Kidney transplant and cryptic hepatitis

Abstract

In June, 2007, a 35-year-old man was admitted to our hospital for investigation of asthenia, anorexia, and bone pain, which started in May, 2007. He had a congenital malformative uropathy that led to chronic renal failure and to a kidney transplantation in 1989. In 2006, posttransplant follow-up showed an apparently resolved hepatitis B virus (HBV) infection. Markers of liver function were normal, HBsAg was not detectable but tests for anti-HBc and anti-HBs were positive. In May, 2007, the patient resumed dialysis for kidney failure related to chronic allograft nephropathy. Immunosuppressive medications (IS) were withdrawn. On admission, he had painless hepatosplenomegaly on clinical examination. Blood test results showed: high concen trations of γ-glutamyltranspeptidase (231 IU/L), aspartate aminotransferase (AST; 1026 IU/L), alanine amino transferase (704 IU/L), and total alkaline phosphatase (414 IU/L). Plasma albumin, factor V, and bilirubin were normal. Ultrasonography and CT showed hepato splenomegaly without dilatation of the biliary tract. Serological tests for hepatitis A and C viruses, HIV 1 and 2, leptospirosis, rickettsiosis, hepatitis-δ virus, and cytomega lovirus were negative, as were PCRs for Epstein-Barr virus and GB virus. The HBV markers remained unchanged: anti-HBs and anti-HBc were present; HBsAg was retrospectively undetectable with seven diff erent commercial detection kits. However, HBeAg was present, anti-HBe antibody was absent, and high concentrations of HBV DNA were detected by PCR (1 698 244 copies per mL). Histology of our patient’s liver biopsy specimen showed sinusoidal cellular infi ltrates composed of macrophages (CD68-positive) and T lymphocytes (CD3-positive). Immunostaining of hepa tocytes was positive for HBsAg and HBcAg, consistent with an acute HBV infection. Retrospective analysis of frozen serum samples from 2004 showed aminotransferases within normal limits, but positive HBeAg and HBV DNA (10 348 745 copies/mL; fi gure). The surface gene (S gene) of the virus was sequenced and the following aminoacid substitutions were found in the envelope protein: Y100S, C121I, T123N, D144E, G145R, L175S, Q182R, P211H. Our patient had had a chronic HBV infection with an HBsAg mutant for many years, which had been wrongly judged to be under control, because of the serological profi le of resolved infection and normal tests of liver function. The rare association of mutations at positions 123, 144, and 145 in the antigenic determinant region explains why HBsAg was not detectable by conventional serological assays. Entecavir was started soon after diagnosis. When last seen in November, 2008, our patient was well. Immunosuppression can lead to reactivation of HBV in transplant recipients. In our case, because of mutations of HBsAg and the immunosuppressive state, it remained clinically and serologically silent. Restoration of immune function, on withdrawal of immunosuppressive therapy, introduced a new imbalance between host immunity and virus infection. This experience has also been reported for HBV infections in HIV-infected patients after introduction of highly active antiretroviral therapy and in patients receiving chemotherapy for cancer. In our patient, it resulted in rapid immune-mediated destruction of HBVinfected hepatocytes, manifested as acute hepatitis. Our case illustrates the complex interactions between host immune response and viruses that chronically infect immunosuppressed patients. The consequences of these interactions may constitute a challenge for the diagnosis of viral infections not only in transplant patients.