Hypercalcemia is a common metabolic abnormality seen in both inpatient and outpatient settings. Depending on the serum calcium levels, hypercalcemia is categorized either as mild when levels are between 10 to 12 mg/dL, moderate when levels are between 12 to 14 mg/dL, or severe when levels are more than 14 mg/dL. Approximately, 40% to 45% of the serum calcium is attached to albumin, and serum calcium levels may fluctuate based on the serum albumin levels. Therefore, ionized or free calcium levels should be measured when hypercalcemia is suspected. The corrected calcium can be calculated by using the following formula: serum calcium + 0.8 x (4- patient’s albumin level); 4 is normal albumin level in g/dL. More than 90% of the cases of hypercalcemia are due to primary hyperparathyroidism and malignancy-induced hypercalcemia. Malignancy remains the most common cause of hypercalcemia in hospitalized patients.
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, and 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 for malignancy as the cause of hypercalcemia. Symptomatic severe hypercalcemia due to malignancy portends a poor prognosis and requires emergent treatment.
Hypercalcemia of malignancy occurs in approximately 20% of all cancer patients during their clinical course. The most common cancer associated with hypercalcemia of malignancy is multiple myeloma which has the highest prevalence of hypercalcemia of malignancy. Based on a prevalence study, hypercalcemia of malignancy in the United States in 2013 was 71,744 and has been gradually decreasing over the years.
The pathophysiology of hypercalcemia of malignancy is mainly through three mechanisms: excessive secretion of parathyroid hormone-related protein (PTHrP), bony metastasis with the release of osteoclast activating factors, and production of 1,25-dihydroxy vitamin D (calcitriol).
Excessive secretion of PTHrP is the most common cause of hypercalcemia of malignancy. 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 few cases of non-Hodgkin lymphoma. The common solid tumors include squamous cell carcinoma of the head, neck, and lungs, breast cancer, ovarian cancers, renal carcinoma, and 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. 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 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 metastasis 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. Common 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 and granulomatous diseases like sarcoidosis and tuberculosis cause hypercalcemia by increasing 1,25-dihydroxy vitamin D production. This subset of the population responds well to steroids.
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 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, renal insufficiency, distal renal tubular acidosis (RTA) secondary to nephrolithiasis. If left untreated, hypercalcemia and hypercalciuria can lead to tubular atrophy, interstitial fibrosis, and calcification and cause nephrocalcinosis. GI symptoms can vary from anorexia, nausea, and constipation. Excessive calcium deposition in the pancreatic duct can cause pancreatitis. Hypercalcemia also enhances 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 interval and, rarely, arrhythmias. Excess calcium can deposit in the heart valves and the coronaries and increase cardiovascular morbidity. CNS symptoms depend on the levels. Mild cases are asymptomatic. Severe hypercalcemia can cause lethargy, confusion, and coma, which is commonly seen in the elderly population. Common psychiatric disturbances include anxiety, depression, or cognitive disturbances.
The initial evaluation of hypercalcemia mandates a thorough history and physical, as it 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, OTC, 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 related 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, and vitamin D intoxication. Familial hypocalciuric hypercalcemia (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 PTHrP, and vitamin D metabolites such as 25-hydroxyvitamin D and 1,25-dihydroxyvitamin 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 normal range. In patients with malignancy-induced hypercalcemia, PTH levels also should be checked, as there is a higher incidence of coexisting PHPT. Very rarely, band keratopathy can be seen via slit lamp examination, which signifies calcium phosphate deposits in the cornea.
Treatment should be tailored to lower the serum calcium levels to treat the patient’s symptoms and target the underlying cause. Serum phosphorus levels need to be monitored and replaced, as hypophosphatemia is usually associated with hypercalcemia and increases the difficulty in treating hypercalcemia. If the patient is not symptomatic, mild and moderate hypercalcemia does not require immediate therapy and management of the underlying cause is required. Patients should be educated about diet, medications, and avoiding dehydration and physical inactivity. Symptomatic patients with severe hypercalcemia need emergent treatment. 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. Calcitonin acts within 4 to 6 hours and lasts for about 2 days, whereas 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 and maintain them.
IV hydration with NS at the rate of 200 to 300 mL/hr is given to maintain adequate urine output of more than 100 mL/hr, thus restoring intravascular volume and increasing urinary calcium excretion. IV hydration is to be given cautiously to patients with heart or renal failure. Loop diuretics, which help in promoting urinary calcium excretion by inhibiting reabsorption of calcium at the Loop of Henle, are given only after adequate IV resuscitation. Calcitonin (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. Bisphosphonates, such as zoledronic acid (ZA) (4mg IV over 15 minutes) or pamidronate (60 to 90 mg IV over 2 hours), are also given. ZA 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 in patients with bone metastasis to prevent any skeletal complications. The main side effects include osteonecrosis of the jaw and nephrotoxicity.
Denosumab acts by inhibiting the RANKL, and it should be considered when there is no response to zoledronic acid. Glucocorticoids are considered in patients with increased 1,25-dihydroxy vitamin D production, such as lymphomas or granulomatous diseases, as they decrease vitamin D production as well as calcium absorption from the intestines. Calcimimetics, such as Cinacalcet, is preferred in hemodialysis patients and hypercalcemia secondary to parathyroid cancer. If these strategies fail, then hemodialysis is done to treat the hypercalcemia. It is also considered in patients with severe heart or renal failure who cannot tolerate adequate IV hydration.
Malignancy-associated hypercalcemia is ideally treated by an interprofessional team that consists of an oncologist, internist, endocrinologist, and a surgeon. It is also important to involve a pain specialist because many patients also have varying degrees of pain. More than 90% of the cases of hypercalcemia are due to primary hyperparathyroidism and malignancy-induced hypercalcemia. Malignancy remains the most common cause of hypercalcemia in hospitalized patients. While most cases are managed as outpatients, severe hypercalcemia requires in-patient treatment. The outcome depends on the stage of the primary malignancy and severity of hypercalcemia. Patients with uncontrolled malignancy and severe hypercalcemia have a poor prognosis.
|||Ramos REO,Perez Mak M,Alves MFS,Piotto GHM,Takahashi TK,Gomes da Fonseca L,Silvino MCM,Hoff PM,de Castro G Jr, Malignancy-Related Hypercalcemia in Advanced Solid Tumors: Survival Outcomes. Journal of global oncology. 2017 Dec; [PubMed PMID: 29244985]|
|||Çullas İlarslan NE,Şıklar Z,Berberoğlu M, Childhood Sustained Hypercalcemia: A Diagnostic Challenge. Journal of clinical research in pediatric endocrinology. 2017 Dec 15; [PubMed PMID: 28443817]|
|||Tagiyev A,Demirbilek H,Tavil B,Buyukyilmaz G,Gumruk F,Cetin M, Severe Hypercalcemia in a Child With Acute Lymphoblastic Leukemia Relapse: Successful Management With Combination of Calcitonin and Bisphosphonate. Journal of pediatric hematology/oncology. 2016 Apr; [PubMed PMID: 26907650]|
|||Mirrakhimov AE, Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. North American journal of medical sciences. 2015 Nov; [PubMed PMID: 26713296]|
|||McCurdy MT,Shanholtz CB, Oncologic emergencies. Critical care medicine. 2012 Jul; [PubMed PMID: 22584756]|
|||Maletkovic J,Isorena JP,Palma Diaz MF,Korenman SG,Yeh MW, Multifactorial hypercalcemia and literature review on primary hyperparathyroidism associated with lymphoma. Case reports in endocrinology. 2014; [PubMed PMID: 24716007]|
|||Riancho JA,Arjona R,Valle R,Sanz J,González-Macías J, The clinical spectrum of hypocalcaemia associated with bone metastases. Journal of internal medicine. 1989 Dec; [PubMed PMID: 2489231]|
|||Schiller JH,Rasmussen P,Benson AB 3rd,Witte RS,Bockman RS,Harvey HA,Siris ES,Citrin DL,Greco FA,Stock JL, Maintenance etidronate in the prevention of malignancy-associated hypercalcemia. Archives of internal medicine. 1987 May; [PubMed PMID: 3107487]|
|||Hasling C,Charles P,Mosekilde L, Etidronate disodium in the management of malignancy-related hypercalcemia. The American journal of medicine. 1987 Feb 23; [PubMed PMID: 3103436]|