A 12-Year-Old Boy with Chronic Hepatitis C Cirrhosis and Posttransplantation Hepatitis

CASE REPORT

The patient is a 12-year-old Hispanic boy who had undergone three orthotopic liver transplantations. He was born full term by normal spontaneous vaginal delivery to a 22-year-old woman with chronic hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection. The patient first presented to his pediatrician at 6 years of age with developmental delay, muscle wasting, and hepatosplenomegaly. Workup at that time revealed a diagnosis of chronic HCV infection. Autoimmune markers and testing for HIV were negative. He was put on interferon-α_2b for several months, which was then discontinued, because of behavioral problems and high fevers.

The patient was referred to the Mount Sinai Hospital at 7 years of age. At this time, he had borderline synthetic liver function, consistent with compensated cirrhosis. Liver biopsy exhibited cirrhosis and chronic hepatitis with moderate piecemeal necrosis and lobular activity. He underwent a cadaveric left-lateral segment liver transplantation at 11 years of age for end-stage liver disease with severe portal hypertension. His postoperative course was complicated by primary graft nonfunction that resulted in retransplantation with an orthotopic cadaveric whole liver 3 days later. He was placed on combination immunosuppression with Tracrolimus, mycophenolate mofetil, and the standard posttransplantation medications, including prednisone (0.3 mg/kg/day). He developed moderate acute rejection 1 month posttransplantation and was treated with intravenous corticosteroids with clinical and biochemical resolution of his rejection episode. Acidophilic bodies were also seen in this biopsy specimen, which suggested a possibility of recurrent HCV infection.[1] His HCV quantitative polymerase chain reaction (HCV-PCR) titer was checked monthly from the time of transplantation. The titer increased incrementally from <2,000 copies/mL immediately posttransplantation to 2.11 × 10⁶ copies/mL 1 month posttransplantation to greater than 7.5 × 10⁶ copies/mL 6 months posttransplantation. Prednisone was discontinued 4 months after transplantation because of severe pansinusitis requiring surgical drainage. Liver biopsies at 4 and 5 months posttransplantation showed hepatitis with increasing severity in the graft. Six months after transplantation he developed ascites and jaundice with bilirubin = 8.8 mg/dL, albumin = 1.9 g/dL, and prothrombin time = 21 seconds (INR 2.2), after parenteral vitamin K. He was hospitalized and begun on anti-HCV monotherapy. Within 6 weeks he had a dramatic improvement with resolution of the ascites, and with bilirubin = 2 mg/dL, albumin = 3.9 g/dL, and prothombin time = 15 seconds. Two weeks later, he presented with increasing serum transaminase activities: alanine aminotransferase = 241 U/L (normal = 1-53), aspartate aminotransferase = 996 U/L (normal = 1-50), γ-glutamyl transpeptidase = 348 U/L (normal = 10-54), bilirubin = 11.7/10.4 mg/dL (normal = 0.1-1.2/ 0.0-0.8), and decreasing serum albumin = 2.5 g/dL (normal = 2.7-4.7). Liver biopsy at this time demonstrated hepatitis with severe activity and periportal fibrosis. Presence of some plasma cells was noted. Autoimmune markers were drawn and showed a positive antinuclear antibody (ANA) titer of 1:160, anti-smooth muscle antibody (ASMA) titer of 1:80, and negative liver-kidney microsomal antibody (anti-LKM). He was restarted on prednisone (0.3 mg/kg/day) and anti-HCV monotherapy (interferon-α_2b, 3 million units subcutaneously, three times weekly) was continued. His laboratory values nearly normalized, and his HCV-PCR titer dropped to below 2,000 copies/mL in 11/2 months. Because of bone marrow suppression associated with interferon treatment, he was started on granulocyte colony-stimulating factor (G-CSF) 145 γ twice weekly.

The patient was stable and doing clinically well until 16 months posttransplantation, when he developed significant ascites. Liver biopsy demonstrated severe exacerbation of the hepatitis with confluent necrosis. Oral prednisone was maintained, azathioprine (1.3 mg/kg/day) was added, and mycophenolate mofetil was discontinued. Aldactone was added for diuresis effect. He continued to deteriorate clinically and biochemically, despite higher doses of prednisone (0.6 mg/kg/day) and azathioprine (2.6 mg/kg/day) for control of his disease. HCV-PCR titers throughout this time remained nondetectable. The patient was listed for retransplantation because of worsening hepatic dysfunction as evidenced by decreasing serum albumin to 2.4 g/dL, a prolonged prothrombin time of >100 seconds, total bilirubin of 23.1 mg/dL, and serum ammonia of 220 μg/dL (normal = 15-50), which was associated with progressive hepatic encephalopathy. He underwent a third orthotopic whole liver transplantation 17 months after his initial transplantation. HCV-PCR (National Genetics Institute, Los Angeles, CA) of RNA extracted from his explanted liver was negative. Immunosuppression with cyclosporine A was instituted because Tacrolimus related cardiomyopathy. Moderate acute pancreatitis and fevers of unknown etiology complicated his postoperative course. However, to date there is no liver dysfunction, and HCV-PCR titers remain undetectable. Five months after his third transplant, he developed moderate acute rejection (Rejection activity index = 7).

REFERENCES

• 1 Park Y-N, Boros P, Zhang D N. Serum HCV-RNA levels and histologic findings in early recurrent hepatitis C in liver allografts.  Arch Pathol Lab Med . 2000;  124 1623-1627
• 2 Wiesner R H, Demetris A J, Belle S H. Acute hepatic allograft rejection: incidence, risk factors and impact on outcome.  Hepatology . 1998;  28 638-645
• 3 Boker K HW, Dalley G, Bahr M J. Long-term outcome of hepatitis C virus infection after liver transplantation.  Hepatology . 1997;  25 203-210
• 4 Schluger L K, Sheiner P A, Thung S N. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation.  Hepatology . 1996;  23 971-976
• 5 Dumoulin F L, Liefeld L, Sauerbruch T. Autoimmunity induced by interferon-therapy for chronic hepatitis.  Biomed Pharmacother . 1999;  53 242-254
• 6 Thung S N, Shim K-S, Shieh C. Hepatitis C in liver allografts.  Arch Pathol Lab Med . 1993;  117 145-149
• 7 Czaja A J, Carpenter H A. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis.  Gastroenterology . 1993;  105 1824-1832
• 8 Birnbaum A H, Benkov K J, Pittman N S. Recurrence of autoimmune hepatitis in children after liver transplantation.  J Pediatr Gastroenterol Nutr . 1997;  25 20-25
• 9 Saxena R, Merati S, Schluger L K. Post transplant autoimmune hepatitis.  Hepatology . 2001;  34 292A
• 10 Heberman R B. Effects of α-interferons on immune function.  Semin Oncol . 1997;  24(Suppl 9) 78-80
• 11 Pfeffer L M, Dinarello C A, Herberman R B. Biological properties of recombinant α-interferons: 40th anniversary of the discovery of interferon.  Cancer Res . 1998;  58 2489
• 12 Matsuda L, Saitoh N, Gotoh M. High prevalence of anti-phospholipid antibodies and anti-thyroglobulin antibody in patients with hepatitis C virus infection treated with interferon-α.  Am J Gastroenterol . 1996;  90 1138
• 13 Deutsch M, Courakis S, Manesis E K. Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon-α therapy.  Hepatology . 1997;  26 206
• 14 Garcia-Buey L, Garcia-Monzon C, Rodriguez S. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis.  Gastroenterology . 1995;  108 1770