SAT-LB309 Amphotericin B Induced Hypocalcemia in a Patient With Severe Hypercalcemia Due to Acute T-Cell Leukemia/Lymphoma
Authors: Janapala Rajesh naldu , jayaraj joseph , Rass bayan , Zarghamravanbakhsh Paria , Sachmechi issac 
Published: May 2020

Abstract
Adult T-cell Leukemia/lymphoma (ATL) is a rare and aggressive type of non-Hodgkin’s lymphoma. Patients with ATL commonly develop severe hypercalcemia leading to life-threatening complications like acute kidney injury, cardiac arrhythmias, altered mental status, and coma. The treatment of hypercalcemia of malignancy is often challenging. Here we present a case of ATL with severe hypercalcemia who was treated prophylactically with amphotericin B, leading to a significant and rapid drop in the calcium levels into the hypocalcemia range. We discussed the possible mechanism that leads to the rapid decline in the calcium levels in this patient. Introduction:Adult T-cell Leukemia/lymphoma (ATL) is a malignancy that develops from mature T-lymphocytes. It is a rare and highly aggressive type of non-Hodgkin’s lymphoma. The incidence of ATL is reported to be high in endemic areas like Japan, south and Central America, Caribbean islands, and Florida state of the United States. Fortunately, the incidence of ATL is about 0.05 cases per hundred thousand people in the United States, which is very low [1]. There is a strong association between human T-lymphotropic virus type 1 (HTLV-1) and ATL, with HTLV-1 genome detectable in 100 percent of tumor clones of ATL [2]. However, the percentage of HTLV-1 carriers that develop ATL is minuscule. ATL is clinically divided into four clinical subtypes (acute, lymphomatous, chronic and smoldering types) with acute and lymphomatous subtypes having a very poor prognosis, median survival despite aggressive regimens being just 7.7 months [3]. Immunodeficiency, hypercalcemia (≥10.8 milligrams per deciliter) and tumor lysis syndrome are common complications of ATL as with many other malignancies. Along with aggressive chemotherapy regimens, the primary malignancy itself causes severe immunodeficiency and puts the patient at a very high risk of developing opportunistic infections [4]. Hence these patients will be needing antibiotic prophylaxis and antifungal prophylaxis during the chemo regimen and are often treated with multiple antibiotics and antifungals during the course of the disease. One such anti-fungal agent is amphotericin B, primarily used to treat aggressive and systemic fungal infections.Amphotericin B targets the fungal cell wall by binding to the ergosterol molecule in it and forms pores that lead to fungal cell death. Amphotericin B is used to treat a wide range of invasive systemic fungal infections and some protozoan infections (visceral leishmaniasis). Amphotericin B is not the first line of choice in most fungal infections due to its well-known severe side effects. Most commonly it causes a universal febrile response with fever, chills, hypotension, tachypnea, nausea, vomiting and headache soon after the infusion probably due to histamine release. Other common side effects of amphotericin B are renal toxicities, hepatic toxicities and electrolyte imbalances, mainly Hypokalemia and Hypomagnesemia. Lipid-based liposomal formulation of amphotericin B has demonstrated fewer side effects compared to the conventional amphotericin B deoxycholate [5,6]. This is a case of ATL with severe hypercalcemia that was treated prophylactically with amphotericin B. Within two days of initiation of amphotericin B, the serum calcium levels fell sharply into the hypocalcemia range (to 6.5 milligrams per deciliter). To the best of our knowledge, no such case has been published in the past. Here we discussed what could be the possible mechanism that lead to such a drastic change in calcium levels. Case presentation:A 63-year-old male presents to our emergency department with altered mental status and high serum calcium. Present medical history was negative for fever, chills or shortness of breath but positive for constipation, reduced oral intake, urinary urgency, and excessive somnolence. His past medical history includes a recent hospitalization, a month ago, because of constipation, high calcium, and poor appetite. On evaluation at that time, he was diagnosed with having an acute subtype of Adult T-cell leukemia/lymphoma (ATL) in stage IV with cutaneous involvement and was reactive for human T- cell leukemia virus, type 1 (HTLV1). He was treated with zidovudine and interferon-alpha as first-line therapy, and intrathecal methotrexate, for suspected intrathecal involvement. His hospital stay was complicated by tumor lysis syndrome (TLS) and acute kidney injury (AKI). He was treated with pamidronate and calcitonin for hypercalcemia after which his AKI has resolved. He was discharged a week prior to his readmission, with a calcium level of 11.8 milligrams per deciliter (mg/dL), and asymptomatic. Apart from being a former smoker (quit 10 years ago), he has no other significant medical history.On physical examination, he was ill-appearing, febrile (100.1oF), confused, and minimally responsive. His abdomen was mildly distended, has an occasional cough and mild crackles on the left side of the chest. Chest X-ray showed left lower lobe consolidation with moderate pleural effusion consistent with pneumonia. CBC revealed 66% lymphocytes (with 8% reactive and 5 percent other lymphocytes), and thrombocytopenia (platelets 83,000 per microliter of blood). His Uric acid, phosphate, and potassium were normal, but had high Lactate dehydrogenase (LDH, 359 units per liter) and calcium (17 mg/dL). Computed tomography (CT) scan of head showed no mass effect but had diffuse mucosal thickening involving frontal, ethmoid and maxillary sinuses (probably from intrathecal chemotherapy from last admission). He was treated with piperacillin/tazobactam for pneumonia. Calcitonin was given for hypercalcemia. He was started prophylactically on liposomal amphotericin B. He developed low potassium and magnesium. Two days later his serum calcium levels (and ionized calcium levels) started dropping steeply to hypocalcemia range. His vitamin D was low at 9.6 nanograms per milliliter (ng/mL). He received supplemental magnesium, calcium, phosphate and vitamin D. Efforts were made to keep his potassium over 4 milliequivalents per liter (mEq/L), magnesium over 2 mEq/L and phosphate over 2.5 mg/dL. However, his calcium levels did not show any improvement. He developed severe electrolyte imbalances and suffered from two episodes of supraventricular tachycardia with hypotension that were stabilized. Further his stay in the hospital was complicated by urinary tract infection with vancomycin-resistant enterococcus which was treated with linezolid. Later the patient died shortly due to progression of his primary malignancy. Legend: units = milligrams per deciliter for total serum calcium and magnesium, Units = millimole per liter for ionized calcium, Units = milliequivalents per liter for potassium, Day 1 is start of amphotericin BDiscussion: Adult T-cell Leukemia/lymphoma (ATL) is a very aggressive T-cell malignancy with poor prognosis. The most common presentation of ATL is immunodeficiency and hypercalcemia. Hypercalcemia in ATL is often very severe with calcium levels more than 16 mg/dL and presents with altered mental status, severe dehydration due to hypercalcemia induced renal insufficiency, and an increased risk for cardiac arrhythmias [7,8]. Hypercalcemia is seen up to 20 to 30 percent of malignancies during their entire course [9], and malignancy is the most common cause of hypercalcemia in inpatients. The three main mechanisms through which hypercalcemia of malignancy occurs are bone metastasis causing localized cytokine-mediated osteolysis, secretion of the parathyroid related peptide by the neoplastic cells, and increased vitamin D production or activation by the malignant cells. Hypercalcemia is often challenging to treat in patients with cancers, and it often relapses. Amphotericin B is known to cause hypomagnesemia, hypokalemia and hyperchloremic acidosis due to increased distal tubular permeability, often needing large supplementations of potassium and magnesium. In our case, it was observed that two days after the initiation of amphotericin B, there was a sharp decline in the serum calcium level along with the expected fall in potassium and magnesium levels. Moreover, that low level of calcium was continuously present throughout the course of amphotericin B even after stopping calcium reducing medication (calcitonin) and providing calcium supplementation. The possible mechanisms by which this phenomenon occurred are 1. Low magnesium (caused by amphotericin B) causing impaired Parathyroid hormone (PTH) secretion and increased PTH resistance in the bone [10]. 2. Low levels of Vitamin D (1,25-dihydroxy vitamin D) relatively common in patients with hypomagnesemia contributing to hypocalcemia, but the reason has not been identified. In a study, it has been observed that even after supplementation of magnesium and normalization of calcium and PTH levels, the vitamin D levels remained low [11]. However, our patient’s magnesium levels were always above the severe hypomagnesemia (less than 1.2 mg/dL) that usually leads to the mechanisms mentioned above to hypocalcemia. Hence, we postulated that there must be an unknown mechanism that leads to hypocalcemia. Maybe amphotericin B has a potentiating effect on the calcium reducing agents like calcitonin, or perhaps it has a direct calcium reducing effect that is usually not seen but is seen here due to other unknown contributing factors. More studies have to be done to know what could be the possible cause of the above-observed phenomenon, so that, this effect can be potentially used in the future to treat treatment-resistant hypercalcemia. Conclusion:Hypercalcemia is commonly seen in patients with HTLV-1 associated ATL. It could often be the presenting lab abnormality that leads to the diagnosis of an ATL. Patients who are being treated for hypercalcemia of malignancy with calcitonin (or pamidronate) should be managed cautiously as starting amphotericin B can lead to hypocalcemia that is difficult to treat.