1. 1 Hepatitis Viruses SAMUEL AGUAZIM.M.D. Lange Chapter 41

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3. 3 HCV- most common cause of post transfusion hepatitis most prevalent blood-borne pathogen in the U.S. HEV: Fatality in pregnant women

4. 4 Many viruses cause hepatitis. Of these, five medically important viruses are commonly described as “hepatitis viruses”: hepatitis A virus (HAV) hepatitis B virus (HBV) non-A, non-B viruses, of which hepatitis C virus (HCV) is the most common hepatitis D virus (HDV, delta agent) Hepatitis E virus (HEV).

5. 5 HEPATITIS A VIRUS Disease: HAV causes hepatitis A. Important Properties: enterovirus classified in the picornavirus family. single-stranded positive polarity RNA genome nonenveloped icosahedral nucleocapsid replicates in the cytoplasm of the cell. known as enterovirus 72. one serotype no antigenic relationship to HBV or other hepatitis viruses.

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9. 9 HAV Transmission & Epidemiology: transmitted by the fecal-oral route. appears in the feces 2 weeks before the appearance of symptoms. Children are the most frequently infected group summer camps and boarding schools. fecally contaminated water or food such as oysters grown in polluted water and eaten raw. Unlike HBV, HAV is rarely transmitted via the blood, because the level of viremia is low chronic infection does not occur.

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11. 11 Pathogenesis HAV: probably replicates in the GI tract and spreads to the liver via the blood. Hepatocytes are infected. infection of cultured cells produces no cytopathic effect. likely that attack by cytotoxic T cells causes the damage to the hepatocytes. no chronic infection occur. HAV Immune response IgM antibody, detectable at the time jaundice appears followed 1—3 weeks later by the production of IgG antibody, which provides lifelong protection. IgM Important in the laboratory diagnosis of hepatitis A.

12. 12 HAV Clinical Findings: Fever, anorexia (diminished appetite) nausea, vomiting, and jaundice are typical. Dark urine, pale feces, and elevated transaminase levels are seen. Most cases resolve spontaneously in 2—4 weeks. short incubation period (3—4 weeks) or ( 15-40 days), in contrast to that of hepatitis B, which is 10—12 weeks. Laboratory Diagnosis: The detection of IgM antibody is the most important test Treatment: No antiviral therapy is available.

13. 13 HAV Prevention: a. Active immunization with a vaccine containing inactivated HAV is available. b. Passive immunization with immune serum globulin prior to infection or early in the incubation period can prevent or mitigate the disease.

14. HAV Prevention: c. A combination vaccine that immunizes against both HAV and HBV called Twinrix is available. Twinrix contains the same immunogens as the individual HAV and HBV vaccines. d. Observation of proper hygiene, e.g., sewage disposal and hand washing after bowel movements, is of prime importance 14

15. Clinical Features of Hepatitis Viruses 15 Virus Mode of Transmission Chronic Carriers Laboratory Test Usually Used for Diagnosis Vaccine Available Immune Globulins Useful HAVFecal–oralNoIgM HAVYes HBVBlood, sexual, at birth YesHBsAg, HBsAb, IgM HBcAb Yes HCVBlood, sexual 1 YesHCV AbNo HDVBlood, sexual 1 YesAb to delta Ag No HEVFecal–oralNoNoneNo

16. 16 HEPATITIS B VIRUS hepadnavirus family. 42-nm enveloped virion, icosahedral nucleocapsid core containing a partially double-stranded circular DNA genome. Important antigens surface antigen (HBsAg): protein in the envelope which is important for laboratory diagnosis and immunization. core antigen (HBcAg): located in the core (nucleocapsid) e antigen (HBeAg): located in the core is an important indicator of transmissibility and active viral replication.

17. 17 HBV Electron microscopy of a patient’s serum reveals three different types of particles: a few 42-nm virions and many 22-nm spheres and long filaments 22 nm wide, which are composed of surface antigen. HBV is the only human virus that produces these spheres and filaments in such large numbers in the patient’s blood.

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19. HBV Within the core is a DNA-dependent DNA polymerase. The genome contains four genes (four open reading frames) that encode five proteins; namely, the S gene encodes the surface antigen, the C gene encodes the core antigen and the e antigen, the P gene encodes the polymerase, and the X gene encodes the X protein (HBx). HBx is an activator of viral RNA transcription and may be involved in oncogenesis. The DNA polymerase has both RNA-dependent (reverse transcriptase) and DNA-dependent activity. 19

20. 20 HBV Transmission & Epidemiology: Four main modes of transmission are: via blood during sexual intercourse perinatally from mother to newborn. Intravenous ( IV)

21. Blood Screening in US In the United States, donated blood is screened for HBsAg and antibodies to HBcAg, HCV, HIV-1, HIV-2, and HTLV-1. Two other tests are also performed: a VDRL test for syphilis and a transaminase assay, which, if elevated, indicates liver damage and is a surrogate marker of viral infection. 21

22. 22 HBV Facts found worldwide but is particularly prevalent in Asia. more than 300 million people are chronically infected with HBV. high incidence of hepatocellular carcinoma (hepatoma) in many Asian countries Immunization against HBV in Taiwan has significantly reduced the incidence of hepatoma in children. HBV vaccine is the first vaccine to prevent a human cancer.

23. HBV HBV travels in the blood to infect and replicate within hepatocytes. Once inside hepatocytes, the partially dsDNA viral genome is completed via a viral DNA polymerase. Newly complete dsDNA generates mRNA transcripts that can be used to generate viral proteins or to make more partially dsDNA via a RNA-dependent DNA polymerase. HBV is unique in that its DNA polymerase activity is both DNA-dependent and RNA-dependent. Normal incubation period of HBV is 45-180 days. 23

24. 24 HBV Pathogenesis & Immunity: After entering the blood, the virus infects hepatocytes viral antigens are displayed on the surface of the cells. Cytotoxic T cells mediate an immune attack against the viral antigens inflammation and necrosis occur. probably the result of this cell-mediated immune injury HBV itself does not cause a cytopathic effect. Antigen-antibody complexes cause some of the early symptoms, eg, arthritis, and some of the complications in chronic hepatitis, eg, immune- complex glomerulonephritis, and vasculitis.

25. 25 HBV Chronic Carrier Unlike hepatitis A patients, about 5% of patients with hepatitis B become chronic carriers of HBV. chronic carrier: someone who has HBsAg persisting in their blood for at least 6 months. a persistent infection of the hepatocytes, which results in the prolonged presence of HBV and HBsAg in the blood. more likely to occur when infection occurs in a newborn than in an adult, probably because a newborn’s immune system is less competent than an adult’s. 90% of those infected as neonates become chronic carriers. neonatal infection is associated with a high risk of hepatocellular carcinoma. Lifelong immunity occurs after the natural infection and is mediated by humoral antibody against HBsAg

26. Chronic Active Hepatitis Active inflammation on biopsy Fibrosis present May progress to liver cancer Will lead to cirrhosis Due to Hep b: Tx with interferon and lamuvidine Due to Hep c: Tx with interferon and ribavarin 26

27. 27 HBV Clinical Findings: Many HBV infections are asymptomatic and are detected only by the presence of antibody to HBsAg. mean incubation period for hepatitis B is 10—12 weeks, which is much longer than that of hepatitis A (3—4 weeks). clinical appearance of acute hepatitis B is similar to that of hepatitis A. However, with hepatitis B, symptoms tend to be more severe, and life-threatening hepatitis can occur. Most chronic carriers are asymptomatic, but some have chronic active hepatitis, which can lead to cirrhosis and death.

28. Liver cirrhosis consequence of repeated immune system attacks cirrhosis cannot be cured progress may be stopped if the cause is treated cessation of enzymatic processes in the liver Ascites, jaundice, internal bleeding, and hepatic encephalopathy candidates for liver transplantation 28

29. Fulminant hepatitis occurs in 1% of acutely infected individuals; more likely if HBV and HDV coinfect. more severe symptoms, can be fatal severe liver damage: ascites and bleeding liver shrinkage 29

30. Primary hepatocellular carcinoma Liver carcinoma follows HBV infection after 9- 35 years Chronic HCV infection can also result in hepatocellular carcinoma 30

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32. Extrahepatic Findings of HBV infections * Polyarteritis Nodosa * Membranous nephropathy * Membranoproliferative glomerulonephritis type 1. 32

33. On histology CHRONIC HEPATITIS B may show pathonomonic ground glass hepatocyte inclusions (arrows heads) which is a granular homogenous eosinophilic staining of cytoplasm caused by presence of HBsAg 33

34. 34 Laboratory Diagnosis HBV: The most important laboratory test for the detection of early HBV infection is the immunoassay for HBsAg. HBsAg appears during the incubation period, first viral marker detected in the blood of HBV infection and is detectable in most patients during the prodrome and acute disease

35. Date of download: 3/2/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved. A: Important diagnostic tests during various stages of hepatitis B. B: Serologic findings in a patient with acute hepatitis B. C: Duration of increased liver enzyme activity and of symptoms in a patient with acute hepatitis B. anti-HBc, hepatitis B core antibody; anti-HBe, hepatitis B e antibody; anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. (Modified and reproduced with permission from Hollinger FB, Dienstag JL. Hepatitis viruses. In: Lennette EH et al., eds. Manual of Clinical Microbiology. 4th ed. Washington, DC: ASM Press; 1985.) Legend : From: Hepatitis Viruses Review of Medical Microbiology and Immunology, 13e, 2014 From: Hepatitis Viruses Review of Medical Microbiology and Immunology, 13e, 2014

36. 36 HBeAg arises during the incubation period and is present during the prodrome and early acute disease and in certain chronic carriers. HBeAg has a high correlation with DNA polymerase activity. presence is an important indicator of transmissibility, and, conversely finding of HBeAb indicates low transmissibility

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38. 38 HBcAg found within the nuclei of infected hepatocytes not generally in peripheral circulation except as an integral component of Dane particle. Anti-HBc may be the only detected serologic marker during the early convalescent phase of an HBV infection “window phase”.

39. HBV TREATMENT No antiviral therapy is typically used in acute hepatitis B. For chronic hepatitis B, entecavir (Baraclude) or tenofovir (Viread) are the drugs of choice. They are nucleoside analogues that inhibit the reverse transcriptase of HBV. Interferon in the form of peginterferon alfa-2a(Pegasys) is also used. Other nucleoside analogues such as lamivudine(Epivir- HBV), adefovir (Hepsera), and telbivudine (Tyzeka) are used less frequently. A combination of tenofovir and emtricitabine (Emtriva) is also used. 39

40. HBV Prevention: involves the use of either the vaccine or hyperimmune globulin or both. (1)The vaccine, eg, Recombivax, contains HBsAg as the immunogen. Second generation vaccine is using recombinant DNA. (2) Hepatitis B immune globulin (HBIG) contains a high titer of HBsAb because it is prepared from sera of patients who have recovered from hepatitis B. 40

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42. Vaccine Recommended Newborns/youth Healthcare Workers IV drug users Individual with multiple sexual partners 42

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44. 44 NON-A, NON-B HEPATITIS VIRUSES describes the cases of hepatitis for which existing serologic tests had ruled out all known viral causes. term is not often used because the main cause of non-A, non-B hepatitis, namely, hepatitis C virus, has been identified.

45. 45 HEPATITIS C VIRUS Disease: HCV causes hepatitis C. Important Properties: enveloped virion containing a genome of single-stranded, positive-polarity RNA. member of the flavivirus family. no virion polymerase. Multiple serotypes exist.

46. 46 HEPATITIS C VIRUS Transmission & Epidemiology: transmitted via blood. most common cause of posttransfusion hepatitis. intravenous drug user: all new HCV infections Sexual transmission and transmission from mother to child have been difficult to document. most prevalent blood-borne pathogen - U.S. 4 million people in the U.S. (1—2% of the population) are chronically infected with HCV. infects hepatocytes: 30-50% of cases progress to chronic liver diseases Alcoholism: hepatocellular carcinoma Cancer: caused by prolonged liver damage and rapid growth rate of hepatocytes as the cells attempt to regenerate rather than by a direct oncogenic effect of HCV.

47. Liver transplant

48. 48 Clinical Findings HCV acute infection with HCV is milder than infection with HBV. Fever, anorexia, nausea, vomiting, and jaundice are common. Dark urine, pale feces, and elevated transaminase levels are seen Laboratory Diagnosis: detecting antibodies to HCV in an ELISA. Blood products can now be tested for Ab to HCV.

49. 49 HCV Treatment & Prevention: Sofosbuvir ( first line) A combination of alpha interferon and ribavirin is the treatment of choice for chronic hepatitis C, but it is expensive and has side effects that can limit its use. Patients with chronic HCV infection should be advised to reduce or eliminate their consumption of alcoholic beverages to reduce the risk of hepatocellular carcinoma and cirrhosis Simeprevir

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51. 51 HEPATITIS D VIRUS (DELTA VIRUS) Disease: Hepatitis D virus (HDV) causes hepatitis D (hepatitis delta). Important Properties & Replicative Cycle: unusual in that it is a defective virus cannot replicate by itself because it does not have the genes for its envelope protein. HDV can replicate only in cells also infected with HBV, because HDV uses the surface antigen of HBV (HBsAg) as its envelope protein. HBV is therefore the helper virus for HDV.

52. 52 Transmission & Epidemiology HDV: transmitted by the same means as is HBV sexually, by blood perinatally. In the United States, most HDV infections occur in intravenous drug users who share needles. HDV infections occur worldwide with a similar distribution to that of HBV infections.

53. 53 HDV Pathogenesis & Immunity: the pathogenesis of hepatitis caused by HDV and HBV is the same the virus-infected hepatocytes are damaged by cytotoxic T cells. There is some evidence that delta antigen is cytopathic for hepatocytes. IgG antibody against delta antigen is not detected for long periods after infection uncertain whether long term immunity to HDV exists. Because HDV can replicate only in cells also infected with HBV, hepatitis delta can occur only in a person infected with HBV. A person can either be infected with both HDV and HBV at the same time, ie, be “coinfected,” or be previously infected with HBV and then be infected with HDV.

54. 54 HDV Laboratory Diagnosis: detecting either delta antigen or IgM antibody to delta antigen in the patient’s serum. Treatment: Alpha interferon can mitigate some of the effects of the chronic hepatitis caused by HDV but does not eradicate the chronic carrier state Prevention of HBV infection: Vaccine hyperimmune globulin

55. 55 HEPATITIS E VIRUS major cause of enterically transmitted hepatitis. common cause of water-borne epidemics of hepatitis in Asia, Africa, India, and Mexico uncommon in the United States. nonenveloped, single-stranded RNA virus tentatively classified as a member of the calicivirus family. Clinically the disease resembles hepatitis A, with the exception of a high mortality rate in pregnant women. Pregnant women who acquire HEV have a 20% fatality rate (compared to 0.5% for the rest of the population). India, a country where HEV is endemic.

56. 56 HEPATITIS G VIRUS member of the flavivirus family, as is HCV. unlike HCV, which is clearly the cause of both acute hepatitis and chronic active hepatitis and predisposes to hepatocellular carcinoma, HGV has not been documented to cause any of these clinical findings.

57. EVERY TIME YOU TAKE 2 STEPS FORWARD YOU HAVE SUCCEEDED IN ELIMINATING FAILURE AND BACKWARDNESS…. DRS 57