Malignancy-Related Hypercalcemia

Etiology

There are multiple causes of hypercalcemia. The most common ones are primary hyperparathyroidism (PHPT), malignancy-induced, medication-induced, familial, or endocrine-related. The initial evaluation of a patient with hypercalcemia requires a clinician to differentiate between the benign and malignant causes. The most common benign cause is PHPT, where patients are usually asymptomatic and have a long-standing history of mild hypercalcemia. Serum calcium levels greater than 13 mg/dL on initial presentation should raise suspicion of malignancy as the cause of hypercalcemia. Symptomatic severe hypercalcemia due to malignancy portends a poor prognosis and requires emergent treatment.[5][6][7]

Epidemiology

Hypercalcemia of malignancy occurs in approximately 20% of all cancer patients during their clinical course.[8] The most common cancer associated with hypercalcemia is multiple myeloma which has the highest prevalence of hypercalcemia of malignancy. Based on a prevalence study, hypercalcemia of malignancy is reported in about 2 to 3% of patients with a cancer diagnosis, and it seems that it has been gradually decreasing over the years due to better treatment choices.[9][10][11]

Pathophysiology

The pathophysiology of hypercalcemia of malignancy is explained mainly through three mechanisms: excessive secretion of parathyroid hormone-related protein (PTHrP), bony metastases with the release of osteoclast activating factors, or the production of 1,25-dihydroxy vitamin D (calcitriol).

Excessive secretion of PTHrP is the most common cause of hypercalcemia of malignancy.[12][13] It is also known as humoral hypercalcemia of malignancy (HHM) and accounts for about 80% of the cases. It is usually seen in solid tumors and a few cases of non-Hodgkin lymphoma. The most common solid tumors complicated by hypercalcemia include squamous cell carcinoma of the head, neck, and lungs, breast cancer, ovarian cancer, renal carcinoma, and a few hematological malignancies like leukemia. HHM should be suspected in patients without any skeletal metastasis. 

Structurally, PTHrP is similar to parathyroid hormone (PTH) in the first 13 amino acid sequences. Due to the similarity in structure, it acts at the same receptor as PTH and causes bone resorption, increased phosphate excretion from the proximal tubules, and calcium reabsorption from the distal tubules in the kidney. It does not have any effect on 1,25-dihydroxy vitamin D production. Lab findings are consistent with elevated PTHrP, low to normal PTH, and normal 1,25-dihydroxy vitamin D levels. Response to treatment can be evaluated by monitoring the levels of PTHrP. Usually, patients with HHM tend to have advanced disease, and it portends a poor prognosis.

Bony metastases causing the release of osteoclast activating factors contribute to 20% of the cases and are commonly seen in patients with multiple myeloma and solid organ tumors, which metastasize to bones, such as breast cancer. Typical findings include skeletal metastasis with low to low-normal PTH, PTHrP, and 1,25-dihydroxy vitamin D levels. Though the levels of PTHrP are low to normal, breast cancer cells in the bone produce PTHrP locally and increase the activity of receptor activator of nuclear factor kappa B ligand (RANKL), which, in turn, promotes osteoclastic activity and hypercalcemia.

Almost all cases of Hodgkin lymphoma and about one-third of non-Hodgkin lymphoma cases, as well as granulomatous diseases like sarcoidosis and tuberculosis, cause hypercalcemia by increasing 1,25-dihydroxy vitamin D production. This subset of the patient population responds well to steroids.

History and Physical

No specific physical examination findings indicate hypercalcemia. However, patients can present with a wide spectrum of symptoms. Depending on the acuity and severity, patients can either be asymptomatic or can have involvement of multiple organ systems such as the gastrointestinal tract (GI), musculoskeletal system, cardiovascular system (CVS), renal involvement, and central nervous system (CNS) or psychiatric disturbances.

The renal manifestations can vary from polyuria, polydipsia, nephrogenic diabetes insipidus, and renal insufficiency to distal renal tubular acidosis (RTA) secondary to nephrolithiasis. If left untreated, hypercalcemia and hypercalciuria can lead to tubular atrophy, interstitial fibrosis, and renal calcification, which can cause nephrocalcinosis. GI symptoms can vary from anorexia to nausea and constipation. Excessive calcium deposition in the pancreatic duct can cause pancreatitis. Hypercalcemia can also enhance the secretion of gastrin levels, which can contribute to peptic ulcer disease.

Musculoskeletal symptoms can manifest as muscle weakness and bone pain. CVS manifestations are subtle and include short QTc intervals and, in rare cases, more serious arrhythmias. Excess calcium can deposit in the heart valves and the coronary arteries and increase cardiovascular morbidity. CNS symptoms depend on the levels of calcium. Patients with mild hypercalcemia are usually asymptomatic, whereas patients with more severe hypercalcemia can present with lethargy, confusion, or even coma, which is more commonly seen in the elderly population. Common psychiatric disturbances include anxiety, depression, or cognitive disturbances.

Evaluation

The initial evaluation of hypercalcemia mandates a thorough history and physical examination, which can prompt the clinician to the underlying cause and pathology. Prior laboratory data is significant and can give clues about the baseline calcium levels and duration of hypercalcemia. Medication history (prescription drugs, over-the-counter vitamins, and supplements), dietary history, family history, and any evidence of prior granulomatous disease need to be reviewed systematically. Initial labs to be checked include PTH levels, as this can differentiate between PTH-related hypercalcemia and non-PTH mediated hypercalcemia. Hypercalcemia secondary to PTH is seen in primary hyperparathyroidism and familial hyperparathyroid syndromes, whereas non-PTH-related hypercalcemia is seen in malignancies, granulomatous diseases, endocrine diseases, and vitamin D intoxication.

Familial hypocalciuric hypercalcemia syndrome (FHH) should be suspected in patients with minimally elevated PTH levels and low urinary calcium excretion on 24-hour urinary calcium. Low-normal or low levels of PTH (less than 20 pg/mL) should raise the suspicion of non-PTH-related causes, and then PTHrP and vitamin D metabolites such as 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D levels should be checked. If PTHrP is elevated, it signifies HHM. Vitamin D intoxication causes elevated 25-hydroxy vitamin D levels. Lymphoma and granulomatous diseases are suspected when 1,25-dihydroxy vitamin D levels are elevated. Serum electrophoresis (SPEP), urine electrophoresis (UPEP) with immunofixation, and serum-free light chains are to be checked to rule out multiple myeloma if the vitamin D levels are in a normal range.

In patients with malignancy-induced hypercalcemia, PTH levels also should be checked, as there is the possibility of coexisting PHPT. Very rarely, band keratopathy can be seen via slit lamp examination, which signifies calcium phosphate deposits in the cornea.

Treatment / Management

Treatment should be tailored to lower the serum calcium levels to treat the patient’s symptoms and target the underlying cause. The serum phosphorus levels need to be monitored and repleted, as hypophosphatemia is usually associated with hypercalcemia, increasing the difficulty in treating hypercalcemia. If the patient is not symptomatic, mild or moderate hypercalcemia does not require immediate therapy, but managing the underlying cause is necessary. Patients should be educated about diet, medications, and avoiding dehydration and physical inactivity. Symptomatic patients with severe hypercalcemia need emergent treatment.[14]

Initial treatment includes intravenous (IV) normal saline (NS) along with calcitonin and bisphosphonates. NS acts immediately, and its effect lasts until the fluids are discontinued. The calcitonin acts within 4 to 6 hours and lasts for about two days, whereas the bisphosphonates exhibit their action in 2 to 3 days, and their effect lasts for 2 to 4 weeks. This approach is tailored to lower the serum calcium levels as well as maintain them within normal limits for as long as possible while the primary cause of the problem is being worked up and treated.[15][16][17](A1)

IV hydration with NS at the rate of 200 to 300 mL/hr is given to maintain an adequate urine output of more than 100 mL/hr, thus restoring intravascular volume and increasing urinary calcium excretion. IV hydration should be given cautiously to patients with heart or renal failure. Loop diuretics, which help promote urinary calcium excretion by inhibiting calcium reabsorption at the loop of Henle, should be given only after achieving adequate IV resuscitation.

Calcitonin (at a dose of 4 international units/kg) should be administered along with NS infusion to help prevent bone resorption and increase urinary calcium excretion. It is a very fast-acting medication, but its effect is limited.[18]

Bisphosphonates, such as zoledronic acid (ZA) at a dose of 4mg IV over 15 to 30 minutes or pamidronate at a dose of 60 to 90 mg IV over 2 hours, are also recommended for patients without any kidney dysfunction. Zoledronic acid is preferred in hypercalcemia secondary to malignancy as it is more potent and can be given over a shorter course of time. Bisphosphonates are also given on a more regular basis to patients with bone metastases to prevent any skeletal complications. The main side effects of this category of drug therapy include osteonecrosis of the jaw and nephrotoxicity.

Denosumab acts by inhibiting RANKL and should be considered when there is no response to zoledronic acid or in patients with kidney impairment, as this drug is not cleared by the kidneys.[19][20] Denosumab is also given on a regular basis to cancer patients for prevention purposes to avoid bone complications.[21](A1)

Glucocorticoid therapy should be considered in patients with increased 1,25-dihydroxy vitamin D production, such as lymphomas or granulomatous diseases, as they decrease vitamin D production and calcium absorption from the intestines.

Calcimimetic agents, such as cinacalcet, are preferred in hemodialysis patients and hypercalcemia secondary to parathyroid cancer.[22][23][24]

If all other strategies fail, then hemodialysis is done to treat the hypercalcemia. It should also be considered in patients with severe heart or renal failure who cannot tolerate adequate IV hydration.[25](B2)

Differential Diagnosis

• Adrenal insufficiency
• Berylliosis
• Coccidioidomycosis
• Crohn disease
• Hyperkalemia
• Hypermagnesemia
• Hypernatremia
• Hyperparathyroidism
• Hyperphosphatemia
• Hyperthyroidism 
• Milk alkali syndrome
• Vitamin D toxicity

Prognosis

The prognosis of malignancy-related hypercalcemia depends on the underlying cause and the kind of cancer causing the problem. Early stages of diseases can have a more favorable prognosis versus more advanced stages, or late diagnosis of the problem might carry a poor prognosis.

Complications

Hypercalcemia of any cause, when undiagnosed or not effectively treated, can ultimately cause serious kidney problems like kidney failure, as well as bone complications, including decreased bone density, osteoporosis, and fractures.