Hypercalcemia is a common electrolyte disorder present in up to 4% of patients in the outpatient population.1 The majority of these patients are asymptomatic due to gradual and mild elevations in serum calcium. Hypercalcemia is commonly noted as an incidental finding on a routine lab evaluation. The two most common causes for hypercalcemia are primary hyperparathyroidism and malignancy with the former being the dominant cause in outpatient settings and the latter more common in acute care settings.1,2 These causes, along with others that are less common, require unique diagnostic decision-making for screening and further evaluation. The purpose of this article is to enable primary care providers to recognize and appropriately evaluate hypercalcemia, and to develop management plans focusing on the most common causes for this electrolyte disturbance in the primary care setting.
Pathophysiology of calcium in the body
Calcium is vital in the development and maintenance of skeletal structure and many other metabolic processes. Over 99% of the body's calcium stores are in the bone with the remaining 1% in the serum and cell mitochondria. About 40% of serum calcium is bound by protein such as albumin and is biologically inert. Another 50% is ionized (free) and affects various physiologic functions such as muscle contraction, nerve impulse conduction, blood clotting, and plasma membrane integrity. The remainder of serum calcium is complexed (chelated), which allows the calcium to travel between body parts or be absorbed by various body tissues.3,4
Serum calcium levels are regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D [1,25(OH)2D; calcitriol], and calcitonin. Low serum calcium levels trigger an increase in PTH secretion from the parathyroid glands. This negative feedback loop increases calcium absorption in the intestines, calcium reabsorption in the kidneys, and bone resorption to maintain homeostasis. 25-hydroxyvitamin D [25(OH)D], an active metabolite of vitamin D, becomes 1,25(OH)2D when activated in the renal system as a result of serum hypocalcemia and increased PTH production. The hormone activity of this vitamin D metabolite causes increased absorption of calcium in the small intestine, bone resorption, and renal tubular reabsorption of calcium resulting in an increase in serum calcium. Conversely, in the setting of hypercalcemia, PTH production and renal activation of 25(OH)D decrease. Calcitonin, a hormone produced by the thyroid gland, suppresses osteoclast activity in the bone when serum calcium is elevated.3,4
Causes of hypercalcemia
Hypercalcemia occurs when the amount of circulating calcium exceeds the excretion of calcium via the urine or deposition of calcium in bone. Hypercalcemia is defined as total serum calcium exceeding 10.5 mg/dL (2.6 mmol/L) or ionized serum calcium exceeding 5.6 mg/dL (1.4 mmol/L). Causes for hypercalcemia can be PTH-mediated and non-PTH-mediated. PTH-dependent causes include primary hyperparathyroidism (PHPT), tertiary hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), lithium therapy, multiple endocrine neoplasia (MEN) syndromes, and ectopic PTH-producing tumors. Non-PTH-mediated causes include malignancy, vitamin A or D intoxication, nonparathyroid endocrine disorders, granulomatous disorders, immobilization, certain medications, Paget disease of bone, milk-alkali syndrome, and rhabdomyolysis. Together, PHPT and malignancy account for more than 90% of cases of hypercalcemia.2
PHPT. PHPT is the most common cause of PTH-mediated hypercalcemia and the third most common endocrine disorder behind diabetes and thyroid disease.5,6 PHPT is caused by oversecretion of PTH by one or more of the parathyroid glands. A benign parathyroid adenoma in one gland accounts for over 80% of cases. Less commonly, multiple adenomas and four-gland hyperplasia may be involved. Parathyroid carcinoma accounts for less than 1% of PHPT cases.7 Disruption in the feedback loop from excess PTH leads to an increase in serum calcium exceeding 10.5 mg/dL (2.6 mmol/L) but usually within 1 mg/dL (0.25 mmol/L) of the upper limit of normal. Sequelae of PHPT include bone loss, increased risk of fracture, renal calculi formation, neuropsychiatric disease, and cardiovascular disease.8,9 Other causes of PTH-mediated hypercalcemia include lithium use, tertiary hyperparathyroidism (which is classically seen in patients with renal failure), and FHH, a genetic inactivation of the calcium-sensing receptor in the parathyroid glands and kidneys.9
Hypercalcemia of malignancy. Hypercalcemia of malignancy (HCM) affects about 30% of patients with cancer with the percentage being higher in those with advanced stages of cancer. Hypercalcemia can be the result of several mechanisms. Approximately 80% of HCM is humoral and caused by the oversecretion of parathyroid hormone-related protein (PTHrP). PTHrP increases osteoclast activity within the bone causing calcium to be released into the bloodstream. Squamous cell carcinomas of the lung, head, and neck, as well as renal, bladder, breast, and ovarian cancers are most often associated with humoral hypercalcemia of malignancy (HHM). These patients generally have a poor prognosis. Another mechanism resulting in HCM is stimulation of osteoclast production causing bone resorption and hypercalcemia. This process is most commonly seen in solid tumors with bone metastasis, as in breast cancer, and multiple myeloma. Finally, vitamin D-secreting lymphomas and ectopic hyperparathyroidism, most commonly associated with small cell lung cancers and adenocarcinomas, account for less than 1% of HCM cases.10
Milk-alkali syndrome. Milk-alkali syndrome, the third leading cause of hypercalcemia, results from ingesting large amounts of calcium carbonate either for treatment of gastrointestinal symptoms or for prevention and treatment of osteoporosis. Excessive absorption occurs when calcium intake exceeds 10-15 grams per day, leading to hypercalcemia, acute kidney injury, and metabolic alkalosis.11
Vitamin D toxicity. Vitamin D toxicity is an uncommon cause of hypercalcemia and usually occurs because of accidental over-the-counter supplement overdose or prescribed doses above acceptable limits with poor follow-up. Rarely, overfortified milk has been associated with toxicity.12,13
Medications. Although rare, some medications can cause hypercalcemia. Lithium can increase PTH secretion leading to mild hypercalcemia. Theophylline toxicity, thiazide diuretics, isotretinoin, estrogens, antiestrogens, denosumab, and teriparatide have also been associated with mild calcium elevations. Of note is the possibility of a clinically significant increase in serum calcium in patients after discontinuing denosumab therapy. This monoclonal antibody suppresses osteoclast formation and is used in the treatment of osteoporosis and skeletal metastasis. A rapid recovery of osteoclast activity after discontinuation of denosumab is thought to lead to hypercalcemia.14,15 Antiestrogens such as tamoxifen have been associated with hypercalcemia when used for treatment of patients with breast cancer and skeletal metastases, possibly due to tumor cells' release of bone resorbing factors.15
Other causes. Additional but less common causes for hypercalcemia include hyperthyroidism, acromegaly, pheochromocytoma, adrenal insufficiency, immobilization, and parenteral nutrition. A careful history and physical exam along with appropriate lab testing can assist in the diagnosis of hypercalcemia from these conditions.2
History and clinical manifestations
An accurate personal and family history and review of systems are vital in evaluating for primary causes of hypercalcemia. The patient should be asked about a current diagnosis of malignancy or any symptoms suspicious for malignancy. The currency and results of appropriate cancer screenings based on risk factors, gender, and age must be reviewed along with current medications, supplements, and dosages; a past diagnosis of osteoporosis or fracture; or a history of renal calculi. A family history including the presence of hyperparathyroidism, asymptomatic hypercalcemia, MEN syndromes, and malignancy must be obtained.
The signs and symptoms of hypercalcemia depend on the degree and rapidity of the elevation and are the same regardless of the source. Mild hypercalcemia (less than 12 mg/dL [less than 3 mmol/L]) is usually asymptomatic and detected in a routine lab evaluation. Symptoms associated with moderate hypercalcemia (12 to 14 mg/dL [3 to 3.5 mmol/L]) are polyuria, polydipsia, fatigue, weakness, lethargy, anorexia, nausea, and constipation.3 Severe hypercalcemia (greater than 14 mg/dL [greater than 3.5 mmol/L]) may manifest with increasing weakness, difficulty concentrating, confusion, stupor, and coma. Cardiac manifestations may include bradycardia, hypertension, and shortening of the QT interval.2 In developed countries, mild hypercalcemia secondary to PHPT is largely asymptomatic due to a higher detection rate from increased routine biochemical screenings and improvements in the accuracy of PTH assays. In developing countries there is a diverse clinical presentation that has been described as "stones (nephrolithiasis), bones (osteoporosis and so on), groans (gastrointestinal symptoms), and moans (depression, anxiety, cognitive dysfunction, and personality changes)".16,17 Additional constitutional symptoms and physical findings may be noted due to underlying malignancy or other previously mentioned causes for hypercalcemia.
Differential diagnoses and evaluation
After discovering an elevated serum calcium level, the NP must ensure that the patient is stable and does not require emergency treatment before proceeding with additional diagnostics. A corrected calcium concentration greater than 14.0 mg/dL (3.5 mmol/L) or elevations with significant signs or symptoms such as lethargy, stupor, ECG changes, and vomiting are medical emergencies with significant mortality. If there is no need for emergency intervention, hypercalcemia must first be confirmed since hemoconcentration from dehydration or tourniquet use can cause a falsely elevated level. Once confirmed, a corrected total calcium level must be obtained. Calcium is 40% protein bound and an accurate measurement is dependent upon serum albumin levels. Hyperalbuminemia as seen in dehydration may result in an increase in total calcium level without a change in ionized calcium. Conversely, a patient with hypoalbuminemia from malnutrition may have normal total calcium levels but, in fact, have high ionized calcium. Corrected total calcium calculators are readily available online. Alternatively, obtaining an ionized calcium level is the gold standard for evaluating the amount of free calcium in the serum since this is unaffected by serum albumin levels.18,19
Once hypercalcemia is confirmed, the NP must first consider the most common causes of hypercalcemia: PHPT and malignancy. PHPT is usually associated with a lower calcium level than malignancy, may be chronic, and is more likely to present in an outpatient setting. Patients with PHPT are usually asymptomatic and have a normal physical exam. In HCM, the patient may have a known malignancy or findings suggestive of a malignancy. Calcium levels are usually higher than in PHPT and patients are more likely to be symptomatic and in an inpatient setting.10,18
A PTH level must be obtained to differentiate between PTH-mediated and non-PTH-mediated hypercalcemia. Note that biotin supplements can falsely lower PTH levels and should be discontinued several weeks before PTH measurement.18,19 A normal PTH level for an adult 19 years and older is 14-64 pg/mL although levels vary based on the age of the patient and lab reference ranges.20
A high or high-normal PTH suggests a PTH-mediated source with the most common being PHPT. Less frequent causes, including lithium use, FHH, MEN syndromes, and tertiary hyperparathyroidism, must also be considered. In FHH, 24-hour urine calcium excretion is low or low normal. This condition is generally benign but should be differentiated from PHPT to avoid unnecessary treatment. These patients should be referred for genetic testing for definitive diagnosis.2,9,19 Conditions associated with MEN syndromes vary by syndrome type and can include multiple parathyroid adenomas, pituitary adenomas, pancreatic islet cell or gastrointestinal endocrine tumors, medullary thyroid cancer, and pheochromocytoma.21 Tertiary hyperparathyroidism should be considered in patients with end-stage kidney disease and elevated calcium.18
Low or low-normal PTH suggests non-PTH-mediated hypercalcemia, with malignancy being the most common cause. The next step is to obtain a PTHrP measurement. PTHrP is an indicator of HHM, which accounts for 80% of malignancy-related hypercalcemia cases. If PTHrP is elevated, further workup should assess for progression of a previously diagnosed malignancy or an initial diagnostic workup as indicated to include squamous cell cancers, breast, renal, bladder, and ovarian cancers, and non-Hodgkin lymphoma.10,18,19 These patients usually have a recent onset of calcium elevation.10,18
A normal PTHrP is present in 20% of cases of HCM. In this situation, the clinician should consider both malignant and nonmalignant causes. Vitamin D metabolites should be checked, as an elevation in 1,25(OH)2D may be associated with lymphoma, granulomatous disorders, or other conditions, and an elevation in 25(OH)D indicates vitamin D intoxication. If PTHrP and vitamin D metabolites are normal or low, alternative diagnoses, such as multiple myeloma, must be considered. Multiple myeloma screening should include serum protein electrophoresis, urine protein electrophoresis, serum free light chain assay, and a skeletal survey. Thyroid function tests and diagnostics used to evaluate the possibility of adrenal insufficiency may be indicated to rule out certain endocrine disorders. A vitamin A level can assess for vitamin A intoxication; the presence of alkalosis, renal insufficiency, and a history of calcium-rich medication ingestion indicate milk-alkali syndrome (see Hypercalcemia diagnostic decision tree).18,19
Management
As mentioned earlier, patients who are unstable or who are symptomatic with moderately elevated calcium levels as well as those with a total corrected calcium of greater than 14 mg/dL require emergency treatment.19
The appropriateness of managing hypercalcemia in the primary care setting depends on the cause. Specialty referral is indicated for most patients with hypercalcemia. The initial evaluation of patients with asymptomatic PHPT should include a biochemistry panel, 25(OH)D level, PTH level, bone mineral density screening using dual-energy X-ray absorptiometry (DXA), and a vertebral spine assessment. 24-hour urine should be evaluated for calcium, creatinine, and creatinine clearance, and a stone risk profile obtained. Finally, abdominal imaging by X-ray, ultrasound, or computed tomography (CT) scan is recommended to evaluate for nephrolithiasis.22
Those diagnosed with PHPT who meet surgical criteria for parathyroidectomy require referral to an endocrinologist or someone skilled in parathyroid surgery, regardless of whether they are symptomatic, since surgical management is the only definitive treatment. Candidates for parathyroidectomy include those who have hypercalcemia symptomatology, nephrolithiasis, or a history of fracture. Surgery may be considered in asymptomatic patients with a diagnosis of osteoporosis on DXA scan or a history of a vertebral fracture, creatinine clearance less than 60 mL/min, presence of nephrolithiasis or risk for the same with an elevated 24-hour urine calcium, or age less than 50. Although beyond the scope of this article, other management strategies for these patients could include vitamin D supplementation and various treatment regimens for osteoporosis depending on associated findings and surgical risk.6,8,22
If PHPT is confirmed in a patient who is asymptomatic and does not meet criteria for surgical intervention, annual monitoring by the primary care provider of serum calcium, creatinine, and estimated glomerular filtration rate to assess for parathyroid disease progression is acceptable. If renal stones are suspected, a 24-hour biochemical profile and renal imaging may be indicated. Additionally, a DXA scan (three sites) every 1 to 2 years is recommended for these patients.8,22
Patients discovered or suspected to have HCM require referral to a hematology/oncology specialist. Management of other etiologies of hypercalcemia varies based on the cause, and may include strategies such as removal of an offending medication (including excessive supplement ingestion) or treating associated conditions such as osteoporosis.2
Other specialty referrals vary according to the cause of the condition and could include general surgery, oncology, nephrology, urology, rheumatology, and endocrinology.
Conclusion
Alterations in serum calcium are common and often incidental findings in the primary care setting. Most cases of mild and chronic hypercalcemia are the result of PHPT. However, some instances are related to malignancy and other less common causes and warrant a separate and individualized evaluation and treatment plan. Other causes have vastly divergent evaluation pathways making appropriate diagnostics vital. Even though most patients with hypercalcemia will warrant referral, the clinician should feel confident in their ability to assess for the need for emergent care or follow the appropriate path toward a correct diagnosis. The application of evidence-based decision-making using a stepwise approach to diagnostics can facilitate appropriate and timely referrals to improve patient outcomes while minimizing unnecessary testing.
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