake

Exogenous intake of phosphorus sufficient to cause clincally significant hyperphosphatemia is rare in the absence of underlying kidney disease. However, oral sodium phosphate administration for bowel preparation has been recognized as a cause of hyperphosphatemia for some time. Even individuals with normal baseline kidney function develop transient hyperphosphatemia.[280a] Caution is required in the administration of phosphate-containing enemas to children and individuals with chronic kidney disease.

Phosphate Nephropathy

Administration of oral sodium phosphate solutions has been increasingly recognized as a cause of acute renal failure (so-called “phosphate nephropathy”).[280b] In a review of over 7000 kidney biopsies processed at their center, Markowitz and colleagues found 16 cases where patients had developed renal failure and intrarenal calcium-phosphate deposits after oral sodium phosphate administration for colonoscopy.[280c] This syndrome may occur in individuals with good baseline kidney function. Kidney injury in this setting does not typically recover.

Redistribution of Phosphorus

Respiratory Acidosis

Chronic respiratory acidosis can lead to hyperphosphatemia, renal PTH resistance, and hypocalcemia.[281] The effect is more pronounced in acute respiratory acidosis. Respiratory acidosis does not appear to significantly alter the renal handling of phosphorus. Rather, efflux of phosphate from cells into the extracellular space is probably responsible for the hyperphosphatemia of respiratory acidosis.[282]

Tumor Lysis

Tumor lysis syndrome is a well-described complication of the treatment of hematologic malignancies.[190] It is seen after the treatment of various forms of lymphoma and lymphoblastic leukemia, and when a particularly heavy tumor burden is present, it may occur spontaneously before treatment. Patients with tumor lysis syndrome have elevated lactate dehydrogenase, uric acid, and phosphate levels shortly after chemotherapy. Lymphoblasts are particularly high in phosphorus. The lactate dehydrogenase level before the initiation of therapy correlates with the development of hyperphosphatemia and azotemia.[283] Hyperphosphatemia is seen in essentially all patients with Burkitt lymphoma after treatment if they had any preexisting kidney disease and in approximately 30% of patients with normal renal function.

In general, common practice is to induce high urine output and phosphate excretion before chemotherapy with a large volume of intravenous fluid. Bicarbonate infusion is often given but requires caution because in the presence of a high calcium phosphate product, the risk of nephrocalcinosis is increased. Hemodialysis is often used in the setting of acute kidney injury with hyperphosphatemia. Continuous dialysis modalities (continuous arteriovenous hemodialysis [CAVHD], continuous venovenous hemodialysis [CVVHD]) that can provide high and continued clearance may be the preferred treatment for patients with tumor lysis and acute kidney injury.


Incorrect hyperphosphatemic laboratory readings from patient samples may occur in certain settings as a result of interference with the analysis. This problem is most common in the case of paraproteinemia (as in multiple myeloma or Waldenström macroglobulinemia).[284] Hyperlipidemia, hyperbilirubinemia, and sample dilution problems are rare causes.

Clinical Manifestations and Treatment

Most of the major clinical manifestations of hyperphosphatemia stem from hypocalcemia, discussed earlier in this chapter. Hyperphosphatemia is also important in the development of secondary HPT, as discussed in Chapter 52 . Hyperphosphatemia leads to secondary hypocalcemia by causing calcium precipitation, by decreasing the production of 1,25(OH)2D, and by decreasing intestinal calcium absorption. Ectopic calcification is the other important clinical manifestation of hyperphosphatemia. When the product of serum calcium and serum phosphorus (expressed in milligrams per deciliter) exceeds 70, the risk for ectopic calcium precipitation is significant. The skin, vasculature, cornea, and joints are often affected in this setting.

Treatment of chronic hyperphosphatemia is generally accomplished through dietary phosphate restriction and oral phosphate binders. Chronic hyperphosphatemia is most commonly observed in association with renal insufficiency and end-stage kidney disease and is discussed in Chapter 52 . Chronic hyperphosphatemia also may be seen in association with tumoral calcinosis and is treated similarly, with a reduction in dietary phosphate and administration of oral phosphate binders.

Acute hyperphosphatemia in association with hypocalcemia requires rapid attention. Severe hyperphosphatemia in patients with reduced renal function or acute kidney injury, particularly in those with tumor lysis syndrome, may require hemodialysis or a continuous form of renal replacement therapy. Volume expansion may increase urinary phosphate excretion, as can administration of acetazolamide.


Only a small percentage (about 1%) of total body phosphorus is extracellular. Thus, although hypophosphatemia may reflect total body phosphorus depletion, such need not be the case. Hypophosphatemia is relatively common in hospitalized patients and is present in a significant fraction of chronic alcoholics.[285] Later, we discuss hypophosphatemia in terms of its underlying cause: increased renal excretion (acquired or inherited), decreased intestinal absorption, and shifts of phosphorus from the extracellular compartment.

Clinical Manifestations

Mild hypophosphatemia does not typically cause symptoms. Patients with symptoms usually have serum phosphate levels below 1 mg/dL. Severe hypophosphatemia can have significant clinical consequences, including disturbances in multiple cellular functions and organ systems.

The clinical manifestations of hypophosphatemia and phosphorus depletion generally result from a decrease in intracellular ATP levels. In addition, erythrocytes experience a decrease in 2,3-diphosphoglycerate levels, which increases hemoglobin-oxygen affinity and alters oxygen transport efficiency.[286]

Hematologic consequences include a predisposition to hemolysis, thought to result from increased red cell rigi-dity.[287] Hemolysis is not typically seen in the absence of other exacerbating features. White cell phagocytosis can be diminished. Presumably, impaired ATP production diminishes the phagocytic capability.[288]

Severe hypophosphatemia impairs muscle function. Again, this sequela is a result of ATP depletion. Overt heart failure and respiratory failure as a result of decreased muscle performance may be observed. [297] [298]Hypophosphatemia may also affect skeletal and smooth muscle performance. Proximal myopathies and intestinal effects of hypophosphatemia have been described.

Rhabdomyolysis is a well-recognized complication of severe hypophosphatemia.[291] Because cell breakdown may lead to the release of intracellular phosphate, normophosphatemia or hyperphosphatemia in this setting may mask the existence of true phosphate depletion.

Chronic phosphate depletion alters bone and kidney function, and hypophosphatemia leads to increased bone resorption. If phosphate depletion is prolonged, rickets and osteomalacia may result. Hypophosphatemia leads to decreased proximal tubule reabsorptive function.[292] A decrease in renal conservation of calcium is also observed, and at times frank hypercalciuria develops. This hypercalciuria is not solely the result of renal calcium handling but also reflects increased calcium release from bone and increased intestinal calcium absorption.[293]


The probable cause of hypophosphatemia may be immediately apparent from the clinical findings (e.g., in a malnourished patient with alcoholism or anorexia). Shifts of phosphorus from the extracellular to the intracellular space generally occur in the acute setting (respiratory alkalosis, treatment of diabetic ketoacidosis). In hospitalized patients, hypophosphatemia caused by shifts of phosphorus into the intracellular compartment are much more common than hypophosphatemia caused by renal losses.[294] In situations where the underlying diagnosis is not immediately apparent, it can be clinically useful to determine the rate of urine phosphorus excretion. High urine phosphorus in the face of hypophosphatemia suggests HPT, a renal tubule defect, or a form of rickets.

Causes of Hypophosphatemia

Increased Renal Excretion

As discussed in Chapter 5 in detail, renal phosphate excretion plays a major role in regulating phosphate metabolism ( Table 16-9 ). Most renal reabsorption of phosphate occurs in the proximal tubule by means of sodium-dependent phosphate transporters (type I cotransporters). Serum phosphate depletion leads to stimulation of phosphate reabsorption. PTH also regulates renal phosphate reabsorption. Phosphate depletion itself decreases proximal tubule and distal nephron phosphate reabsorption. Hypophosphatemia caused by increased urinary phosphate excretion is generally the result of either excess PTH or an inherited disorder of renal phosphate handling in the proximal tubule.

TABLE 16-9   -- Causes of Hypophosphatemia



Increased urinary phosphate excretion






Inherited defects



Volume expansion



Vitamin D deficiency (or resistance)



Fanconi syndrome






Post-renal transplant



Decreased GI absorption of phosphate



Inadequate phosphate intake



Chronic diarrhea



Phosphate-binding antacids



Chronic alcoholism



Altered phosphorus distribution



Acute respiratory alkalosis



“Hungry bone syndrome” (post-parathyroidectomy)



Management of diabetic ketoacidosis



Refeeding of malnourished patients, alcoholics








Both primary and secondary HPT may lead to hyperphosphaturia and hypophosphatemia. Primary HPT is discussed earlier in this chapter. Excess PTH directly decreases renal phosphate reabsorption, thereby leading to increased renal phosphate excretion and hypophosphatemia. The degree of hypophosphatemia observed is highly variable. The secondary HPT observed in patients with chronic kidney disease is typically associated with hyperphosphatemia because of a decreased ability of the kidney to excrete phosphorus. However, other forms of secondary HPT (typically from decreased intestinal calcium absorption and vitamin D deficiency) may be manifested as hypophosphatemia.

Acute Renal Failure and Recovery from Acute Tubular Necrosis

Hyperphosphatemia is the typical derangement of phosphate metabolism observed in patients with acute kidney injury. However, confounding factors in the setting of critical illness may contribute to the development of hypophosphatemia in some instances: administration of phosphate-binding antacids, refeeding syndrome, and mechanically induced respiratory alkalosis. In addition, during the diuretic phase of recovery from acute tubular necrosis, significant urinary losses of phosphate may lead to hypophosphatemia. Similarly, significant urinary phosphate losses leading to frank hypophosphatemia may be seen after recovery from obstructive uropathy.

Renal Transplantation

Hypophosphatemia is well described in patients after renal transplantation, and a typically mild to moderate form develops in a high fraction of recipients.[295] Severe hypophosphatemia and phosphate depletion is uncommon. Persistent secondary HPT does not appear to be the sole mechanism of hypophosphatemia. Renal tubule dysfunction in the allograft leading to hyperphosphaturia is a contributory factor,[295] and excess FGF-23 may play a role in the etiology.[296] Therapy with diuretics and immunosuppressive medications also contributes to post-transplant hypophosphatemia.

Fanconi Syndrome

Increased urine phosphorus excretion is a typical feature of the defect in proximal tubule transport known as Fanconi syndrome.[297] Hypophosphatemia is usually observed in association with glucosuria, uricosuria, aminoaciduria, and proximal renal tubular acidosis.

Decreased Intestinal Absorption


Malnutrition from poor phosphate intake is not a common cause of hypophosphatemia. Increased renal reabsorption of phosphorus can compensate for all but the most severe decreases in oral phosphate intake. Most dietary phosphate comes from protein. Children from parts of the world where protein malnutrition is common are most susceptible to this problem.


More common is hypophosphatemia resulting from malabsorption. Most phosphorus absorption occurs in the duodenum and jejunum, and intestinal disorders affecting the small intestine may lead to hypophosphatemia.[298] Heavy use of phosphate-binding antacids may also result in hypophosphatemia. Hypophosphatemia can develop quickly, even in patients given a relatively moderate, but sustained dosage. Prolonged use of phosphate-binding antacids can lead to clinically significant osteomalacia.[299]

Vitamin D-Mediated Disorders

Vitamin D is critical for normal control of phosphorus. Deficiency of vitamin D leads to decreased intestinal absorption of phosphorus. In addition, vitamin D deficiency leads to hypocalcemia, HPT, and a consequent PTH-mediated increase in renal phosphorus excretion. The vitamin D deficiency and resistance syndromes known as rickets are characterized by hypophosphatemia, hypocalcemia, and bone disease.


Respiratory Alkalosis

Respiratory alkalosis decreases serum phosphorus levels. When the alkalosis is prolonged and severe, phosphorus levels can drop below 1 mg/dL.[300] In mechanically ventilated patients, hypophosphatemia is common, and urinary phosphate excretion drops to undetectable levels. This drop in phosphaturia contrasts with the high urine phosphate excretion and hypophosphatemia that may be observed with metabolic alkalosis from sodium bicarbonate administration. It has been suggested that in the hypophosphatemia seen in respiratory alkalosis, carbon dioxide diffusion from the intracellular space increases intracellular pH, stimulates glycolysis, and increases the formation of phosphorylated carbohydrates, thereby leading to a fall in extracellular phosphorus levels.[301]


In chronically malnourished individuals, rapid refeeding can result in significant hypophosphatemia. The mechanism is related to increased cellular phosphate uptake and utilization. The incidence of refeeding-related hypophosphatemia is quite high in hospitalized patients receiving parenteral nutrition, as high as one in three in one series.[302] Refeeding after even very short periods of starvation can lead to hypophosphatemia.[303] Adequate phosphate in the parenteral nutrition formulation generally prevents this complication. In most patients, 13.6 mEq phosphorus per liter appears to be adequate. Even higher amounts may be required in patients with diabetes or chronic alcoholism. Hypophosphatemia and phosphate depletion are common in individuals with anorexia nervosa, and phosphorus supplementation is required in over 25% of such patients during hospitalization and refeeding.[304]

Special Situations: Alcoholism and Diabetes

Hypophosphatemia is a particularly common and often severe problem in alcoholic patients with poor intake, vitamin D deficiency, and heavy use of phosphate-binding antacids.[305] Alcohol-induced proximal tubule dysfunction also contributes to phosphate depletion.[204] Phosphorus deficiency is often not manifested as hypophosphatemia immediately at initial evaluation for medical care. Typically, refeeding or administration of intravenous glucose (or both) in this patient population stimulates shifts of phosphorus into cells and thereby leads to the development of severe hypophosphatemia. Hypophosphatemic alcoholics are at particular risk for rhabdomyolysis.

In uncontrolled diabetes, increased urine phosphate excretion can be observed, and in diabetic ketoacidosis, phosphate is released from cells and excreted in urine.[306] Although serum phosphate levels may be normal, total phosphate stores are usually low. During treatment of diabetic ketoacidosis, the development of hypophosphatemia is extremely common.[307] Administration of insulin stimulates the cellular uptake of phosphorus, and thus the serum phosphate level can fall dramatically with treatment.[308] However, routine administration of phosphate in this setting before the development of frank hypophosphatemia is discouraged because it may lead to significant hypocalcemia.[309]

Drug-induced Hypophosphatemia

In addition to the phosphate-binding antacids mentioned earlier, other medications may cause hypophosphatemia. Diuretics, particularly those acting on the proximal nephron, may result in hypophosphatemia. Corticosteroids both decrease intestinal phosphorus absorption and increase renal phosphorus excretion and thus may cause mild to moderate hypophosphatemia.[310] Agents that damage the proximal tubule (such as certain antineoplastic agents) may lead to phosphate wasting. Hypophosphatemia has also been reported in acetaminophen toxicity, but the mechanism is not clear. Theophylline administered in the setting of acute bronchospasm is associated with hypophosphatemia, apparently by causing phosphorus flux into the intracellular compartment.


Moderate and at times severe hypophosphatemia may be observed in acute leukemia and in the leukemic phases of lymphomas.[311] It is thought that rapid cell growth with consequent phosphorus utilization is responsible for the drop in extracellular phosphorus. Toxic shock may be associated with hypophosphatemia. In one study of 22 women with toxic shock syndrome, hypophosphatemia and hypocalcemia were common features.[312] The underlying mechanism is not clear. Rapid volume expansion diminishes proximal tubule sodium phosphate reabsorption and may lead to transient hypophosphatemia.[313] Hepatic disease may cause hypophosphatemia; hypophosphatemia is an almost universal observation after hepatic lobectomy for liver transplantation. Hypophosphatemia is frequently observed in the setting of sepsis, but the complicated clinical picture in septic patients makes it difficult to attribute the hypophosphatemia to a unique mechanism. Hypophosphatemia is seen in patients with heat stroke, as well as hyperthermia. In this setting, renal phosphorus excretion is increased.

Inherited Disorders

X-Linked Hypophosphatemia

X-linked hypophosphatemia (XLH) is a rare X-linked dominant disorder characterized by hypophosphatemia, rickets and osteomalacia, growth retardation, decreased intestinal calcium and phosphate absorption, and decreased renal phosphate reabsorption ( Table 16-10 ). Penetrance is high, and both females and males are affected. Serum calcium levels are normal. Genotype does not predict phenotype severity.[314]

TABLE 16-10   -- Inherited Hypophosphatemia



Mendelian Inheritance in Man Number

Hypophosphatemic rickets with hypercalciuria



X-linked hypophosphatemia



Autosomal dominant hypophosphatemic rickets



Nephrolithiasis, osteoporosis, and hypophosphatemia



Autosomal recessive hypophosphatemic rickets



Renal hypophosphatemia with intracerebral calcifications






The gene responsible, PHEX, is named for its putative function: phosphate regulating gene with homology to endopeptidases on the X chromosome. PHEX was identified by positional cloning.[315] Well over 100 independent PHEX mutations have been described.[316]

The term phosphatonin refers to a circulating factor or factors with phosphaturic activity. PHEX mutations are thought to inactivate this activity and thereby lead to increased serum phosphatonin activity and increased urine phosphate excretion. The hyp mouse, like humans with XLH, has a defect in the PHEX gene. Transplantation studies of normal and hyp mouse kidneys supported the idea that an altered circulating activity rather than a kidney defect was responsible for the phenotype.[317] PHEX is not expressed in the kidney; its predominant expression is in bone.[318]

FGF-23 has received considerable attention as a candidate phosphatonin. FGF-23 is a PHEX substrate,[319] and FGF-23 mutations have been shown to cause autosomal dominant hypophosphatemic rickets. Of interest, normal or slightly reduced plasma 1,25(OH)2D levels, despite the presence of hypophosphatemia, suggest that 1,25(OH)2D synthesis is abnormal in XLH. FGF-23 may down-regulate 1-alpha hydroxylase.[320]

Treatment of XLH patients with oral phosphate and calcitriol improves their growth rate. Treatment does not reduce renal phosphate excretion. The goal of therapy is to allow normal growth and reduce bone pain.[321]

Autosomal Dominant Hypophosphatemic Rickets

Autosomal dominant hypophosphatemic rickets (ADHR) is an extremely rare disorder of phosphate wasting with variable penetrance. The phenotype is similar to that of XLH. Some individuals are initially seen in childhood with lower extremity deformities, as well as rickets and phosphate wasting. Others have bone pain, weakness, and phosphate wasting as adolescents or adults. In some individuals with early-onset disease, the phosphate wasting returns to normal after puberty.

The ADHR locus was mapped to chromosome 12p13.3 and subsequently identified as FGF-23.[322] Mutations on FGF-23 appear to interfere with proteolytic cleavage by PHEX.[323]

FGF-23 is a substrate for the XLH gene product PHEX, and it directly inhibits renal phosphate reabsorption. In addition, FGF-23 is responsible for tumor-induced osteomalacia (TIO) (also called oncogenic hypophosphatemic osteomalacia).[324] TIO is an acquired hypophosphatemic disorder seen in association with mesenchymal tumors. Whereas mutations in FGF-23 cause ADHR, overexpression of FGF-23 by tumor causes TIO. FGF-23 is probably not the only phosphatonin, and other factors with appropriate biologic characteristics have been identified.[325] The anti-aging protein Klotho regulates FGF23 action. [334] [335] Tumors causing this syndrome are usually benign. The diagnosis may be made by detection of osteomalacia and phosphate wasting, which suggest the presence of a responsible tumor.

Other candidate phosphatonins are under study. The bone-expressed gene MEPE, or matrix extracellular phosphoglycoprotein, is a strong candidate as another phosphaturic factor in TIO.[326]

Hereditary Hypophosphatemic Rickets with Hypercalciuria

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive syndrome characterized by rickets, short stature, renal phosphate wasting, and hypercalciuria. HHRH is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate cotrans-porter NaP(i)-IIc.[327] Unlike X-linked hypophosphatemia and autosomal dominant hypophosphatemic rickets, patients have an appropriate elevation in 1,25(OH)2D, which results in hypercalciuria. Patients are treated with phosphorus supplementation.

Although defects in the NPT2 gene, which encodes the type IIa sodium-phosphate cotransporter, are not the cause of HHRH, mutations have been found in two patients with nephrolithiasis, osteoporosis, and hypophosphatemia. Sodium-dependent phosphate uptake was impaired in oocytes expressing the mutant NPT2.[328]

Other Mendelian Forms of Hypophosphatemia

An unusual form of mendelian hypophosphatemia was reported by Stamp and Baker.[329] Children of a consanguineous mating demonstrated hypophosphatemia as well as childhood rickets, deafness, and high bone density. Recessive inheritance was suggested by the absence of disease in both parents. Mutations in the DMP1 gene are responsible for disease in at least some families with this disorder.[329a]

Chitayat and co-workers[330] described a family with apparent recessive inheritance of renal hypophosphatemia, facial anomalies, intracerebral calcifications, and recurrent dental abscesses. Affected children had normal calcium, vitamin D, and PTH levels but significant hypophosphatemia. The inheritance pattern was consistent with autosomal recessive transmission.


As noted, serum levels of phosphorus may not be a good reflection of total body stores. Therefore, it is essentially impossible to predict the amount of phosphorus necessary to correct phosphorus deficiency and hypophosphatemia. The clinical circumstances will suggest whether severe underlying phosphate deficiency is present. In chronically malnourished patients (e.g., anorectics, alcoholics), significant phosphorus repletion will be necessary, whereas in patients who are hypophosphatemic from other causes (antacid ingestion, acetazolamide use), correction of the underlying problem may be sufficient.

In mild or moderate hypophosphatemia (∼2 mg/dL), oral repletion with low-fat milk (containing 0.9 mg phosphorus per milliliter) is effective. In individuals intolerant of milk, potassium phosphate or sodium phosphate preparations can be used. Intravenous phosphorus repletion is gene-rally reserved for individuals with severe (∼1 mg/dL) hypophosphatemia. One standard regimen is to administer 2.5 mg/kg body mass of elemental phosphorus over a 6-hour period for severe asymptomatic hypophosphatemia and 5 mg/kg body mass of elemental phosphorus over a 6-hour period for severe symptomatic hypophosphatemia.[331] Intravenous phosphorus repletion is generally safe and effective.[332] Malnourished patients receiving hyperalimentation should have adequate phosphorus supplementation to avoid the frequently observed refeeding hypophosphatemia.


1. Ladenson JH, Lewis JW, Boyd JC: Failure of total calcium corrected for protein, albumin, and pH to correctly assess free calcium status.  J Clin Endocrinol Metab  1978; 46:986-993.

2. Motoyama HI, Friedman PA: Calcium-sensing receptor regulation of PTH-dependent calcium absorption by mouse cortical ascending limbs.  Am J Physiol Renal Physiol  2002; 283:F399-F406.

3. Simon DB, Nelson-Williams C, Bia MJ, et al: Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.  Nat Genet  1996; 12:24-30.

4. Palmer M, Jakobsson S, Akerstrom G, Ljunghall S: Prevalence of hypercalcaemia in a health survey: A 14-year follow-up study of serum calcium values.  Eur J Clin Invest  1988; 18:39-46.

5. Christensson T, Hellstrom K, Wengle B, et al: Prevalence of hypercalcaemia in a health screening in Stockholm.  Acta Med Scand  1976; 200:131-137.

6. Lundgren E, Rastad J, Thrufjell E, et al: Population-based screening for primary hyperparathyroidism with serum calcium and parathyroid hormone values in menopausal women.  Surgery  1997; 121:287-294.

7. Lind L, Skarfors E, Berglund L, et al: Serum calcium: A new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years.  J Clin Epidemiol  1997; 50:967-973.

8. Melton LR: The epidemiology of primary hyperparathyroidism in North America.  J Bone Miner Res  2002; 17(Suppl 2):N12-N17.

9. Wermers RA, Khosla S, Atkinson EJ, et al: The rise and fall of primary hyperparathyroidism: A population-based study in Rochester, Minnesota, 1965-1992.  Ann Intern Med  1997; 126:433-440.

10. Wermers RA, Khosla S, Atkinson EJ, et al: Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993-2001: An update on the changing epidemiology of the disease.  J Bone Miner Res  2006; 21:171-177.

11. Hsi ED, Zukerberg LR, Yang WI, Arnold A: Cyclin D1/PRAD1 expression in parathyroid adenomas: An immunohistochemical study.  J Clin Endocrinol Metab  1996; 81:1736-1739.

12. Hemmer S, Wasenius VM, Haglund C, et al: Deletion of 11q23 and cyclin D1 overexpression are frequent aberrations in parathyroid adenomas.  Am J Pathol  2001; 158:1355-1362.

13. Heppner C, Kester MB, Agarwal SK, et al: Somatic mutation of the MEN1 gene in parathyroid tumours.  Nat Genet  1997; 16:375-378.

14. Farnebo F, Teh BT, Kytola S, et al: Alterations of the MEN1 gene in sporadic parathyroid tumors [see comments].  J Clin Endocrinol Metab  1998; 83:2627-2630.

15. Arnold A, Shattuck TM, Mallya SM, et al: Molecular pathogenesis of primary hyperparathyroidism.  J Bone Miner Res  2002; 17(Suppl 2):N30-N36.

16. Lind L, Hvarfner A, Palmer M, et al: Hypertension in primary hyperparathyroidism in relation to histopathology.  Eur J Surg  1991; 157:457-459.

17. Lind L, Jacobsson S, Palmer M, et al: Cardiovascular risk factors in primary hyperparathyroidism: A 15-year follow-up of operated and unoperated cases.  J Intern Med  1991; 230:29-35.

18. Hagstrom E, Lundgren E, Lithell H, et al: Normalized dyslipidaemia after parathyroidectomy in mild primary hyperparathyroidism: Population-based study over five years.  Clin Endocrinol (Oxf)  2002; 56:253-260.

19. Procopio M, Magro G, Cesario F, et al: The oral glucose tolerance test reveals a high frequency of both impaired glucose tolerance and undiagnosed Type 2 diabetes mellitus in primary hyperparathyroidism.  Diabet Med  2002; 19:958-961.

20. Nuzzo V, Tauchmanova L, Fonderico F, et al: Increased intima-media thickness of the carotid artery wall, normal blood pressure profile and normal left ventricular mass in subjects with primary hyperparathyroidism.  Eur J Endocrinol  2002; 147:453-459.

21. Palmer M, Adami HO, Bergstrom R, et al: Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of follow-up.  Lancet  1987; 1:59-62.

22. Leifsson BG, Ahren B: Serum calcium and survival in a large health screening program.  J Clin Endocrinol Metab  1996; 81:2149-2153.

23. Hedback G, Oden A: Increased risk of death from primary hyperparathyroidism—an update.  Eur J Clin Invest  1998; 28:271-276.

24. Palmer M, Adami HO, Bergstrom R, et al: Mortality after surgery for primary hyperparathyroidism: A follow-up of 441 patients operated on from 1956 to 1979.  Surgery  1987; 102:1-7.

25. Stefenelli T, Abela C, Frank H, et al: Cardiac abnormalities in patients with primary hyperparathyroidism: Implications for follow-up.  J Clin Endocrinol Metab  1997; 82:106-112.

26. Nilsson IL, Yin L, Lundgren E, et al: Clinical presentation of primary hyperparathyroidism in Europe—nationwide cohort analysis on mortality from nonmalignant causes.  J Bone Miner Res  2002; 17(Suppl 2):N68-N74.

27. Silverberg SJ, Shane E, de la Cruz L, et al: Skeletal disease in primary hyperparathyroidism [see comments].  J Bone Miner Res  1989; 4:283-291.

28. Bilezikian JP, Silverberg SJ, Shane E, et al: Characterization and evaluation of asymptomatic primary hyperparathyroidism.  J Bone Miner Res  1991; 6(Suppl 2):S85-S89.discussion S121-124

29. Bilezikian JP, Potts Jr JT, Fuleihan Gel H, et al: Summary statement from a workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century.  J Clin Endocrinol Metab  2002; 87:5353-5361.

30. Shoback DM, Bilezikian JP, Turner SA, et al: The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.  J Clin Endocrinol Metab  2003; 88:5644-5649.

31. Silverberg SJ, Bone 3rd HG, Marriott TB, et al: Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism.  N Engl J Med  1997; 337:1506-1510.

32. Peacock M, Bilezikian JP, Klassen PS, et al: Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism.  J Clin Endocrinol Metab  2005; 90:135-141.

32a. Politz D, Norman J: Hyperparathyroidism in patients over 80: clinical characteristics and their ability to undergo outpatient parathyroidectomy.  Thyroid  2007; 17:333-339.

33. Saxe AW, Brennan MF: Reoperative parathyroid surgery for primary hyperparathyroidism caused by multiple-gland disease: Total parathyroidectomy and autotransplantation with cryopreserved tissue.  Surgery  1982; 91:616-621.

34. Rudberg C, Akerstrom G, Palmer M, et al: Late results of operation for primary hyperparathyroidism in 441 patients.  Surgery  1986; 99:643-651.

35. Ruda JM, Hollenbeak CS, Stack Jr BC: A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003.  Otolaryngol Head Neck Surg  2005; 132:359-372.

36. Anderson BJ, Samaan NA, Vassilopoulou-Sellin R, et al: Parathyroid carcinoma: Features and difficulties in diagnosis and management.  Surgery  1983; 94:906-915.

37. Hoelting T, Weber T, Werner J, Herfarth C: Surgical treatment of parathyroid carcinoma (review).  Oncol Rep  2001; 8:931-934.

38. Shattuck TM, Valimaki S, Obara T, et al: Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma.  N Engl J Med  2003; 349:1722-1729.

39. Kremer R, Shustik C, Tabak T, et al: Parathyroid-hormone-related peptide in hematologic malignancies.  Am J Med  1996; 100:406-411.

40. Grill V, Ho P, Body JJ, et al: Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer.  J Clin Endocrinol Metab  1991; 73:1309-1315.

41. Strewler GJ, Nissenson RA: Parathyroid-hormone-related protein.   In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism,  Philadelphia: Lippincott-Raven; 1996.

42. Stewart AF, Mangin M, Wu T, et al: Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats.  J Clin Invest  1988; 81:596-600.

43. Karaplis AC, Luz A, Glowacki J, et al: Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene.  Genes Dev  1994; 8:277-289.

44. Breslau NA, McGuire JL, Zerwekh JE, et al: Hypercalcemia associated with increased serum calcitriol levels in three patients with lymphoma.  Ann Intern Med  1984; 100:1-6.

45. Rosenthal N, Insogna KL, Godsall JW, et al: Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia.  J Clin Endocrinol Metab  1985; 60:29-33.

46. Fetchick DA, Bertolini DR, Sarin PS, et al: Production of 1,25-dihydroxyvitamin D3 by human T cell lymphotrophic virus-I-transformed lymphocytes.  J Clin Invest  1986; 78:592-596.

47. Nussbaum SR, Gaz RD, Arnold A: Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone.  N Engl J Med  1990; 323:1324-1328.

48. Ross JR, Saunders Y, Edmonds PM, et al: Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer.  BMJ  2003; 327:469.

49. Neville-Webbe H, Holen I, Coleman R: The anti-tumour activity of bisphosphonates.  Cancer Treat Rev  2002; 28:305-319.

50. Mundy GR: Myeloma bone disease.  Eur J Cancer  1998; 34:246-251.

51. Durie BG, Salmon SE, Mundy GR: Relation of osteoclast activating factor production to extent of bone disease in multiple myeloma.  Br J Haematol  1981; 47:21-30.

52. Berenson J, Hillner B, Kyle R, et al: American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma.  J Clin Oncol  2002; 20:3719-3736.

53. Huang S-M, Duh QY, Shaver J, et al: Familial hyperparathyroidism without multiple endocrine neoplasia.  World J Surg  1997; 21:22-29.

54. Simonds W, James-Newton L, Agarwal S, et al: Familial isolated hyperparathyroidism: Clinical and genetic characteristics of 36 kindreds.  Medicine (Baltimore)  2002; 81:1-26.

55. Teh BT, Farnebo F, Twigg S, et al: Familial isolated hyperparathyroidism maps to the hyperparathyroidism- jaw tumor locus in 1q21-q32 in a subset of families.  J Clin Endocrinol Metab  1998; 83:2114-2120.

56. Simonds WF, Robbins CM, Agarwal SK, et al: Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome.  J Clin Endocrinol Metab  2004; 89:96-102.

57. Teh BT, Esapa CT, Houlston R, et al: A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors.  Am J Hum Genet  1998; 63:1549-1554.

58. Villablanca A, Wassif W, Smith T, et al: Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism.  Eur J Endocrinol  2002; 147:313-322.

59. Schipani E, Langman CB, Parfitt AM, et al: Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia [see comments].  N Engl J Med  1996; 335:708-714.

60. Schipani E, Kruse K, Juppner H: A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia.  Science  1995; 268:98-100.

61. Guo S, Sawicki M: Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1.  Mol Endocrinol  2001; 15:1653-1664.

62. Bystrom C, Larsson C, Blomberg C, et al: Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors.  Proc Natl Acad Sci U S A  1990; 87:1968-1972.

63. Lemmens I, Van de Ven WJ, Kas K, et al: Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.  Hum Mol Genet  1997; 6:1177-1183.

64. Guru SC, Goldsmith PK, Burns AL, et al: Menin, the product of the MEN1 gene, is a nuclear protein.  Proc Natl Acad Sci U S A  1998; 95:1630-1634.

65. Marx SJ, Agarwal SK, Kester MB, et al: Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MEN1).  J Intern Med  1998; 243:447-453.

66. Bassett JH, Forbes SA, Pannett AA, et al: Characterization of mutations in patients with multiple endocrine neoplasia type 1.  Am J Hum Genet  1998; 62:232-244.

67. Donis-Keller H, Dou S, Chi D, et al: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.  Hum Mol Genet  1993; 2:851-856.

68. Marx SJ, Simonds WF, Agarwal SK, et al: Hyperparathyroidism in hereditary syndromes: special expressions and special managements.  J Bone Miner Res  2002; 17(Suppl 2):N37-N43.

69. Brandi M, Gagel R, Angeli A, et al: Guidelines for diagnosis and therapy of MEN type 1 and type 2.  J Clin Endocrinol Metab  2001; 86:5658-5671.

70. Jackson CE, Norum RA, Boyd SB, et al: Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: A clinically and genetically distinct syndrome.  Surgery  1990; 108:1006-1012.discussion 1012-1013

71. Carpten J, Robbins C, Villablanca A, et al: HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.  Nat Genet  2002; 32:676-680.

72. Marx SJ, Attie MF, Levine MA, et al: The hypocalciuric or benign variant of familial hypercalcemia: Clinical and biochemical features in fifteen kindreds.  Medicine (Baltimore)  1981; 60:397-412.

73. Attie M, Gill J, Stock J, et al: Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism.  J Clin Invest  1983; 72:667-676.

74. Pollak MR, Seidman CE, Brown EM: Three inherited disorders of calcium sensing.  Medicine (Baltimore)  1996; 75:115-123.

75. Hendy GN, D'Souza-Li L, Yang B, et al: Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.  Hum Mutat  2000; 16:281-296.

76. Bai M, Quinn S, Trivedi S, et al: Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor.  J Biol Chem  1996; 271:19537-19545.

77. Bai M, Pearce SH, Kifor O, et al: In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: Normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.  J Clin Invest  1997; 99:88-96.

78. Bai M, Janicic N, Trivedi S, et al: Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.  J Clin Invest  1997; 99:1917-1925.

79. Pollak MR, Brown EM, Chou YH, et al: Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.  Cell  1993; 75:1297-1303.

80. Marx S, Fraser D, Rapaport A: Familial hypocalciuric hypercalcemia. Mild expression of the gene in heterozygotes and severe expression in homozygotes.  Am J Med  1985; 78:15-22.

81. Pollak M, Chou Y-H, Marx S, et al: Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.  J Clin Invest  1994; 93:1108-1112.

82. Herman SP: Lithium, hypercalcemia, and hyperparathyroidism.  Biol Psychiatry  1981; 16:593-595.

83. Spiegel AM, Rudorfer MV, Marx SJ, Linnoila M: The effect of short term lithium administration on suppressibility of parathyroid hormone secretion by calcium in vivo.  J Clin Endocrinol Metab  1984; 59:354-357.

84. McHenry CR, Racke F, Meister M, et al: Lithium effects on dispersed bovine parathyroid cells grown in tissue culture.  Surgery  1991; 110:1061-1066.

85. Mallette LE, Eichhorn E: Effects of lithium carbonate on human calcium metabolism.  Arch Intern Med  1986; 146:770-776.

86. Fishbane S, Frei GL, Finger M, et al: Hypervitaminosis A in two hemodialysis patients.  Am J Kidney Dis  1995; 25:346-349.

87. Ragavan VV, Smith JE, Bilezikian JP: Vitamin A toxicity and hypercalcemia.  Am J Med Sci  1982; 283:161-164.

88. Suzumiya J, Asahara F, Katakami H, et al: Hypercalcaemia caused by all-trans retinoic acid treatment of acute promyelocytic leukaemia: Case report [letter] [see comments].  Eur J Haematol  1994; 53:126-127.

89. Valentic JP, Elias AN, Weinstein GD: Hypercalcemia associated with oral isotretinoin in the treatment of severe acne.  JAMA  1983; 250:1899-1900.

90. Larsen W, Fellowes G, Rickman LS: Life-threatening hypercalcemia and tamoxifen.  Am J Med  1990; 88:440-442.

91. Duarte CG, Winnacker JL, Becker KL, Pace A: Thiazide-induced hypercalcemia.  N Engl J Med  1971; 284:828-830.

92. Christensson T, Hellstrom K, Wengle B: Hypercalcemia and primary hyperparathyroidism. Prevalence in patients receiving thiazides as detected in a health screen.  Arch Intern Med  1977; 137:1138-1142.

93. Parfitt AM: The interactions of thiazide diuretics with parathyroid hormone and vitamin D: Studies in patients with hypoparathyroidism.  J Clin Invest  1972; 51:1879-1888.

94. Popovtzer MM, Subryan VL, Alfrey AC, et al: The acute effect of chlorothiazide on serum-ionized calcium. Evidence for a parathyroid hormone-dependent mechanism.  J Clin Invest  1975; 55:1295-1302.

95. McPherson ML, Prince SR, Atamer ER, et al: Theophylline-induced hypercalcemia.  Ann Intern Med  1986; 105:52-54.

96. Burnett CH, Commons RR, Albright F, et al: Hypercalcemia without hypercalciuria or hypophosphatemia, calcinosis and renal insufficiency: A syndrome following prolonged intake of milk and alkali.  N Engl J Med  1949; 240:787.

97. Picolos MK, Lavis VR, Orlander PR: Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.  Clin Endocrinol (Oxf)  2005; 63:566-576.

98. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia.  Medicine (Baltimore)  1995; 74:89-96.

99. Sutton RA, Wong NL, Dirks JH: Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney.  Kidney Int  1979; 15:520-533.

100. Bell NH, Stern PH: Hypercalcemia and increases in serum hormone value during prolonged administration of 1alpha,25-dihydroxyvitamin D.  N Engl J Med  1978; 298:1241-1243.

101. Jacobus CH, Holick MF, Shao Q, et al: Hypervitaminosis D associated with drinking milk [see comments].  N Engl J Med  1992; 326:1173-1177.

102. Blank S, Scanlon KS, Sinks TH, et al: An outbreak of hypervitaminosis D associated with the overfortification of milk from a home-delivery dairy.  Am J Public Health  1995; 85:656-659.

103. Stewart AF, Adler M, Byers CM, et al: Calcium homeostasis in immobilization: An example of resorptive hypercalciuria.  N Engl J Med  1982; 306:1136-1140.

104. Singer FR, Minoofar PN: Bisphosphonates in the treatment of disorders of mineral metabolism.  Adv Endocrinol Metab  1995; 6:259-288.

105. Studdy PR, Bird R, Neville E, James DG: Biochemical findings in sarcoidosis.  J Clin Pathol  1980; 33:528-533.

106. Barbour GL, Coburn JW, Slatopolsky E, et al: Hypercalcemia in an anephric patient with sarcoidosis: Evidence for extrarenal generation of 1,25-dihydroxyvitamin D.  N Engl J Med  1981; 305:440-443.

107. Mason RS, Frankel T, Chan YL, et al: Vitamin D conversion by sarcoid lymph node homogenate.  Ann Intern Med  1984; 100:59-61.

108. Sandler LM, Winearls CG, Fraher LJ, et al: Studies of the hypercalcaemia of sarcoidosis: Effect of steroids and exogenous vitamin D3 on the circulating concentrations of 1,25- dihydroxy vitamin D3.  Q J Med  1984; 53:165-180.

109. Adams JS, Sharma OP, Diz MM, Endres DB: Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia.  J Clin Endocrinol Metab  1990; 70:1090-1095.

110. O'Leary TJ, Jones G, Yip A, et al: The effects of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis.  N Engl J Med  1986; 315:727-730.

111. Fuss M, Pepersack T, Gillet C, et al: Calcium and vitamin D metabolism in granulomatous diseases.  Clin Rheumatol  1992; 11:28-36.

112. Kelestimur F, Guven M, Ozesmi M, Pasaoglu H: Does tuberculosis really cause hypercalcemia?.  J Endocrinol Invest  1996; 19:678-681.

113. Burman KD, Monchik JM, Earll JM, Wartofsky L: Ionized and total serum calcium and parathyroid hormone in hyperthyroidism.  Ann Intern Med  1976; 84:668-671.

114. Mundy GR, Shapiro JL, Bandelin JG, et al: Direct stimulation of bone resorption by thyroid hormones.  J Clin Invest  1976; 58:529-534.

115. Stewart AF, Hoecker JL, Mallette LE, et al: Hypercalcemia in pheochromocytoma. Evidence for a novel mechanism.  Ann Intern Med  1985; 102:776-779.

116. Diamond T, Thornley S: Addisonian crisis and hypercalcaemia.  Aust N Z J Med  1994; 24:316.

117. Mao C, Carter P, Schaefer P, et al: Malignant islet cell tumor associated with hypercalcemia.  Surgery  1995; 117:37-40.

118. Knox JB, Demling RH, Wilmore DW, et al: Hypercalcemia associated with the use of human growth hormone in an adult surgical intensive care unit.  Arch Surg  1995; 130:442-445.

119. Aloia J, Powell D, Mendizibal E, Roginsky M: Parathyroid function in acromegaly.  Horm Res  1975; 6:145-149.

120. Grimm T, Wesselhoeft H: The genetic aspects of Williams-Beuren syndrome and the isolated form of the supravalvular aortic stenosis. Investigation of 128 families (author's transl)].  Z Kardiol  1980; 69:168-172.

121. Perez Jurado LA, Peoples R, Kaplan P, et al: Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth.  Am J Hum Genet  1996; 59:781-792.

122. Cook JS, Stone MS, Hansen JR: Hypercalcemia in association with subcutaneous fat necrosis of the newborn: Studies of calcium-regulating hormones.  Pediatrics  1992; 90:93-96.

123. Bilezikian JP: Management of acute hypercalcemia [see comments].  N Engl J Med  1992; 326:1196-1203.

124. Sato M, Grasser W, Endo N, et al: Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure.  J Clin Invest  1991; 88:2095-2105.

125. Major P, Lortholary A, Hon J, et al: Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials.  J Clin Oncol  2001; 19:558-567.

126. Deftos LJ, First BP: Calcitonin as a drug.  Ann Intern Med  1981; 95:192-197.

127. Chitambar CR: Gallium nitrate revisited.  Semin Oncol  2003; 30:1-4.

128. Cvitkovic F, Armand JP, Tubiana-Hulin M, et al: Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia.  Cancer J  2006; 12:47-53.

129. Seymour JF, Gagel RF: Calcitriol: The major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas.  Blood  1993; 82:1383-1394.

130. Cardella CJ, Birkin BL, Rapoport A: Role of dialysis in the treatment of severe hypercalcemia: Report of two cases successfully treated with hemodialysis and review of the literature.  Clin Nephrol  1979; 12:285-290.

131. Kaiser W, Biesenbach G, Kramar R, Zazgornik J: Calcium free hemodialysis: an effective therapy in hypercalcemic crisis—report of 4 cases.  Intensive Care Med  1989; 15:471-474.

132. Falzon M, Zong J: The noncalcemic vitamin D analogs EB1089 and 22-oxacalcitriol suppress serum-induced parathyroid hormone-related peptide gene expression in a lung cancer cell line.  Endocrinology  1998; 139:1046-1053.

132a. Lomonte C, Antonelli M, Losurdo N, et al: Cinacalcet is effective in relapses of secondary hyperparathyroidism after parathyroidectomy.  Nephrol Dial Transplant  2007 Apr 20;[Epub ahead of print].

132b. Sloand JA, Shelly MA: Normalization of lithium-induced hypercalcemia and hyperparathyroidism with cinacalcet hydrochloride.  Am J Kidney Dis  2006; 48:832-837.

133. Connor TB, Rosen BL, Blaustein MP, et al: Hypocalcemia precipitating congestive heart failure.  N Engl J Med  1982; 307:869-872.

133a. Kazmi AS, Wall BM: Reversible congestive heart failure related to profound hypocalcemia secondary to hypoparathyroidism.  Am J Med Sci  2007; 333:226-229.

134. Illum F, Dupont E: Prevalences of CT-detected calcification in the basal ganglia in idiopathic hypoparathyroidism and pseudohypoparathyroidism.  Neuroradiology  1985; 27:32-37.

135. Prince MR, Erel HE, Lent RW, et al: Gadodiamide administration causes spurious hypocalcemia.  Radiology  2003; 227:639-646.

136. Pollak MR, Brown EM, Estep HL, et al: Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.  Nat Genet  1994; 8:303-307.

137. Pearce SH, Williamson C, Kifor O, et al: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.  N Engl J Med  1996; 335:1115-1122.

138. Watanabe S, Fukumoto S, Chang H, et al: Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.  Lancet  2002; 360:692-694.

139. Ahn TG, Antonarakis SE, Kronenberg HM, et al: Familial isolated hypoparathyroidism: A molecular genetic analysis of 8 families with 23 affected persons.  Medicine (Baltimore)  1986; 65:73-81.

140. Arnold A, Horst SA, Gardella TJ, et al: Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism.  J Clin Invest  1990; 86:1084-1087.

141. Parkinson DB, Thakker RV: A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism.  Nat Genet  1992; 1:149-152.

142. Bowl MR, Nesbit MA, Harding B, et al: An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism.  J Clin Invest  2005; 115:2822-2831.

143. Raatikka M, Rapola J, Tuuteri L, et al: Familial third and fourth pharyngeal pouch syndrome with truncus arteriosus: DiGeorge syndrome.  Pediatrics  1981; 67:173-175.

144. Scambler PJ, Carey AH, Wyse RK, et al: Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome.  Genomics  1991; 10:201-206.

145. Yagi H, Furutani Y, Hamada H, et al: Role of TBX1 in human del22q11.2 syndrome.  Lancet  2003; 362:1366-1373.

146. Scire G, Dallapiccola B, Iannetti P, et al: Hypoparathyroidism as the major manifestation in two patients with 22q11 deletions.  Am J Med Genet  1994; 52:478-482.

147. Zupanc ML, Moraes CT, Shanske S, et al: Deletion of mitochondrial DNA in patients with combined features of Kearns-Sayre and MELAS syndromes.  Ann Neurol  1991; 29:680-683.

148. Neufeld M, Maclaren N, Blizzard R: Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes.  Medicine (Baltimore)  1981; 60:355-362.

149. Parvari R, Hershkovitz E, Grossman N, et al: Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.  Nat Genet  2002; 32:448-452.

150. Ringel MD, Schwindinger WF, Levine MA: Clinical implications of genetic defects in G proteins. The molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy.  Medicine (Baltimore)  1996; 75:171-184.

151. Chase LR, Melson GL, Aurbach GD: Pseudohypoparathyroidism: Defective excretion of 3′,5′-AMP in response to parathyroid hormone.  J Clin Invest  1969; 48:1832-1844.

152. Farfel Z, Brickman AS, Kaslow HR, et al: Defect of receptor-cyclase coupling protein in psudohypoparathyroidism.  N Engl J Med  1980; 303:237-242.

153. Nakamoto JM, Sandstrom AT, Brickman AS, et al: Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsalpha gene mutation.  Am J Med Genet  1998; 77:261-267.

154. Bastepe M, Frohlich LF, Hendy GN, et al: Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS.  J Clin Invest  2003; 112:1255-1263.

155. Bastepe M, Frohlich LF, Linglart A, et al: Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib.  Nat Genet  2005; 37:25-27.

156. Weinstein LS, Shenker A, Gejman PV, et al: Activating mutations of the stimulatory G protein in the McCune-Albright syndrome [see comments].  N Engl J Med  1991; 325:1688-1695.

157. Iiri T, Herzmark P, Nakamoto JM, et al: Rapid GDP release from Gs alpha in patients with gain and loss of endocrine function [see comments].  Nature  1994; 371:164-168.

158. Farfel Z, Brothers VM, Brickman AS, et al: Pseudohypoparathyroidism: Inheritance of deficient receptor-cyclase coupling activity.  Proc Natl Acad Sci U S A  1981; 78:3098-3102.

159. Drezner M, Neelon FA, Lebovitz HE: Pseudohypoparathyroidism type II: A possible defect in the reception of the cyclic AMP signal.  N Engl J Med  1973; 289:1056-1060.

160. See AC, Soo KC: Hypocalcaemia following thyroidectomy for thyrotoxicosis.  Br J Surg  1997; 84:95-97.

161. Demeester-Mirkine N, Hooghe L, Van Geertruyden J, De Maertelaer V: Hypocalcemia after thyroidectomy.  Arch Surg  1992; 127:854-858.

162. Yamashita H, Noguchi S, Tahara K, et al: Postoperative tetany in patients with Graves' disease: a risk factor analysis.  Clin Endocrinol (Oxf)  1997; 47:71-77.

163. Laitinen K, Lamberg-Allardt C, Tunninen R, et al: Transient hypoparathyroidism during acute alcohol intoxication.  N Engl J Med  1991; 324:721-727.

164. Cholst IN, Steinberg SF, Tropper PJ, et al: The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects.  N Engl J Med  1984; 310:1221-1225.

165. Quitterer U, Hoffmann M, Freichel M, Lohse MJ: Paradoxical block of parathormone secretion is mediated by increased activity of G alpha subunits.  J Biol Chem  2001; 276:6763-6769.

166. Rude RK, Oldham SB, Singer FR: Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency.  Clin Endocrinol (Oxf)  1976; 5:209-224.

167. Elisaf M, Milionis H, Siamopoulos KC: Hypomagnesemic hypokalemia and hypocalcemia: Clinical and laboratory characteristics.  Miner Electrolyte Metab  1997; 23:105-112.

168. Brown E, Vassilev P, Hebert S: Calcium ions as extracellular messengers.  Cell  1995; 83:679-682.

169. Betterle C, Greggio NA, Volpato M: Clinical review 93: Autoimmune polyglandular syndrome type 1.  J Clin Endocrinol Metab  1998; 83:1049-1055.

170. Heino M, Peterson P, Kudoh J, et al: APECED mutations in the autoimmune regulator (AIRE) gene.  Hum Mutat  2001; 18:205-211.

171. Li Y, Song YH, Rais N, et al: Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism [see comments].  J Clin Invest  1996; 97:910-914.

172. Preece MA, Tomlinson S, Ribot CA, et al: Studies of vitamin D deficiency in man.  Q J Med  1975; 44:575-589.

173. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al: Hypovitaminosis D in medical inpatients [see comments].  N Engl J Med  1998; 338:777-783.

174. Honasoge M, Rao DS: Metabolic bone disease in gastrointestinal, hepatobiliary, and pancreatic disorders and total parenteral nutrition.  Curr Opin Rheumatol  1995; 7:249-254.

175. Morgan DB, Paterson CR, Woods CG, et al: Search for osteomalacia in 1228 patients after gastrectomy and other operations on the stomach.  Lancet  1965; 2:1085-1088.

176. Hajjar ET, Vincenti F, Salti IS: Gluten-induced enteropathy. Osteomalacia as its principal manifestation.  Arch Intern Med  1974; 134:565-566.

177. Parfitt AM, Miller MJ, Frame B, et al: Metabolic bone disease after intestinal bypass for treatment of obesity.  Ann Intern Med  1978; 89:193-199.

178. Crippin JS, Jorgensen RA, Dickson ER, Lindor KD: Hepatic osteodystrophy in primary biliary cirrhosis: Effects of medical treatment.  Am J Gastroenterol  1994; 89:47-50.

179. Barragry JM, France MW, Carter ND, et al: Vitamin-D metabolism in nephrotic syndrome.  Lancet  1977; 2:629-632.

180. Hahn TJ: Drug-induced disorders of vitamin D and mineral metabolism.  Clin Endocrinol Metab  1980; 9:107-127.

181. Hahn TJ, Birge SJ, Scharp CR, Avioli LV: Phenobarbital-induced alterations in vitamin D metabolism.  J Clin Invest  1972; 51:741-748.

182. Kitanaka S, Takeyama K, Murayama A, et al: Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets [see comments].  N Engl J Med  1998; 338:653-661.

183. Brooks MH, Bell NH, Love L, et al: Vitamin-D-dependent rickets type II: Resistance of target organs to 1,25-dihydroxyvitamin D.  N Engl J Med  1978; 298:996-999.

184. Haussler MR, Haussler CA, Jurutka PW, et al: The vitamin D hormone and its nuclear receptor: Molecular actions and disease states.  J Endocrinol  1997; 154(Suppl):S57-S73.

185. Rudolph R, Boyd CR: Massive transfusion: Complications and their management.  South Med J  1990; 83:1065-1070.

186. Silberstein LE, Naryshkin S, Haddad JJ, Strauss JF: Calcium homeostasis during therapeutic plasma exchange.  Transfusion  1986; 26:151-155.

187. Jacobson MA, Gambertoglio JG, Aweeka FT, et al: Foscarnet-induced hypocalcemia and effects of foscarnet on calcium metabolism.  J Clin Endocrinol Metab  1991; 72:1130-1135.

188. Ranson JH, Rifkind KM, Roses DF, et al: Prognostic signs and the role of operative management in acute pancreatitis.  Surg Gynecol Obstet  1974; 139:69-81.

189. Chernow B, Rainey TG, Georges LP, O'Brian JT: Iatrogenic hyperphosphatemia: A metabolic consideration in critical care medicine.  Crit Care Med  1981; 9:772-774.

190. Zusman J, Brown DM, Nesbit ME: Hyperphosphatemia, hyperphosphaturia and hypocalcemia in acute lymphoblastic leukemia.  N Engl J Med  1973; 289:1335-1340.

191. Zivin JR, Gooley T, Zager RA, Ryan MJ: Hypocalcemia: A pervasive metabolic abnormality in the critically ill.  Am J Kidney Dis  2001; 37:689-698.

192. Sperber SJ, Blevins DD, Francis JB: Hypercalcitoninemia, hypocalcemia, and toxic shock syndrome.  Rev Infect Dis  1990; 12:736-739.

193. Boyce BF, Yates AJ, Mundy GR: Bolus injections of recombinant human interleukin-1 cause transient hypocalcemia in normal mice.  Endocrinology  1989; 125:2780-2783.

194. Mimouni F, Tsang RC: Neonatal hypocalcemia: To treat or not to treat? (A review).  J Am Coll Nutr  1994; 13:408-415.

195. Specker BL, Tsang RC, Ho ML, et al: Low serum calcium and high parathyroid hormone levels in neonates fed ‘humanized’ cow's milk-based formula.  Am J Dis Child  1991; 145:941-945.

196. Thomas BR, Bennett JD: Symptomatic hypocalcemia and hypoparathyroidism in two infants of mothers with hyperparathyroidism and familial benign hypercalcemia [see comments].  J Perinatol  1995; 15:23-26.

197. Lim P, Jacob E: Tissue magnesium level in chronic diarrhea.  J Lab Clin Med  1972; 80:313-321.

198. Ryzen E, Elbaum N, Singer FR, Rude RK: Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency.  Magnesium  1985; 4:137-147.

199. Carney SL, Wong NL, Quamme GA, Dirks JH: Effect of magnesium deficiency on renal magnesium and calcium transport in the rat.  J Clin Invest  1980; 65:180-188.

200. Wong ET, Rude RK, Singer FR, Shaw Jr ST: A high prevalence of hypomagnesemia and hypermagnesemia in hospitalized patients.  Am J Clin Pathol  1983; 79:348-352.

201. Tong GM, Rude RK: Magnesium deficiency in critical illness.  J Intensive Care Med  2005; 20:3-17.

202. Elisaf M, Panteli K, Theodorou J, Siamopoulos KC: Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia.  Magnes Res  1997; 10:315-320.

203. Sutton RA, Domrongkitchaiporn S: Abnormal renal magnesium handling.  Miner Electrolyte Metab  1993; 19:232-240.

204. De Marchi S, Cecchin E, Basile A, et al: Renal tubular dysfunction in chronic alcohol abuse—effects of abstinence.  N Engl J Med  1993; 329:1927-1934.

205. Dickerson RN, Brown RO: Hypomagnesemia in hospitalized patients receiving nutritional support.  Heart Lung  1985; 14:561-569.

206. Bowling TE, Silk DB: Refeeding remembered.  Nutrition  1995; 11:32-34.

207. Booth CC, Babouris N, Hanna S, MacIntyre I: Incidence of hypomagneaemia in intestinal malabsorption.  Br Med J  1963; 2:141-144.

208. Thorén L: Magnesium deficiency in gastrointestinal fluid loss.  Acta Chir Scand Suppl  1963; 306:1-65.

209. Cohen L, Zimmerman AL: Changes in serum electrolyte levels during marathon running.  S Afr Med J  1978; 53:449-453.

210. Berger MM, Rothen C, Cavadini C, Chiolero RL: Exudative mineral losses after serious burns: A clue to the alterations of magnesium and phosphate metabolism.  Am J Clin Nutr  1997; 65:1473-1481.

211. Davies DR, Friedman M: Complications after parathyroidectomy: Fractures from low calcium and magnesium convulsions.  J Bone Joint Surg Br  1966; 48B:117-126.

212. Nabarro JDN, Spencer AG, Stowers JM: Metabolic studies in severe diabetic ketosis.  Q J Med  1952; 82:225-243.

213. Martin HE, Smith K, Wilson ML: The fluid and electrolyte therapy of severe diabetic acidosis and ketosis: A study of twenty-nine episodes (twenty-six patients).  Am J Med  1958; 24:376-389.

214. Mader IJ, Iseri LT: Spontaneous hypopotassemia, hypomagnesemia, alkalosis and tetany due to hypersecretion of corticosterone-like mineralocorticoid.  Am J Med  1955; 19:976-988.

215. Dyckner T, Wester PO: Renal excretion of electrolytes in patients on long-term diuretic therapy for arterial hypertension and/or congestive heart failure.  Acta Med Scand  1985; 218:443-448.

216. Kuller L, Farrier N, Caggiula A, et al: Relationship of diuretic therapy and serum magnesium levels among participants in the Multiple Risk Factor Intervention Trial.  Am J Epidemiol  1985; 122:1045-1059.

217. Quamme GA: Effect of hypercalcemia on renal tubular handling of calcium and magnesium.  Can J Physiol Pharmacol  1982; 60:1275-1280.

218. Johansson G, Danielson BG, Ljunghall S: Magnesium homeostasis in mild-to-moderate primary hyperparathyroidism.  Acta Chir Scand  1980; 146:85-91.

219. Buckley JE, Clark VL, Meyer TJ, Pearlman NW: Hypomagnesemia after cisplatin combination chemotherapy.  Arch Intern Med  1984; 144:2347-2348.

220. Brock PR, Koliouskas DE, Barratt TM, et al: Partial reversibility of cisplatin nephrotoxicity in children.  J Pediatr  1991; 118:531-534.

221. Ettinger L, Gaynon P, Krailo M, et al: A phase II study of carboplatin in children with recurrent or progressive solid tumors. A report from the Childrens Cancer Group.  Cancer  1994; 73:1297-1301.

222. Lajer H, Kristensen M, Hansen HH, et al: Magnesium and potassium homeostasis during cisplatin treatment.  Cancer Chemother Pharmacol  2005; 55:231-236.

223. Barton CH, Pahl M, Vaziri ND, Cesario T: Renal magnesium wasting associated with amphotericin B therapy.  Am J Med  1984; 77:471-474.

224. Wilkinson R, Lucas GL, Heath DA, et al: Hypomagnesaemic tetany associated with prolonged treatment with aminoglycosides.  Br Med J  1986; 292:818-819.

225. Zaloga GP, Chernow B, Pock A, et al: Hypomagnesemia is a common complication of aminoglycoside therapy.  Surg Gynecol Obstet  1984; 158:561-565.

226. Mani S: Pentamidine-induced renal magnesium wasting [letter].  AIDS  1992; 6:594-595.

227. Palestine AG, Polis MA, De Smet MD, et al: A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS.  Ann Intern Med  1991; 115:665-673.

228. Barton CH, Vaziri ND, Martin DC, et al: Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine.  Am J Med  1987; 83:693-699.

229. June CH, Thompson CB, Kennedy MS, et al: Profound hypomagnesemia and renal magnesium wasting associated with the use of cyclosporine for marrow transplantation.  Transplantation  1985; 39:620-624.

230. Yuan J, Zhou J, Chen BC, et al: Magnesium supplementation prevents chronic cyclosporine nephrotoxicity via adjusting nitric oxide synthase activity.  Transplant Proc  2005; 37:1892-1895.

231. Konrad M, Weber S: Recent advances in molecular genetics of hereditary magnesium-losing disorders.  J Am Soc Nephrol  2003; 14:249-260.

232. Geven WB, Monnens LA, Willems HL, et al: Renal magnesium wasting in two families with autosomal dominant inheritance.  Kidney Int  1987; 31:1140-1144.

233. Geven WB, Monnens LA, Willems JL, et al: Isolated autosomal recessive renal magnesium loss in two sisters.  Clin Genet  1987; 32:398-402.

234. Meij IC, Koenderink JB, van Bokhoven H, et al: Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit.  Nat Genet  2000; 26:265-266.

235. Meij IC, Koenderink JB, De Jong JC, et al: Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit.  Ann N Y Acad Sci  2003; 986:437-443.

236. Kantorovich V, Adams J, Gaines J, et al: Genetic heterogeneity in familial renal magnesium wasting.  J Clin Endocrinol Metab  2002; 87:612-617.

237. Simon DB, Lu Y, Choate KA, et al: Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption.  Science  1999; 285:103-106.

238. Kausalya PJ, Amasheh S, Gunzel D, et al: Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of Claudin-16.  J Clin Invest  2006; 116:878-891.

239. Weber S, Schneider L, Peters M, et al: Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.  J Am Soc Nephrol  2001; 12:1872-1881.

240. Walder R, Shalev H, Brennan T, et al: Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: Genetic linkage mapping and analysis of a balanced translocation breakpoint.  Hum Mol Genet  1997; 6:1491-1497.

241. Walder R, Landau D, Meyer P, et al: Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia.  Nat Genet  2002; 31:171-174.

241a. Groenestege WM, Hoenderop JG, van den Heuvel L, et al: The epithelial Mg2+ channel transient receptor potential melastatin 6 is regulated by dietary Mg2+ content and estrogens.  J Am Soc Nephrol  2006; 17:1035-1043.

242. Kristiansen JH, Brochner Mortensen J, Pedersen KO: Familial hypocalciuric hypercalcaemia I: Renal handling of calcium, magnesium and phosphate.  Clin Endocrinol (Oxf)  1985; 22:103-116.

243. Kingston ME, Al-Siba'i MB, Skooge WC: Clinical manifestations of hypomagnesemia.  Crit Care Med  1986; 14:950-954.

244. Skou JC: The influence of some cations on an adenosine triphosphatase from peripheral nerves.  Biochim Biophys Acta  1957; 23:394-401.

245. Whang R, Morosi HJ, Rodgers D, Reyes R: The influence of sustained magnesium deficiency on muscle potassium repletion.  J Lab Clin Med  1967; 70:895-902.

246. Agus ZS: Hypomagnesemia.  J Am Soc Nephrol  1999; 10:1616-1622.

247. Seller RH, Cangiano J, Kim KE, et al: Digitalis toxicity and hypomagnesemia.  Am Heart J  1970; 79:57-68.

248. Dyckner T: Serum magnesium in acute myocardial infarction. Relation to arrhythmias.  Acta Med Scand  1980; 207:59-66.

249. England MR, Gordon G, Salem M, Chernow B: Magnesium administration and dysrhythmias after cardiac surgery. A placebo-controlled, double-blind, randomized trial.  JAMA  1992; 268:2395-2402.

250. Hazelrigg SR, Boley TM, Cetindag IB, et al: The efficacy of supplemental magnesium in reducing atrial fibrillation after coronary artery bypass grafting.  Ann Thorac Surg  2004; 77:824-830.

251. Klevay L, Milne D: Low dietary magnesium increases supraventricular ectopy.  Am J Clin Nutr  2002; 75:550-554.

252. Tsuji H, Venditti Jr FJ, Evans JC, et al: The associations of levels of serum potassium and magnesium with ventricular premature complexes (the Framingham Heart Study).  Am J Cardiol  1994; 74:232-235.

253. Vallee BL, Wacker WEC, Ulmer DD: The magnesium-deficiency tetany syndrome in man.  N Engl J Med  1960; 262:155-161.

254. Mody I, Lambert JD, Heinemann U: Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices.  J Neurophysiol  1987; 57:869-888.

255. Saul RF, Selhorst JB: Downbeat nystagmus with magnesium depletion.  Arch Neurol  1981; 38:650-652.

256. Whang R, Whang DD, Ryan MP: Refractory potassium repletion. A consequence of magnesium deficiency.  Arch Intern Med  1992; 152:40-45.

257. Dietary Reference Intakes: Intakes: Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride.  Board IoMFaN (ed),  Washington, DC, National Academy Press, 1999.

258. Oster JR, Epstein M: Management of magnesium depletion.  Am J Nephrol  1988; 8:349-354.

259. Eisenbud E, LoBue CC: Hypocalcemia after therapeutic use of magnesium sulfate.  Arch Intern Med  1976; 136:688-691.

260. Navarro J, Oster JR, Gkonos PJ, et al: Tetany induced on separate occasions by administration of potassium and magnesium in a patient with hungry-bone syndrome.  Miner Electrolyte Metab  1991; 17:340-344.

261. Farkas RA, McAllister CT, Blachley JD: Effect of magnesium salt anions on potassium balance in normal and magnesium-depleted rats.  J Lab Clin Med  1987; 110:412-417.

262. Bundy JT, Connito D, Mahoney MD, Pontier PJ: Treatment of idiopathic renal magnesium wasting with amiloride.  Am J Nephrol  1995; 15:75-77.

263. Coburn JW, Popovtzer MM, Massry SG, Kleeman CR: The physicochemical state and renal handling of divalent ions in chronic renal failure.  Arch Intern Med  1969; 124:302-311.

264. Clark BA, Brown RS: Unsuspected morbid hypermagnesemia in elderly patients.  Am J Nephrol  1992; 12:336-343.

265. Mordes JP, Wacker WE: Excess magnesium.  Pharmacol Rev  1977; 29:273-300.

266. Touyz RM: Magnesium in clinical medicine.  Front Biosci  2004; 9:1278-1293.

267. del Castillo J, Engbaek L: The nature of the neuromuscular block produced by magnesium.  J Physiol  1954; 124:370-384.

268. Kelber J, Slatopolsky E, Delmez JA: Acute effects of different concentrations of dialysate magnesium during high-efficiency dialysis.  Am J Kidney Dis  1994; 24:453-460.

269. Boen ST: Kinetics of peritoneal dialysis  1961; 40:243-287.

270. Burritt M, Slockbower J, Forsman R, et al: Pediatric reference intervals for 19 biologic variables in healthy children.  Mayo Clin Proc  1990; 65:329-336.

271. Markowitz M, Rotkin L, Rosen J: Circadian rhythms of blood minerals in humans.  Science  1981; 213:672-674.

272. Hsu CY, Chertow GM: Elevations of serum phosphorus and potassium in mild to moderate chronic renal insufficiency.  Nephrol Dial Transplant  2002; 17:1419-1425.

273. Quigley R, Baum M: Effects of growth hormone and insulin-like growth factor I on rabbit proximal convoluted tubule transport.  J Clin Invest  1991; 88:368-374.

274. Mitnick P, Goldfarb S, Slatopolsky E, et al: Calcium and phosphate metabolism in tumoral calcinosis.  Ann Intern Med  1980; 92:482-487.

275. Topaz O, Shurman DL, Bergman R, et al: Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.  Nat Genet  2004; 36:579-581.

276. Araya K, Fukumoto S, Backenroth R, et al: A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis.  J Clin Endocrinol Metab  2005; 90:5523-5527.

277. Chefetz I, Heller R, Galli-Tsinopoulou A, et al: A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification.  Hum Genet  2005; 118:261-266.

278. Yamaguchi T, Sugimoto T, Imai Y, et al: Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide.  Bone  1995; 16:247S-250S.

279. Walton R, Russell R, Smith R: Changes in the renal and extrarenal handling of phosphate induced by disodium etidronate (EHDP) in man.  Clin Sci Mol Med  1975; 49:45-56.

280. McCloskey E, Yates A, Gray R, et al: Diphosphonates and phosphate homoeostasis in man.  Clin Sci (Lond)  1988; 74:607-612.

280a. Gumurdulu Y, Serin E, Ozer B, et al: Age as a predictor of hyperphosphatemia after oral phosphosoda administration for colon preparation.  J Gastroenterol Hepatol  2004; 19:68-72.

280b. Desmeules S, Bergeron MJ, Isenring P: Acute phosphate nephropathy and renal failure.  N Engl J Med  2003; 349:1006-1007.

280c. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD: Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure.  J Am Soc Nephrol  2005; 16:3389-3396.

281. Krapf R, Jaeger P, Hulter H: Chronic respiratory alkalosis induces renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans.  Kidney Int  1992; 42:727-734.

282. Thompson C, Kemp G, Radda G: Changes in high-energy phosphates in rat skeletal muscle during acute respiratory acidosis.  Acta Physiol Scand  1992; 146:15-19.

283. Tsokos G, Balow J, Spiegel R, Magrath I: Renal and metabolic complications of undifferentiated and lymphoblastic lymphomas.  Medicine (Baltimore)  1981; 60:218-229.

284. Larner A: Pseudohyperphosphatemia.  Clin Biochem  1995; 28:391-393.

285. Knochel J: The pathophysiology and clinical characteristics of severe hypophosphatemia.  Arch Intern Med  1977; 137:203-220.

286. Lichtman M, Miller D, Cohen J, Waterhouse C: Reduced red cell glycolysis, 2, 3-diphosphoglycerate and adenosine triphosphate concentration, and increased hemoglobin-oxygen affinity caused by hypophosphatemia.  Ann Intern Med  1971; 74:562-568.

287. Jacob H, Amsden T: Acute hemolytic anemia with rigid red cells in hypophosphatemia.  N Engl J Med  1971; 285:1446-1450.

288. Craddock P, Yawata Y, VanSanten L, et al: Acquired phagocyte dysfunction. A complication of the hypophosphatemia of parenteral hyperalimentation.  N Engl J Med  1974; 290:1403-1407.

289. Newman J, Neff T, Ziporin P: Acute respiratory failure associated with hypophosphatemia.  N Engl J Med  1977; 296:1101-1103.

290. Fuller T, Nichols W, Brenner B, Peterson J: Reversible depression in myocardial performance in dogs with experimental phosphorus deficiency.  J Clin Invest  1978; 62:1194-1200.

291. Knochel J: Hypophosphatemia and rhabdomyolysis.  Am J Med  1992; 92:455-457.

292. Goldfarb S, Westby G, Goldberg M, Agus Z: Renal tubular effects of chronic phosphate depletion.  J Clin Invest  1977; 59:770-779.

293. Coburn J, Massry S: Changes in serum and urinary calcium during phosphate depletion: studies on mechanisms.  J Clin Invest  1970; 49:1073-1087.

294. Juan D, Elrazak M: Hypophosphatemia in hospitalized patients.  JAMA  1979; 242:163-164.

295. Torres A, Lorenzo V, Salido E: Calcium metabolism and skeletal problems after transplantation.  J Am Soc Nephrol  2002; 13:551-558.

296. Bhan I, Shah A, Holmes J, et al: Post-transplant hypophosphatemia: Tertiary ‘hyper-phosphatoninism’?.  Kidney Int  2006; 70:1486-1494.

297. Roth K, Foreman J, Segal S: The Fanconi syndrome and mechanisms of tubular transport dysfunction.  Kidney Int  1981; 20:705-716.

298. Gannage M, Abikaram G, Nasr F, Awada H: Osteomalacia secondary to celiac disease, primary hyperparathyroidism, and Graves' disease.  Am J Med Sci  1998; 315:136-139.

299. Chines A, Pacifici R: Antacid and sucralfate-induced hypophosphatemic osteomalacia: A case report and review of the literature.  Calcif Tissue Int  1990; 47:291-295.

300. Mostellar ME, Tuttle EP: Effects of alkalosis on plasma concentration and urinary excretion of urinary phosphate in man.  J Clin Invest  1964; 43:138-149.

301. Brautbar N, Leibovici H, Massry S: On the mechanism of hypophosphatemia during acute hyperventilation: Evidence for increased muscle glycolysis.  Miner Electrolyte Metab  1983; 9:45-50.

302. ChrisAnderson D, Heimburger D, Morgan S, et al: Metabolic complications of total parenteral nutrition: Effects of a nutrition support service.  JPEN J Parenter Enter Nutr  1996; 20:206-210.

303. Marik P, Bedigian M: Refeeding hypophosphatemia in critically ill patients in an intensive care unit. A prospective study.  Arch Surg  1996; 131:1043-1047.

304. Ornstein R, Golden N, Jacobson M, Shenker I: Hypophosphatemia during nutritional rehabilitation in anorexia nervosa: Implications for refeeding and monitoring.  J Adolesc Health  2003; 32:83-88.

305. Knochel J: Hypophosphatemia in the alcoholic.  Arch Intern Med  1980; 140:613-615.

306. Seldin DW, Tarail R: The metabolism of glucose and electrolytes in diabetic acidosis.  J Clin Invest  1950;552-560.

307. Atchley DW, Loeb RF, Richards DW: On diabetic acidosis. A detailed study of electrolyte balances following the withdrawal and reestablishment of insulin therapy.  J Clin Invest  1933; 12:297.

308. Kebler R, McDonald F, Cadnapaphornchai P: Dynamic changes in serum phosphorus levels in diabetic ketoacidosis.  Am J Med  1985; 79:571-576.

309. Fisher J, Kitabchi A: A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis.  J Clin Endocrinol Metab  1983; 57:177-180.

310. Turner S, Kiebzak G, Dousa T: Mechanism of glucocorticoid effect on renal transport of phosphate.  Am J Physiol  1982; 243:C227-C236.

311. Zamkoff K, Kirshner J: Marked hypophosphatemia associated with acute myelomonocytic leukemia. Indirect evidence of phosphorus uptake by leukemic cells.  Arch Intern Med  1980; 140:1523-1524.

312. Chesney P, Davis J, Purdy W, et al: Clinical manifestations of toxic shock syndrome.  JAMA  1981; 246:741-748.

313. Suki W, Martinez-Maldonado M, Rouse D, Terry A: Effect of expansion of extracellular fluid volume on renal phosphate handling.  J Clin Invest  1969; 48:1888-1894.

314. Dixon P, Christie P, Wooding C, et al: Mutational analysis of PHEX gene in X-linked hypophosphatemia.  J Clin Endocrinol Metab  1998; 83:3615-3623.

315. The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium.  Nat Genet  1995; 11:130-136.

316. Sabbagh Y, Jones A, Tenenhouse H: PHEXdb, a locus-specific database for mutations causing X-linked hypophosphatemia.  Hum Mutat  2000; 16:1-6.

317. Nesbitt T, Coffman T, Griffiths R, Drezner M: Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.  J Clin Invest  1992; 89:1453-1459.

318. Meyer M, Meyer RJ: MRNA expression of Phex in mice and rats: The effect of low phosphate diet.  Endocrine  2000; 13:81-87.

319. Bowe A, Finnegan R, Jan dBS, et al: FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate.  Biochem Biophys Res Commun  2001; 284:977-981.

320. Shimada T, Hasegawa H, Yamazaki Y, et al: FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.  J Bone Miner Res  2004; 19:429-435.

321. Sullivan W, Carpenter T, Glorieux F, et al: A prospective trial of phosphate and 1,25-dihydroxyvitamin D3 therapy in symptomatic adults with X-linked hypophosphatemic rickets.  J Clin Endocrinol Metab  1992; 75:879-885.

322. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. The ADHR Consortium.  Nat Genet  2000; 26:345-348.

323. White K, Carn G, Lorenz-Depiereux B, Benet-Pages A, et al: Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23.  Kidney Int  2001; 60:2079-2086.

324. Shimada T, Mizutani S, Muto T, et al: Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc natl.  Acad Sci U S A  2001; 98:6500-6505.

325. Schiavi S, Moe O: Phosphatonins: A new class of phosphate-regulating proteins.  Curr Opin Nephrol Hypertens  2002; 11:423-430.

325a. Urakawa I, Yamazaki Y, Shimada T, et al: Klotho converts canonical FGF receptor into a specific receptor for FGF23.  Nature  2006; 444:770-774.

325b. Torres PU, Prie D, Molina-Bletry V, et al: Klotho: an antiaging protein involved in mineral and vitamin D metabolism.  Kidney Int  2007; 71:730-737.

326. Rowe P, de ZP, Dong R, et al: MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia.  Genomics  2000; 67:54-68.

327. Bergwitz C, Roslin NM, Tieder M, et al: SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis.  Am J Hum Genet  2006; 78:179-192.

328. Prie D, Huart V, Bakouh N, et al: Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter.  N Engl J Med  2002; 347:983-991.

329. Stamp T, Baker L: Recessive hypophosphataemic rickets, and possible aetiology of the ‘vitamin D-resistant’ syndrome.  Arch Dis Child  1976; 51:360-365.

329a. Feng JQ, Ward LM, Liu S, et al: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.  Nat Genet  2006; 38:1310-1315.

330. Chitayat D, McGillivray B, Rothstein R, et al: Familial renal hypophosphatemia, minor facial anomalies, intracerebral calcifications, and non-rachitic bone changes: Apparently new syndrome?.  Am J Med Genet  1990; 35:406-414.

331. Lentz R, Brown D, Kjellstrand C: Treatment of severe hypophosphatemia.  Ann Intern Med  1978; 89:941-944.

332. Perreault M, Ostrop N, Tierney M: Efficacy and safety of intravenous phosphate replacement in critically ill patients.  Ann Pharmacother  1997; 31:683-688.

If you find an error or have any questions, please email us at Thank you!