Hepatitis D pathophysiology
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Hepatitis D |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Jolanta Marszalek, M.D. [2] João André Alves Silva, M.D. [3]
Overview
The pathogenesis of HDV infection is not fully understood. Limited data points to HDV as being mostly an immune mediated process, at least in certain genotypes. There is evidence supporting the notion that the virus itself can be cytopathic. HDV and HBV co-infection or superinfection cause more severe liver disease than HBV alone.
Pathogenesis
There is limited knowledge concerning the pathogenesis of hepatitis delta virus (HDV) infection. The mechanisms determining whether a person will spontaneously clear HDV, become chronically infected, or rapidly progress to hepatic fibrosis are not yet fully understood.
Pathological changes in HDV are limited to the liver, the only organ in which HDV can replicate. Hepatitis delta angtigen (HDAg) is not directly cytotoxic to human hepatocytes, nor has viral load shown to be associated with severity of liver injury. HDV viremia has however, been associated with an increased level of ALT and suppressed HBV in the acute phase of the disease. HBV is an essential co-factor in the evolution of hepatocellular damage, and infection with both HBV and HDV leads to more severe liver injury than HBV infection alone.
The fluctuating viral load of both HDV and HBV in different stages of infection may signify a direct association with the pathogenesis of disease progression.Studies have shown that during the acute phase of HDV infection, HDV viremia is associated with an increased level of alanine transaminase (ALT) and suppressed HBV. In the later stages of the chronic phase, HDV RNA decreases, HBV reactivates, and levels of transaminases are moderately elevated. At this point, either HDV or HBV replicate and lead to cirrhosis and hepatocellular carcinoma(HCC) or both viruses are cleared and there is remission. [1]
HDV suppresses HBV replication among patients with either co-infection or superinfection. In fact, up to 90% of patients with HDV co-infection are HBeAg negative and have a low HBV viral load. Furthermore, once HDV infection is cleared, replication of HBV can reactivate.[1] Evidence points to the possible role of the small(p24) and large(p27) HDV proteins in suppressing HBV replication by:[2]
- repressing the activity of two enhancer regions (pIIE1 and pIIE2)in the HBV genome
- transactivation of the MxA gene leading to the reduction of viral HBV mRNA export from the nucleus
Studies demonstrate that both the adaptive and innate immune systems may play an important role in liver injury and clearance of the virus, although these immune responses are poorly defined. Specifically, the quantity and quality of host T-cell responses may be associated with the level of infection control.
Inactive, acute, and chronic infections appear to elicit different arms of the host immune response. In one study, CD4 T cells responded weakly to HDAg in patients with inactive HDV infection(anti-HDV Ab positive but RNA negative) and not at all in those with chronic HDV infection.Further studies have demonstrated that the main response to chronic HDV infection is elicited by Th-2 cells with a high secretion of IL-10.
Studies demonstrate that both the adaptive and innate immune systems may be involved in the pathogenesis of HDV, although further investigations are necessary. Inactive, acute, and chronic infections appear to elicit different arms of the host immune response. In one study, CD4 T cells responded weakly to HDAg in patients with inactive HDV infection(anti-HDV Ab positive but RNA negative) and not at all in those with chronic HDV infection. Further studies have demonstrated that the main response to chronic HDV infection is elicited by Th-2 cells with a high secretion of IL-10.
Although hepatitis D is thought to be a largely immune-mediated disease process, there is evidence demonstrating that HDV may be cytopathic. Specifically, outbreaks of fulminant hepatitis induced by HDV genotype 3 link uncommon histological features to the potentially cytopathic nature of HDV.[3] More data is necessary to further the understanding of underlying mechanisms of HDV-induced disease.[1]
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.
Transmission is similar to that of HBV:
- Bloodborne and sexual
- Percutaneous (IV drug use, haemophiliacs)
- Permucosal (sexual)
- Perinatal (rare)
HDV is transmitted percutaneously or sexually through contact with infected blood or blood products.
Blood is potentially infectious during all phases of active hepatitis D infection. Peak infectivity probably occurs just before the onset of acute disease.
Associated Conditions
Macroscopic Pathology
Microscopic Pathology
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References
- ↑ 1.0 1.1 1.2 Hughes SA, Wedemeyer H, Harrison PM (2011). "Hepatitis delta virus". Lancet. 378 (9785): 73–85. doi:10.1016/S0140-6736(10)61931-9. PMID 21511329.
- ↑ Williams V, Brichler S, Radjef N, Lebon P, Goffard A, Hober D; et al. (2009). "Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene". J Gen Virol. 90 (Pt 11): 2759–67. doi:10.1099/vir.0.011239-0. PMID 19625466.
- ↑ Wedemeyer H, Manns MP (2010). "Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead". Nat Rev Gastroenterol Hepatol. 7 (1): 31–40. doi:10.1038/nrgastro.2009.205. PMID 20051970.