Recurrence of clinically significant hepatitis A following liver transplantation for fulminant hepatitis A

Abstract

Background

We report hepatitis A virus (HAV) infection of a liver allograft following transplantation for fulminant liver failure due to HAV infection. This rare condition has been described in only three patients to date. After liver transplantation allograft function was good, but starting 80 days after transplantation, episodes of acute graft dysfunction were observed.

Objectives

To elucidate the reason for acute hepatic dysfunction a large number of differential diagnoses were tested.

Results

HAV RNA was undetectable for more than 80 days after transplantation. Detection of genomic HAV RNA by RT-PCR in serum and stool at the time of graft dysfunction led to the diagnosis of recurrent HAV infection.

Conclusions

We suggest that the risk of HAV reinfection after liver transplantation may be far higher than expected as results may be misinterpreted as rejection episodes.

Introduction

The hepatotropic positive-stranded RNA virus hepatitis A virus (HAV) belongs to the family of picornaviridae and causes usually an acute, self-limiting hepatitis after fecal-oral infection. The incubation time is approximately 4 weeks before the onset of clinical disease with icterus and elevated transaminases. The disease intensity varies from subclinical to severe hepatitis, sometimes with a pronounced cholestatic phenotype (Cuthbert, 2001).

Although the virus replicates in hepatocytes, it has been argued that the host's immune response seems to be largely responsible for the liver damage (Vallbracht et al., 1986). This hypothesis has been recently strengthened by the finding that fulminant hepatitis A is associated with low or undetectable viremia (Rezende et al., 2003).

Infectivity has been thought to be limited to the pre-symptomatic period and the initial week of disease, when HAV particles are detected in the feces. When transaminases normalize, HAV usually disappears from the stool. Viremia was believed to be limited to the week before onset of symptoms. With novel molecular techniques, however, several groups have demonstrated that genomic viral RNA can be detected by RT-PCR in tissue samples, serum and stool (Cuthbert, 2001). It has been shown that HAV viremia regularly paralleled the clinical and biochemical course of the disease even in cases of relapsing disease (Sagnelli et al., 2003). Viremia was detectable for up to 490 days after the onset of icterus and was correlated with elevated transaminases but not with anti-HAV (Normann et al., 2004). HAV RNA was detected in stools up to 3 months after the onset of clinical symptoms, in one case even after alanine aminotransferase (ALT) levels fell to normal (Yotsuyanagi et al., 1996).

Usually HAV infection imposes as a self-limiting acute hepatitis of varying intensity leading to life-long protective immunity. There are, however, some reports of a biphasic or relapsing hepatitis. After a period of partial or complete remission, a relapse may occur. A relapse may be associated with immune-mediated effects, possibly due to antigenic stimulation of the immune system by the persistent HAV infection. Consistent with this hypothesis, steroid treatment results in marked clinical improvement (Glikson et al., 1992).

The detection of anti-HAV-IgM antibodies is still considered the gold standard to diagnose an acute HAV infection. However, IgM antibodies may persist far beyond the acute illness, asking the question whether chronicity may exist (Kao et al., 1984).