Pathogenesis and clinical manifestations of hepatitis D virus infection
Francesco Negro, MD
Anna SF Lok, MD

UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on April 8, 2005. The next version of UpToDate (14.3) will be released in October 2006. INTRODUCTION — Hepatitis D is caused by a defective virus: the hepatitis D virus (HDV). HDV is often referred to as hepatitis delta virus or delta agent. However, the term HDV is preferred. HDV infection is closely associated with hepatitis B virus (HBV) infection. Although HDV can replicate autonomously [ 1 ] , the simultaneous presence of HBV is required for complete virion assembly and secretion ( see "Virion structure" below ). As a result, individuals with hepatitis D are always dually infected with HDV and HBV. Due to interference mechanisms that are not well understood, HBV replication is suppressed in most HDV-infected individuals. This topic review will provide general information concerning the HDV structure and replication strategy, the nature of its strict association with HBV, and the epidemiology, pathogenesis, and clinical features of HDV infection. Issues related to diagnosis, treatment, prevention, and liver transplantation are discussed separately. (See appropriate topic reviews.) VIRION STRUCTURE — The HD virion comprises an RNA genome, a single HDV encoded antigen, and a lipoprotein envelope provided by HBV ( show figure 1 ). HDV genome — The HDV genome is a small RNA molecule (1676 to 1683 nucleotides in size) bearing some structural analogies with plant viroids and virusoids [ 1 ] . HDV RNA is a single-stranded circle, with a high degree of self-complementarity and G+C content causing the circle to collapse as a rod-like structure [ 1 ] . Significant sequence heterogeneity (as high as 39 percent) exists among the different HDV isolates that have been sequenced, and a classification into three HDV genotypes has been proposed [ 2 ] . Hepatitis D antigen — The only antigen associated with HDV, the hepatitis D antigen (HDAg), is a structural component of the virion. It consists of a phosphoprotein encoded by an open reading frame present on the RNA strand complementary to the RNA genome (antigenomic strand) [ 1 ] . Approximately 70 molecules of HDAg are complexed with each molecule of HDV RNA to form a ribonucleic core-like structure. Two forms of HDAg (with different functions as described below) are coexpressed in infected individuals, differing by 19 amino acids at the C-terminus. The molecular weights of the two HDAg molecules are approximately 24 and 27 kilodaltons (kd). Their synthesis arises via an RNA editing process during HDV replication [ 3 ] .

• The stop codon UAG of the antigenomic HDV RNA causes the translation of HDAg to terminate, thereby giving rise to the small HDAg. This stop codon is deaminated by a cellular enzyme to UIC (where I stands for inosine).

• Further base changes occur during the next replication cycle, resulting in the replacement of UAG by UGG, which directs the incorporation of tryptophan into the nascent HDAg. Translation of HDAg then proceeds until a new stop codon is reached, 19 amino acids downstream, thereby giving rise to the large HDAg.

Lipoprotein envelope of HDV — The lipoprotein envelope of HDV is provided by the HBV and consists of the same proteins (large, middle and small S) that are found in the HB virion; their relative proportion depends upon the level of HBV replication [ 4 ] . HDV LIFE CYCLE — HDV replicates at very high levels in hepatocytes [ 5 ] . The receptor of HDV is unknown. The steps in HDV replication cycle can be summarized as follows:

• Once inside the hepatocyte, HDV RNA is found within the nucleus, where it is transcribed into its complementary RNA (antigenomic HDV RNA). Two forms of antigenomic HDV RNA exist: a 0.8 kilobase (kb) RNA, which is the messenger RNA being translated into the HDAg [ 6 ] , and the full-length 1.7 kb RNA, which is the template directing the transcription back into the HDV genome [ 1 ] . The host RNA polymerase II appears to be involved in the transcription of the 0.8 kb mRNA in a process that is regulated by direct binding with the HDAg itself [ 7,8 ] . The synthesis of the full-length genomic and antigenomic RNAs involves distinct cellular enzymes, but the respective mechanisms have not been elucidated [ 9 ] .

• HDV RNA replication is activated by the small HDAg through direct binding of the HDAg to the HDV RNA.

• The large HDAg suppresses HDV replication. In addition, it directs packaging of the HD virion through an interaction between the extra 19 amino acids at the C-terminal end and the small S protein (HBsAg) of the helper HBV [ 3 ] .

• Completion of the HD virion assembly and release is dependent on the simultaneous presence of HBV which provides the envelope. In the absence of HBV, HDV infection is abortive, unless rescued by HBV at a later time (see below).

HDV INFECTION — Due to its dependence upon HBV, HDV infection always occurs in association with HBV infection. The clinical and laboratory findings vary with the type of infection ( show table 1 ). ( See "Diagnosis of hepatitis D virus infection" ). Coinfection — Coinfection of HBV and HDV in an individual susceptible to HBV infection (ie, anti-HBs-negative) results in acute hepatitis B + D. This entity is clinically indistinguishable from classical acute hepatitis B and is usually transient and self-limited. However, a high incidence of liver failure has been reported among drug addicts [ 10 ] . The rate of progression to chronic infection is not different from that observed after classical acute hepatitis B, since persistence of HDV infection is dependent upon persistence of HBV infection [ 11 ] . Superinfection — HDV superinfection of a chronic HBsAg carrier may present as an usually severe acute hepatitis in a previously unrecognized HBV carrier, or as an exacerbation of preexisting chronic hepatitis B. Progression to chronic HDV infection occurs in almost all patients [ 12 ] . However, HBV replication is usually suppressed by HDV. Helper-independent latent infection — A third form of infection is a helper-independent latent infection which can be rescued by the helper virus at a later time. This form of infection was initially observed in the liver transplantation setting. ( See "Hepatitis D virus infection and liver transplantation" ). Intranuclear HDAg can be detected in the grafted liver as early as a few hours after transplantation in the absence of both productive HDV infection (ie, serum HDV RNA cannot be detected by hybridization assays) and HBV reinfection (ie, HBsAg not detected in serum) [ 13 ] . This situation is probably due to reinfection of the allograft by HDV alone, while simultaneous infection of hepatocytes by HBV is prevented by hepatitis B immunoglobulin (HBIG), which is administered to prevent HBV reinfection. During this phase, there is no evidence of liver disease. HD viremia and hepatitis recur only when HBV evades neutralization, resulting in coinfection of the allograft and establishment of productive HDV infection [ 13 ] . This phenomenon was reproduced by inoculating woodchucks that have never been exposed to the woodchuck hepatitis virus (WHV) with sera containing a high ratio of HDV versus WHV particles [ 14 ] . HD viremia was not detected, despite the presence of intrahepatic HDV replication. Productive HDV infection occurred only when the woodchucks were challenged (up to one month after the first inoculation) with a high infectious dose of WHV, which apparently rescued the replicating HDV. Pathogenesis of HDV-induced hepatitis — The detailed mechanisms by which HDV induces liver damage are unknown. However, the pathogenesis of hepatitis D-related liver disease appears to depend on the interplay of three major factors:

• HDV-associated factors, such as genotype [ 2 ] and the expression of specific HDAg species (see below) [ 15 ] .

• Host-associated factors, such as the immune response.

• Helper virus-associated factors, such as the HBV genotype and the level of HBV replication [ 16 ] .

HDV is believed to cause directly cytopathic damage during acute infection, whereas immune-mediated damage predominates during chronic infection [ 1 ] . NATURAL HISTORY OF CHRONIC HEPATITIS D — The clinical sequelae of HDV infection encompass a spectrum of manifestations from fulminant liver failure to the healthy carrier state. The severity of the clinical course is influenced by several factors (see below). A number of studies have suggested that clinical outcomes may be related to the different HDV genotypes [ 2,17,18 ] . HDV genotypes and, more interestingly, specific clinical features of hepatitis D, seem to cluster in distinct geographical areas. However, superinfection, or mixed infection with different genotypes can occur, particularly in patients who are at high risk for multiple exposures. In such patients, a single genotype usually predominates, with the minor genotype representing only approximately 10 percent of the total viral population [ 19 ] . Genotype I — In the Western world, where the predominant genotype is genotype I [ 18 ] , acute hepatitis D has an increased risk of a fulminant course when compared to acute hepatitis B [ 10 ] . Once chronic HDV infection is established, it usually exacerbates the preexisting liver disease due to HBV [ 12 ] . Progression towards cirrhosis may be rapid [ 20,21 ] . HDV-associated chronic liver disease may also run an indolent course [ 22 ] and asymptomatic HDV carriers have been found in some geographical areas [ 23 ] . Patients who are currently referred for HDV infection appear to represent cohorts infected years ago in whom the HDV-related disease rapidly developed to cirrhosis, but whose subsequent disease progression has been slow. This was illustrated in a report from Italy in which the estimated 5- and 10-year probability of survival free of liver transplantation in patients who had already developed clinically overt cirrhosis was 49 and 40 percent, respectively [ 24 ] . A more ominous course toward liver decompensation has been documented in patients with active HBV and HDV replication [ 16 ] . Whether superimposed HDV infection accelerates the development of hepatocellular carcinoma in patients with HBsAg-positive cirrhosis is controversial. However, a retrospective study involving 200 patients with compensated HBV-related cirrhosis, of whom 20 percent were anti-HDV positive, found that HDV infection increased the risk for HCC threefold and mortality twofold [ 25 ] . After adjustment for clinical and serological differences at baseline, the estimated five-year risk for developing HCC was 13, 4, and 2 percent for anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive patients, respectively. The corresponding figures for hepatic decompensation were 18, 8, and 14 percent, respectively. Genotype II — In the Far East, where the predominant genotype is genotype II, there is a less frequent association between fulminant hepatitis and acute HDV infection and between rapidly progressive liver disease and chronic HDV infection [ 17,26 ] . Genotype III — Severe outbreaks of acute hepatitis D with a high incidence of liver failure have been reported among the Yucpa Indians of Venezuela [ 27 ] , the Sierra Nevada de Santa Marta in Colombia [ 28 ] , some remote areas of the Brazilian [ 29 ] and Peruvian [ 2 ] Amazon basin, the Kashmir region [ 30 ] and the Central African Republic [ 15 ] . Viral factors have been postulated to be related to the fulminant course in these outbreaks, as HDV isolates from Colombia and Peru belong to a distinct viral genotype denoted genotype III [ 2 ] . EPIDEMIOLOGY OF HDV INFECTION — The commercial availability of assays for the detection of HDV antibody (anti-HDV) has improved our understanding of the epidemiology of HDV infection. However, these assays have limitations in the diagnosis of HDV infection [ 31 ] . ( See "Diagnosis of hepatitis D virus infection" ). The assay most readily available for the diagnosis of HDV infection detects total anti-HDV. In acute hepatitis D, anti-HDV appears very late and may be missed if repeated testing is not performed. Thus, the true incidence of acute hepatitis D may be underestimated. This is especially true in immunodeficient individuals (eg, anti-HIV-positive) in whom a strong antibody response to HDV may be delayed or absent. Furthermore, after resolution of acute hepatitis D, anti-HDV may disappear with time. Thus, recognition of past HDV infection may be impossible. Data on HDV epidemiology have mostly been gathered in chronic HBV carriers superinfected with HDV in whom HDV infection has progressed to chronicity. Anti-HDV is present in high titers in these patients, and the prevalence of chronic HDV infection can be reliably determined. Available data suggest that approximately 5 percent of the HBV carriers worldwide may be infected with HDV [ 31 ] . Since the number of HBV carriers has been estimated to be around 300 million, the number of individuals infected with HDV worldwide is estimated to be 15 million. The geographical distribution of HDV infection, however, does not parallel that of HBV, as areas endemic for HBV may be almost HDV-free. The level of HDV endemicity is partly related to the route of transmission. The Mediterranean basin — HDV infection is endemic in the Mediterranean basin. Infection tends to occur early, affecting mainly children and young adults. The main route of transmission is inapparent, permucosal, or percutaneous spread. Intrafamilial transmission is common and may be facilitated by poor hygiene. Thus, economically and socially disadvantaged populations are more affected. A study from Italy suggested that the prevalence of HDV infection has declined in the past two decades [ 32 ] . Anti-HDV antibodies were detected in only 69 of 834 HBsAg positive patients (8.3 percent) compared to 23 and 14 percent in studies from 1987 and 1992, respectively. The decrease resulted principally from a reduction in chronic HDV infection in young adults. The Far East — The prevalence of HDV infection among HBV carriers varies from 90 percent in the Pacific islands to 5 percent in Japan [ 31 ] . HDV infection is not infrequent in Taiwan [ 33 ] , being predominantly transmitted sexually, but is rare in Hong Kong where it is largely confined to intravenous drug users [ 34 ] . Western countries — HDV infection is uncommon in Western countries and predominantly confined to high-risk groups: intravenous drug addicts and multiply transfused individuals (eg, hemophiliacs). Interestingly, transmission of HDV among HBsAg-positive homosexuals is extremely rare [ 35 ] . Changes in HDV epidemiology have occurred in the past 10 years. These changes are most noticeable in Italy, a country which was endemic for HDV infection and where HDV was initially described. Improvements in socioeconomic conditions, an increased awareness of the risk of transmitting infectious diseases fostered by AIDS prevention policy, and aggressive vaccination campaigns against HBV have all contributed to a dramatic decrease in the incidence of HBV infection and the spread of HDV infection among young Italian adults [ 36 ] .
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