Hepatitis Vaccination in Patients With Chronic Liver Disease

G. Reiss; E.B. Keeffe


Aliment Pharmacol Ther. 2004;19(7) 

In This Article

Hepatitis A Super-Infection in Chronic Liver Disease

Hepatitis A virus (HAV) infection is common, accounting for up to half of the reported cases of acute viral hepatitis in the USA.[9] In general, hepatitis A is a self-limited illness with a recovery time measured in months. Young children are often asymptomatic, whereas adults are more likely to be symptomatic and may present with jaundice. Although most patients recover relatively quickly and without long-term sequelae, about 15% may have a prolonged cholestatic syndrome or a relapsing course over 6-9 months. A smaller subset will progress to fulminant hepatic failure and death or transplantation, with estimated case fatality rates ranging from 0.01-0.03% to 0.2% of cases amongst hospitalized patients.[10,11] Two major risk factors have been identified in patients who develop fulminant hepatic failure: age over 40 years and the presence of underlying chronic liver disease.[10,11,12]

A number of epidemiological studies have assessed the outcome of acute HAV infection superimposed on chronic HBV infection. Two large studies are commonly cited to support the contention that acute HAV super-infection results in higher morbidity and mortality than isolated acute HAV infection.[12,13,14] The first study analysed a large outbreak of hepatitis A that occurred in Shanghai in the late 1980s.[13] Over 300 000 cases of acute hepatitis A were reported, and nearly 30 000 of these cases probably occurred in HBV carriers, based on the estimated regional seroprevalence of hepatitis B surface antigen (HBsAg). The fatality rate was subsequently analysed and shown to be 5.6 times higher in HBsAg carriers than in HBsAg-negative patients, although the absolute fatality rate was low: 0.05% for HBsAg-positive compared with 0.009% for HBsAg-negative patients.[12] Persuasive though this evidence is, differences exist between HBV carriers in the USA and China. In Shanghai, much of the population, particularly the older population, has serological evidence of past HAV infection, which is associated with life-long immunity against hepatitis A. Indeed, the mean age of affected patients in the Shanghai epidemic was 28 years.[13] Furthermore, the age of HBV infection probably differs between the two populations, with most Chinese being infected at birth or early in life. The age of hepatitis B e-antigen (HBeAg) seroconversion is also known to affect the clinical course of chronic hepatitis B, with infection at a young age often leading to quiescent disease by early adult life.[15] As such, it is not unreasonable to suggest that HAV super-infection may follow a different course in the USA when compared with outcomes in China.

In addition to the Shanghai data, epidemiological data from the Centers for Disease Control and Prevention are often cited to quantify the risks of HAV super-infection of patients with chronic HBV infection in the USA, as well as HAV infection superimposed on other forms of chronic liver disease.[12,14] Between 1983 and 1988, a total of 115 551 cases of hepatitis A were reported to state branches of the Centers for Disease Control and Prevention.[14] Amongst these patients, there were 381 deaths, resulting in a case fatality rate of 0.33%. Within this group of 381 deaths, there were 27 patients with chronic HBV infection and 107 patients with other chronic liver disease. Based on the HBsAg carrier rate in the USA, the fatality rate amongst chronic HBsAg carriers was subsequently analysed and calculated to be 11.7%, compared with 0.2% for patients with no liver disease, a greater than 50-fold increased risk of death.[12]

Other studies paint a more complex picture. A study from Japan suggests that chronic HBV infection with histological disease is the predisposing factor accounting for a more adverse outcome from superimposed acute hepatitis A.[16] Six patients with HAV super-infection of chronic HBV infection were compared with 80 cases of isolated HAV infection. No significant differences in laboratory markers of hepatic inflammation were found. The authors then reviewed an additional 23 patients with HAV super-infection of chronic hepatitis B reported in the Japanese literature. Based on liver biopsy data available from 17 of these 23 patients, the authors concluded that histological disease, rather than HBsAg seropositivity, might predispose patients to a worse outcome associated with HAV super-infection.[16] Asymptomatic HBsAg-positive carriers might well have a clinical course similar to patients with acute hepatitis A alone. Although the Japanese study did not reveal a difference in hepatic markers of inflammation, a Greek study did.[17] Fourteen of 90 patients with acute hepatitis A had serological evidence of HBV carrier status, whilst another nine had evidence of previous infection. The mean serum alanine aminotransferase levels were significantly higher in patients with evidence of current or previous HBV infection, compared with those with acute hepatitis A without the presence of HBV markers. However, there were no deaths, and the mean bilirubin levels did not differ. Another case series in Thailand found worse outcomes associated with HAV super-infection.[18] Twenty asymptomatic HBsAg-positive patients, eight HBsAg-positive patients with cirrhosis and four anti-HCV-positive patients with cirrhosis were compared with 100 patients with HAV infection without underlying liver disease. None of the patients with isolated HAV infection developed severe hepatitis. However, of the patients with pre-existing liver disease, nearly half (47%) developed fulminant or submassive hepatitis and 28% died. This raw difference in mortality rates does not, unfortunately, account for age differences. Patients with existing liver disease were decades older than patients with isolated HAV infections, and all deaths occurred in patients over 50 years of age.[18] It can thus be hypothesized that the patients who died (already more ill than an average group referred to a tertiary care centre) were more likely to do so as a result of either their age or their underlying liver disease, as the relative risk of these intertwined factors cannot be separated.

Other case series have not found underlying chronic HBV infection to predict a worse outcome of acute hepatitis A. A case series in Taiwan analysed 143 patients with hepatitis A, 28 of whom were HBsAg carriers, and failed to find any clinical or biochemical difference between the two groups.[19] It is noteworthy that the patients were young, ranging from 5 to 30 years of age, lending credence to the argument that it is age and/or underlying histological chronic hepatitis or cirrhosis that leads to a worse outcome, rather than merely the presence of HBV infection. A recent review of 50 patients with acute hepatitis A, 19 of whom developed fulminant hepatitis (10 eventually requiring transplantation), failed to reveal serological evidence of chronic viral hepatitis.[20] Furthermore, in a multivariate analysis, age did not emerge as an independent risk factor for the development of a fulminant course. In addition to these studies, a number of other small case series have failed to reveal a difference in outcomes of isolated HAV infection compared with HAV/HBV super-infection.[21,22,23,24]

Acute hepatitis A, when occurring in patients with underlying chronic hepatitis C, may also cause significantly increased morbidity and mortality. The most dramatic observation of HAV super-infection in HCV patients was seen in a well-cited Italian study.[25] Over a 7-year period, 432 patients with chronic hepatitis C and no serological evidence of previous HAV infection were followed. Seventeen (3.9%) developed acute hepatitis A. Out of this subset, seven patients (41%) developed fulminant hepatitis, six of whom died. Interestingly, patients with chronic HBV infection did not have worse outcomes with HAV super-infection, in contrast with the data from the studies in Shanghai and by the Centers for Disease Control and Prevention. Ten patients with chronic HBV infection developed acute hepatitis A, and all recovered. In addition to this seeming refutation of previous large epidemiological studies in Shanghai and by the Centers for Disease Control and Prevention, questions have been raised about the unexpectedly high rate of fulminant hepatitis A. This high rate was not seen in data from the Italian specific surveillance system of acute viral hepatitis.[26] Furthermore, other trials and national surveillance systems, such as in Finland, Switzerland and Norway, have failed to confirm this high rate of fulminant HAV infection in patients with chronic HCV infection.[27,28] Case series in Brazil and Switzerland reporting hundreds of patients with hepatitis A and hepatitis C have not revealed an increased rate of fulminant hepatitis.[29,30] In addition, two large reviews of fulminant hepatitis A cases in tertiary care centres have failed to reveal a large number of cases with underlying chronic HCV infection.[20,31] The Italian study, although provocative, requires confirmation.

There is only limited published evidence suggesting that other chronic liver diseases may predispose to a worse outcome associated with chronic hepatitis A. An analysis of data from the Centers for Disease Control and Prevention revealed that patients with forms of chronic liver diseases other than HBV were at a 23-fold increased risk of death.[12,14] Poor outcomes from hepatitis A superimposed on chronic liver disease other than chronic HBV or HCV infection have been seen in other small case series. A report of four occurrences of fatal fulminant hepatitis A in patients with alcoholic liver disease (two cases) and cryptogenic cirrhosis (two cases) supports the contention that, in addition to chronic hepatitis B, other chronic liver disease can increase the morbidity and mortality of acute hepatitis A.[32] A review of all patients admitted with severe hepatitis A to a tertiary care hospital in London between 1974 and 1999 revealed 97 cases, but only four had underlying chronic HCV or HBV infection.[31] However, three of these patients, all with cirrhosis, were amongst the 29 who died, and an additional six patients required transplantation. Interestingly, post-mortem examination revealed that 20% of patients had evidence of underlying chronic liver disease, supporting the assertion that chronic liver disease, regardless of the aetiology, predisposes to worse outcomes.[31]

By reviewing this growing experience with acute hepatitis A in patients with chronic liver diseases, four points can be made. First, patients with acute hepatitis A and chronic hepatitis B have a more severe clinical course and a higher death rate compared with otherwise healthy individuals with hepatitis A. Second, these differences are most pronounced in older patients with histological evidence of chronic hepatitis or frank cirrhosis, rather than younger, asymptomatic HBsAg carriers. The natural experiments that provide much of the data have not allowed the clear separation and examination of confounding factors of age and histology. Third, patients with acute hepatitis A super-infection and chronic hepatitis C may have an increased risk of fulminant hepatitis and death, although this still needs corroboration. Finally, patients with other chronic liver diseases, apart from chronic HBV and HCV infection, also appear to be at increased risk for more severe disease.