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Hepatitis D - Causes and Pathogenesis
Medical expert of the article
Last reviewed: 04.07.2025
In 1977, a group of Italian researchers discovered a previously unknown antigen in the hepatocytes of patients with viral hepatitis B. It was assumed that this was the 4th antigen of the B virus (by analogy with the already known antigens HBs, HBc, HBe), and in this regard it was named after the 4th letter of the Greek alphabet - delta. Subsequently, experimental infection of chimpanzees with blood serum containing the delta antigen proved that this was a new virus. At the suggestion of the WHO, the causative agent of viral hepatitis D was named hepatitis delta virus - HDV. Most researchers do not assign it to any of the known taxonomic categories, considering it the only representative of a new genus - Deltavirus. The peculiarities of HDV are associated with the fact that the genome of the delta particle does not contain sections encoding the envelope proteins of the virus. This feature of HDV, along with the inability to cause an infection without infection with another virus (HBV). allowed it to be classified as a viroid or virusoid in the early years of studying this infectious agent.
HDV (hepatitis D virus) is a spherical particle with a diameter of about 36 nm (28 to 39 nm), the smallest of the known animal viruses. It consists of a nucleocapsid (18 nm) built from approximately 70 subunits of delta antigen (HDAg) and HDV RNA. The outer shell is formed by the HBV surface antigen. The outer shell of HDV is represented by HBsAg.
There are two types of HDAg with a molecular weight of 24 kDa (HDAg-S) and 27 kDa (HDAg-L) with pronounced functional differences in the vital activity of the virus. Currently, it is believed that the small form - HDAg-S is necessary for HDV replication and increases the rate of HDV RNA replication (transactivator of viral replication), and the large one (HDAg-L) is involved in the assembly of the viral particle and reduces the rate of HDV replication. In addition, HDAg-L is involved in the intracellular movement of viral proteins. Delta antigen is localized in the nuclei of infected hepatocytes, in the nucleoli and, or nucleoplasm. HDAg has pronounced RNA-binding activity. The specificity of this binding determines the absence of interaction with other viral and cellular RNA. The HDV genome is represented by a single-stranded cyclic RNA molecule of negative polarity with a length of about 1700 nucleotides.
The interaction of HBV and HDV determines not only the formation of the outer envelope of HDV with the help of HB-Ag, but also, possibly, other mechanisms that are not yet fully understood. At present, there is no doubt about the ability of HDV to inhibit HBV replication, leading to a decrease in the expression of HBeAg and HBsAg and suppression of DNA polymerase activity during acute infection - coinfection.
There are three genotypes and several subtypes of HDV. Genotype I is common in all regions of the world and circulates mainly in Europe, Russia, North America, the South Pacific region, and the Middle East. Genotype II is common in Taiwan and the Japanese islands. Genotype III is found mainly in South America and the Central African Republic. All HDV genotypes belong to one serotype.
HDV is resistant to high temperatures, acids and UV radiation do not affect it. The virus can be inactivated by alkalis and proteases. Repeated freezing and thawing do not affect its activity.
[ Pathogenesis of hepatitis D
Once in the body of an HBV carrier, the delta virus finds favorable conditions for its replication, as it immediately surrounds itself with a shell of HBs antigen and then penetrates into hepatocytes due to the presence of polymerized albumin on their surface, which has an affinity for HBsAg, which forms the outer shell of HDV. Extrahepatic reproduction of HDV has not been established.
Delta virus has both direct cytopathic action and immune-mediated action similar to HBV. One of the proofs of cytopathic action is a significant predominance of necrotic changes over inflammatory ones, revealed during morphological examination of liver tissue of patients with viral hepatitis D. At the same time, data have been obtained on the absence of cytopathic action of HDV in severe immune disorders, which suggests the presence of an immunologically mediated mechanism of hepatocyte damage.
When infected with the delta virus, two types of delta infection are possible: coinfection and superinfection. The first occurs when HDV enters the body of a healthy person simultaneously with HBV. Superinfection develops in those previously infected with the B virus (in patients with viral hepatitis B or HBsAg carriers) when they are additionally infected with the delta virus.
Hepatitis that occurs as a result of coinfection is usually called acute hepatitis of mixed etiology HBV, HDV or acute hepatitis B with delta agent, emphasizing the participation of both viruses in the pathogenesis of the disease. HDV production occurs simultaneously with HBV, but probably active replication of the delta virus follows the development of structural components of HBV (HBsAg), and its duration is limited by the duration of HBs antigenemia. Hepatitis of mixed etiology ends after the elimination of both viruses from the body. In case of superinfection, acute viral hepatitis delta develops, which is usually called acute delta (super) infection of a carrier of viral hepatitis B.
In this case, the participation of HBV in the development of liver damage is minimal, and all the resulting pathological changes and clinical manifestations are caused by the action of the delta virus. Unlike coinfection, which usually has an acute self-limiting course, superinfection is characterized by a severe progressive course up to the occurrence of massive liver necrosis or rapidly progressing development of cirrhosis. This is due to the fact that in chronic HBV infection (in HBsAg carriers, patients with viral hepatitis B), HBsAg is constantly formed in the liver in large quantities, and HDV finds very favorable conditions for replication and implementation of its damaging effect. Most researchers do not find any specific pathomorphological signs inherent in hepatitis delta. In coinfection, there are changes similar to those in "pure" acute hepatitis B, but the necrotic process in hepatocytes is usually more pronounced. Chronic viral hepatitis D is characterized by significant inflammatory and necrotic changes in the lobules with pronounced periportal hepatitis, high activity of the process in the liver (chronic active hepatitis of moderate and severe activity predominates), rapid disruption of the liver architecture and the possibility of the appearance of morphological signs of liver cirrhosis in the early stages of the disease (from 2 to 5 years).