Surfactant and lung inflammation
Authors: K B M Reid
Journal: Thorax (2005)

<h3>Aims</h3> All Trans Retinoic Acid (ATRA) has revolutionized the treatment of acute promyelocytic leukemia (APML) and has been the backbone of all standard treatment protocols. Differentiation syndrome, pseudotumor cerebri and hyperlipidemia are well documented side effects of ATRA. Herein, we report a rare adverse effect of ATRA induced hypercalcemia further precipitated by interaction with fluconazole in a pediatric case of APML. <h3>Methods</h3> A 11-year-old boy with APML was put on standard chemotherapy with ATRA based induction during which he developed differentiation syndrome. He presented with features of pseudotumor cerebri in the form of sudden onset headache, blurred vision and left lateral rectus palsy which responded well to steroids and discontinuation of ATRA. Subsequently, he was administered consolidation chemotherapy with four doses of idarubicin and ATRA (in the dose of 45 mg/m2/day) per cycle, each lasting for 15 days. Due to severe cytopenia, he was also initiated on antifungal prophylaxis with fluconazole. Within a week, he presented with severe backache, bone and flank pains. Radiographic imaging of the lumbar spine and sonography of the pelvis were unremarkable; however, serum calcium level was incidentally found to be elevated at 14.2 mg/dL (iCa 1.76 mmol/L). His urine calcium: creatinine ratio was 1.34, vitamin D level was 22 ng/ml with normal phosphorous and alkaline phosphatase levels. Parathyroid hormone (PTH) was 3.1 pg/ml which precluded the possibility of primary hyperparathyroidism or ectopic PTH secretion as a cause of the hypercalcemia. <h3>Results</h3> Further therapy with ATRA was withheld and the hypercalcemia was treated with hyperhydration, diuresis and pamidronic acid. As a result, the serum calcium level dropped to 12.1 mg/dL (iCa 1.56 mmol/L) and normalized within a week. Hypercalcemia was observed on two more occasions despite a reduced dose of ATRA at 25mg/m<sup>2</sup>/day, both documented after the fifth to eighth day of starting ATRA with calcium levels of 15.7 mg/dL (iCa1.75 mmol/L) and 14.2 mg/dL(1.76mmol/L) respectively. He was treated successfully with hyperhydration and palmidronic acid. On completion of the intensive phase chemotherapy, antifungal prophylaxis was stopped. He is currently on maintenance chemotherapy with ATRA every 15 days, 6-mercaptopurine and methotrexate and till date has not developed hypercalcemia, thus surmising that hypercalcemia may have been precipitated by interaction of ATRA with fluconazole. <h3>Conclusion</h3> ATRA metabolism involves liver cytochrome P450 subtypes 2C9 and 3A4. Azoles are inhibitors of these enzymes causing increased plasma concentration of ATRA thereby potentiating the effect on calcium metabolism. Studies show direct effect of ATRA causing enhanced osteoclastic activity leading to bone mineral resorption similar to PTH. Further, ATRA down regulates interleukin-6 (IL-6) receptors which may have a positive effect on bone resorption and hypercalcemia. ATRA induced severe hypercalcemia is not a very well-known complication. A few cases have been reported, similar to ours, as a result of possible interaction with posaconazole and itraconazole as a cause of hypercalcemia and calcium levels normalized once discontinued. This case further highlights the need to look out for hypercalcemia throughout the treatment of APML as its occurrence is independent of the dose of ATRA as well as the duration of treatment.