Hepatitis D

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

Hepatitis D is a disease caused by a small circular RNA virus (Hepatitis delta virus or hepatitis D virus, HDV). HDV is considered to be a subviral satellite because it can propagate only in the presence of another virus, the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or via infection of an individual previously infected with HBV (superinfection). [4] Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a greater likelihood of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections of 20%.

The hepatitis D virus was first reported in mid-1977 by an italian researcher, Mario Rizzetto. ^[1]

Despite the limited knowledge concerning the pathogenesis of hepatitis delta virus (HDV) infection, the adaptive and innate immune systems are thought to play a pivotal role on hepatocellular injury. HDV requires the presence of HBV to be able to cause infection. Pathological changes in HDV are limited to the liver, the only organ in which HDV can replicate. Hepatitis B virus (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. There is evidence supporting the possibility that the virus can be cytopathic in certain genotypes. HDV is transmitted percutaneously, sexually, or through contact with infected blood or blood products. In rare occasions transmission may be perinatal. The different genotypes will influence viral assembly, and consequently infectivity.

The hepatitis D virus belongs to the genus deltavirus. Its genome consists of a single circular RNA molecule (ssRNA), with a high degree of complementarity, which gives it the ability to survive at high temperatures. Its life cycle requires cooperation with the host cell at all stages, including: attachment, penetration, uncoating, provision of adequate metabolic conditions, assembly and release of new virions. The replication cycle also requires the presence of an hepadnavirus to provide the protein components for the new HDV envelopes. The HDV is composed by the following particles: HBsAg; HDAg-S; HDAg-L; and RNA. Different HDV genotypes have been associated with different courses of the disease. The virus has tropism for hepatocytes and humans are its natural reservoir.^[2][3]

Hepatitis D must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, elevated ALT, AST, such as viral hepatitis(caused by other etiologic agents), alcoholic hepatitis, and autoimmune hepatitis.

HDV infection affects more than 15 million people chronically infected with HBV worldwide. Regions with high rates of HDV infection include Central Africa, Mediterranean Basin, the Amazon Basin, and parts of Asia. With the implementation of HBV vaccination programs, better education and awareness about the virus, and improving socioeconomic conditions, HDV prevalence is decreasing in many areas of the world.

Risk factors for hepatitis D, either in coinfection or superinfection with HBV, include: IV drug use; infection during pregnancy; sexual intercourse with infected persons; exposure to unscreened blood or blood products; hemodialysis patients; and healthcare and public service workers who deal with infected patients.^[2][4]

The general population, with low risk of HBV and HDV infection does not need to be screened. However, individuals known to be HBsAg positive, with acute or chronic hepatitis, or those HBsAg negative, but who are IgM anti-HBc positive, should be screened for HDV. Blood products should also be screened in order to avoid transmission of the virus through blood transfusions or hemodialysis.

HDV is a defective virus that requires individuals to be previously, or concomitantly, infected with HBV. The clinical manifestations of HDV infection are similar to those of HBV, including: fatigue, lethargy, nausea, jaundice, acholic stools and dark urine. The disease progresses throughout 4 phases: incubation period; preicteric phase; icteric phase; and convalescence phase. Infection with HDV may occur at the time of infection with HBV, in which case both acute type B and type D hepatitis may develop. 95% of these patients will clear the infection. HDV may also infect a previous HBV carrier, often causing fulminant hepatitis and chronic active hepatitis, frequently progressing to cirrhosis. Complications of hepatitis D may include: chronic active hepatitis; fulminant hepatitis; hepatic cirrhosis and hepatic failure. The mortality rate for HDV infection is higher than that of hepatitis B, between 2% and 20%.

Hepatitis D can only occur in patients who are simultaneously (coinfection) or previously (superinfection) infected with HBV. Common symptoms of hepatitis D include: fever; yellowish discoloration of the eyes and skin; fatigue; abdominal pain; loss of appetite; nausea; vomiting; and dark urine. Coinfection is associated with a more severe form of the disease, often leading to fulminant hepatitis. In superinfection, symptoms may be unspecific initially, and the majority of these cases progress into chronicity.^[5][4]

Physical examination of patients with acute HDV infection may be normal, or include findings, such as jaundice, and some degree of impairment of joint movement due to arthralgia. Physical examination of patients with chronic disease, depending on the its stage, may include: jaundice; palmar erythema; spider angiomata;gynecomastia; hepatomegaly; splenomegaly; ascites; peripheral edema; and asterixis.

The diagnosis of hepatitis D is made by the detection of HDV RNA in circulation, with RT-PCR. The levels of HBsAg may be used during treatment to evaluate the response, and determine the duration of therapy. After recovery, markers of HDV infection, such as IgM and IgG antibodies disappear within months. Liver biopsy is indicated in HDV RNA positive patients, to assess the stage of liver disease. Findings in liver biopsy are similar to those observed in HBV infection. Coinfection with HIV and HCV should be ruled out in HDV infected patients. Serologic markers such as HDV RNA, HDAg, and IgM and IgG anti-HD antibodies may persist for longer periods in chronic hepatitis D.

CT scan may diagnose and/or monitor biliary obstruction, cirrhosis and hepatocellular carcinoma, in patients with hepatitis D.

The MRI may be used to diagnose/monitor biliary obstruction, cirrhosis, and hepatocellular carcinoma in patients with hepatitis D. MRI findings in these patients may include: nodular appearance of the liver and signs of portal hypertension, such as ascites and splenomegaly.

The liver ultrasound of a patient with hepatitis D may reveal unspecific findings, such as: hepatomegaly, gallbladder wall thickening, increased echogenicity, and signs of portal hypertension. It may also be used in the diagnosis and monitoring of hepatic cirrhosis, as well as for hepatocellular carcinoma. Attending to the simultaneous occurrence of HDV and HBV, HBsAg carriers with cirrhosis should be echographically evaluated every 6 months.^[6]

The identification of the genotype of HDV helps to predict the potential severity of liver disease, as well as the response to treatment. Endoscopy may be useful in patients with advanced stage of the disease, who present with liver cirrhosis, to evaluate the presence of esophageal varices.^[7][5][8]

Currently there is no effective antiviral therapy available for the treatment of acute or chronic hepatitis D.^[9] Interferon-α is the only drug that has shown antiviral activity against HDV, however despite improvements in patients’ health, most remained HDV RNA positive. Long-term treatment with NUCs has shown a decline in the levels of HBsAg of some patients. Patients with chronic hepatitis should be treated with weekly injections of pegylated interferon, for at least 48 weeks.^[3][2]

Treatment of hepatitis D does not involve surgery. Some procedures may be indicated for certain complications, such as ascites, in which peritoneal drainage may be performed. Liver transplantation may be indicated for: end-stage liver disease; liver failure secondary to HDV infection, for patients in which treatment with interferon is not indicated; and hepatocellular carcinoma.^[5][10]

HDV infection requires the person to be co-infected with HBV, therefore, vaccination against hepatitis B confers immunity against hepatitis D. Since a vaccine against hepatitis D, for patients infected with HBV, is not available, these individuals should prevent superinfection by avoiding risk behaviors, such as: contact with blood from infected individuals, and sharing of sharp objects.

Considering that patients who develop symptomatic hepatitis D may progress into cirrhosis, liver failure and hepatocellular carcinoma, research for an adequate therapeutic regimen and for new and more effective drugs, with less side-effects, and lower costs may be considered cost-effective.

Potential targets for antiviral therapy of HDV include drugs that interfere with postranslational modification and viral assembly. New drugs, such as prenylation inhibitors, HBV entry inhibitors, and new forms of interferons are currently being studied and tested for the treatment of hepatitis D, with better efficacy and tolerability.^{[5][11][12][13]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The hepatitis D virus was first reported in mid-1977 by an italian researcher, Mario Rizzetto.^[1] It was first detected in patients with severe liver disease, from chronic hepatitis B.^[2]

In 1977, a previously unrecognized nuclear antigen was detected in hepatocytes of patients with chronic hepatitis B, especially in those with severe liver disease.^[3] The antigen resembled hepatitis B core antigen (HBcAg) in its subcellular localization. Its presence was always associated with hepatitis B virus (HBV) infection, but it rarely coexisted with HBcAg.^[4][5]

Subsequent experiments in chimpanzees showed that the hepatitis delta antigen (HDAg) was a structural part of a pathogen that required HBV infection to replicate^[6] It was termed “delta antigen”.

The entire virus was cloned and sequenced in 1986, and obtained its own genus deltavirus.^[7][8]

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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]

Despite the limited knowledge concerning the pathogenesis of hepatitis delta virus (HDV) infection, the adaptive and innate immune systems are thought to play a pivotal role on hepatocellular injury. HDV requires the presence of HBV to be able to cause infection. Pathological changes in HDV are limited to the liver, the only organ in which HDV can replicate. Hepatitis B virus (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. There is evidence supporting the possibility that the virus can be cytopathic in certain genotypes. HDV is transmitted percutaneously, sexually, or through contact with infected blood or blood products. In rare occasions transmission may be perinatal. The different genotypes will influence viral assembly, and consequently infectivity.

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. Evidence points to an association between the quantity and quality of host T-cell responses and the level of infection control.^[1] HDV appears to subvert the adaptive immune system away from Th-1 biased CD4 and CD8 T-cell response, a necessary process for viral clearance.

Hepatitis B virus (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 mechanisms determining whether a person will spontaneously clear HDV, become chronically infected, or rapidly progress to hepatic fibrosis are not yet fully understood.^[2] 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. ^[2]

HDV suppresses HBV replication among patients with either coinfection or superinfection. In fact, up to 90% of patients with HDV coinfection are HBeAg negative and have a low HBV viral load. Furthermore, once HDV infection is cleared, replication of HBV can reactivate.^[2] Evidence points to the possible role of the small(p24) and large(p27) HDV proteins in suppressing HBV replication by:^[3]

• 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

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.^[4] More data is necessary to further the understanding of underlying mechanisms of HDV-induced disease.^[2]

HDV is transmitted percutaneously, sexually, or through contact with infected blood or blood products. Perinatal transmission is possible but uncommon. Blood is potentially infectious during all phases of active hepatitis D infection and a very small inoculum is sufficient to transmit HDV infection. Peak infectivity probably occurs just before the onset of acute disease. ^[5]

The HDV genotype influences the sequence of the C-terminal moiety of the large HDAg. These changes in the C-terminal moiety will influence the packaging ability of the virus, which will ultimately dictate interaction with clathrin and consequently the efficiency of viral assembly and infectivity.^[6][7][8] The fact that all genotypes are able to bind clathrin supports the importance of clathrin in HDV assembly.^[9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

Hepatitis D infection is caused by the hepatitis D virus.

Viruses; Deltavirus; Hepatitis delta virus

The hepatitis D virus belongs to the genus Deltavirus. Its genome is a single, negative stranded, circular RNA molecule nearly 1.7 kb in length containing about 60% C+G. A high degree of intramolecular complementarity allows about 70% of the nucleotides to be basepaired to each other to form an unbranched, double-stranded, stable, rod-shaped structure.^[2][3] Because the viral genome is double-stranded, the virus is relatively stable, being able to survive dry heat at 60°C for 30h. The genome of HDV is unrelated to the genomes of hepadnaviruses, of which hepatitis B virus (HBV) is a member.^[4] HDV is a replication defective, helper (HBV) dependent ssRNA virus that requires the surface antigen of HBV (HBsAg) for the “encapsidation” of its own genome. The envelope proteins on the outer surface of HDV are entirely provided by HBV.^[5][6]

The outer envelope of HDV particles contains lipids and the three forms (S, M, and L) of HBV surface antigen (HBsAg), but predominantly the major form of HBsAg with very few middle (pre S1) and large (pre S2) proteins. The internal nucleocapsid structure of HDV is composed of the viral single stranded RNA genome and about 60 copies of delta antigen, the only HDV-encoded protein.^[6]

HDV does not infect established tissue culture cell lines. Complete viral replication cycles in vitro are limited to primary hepatocytes that are coinfected with a hepadnavirus or cotransfected with hepadnavirus cDNA.^[6][2]

To replicate efficiently, a virus requires the cooperation of the host cell at all stages of the viral replication cycle. These stages include:^[6]

1. Atthment
2. Penetration
3. Uncoating
4. Provision of appropriate metabolic conditions for the synthesis of viral macromolecules
5. Final assembly of viral subunits
6. Release of new virions

Hepatitis D virus requires the presence of an helper hepadnavirus to provide the protein components for its own envelope. How HDV enters hepatocytes is still unknown, however, it may involve the interaction between HBsAg-L and the HBV cellular receptor. This assumption is due to the similarities between the outer coats of these two viruses.^[7] After entering the host cell, the virus loses its coat.^[7] The incoming HDV RNA is then transported into the nucleus, probably by the small form of viral delta antigen, HDAg-S. Binding of HDAg to RNA also protects the HDV RNAs from cellular degradation.^[6]

HDV RNA replication is carried out by cellular RNA polymerase II, without a DNA intermediate or help from HBV. During the replication of the HDV genome three forms of RNA are produced:

• Circular genomic RNA
• Circular complementary antigenomic RNA
• Linear polyadenylated antigenomic RNA – mRNA containing the open reading frame for the HDAg.

Synthesis of antigenomic RNA occurs in the nucleus, mediated by RNA polymerase I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Polymerase II.^[8] The translation of the HDV mRNA yields:^{[6][9][2][10]}

• Small (p24) form of HDAg (HDAg-S) – after translated in the cytoplasm, returns to the nucleus to support transcription
• Large (p27) form of HDAg (HDAg-L) – inhibitor of RNA synthesis and initiator of virion assembly with HBsAg

The HDV particle is composed by:

• HBsAg
• HDAg-S
• HDAg-L
• RNA

These elements are only assembled in the presence of the hepatitis B virus, which works as an helper virus. HBsAg and HDAg-L are necessary and sufficient for viral assembly. HDV RNA or HDAg-S, despite present, are not required for this phase. The primary initiation event for HDV assembly is the interaction of HDAg-L with HBsAg. HDAg is localized in the nuclei while HBsAg is present in the cytoplasm of the infected cells. In the nucleus, complexes of small and large HDAg, and new fragments of RNA are formed. These are then transferred to the Golgi membranes, where they will be conjugated with hepatitis B virus envelope proteins, thereby forming the final virion.^{[7][6][11][12]}

The RNA sequence of HDV has great variability. Genotyping techniques have shown the existence of more than 8 different genotypes of HDV.^[7]

Different HDV genotypes have been associated with different courses of natural history. Different studies have shown that:^[7]

• Patients with genotype 1 have worst outcomes and lower remission rates than those with HDV genotype 2
• Genotype 1 commonly leads to a wide range of manifestations of the disease, making it hard to establish a relationship between natural history and genotype
• Genotype 3 is associated with outbreaks in South America of florid hepatitis, leading to liver failure and death
• Mild liver disease is often associated with HDV genotype 4
• In Japan there is a variant of the HDV genotype 4 prone to the development of cirrhosis

Although the genotype of the underlying HBV may also influence the progression of the disease, the effects are difficult to study due to low levels of HBV DNA for genotyping.^[7]

Hepatitis D shows tropism for hepatocytes.

Humans are the only known natural reservoir of hepatitis D virus. However, when in the presence of hepatitis B virus, or woodchuck hepatitis virus, HDV can be experimentally transmitted to chimpanzees and woodchucks, respectively.^{[6][2][3][13]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]; Jolanta Marszalek, M.D. [3]

Hepatitis D must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, and elevated ALT and AST such as viral hepatitis (caused by other etiologic agents), alcoholic hepatitis, and autoimmune hepatitis.

Shown below is a table that summarizes the findings that differentiate hepatitis D from other conditions that cause fever, nausea, vomiting, jaundice, hepatomegaly, and icteric sclera.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Varun Kumar, M.B.B.S. [2]

HDV infection affects more than 15 million people chronically infected with HBV worldwide. Regions with high rates of HDV infection include Central Africa, Mediterranean Basin, the Amazon Basin, and parts of Asia. With the implementation of HBV vaccination programs, better education and awareness about the virus, and improving socioeconomic conditions, HDV prevalence is decreasing in many areas of the world.

Worldwide, between 15-20 million people with chronic HBV infection are thought to have HDV co-infection or superinfection. The prevalence ranges from 70% in the Amazon basin to 20% in Africa to <1% in North America. ^[1]

Areas of high endemicity include Central Africa, the Horn of Africa, the Middle East, eastern and Mediterranean Europe, the Amazon Basin, and parts of Asia. HDV infection rates usually correlate with HBV endemicity except in countries such as Indonesia and Vietnam, where co-infection is uncommon. Prevalence of HDV infection ranges between provinces in China, a country with high a endemicity of HBV. ^[2] New foci of HDV superinfection continue to be identified in Mongolia, Greenland, Ecuador, and Venezuela.

HDV prevalence is decreasing in many areas of the world including Spain, Turkey, and Taiwan, especially in the last three decades. This has been attributed to vaccination programs for HBV, increased awareness, and an overall improvement in socioeconomic conditions. ^[2] It should be noted that data for HBV prevalence in developing countries is sparse.

HDV infection remains prevalent in France whereas in Germany and the UK, the prevalence has increased. In Italy, HDV prevalence was previously decreasing, and has now recently plateaued. These changes in prevalence are mainly attributable to the immigration of persons from regions of high endemicity.^[4] HDV prevalence has not been systematically measured for over 10 years in the U.S., but previous reports show a prevalence from 1.4% to 12.1% in chronic HBV carriers depending on the region.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

Common risk factors in the development of hepatitis D include intravenous drug use, sexual intercourse with infected individuals, hemodialysis, and occupational exposure to infected individuals and blood products ^[1][2].

Since HDV requires the support of hepatitis B virus for its own replication, inoculation with HDV in the absence of HBV will not cause hepatitis D. Alone, the viral genome replicates in a helper-independent manner, but the viral particles do not exit the cell.^[1][2]

When in the presence of hepatitis B virus, risk factors for hepatitis D include:

• Using intravenous (IV) or injection drugs
• Being infected while pregnant (the mother can pass the virus to the baby)
• Carrying the hepatitis B virus
• Men having sexual intercourse with other men
• Sexual intercourse with HDV infected persons
• Receiving many blood transfusions
• People exposed to unscreened blood or blood products
• Haemophiliacs
• Hemodialysis patients
• Health care and public safety workers
• Individuals who are not infected with HBV, and have not been immunized against HBV, are at risk of infection with HBV with simultaneous or subsequent infection with HDV.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

The general population, with low risk of HBV and HDV infection does not need to be screened. However, individuals known to be HBsAg positive, with acute or chronic hepatitis, or those HBsAg negative, but who are IgM anti-HBc positive, should be screened for HDV. Blood products should also be screened in order to avoid transmission of the virus through blood transfusions or hemodialysis.

The following groups of patients should be screened for hepatitis D:

• Patients known to be HBsAg positive, who have acute or chronic hepatitis
• Patients who have acute hepatitis B, who are not HBsAg positive and who are IgM anti-HBc positive

The general population, without risk for HBV and HDV does not need to be screened.

Blood products should also be screened for the presence of HDV and HBV, in order to prevent infection by blood transfusion and hemodialysis.^[1]

For recommendations regarding HBV and HCC screening, refer to Hepatitis B screening^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Varun Kumar, M.B.B.S. [2]; Jolanta Marszalek, M.D. [3]; João André Alves Silva, M.D. [4]

HDV is a defective virus that requires individuals to be previously, or concomitantly, infected with HBV. The clinical manifestations of HDV infection are similar to those of HBV, including: fatigue, lethargy, nausea, jaundice, acholic stools and dark urine. The disease progresses throughout 4 phases: incubation period; preicteric phase; icteric phase; and convalescence phase. Infection with HDV may occur at the time of infection with HBV, in which case both acute type B and type D hepatitis may develop. 95% of these patients will clear the infection. HDV may also infect a previous HBV carrier, often causing fulminant hepatitis and chronic active hepatitis, frequently progressing to cirrhosis. Complications of hepatitis D may include: chronic active hepatitis; fulminant hepatitis; hepatic cirrhosis and hepatic failure. The mortality rate for HDV infection is higher than that of hepatitis B, between 2% and 20%.

After an initial incubation period of 3-7 weeks, the preicteric phase of acute HDV infection occurs with symptoms of fatigue, lethargy, anorexia and nausea, that last for 3 to 7 days. ALT and AST levels raise at this stage. Following the preicteric phase, the icteric phase is characterized by the manifestation of jaundice, acholic stools and dark urine. Serum bilirubin levels are also elevated at this stage. Fatigue and nausea continue to be present. In patients with acute, self-limiting infection, convalescence begins with the disappearance of clinical symptoms.^[1]

Fulminant viral hepatitis is rare, however, its mortality rate may reach 80%, and is about 10 times more common in hepatitis D than in other types of viral hepatitis. It is characterized by:^[1][2]

• Hepatic encephalopathy
• Sleep disturbances
• Confusion
• Concentration difficulties
• Abnormal behavior
• Somnolence
• Coma

About 60 to 70% of patients with chronic hepatitis D develop cirrhosis. Progression to cirrhosis usually takes 5 – 10 yrs, but it can appear 2 years after the onset of infection. Many of these patients die of hepatic failure.^[1][3]

Coinfection with HBV and HDV results in both acute type B and type D hepatitis. The incubation depends on the HBV titer of the infective inoculum. One or two bouts of hepatitis may be seen depending on the relative titers of HBV and HDV.^[4][5]

The host’s response to HBV determines the fate of HDV. In more than 95% of adults, HDV is cleared, whereas the chronic form occurs in less than 5% of co-infected patients. Although disease presentation may differ greatly among patients, acute coinfection of HBV and HDV can result in a more severe disease state than acute mono-infection with HBV.^[4][5]

HDV infection of a chronically infected HBV carrier frequently causes severe acute hepatitis with a short incubation period. The majority of cases lead to chronic hepatitis D.^[4] This form of the disease often presents as acute hepatitis in a previously undiagnosed HBsAg carrier. Most times it is misdiagnosed as an acute form of HBV infection.^[6]

Superinfection is associated with fulminant hepatitis and severe chronic active hepatitis, often progressing to cirrhosis. Less frequently, HDV replication stops and the natural history becomes that of the HBV infection. In these cases residual liver disease may still be more advanced. Superinfection can present as acute hepatitis in a previously undiagnosed carrier of HBsAg. It is sometimes misdiagnosed as acute HBV or as chronic HBV causing a worsening of the liver disease.^[4]

Although it is associated with a higher rate of cirrhosis, a concomitant increase in the rate of HCC was not noted, possibly due to the suppression of HBV replication, caused by HDV.^[7]

Common complications of hepatitis D include:^[5]

• Chronic active hepatitis
• Fulminant hepatitis
• Hepatic cirrhosis
• Hepatic failure

• Hepatocellular carcinoma (HCC) occurs in chronically infected HDV patients with advanced liver disease, with the same frequency as in those with hepatitis B.^[1]
• HCC may be considered more a secondary effect of the associated cirrhosis than a direct carcinogenic effect of the virus, however further studies are required to evaluate this relationship.^{[1][8][9][10][11]}

The mortality rate for HDV infections is between 2% and 20%. These values are ten times higher than those of hepatitis B.^[1]

Patients with coinfection are more likely to have fulminant hepatitis than those with HBV infection alone. When acute infection with HDV occurs in a patient who has existing chronic HBV infection, especially in persons with progressive, symptomatic chronic disease, there is increased progression of hepatic cirrhosis and hepatic failure.^[12]

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