Which clinical manifestations would the nurse identify when assessing a client with hypercalcemia?

Primary hyperparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands. It probably is the most common cause of hypercalcemia, particularly among patients who are not hospitalized. Incidence increases with age and is higher in postmenopausal women. It also occurs in high frequency ≥ 3 decades after neck irradiation. Familial and sporadic forms exist.

Familial forms due to parathyroid adenoma Mitral Stenosis Mitral stenosis is narrowing of the mitral orifice that impedes blood flow from the left atrium to the left ventricle. The usual cause is rheumatic fever. Common complications are pulmonary... read more occur in patients with other endocrine tumors (see also Overview of Multiple Endocrine Neoplasia Overview of Multiple Endocrine Neoplasias (MEN) The multiple endocrine neoplasia (MEN) syndromes comprise 3 genetically distinct familial diseases involving adenomatous hyperplasia and malignant tumors in several endocrine glands. MEN 1 involves... read more ). Primary hyperparathyroidism causes hypophosphatemia Hypophosphatemia Hypophosphatemia is a serum phosphate concentration 2.5 mg/dL (0.81 mmol/L). Causes include alcohol use disorder, burns, starvation, and diuretic use. Clinical features include muscle weakness... read more and excessive bone resorption. Although asymptomatic hypercalcemia is the most frequent presentation, nephrolithiasis Urinary Calculi Urinary calculi are solid particles in the urinary system. They may cause pain, nausea, vomiting, hematuria, and, possibly, chills and fever due to secondary infection. Diagnosis is based on... read more is also common, particularly when hypercalciuria occurs due to long-standing hypercalcemia. Histologic examination shows a parathyroid adenoma in about 85% of patients with primary hyperparathyroidism, although it is sometimes difficult to distinguish an adenoma from a normal gland. About 15% of cases are due to hyperplasia of ≥ 2 glands. Parathyroid cancer occurs in < 1% of cases.

The syndrome of familial hypocalciuric hypercalcemia (FHH) is transmitted as an autosomal dominant trait. FHH involves an inactivating mutation of the calcium-sensing receptor gene CASR (most commonly), GNA11, or AP2S1 (peptides related to control or expression of CASR), resulting in higher concentrations of serum calcium being needed to inhibit PTH secretion. Subsequent PTH secretion induces renal phosphate excretion. Persistent hypercalcemia (usually asymptomatic) and often from an early age, normal to slightly elevated concentrations of PTH, hypocalciuria, and hypermagnesemia Hypermagnesemia Hypermagnesemia is a serum magnesium concentration > 2.6 mg/dL (> 1.05 mmol/L). The major cause is renal failure. Symptoms include hypotension, respiratory depression, and cardiac arrest. Diagnosis... read more occur. Renal function is normal, and nephrolithiasis is unusual. However, severe pancreatitis Overview of Pancreatitis Pancreatitis is classified as either acute or chronic. Acute pancreatitis is inflammation that resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic... read more occasionally occurs. This syndrome, which is associated with parathyroid hyperplasia, is not relieved by subtotal parathyroidectomy.

Tertiary hyperparathyroidism results in autonomous hypersecretion of PTH regardless of serum calcium concentration. Tertiary hyperparathyroidism generally occurs in patients with long-standing secondary hyperparathyroidism, as in patients with end-stage renal disease of several years’ duration.

Cancer is a common cause of hypercalcemia, usually in hospitalized patients. Although there are several mechanisms, elevated serum calcium ultimately occurs as a result of bone resorption.

Humoral hypercalcemia of cancer (ie, hypercalcemia with no or minimal bone metastases) occurs most commonly with squamous cell carcinoma, renal cell carcinoma Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more , breast cancer Breast Cancer Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more

Granulomatous disorders, such as sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more

Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more

Leprosy Leprosy is a chronic infection usually caused by the acid-fast bacilli Mycobacterium leprae or the closely related organism M. lepromatosis. These organisms have a unique tropism... read more

Histoplasmosis Histoplasmosis is a pulmonary and hematogenous disease caused by Histoplasma capsulatum; it is often chronic and usually follows an asymptomatic primary infection. Symptoms are those... read more

Coccidioidomycosis Coccidioidomycosis is a pulmonary or hematogenously spread disseminated disease caused by the fungi Coccidioides immitis and C. posadasii; it usually occurs as an acute benign... read more

Silicosis Silicosis is caused by inhalation of unbound (free) crystalline silica dust and is characterized by nodular pulmonary fibrosis. Chronic silicosis initially causes no symptoms or only mild dyspnea... read more

Idiopathic infantile hypercalcemia (Williams syndrome—see table Microdeletion Syndromes ) is an extremely rare sporadic disorder with dysmorphic facial features, cardiovascular abnormalities, renovascular hypertension, and hypercalcemia. It leads to nephrocalcinosis in some patients. The cause of hypercalcemia is unknown.

Symptoms and Signs of Hypercalcemia

In mild hypercalcemia, many patients are asymptomatic. Clinical manifestations of hypercalcemia include constipation, anorexia, nausea and vomiting, abdominal pain, and ileus. Impairment of the renal concentrating mechanism leads to polyuria, nocturia, and polydipsia. Elevation of serum calcium > 12 mg/dL (> 3.00 mmol/L) can cause emotional lability, confusion, delirium, psychosis, stupor, and coma. Hypercalcemia may cause neuromuscular symptoms, including skeletal muscle weakness. Hypercalciuria with nephrolithiasis is common.

Less often, prolonged or severe hypercalcemia causes reversible acute kidney injury or irreversible kidney damage due to nephrocalcinosis (precipitation of calcium salts within the kidney parenchyma).

In severe hypercalcemia a shortened QTc interval is shown on ECG, and arrhythmias may occur, particularly in patients taking digoxin. Hypercalcemia > 18 mg/dL (> 4.50 mmol/L) may cause shock, renal failure, and death.

Initial evaluation should include

• Review of the history, particularly of past serum calcium concentrations

• Physical examination

• Chest x-ray

• Laboratory studies, including electrolytes, BUN, creatinine, ionized calcium, phosphate, PTH, alkaline phosphatase, and serum protein immunoelectrophoresis

The cause is apparent from clinical data and results of these tests in ≥ 95% of patients. Patients without an obvious cause of hypercalcemia after this evaluation should undergo measurement of intact parathyroid hormone and 24-hour urinary calcium. When no cause is obvious, serum calcium < 11 mg/dL (< 2.75 mmol/L) suggests hyperparathyroidism or other nonmalignant causes, whereas serum calcium > 13 mg/dL (> 3.25 mmol/L) suggests cancer.

Asymptomatic hypercalcemia that has been present for years or is present in several family members raises the possibility of familial hypocalciuric hypercalcemia. Primary hyperparathyroidism generally manifests late in life but can be present for several years before symptoms occur.

Measurement of intact PTH levels help differentiate PTH-mediated hypercalcemia (eg, caused by hyperparathyroidism or familial hypocalciuric hypercalcemia), in which PTH levels are high or high-normal, from most other (PTH-independent) causes. In PTH-independent causes, levels are usually < 20 pg/mL.(< 2.1 pmol/L)

The chest x-ray is particularly helpful, revealing most granulomatous disorders, such as tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more

Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more

Silicosis Silicosis is caused by inhalation of unbound (free) crystalline silica dust and is characterized by nodular pulmonary fibrosis. Chronic silicosis initially causes no symptoms or only mild dyspnea... read more

Lung Carcinoma Lung carcinoma is the leading cause of cancer-related death worldwide. About 85% of cases are related to cigarette smoking. Symptoms can include cough, chest discomfort or pain, weight loss... read more

Chest and bone (eg, skull, extremity) x-rays can also show the effects on bone of secondary hyperparathyroidism, most commonly in patients receiving long-term dialysis. In osteitis fibrosa cystica (often due to primary hyperparathyroidism), increased osteoclastic activity from overstimulation by PTH causes rarefaction of bone with fibrous degeneration and cyst and fibrous nodule formation. Because characteristic bone lesions occur only with relatively advanced disease, bone x-rays are recommended only for symptomatic patients. X-rays typically show bone cysts, a heterogeneous appearance of the skull, and subperiosteal resorption of bone in the phalanges and distal clavicles.

In hyperparathyroidism, the serum calcium is rarely > 12 mg/dL (> 3 mmol/L), but the ionized serum calcium is almost always elevated. Low serum phosphate concentration suggests hyperparathyroidism, especially when coupled with elevated renal excretion of phosphate. When hyperparathyroidism results in increased bone turnover, serum alkaline phosphatase is frequently increased. Increased intact PTH, particularly inappropriate elevation (ie, a high concentration in the absence of hypocalcemia) or an inappropriate high-normal concentration (ie, despite hypercalcemia), is diagnostic.

The need for localization of parathyroid tissue before surgery on the parathyroid(s) is controversial. High-resolution CT with or without CT-guided biopsy and immunoassay of thyroid venous drainage, MRI, high-resolution ultrasonography, digital subtraction angiography, and thallium-201–technetium-99 scanning all have been used and are highly accurate, but they have not improved the usually high cure rate of parathyroidectomy done by experienced surgeons. Technetium-99 sestamibi, a radionuclide agent for parathyroid imaging, is more sensitive and specific than older agents and may be useful for identifying solitary adenomas.

For residual or recurrent hyperparathyroidism after initial parathyroid surgery, imaging is necessary and may reveal abnormally functioning parathyroid glands in unusual locations throughout the neck and mediastinum. Technetium-99 sestamibi is probably the most sensitive imaging test. Use of several imaging studies (MRI, CT, or high-resolution ultrasonography in addition to technetium-99 sestamibi) before repeat parathyroidectomy is sometimes necessary.

A serum calcium measurement > 13 mg/dL (> 3 mmol/L) suggests some cause of hypercalcemia other than hyperparathyroidism. Urinary calcium excretion is usually normal or high in cancer. In humoral hypercalcemia of cancer, PTH is often decreased or undetectable; phosphate is often decreased; and metabolic alkalosis, hypochloremia, and hypoalbuminemia are often present. Suppressed PTH differentiates humoral hypercalcemia of cancer from primary hyperparathyroidism. Humoral hypercalcemia of cancer can also be diagnosed by detection of PTH-related peptide in serum.

FHH is very rare but should be considered in patients with hypercalcemia and elevated or high-normal intact PTH levels. FHH is distinguished from primary hyperparathyroidism by the

• Early age of onset

• Absence of symptoms

• Frequent occurrence of hypermagnesemia

• Presence of hypercalcemia without hypercalciuria in other family members

• Low fractional excretion of calcium, which is the ratio of calcium clearance to creatinine clearance (< 1% in FHH; 1 to 4% in primary hyperparathyroidism)

• Elevated or normal intact PTH

Altered feedback regulation of the parathyroid glands may be responsible for the elevated or normal intact PTH level.

Testing for mutations of the CASR, GNA11, or AP2S1 genes may identify the genetic cause of the autosomal dominant forms of the disease that affect a specific family.

In addition to a history of increased intake of calcium antacids, milk-alkali syndrome is recognized by the combination of hypercalcemia, metabolic alkalosis, and, occasionally, azotemia with hypocalciuria. The diagnosis can be confirmed when the serum calcium concentration rapidly returns to normal when calcium and alkali ingestion stops, although renal insufficiency can persist when nephrocalcinosis is present. Circulating PTH usually is suppressed.

Vitamin D toxicity is characterized by elevated 25(OH)D concentration. In hypercalcemia due to sarcoidosis, other granulomatous disorders, and some lymphomas, serum concentration of 1,25(OH)2D may be elevated.

In mild hypercalcemia (serum calcium < 11.5 mg/dL [< 2.9 mmol/L]), in which symptoms are mild or absent, treatment is deferred pending definitive diagnosis. After diagnosis, the underlying disorder is treated.

When symptoms are significant, treatment aimed at lowering serum calcium is necessary. Oral phosphate can be used. When taken with meals, phosphate binds some calcium, preventing its absorption. A starting dose is 250 mg of elemental phosphate (as sodium or potassium salt) 4 times a day. The dose can be increased to 500 mg 4 times a day as needed unless diarrhea develops.

Moderate hypercalcemia (serum calcium > 11.5 mg/dL [> 2.88 mmol/L] and < 18 mg/dL [< 4.51 mmol/L]) can be treated with isotonic saline and a loop diuretic as is done for mild hypercalcemia or, depending on its cause, with drugs that decrease bone resorption (usually bisphosphonates, calcitonin, or infrequently plicamycin or gallium nitrate), corticosteroids, or chloroquine.

Bisphosphonates inhibit osteoclasts. They are usually the drugs of choice for cancer-associated hypercalcemia. Zoledronate can be given as a one-time dose of 4 to 8 mg IV and lowers serum calcium very effectively for an average of > 40 days.

Pamidronate can be given for cancer-associated hypercalcemia as a one-time dose of 30 to 90 mg IV, repeated only after 7 days. It lowers serum calcium for ≤ 2 weeks.

Ibandronate as a one-time dose of 4 to 6 mg IV can be given for cancer-associated hypercalcemia; it is effective for about 14 days.

Etidronate 7.5 mg/kg IV once a day for 3 to 5 days is used to treat Paget disease and cancer-associated hypercalcemia. Maintenance dosage is 20 mg/kg orally once a day, but the dose must be reduced when glomerular filtration rate is low.

Denosumab, 120 mg subcutaneously every 4 weeks with additional doses on days 8 and 15 of the first month of treatment, is a monoclonal antibody inhibitor of osteoclastic activity that can be used for cancer-associated hypercalcemia that does not respond to bisphosphonates. Calcium and vitamin D are given as needed to avert hypocalcemia.

Calcitonin (thyrocalcitonin) is a rapidly acting peptide hormone normally secreted in response to hypercalcemia by the C cells of the thyroid. Calcitonin appears to lower serum calcium by inhibiting osteoclastic activity. A dosage of 4 to 8 IU/kg subcutaneously every 12 hours of salmon calcitonin is safe. Calcitonin can lower serum calcium levels by 1 to 2 mg/dL within a few hours. Its usefulness in the treatment of cancer-associated hypercalcemia is limited by its short duration of action with the development of tachyphylaxis (often after about 48 hours) and by the lack of response in ≥ 40% of patients. However, the combination of salmon calcitonin and prednisone may control serum calcium for several months in some patients with cancer. If calcitonin stops working, it can be stopped for 2 days (while prednisone is continued) and then resumed.

Corticosteroids (eg, prednisone 20 to 40 mg orally once a day) can help control hypercalcemia as adjunctive therapy by decreasing calcitriol production and thus intestinal calcium absorption in most patients with vitamin D toxicity, idiopathic hypercalcemia of infancy, and sarcoidosis. Some patients with myeloma, lymphoma, leukemia, or metastatic cancer require 40 to 60 mg of prednisone once a day. However, > 50% of such patients fail to respond to corticosteroids, and response, when it occurs, takes several days; thus, other treatment usually is necessary.

Chloroquine phosphate 500 mg orally once a day inhibits 1,25(OH)2D synthesis and reduces serum calcium concentration in patients with sarcoidosis. Routine ophthalmologic surveillance (eg, retinal examinations every 6 to 12 months) is mandatory to detect dose-related retinal damage.

Plicamycin 25 mcg/kg IV once a day in 50 mL of 5% dextrose in water (D/W) over 4 to 6 hours is effective in patients with hypercalcemia due to cancer but is rarely used because other treatments are safer.

Gallium nitrate is also effective in hypercalcemia due to cancer but is used infrequently because of renal toxicity and limited clinical experience.

IV phosphate (disodium phosphate or monopotassium phosphate) should be used only when hypercalcemia is life threatening and unresponsive to other methods and when short-term hemodialysis is not possible. No more than 1 g should be given IV in 24 hours; usually 1 or 2 doses over 2 days lower serum calcium for 10 to 15 days. Soft-tissue calcification and acute renal failure may result. (NOTE: IV infusion of sodium sulfate is even more hazardous and less effective than phosphate infusion and should not be used.)

Treatment for hyperparathyroidism depends on severity.

Patients with asymptomatic primary hyperparathyroidism with no indications for surgery may be treated conservatively with methods to ensure that serum calcium concentrations remain low. Patients should remain active (ie, avoid immobilization that could exacerbate hypercalcemia), follow a low-calcium diet, drink plenty of fluids to minimize the chance of nephrolithiasis, and avoid drugs that can raise serum calcium, such as thiazide diuretics. Serum calcium and renal function are monitored every 6 months. Bone density is monitored every 12 months. However, subclinical bone disease, hypertension, and longevity are concerns. Osteoporosis is treated with bisphosphonates.

In patients with symptomatic or progressive hyperparathyroidism, surgery is indicated. The indications for surgery in patients with asymptomatic, primary hyperparathyroidism are controversial. Surgical parathyroidectomy increases bone density and may have modest effects on some quality of life symptoms, but most patients do not have progressive deterioration in biochemical abnormalities or bone density. Still, concerns about hypertension and longevity remain. Many experts recommend surgery in the following circumstances:

• Serum calcium 1 mg/dL (0.25 mmol/L) greater than the upper limits of normal

• Calciuria > 400 mg/day (> 10 mmol/day)

• Creatinine clearance < 60 mL/min

• Peak bone density at the hip, lumbar spine, or radius 2.5 standard deviations below controls (T score = −2.5)

• Age < 50 years

• The possibility of poor adherence with follow-up

Surgery consists of removal of adenomatous glands. Parathyroid hormone concentration can be measured before and after removal of the presumed abnormal gland using rapid assays. A fall of ≥ 50% 10 minutes after removal of the adenoma indicates successful treatment. In patients with disease of > 1 gland, several glands are removed, and often a small portion of a normal-appearing parathyroid gland is reimplanted in the belly of the sternocleidomastoid muscle or subcutaneously in the forearm to prevent hypoparathyroidism. Parathyroid tissue is also occasionally preserved using cryopreservation to allow for later autologous transplantation in case persistent hypoparathyroidism develops.

In patients with severe hypercalcemia with primary hyperparathyroidism who are unable to undergo parathyroidectomy, medical treatment is indicated. Cinacalcet, a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to extracellular calcium, may lower parathyroid hormone and calcium levels.

Hyperparathyroidism in patients with renal failure is usually secondary. Measures used for treatment can also be used for prevention. One aim is to prevent hyperphosphatemia. Treatment combines dietary phosphate restriction and phosphate binding agents, such as calcium carbonate or sevelamer. Despite the use of phosphate binders, dietary restriction of phosphate is needed. Aluminum-containing compounds have been used to limit phosphate concentration, but they should be avoided, especially in patients receiving long-term dialysis, to prevent aluminum accumulation in bone resulting in severe osteomalacia. Vitamin D administration is potentially hazardous in renal failure because it can increase phosphate absorption and contribute to hypercalcemia; administration requires frequent monitoring of calcium and phosphate levels. Treatment should be limited to patients with any of the following:

• Symptomatic osteomalacia (unrelated to aluminum)

• Secondary hyperparathyroidism

• Postparathyroidectomy hypocalcemia

Although oral calcitriol is often given along with oral calcium to suppress secondary hyperparathyroidism, the results are variable in patients with end-stage renal disease. The parenteral form of calcitriol, or vitamin D analogs such as paricalcitol, may better prevent secondary hyperparathyroidism in such patients, because the higher attained serum concentration of 1,25(OH)2D directly suppresses PTH release. Simple osteomalacia may respond to calcitriol 0.25 to 0.5 mcg orally once a day, whereas correction of postparathyroidectomy hypocalcemia may require prolonged administration of as much as 2 mcg of calcitriol po once/day and ≥ 2 g of elemental calcium/day.

The calcimimetic, cinacalcet, modulates the set point of the calcium-sensing receptor on parathyroid cells and decreases PTH concentration in dialysis patients without increasing serum calcium. In patients with osteomalacia caused by having taken large amounts of aluminum-containing phosphate binders, removal of aluminum with deferoxamine is necessary before calcitriol administration reduces bone lesions.

Although FHH results from histologically abnormal parathyroid tissue, the response to subtotal parathyroidectomy is unsatisfactory. Because overt clinical manifestations are rare, drug therapy is not routinely indicated.