PHPT is caused by excessive and incompletely regulated secretion of PTH, with consequent hypercalcemia and hypophosphatemia (see eBox 17.1 ). It is the underlying cause of approximately 50% of hypercalcemic cases in the general outpatient population. The estimated prevalence of PHPT is about 1% but may be as high as 2% in postmenopausal women. ^, The annual incidence is approximately 0.04%. A single enlarged parathyroid gland (adenoma) is the cause of PHPT in 85% of cases. These adenomas are benign clonal neoplasms of parathyroid chief cells, which lose their normal sensitivity to calcium. In about 15% of patients with PHPT, all four parathyroid glands are hyperplastic. This occurs in sporadic PHPT or in conjunction with MEN1 or MEN2. In diffuse hyperplasia, the set point for calcium is not changed in any given parathyroid cell, but the increased number of cells causes excess PTH production and hypercalcemia. Parathyroid carcinoma is seen in no more than 0.5% to 1% of patients with PHPT.

PHPT occurs at all ages but is most common in older individuals; peak incidence is in the sixth decade of life. After age 50 years, women are about three times more frequently affected than men. Sporadic PHPT is the most common. External neck irradiation during childhood is recognized as a risk factor for PHPT. The somatic DNA alterations underlying parathyroid adenomas have been partially elucidated. For example, rearrangements and overexpression of the PRAD-1–cyclin D1 oncogene have been observed in about 20% of parathyroid adenomas. ^, Moreover, the MEN1 tumor suppressor gene is functionally inactivated in about 15% of adenomas. ^,

PHPT typically presents in one of three ways. In 60% to 80% of cases, there are minimal or no symptoms, and mild hypercalcemia is usually discovered during routine laboratory examination. Another 20% to 25% of patients have a chronic course manifested by mild or intermittent hypercalcemia and recurrent kidney stones; in these patients, the parathyroid tumor is small (<1.0 g) and slow growing. In 5% to 10% of patients, there is severe and symptomatic hypercalcemia and overt osteitis fibrosa cystica; in these patients, the parathyroid tumor is usually large (>5.0 g). Patients with parathyroid carcinoma typically have severe hypercalcemia, with classic kidney and bone involvement.

The diagnosis of PHPT is now usually suggested by the incidental finding of hypercalcemia rather than by any of the sequelae of PTH excess, such as skeletal and kidney complications or symptomatic hypercalcemia. Hypercalcemia may be mild and intermittent. Hypercalciuria was noted in 40% of PHPT, nephrolithiasis in 19%, and classic bone disease and osteitis fibrosa cystica only in 2% of studies performed between 1984 and 2000 in the United States. However, even in individuals with mild PHPT, there is also progressive bone loss, as measured by bone mineral densitometry over 15 years of observation.

The diagnosis of PHPT is established by laboratory tests showing hypercalcemia, inappropriately normal or elevated blood levels of PTH, hypercalciuria, hypophosphatemia, phosphaturia, and increased urinary excretion of cAMP. Hyperchloremic acidosis may be present, and the ratio of serum chloride to phosphorus is elevated. The serum levels of alkaline phosphatase and uric acid may also be elevated.

Some controversy surrounds the potential relationship between PHPT and increased mortality. A number of studies have shown that PHPT may be associated with hypertension, dyslipidemia, diabetes, increased thickness of the carotid artery, and increased mortality, primarily from cardiovascular disease. ^, The morbidity from PHPT can also be substantial, especially in symptomatic patients with severe hypercalcemia and a late diagnosis.

The classic bone lesion in PHPT, osteitis fibrosa cystica, is now rarely seen. Diffuse osteopenia is more common. ^, Even in asymptomatic patients, increased rates of bone turnover are always present. ^,

Surgery is still the standard of therapy for PHPT. ^{, ,} It is generally agreed that parathyroidectomy is indicated for all patients with biochemically confirmed PHPT who have specific symptoms or signs of disease, such as a history of life-threatening hypercalcemia, CKD, and/or kidney stones. In 2013, a Fourth International Workshop on Hyperparathyroidism updated the guidelines for the management of asymptomatic HPT. Surgery is advised for asymptomatic disease in patients with serum calcium levels >1 mg/dL above normal, reduced bone mass (T-score < −2.5 at lumbar spine, total hip, femoral neck, or distal third of the radius), CKD, or age younger than 50 years. Hypercalciuria (>400 mg calcium/24 hours) with increased stone risk by biochemical stone risk analysis and the presence of nephrolithiasis or nephrocalcinosis by imaging techniques are currently considered an indication for parathyroid surgery. Patients older than 50 years with no obvious symptoms should receive close follow-up including measurements of bone density every 1 to 2 years and serum creatinine and calcium levels annually.

Preoperative localization of the parathyroid glands has generally been considered unnecessary in uncomplicated patients undergoing surgery for the first time with bilateral neck exploration. However, imaging studies are recommended to be used in complicated cases and if minimally invasive surgery is planned. Sestamibi scanning is the most popular and sensitive technique to localize PTH glands, with accuracy rates up to 94%, followed by ultrasound of the neck. ^, If a single adenoma is visualized, minimally invasive parathyroidectomy may be an option, with a cure rate of 95% to 98%. Otherwise, all four parathyroid glands should be surgically identified. Recurrence of HPT is rare after identification and removal of one enlarged gland. If the initial exploration fails, and hypercalcemia persists or recurs, more extensive preoperative parathyroid localization should be performed. ^{, ,} Ectopic parathyroid glands can arise due to abnormal migration during early development, and failure to accurately identify them can lead to unsuccessful parathyroid surgery.

Although parathyroidectomy remains the definitive treatment of PHPT, patients refusing surgery, those with contraindications for surgery, or those who do not meet current operative guidelines can be treated pharmacologically. There are four classes of medications that can be useful—calcimimetics, bisphosphonates, estrogens, and selective estrogen receptor modulators. ^, There are insufficient long-term data to recommend any of these medications as alternatives to surgery. The CaSR agonist, cinacalcet, has been approved in Europe for PHPT and in the United States for severe hypercalcemia in adult patients with PHPT who are unable to undergo parathyroidectomy. Cinacalcet therapy in PHPT patients reduced plasma PTH levels, normalized serum calcium levels in the short and long terms and preserved bone mineral density (BMD). Bisphosphonates and hormone replacement therapy decreased bone turnover and increased BMD in PHPT patients without changes in serum calcium levels.

Parathyroid carcinoma probably accounts for <1% of PHPT cases. 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. In general, parathyroid carcinomas are typically large (3 cm), irregular, hard tumors with a low degree of aggressive growth, and survival is common if the entire gland can be removed. ^, Cinacalcet is approved for patients with inoperable parathyroid cancer to control hypercalcemia.

Hypercalcemia occurs in approximately 10% to 25% of patients with some cancer, especially during the last 4 to 6 weeks of their life. It can be classified into four categories—HHM, local osteolytic hypercalcemia (LOH), 1,25 (OH) ₂ vitamin D−induced hypercalcemia, and ectopic secretion of authentic PTH. ^,

HHM from secretion of PTHrP by a malignant tumor accounts for approximately 80% of cases. Numerous types of malignancies are associated with HHM, including squamous cell cancer (e.g., head and neck, esophagus, cervix, and lung), renal cell carcinoma, breast cancer, and ovarian carcinoma. Lymphomas associated with human T-lymphotropic virus type 1 (HTLV-1) infection may cause PTHrP-mediated HHM and other non-Hodgkin lymphomas may also be associated with PTHrP-mediated hypercalcemia. ^, PTHrP is a large protein encoded by a gene on chromosome 12; it is similar to PTH only at the NH ₂ terminus, where the initial eight amino acids are identical. PTHrP is widely expressed in a variety of tissues including keratinocytes, mammary gland, placenta, cartilage, nervous system, vascular smooth muscle, and various endocrine sites. Injection of PTHrP produces hypercalcemia in rats and essentially reproduces the entire clinical syndrome of HHM. Normal circulating levels of PTHrP are negligible; these are probably unimportant in normal calcium homeostasis. However, mice with a targeted disruption in the PTHrP gene exhibit a lethal defect in bone development, thus demonstrating its importance in normal development, at least in the mouse.

Circulating PTHrP interacts with the PTH/PTHrP receptor in bone and the kidney tubule. It activates bone resorption and suppresses osteoblastic bone formation, thus causing efflux of calcium (up to 700−1000 mg/day) from bone into the ECF. The reason for this uncoupling of bone formation from bone resorption remains unclear. One possible explanation is a difference in the affinity of PTH versus that of PTHrP for the PTH receptor on osteoblasts. PTHrP mimics the anticalciuric effect of PTH on the kidney, which exacerbates hypercalcemia. Other effects of PTHrP include phosphaturia, hypophosphatemia, and increased cAMP excretion by the kidney.

LOH accounts for 20% of patients with malignancy-associated hypercalcemia. LOH-producing tumors include breast and prostate cancers and hematologic neoplasms (e.g., multiple myeloma, lymphoma, and leukemia). LOH is caused by locally produced osteoclast-activating cytokines, which include PTHrP, interleukin-1 (IL-1), IL-6, and IL-8. PTHrP increases RANKL expression in osteoblasts and RANK-mediated osteoclast bone resorption. The resorbing bone releases transforming growth factor-β (TGF-β), which in turn stimulates PTHrP expression on tumor cells. ^, The bone metastases can be classified as osteolytic, osteoblastic, or mixed. Osteolytic lesions are caused by osteoclast activation by malignant cells and appear as areas of increased radiolucency on radiographs. LOH leads to predictable pathophysiologic events, which include hypercalcemia, suppression of circulating PTH and 1,25(OH) ₂ D, hyperphosphatemia, and hypercalciuria. Bone metastases may produce severe pain and pathologic fractures.

Hypercalcemia in breast cancer is associated with the presence of extensive osteolytic metastases and HHM. ^, Extensive osteolytic bone destruction is also seen in multiple myeloma. Although bone lesions develop in all patients with myeloma, hypercalcemia occurs only in 15% to 20% of patients in later stages of disease and with impaired kidney function. The degree of hypercalcemia and bone destruction has not been well correlated. Treatment with bisphosphonates appears to protect against the development of skeletal complications (including hypercalcemia) in patients with myeloma and lytic bone lesions.

Hypercalcemia caused by 1,25(OH) ₂ vitamin D production by malignant lymphomas has been reported. ^, All types of lymphoma can cause this syndrome. The malignant cells or adjacent cells overexpress the enzyme 1α-hydroxylase, which converts 25(OH)D to 1,25(OH) ₂ D. Hypercalcemia is mainly secondary to increased intestinal calcium, although decreased kidney clearance and bone resorption may also develop. In addition, increased osteoclastic activity mediated through activation of the RANKL pathway by 1,25(OH) ₂ D−augmented hypercalcemia. Ectopic production of authentic PTH by a nonparathyroid tumor may occur but is rare.

Familial primary HPT syndromes are defined by a combination of hypercalcemia and elevated or nonsuppressed serum PTH levels.

Hypercalcemia may occur in patients with other endocrine diseases. Mild hypercalcemia is present in up to 20% of patients with hyperthyroidism, but severe hypercalcemia is uncommon. ^, Thyroid hormones (e.g., thyroxine and triiodothyronine) increase bone resorption and lead to hypercalcemia and/or hypercalciuria when bone resorption exceeds bone formation significantly. The hypercalcemia in a patient with thyrotoxicosis should be attributed to this disease only if it resolves after achieving an euthyroid state.

Pheochromocytoma may be associated with hypercalcemia ; it is usually caused by coincident PHPT and MEN2A. In some patients, hypercalcemia disappears after removal of the adrenal tumor, and some of these tumors produce PTHrP. Acute adrenal insufficiency is a rare cause of hypercalcemia. Because these patients may be dehydrated and have hemoconcentration, a rise in the serum albumin concentration and increased binding of calcium to serum albumin secondary to hyponatremia may contribute to the increase in serum calcium levels. In addition, isolated adrenocorticotropic hormone (ACTH) deficiency can result in hypercalcemia.

Growth hormone administration and acromegaly have both been associated with hypercalcemia. Acromegaly is often (15%−20% of cases) accompanied by mild hypercalcemia, which results from enhanced intestinal calcium absorption and augmented bone resorption. ^, In acromegalic patients with hypercalcemia, the serum levels of PTH are normal but may be inappropriately high for the levels of serum calcium.

Vitamin D is naturally generated in skin under exposure to ultraviolet B (UVB) light or is acquired from the diet and medical supplements. Excess of vitamin D or its metabolites can cause hypercalcemia and hypercalciuria. The mechanism of hypercalcemia is a combination of increased intestinal calcium absorption and bone resorption induced by vitamin D and decreased kidney calcium clearance resulting from dehydration. The effect of toxic amounts of vitamin D is due to an increase in total plasma 25(OH)D, well in excess of 100 ng/mL, which exceeds the binding capacity of vitamin D–binding protein (DBP) for 25(OH)D. The resulting increase in free circulating 25(OH)D may activate the vitamin D nuclear receptor (VDR). Vitamin D metabolites may also displace 1α,25(OH) ₂ D from DBP, increasing free 1α,25(OH) ₂ D levels and thus increasing signal transduction.

Hypercalcemia has been reported in accidental overdoses of vitamin D from fortified cow’s milk, ^, consumption by children of fish oil with manufacturing error that caused an excess of vitamin D, and over-the-counter supplements. Serum 25(OH)D levels were elevated, 1,25(OH) ₂ D levels were normal, and PTH levels were depressed or normal in these settings. However, vitamin D well in excess of the tolerable upper intake of 2000 IU/day is required for this form of hypercalcemia to develop. Polymorphism in genes that regulate vitamin D metabolism may predispose certain individuals to develop toxicity, even with exposure to small vitamin D doses. The diagnosis is made by the history and detection of elevated 25(OH)D levels. In the syndrome of idiopathic infantile hypercalcemia, a defect in degradation of 1,25(OH) ₂ D to 24,25(OH) ₂ D caused by a CYP24A1 loss-of-function mutation is responsible for extremely high levels of 1,25(OH) ₂ D and hypercalcemia. Vitamin D analogs including 1,25(OH) ₂ D used in the treatment of HPT and metabolic bone disease in CKD patients can also cause hypercalcemia. Typically, intoxication with 25(OH)D Vitamin D analogs takes longer to abate than intoxication with 1,25(OH)D Vitamin D analogs, which reflects, in part, the rapid degradation of 1,25(OH) ₂ D to 24,25(OH) ₂ D by CYP24A1.

Hypercalcemia and HPT is a long-recognized, well-described consequences of lithium therapy. The prevalence of lithium-associated hypercalcemia has been estimated to be 4% to 6%. ^, Lithium probably interferes with signal transduction elicited by the CaSR, which increases the set point for extracellular calcium to inhibit PTH secretion. This leads to parathyroid hyperplasia or adenoma. The spectrum of lithium-induced calcium disorders is wide and includes patients with overt HPT and mild or severe hypercalcemia, with or without elevated PTH levels. Hypocalciuria is common, although hypercalciuria was reported in a few case series. Hypercalcemia can be reversible after a few weeks of discontinuing lithium in most patients with short lithium treatment (<5 years). The CaSR agonist cinacalcet was also used with good results in those patients when cessation of lithium therapy was not an option. Symptomatic patients with HPT should be treated with parathyroidectomy. ^,

Vitamin A intake in doses exceeding the recommended daily allowance over prolonged periods, especially in older adults and patients with impaired kidney function, may cause hypercalcemia, with increased alkaline phosphatase levels, presumably from increased osteoclast-mediated bone resorption. The hypercalcemia is accompanied by high retinol plasma levels, and discontinuation of vitamin A caused normalization of plasma calcium levels. Cis-retinoic acid, used to treat certain cancers, and all-trans retinoic acid for promyelocytic leukemia, are associated with high rates of hypercalcemia. ^, Vitamin A analogs used in the management of dermatologic and hematologic malignant diseases have also been reported to cause hypercalcemia. ^,

Estrogens and selective estrogen receptor modifiers (e.g., tamoxifen) used in the management of breast cancer may cause hypercalcemia early during treatment, even in the presence of bone metastasis.

The incidence of thiazide-associated hypercalcemia increased after 1997 and peaked in 2006, with an annual incidence of 20 cases/100,000, compared with an overall rate of 12 cases/100,000 in 1992−2010 in the population of Olmsted County, Minnesota. ^, A reduction in urinary calcium excretion, volume contraction, and metabolic alkalosis are the major reasons for thiazide-induced hypercalcemia. Also, thiazides may increase intestinal calcium absorption and reveal PHPT. Hypercalcemia is usually mild and asymptomatic.

Milk-alkali syndrome was originally described in patients with duodenal ulcers receiving therapy with sodium bicarbonate and large amounts of milk. These patients have hypercalcemia, hyperphosphatemia, hypocalciuria, and CKD, together with kidney and other soft tissue calcifications. Calcium supplements in the form of calcium carbonate for the prevention and treatment of osteoporosis have become the main cause of this syndrome. ^, In the most recent literature, the name “calcium-alkali syndrome” was proposed. In some studies, milk-alkali syndrome was the third most common cause of hypercalcemia in non–end-stage kidney disease (ESKD) hospitalized patients. The pathogenesis of milk-alkali syndrome can be divided into two phases, the generation of hypercalcemia by the intake of calcium and the maintenance phase. Usually, oral intake of more than 4 g of elemental calcium/day has been reported, but even 2 g of calcium/day, especially if taken together with vitamin D, may induce this syndrome. Hypercalcemia activates the kidney CaSR, causing natriuresis and water diuresis, with volume depletion and a decrease in the GFR. Increased tubular reabsorption of calcium as a result of metabolic alkalosis and volume depletion contributes to the maintenance of hypercalcemia. The diagnosis is made largely by the history and may not be obvious because of atypical dietary sources of calcium and alkali.

Immobilization, especially in high bone turnover states (e.g., in young people and in those with hyperparathyroidism, breast cancer with bone involvement, and Paget disease), suppresses osteoblastic bone formation and increases osteoclastic bone resorption, leading to uncoupling of these two processes, with subsequent release of calcium from the bone and hypercalcemia. ^, Typically, it takes from 10 days to a few weeks for the development of immobilization hypercalcemia. Increased sclerostin production by osteocytes during mechanical unloading and disuse of the bone is implicated in the pathogenesis of hypercalcemia. Sclerostin is a glycoprotein that inhibits Wnt/β catenin signaling in the osteoblast and decreases bone formation. It is of interest that antisclerostin antibodies (e.g., romosozumab) are being studied for the treatment of osteoporosis. Bisphosphonates may help decrease hypercalcemia and osteopenia in the setting of immobilization-induced hypercalcemia. There are case reports showing that denosumab also can correct hypercalcemia of immobilization. Denosumab is a fully humanized monoclonal antibody that prevents the binding of RANK to RANKL, thereby reducing the formation, function, and survival of osteoclasts. Mobilization remains the ultimate cure for immobilization-associated hypercalcemia.

A variety of granulomatous diseases are associated with hypercalcemia. The most common is sarcoidosis—prevalence of hypercalcemia and hypercalciuria of 10% and 20%, respectively—but tuberculosis, berylliosis, histoplasmosis, coccidioidomycosis, pneumocystosis, leprosy, histiocytosis X, eosinophilic granulomatosis, and inflammatory bowel disease may present with hypercalcemia. ^, Hypercalcemia is more common in chronic and disseminated granulomatous diseases. Sun exposure, or even small doses of vitamin D supplementation, may precipitate or worsen this syndrome. Hypercalcemia, which has been best studied in sarcoidosis, is caused by inappropriate extrarenal production of 1,25(OH) ₂ D by activated macrophages with increased 1α-hydroxylase activity. ^, Elevated circulating 1,25(OH) ₂ D levels have been described in most granulomatous diseases during hypercalcemia, except in coccidioidomycosis. The 1,25(OH) ₂ D in turn leads to intestinal hyperabsorption of calcium, hypercalciuria, and hypercalcemia. Osteopontin, highly expressed by histiocytes in granulomas, may contribute to hypercalcemia via osteoclast activation and bone resorption. Bone mineral content tends to be reduced in these patients. Hypercalciuria may precede hypercalcemia and may be an early indicator of this complication.

Standard treatment consists of administration of glucocorticoids, which decreases the abnormal 1,25(OH) ₂ D production. Chloroquine and ketoconazole, which also decrease 1,25(OH) ₂ D production by competitive inhibition of CYP450-dependent 1α-hydroxylase, have also been shown to be efficacious.

Correction of the ECF volume is the first and most important step in the treatment of severe hypercalcemia from any cause. It can be achieved with a normal isotonic saline infusion at 200 to 500 mL/hour, adjusted to obtain a urine output of 150 to 200 mL/hour and with appropriate hemodynamic monitoring. ^{, ,} Volume repletion can lower the calcium concentration by approximately 1 to 3 mg/dL by increasing GFR and decreasing sodium and calcium reabsorption in the proximal and distal tubules.

Once volume expansion is achieved, loop diuretics can be considered for concurrent administration with saline to increase the calciuresis by blocking the Na ⁺ -K ⁺ -2Cl ^– cotransporter in the TAL. Usually, furosemide is given at a dose of 40 to 80 mg every 6 hours and this, together with saline therapy, may decrease the serum calcium concentration by 2 to 4 mg/dL. Volume status, and serum potassium, and magnesium should be evaluated at intervals of 2 to 4 hours and quantitatively replaced to prevent dehydration, hypokalemia, and hypomagnesemia. 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. It must be noted that the use of loop diuretics for hypercalcemia is not supported by any randomized controlled studies and has been criticized for this reason. However, in our opinion, loop diuretics still remain an important tool in the management of hypercalcemia, especially for patients with cardiac failure or CKD who are at risk of volume overload.

Calcitonin is recommended for initial treatment of moderate-to-severe hypercalcemia once patients are volume replete because of its rapid onset (within 12 hours) and minimal toxicity. ^{, ,} Calcitonin is usually given as 4 to 8 U/kg subcutaneously every 6 to 12 hours. ^, It is an effective inhibitor of osteoclast bone resorption. However, its effect is transient, and tachyphylaxis occurs after 2 to 3 doses, thus its role is mainly to lower the calcium level acutely while waiting for the more sustained effect of bisphosphonates or denosumab.

Bisphosphonates are currently the agents of choice in the treatment of hypercalcemia, especially those associated with cancer and vitamin D toxicity. They are pyrophosphate analogs with a high affinity for hydroxyapatite and inhibit osteoclast function in areas of high bone turnover. The U.S. Food and Drug Administration (FDA) has approved two bisphosphonates for the treatment of hypercalcemia, zoledronate (4–8 mg intravenous [IV] over 15 minutes or longer), and pamidronate (60−90 mg IV over 2−24 hours). Both medications require dose adjustments and should be infused over longer durations when GFR is low. The clinical response takes 48 to 96 hours and is sustained for up to 3 weeks. Doses can be repeated no sooner than every 7 days. Both agents are effective in lowering calcium levels. Zoledronate was slightly more efficacious than pamidronate in a randomized clinical trial. In Europe, other bisphosphonates, such as clodronate and ibandronate, have also been approved.

Fever is observed in about 20% of patients taking bisphosphonates; rare side effects include acute kidney injury, collapsing glomerulopathy, and osteonecrosis of the jaw. The 8 mg compared to 4 mg dose of zoledronic acid appears to be associated with greater grade 3–4 renal toxicity (5.2% vs. 2.3%) and all-cause mortality. For these reasons, the 4 mg dose is recommended for initial treatment, with 8 mg reserved for refractory or recurrent hypercalcemia. Ibandronate seems to have minimal to no kidney toxicity. The dose of bisphosphonates should be adjusted in patients with preexisting kidney disease. The kidney component of hypercalcemia, which includes increased distal tubular calcium reabsorption driven by PTH-PTHrP, does not respond to bisphosphonates.

For patients with significant renal impairment, denosumab may be preferred over bisphosphonates. Denosumab is a fully humanized monoclonal antibody that binds to RANKL and inhibits osteoclasts. Denosumab inhibits the maturation of preosteoclasts to osteoclasts by binding to and inhibiting RANKL and has been approved for the treatment of hypercalcemia of malignancy not corrected by bisphosphonates. ^, Denosumab is not renally cleared, and doses do not need to be adjusted for renal function. However, there is a higher rate of hypocalcemia with denosumab compared with bisphosphonates.

Other treatments such as gallium nitrate and plicamycin are no longer in common usage. Gallium inhibits bone resorption by increasing the solubility of hydroxyapatite crystals. Gallium nitrate is effective but can be nephrotoxic. ^, Plicamycin can be used in patients with advanced kidney disease.

Glucocorticoids are useful therapy for hypercalcemia in a specific subset of causes. They are most effective in hematologic malignancies (e.g., multiple myeloma and Hodgkin disease) and disorders of vitamin D metabolism (e.g., granulomatous diseases like sarcoidosis and vitamin D toxicity). ^,

In severely hypercalcemic patients who are comatose, have changes in the ECG, who have severe acute kidney injury, or who cannot receive aggressive hydration, hemodialysis with a low- or no-calcium dialysate is an effective treatment. Continuous kidney replacement therapy can also be used to treat severe hypercalcemia. The effect of dialysis is transitory and needs to be followed by other measures.

As discussed previously, cinacalcet, an allosteric activator of CaSR, is approved for patients with inoperable parathyroid cancer to control hypercalcemia. The off-label use of cinacalcet has been reported in patients with PHPT who have mild disease, failed parathyroid surgery, or contraindications to surgery. ^{, , ,} Other hypercalcemic disorders, such as FHH and lithium-induced HPT, have also been treated with cinacalcet. ^,

This group of disorders presents with hypocalcemia and hyperphosphatemia caused by failure of the parathyroid gland to secrete adequate amounts of biologically active PTH or resistance to PTH action at the tissue level. Both can be inherited or acquired. The levels of PTH are low or absent in hypoparathyroidism (HP) due to lack of PTH production but elevated in pseudohypoparathyroidism (PHP) due to a secondary or adaptive increase in PTH secretion. The fractional calcium excretion is elevated in HP and low in PHP. Insufficient 1,25(OH) ₂ D is generated for efficient intestinal calcium absorption because of decreased activity of 1α-hydroxylase in the proximal tubules. Skeletal response in both categories is appropriate to the levels of circulating PTH, with low bone turnover in HP and excessive bone remodeling in PHP. ^, Hypoparathyroidism is a rare disorder. One study from Japan has found the prevalence to be 7.2 cases/million people.

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The most common cause of acquired hypoparathyroidism in adults is surgical removal of or damage to the parathyroid glands. Transient hypocalcemia after thyroid surgery has been observed in 2% to 23% of cases, whereas permanent hypocalcemia occurred in approximately 1% to 2% of cases. ^, Hypocalcemia was more likely to occur after total thyroidectomy for cancer, Graves disease, radical neck dissection for other cancers, and repeated operations for parathyroid adenoma removal. Hypoparathyroidism may result from inadvertent removal of the parathyroids, damage from bleeding, or devascularization-infarction (e.g., sickle cell crisis). Removal of a single hyperfunctioning parathyroid adenoma can result in transient hypocalcemia because of hypercalcemia-induced suppression of PTH secretion from the normal glands. Surgical experience and use of appropriate surgical techniques may reduce the frequency of hypothyroidism.

The so-called hungry bone or recalcification syndrome represents an important cause of prolonged hypocalcemia after parathyroidectomy or thyroidectomy for any form of HPT or hyperthyroidism, respectively. Postoperative withdrawal of PTH decreases osteoclastic bone resorption, presumably mediated by decreased RANKL release from osteoblasts, without affecting osteoblastic bone formation activity, which leads to increased bone uptake of calcium, phosphate, and magnesium. Risk factors for the development of this hungry bone syndrome include large parathyroid adenomas, age older than 60 years, and high preoperative levels of serum PTH, calcium, and alkaline phosphatase. There have been reports that bisphosphonate therapy for Paget disease and cinacalcet use for secondary HPT can also cause a medical hungry bone syndrome. ^,

Acquired HP from nonsurgical causes is rare, with the exception of autoimmune disorders and magnesium deficiency. Although metal overload diseases (e.g., hemochromatosis and Wilson disease), ^, granulomatous diseases, miliary tuberculosis, amyloidosis, or neoplastic infiltrate are often mentioned as causes of hypoparathyroidism, these entities are rare. Alcohol consumption has been reported to cause transient hypocalcemia.

The diagnosis of kidney magnesium wasting is made by demonstrating an inappropriately high rate of kidney magnesium excretion. The causes are summarized in Fig. 17.4 .

Magnesium has protean and complex effects on myocardial ion fluxes. Because magnesium is an obligate cofactor in all reactions that require ATP, it is essential for the activity of Na ⁺ -K ⁺ -ATPase. During magnesium deficiency, Na ⁺ -K ⁺ -ATPase function is impaired. The intracellular potassium concentration falls, which may potentially result in a relatively depolarized resting membrane potential and predispose to ectopic excitation and tachyarrhythmias. Furthermore, the magnitude of the outward potassium gradient is decreased, thereby reducing the driving force for the potassium efflux needed to terminate the cardiac action potential. As a result, repolarization is delayed. Changes in the ECG 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.

Numerous anecdotal reports have indicated 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 magnesium repletion. Many of the reported patients also had a prolonged QT interval, an abnormality known to predispose to torsades de pointes, and may also increase the period of vulnerability to the R-on-T phenomenon. In the setting of exaggerated cardiac excitability, hypomagnesemia may be the trigger for other types of ventricular tachyarrhythmias. In addition, hypomagnesemia, like hypokalemia, facilitates the development of digoxin cardiotoxicity. Because cardiac glycosides and magnesium depletion inhibit Na ⁺ -K ⁺ -ATPase, their additive effects on intracellular potassium depletion may account for their enhanced toxicity in combination.

It is clear that patients with underlying cardiac disease who have severe hypomagnesemia, particularly in combination with hypokalemia, may develop arrhythmias. The issue of whether mild isolated hypomagnesemia and magnesium depletion in individuals without overt heart disease carry the same risk has been controversial. 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. In the Framingham Offspring Study, lower levels of serum magnesium were associated with a higher prevalence of ventricular premature complexes. A low serum magnesium level is also associated with the development of atrial fibrillation. In the Framingham Offspring Study, individuals in the lowest quartile of serum magnesium were, after up to 20 years of follow-up, approximately 50% more likely to develop atrial fibrillation compared with those in the upper quartiles.

Several large population-based studies have shown a strong association between low serum magnesium levels and increased cardiovascular and all-cause mortality. Higher magnesium intake is associated with reduced risk of coronary heart disease and cardiac death, stroke, and coronary calcification.

An inverse relationship between dietary magnesium intake and blood pressure has also been observed. Hypomagnesemia and/or reduction of intracellular magnesium have also been inversely correlated with blood pressure. This may be especially important in diabetes mellitus. Patients with essential hypertension were found to have reduced free magnesium concentrations in red blood cells. The magnesium levels were inversely related to systolic and diastolic blood pressures. Intervention studies with magnesium therapy in hypertension have led to conflicting results. Several have shown a positive blood pressure–lowering effect of supplements, but others have not. Other dietary factors may also play a role. In the DASH study, a diet rich in fruits and vegetables, which increased magnesium intake from 176 to 423 mg/day (along with an increase in potassium), significantly lowered blood pressure. The mechanism whereby magnesium deficit may affect blood pressure is not clear, but magnesium does regulate vascular tone and reactivity and attenuates agonist-induced vasoconstriction. Importantly, in none of these studies has magnesium therapy been rigorously studied, whether as a therapy for blood pressure reduction or prophylaxis against cardiovascular disease, arrhythmias, or stroke.

The only setting in which the role of magnesium deficiency and clinical utility of adjunctive magnesium therapy has been extensively studied is in acute myocardial infarction (AMI). Magnesium deficiency may be a risk factor because it has been shown to play a role in systemic and coronary vascular tone, in cardiac dysrhythmias (see earlier), and in the inhibition of steps in the coagulation process and platelet aggregation. Although several small controlled trials have suggested that adjunctive magnesium therapy reduces mortality from AMI by 50%, three major trials have defined our understanding of magnesium therapy in AMI. The LIMIT-2 study was the first study involving large numbers of participants. Magnesium treatment showed an approximately 25% lower mortality rate. In the Fourth International Study of Infarct, unlike LIMIT-2, the mortality rate in the magnesium-treated group was not significantly different from that in the control group. The Magnesium in Coronaries (MAGIC) trial was designed to address early intervention in higher-risk patients. Over a 3-year period, 6213 participants were studied. The magnesium-treated group mortality at 30 days was not significantly different from that of those given placebo. The overall evidence from clinical trials does not support the routine application of adjunctive magnesium therapy in patients with AMI at this time.

Symptoms and signs of neuromuscular irritability, including tremor, muscle twitching, Trousseau and Chvostek signs, and frank tetany, may develop in patients with isolated hypomagnesemia and in patients with concomitant hypocalcemia. Hypomagnesemia is also frequently manifested as generalized and tonic-clonic seizures or multifocal motor seizures, sometimes triggered by loud noises. Interestingly, noise-induced seizures and sudden death are also characteristic of mice in which hypomagnesemia was induced by dietary magnesium deprivation. The effects of magnesium 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 magnesium normally blocks NMDA receptors, so hypomagnesemia may release the inhibition of glutamate-activated depolarization of the postsynaptic membrane and thereby trigger epileptiform electrical activity. Vertical nystagmus is a rare but diagnostically useful neurologic sign of severe hypomagnesemia. In the absence of a structural lesion of the cerebellar or vestibular pathways, the only recognized metabolic causes are Wernicke encephalopathy and severe magnesium deficiency.

Dietary magnesium depletion in animals has been shown to lead to a decrease in skeletal growth and increased skeletal fragility. A decrease in osteoblastic bone formation and an increase in osteoclastic bone resorption are implicated as the cause of decreased bone mass. In humans, epidemiologic studies have suggested a correlation between bone mass and dietary magnesium intake. Few studies have been conducted assessing magnesium status in patients with osteoporosis. Low serum and red blood cell (RBC) magnesium concentrations, as well as high retention of parenterally administered magnesium, have suggested a deficit. Low skeletal magnesium content has been observed in some, but not all, studies. The effect of supplements on bone mass has generally led to an increase in BMD, although study design limits useful information. Larger long-term, placebo-controlled, double-blind investigations are required.

Several potential mechanisms may account for a decrease in bone mass in magnesium deficiency. Magnesium is mitogenic for bone cell growth; therefore deficiency may directly result in a decrease in bone formation. It also affects bone crystal formation—a lack of magnesium results in a larger, more perfect crystal, which may affect bone strength. Magnesium deficiency may result in a fall in serum PTH and 1,25 (OH) ₂ vitamin D levels (see earlier). Because both hormones are trophic for bone, impaired secretion or skeletal resistance may result in osteoporosis. A low serum 1,25 (OH) ₂ vitamin D level may also result in decreased intestinal calcium absorption. An observed increased release of inflammatory cytokines in bone may result in the activation of osteoclasts and increased bone resorption in rodents. ^,

Patients with hypomagnesemia are frequently also hypokalemic. Many of the conditions associated with hypomagnesemia that have been outlined earlier can cause simultaneous magnesium and potassium loss. However, hypomagnesemia by itself can induce hypokalemia in humans and experimental animals, and such patients are often refractory to potassium repletion until their magnesium deficit is corrected. The cause of the hypokalemia appears to be increased secretion in the distal nephron. The mechanism has been attributed to cytosolic magnesium depletion, which would release intracellular block of the apical secretory potassium channel, ROMK.

Hypocalcemia is present in approximately 50% of patients with hypomagnesemia. The major cause is impairment of PTH secretion by magnesium deficiency, which is reversed within 24 hours by magnesium repletion. In addition, hypomagnesemic patients also have low-circulating 1,25(OH) ₂ D levels and end-organ resistance to PTH and vitamin D.

Magnesium depletion has also been associated with several other disorders, such as insulin resistance and the metabolic syndrome in type 2 diabetes mellitus. ^, Magnesium deficiency has been associated with migraine headaches, and magnesium therapy has been reported to be effective in the treatment of migraine. Because magnesium deficiency results in smooth muscle spasms, it has also been implicated in asthma, and magnesium therapy has been effective in asthma in some studies. ^, Finally, a high dietary magnesium intake has been associated with a reduced risk of colon cancer. ^,

In the inpatient setting, the IV route of administration of magnesium is favored because it is highly effective, inexpensive, and usually well tolerated. The standard preparation is MgSO ₄ • 7H ₂ O. 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 to 16 mEq (1−2 g) may be administered IV over a 2- to 4-minute period; otherwise, a slower rate of repletion is safer. Because the added extracellular magnesium equilibrates slowly with the intracellular compartment, and because kidney excretion of extracellular magnesium exhibits a threshold effect, approximately 50% of parenterally administered magnesium is excreted into urine.

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 replenishing body magnesium stores. The magnitude of the magnesium deficit is difficult to gauge clinically and cannot be readily deduced from the serum magnesium concentration. In general, however, the average deficit can be assumed to be 1 to 2 mEq/kg body weight. A simple regimen for nonemergency magnesium repletion is to administer 64 mEq (8 g) of MgSO ₄ 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 magnesium levels rise early, whereas intracellular stores take longer to replete, so magnesium repletion should continue for at least 1 to 2 days after the serum magnesium level normalizes. In patients with kidney magnesium wasting, additional magnesium may be needed to replace ongoing losses. In patients with a reduced GFR, the rate of repletion should be reduced by 25% to 50%, the patient should be carefully monitored for signs of hypermagnesemia, and the serum magnesium level should be checked frequently.

The main adverse effects of magnesium repletion are due to hypermagnesemia as a consequence of an excessive rate or amount of magnesium administered. These effects include facial flushing, loss of deep tendon reflexes, hypotension, and atrioventricular block. Monitoring the tendon reflexes is a useful bedside test to detect magnesium overdose. In addition, IV administration of large amounts of MgSO ₄ results in an acute decrease in the serum ionized Ca ²⁺ level, which is related to increased urinary calcium excretion and complexing of calcium by sulfate. Thus in an asymptomatic patient who is already hypocalcemic, administration of MgSO ₄ may further lower the ionized Ca ²⁺ level and thereby precipitate tetany.

Oral magnesium administration is used initially for the repletion of mild cases of hypomagnesemia or for continued replacement of ongoing losses in the outpatient setting after an initial course of IV repletion. A number of oral magnesium salts are available that vary in their content of elemental magnesium and their oral bioavailability. All of them cause diarrhea, which limits the dose that can be used. Magnesium supplements come in various salt forms, such as magnesium oxide, magnesium hydroxide, magnesium citrate, magnesium chloride, magnesium sulfate, magnesium gluconate, magnesium malate, and magnesium glycinate. Among these, magnesium gluconate and magnesium chloride are often preferred for oral supplementation, as they tend to cause diarrhea less frequently than other forms. Magnesium hydroxide and magnesium oxide are alkalinizing salts with the potential to cause systemic alkalosis, whereas the sulfate and gluconate salts, which present nonreabsorbable anions to the collecting duct, may potentially exacerbate potassium wasting.

A typical daily dose in a patient with normal kidney function and severe hypomagnesemia is 10 to 40 mmol of elemental magnesium in divided doses. Half of this may be sufficient in cases of mild hypomagnesemia, whereas in patients with intestinal magnesium malabsorption, the dose may need to be increased twofold to fourfold. Sustained-release preparations, such as magnesium chloride (Mag-Delay, Slow-Mag) and magnesium l -lactate sustained release (Mag-Tab SR), have the advantage that they are slowly absorbed and thereby minimize kidney excretion of the administered magnesium.

In patients with inappropriate kidney magnesium wasting, potassium-sparing diuretics that block the distal tubule epithelial sodium channel, such as amiloride and triamterene, may reduce kidney magnesium losses. These drugs may be particularly useful in patients who are refractory to oral repletion or who require such high doses of oral magnesium that diarrhea develops. A possible mechanism is that these drugs, by reducing luminal sodium uptake and inhibiting the development of a negative luminal transepithelial potential difference, may favor passive reabsorption of magnesium in the late distal tubule or collecting duct.

In clinical trials, SGLT2 inhibitors, as a drug class, are associated with higher serum magnesium. Several case series have reported the use of SGLT2 inhibitors to increase serum magnesium levels and treat hypomagnesemia in patients with and without diabetes mellitus. The mechanism by which SGLT2 inhibitors increase magnesium is unknown. In one study, two out of three patients had reduced fractional urinary excretion of magnesium, suggesting that they increased renal tubular magnesium reabsorption. One hypothesis is that by inhibiting electrogenic Na ⁺ reabsorption, they create a lumen-positive transepithelial voltage that favors magnesium reabsorption in the proximal tubule. Most recently, it has been found that SGLT2 inhibitors increase EGF expression in kidney tissue and urine of patients with type 2 diabetes mellitus. This suggests that increased EGF signaling in the DCT, which would increase magnesium reabsorption, might account for the effect of SGLT2 inhibitors.

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

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

Modest elevations in serum magnesium levels have occasionally been described in patients receiving lithium therapy, as well as in postoperative patients and in those with bone metastases, milk-alkali syndrome, familial hypocalciuric hypercalcemia, hypothyroidism, pituitary dwarfism, and Addison disease.

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

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

Mild cases of magnesium toxicity in individuals with good kidney function may require no treatment other than cessation of magnesium supplements because kidney magnesium clearance is usually quite rapid. The normal half-life of serum magnesium is approximately 28 hours. In the event of serious toxicity, particularly cardiac toxicity, temporary antagonism of the effect of magnesium may be achieved by the administration of IV calcium (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). Kidney excretion of magnesium can be enhanced by saline diuresis and the administration of furosemide, which inhibits tubular reabsorption of magnesium in the medullary TAL.

In patients with ESKD, the only way to clear the excess magnesium may be by dialysis or hemofiltration. The typical dialysate for hemodialysis contains 0.6 to 1.2 mg/dL of magnesium, but magnesium-free dialysate can also be used and is generally well tolerated, except for muscle cramps. Hemodialysis is extremely effective at removing excess magnesium and can achieve clearances of up to 100 mL/min. As a rough rule of thumb, the expected change in the serum magnesium level 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 Mg ²⁺ concentration and predialysis serum ultrafilterable magnesium (estimated at 70% of total serum magnesium). Note that when hemodialysis is performed using a bath with the same total concentration of magnesium as in serum, the net transfer of magnesium into the patient occurs because the ultrafilterable (and therefore free) magnesium concentration in serum is less than the total concentration; thus the gradient of free Mg ²⁺ is directed from the dialysate to blood.