Abstract
Incidentally detected hypercalcemia usually presents in an indolent manner and is most likely caused by primary hyperparathyroidism. In contrast, hypercalcemia in the patient with a history of cancer presents in a wide range of clinical settings and may be severe enough to warrant hospitalization. This form of hypercalcemia is usually secondary to hypercalcemia of malignancy and can be fatal. Hypercalcemia of malignancy is most commonly mediated by tumoral production of parathyroid hormone–related protein or by cytokines activating osteoclast degradation of bone. The initial workup, differential diagnoses, confirmatory laboratory testing, imaging, and medical and surgical management of hypercalcemia are described in the patient with cancer.
Introduction
Calcium homeostasis is tightly regulated but can be derailed by multiple benign or malignant processes, all of which may occur in the patient with cancer. Presentations of these conditions range from asymptomatic disease incidentally detected on screening laboratory tests to severe metabolic derangements. This article reviews the causes of hypercalcemia in the patient with cancer and describes the diagnostic steps and treatment options for the most common causes of hypercalcemia.
Many organs are involved in the regulation of calcium. Chief among these are the parathyroid glands and, when calcium levels drop, the parathyroid glands increase secretion of parathyroid hormone (PTH). PTH binds to the PTH receptor and causes several downstream effects, which cause serum calcium levels to increase. PTH causes osteoblast induction of osteoclasts’ resorption of calcium from the bone. It also causes the kidney to increase calcium reabsorption and convert vitamin D to its active form, as discussed below. All of these mechanisms serve to increase serum calcium levels.1
Vitamin D, which is partially regulated through PTH, also plays an important role in the regulation of calcium. The first step of vitamin D metabolism occurs at the skin, where ultraviolet light catalyzes the production of Vitamin D3, also called cholecalciferol, from 7‐dehydrocholesterol. Cholecalciferol is then hydroxylated at the 25 position by the liver to form 25‐hydroxycholecalciferol, also called calcifediol. Calcifediol is then hydroxylated at the 1 position in the kidney to form 1,25‐dihydroxycholecalciferol, or calcitriol. This final step is regulated by PTH, and calcitriol is the active form of vitamin D. Calcitriol increases serum calcium by causing increased calcium absorption in the intestines, increased calcium reabsorption in the kidneys, and stimulation of osteoblasts to reabsorb calcium from bone.1, 2
The parafollicular C cells of the thyroid gland secrete calcitonin. Calcitonin decreases calcium levels by inhibiting osteoclast activity and renal reabsorption of calcium. In the adult, this has a small to negligible effect on calcium homeostasis. 1
In the healthy adult, the net daily calcium balance is zero. The majority of calcium is stored in the bone. The bone stores approximately 1000 g of calcium, and about 280 mg of this is turned over each day. Another 1000 mg is in circulation in the extracellular fluid. The average adult consumes approximately 1000 mg of calcium in their diet, of which 500 mg is absorbed, and the intestines secrete 325 mg, leading to a net absorption of 175 mg daily, and the rest is excreted in the feces. The kidney excretes about 175 mg of calcium a day in the urine, leading to a net balance of zero.1
Calcium exists in the serum as both free ionized calcium and bound calcium. Most of the bound calcium is attached to albumin, and the rest is bound to other proteins or small anions. Tests for total serum calcium measure both forms of calcium. This level can vary based on the level of calcium‐binding proteins. If a patient has hypoalbuminemia, the total serum calcium will be artificially low, and a corrected calcium level should be calculated. Another option is to measure the ionized calcium level directly, which will be a better indicator of bioavailable calcium in the serum. The ionized calcium level is also regulated by the pH of the serum. Calcium binding to extracellular proteins is increased with increasing pH.
Hypercalcemia has many clinical manifestations, which are mostly independent of etiology and affect multiple organ systems. In the kidney, hypercalcemia can lead to nephrolithiasis, which may be silent or symptomatic. Chronic renal insufficiency may occur. Polyuria is also common and, combined with decreased oral intake, can lead to hypovolemia. Gastrointestinal manifestations include nausea, vomiting, and constipation and may be attributable to calcium's influence on smooth muscle. Pancreatitis may also occur, although the mechanism for this is unknown. Calcium also induces increased gastrin secretion, so that hypercalcemia may lead to peptic ulcers. The effects of hypercalcemia on the central nervous system include anxiety, depression, and cognitive dysfunction, and patients who have markedly elevated serum calcium levels may present with lethargy, confusion, stupor, or even coma. Mild neurocognitive dysfunction occurs more frequently in hyperparathyroidism than in hypercalcemia from other causes and may be caused by the direct effect of PTH on the brain.3 Finally, when hypercalcemia is the result of a resorptive process, patients may also present with fragility fractures caused by osteopenia and osteoporosis.1
Patients with cancer who have hypercalcemia can be divided into 2 major groups: those with and those without an elevated PTH level. The most common cause of inappropriately elevated PTH in all patients is primary hyperparathyroidism (PHPT). In developed countries, it usually presents incidentally with an indolent course and is most often discovered from a screening serum calcium level obtained for other reasons.4, 5 Interestingly, with the advent of the electrolyte panel, which automatically includes a serum calcium level, the incidence of PHPT has increased. Parathyroid cancer is also a possibility in patients who present with an extremely elevated PTH level—although it is rare. Other forms of malignancy may also disrupt calcium homeostasis, and, in this situation, PTH levels typically are low. Hypercalcemia of malignancy (HCM) typically is associated with severe clinical signs and symptoms and is often an oncologic emergency.6 Ninety percent of all cases of hypercalcemia in patients with and without cancer are caused by either HCM or PHPT. In ambulatory patients, a higher proportion will have PHPT and, in hospitalized patients, a higher proportion will have HCM.7, 8 Figure 1 is a general algorithm that can be used when evaluating and treating a patient with hypercalcemia and a history of cancer.
Initial Evaluation of the Patient With Hypercalcemia
The initial evaluation of a patient with hypercalcemia should include a thorough history and physical. A focus should be placed on the above‐mentioned signs, symptoms, and associated diagnoses of hypercalcemia. Incidental hypercalcemia may be the first manifestation of an undiagnosed malignancy. The patient should be asked about the presence of cough, weight loss, or new masses and should be up to date with current guidelines regarding screening for colorectal, breast, and other cancers appropriate for the patient’s age, sex, and risk factors. Past medical history should include information about cardiac and renal function and previous or current malignancies. A history of smoking and exposure to other carcinogens, such as alcohol abuse and sunburns at an early age, also should be elicited as well as the use of medications that may alter calcium homeostasis (commonly, thiazide diuretics or lithium).9
In addition to a thorough physical examination evaluating for masses (head and neck, oropharynx, breast, abdomen, rectal), physical manifestations of hypovolemia, such as tachycardia, mucosal dryness, and skin tenting, should be noticed. As discussed above, these patients can become markedly hypovolemic. Attention should be paid to family history of hyperparathyroidism, renal stones, or cancer. Occasionally, hypercalcemia is the presenting sign of cancer, and a retrospective study found that patients with hypercalcemia had a higher incidence of cancer at 1 year than those without hypercalcemia.10
After a thorough physical examination, the next step is to obtain laboratory values for levels of serum calcium, intact PTH, creatinine (to assess renal function), and a 24‐hour urine collection for calcium and creatinine.9 The 24‐hour urine can help rule out other causes of hypercalcemia, such as familial hypocalciuric hypercalcemia (FHH), as discussed below. An ionized calcium level, an albumin level, and a pH level can be obtained when there is a suspicion of spurious calcium elevations.
The PTH level will act as a fork in the diagnostic road: in a patient with high PTH, the most likely diagnosis is primary hyperparathyroidism, and the next step will be to determine whether the patient has indications for surgical treatment (see below). In a patient with low PTH, the most likely diagnosis is HCM, and evaluation for an underlying malignancy should be pursued.6, 8 Patients with low PTH should have their PTH‐related protein (PTHrP) level checked to evaluate for humoral HCM (HHM). PTHrP is a protein produced by some cancers and, in some tissues, has effects similar to those of PTH. It is discussed further below. If the PTHrP is normal, then levels of 1,25‐dihydroxyvitamin D and 25‐hydroxyvitamin D can be assessed to help diagnose other forms of HCM.
The initial evaluation of a patient with hypercalcemia should include a thorough history and physical. A focus should be placed on the above‐mentioned signs, symptoms, and associated diagnoses of hypercalcemia. Incidental hypercalcemia may be the first manifestation of an undiagnosed malignancy. The patient should be asked about the presence of cough, weight loss, or new masses and should be up to date with current guidelines regarding screening for colorectal, breast, and other cancers appropriate for the patient’s age, sex, and risk factors. Past medical history should include information about cardiac and renal function and previous or current malignancies. A history of smoking and exposure to other carcinogens, such as alcohol abuse and sunburns at an early age, also should be elicited as well as the use of medications that may alter calcium homeostasis (commonly, thiazide diuretics or lithium).9
In addition to a thorough physical examination evaluating for masses (head and neck, oropharynx, breast, abdomen, rectal), physical manifestations of hypovolemia, such as tachycardia, mucosal dryness, and skin tenting, should be noticed. As discussed above, these patients can become markedly hypovolemic. Attention should be paid to family history of hyperparathyroidism, renal stones, or cancer. Occasionally, hypercalcemia is the presenting sign of cancer, and a retrospective study found that patients with hypercalcemia had a higher incidence of cancer at 1 year than those without hypercalcemia.10
After a thorough physical examination, the next step is to obtain laboratory values for levels of serum calcium, intact PTH, creatinine (to assess renal function), and a 24‐hour urine collection for calcium and creatinine.9 The 24‐hour urine can help rule out other causes of hypercalcemia, such as familial hypocalciuric hypercalcemia (FHH), as discussed below. An ionized calcium level, an albumin level, and a pH level can be obtained when there is a suspicion of spurious calcium elevations.
The PTH level will act as a fork in the diagnostic road: in a patient with high PTH, the most likely diagnosis is primary hyperparathyroidism, and the next step will be to determine whether the patient has indications for surgical treatment (see below). In a patient with low PTH, the most likely diagnosis is HCM, and evaluation for an underlying malignancy should be pursued.6, 8 Patients with low PTH should have their PTH‐related protein (PTHrP) level checked to evaluate for humoral HCM (HHM). PTHrP is a protein produced by some cancers and, in some tissues, has effects similar to those of PTH. It is discussed further below. If the PTHrP is normal, then levels of 1,25‐dihydroxyvitamin D and 25‐hydroxyvitamin D can be assessed to help diagnose other forms of HCM.
Patients With Inappropriately Elevated PTH
Primary Hyperparathyroidism
Unsuppressed or inappropriately elevated PTH refers to a high PTH level in the setting of a high or high‐normal calcium level. Patient with low calcium may have an appropriate increase in their serum PTH as a compensatory mechanism. Although there is no standard, any PTH greater than 20 pg/mL is often considered unsuppressed. Hypercalcemic patients with an unsuppressed PTH level may have PHPT from a single parathyroid adenoma, multigland disease (more than 1 parathyroid adenoma), 4‐gland parathyroid hyperplasia associated with multiple endocrine neoplasia type 1, secondary hyperparathyroidism from chronic kidney disease, chronic lithium use, parathyroid carcinoma, or (rarely) familial hypercalciuric hypercalcemia.9 Of these, PHPT associated with a single adenoma is the most common cause of hypercalcemia in the general population and also can be seen in the cancer population, although it is less common. PHPT is responsible for 6% to 21% of hypercalcemia among patients with cancer,11, 12 so it is important to remember that not all cases of hypercalcemia in patients with cancer are because of their malignancy. One retrospective study indicated that noncancer causes of hypercalcemia accounted for 97% of patients in remission and 21% of those who had active cancer, with PHPT causing 75% of those cases. Other benign causes included sarcoidosis, milk alkali syndrome, and undiagnosed causes.13 Therefore, the PTH level must always be checked in a patient with cancer who presents with hypercalcemia.
The most predominant presentation of PHPT in the United States, Canada, and Europe is that of the seemingly asymptomatic patient who has incidentally identified hypercalcemia noted on routine laboratory testing.4, 5 Clinical manifestations of PHPT that initially may be attributed to other causes include nephrolithiasis, osteopenia/osteoporosis with or without pathologic fractures, neurocognitive decline, gastrointestinal symptoms, musculoskeletal pain, and potentially increased cardiovascular mortality.9, 14, 15 In areas with poor access to health care, patients may present with brown tumors of bone, which are the product of long‐standing osteoclast overactivity (Fig. 2A).
Unsuppressed or inappropriately elevated PTH refers to a high PTH level in the setting of a high or high‐normal calcium level. Patient with low calcium may have an appropriate increase in their serum PTH as a compensatory mechanism. Although there is no standard, any PTH greater than 20 pg/mL is often considered unsuppressed. Hypercalcemic patients with an unsuppressed PTH level may have PHPT from a single parathyroid adenoma, multigland disease (more than 1 parathyroid adenoma), 4‐gland parathyroid hyperplasia associated with multiple endocrine neoplasia type 1, secondary hyperparathyroidism from chronic kidney disease, chronic lithium use, parathyroid carcinoma, or (rarely) familial hypercalciuric hypercalcemia.9 Of these, PHPT associated with a single adenoma is the most common cause of hypercalcemia in the general population and also can be seen in the cancer population, although it is less common. PHPT is responsible for 6% to 21% of hypercalcemia among patients with cancer,11, 12 so it is important to remember that not all cases of hypercalcemia in patients with cancer are because of their malignancy. One retrospective study indicated that noncancer causes of hypercalcemia accounted for 97% of patients in remission and 21% of those who had active cancer, with PHPT causing 75% of those cases. Other benign causes included sarcoidosis, milk alkali syndrome, and undiagnosed causes.13 Therefore, the PTH level must always be checked in a patient with cancer who presents with hypercalcemia.
The most predominant presentation of PHPT in the United States, Canada, and Europe is that of the seemingly asymptomatic patient who has incidentally identified hypercalcemia noted on routine laboratory testing.4, 5 Clinical manifestations of PHPT that initially may be attributed to other causes include nephrolithiasis, osteopenia/osteoporosis with or without pathologic fractures, neurocognitive decline, gastrointestinal symptoms, musculoskeletal pain, and potentially increased cardiovascular mortality.9, 14, 15 In areas with poor access to health care, patients may present with brown tumors of bone, which are the product of long‐standing osteoclast overactivity (Fig. 2A).
Treatment of Primary Hyperparathyroidism
After a diagnosis of PHPT is made, parathyroidectomy should be considered for all symptomatic patients and most asymptomatic patients. Nephrolithiasis, fragility fractures (also known as pathologic fractures), osteoporosis, or evidence of spinal compression fractures are manifestations of symptomatic PHPT. In patients without objective evidence of disease, parathyroidectomy is indicated in the following situations: a serum (albumin‐corrected) calcium level greater than 1 mg/dL above normal, bone health risk (a dual‐energy x‐ray absorptiometry scan less than −2.5, indicating osteoporosis or vertebral fracture on imaging), patients younger than age 50 years (who require prolonged monitoring and have a higher incidence of progressive signs and symptoms), or evidence of silent renal involvement (asymptomatic nephrolithiasis on imaging, nephrocalcinosis, hypercalciuria [defined as a 24‐hour urine calcium level greater than 400 mg/dL], or impaired renal function [defined as a glomerular filtration rate less than 60 mL/minute]).9 Other findings that should prompt consideration for parathyroidectomy in patients without frank, objective evidence of disease were previously debated, because there is less definitive evidence that they are caused by the PHPT, and they are often multifactorial in nature. These include frailty or diminished functional capacity, gastroesophageal reflux, neurocognitive dysfunction, and (less commonly) fibromyalgia or cardiovascular disease.9, 16, 17 In patients with normocalcemic hyperparathyroidism, it is important to rule out secondary hyperparathyroidism—most commonly from vitamin D deficiency.
Once the diagnosis is rendered, it must be determined whether the patient is a surgical candidate for parathyroidectomy. This should be a decision that includes the patient and a surgeon. The next step in management is to determine whether the disease is because of a single adenoma or multiple‐gland disease. Imaging modalities, including ultrasound, 4‐dimensional computed tomography, and sestamibi scanning, can help localize the overactive gland; the exact modality chosen depends on the expertise and availability of the region. If the disease is localized to a single adenoma on imaging, then a focused resection is planned. In this approach, the suspected gland is resected without exploring the other 3 glands. Adequacy of resection of all hyperfunctional tissue is confirmed by using an intraoperative PTH measurement. If the PTH level does not drop after resection of a single suspected adenoma, then all 4 glands are examined intraoperatively. This is termed bilateral cervical exploration and was historically the standard operative approach for patients with PHPT. It is also recommended for patients who have a family history of disease or are at risk for multigland disease, and it remains as a viable approach for all patients with PHPT.18
Observation and/or pharmacologic management of PHPT is not therapeutically or cost‐effective for patients who are surgical candidates, regardless of symptomatology.9 For the patient who cannot undergo surgery, medical options tailored to the individual patient include antiresorptives for osteoporosis (bisphosphonates or denosumab) or the calcium‐sensing receptor agonist cinacalcet for hypercalcemia control.19
After a diagnosis of PHPT is made, parathyroidectomy should be considered for all symptomatic patients and most asymptomatic patients. Nephrolithiasis, fragility fractures (also known as pathologic fractures), osteoporosis, or evidence of spinal compression fractures are manifestations of symptomatic PHPT. In patients without objective evidence of disease, parathyroidectomy is indicated in the following situations: a serum (albumin‐corrected) calcium level greater than 1 mg/dL above normal, bone health risk (a dual‐energy x‐ray absorptiometry scan less than −2.5, indicating osteoporosis or vertebral fracture on imaging), patients younger than age 50 years (who require prolonged monitoring and have a higher incidence of progressive signs and symptoms), or evidence of silent renal involvement (asymptomatic nephrolithiasis on imaging, nephrocalcinosis, hypercalciuria [defined as a 24‐hour urine calcium level greater than 400 mg/dL], or impaired renal function [defined as a glomerular filtration rate less than 60 mL/minute]).9 Other findings that should prompt consideration for parathyroidectomy in patients without frank, objective evidence of disease were previously debated, because there is less definitive evidence that they are caused by the PHPT, and they are often multifactorial in nature. These include frailty or diminished functional capacity, gastroesophageal reflux, neurocognitive dysfunction, and (less commonly) fibromyalgia or cardiovascular disease.9, 16, 17 In patients with normocalcemic hyperparathyroidism, it is important to rule out secondary hyperparathyroidism—most commonly from vitamin D deficiency.
Once the diagnosis is rendered, it must be determined whether the patient is a surgical candidate for parathyroidectomy. This should be a decision that includes the patient and a surgeon. The next step in management is to determine whether the disease is because of a single adenoma or multiple‐gland disease. Imaging modalities, including ultrasound, 4‐dimensional computed tomography, and sestamibi scanning, can help localize the overactive gland; the exact modality chosen depends on the expertise and availability of the region. If the disease is localized to a single adenoma on imaging, then a focused resection is planned. In this approach, the suspected gland is resected without exploring the other 3 glands. Adequacy of resection of all hyperfunctional tissue is confirmed by using an intraoperative PTH measurement. If the PTH level does not drop after resection of a single suspected adenoma, then all 4 glands are examined intraoperatively. This is termed bilateral cervical exploration and was historically the standard operative approach for patients with PHPT. It is also recommended for patients who have a family history of disease or are at risk for multigland disease, and it remains as a viable approach for all patients with PHPT.18
Observation and/or pharmacologic management of PHPT is not therapeutically or cost‐effective for patients who are surgical candidates, regardless of symptomatology.9 For the patient who cannot undergo surgery, medical options tailored to the individual patient include antiresorptives for osteoporosis (bisphosphonates or denosumab) or the calcium‐sensing receptor agonist cinacalcet for hypercalcemia control.19
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