A 47-year-old man with compensated hepatic cirrhosis due to a 28-year history of hepatitis B infection underwent OLT from a 19-year-old ABO-identical male donor after cardiac death in November 2013. The warm ischemic time and cold ischemic time were 5 minutes and 265 minutes, respectively. The recipient had severe complications of liver cirrhosis including hepatic encephalopathy and hypersplenism; and his Model for End-Stage Liver Disease (MELD) score was 30. Total blood loss during the surgery was 1956 ml, and the patient was given 8 units of red blood cells and 1000 ml plasma. Post-transplant immunosuppression regimens consisted of induction with anti-interleukin-2 receptor monoclonal antibody (basiliximab) followed by maintenance with steroids (methylprednisolone and prednisolone), tacrolimus (4.5 mg/d), and mycophenolate mofetil (750 mg, twice per day). The tacrolimus dose was adjusted to maintain the whole blood trough level at 8-12 ng/ml. Methylprednisolone and prednisolone were given at initial doses of 240 mg and 20 mg on postoperative day (POD) 1, respectively, and gradually tapered to 0 within 3 months. The postoperative course was uneventful, and the patient was discharged from the hospital approximately 3 weeks after surgery.

On POD 28, the patient developed a fever of 38.7℃, and he was treated with cephalosporin at a local hospital due to suspected bacterial infection. Unfortunately, the patient's condition deteriorated rapidly, and he showed signs of systemic inflammatory response syndrome (SIRS). He was then transferred to the intensive care unit in our hospital. On POD 29, the patient developed skin rashes on his limbs and trunk (Fig. 1A-C), and the rashes gradually spread to the whole body and integrated with each other. The patient also developed multiple oropharyngeal ulcers (Fig. 1D) and complained of dysphagia. The patient did not suffer from watery diarrhea during the entire clinical course. The blood tests showed that white blood cell (WBC) and platelet counts had dropped to 2.7×10⁹/L and 22×10⁹/L, respectively. Abdominal and chest computed tomography (CT) scans showed no positive findings. Cultures of blood, urine, and sputum for bacteria and viral serologic tests for cytomegalovirus (CMV) were all negative. A skin biopsy showed histological features consistent with GVHD (grade II), including focal liquefaction degeneration of the basal cells, scattered necrotic keratinocytes in stratum spinosum, and moderate lymphocytic infiltration in the dermis (Fig. 2).8,9 GVHD was suspected despite lack of chimerism of host- and donor-circulating lymphocytes among peripheral blood cells.

Because his fever did not improve, the patient was given cefmenoxime, cefoperazone/shuba tanner, meropenem, and teicoplanin to treat a possible bacterial infection, and fluconazole, caspofungin, and voriconazole for possible fungal infection. The immunosuppression therapy was gradually withdrawn, and only steroid (methylprednisolone, 2 mg/kg/day) was used in combination with gammaglobulin. Interleukin-11, colony-stimulating factors, and platelets were used for improving thrombocytopenia and promoting blood cell production. From POD 32, we noted a gradual disappearance of the skin rashes, followed by a decrease in temperature (36.5℃). On POD 35, the GVHD was finally confirmed by a skin biopsy and peripheral blood analysis employing fluorescence-activated cell sorting (FACS) and the immunosuppressive drugs including tacrolimus and mycophenolate mofetil were completely withdrawn. The plasma concentration of tacrolimus decreased to 0 on POD 38, and no immunosuppressive therapy was given between POD 35 and POD 42.

On POD 42, the patient's aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), and direct bilirubin (DBIL) levels were elevated to high levels (Fig. 3). Immunosuppressive drugs, included tacrolimus, mycophenolate mofetil, and high-dose methylprednisolone (500 mg/day for 3 days), were immediately used in the patient due to the risk of acute rejection. However, liver functions deteriorated despite these treatments, and the patient's clinical condition grew progressively worse. Thus, a liver biopsy was planned to explore the actual cause of abnormal liver function. The results of a subsequent liver biopsy were compatible with drug-induced liver injury (DILI, Fig. 4). On POD 53, rapamycin was used instead of tacrolimus, and drugs that might induce liver injury, such as meropenem, teicoplanin, and caspofungin, were withdrawn. The artificial liver support system was implemented in the patient to treat hepatic insufficiency on POD 55 and POD 59. Another liver biopsy was performed on POD 64, which confirmed the recovery of the liver from drug-induced injury. The patient was discharged with satisfactory clinical outcomes on POD 86 (Fig. 5).