Hepatitis D (original) (raw)

Continuing Education Activity

Hepatitis D virus (HDV) is a unique pathogen that requires the presence of hepatitis B virus (HBV) for its replication and spread. HDV uses the HBV surface antigen as its envelope protein, making it dependent on the coinfection or superinfection with HBV to cause disease. Clinically, HDV infection can lead to more severe liver disease than HBV alone. In acute HBV-HDV coinfection, patients may experience a biphasic course with 2 distinct peaks in serum alanine aminotransferase, reflecting the sequential spread of HBV and HDV. Chronic infection with both viruses can result in faster progression to cirrhosis and liver failure. HDV also has the unique characteristic of suppressing HBV replication, although the mechanism remains unknown. Timely serological testing is crucial for identifying HDV infection in patients with HBV, as this coinfection requires specific management approaches.

Participants in this course gain a comprehensive understanding of HDV, including its dependence on HBV for transmission, the clinical presentation of coinfection, and the associated complications. They learn how to evaluate patients with suspected HDV by conducting appropriate serological tests and recognize the importance of early diagnosis in improving outcomes. The course emphasizes the role of an interprofessional healthcare team, including hepatologists, infectious disease specialists, and nurses, in providing holistic care. Collaborating with this team enhances patient outcomes by ensuring that the complexities of managing HBV-HDV coinfection are addressed through coordinated efforts, tailored treatment plans, and comprehensive monitoring strategies.

Objectives:

Access free multiple choice questions on this topic.

Introduction

Hepatitis D virus (HDV) was discovered in 1977 in patients with chronic hepatitis B virus (HBV) infection.[1] Originally thought to be an unrecognized HBV antigen, the HDV nuclear antigen was later discovered to be a part of a new pathogen, initially known as the delta agent. HDV is considered a hybrid virus as it uses Hepatitis B surface antigen (HBsAg) as its envelope protein, rendering it able to infect only patients that concomitantly harbor HBV.[2] Due to unknown reasons, HBV replication is suppressed in HDV-infected individuals.[3]

Etiology

HDV infection is an acute and chronic inflammatory process transmitted parenterally. HDV replicates independently within hepatocytes but requires HBsAg for propagation. Hepatic cell death occurs due to direct cytotoxic effects of HDV or a host-mediated immune response.[2] Risk factors include blood transfusions and intravenous drug use.[4]

Epidemiology

Even though HDV is dependent on HBV, its geographical distribution differs from that of HBV, partly due to the differences in mode of transmission. HDV is mainly transmitted via the parenteral route through blood or blood product exposure. Although sexual transmission is infrequent, vertical transmission is rare.[5][6] Information on HDV epidemiology has mostly been obtained from HBV carriers who are superinfected with HDV; approximately 5% of the HBV carriers are estimated to also be infected with HDV.[7] Recently, there has been a significant decline in HDV transmission due to the decrease in the incidence of HBV infection; this is mainly due to improved socioeconomic conditions, increased awareness of infectious disease transmission, and improved HBV vaccination rates.[7] HDV is most prevalent in the Mediterranean, East Africa, the Amazon basin, the Middle East, Central and Northern Asia, and certain areas of the Pacific.[8] In Western countries, HDV infection is infrequent and occurs only in high-risk populations such as intravenous drug users, individuals from areas with a high prevalence of HDV, and recipients of multiple transfusions.

Pathophysiology

Structurally, HDV comprises a ribonucleic acid (RNA) genome, hepatitis D antigen (HDAg), and a lipoprotein envelope from HBV. The genome only codes for the HDAg. There are 2 types of HDAgs, which are named after their size: long and short. Viral replication occurs in the hepatocytes, and the virus is unique as it uses the host RNA polymerase II to transcribe its messenger RNA. Although the short HDAg activates viral replication via direct binding to the HDV RNA, the long HDAg directs viral assembly and inhibits viral replication. The virus is completely assembled after incorporating the HBV envelope, after which it is released.[2][9][10]

HDV infection only occurs in the presence of HBV. In individuals susceptible to HBV, coinfection with both viruses results in an acute HBV and HBD infection. Clinically, coinfection resembles classic acute HBV, except for a biphasic course of 2 peaks of serum alanine aminotransferase, which may be seen several weeks apart. This is because HBV infection must be established first during the acute coinfection before HDV starts to spread. More severe cases than acute HBV mono-infection may be seen in some cases with an increased risk for liver failure. Most patients recover during the acute coinfection with HBV and HDV, and only about 5% of the patients go on to develop chronic infection (defined as persistence of infection beyond 6 months).[5][11]

In individuals who are chronic carriers of HBsAg, a full-blown superinfection can occur, which may present as severe acute hepatitis or exacerbation of preexisting chronic HBV. In patients with chronic HBV infection, acute HDV infection may be mistaken for an HBV virus flare. In those with undiagnosed HBV infection, clinical presentation and initial investigations may be mistaken for acute HBV infection if HDV superinfection is not entertained as a diagnostic possibility. The clinical course during a superinfection is often more severe than HBV/HDV coinfection. As the presence of HBsAg allows for continuous viral replication, 90% of these individuals progress to chronic HDV. Chronic HDV infection causes more severe morbidity and complications (progressive fibrosis, cirrhosis, hepatocellular carcinoma, and hepatic decompensation) than chronic HBV infection.[12] In cases of triple infection with HBV, hepatitis C virus (HCV), and HDV, either HDV or HCV will dominate the other viruses depending on the geographic region, host immune factors, activity, and genotype of the HDV involved.

Although the mechanism by which HDV induces liver damage is not entirely known, it is thought to be due to the host immune response.[13] The spectrum of damage can range from no symptoms to fulminant liver failure. HDV superinfection tends to have a more rapid course and increases the risk of hepatocellular carcinoma.[14] The degree of injury depends on various factors, including HDV genotype, host immune response, and HBV genotype. Classically, there are 3 main HDV genotypes: 1, 2, and 3. Additionally, other genotypes have been identified but are not yet as well characterized. Genotype 1 is the predominant type in Western countries.[15] When associated with acute hepatitis D, it has a fulminant course. Once chronic, it can exacerbate previously existing HBV disease and can rapidly progress toward liver cirrhosis, but it can also have an indolent course. Genotype 2 is most common in the far East countries. Contrary to genotype 1, it is less frequently associated with fulminant liver disease and the progression of chronic liver disease.[16] Genotype 3 is most prevalent in South America and tends to cause severe acute hepatitis, which can progress to liver failure.[17]

Histopathology

HDV causes the same histological changes in the liver parenchyma as other viral infections and can result in necrosis and inflammation of the hepatic cells. In acute disease, there is intralobular infiltration of inflammatory cells (lymphocytes, macrophages) and cytoplasmic eosinophilia. Chronic hepatitis is characterized by periportal necrosis and is often accompanied by nodular changes.

History and Physical

Hepatitis D is clinically similar to other forms of hepatic viral infections. Most patients are asymptomatic, but signs and symptoms can include fever, abdominal pain, nausea, vomiting, jaundice, confusion, bruising, or bleeding, depending on the severity of the illness.

Evaluation

In response to the HDAg, antibodies of the immunoglobulin M (IgM) and immunoglobulin G (IgG class) (anti-HDV) are produced. The 3 infective patterns (acute HDV/HBV coinfection, acute HDV superinfection, and chronic HDV infection) vary concerning appearance and levels of HDV RNA, HDAg, and anti-HDV as well as HBV markers (see Image. Hepatitis D Stages and Serological Markers). As HDV depends on HBV, the presence of HBsAg is essential for diagnosis. Additionally, IgM antibody to hepatitis B core antigen (IgM anti-HBc) is necessary to diagnose acute HBV/HDV coinfection.[18]

In acute HDV infection, the appearance of HDAg is early but short-lived and often requires repeat testing for detection. The appearance of anti-HDV is late in acute infection and may be the only way to diagnose acute HDV if other HDV infection markers are absent. The pattern of the IgM class of anti-HDV depends on the course of acute hepatitis D. If HDV infection is self-limited, the appearance of anti-HDV IgM is transient and delayed.[18][19][20] If HDV infection progresses to chronicity, anti-HDV IgM is found in high titers and for a prolonged duration. Anti-HDV IgM is found in acute HDV infection but is not very specific as it is also found in chronic HDV infection.[21][22]

Historically, HDAg detection was considered the gold standard for diagnosis of active HBV infection. As anti-HDV forms immune complexes with HDAg, detecting HDAg by the required immunoblot assay is difficult and time-consuming. Therefore, HDV RNA detection via reverse transcriptase-polymerase chain reaction (RT-PCR) is the most sensitive and practical test for detecting active HDV infection.[23][24]

High-risk individuals (intravenous drug users, individuals from HDV-endemic areas) or those who present with severe course who have acute hepatitis B should be suspected of HDV coinfection. As mentioned, patients with coinfection have high titers of IgM anti-HBc. In these individuals, HDV markers can come before or after HBV markers. Occasionally, patients who present during the second phase of biphasic hepatitis seroconvert to anti-HBs, but they could still test positive for high titer IgM anti-HBc. When the etiology of hepatitis is undetermined in chronic HBV carriers, HDV testing should be performed to rule out an acute HDV superinfection. Distinguishing between HDV superinfection and HBV/HDV coinfection can be difficult when superinfection occurs in unidentified chronic HBV carriers.

In individuals with chronic hepatitis B, HDV testing should be considered in high-risk individuals to rule out concurrent chronic HDV infection. This can be obtained by the detection of total anti-HDV antibody followed by confirmatory staining for HDAg in liver tissues and/or measurement of serum HDV RNA. As HBV replication is suppressed in chronic HDV infection, hepatitis B e-antibodies are typically present.

Treatment / Management

Treatment options for HDV are limited, and optimal treatment is not known; there are no known treatments for acute HDV. Although not United States Food and Drug Administration-approved for chronic HDV, interferon alpha (IFN alpha) is beneficial in most clinical trials.[25] The pegylated form of IFN alpha is recommended as the preferred agent per expert guidelines. Treatment is administered once weekly for at least 1 year.[26] The goal of treatment is to suppress HDV replication, which is shown by the inability to detect HDV RNA in serum and HDAg in the liver. Treatment end-points include normalization of alanine aminotransferase and inflammation on liver biopsy. When the disease progresses to cirrhosis, liver transplantation is the only viable option.

Differential Diagnosis

The differential diagnoses for HDV include the following:

Pearls and Other Issues

As HDV depends on HBV, prevention can be achieved with HBV vaccination. If the host is immune to HBV, they are subsequently protected against HDV. Patients at risk of contracting HDV infection should be encouraged to receive the hepatitis B vaccine.

Enhancing Healthcare Team Outcomes

HDV only occurs in patients with HBV. Thus, healthcare professionals should consider serological testing for HDV in patients with HBV. This can be obtained by detecting total anti-HDV antibodies followed by confirmatory staining for HDAg in liver tissues or measuring serum HDV RNA. As HBV replication is suppressed in chronic HDV infection, anti-HBe are typically present. As HDV depends on HBV, prevention can be achieved with HBV vaccination. If the host is immune to HBV, they are subsequently protected against HDV. Patients who are at risk of contracting HDV infection should be encouraged to receive the HBV vaccine. Currently, there is no specific treatment for HDV, but unlike HBV, the former is a benign infection.

Review Questions

Hepatitis D Stages, Serological Markers, and the Three Infective Patterns

Figure

Hepatitis D Stages, Serological Markers, and the Three Infective Patterns. The three infective patterns vary in appearance and levels of HDV RNA, HDAg, and anti-HDV and HBV markers. Contributed by U Masood, MD

References

Rizzetto M, Canese MG, Gerin JL, London WT, Sly DL, Purcell RH. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. J Infect Dis. 1980 May;141(5):590-602. [PubMed: 6989929]

Polson AG, Bass BL, Casey JL. RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature. 1996 Apr 04;380(6573):454-6. [PubMed: 8602246]

Kiesslich D, Crispim MA, Santos C, Ferreira Fde L, Fraiji NA, Komninakis SV, Diaz RS. Influence of hepatitis B virus (HBV) genotype on the clinical course of disease in patients coinfected with HBV and hepatitis delta virus. J Infect Dis. 2009 Jun 01;199(11):1608-11. [PubMed: 19388852]

Patel EU, Thio CL, Boon D, Thomas DL, Tobian AAR. Prevalence of Hepatitis B and Hepatitis D Virus Infections in the United States, 2011-2016. Clin Infect Dis. 2019 Aug 01;69(4):709-712. [PMC free article: PMC6669285] [PubMed: 30605508]

Liaw YF, Chiu KW, Chu CM, Sheen IS, Huang MJ. Heterosexual transmission of hepatitis delta virus in the general population of an area endemic for hepatitis B virus infection: a prospective study. J Infect Dis. 1990 Nov;162(5):1170-2. [PubMed: 2121838]

Weisfuse IB, Hadler SC, Fields HA, Alter MJ, O'Malley PM, Judson FN, Ostrow DG, Altman NL. Delta hepatitis in homosexual men in the United States. Hepatology. 1989 Jun;9(6):872-4. [PubMed: 2714738]

Gaeta GB, Stroffolini T, Chiaramonte M, Ascione T, Stornaiuolo G, Lobello S, Sagnelli E, Brunetto MR, Rizzetto M. Chronic hepatitis D: a vanishing Disease? An Italian multicenter study. Hepatology. 2000 Oct;32(4 Pt 1):824-7. [PubMed: 11003629]

Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010 Jan;7(1):31-40. [PubMed: 20051970]

Negro F, Korba BE, Forzani B, Baroudy BM, Brown TL, Gerin JL, Ponzetto A. Hepatitis delta virus (HDV) and woodchuck hepatitis virus (WHV) nucleic acids in tissues of HDV-infected chronic WHV carrier woodchucks. J Virol. 1989 Apr;63(4):1612-8. [PMC free article: PMC248403] [PubMed: 2926865]

Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Fälth M, Stindt J, Königer C, Nassal M, Kubitz R, Sültmann H, Urban S. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology. 2014 Apr;146(4):1070-83. [PubMed: 24361467]

Smedile A, Farci P, Verme G, Caredda F, Cargnel A, Caporaso N, Dentico P, Trepo C, Opolon P, Gimson A, Vergani D, Williams R, Rizzetto M. Influence of delta infection on severity of hepatitis B. Lancet. 1982 Oct 30;2(8305):945-7. [PubMed: 6127458]

Smedile A, Dentico P, Zanetti A, Sagnelli E, Nordenfelt E, Actis GC, Rizzetto M. Infection with the delta agent in chronic HBsAg carriers. Gastroenterology. 1981 Dec;81(6):992-7. [PubMed: 7286594]

Bichko V, Netter HJ, Wu TT, Taylor J. Pathogenesis associated with replication of hepatitis delta virus. Infect Agents Dis. 1994 Apr-Jun;3(2-3):94-7. [PubMed: 7812659]

Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, de Franchis R, Ronchi G, Colombo M. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009 May;136(5):1629-38. [PubMed: 19208358]

Niro GA, Smedile A, Andriulli A, Rizzetto M, Gerin JL, Casey JL. The predominance of hepatitis delta virus genotype I among chronically infected Italian patients. Hepatology. 1997 Mar;25(3):728-34. [PubMed: 9049226]

Wu JC, Choo KB, Chen CM, Chen TZ, Huo TI, Lee SD. Genotyping of hepatitis D virus by restriction-fragment length polymorphism and relation to outcome of hepatitis D. Lancet. 1995 Oct 07;346(8980):939-41. [PubMed: 7564729]

Casey JL, Brown TL, Colan EJ, Wignall FS, Gerin JL. A genotype of hepatitis D virus that occurs in northern South America. Proc Natl Acad Sci U S A. 1993 Oct 01;90(19):9016-20. [PMC free article: PMC47492] [PubMed: 8415646]

Aragona M, Macagno S, Caredda F, Crivelli O, Lavarini C, Maran E, Farci P, Purcell RH, Rizzetto M. Serological response to the hepatitis delta virus in hepatitis D. Lancet. 1987 Feb 28;1(8531):478-80. [PubMed: 2881041]

Shattock AG, Morgan BM. Sensitive enzyme immunoassay for the detection of delta antigen and anti-delta, using serum as the delta antigen source. J Med Virol. 1984;13(1):73-82. [PubMed: 6363622]

Buti M, Esteban R, Jardí R, Esteban JI, Guardia J. Serological diagnosis of acute delta hepatitis. J Med Virol. 1986 Jan;18(1):81-5. [PubMed: 3944592]

Bonino F, Heermann KH, Rizzetto M, Gerlich WH. Hepatitis delta virus: protein composition of delta antigen and its hepatitis B virus-derived envelope. J Virol. 1986 Jun;58(3):945-50. [PMC free article: PMC253003] [PubMed: 3701932]

Buti M, Esteban R, Jardi R, Rodriguez-Frias F, Casacuberta J, Esteban JI, Allende E, Guardia J. Chronic delta hepatitis: detection of hepatitis delta virus antigen in serum by immunoblot and correlation with other markers of delta viral replication. Hepatology. 1989 Dec;10(6):907-10. [PubMed: 2583685]

Dinolfo L, Abate ML, Bertolo P, Bosio P, Rosina F, Cavicchini A, Rizzetto M, Negro F. Detection of hepatitis D virus RNA in serum by a reverse transcription, polymerase chain reaction-based assay. Int J Clin Lab Res. 1995;25(1):35-9. [PubMed: 7787208]

Mederacke I, Bremer B, Heidrich B, Kirschner J, Deterding K, Bock T, Wursthorn K, Manns MP, Wedemeyer H. Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics. J Clin Microbiol. 2010 Jun;48(6):2022-9. [PMC free article: PMC2884474] [PubMed: 20351206]

Abbas Z, Khan MA, Salih M, Jafri W. Interferon alpha for chronic hepatitis D. Cochrane Database Syst Rev. 2011 Dec 07;2011(12):CD006002. [PMC free article: PMC6823236] [PubMed: 22161394]

Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. [PMC free article: PMC5975958] [PubMed: 29405329]

Disclosure: Umair Masood declares no relevant financial relationships with ineligible companies.

Disclosure: Savio John declares no relevant financial relationships with ineligible companies.