Online Medical Reference

Hypercalcemia

Mario Skugor, MD

Published: June 5, 2019

Hypercalcemia is a common clinical problem that typically leads to a chronic and mild elevation of calcium blood levels. Hypercalcemic emergencies are possible but uncommon. Most cases are caused either by primary hyperparathyroidism (HPT) or malignancy. The condition can affect almost every organ system in the body. Symptoms are nonspecific and are related to the severity and rate of change of the serum calcium level, although neurologic dysfunction is an uncommon feature with mild hypercalcemia—patients can experience slight difficulties in concentrating but also experience depression, confusion, and coma as the condition becomes more severe. Treatment depends on the cause of the disorder.

Definition and Causes

Hypercalcemia is usually detected initially as an elevation of total plasma calcium levels rather than ionized calcium levels. Approximately 50% of total calcium is protein bound, and the total calcium level will vary with protein-binding capacity.

The total calcium level is low in patients with low levels of binding proteins (hypoalbuminemia) and higher in those with high levels of binding proteins. Although rare, this can result in pseudohypercalcemia—for example, in patients with hyperalbuminemia secondary to dehydration and in some patients with multiple myeloma.

The total plasma calcium level, therefore, must be corrected for the albumin level. Normal calcium levels range from 8.5 to 10.5 mg/day, assuming an albumin level of 4.5 g/dL. The calcium concentration [Ca] usually changes by 0.8 mg/dL for every 1.0-g/dL change in plasma albumin concentration. Thus, this formula estimates the actual total plasma calcium level:

Corrected [Ca] = Total [Ca] + (0.8 × [4.5 − albumin level])

Acidosis decreases the amount of calcium bound to albumin whereas alkalosis increases the bound fraction of calcium. A small amount of calcium (about 6%) is also complexed to anions such as citrate and sulfate. The remainder is ionized calcium that is biologically active. Measuring ionized calcium avoids issues with binding proteins.

Approximately 90% of all cases of hypercalcemia in the outpatient setting are caused by either primary HPT or hypercalcemia of malignancy. These and other causes are summarized in Table 1.

Table 1: Causes of Hypercalcemia
Primary hyperparathyroidism
  • Sporadic
  • Familial
Hypercalcemia of malignancy
  • Osteolytic hypercalcemia
  • Humoral hypercalcemia of malignancy
  • Ectopic production of calcitriol (by lymphoma)
  • Ectopic production of parathyroid hormone
Hypercalcemia of granulomatous disease
Chronic renal failure with aplastic bone disease
Tertiary hyperparathyroidism
Acute renal failure
Familial hypercalcemic hypocalciuria
Lithium-associated hypercalcemia
Vitamin D intoxication
Other rare causes
  • Increased calcium intake
  • Pheochromocytoma
  • Congenital lactase deficiency
  • Hyperthyroidism
  • Vitamin A intoxication
  • Thiazides
  • Milk-alkali syndrome
  • Immobilization
  • Theophylline

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Signs and Symptoms

Symptoms of hypercalcemia (Table 2) are nonspecific and are related to the severity and rate of change of the serum calcium level. Symptoms are more severe with acute changes than with chronic calcium level elevation. Patients with a chronic calcium level as high as 12 to 14 mg/dL may tolerate those levels well whereas sudden development of hypercalcemia in this range or higher may lead to dramatic changes in a patient's mental status. Symptoms of underlying diseases—malignancy, sarcoidosis, and tuberculosis, for example—causing hypercalcemia may dominate the clinical picture.

Table 2: Clinical Manifestations of Hypercalcemia
Symptoms and Signs Associated Conditions
Neuropsychiatric
Depression Organic brain syndromes
Anxiety  
Cognitive dysfunction  
Headache
Fatigue  
Renal
Polyuria Nephrolithiasis
Polydipsia Nephrogenic diabetes insipidus
Nocturia Renal insufficiency
  Renal tubular acidosis
Cardiovascular
Short QT interval Hypertension
  Cardiovascular calcifications
Gastrointestinal  
Constipation Peptic ulcer disease
Anorexia Acute pancreatitis
Abdominal pain  
Musculoskeletal
Muscle weakness Osteopenia, osteoporosis
Aches, pains Gout, pseudogout
Fractures Chondrocalcinosis
  Osteitis fibrosa cystica
  Calciphylaxis
  Brown tumors
Other
  Hypercalcemic crisis

A normal extracellular calcium concentration is necessary for normal neuromuscular function. Thus, neurologic dysfunction is the major feature of hypercalcemic states. Patients can experience slight difficulties in concentrating to depression, confusion, and coma. These symptoms may resolve or improve after the hypercalcemia is corrected.1 Muscle weakness may also occur.

Chronic hypercalcemia may result in the formation of renal calculi. Hypercalciuria is the main factor in stone formation, but increased calcitriol production in primary HPT also plays a role. Nephrogenic diabetes insipidus resulting in polydipsia and polyuria is seen in about 20% of patients. Mechanisms include downregulation of water channels (aquaporin 2) and tubulointerstitial injury caused by calcium deposition. Renal tubular acidosis and renal insufficiency are rare. Chronic hypercalcemic nephropathy may continue to worsen after the hypercalcemia is corrected.

Hypertension can develop in patients with hypercalcemia as a result of renal insufficiency, calcium-mediated vasoconstriction, or both. Hypertension may or may not resolve after the hypercalcemia is corrected. Cardiac effects include short QT intervals, which may increase sensitivity to digitalis, and deposition of calcium in the heart valves, myocardium, or coronary arteries.

Constipation, anorexia, nausea, and vomiting are often prominent symptoms whereas acute pancreatitis (via activation of trypsinogen in pancreatic parenchyma) and peptic ulcer disease (via stimulation of gastrin secretion) are unusual. Fatigue, musculoskeletal weakness, and pain are the only symptoms that correlate with increasing levels of serum calcium.

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Primary Hyperparathyroidism

Overview

Primary HPT can occur at any age but is most common in the 6th decade of life. It is 3 to 4 times more common in women than in men. When primary HPT affects children, it is likely to be a component of familial endocrinopathies such as the multiple endocrine neoplasia (MEN) syndrome types I and II or familial HPT.

The incidence of primary HPT increases with age in both sexes but more so in women after menopause.2 The incidence is 12 to 24 per 100,000 person years for both sexes younger than 50 years but at ages 50 to 59, the incidence rises to 80 per 100,000 for women versus 36 for men. The incidence greatly increases again at ages 70 to 79 for women—to 196—but remains lower at 95 for men.

The incidence of primary HPT is highest among blacks (92 women; 46 men) followed by whites (81 women; 29 men) while rates for Asians (52 women, 28 men) and Hispanics (49 women, 17 men) are lower.2

The underlying pathophysiology of primary HPT is excessive secretion of parathyroid hormone (PTH), which leads to increased bone resorption by osteoclasts, increased intestinal calcium absorption, and increased renal tubular calcium reabsorption. The resulting hypercalcemia is often also accompanied by low-normal or decreased serum phosphate levels because PTH inhibits proximal tubular phosphate reabsorption.

Most cases of primary HPT (80%) are detected accidentally during routine blood work when asymptomatic hypercalcemia is discovered. Patients have few or no symptoms, and calcium levels are only mildly elevated (< 12 mg/dL). Patients with primary HPT can present with any of the clinical manifestations summarized in Table 2. This diagnosis should be considered in any patient presenting with kidney stones, bone disease, or hypercalcemic crisis.

Renal calculi are seen in 15% to 20% of patients with HPT and, conversely, about 5% of patients with renal calculi have HPT. Some of these patients may have calcium levels in the upper range of normal. Most calculi are composed of calcium oxalate, and the main factor in their pathogenesis is hypercalciuria. Although PTH stimulates calcium reabsorption in the distal tubule, the kidney is overwhelmed by the increased amount of filtered calcium resulting from increased serum calcium levels. Patients with increased vitamin D levels are more likely to have hypercalciuria and nephrolithiasis.

Although bone disease is rare in HPT, it can develop in severe, long-standing cases or those caused by parathyroid carcinoma and in secondary or tertiary HPT associated with chronic renal insufficiency.3 Classic skeletal lesions include brown tumors, osteitis fibrosa cystica, and subperiosteal resorption on the radial aspect of middle phalanges.3

Some patients with HPT also have low bone mineral density, but it is unclear whether the incidence is higher in these patients than in healthy people. Some studies have reported decreased bone mineral density in untreated cases3 but others have not.4 However, most studies have shown that patients with primary HPT generally have an increased risk for vertebral fractures. In one cohort of 1,800 patients with primary HPT in Uppsala, Sweden, only the men had an increased risk for cervical hip fractures.5

Hypercalcemic crisis is a rare manifestation and is characterized by calcium levels above 15 mg/dL and severe symptoms, particularly central nervous system dysfunction. Abdominal pain, pancreatitis, peptic ulcer disease, nausea, and vomiting are common in these patients. The mechanism whereby a crisis develops is not clear, but dehydration, intercurrent illness, and infarction of a parathyroid adenoma may play a role.

Several studies have found excessive mortality in patients with HPT, with most of the excess caused by cardiovascular disease. The largest study, which included 4,461 Swedish patients, showed risk ratios for death from cardiovascular disease of 1.71 for men and 1.85 for women.6

Diagnosis of HPT

The diagnosis of primary HPT requires an elevated serum calcium level either with a simultaneous elevation of PTH levels (in 80% to 90% of patients) or normal PTH levels (10% to 20% of patients). Note that patients with hypercalcemia should have their PTH level suppressed and that the “normal” level is inappropriately high in these patients. The PTH elevation should be determined by an assay that measures the intact PTH molecule. The phosphorus level may be low but is usually just in the low-normal range. A subgroup of individuals with normal calcium levels and permanently elevated PTH levels may be recognized as having primary HPT if all causes of secondary HPT have been ruled out.7

Urinary calcium excretion is measured by a 24-hour urine collection, which should also specify total volume and urine creatinine levels. Hypercalciuria is defined as urinary calcium excretion higher than 400 mg/day. Importantly, low calcium excretion (< 150 mg/day) may signify familial hypercalcemic hypocalciuria, which should not be treated.

A careful family history is paramount to recognizing familial forms of primary HPT. In these cases, screening for pheochromocytoma is important before considering surgical treatment.

In some cases, a less invasive surgical approach can be used in which the abnormal parathyroid glands are localized preoperatively using ultrasound, Tc-99m sestamibi scintigraphy, or magnetic resonance imaging. The accuracy of these radiologic modalities is variable. They are not required for the diagnosis of HPT but serve mainly as guides for surgical strategy. The selection of these tests should be left to the surgeon.

Treatment of HPT

Indications

Removal of the abnormal and hyperfunctioning parathyroid tissue results in a long-term cure of HPT in 96% of patients and significant improvement in associated symptoms. The following criteria were proposed as indications for parathyroidectomy by the American Association of Endocrine Surgeons8:

  1. Patients with symptomatic disease.
  2. Serum calcium level greater than 1 mg/dL above the upper limit of normal.
  3. Objective evidence of renal involvement.
    1. Nephrolithiasis (even clinically silent)
    2. Nephrocalcinosis
    3. Marked hypercalciuria (> 400 mg/day)
    4. Glomerular filtration rate (< 60 mL/min)
  4. Reduction in bone mineral density of the femoral neck, lumbar spine, or distal radius of more than 2.5 standard deviations below peak bone mass (T score < –2.5), fragility fracture, or evidence of vertebral compression fracture.
  5. Patients for whom medical surveillance is not possible.
  6. If parathyroid carcinoma is suspected.
  7. Age younger than 50 years.

However, because no effective medical therapy for HPT exists, patients of all ages with HPT who are otherwise healthy should be considered for surgical treatment.

Surgical Treatment

Parathyroid surgery remains the single most effective treatment option in HPT and requires the removal of all abnormal parathyroid tissue. Traditionally, in the vast majority of U.S. practices, this has meant bilateral exploration of the neck to identify all (typically 4) parathyroid glands.

The setting of multiglandular hyperplasia requires subtotal parathyroidectomy or total parathyroidectomy with reimplantation of parathyroid tissue into the sternocleidomastoid or forearm muscles. The removed parathyroid glands may be cryopreserved as a safeguard against future hypocalcemia, in which case the patient may undergo autotransplantation of autogenous, stored parathyroid tissue. In experienced hands, this approach has an exceptionally high rate of long-term cure (> 96% on first attempt) and a low rate of surgical complications (persistent hypocalcemia < 1%, recurrent laryngeal nerve injury 2% to 5%, neck hematoma or infection < 1%).9

Many parathyroid procedures can be performed with the patient under light sedation and local anesthesia on an outpatient basis. Minimally invasive parathyroid surgery has become more frequently requested by patients and primary care physicians alike, even though there is not a uniform set of techniques. For example, depending on regional practices, minimally invasive parathyroid surgery may mean using laparoscopic radio-guided techniques or a unilateral surgical approach to abnormal glands identified by imaging.

The success of these approaches in curing HPT and minimizing complications is relatively unknown because clinical follow-up periods are short. Minimally invasive parathyroid surgery is appropriate only for patients who have a single, clearly defined parathyroid abnormality on ultrasound, sestamibi scan, or both, and when PTH levels can be monitored intraoperatively. Bilateral neck exploration is mandatory in all other cases and for patients with familial or genetic syndromes.

Medical Treatment for Primary HPT

Patients who are not treated surgically should be encouraged to stay adequately hydrated, avoid thiazide diuretics, ambulate when possible, and consume a moderate level of calcium because excessive intake may aggravate hypercalcemia, especially in patients with high calcitriol levels, and low intake may stimulate PTH secretion. Bisphosphonates may be used to lower the serum calcium level in patients with symptomatic hypercalcemia (see later, "Treatment of Hypercalcemia"), although they are usually only temporarily effective.

Familial Forms of HPT

Up to 10% of cases of primary HPT are hereditary forms. Recognition is important because management of many patients and their families may be affected.

The most common familial form is MEN-I. In this disorder, primary HPT is almost invariably present (> 95% of patients) by the age of 65 years, but it can develop in children and infants. Indications for surgical intervention are generally the same as those for sporadic cases. Pancreatic tumors are present in 30% to 80% of patients. These are usually islet cell tumors secreting gastrin and causing Zollinger-Ellison syndrome in about two-thirds of cases. The second most common pancreatic tumor is insulinoma. Neuroendocrine tumors secreting various different substances have been described.

Pituitary adenomas affect 15% to 50% of patients and are mostly prolactinomas, although tumors causing acromegaly and Cushing's disease also occur. Adrenocortical hyperplasia is seen in about one-third of patients.

MEN-I is caused by autosomal dominant mutation of the menin gene on chromosome 11. Genetic testing is cumbersome, and family members should have their serum calcium levels checked. Some patients develop MEN-1–associated lesions as late as age 35.

MEN-II is characterized by the development of medullary thyroid carcinoma, which occurs in almost all patients. HPT occurs in about one-half of affected individuals; most are asymptomatic. Pheochromocytoma or adrenal medullary hyperplasia is an associated feature. The mutated gene is the RET protooncogene. Genetic testing of family members is desirable because it clearly identifies individuals at risk, and timely thyroidectomy is lifesaving.

Other familial syndromes are rare and include the HPT—jaw tumor syndrome and familial isolated primary HPT.

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Other Types and Causes of Hypercalcemia

Tertiary HPT

In cases of prolonged states of secondary HPT, as seen in patients with end-stage renal disease, vitamin D deficiency, and states of vitamin D resistance, the parathyroid glands undergo hypertrophy, eventually causing autonomous PTH secretion, which in turn leads to hypercalcemia resembling primary HPT. This condition is called tertiary HPT. The cure requires surgical intervention to reduce the amount of parathyroid tissue.

Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a rare condition caused by an inactivating disorder of calcium-sensing receptors. These receptors are expressed in many tissues but play a major role in regulating calcium metabolism through their effects on parathyroid tissue and handling of renal calcium. The disorder is autosomal dominant with high penetrance. Several mutations have been described but all decrease the sensitivity of receptors to calcium, requiring higher calcium levels to suppress PTH secretion. Heterozygous patients present with hypercalcemia, hypocalciuria, and mild hypermagnesemia. Fractional excretion of calcium is lower than 1%, despite hypercalcemia. The PTH level is normal or slightly elevated (up to twice the normal in our clinical experience).

The clinical significance of this disease lies mostly in mistaken diagnosis of primary HPT and referral for parathyroidectomy. However, parathyroidectomy will not correct hypercalcemia, and these patients sometimes undergo multiple surgeries before a correct diagnosis is reached.

Genetic testing is not routinely available and usually is unnecessary—these patients are free of symptoms and have always had hypercalcemia. A family history will uncover additional family members with hypercalcemia, and urinary calcium excretion is low (about 75% of patients excrete < 100 mg/day). The ratio of calcium (Ca) clearance to creatinine (Cr) clearance may be used for the diagnosis of FHH using the following formula:

CICa/CICr = (Cau x Crs) / (Cru x Cas)

where Cau = urinary Ca concentration, Crs = serum Cr concentration, Cru = urinary Cr concentration, and Cas = serum Ca concentration. A ratio of 0.01 or less is typically seen in individuals with FHH. However, one study reported a sensitivity of only 64.3% and a specificity of 79.9% for this formula.10

Hypercalcemia of Malignancy

Humoral Hypercalcemia of Malignancy

Humoral hypercalcemia of malignancy (HHM) is a clinical syndrome in which elevated calcium levels are caused by the humoral factor synthesized by the tumoral process. Usually, this term is applied to patients with excessive tumoral production of PTH-related peptide (PTHrP).11 However, rare cases characterized by excessive production of PTH and calcitriol have also been described. Patients with HHM constitute about 80% of all patients with hypercalcemia associated with malignancy.

PTHrP and PTH share the same receptor but there are some differences in clinical presentation. HHM patients have a markedly larger degree of renal calcium excretion—PTH potently stimulates tubular calcium resorption, and hypercalciuria is less pronounced. HHM is usually associated with low serum calcitriol levels—PTH stimulates calcitriol production and its level is usually elevated. Also, PTH stimulates bone resorption and formation whereas PTHrP stimulates only bone resorption with very low osteoblastic activity. Therefore alkaline phosphatase levels are usually normal in patients with HHM.

Patients with HHM have suppressed levels of immunoreactive PTH whereas the immunoreactive PTHrP level is elevated. In addition, these patients are usually dehydrated due to the hypercalcemia as well as poor oral intake.

Patients with HHM usually have clinically obvious malignant disease and a poor prognosis. The only exceptions to this rule are patients with small, well-differentiated neuroendocrine tumors (e.g., pheochromocytomas or islet cell tumors). However, these tumors constitute a minority of cases. The HHM is most commonly seen with squamous cell carcinomas (e.g., lung, esophagus, cervix, head and neck) and renal, bladder, and ovarian cancers. Therapy is aimed at reducing the tumor burden, reducing osteoclastic resorption of the bone, and increasing calcium excretion through the urine.

Most hypercalcemia cases associated with Hodgkin's disease and about one third of those seen in non-Hodgkin's lymphoma are caused by increased production of calcitriol by the malignant cells. Hypercalcemia usually responds well to treatment with corticosteroids.

Hypercalcemia of Malignancy Associated with Localized Bone Destruction

Multiple myeloma affects the skeleton extensively in almost all patients. In addition, common malignant tumors (e.g., breast, prostate, and lung) frequently metastasize to the bone. In patients who develop hypercalcemia, bone metastases can destroy the bone tissue (osteolytic).

When multiple myeloma affects the bone, it can cause discrete lesions or affect the skeleton diffusely. Bone involvement is responsible for pathologic fractures, bone pain (about 80% of patients first present with bone pain), and hypercalcemia (seen in 20% to 40% of patients in the course of disease). Myelomas cause bone destruction by cytokine secretion that activates osteoclasts locally.

In vitro, lymphotoxin produced by myeloma cells accounts for most bone resorption activity. Interleukin-1, interleukin-6, and PTHrP may also be involved in the process in some patients. The fact that most patients with multiple myeloma demonstrate extensive bone destruction whereas far fewer develop hypercalcemia may be explained by impaired glomerular filtration—a result of nephropathy caused by Bence-Jones protein, uric acid nephropathy, amyloidosis, or infection—all of which decrease calcium excretion.

The treatment of hypercalcemia in these patients is complicated by renal failure. Calcitonin is not nephrotoxic and thus can be used freely. Treatment of myeloma with corticosteroids and alkylating agents is also effective in correcting hypercalcemia. A combination of calcitonin and corticosteroids is frequently used. It is important to recognize that corticosteroids may have detrimental effects on bone metabolism but can be used for patients with a poor prognosis where the goal is to prevent symptomatic hypercalcemia.

Treatment with bisphosphonates improves hypercalcemia and also inhibits bone resorption and decreases bone fragility. Intravenous (IV) pamidronate or zoledronate is effective in correcting hypercalcemia in almost every patient and is also approved by the U.S. Food and Drug Administration for the treatment of patients with multiple myeloma who do not have hypercalcemia. Which bisphosphonate is most effective, which dose is optimal, and how often to treat are questions that await answers.

Osteolytic bone metastases from solid tumors are another important cause of bone fragility and hypercalcemia. The prototypic example is bone metastasis of breast cancer. Metastatic mass in bone is affected by the bone microenvironment. In response to bone resorption, bone-derived peptide–transforming growth factor-beta is released and, in turn, causes excessive production of PTHrP by breast cancer cells inside the bone (but not by the primary tumor). It is likely that various other substances are also involved in this process.

The principles of therapy are the same as for other patients with hypercalcemia of malignancy. Bisphosphonates have been shown to diminish the size of bone metastases from breast cancers in mice.10 No such data are available for human disease.

Hypercalcemia Associated with Granulomatous Diseases

Although sarcoidosis is probably most commonly associated with hypercalcemia, almost all granulomatous diseases can lead to abnormal calcium level elevation, including sarcoidosis, tuberculosis, berylliosis, histoplasmosis, candidiasis, coccidioidomycosis, histiocytosis X, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Crohn's disease, Wegener's granulomatosis, Pneumocystis jiroveci pneumonia, and silicone-induced granulomas.

The predominant mechanism for the development of hypercalcemia and hypercalciuria is increased intestinal absorption of calcium induced by elevated calcitriol levels, although calcitriol-mediated increases in bone resorption and PTHrP production also may play a role.

The macrophage-monocyte line of immune cells expresses the identical 1alpha-hydroxylase expressed in the kidneys that converts 25-hydroxyvitamin D to 1,25-hydroxyvitamin D. The activity of this enzyme is under negative feedback control in normal tissues. However, in granulomatous disorders, normal feedback inhibition is abolished, probably by the effects of interferon gamma. An abnormality in calcitriol production is seen even in patients who do not develop hypercalciuria or hypercalcemia.

The proportion of patients who develop hypercalcemia or hypercalciuria varies by geographic area. This is likely caused by the differences in dietary vitamin D and calcium intake and the amount of sun exposure. An increase in any these factors is associated with hypercalcemia.

Therapy is aimed at diminishing intestinal calcium absorption by limiting calcium intake, eliminating vitamin D supplementation, and limiting sun exposure. Corticosteroid treatment (10 to 30 mg of prednisone in cases of sarcoidosis and more in cases of lymphoma) will diminish the production of 1,25-hydroxyvitamin D (calcitriol) in the macrophages. Serum calcium levels start to gradually decrease after 2 days of treatment and fully normalize in 7 to 10 days.

Antimalarial medications such as chloroquine and the less toxic hydroxychloroquine could be used to diminish calcitriol production in macrophages as well. However, the use of these medications should be left to endocrinologists.

Bisphosphonates have been used with good success in patients who do not respond to these measures. See later, “Treatment of Hypercalcemia.”

The risk of renal calculi formation can be diminished by dietary oxalate restriction to prevent hyperoxaluria. It is important to note that thiazide diuretics should not be used to prevent renal calculi (by means of inhibition of renal calcium excretion) in these patients because they can cause marked hypercalcemia.

Additional Causative Factors
Vitamin D Intoxication

Both 25-hydroxyvitamin D and 1,25-hydroxyvitamin D circulate in blood partially bound to vitamin D–binding protein. When large amounts of amounts of vitamin D (which is converted to 25-hydroxyvitamin D in the liver) or 25-hydroxyvitamin D are ingested, calcitriol will be displaced from the binding protein, resulting in increased free calcitriol levels; the total level can be low because calcitriol production is inhibited. Elevated free calcitriol levels, in turn, will cause hypercalcemia because of increased intestinal calcium absorption and increased bone resorption. This mechanism is seen also with the use of the topical vitamin D analogue, calcipotriol, which is used to treat some dermatologic disorders. A hypercalcemic episode is usually prolonged and often requires therapy with bisphosphonates along with routine nonspecific measures.

Another cause of vitamin D intoxication is excessive use of calcitriol as a treatment for hypoparathyroidism and for hypocalcemia and secondary HPT in patients with renal insufficiency. In these patients, the total calcitriol level in serum is increased. However, calcitriol has a short half-life, so once it is stopped, hypercalcemia quickly resolves. Adequate hydration usually resolves hypercalcemia quickly.

Thiazide Diuretics

Thiazide diuretics decrease renal calcium excretion by about 50 to 150 mg/day. This rarely leads to hypercalcemia in patients with otherwise normal calcium metabolism. However, it can result in hypercalcemia in patients with increased bone resorption—even those with mild HPT.

Lithium Therapy

Patients treated with lithium commonly develop mild hypercalcemia. Lithium increases the set point for PTH suppression by calcium. Hypercalcemia usually resolves when lithium is discontinued.

Thyrotoxicosis

Mild hypercalcemia may occur in up to one-half of patients with severe thyrotoxicosis. The PTH and 1,25-hydroxyvitamin D levels are both low. Increased bone resorption caused by thyroxine (T4) and triiodothyronine (T3) is believed to be responsible for hypercalcemia. Treatment of the thyrotoxicosis resolves hypercalcemia unless concomitant primary HPT is present.

Adrenal Gland Abnormalities

Most hypercalcemia cases associated with pheochromocytoma are caused by concomitant primary HPT. However, in some cases, resection of the adrenal tumor resolves the hypercalcemia. Most of these cases are caused by a tumor that produces PTHrP. Hypercalcemia is usually seen with adrenal insufficiency during the adrenal crisis due to volume contraction and hemoconcentration. Hypercalcemia responds to volume and glucocorticoid replacement.

Immobilization

Immobilization causes hypercalcemia in patients whose underlying bone resorption is elevated, including children and adolescents, patients with Paget's disease, and those with mild primary and secondary HPT or mild hypercalcemia of malignancy. These patients are at risk for osteopenia. Some data suggest that use of bisphosphonates may diminish hypercalcemia and osteopenia, but resumption of weight-bearing exercise is essential to resolve hypercalcemia and hypercalciuria.

Milk-Alkali Syndrome

Milk-alkali syndrome is a rare condition caused by ingesting large amounts of calcium together with sodium bicarbonate. It is associated with the use of calcium carbonate in over-the-counter antacid preparations and those used to treat and prevent osteoporosis. Features of the syndrome include hypercalcemia, renal failure, and metabolic alkalosis. The exact pathophysiologic mechanism is unknown. The amount of ingested calcium may be as low as 2,000 to 3,000 mg/day (rare), but in most patients, it ranges between 6,000 and 15,000 mg/day. Therapy consists of rehydration, diuresis, and stopping calcium and antacid ingestion. If diuresis is impossible because of renal failure, dialysis against a dialysate with a low calcium concentration is effective. Kidney failure usually resolves in short-term cases but may persist in chronic cases.

Vitamin A Intoxication

Large doses of vitamin A (> 50,000 IU/day) can cause hypercalcemia by increasing osteoclast bone resorption. It is seen in patients taking retinoic acid derivatives for the treatment of acne, neuroblastoma, and other malignancies.

Theophylline

Cases of hypercalcemia associated with theophylline are usually seen in asthmatic patients. The theophylline level is usually above the normal therapeutic level. Hypercalcemia resolves when the level returns to the normal range. The mechanism is unknown.

Hypercalcemia and Renal Failure

Hypercalcemia of acute renal failure occurs mainly in patients with rhabdomyolysis. Initially, hyperphosphatemia causes calcium to deposit in the soft tissues, which leads to hypocalcemia and secondary HPT. As renal function starts to recover, the re-entry of calcium salts into the circulation associated with high PTH levels leads to transient hypercalcemia. In patients with chronic renal failure, especially those on hemodialysis, hypercalcemia occurs as a result of vitamin D overdose, immobilization, calcium antacid ingestion, autonomous PTH secretion, or a combination of any of these factors. In the past, aluminum intoxication was a common cause.

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Treatment of Hypercalcemia

The need to treat hypercalcemia depends on the degree of hypercalcemia and the presence or absence of clinical symptoms. If calcium levels are lower than 12 mg/dL and a patient has no symptoms, it is unnecessary to treat the hypercalcemia. In patients with moderate hypercalcemia (12 to 14 mg/dL) and symptoms, specific treatment is necessary. Patients with moderate calcium level elevation but no symptoms may only need adequate hydration. Patients with calcium levels higher than 14 mg/dL should be treated aggressively, regardless of symptoms.

Medical treatment of hypercalcemia can include increasing renal calcium excretion and decreasing intestinal absorption of calcium, slowing bone resorption, directly removing calcium from circulation, and controlling the underlying diseases causing hypercalcemia.

Calcium is passively reabsorbed by the favorable electrochemical gradient created by sodium and chloride reabsorption in the proximal tubule and in the thick ascending limb of the loop of Henle. Calcium is actively reabsorbed via PTH action in the distal tubule. Calcium excretion can be achieved by inhibiting proximal tubular and loop sodium reabsorption. This is best done by volume expansion using an IV normal saline infusion (1 to 2 L over 1 hour), which will markedly increase sodium, calcium, and water delivery to the loop of Henle. Using a loop diuretic (furosemide, 20 to 40 mg IV, every 2 hours) will block transport of sodium in the loop. These actions will markedly increase urinary excretion of calcium, sodium, potassium, chloride, magnesium, and water. It is important to replace water, sodium, potassium, and chloride continuously and, if this regimen is prolonged for longer than 10 hours, to replace magnesium (15 mg/hr). Urinary flow should exceed 250 mL/hr during this time. The serum calcium level will start to decrease within 2 to 4 hours and approach the normal range in 12 to 24 hours. It is paramount to avoid recurrent hypovolemia.

In cases of hypercalcemia with high calcitriol levels, intestinal absorption may be the main mechanism. Increased calcitriol production by activated macrophages in cases of granulomatous diseases and lymphomas can be diminished using corticosteroids (10 to 30 mg/day of prednisone, or more in cases of lymphoma). In rare cases when this is ineffective, ketoconazole, chloroquine, and hydroxychloroquine can be used to block calcitriol production.

Intestinal calcium absorption can be partially blocked by ingesting phosphate-containing drugs (250 to 500 mg 4 times/day; the dosage should be adjusted to prevent diarrhea), which form insoluble calcium phosphate complexes and prevent absorption. Reducing calcium intake to 400 mg/day or lower is also beneficial.

When bone resorption is the main source of calcium, inhibiting this process lowers the serum calcium level. Medications primarily used for this purpose include calcitonin and bisphosphonates. In rare cases, gallium nitrate and plicamycin (formerly mithramycin) are used.

Calcitonin can be given subcutaneously or intramuscularly every 12 hours (4 IU/kg). Its action is rapid (4 to 6 hours), and the calcium level is usually lowered by 1 to 2 mg/dL. However, calcitonin is effective in only 60% to 70% of patients, and most of them develop tachyphylaxis after 48 to 72 hours—most likely due to receptor downregulation.

Bisphosphonates are a group of medications that accumulate in bone and powerfully inhibit osteoclast-mediated bone resorption. They effectively lower the serum calcium level. They require 2 to 4 days to achieve therapeutic blood levels and their effects usually last several weeks, although this can vary by patient and by the specific bisphosphonate used.

A number of bisphosphonates are available in the United States including pamidronate, etidronate, alendronate, and zoledronate. Zoledronate appears to have the longest lasting effect (1 to 1.5 months); it is given in a 15-minute IV infusion (4 mg). Pamidronate is the most commonly used medication for the treatment of hypercalcemia. It is given by IV infusion over 4 to 24 hours. The initial dose varies: 30 mg if the calcium level is lower than 12 mg/dL, 60 mg if the calcium level is 12 to 13.5 mg/dL, and 90 mg if the calcium level is above that level. A subsequent dose should not be given until after 7 days.

Because of the lag in onset of effect, bisphosphonates should be combined with faster acting therapeutic modalities such as IV saline infusion and calcitonin injections.12 Bisphosphonates also appear to be promising in the prevention of hypercalcemia in patients with breast carcinoma.

Several reports describe the use of denosumab in bisphosphonate-resistant hypercalcemia of malignancy. Denosumab acts as a soluble decoy receptor for RANK ligand and neutralizes its effect on osteoclast activation. Denosumab is given as a subcutaneous injection 120 mg weekly for the first 4 weeks and then once monthly. Denosumab is not metabolized by the kidneys, and there are no restrictions on its use in the setting of renal insufficiency.13

Cinacalcet—a type of calcimimetic—stimulates calcium sensing receptors and suppresses PTH secretion. This drug is approved for the treatment of hypercalcemia in patients with parathyroid carcinoma or hypercalcemia caused by tertiary HPT. It can also be used to lower elevated calcium-phosphorus products in patients with end-stage renal disease who are on hemodialysis with secondary HPT.14 It can only be used in PTH-mediated hypercalcemia.

Hemodialysis or peritoneal dialysis using dialysis fluid with low levels of calcium is effective for removing calcium from the circulation. These methods are used for patients with renal insufficiency and congestive heart failure when saline infusion is not feasible. Chelation of ionized calcium using ethylenediaminetetraacetic acid and IV phosphate will decrease calcium levels immediately but because they are toxic, these methods have been largely abandoned.

Gallium nitrate is potent but nephrotoxic and requires prolonged infusion (usually 5 days). Its use in clinical practice is limited. This compound cannot be recommended for routine use. Plicamycin is also limited by its toxicity, particularly in patients with renal, liver, or bone marrow disease.

 

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Summary

  • The most common cause of hypercalcemia in the outpatient setting is primary HPT.
  • Surgery remains the only effective therapy for primary HPT, and all patients with this condition should be referred to a surgeon.
  • Management of hypercalcemia from other causes must be tailored to the underlying diagnosis.

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References

  1. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994; 96(2):101–106.
  2. Yeh MW, Ituarte HG, Zhou HC, et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab 2013; 98(3):1122–1129.
  3. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989; 4(3):283–291.
  4. Grey AB, Evans MC, Stapleton JP, Reid IR. Body weight and bone mineral density in postmenopausal women with primary hyperparathyroidism. Ann Intern Med 1994; 121(10):745–749.
  5. Larsson K, Ljunghall S, Krusemo UB, Naessén T, Lindh E, Persson I. The risk of hip fractures in patients with primary hyperparathyroidism: a population-based cohort study with a follow-up of 19 years. J Intern Med 1993; 234(6):585–593.
  6. Hedbäck G, Odén A. Increased risk of death from primary hyperparathyroidism—an update. Eur J Clin Invest 1998; 28(4):271–276.
  7. Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab 2014; 99(10):3570-3579.
  8. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg 2016; 151(10):959–968.
  9. Clark OH. How should patients with primary hyperparathyroidism be treated? J Clin Endocrinol Metab 2003; 88(7):3011–3014.
  10. Bhangu JS, Selberherr A, Brammen L, et al. Efficacy of calcium excretion and calcium/creatinine clearance ratio in the differential diagnosis of familial hypocalciuric hypercalcemia and primary hyperparathyroidism. Head Neck Dec. 15, 2018 [Epub ahead of print] doi: 10.1002/hed.25568
  11. Rosol TJ, Capen CC. Mechanisms of cancer-induced hypercalcemia. Lab Invest 1992; 67(6):680–702.
  12. Berenson JR. Treatment of hypercalcemia of malignancy with bisphosphonates. Semin Oncol 2002; 29(6 suppl 21):12.
  13. Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab 2014; 99(9):3144–3152.
  14. Torres PU. Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease. J Ren Nutr 2006; 16(3):253–258.

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