Hepatitis D
Hepatitis D is a type of viral hepatitis caused by the hepatitis delta virus. HDV is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a satellite because it can propagate only in the presence of the hepatitis B virus. Transmission of HDV can occur either via simultaneous infection with HBV or superimposed on chronic hepatitis B or hepatitis B carrier state.
HDV infecting a person with chronic hepatitis B is considered the most serious type of viral hepatitis due to its severity of complications. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%. A recent estimate from 2020 suggests that currently 48 million people are infected with this virus.
Virology
Structure and genome
The hepatitis delta viruses, or HDV, are eight species of negative-sense single-stranded RNA viruses classified together as the genus Deltavirus, within the realm Ribozyviria. The HDV virion is a small, spherical, enveloped particle with a 36 nm diameter; its viral envelope contains host phospholipids, as well as three proteins taken from the hepatitis B virus—the large, medium, and small hepatitis B surface antigens. This assembly surrounds an inner ribonucleoprotein particle, which contains the genome surrounded by about 200 molecules of hepatitis D antigen for each genome. The central region of HDAg has been shown to bind RNA. Several interactions are also mediated by a coiled-coil region at the N terminus of HDAg.The HDV genome is negative sense, single-stranded, closed circular RNA; with a genome of approximately 1700 nucleotides, HDV is the smallest "virus" known to infect animals. It has been proposed that HDV may have originated from a class of plant pathogens called viroids, which are much smaller than viruses. Its genome is unique among animal viruses because of its high GC nucleotide content. Its nucleotide sequence is about 70% self-complementary, allowing the genome to form a partially double-stranded, rod-like RNA structure. HDV strains are highly divergent; fusions of different strains exist and sequences had been deposited in public databases employing different start sites for the circular viral RNA involved. This had resulted in disagreement with respect to molecular classification of this virus, a situation which has been resolved with the adoption of a proposed reference genome and a uniform classification system.
Life cycle
Like hepatitis B, HDV gains entry into liver cells via the sodium taurocholate cotransporting polypeptide bile transporter. HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg. Mapping by mutagenesis of this domain has shown that amino acid residues 9–15 make up the receptor-binding site. After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg. Since the HDV genome does not code for an RNA polymerase to replicate the virus' genome, the virus makes use of the host cellular RNA polymerases. Initially thought to use just RNA polymerase II, now RNA polymerases I and III have also been shown to be involved in HDV replication.Normally RNA polymerase II utilizes DNA as a template and produces mRNA. Consequently, if HDV indeed utilizes RNA polymerase II during replication, it would be the only known animal pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase.
The RNA polymerases treat the RNA genome as double-stranded DNA due to the folded rod-like structure it is in. Three forms of RNA are made; circular genomic RNA, circular complementary antigenomic RNA, and a linear polyadenylated antigenomic RNA, which is the mRNA containing the open reading frame for the HDAg. Synthesis of antigenomic RNA occurs in the nucleolus, mediated by RNA polymerase I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA polymerase II. HDV RNA is synthesized first as linear RNA that contains many copies of the genome. The genomic and antigenomic RNA contain a sequence of 85 nucleotides, the hepatitis delta virus ribozyme, that acts as a ribozyme, which self-cleaves the linear RNA into monomers. These monomers are then ligated to form circular RNA.
Delta antigens
A significant difference between viroids and HDV is that, while viroids produce no proteins, HDV is known to produce one protein, namely HDAg. It comes in two forms; a 27 large-HDAg, and a small-HDAg of 24 kDa. The N-terminals of the two forms are identical, they differ by 19 more amino acids in the C-terminal of the large HDAg. Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg. However, editing by cellular enzyme adenosine deaminase acting on RNA changes the stop codon to UGG, allowing the large-HDAg to be produced. Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection. HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication. HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles. Thus RNA editing by the cellular enzymes is critical to the virus' life cycle because it regulates the balance between viral replication and virion assembly.Antigenic loop infectivity
The HDV envelope protein has three of the HBV surface proteins anchored to it. The S region of the genome is most commonly expressed and its main function is to assemble subviral particles. HDV antigen proteins combine with the viral genome to form a ribonucleoprotein which when enveloped with the subviral particles can form viral-like particles that are almost identical to mature HDV, but they are not infectious. Researchers had concluded that the determinant of infectivity of HDV was within the N-terminal pre-S1 domain of the large protein. It was found to be a mediator in binding to the cellular receptor. Researchers Georges Abou Jaoudé and Camille Sureau published an article in 2005 that studied the role of the antigenic loop, found in HDV envelope proteins, in the infectivity of the virus. The antigenic loop, like the N-terminal pre-S1 domain of the large protein, is exposed at the virion surface. Jaoudé and Sureau's study provided evidence that the antigenic loop may be an important factor in HDV entry into the host cell and by mutating parts of the antigenic loop, the infectivity of HDV may be minimized.Transmission
The routes of transmission of hepatitis D are similar to those for hepatitis B. Infection is largely restricted to persons at high risk of hepatitis B infection, particularly injecting drug users and persons receiving clotting factor concentrates. Worldwide more than 15 million people are co-infected. HDV is rare in most developed countries, and is mostly associated with intravenous drug use. However, HDV is much more common in the immediate Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America. In all, about 20 million people may be infected with HDV.People at risk
As previously stated, patients previously diagnosed with hepatitis B are at risk for hepatitis D infection. Hepatitis D infection risk increases if a person uses injecting drugs, is a hemophiliac, if they are a hemodialysis patient, or through sexual contact with other infected persons.Prevention
Vaccination against hepatitis B protects against hepatitis D viral infection as hepatitis D requires hepatitis B viral infection to be present in order to infect and replicate in people. Universal vaccination against hepatitis B virus is recommended by the World Health Organization. The hepatitis B vaccine is routinely given soon after birth to protect against hepatitis B and D viral infection.Latex or polyurethane condoms have been shown to prevent the transmission of hepatitis B, and most likely hepatitis D viral infection.
Women who are pregnant or trying to become pregnant should undergo testing for HBV to know if they carry the virus, this will allow prevention strategies to be implemented during the birth of the child. The CDC recommends that all women who are pregnant be tested for hepatitis B viral infection and that all infants of women with HBV infection be given hepatitis B immune globulin and the hepatitis B vaccine within 12 hours of birth to prevent transmission of the virus from mother to child.
Those who get tattoos or body piercings should do so using sterile equipment to prevent the transmission of hepatitis B and D via infected bodily fluids. Hepatitis B and D can also be transmitted from contaminated needles, so those who inject drugs should seek help to stop drug use or use sterile needles and avoid sharing needles with others. Those with hepatitis B or D should also not share razors or other personal care items which may have been contaminated by potentially infectious bodily fluids.