Hepatitis A-related Acute Liver Failure
Hepatitis A-related Acute Liver Failure
The reason(s) that hepatitis A virus (HAV) infection may progress infrequently to acute liver failure are poorly understood. We examined host and viral factors in 29 consecutive adult patients with HAV-associated acute liver failure enrolled at 10 sites participating in the US ALF Study Group. Eighteen of twenty-four acute liver failure sera were PCR positive while six had no detectable virus. HAV genotype was determined using phylogenetic analysis and the full-length genome sequences of the HAV from a cute liver failure sera were compared to those from self-limited acute HAV cases selected from the CDC database. We found that rates of nucleotide substitution did not vary significantly between the liver failure and non-liver failure cases and there was no significant variation in amino acid sequences between the two groups. Four of 18 HAV isolates were sub-genotype IB, acquired from the same study site over a 3.5-year period. Sub-genotype IB was found more frequently among acute liver failure cases compared to the non-liver failure cases (chi-square test, P < 0.01). At another centre, a mother and her son presented with HAV and liver failure within 1 month of each other. Predictors of spontaneous survival included detectable serum HAV RNA, while age, gender, HAV genotype and nucleotide substitutions were not associated with outcome. The more frequent appearance of rapid viral clearance and its association with poor outcomes in acute liver failure as well as the finding of familial cases imply a possible host genetic predisposition that contributes to a fulminant course. Recurrent cases of the rare sub-genotype IB over several years at a single centre imply a community reservoir of infection and possible increased pathogenicity of certain infrequent viral genotypes.
Hepatitis A virus (HAV), a single stranded RNA virus, is endemic throughout most of the world and is also highly genetically conserved. In the United States, rates of infection have dropped significantly with increased use of the hepatitis A vaccine, however the estimated incidence is still above 30 000 new infections per year. The infection usually follows an innocuous course, remaining sub-clinical in most children, while appearing as acute self-limited hepatitis in adults. Less than 1% of acute hepatitis A cases result in acute liver failure. HAV infection currently accounts for only 3% of adult acute liver failure (ALF) cases in the United States. Although hepatitis A-related ALF patients experience a relatively high spontaneous survival rate (69%), the remaining patients either die or require emergency liver transplantation.
The relationship between self-limited hepatitis A cases and those HAV infections resulting in ALF (HAV ALF) is poorly understood. Host factors including age and underlying liver disease are thought to increase the likelihood of a fulminant course. Viral factors including low viral load and a higher rate of substitution in the 5' untranslated region (UTR) of the viral RNA have also been correlated with increased frequency of HAV-related ALF. Another potential viral factor is genotype. Epidemiologic studies in the United States have demonstrated that sub-genotype IA is most common, comprising 98% of infections, while sub-genotype IB is found in only 2%; most IB infections have been associated with international travel. To date, no correlation between ALF and HAV genotype has been evident but this has not been systematically examined. Previous studies have focused on the 5' UTR and VP1-P2B regions, while only small case series have evaluated the entire HAV genome of HAV ALF cases. This study aimed to further explore both host and viral factors, including genotype and nucleotide sequence variation in the entire HAV genome among consecutive adult cases of HAV ALF from the multicentre adult US acute liver failure registry. To identify factors contributing to variation in outcomes, full genome sequences of 18 HAV ALF cases were compared to geographically matched controls: patients with self-limited acute HAV identified in the CDC database.
Abstract and Introduction
Abstract
The reason(s) that hepatitis A virus (HAV) infection may progress infrequently to acute liver failure are poorly understood. We examined host and viral factors in 29 consecutive adult patients with HAV-associated acute liver failure enrolled at 10 sites participating in the US ALF Study Group. Eighteen of twenty-four acute liver failure sera were PCR positive while six had no detectable virus. HAV genotype was determined using phylogenetic analysis and the full-length genome sequences of the HAV from a cute liver failure sera were compared to those from self-limited acute HAV cases selected from the CDC database. We found that rates of nucleotide substitution did not vary significantly between the liver failure and non-liver failure cases and there was no significant variation in amino acid sequences between the two groups. Four of 18 HAV isolates were sub-genotype IB, acquired from the same study site over a 3.5-year period. Sub-genotype IB was found more frequently among acute liver failure cases compared to the non-liver failure cases (chi-square test, P < 0.01). At another centre, a mother and her son presented with HAV and liver failure within 1 month of each other. Predictors of spontaneous survival included detectable serum HAV RNA, while age, gender, HAV genotype and nucleotide substitutions were not associated with outcome. The more frequent appearance of rapid viral clearance and its association with poor outcomes in acute liver failure as well as the finding of familial cases imply a possible host genetic predisposition that contributes to a fulminant course. Recurrent cases of the rare sub-genotype IB over several years at a single centre imply a community reservoir of infection and possible increased pathogenicity of certain infrequent viral genotypes.
Introduction
Hepatitis A virus (HAV), a single stranded RNA virus, is endemic throughout most of the world and is also highly genetically conserved. In the United States, rates of infection have dropped significantly with increased use of the hepatitis A vaccine, however the estimated incidence is still above 30 000 new infections per year. The infection usually follows an innocuous course, remaining sub-clinical in most children, while appearing as acute self-limited hepatitis in adults. Less than 1% of acute hepatitis A cases result in acute liver failure. HAV infection currently accounts for only 3% of adult acute liver failure (ALF) cases in the United States. Although hepatitis A-related ALF patients experience a relatively high spontaneous survival rate (69%), the remaining patients either die or require emergency liver transplantation.
The relationship between self-limited hepatitis A cases and those HAV infections resulting in ALF (HAV ALF) is poorly understood. Host factors including age and underlying liver disease are thought to increase the likelihood of a fulminant course. Viral factors including low viral load and a higher rate of substitution in the 5' untranslated region (UTR) of the viral RNA have also been correlated with increased frequency of HAV-related ALF. Another potential viral factor is genotype. Epidemiologic studies in the United States have demonstrated that sub-genotype IA is most common, comprising 98% of infections, while sub-genotype IB is found in only 2%; most IB infections have been associated with international travel. To date, no correlation between ALF and HAV genotype has been evident but this has not been systematically examined. Previous studies have focused on the 5' UTR and VP1-P2B regions, while only small case series have evaluated the entire HAV genome of HAV ALF cases. This study aimed to further explore both host and viral factors, including genotype and nucleotide sequence variation in the entire HAV genome among consecutive adult cases of HAV ALF from the multicentre adult US acute liver failure registry. To identify factors contributing to variation in outcomes, full genome sequences of 18 HAV ALF cases were compared to geographically matched controls: patients with self-limited acute HAV identified in the CDC database.