Abnormal liver enzymes 2-3 months after liver transplantation in a patient with hepatitis C: Report of a case

A 50-year-old man, paraplegic from a motor vehicle accident in 1973, contracted hepatitis C virus (HCV) through multiple blood transfusions at the time of his severe injuries relating to his accident. He was diagnosed with HCV when he sought care for fatigue in 2003. In August 2004, he developed ascites and peripheral edema and was treated locally for several months. He had no variceal bleeding, no encephalopathy, and no other evidence of decompensated liver disease. He was otherwise healthy. He had never smoked and only drank 1-2 alcoholic beverages at a time every 4-8 weeks. He was an active individual who used a manual wheelchair, performed mechanical work with moderate lifting, and drove all-terrain vehicles. He was listed for a liver transplant in May 2005. He was a blood group A and was stable on diuretics and sodium restriction, with no other evidence of further decompensation through his follow-up on the waiting list. On October 17, 2005, the patient underwent a cadaveric liver transplantation without major complications. His preoperative Model for End-Stage Liver Disease score was 15. Both the donor and recipient were negative for cytomegalovirus. A duct-to-duct anastomosis was performed. The immunosuppression protocol at our institution consists of basiliximab 20 mg intraoperatively, then repeated on day 4 of the postoperative course; cyclosporine A (CyA) intravenously, changed to oral administration when the patient is eating well with a goal of cyclosporine blood level 2 hours after dose (C2) between 1000 to 1200 μg/L; and mycophenolate mofetil (MMF) started when eating well. Corticosteroids are not used to treat our patients with hepatitis B and C. This patient received intravenous CyA for 4 days, and changed to oral dose on day 5. At that time, he also initiated MMF treatment. He spent a total of 3 uneventful days in the intensive care unit and was transferred to the ward. Postoperatively, his transaminases peaked on day 2 with an alanine aminotransferase (ALT) 1646 U/L (normal [N] = <54) and an aspartate aminotransferase (AST) 1358 U/L (N = <41). His bilirubin peaked on day 5 at 105 μmol/L (6.2 mg/dL), as did his alkaline phosphatase (AP) at 208 U/L (N = <92) and his gamma-glutamyl transferase (GGT) at 239 U/L (N = <50). The only complications throughout his postoperative course were mild fluid overload during early postoperative days 2-5, which was easily managed with diuretics; a urinary tract infection; and a superficial heel ulcer. His renal function remained stable throughout his posttransplantation course. His transaminases normalized by day 13 after transplant (ALT 18 U/L, AST 24 U/L; Table 1). At that time, his bilirubin continued to be mildly abnormal at 68 μmol/L (4 mg/dL) and his alkaline phosphatase 129 U/L, but he steadily improved over the next few weeks. His creatinine was 60-90 μmol/L (0.8-1 mg/dL) and CyA C2 levels were 1000-1500 μg/L. He was discharged from the hospital on November 9, 2005, with cyclosporine 450 mg twice a day (bid), MMF 1 g bid, acyclovir 400 mg bid, dapsone 100 mg daily, aspirin, and Prilosec 20 mg daily. On November 30, 2005 (1 month after transplantation), he underwent blood work, the results of which were as follows: ALT 222 U/L, AST 112 U/L, AP 97 U/L, GGT 48 U/L, bilirubin 29 μmol/L, and CyA 1800-2300 μg/L. Doppler ultrasonography revealed nothing abnormal. His CyA and MMF doses were decreased, and his liver biochemistry improved over the next few weeks to the following: ALT 153 U/L, AST 65 U/L, AP 91 U/L, GGT 39 U/L, and bilirubin 22 μmol/L (1.3 mg/dL). On December 28, 2005 (2 months after transplantation), the patient was admitted to his local hospital with a urinary tract infection and Klebsiella bacteremia and was treated with ciprofloxacin. His liver enzymes were abnormal at the time of admission, with values as follows: ALT 450 U/L, AST 117 U/L, AP 100 U/L, GGT 59 U/L, and bilirubin 23 μmol/L (1.3 mg/dL). His bacteremia and sepsis responded to antibiotics, but his liver enzymes continued to rise. His CyA C2 levels remained 900-1600 μg/L, but his liver enzymes continued to increase. His renal function remained normal. He was transferred to the transplant center for further investigation. During that hospital admission, Doppler ultrasonography and computed tomographic scan were normal, a septic workup was negative, cytomegalovirus polymerase chain reaction was negative, and the HCV virus load was >700,000 IU/mL. No new medications had been initiated (other than the ciprofloxacin, which he had been on many times before). The patient was feeling very well and had no specific complaints. On January 24, 2006, at the time of his liver biopsy, findings were as follows: ALT 970 U/L, AST 704 U/L, AP 177 U/L, GGT 308 U/L, and bilirubin 119 μmol/L. He was receiving CyA 100 mg bid with C2 1200-1400 μg/L, and MMF 500 mg bid. His biopsy sample showed inflammation in all portal tracts with a mixed inflammatory infiltrate including lymphocytes, histiocytes, eosinophils, and rare plasma cells (Fig. 1). Interface hepatitis was noted in many of the portal tracts. Only one bile duct appeared injured, but marked endotheliitis of both hepatic and portal veins was seen. In addition, lobular inflammation with apoptotic cells was noted, but fibrosis was limited to the portal areas. Overall, the biopsy sample was interpreted as consistent with moderate rejection (with an element of recurrent hepatitis C). Liver biopsy findings 3 months after transplantation. Portal tract inflammation with interface hepatitis in many tracts, rare bile duct injury, and marked endotheliitis of portal and hepatic veins are evident, which are findings consistent with moderate rejection. Lobular inflammation and apoptotic cells with mild portal fibrosis are interpreted as elements of recurrent hepatitis C. Considering that this rejection occurred in the setting of high immunosuppression levels and there appeared a clear element of recurrent HCV, it was elected to try low-dose oral prednisone (10 mg/d) and to continue his current doses of MMF 500 mg bid and CyA 100 mg bid. Over the next few weeks, his liver enzymes improved considerably: ALT 129 U/L, AST 53 U/L, AP 62 U/L, GGT 42 U/L, and bilirubin 20 μmol/L (1.2 mg/dL). His CyA dose had been decreased to 75 mg bid, and during his continued biochemical improvement, he actually had lower level of CyA (C2 400-700 μg/L). The prednisone was tapered to 7.5 mg/d, and his CyA dose increased slightly to 100 mg bid. His liver enzymes started to increase again, so his prednisone dose was increased back to 10 mg/d. Unfortunately, his liver enzymes continued to rise rapidly, to the following values: ALT 763 U/L, AST 268 U/L, AP 75 U/L, GGT 152 U/L, and bilirubin 18 μmol/L (1.1 mg/dL). At the time of his second liver biopsy (at 6 months after transplantation), he was receiving CyA 100 mg/d, with C2 700-1100 μg/L, prednisone 10 mg/d, and MMF 500 mg bid. His second liver biopsy revealed lymphocytic portal infiltrate and lymphoid aggregates, but occasional eosinophils were present (Fig. 2). There was no bile duct injury or significant endotheliitis, but lobular inflammation and Stage 1 fibrosis were present. These findings were consistent with recurrent hepatitis C, with minimal evidence of ongoing rejection. Liver biopsy findings 6 months after transplantation demonstrating lobular inflammation. Portal tract inflammation with lymphoid aggregates and no bile duct injury or endotheliitis is evident. Recurrent hepatitis C is a difficult problem in liver transplant recipients, and differentiating recurrent disease from acute rejection is often difficult. Treating acute cellular rejection in patients with HCV is also fraught with difficulty and anxiety. These issues are addressed in our subsequent discussions by Dr. Hugo Rosen and Dr. Lydia Petrovic.

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