Hepatic veno-occlusive disease resulting in tacrolimus toxicity after allogeneic hematopoietic stem cell transplantation
A 40-year-old man with myelodysplastic syndrome (refractory anemia with excess blasts-2) underwent HSCT from a familial haploidentical donor. The conditioning began with 400 cGy total body irradiation (day -9 to -8), 30 mg/m2 fludarabine (day -7 to -3), 3.2 mg/kg intravenous busulfan (day -6 to -5), and 1.25 mg/kg rabbit anti-thymocyte globuline (day -4 to -1). The results of all the baseline liver function tests and Doppler ultrasonography examination were within normal ranges before HSCT. Continuous infusion of low-dose heparin accompanied by administration of ursodeoxycholic acid was conducted for the prophylaxis of VOD. GVHD prophylaxis consisted of tacrolimus and 5 mg/m2 methotrexate (day 1, 3, 6, and 11). Tacrolimus was administered by continuous intravenous infusion at an initial dose of 0.03 mg/kg, and the dose was adjusted to maintain a constant blood trough level between 10-20 ng/mL. Neutrophil and platelet engraftment occurred on days 11 and 13, respectively. Intravenous tacrolimus was converted to oral form with a 4-fold increase, and the dose was adjusted to maintain a blood trough level between 5-10 ng/mL. The patient was discharged without any early complications. On day 41, the patient visited the emergency room complaining of right upper quadrant pain along with abdominal distension, progressive thrombocytopenia, and weight gain. The patient's serum bilirubin level began to rise on day 45 (1.55 mg/dL), and his body weight increased consistently. The blood trough level of tacrolimus was 19.2 mg/dL, and the patient complained of depressed mood and suicidal thoughts. We began to taper tacrolimus rapidly, and the drug was substituted with steroids. Examination with Doppler ultrasonography on day 46 showed a flow reversal in the portal vein, presence of ascites, and thickening of the gallbladder wall. These findings led to a diagnosis of hepatic VOD. Patient management included water restriction and diuretics to control body weight in addition to tacrolimus tapering; however, the maximum serum bilirubin level reached 2.32 mg/dL on day 49 (). The low albumin level (3.0 mg/dL) and prolonged prothrombin time (53% of normal) were indicative of concomitant hepatic dysfunction. On day 52, the patient experienced complications associated with acute pancreatitis. Serum amylase and lipase levels were 584.0 mg/dL and 561.3 mg/dL, respectively. Despite rapid tapering and, ultimately, complete discontinuation of tacrolimus due to its sustained high level, the trough level of tacrolimus remained above 9 ng/mL for 7 days. The calculated half-life of tacrolimus was 96 hours. The symptoms and signs associated with hepatic VOD and psychological manifestations gradually disappeared following day 53. The clinical manifestations of acute pancreatitis, serum amylase, and lipase levels also slowly improved after day 62. Doppler ultrasonography examination on day 69 showed regression of hepatic VOD, following which the trough blood level of tacrolimus dropped and eventually became undetectable by day 69.