Lecture 12.vha vhe


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Lecture 12.vha vhe

  1. 1. Viral hepatitides A and E Sorokhan MD, PhD Bukovinian State Medical University Department of the infectious diseases and epidemiology
  2. 2. Hepatitis A <ul><li>One of the more common causes of acute hepatitis is hepatitis A virus (HAV). </li></ul><ul><li>Etiology . The hepatitis A virus is a single-stranded, positive-sense, linear RNA enterovirus and a member of the Picornaviridae family. The hepatitis A virus is an icosahedral nonenveloped virus measuring approximately 28 nm in diameter. </li></ul>Hepatitis A virus as viewed through electron microscopy.
  3. 3. Etiology <ul><li>Its resilience is demonstrated by its resistance to denaturation by ether, acid (pH 3.0), drying, and temperatures as high as 56°C and as low as -20°C. The hepatitis A virus can remain viable for many years. Boiling water is an effective means of destroying it, and chlorine and iodine are similarly effective. Various genotypes of the hepatitis A virus exist; however, there appears to be only 1 serotype. Virion proteins 1 and 3 are the primary sites of antibody recognition and subsequent neutralization. No antibody cross-reactivity has been identified with other viruses causing acute hepatitis. </li></ul>Hepatitis A
  4. 4. Epidemiology <ul><li>Acquisition results almost exclusively from ingestion (ie, fecal-oral transmission), although isolated cases of parenteral transmission have been reported. Humans appear to be the only reservoir for the hepatitis A virus. Person-to-person contact is the most common means of transmission and is generally limited to close contacts. Transmission through blood products has been described. The hepatitis A virus has a worldwide distribution. The highest seropositivity (antibody to hepatitis A virus) is observed in adults in urban Africa, Asia, and South America, where evidence of past infection is nearly universal. Acquisition in early childhood is the norm in these nations and is usually asymptomatic. </li></ul>
  5. 5. Epidemiology <ul><li>Factors predisposing humans to early acquisition include overcrowding, poor sanitation, certain social practices, and lack of a reliable clean water resource. Within the socioeconomic framework (ie, class structure) of some developing nations are differing frequencies of hepatitis A virus antibody in the older population; accordingly, sporadic cases may be observed in some individuals. The period of greatest shedding of the hepatitis A virus is during the anicteric prodrome (14-21 d) of infection and corresponds to the time when transmission is highest. Recognizing that the active virus is shed after the development of jaundice is important, although amounts fall rapidly . </li></ul>
  6. 6. Epidemiology Hepatitis A. Time course of infection.
  7. 7. Its resilience is demonstrated by its resistance to denaturation by ether, acid (pH 3.0), drying, and temperatures as high as 56°C and as low as -20°C. The hepatitis A virus can remain viable for many years. Boiling water is an effective means of destroying it, and chlorine and iodine are similarly effective. Various genotypes of the hepatitis A virus exist; however, there appears to be only 1 serotype. Virion proteins 1 and 3 are the primary sites of antibody recognition and subsequent neutralization. No antibody cross-reactivity has been identified with other viruses causing acute hepatitis. Epidemiology
  8. 8. Most patients have no defined risk factors for hepatitis A. Risk factors for acquisition of hepatitis A include the following: Personal contacts; Institutionalization; Occupation (eg, daycare); Foreign travel; Male homosexuality; Illicit parenteral drug use; Persons in high-risk populations (eg, sewage workers, childcare workers, aid workers, male homosexuals). Epidemiology
  9. 9. In humans, viral replication depends on hepatocyte uptake and synthesis, and assembly occurs exclusively in liver cells. Hepatocyte uptake involves a receptor, identified by Kaplan et al, on the plasma membrane of the cell, and viral replication is believed to occur exclusively in hepatocytes. The demonstration of the hepatitis A virus in saliva has raised questions about this exclusivity. After entry into the cell, viral RNA is uncoated, and host ribosomes bind to form polysomes. Viral proteins are synthesized, and the viral genome is copied by a viral RNA polymerase. Assembled virus particles are shed into the biliary tree and excreted in the feces Pathogenesis
  10. 10. Pathogenesis Hepatitis A.
  11. 11. Minimal cellular morphologic changes result from hepatocyte infection. The development of an immunologic response to infection is accompanied by a predominantly portal and periportal lymphocytic infiltrate and varying degree of necrosis. Many authorities believe that hepatocyte injury is secondary to the host's immunologic response. This hypothesis is supported by the lack of cytotoxic activity in tissue culture and correlations between immunologic response and manifestations of hepatocyte injury. Pathogenesis
  12. 12. Signs and symptoms <ul><li>The incubation period is 2-6 weeks, with a mean of 4 weeks. Shorter incubation periods may result from higher total dose of viral inoculum. </li></ul><ul><li>Prodrome. </li></ul><ul><ul><ul><li>Patients may have mild flulike symptoms of anorexia, nausea and vomiting, fatigue, malaise, low-grade fever (usually <39.5°C), myalgia, and mild headache. </li></ul></ul></ul><ul><ul><ul><li>Smokers often lose their taste for tobacco, similar to those presenting with appendicitis. </li></ul></ul></ul>
  13. 13. Signs and symptoms <ul><li>Icteric phase. </li></ul><ul><li>Dark urine appears first (bilirubinuria). </li></ul><ul><li>Pale stool soon follows, although this is not universal. </li></ul><ul><li>Jaundice occurs in most (70-85%) adults with acute hepatitis A virus infection. </li></ul><ul><li>Abdominal pain occurs in approximately 40% of patients. </li></ul><ul><li>Itch (pruritus), although less common than jaundice, is generally accompanied by jaundice. </li></ul><ul><li>Arthralgias and skin rash, although associated, are less frequent than the above symptoms. Rash more often occurs on the lower limbs and may have a vasculitic appearance. </li></ul>Man with jaundice
  14. 14. Physical examination <ul><li>The physical examination focuses on detecting features to support a diagnosis of acute hepatitis and should include assessment for features of chronic liver disease or similarly assessment for evidence of decompensation. Hepatomegaly is common. Jaundice or scleral icterus may occur. Patients may have a fever with temperatures of up to 40°C. </li></ul>
  15. 15. Differential diagnoses <ul><li>The differential diagnosis for acute hepatitis A virus infection is acute hepatitis E virus infection. Both viruses have a similar clinical presentation, are common in the third world, and have the same mode of transmission. Dual infection is believed to occur. Other problems to be considered: cytomegalovirus, acute drug-induced liver injury. </li></ul>
  16. 16. Diagnosis <ul><li>Anti-hepatitis A virus immunoglobulin M. </li></ul><ul><li>The diagnosis of acute hepatitis A virus infection is based on serologic testing for IgM antibody to the hepatitis A virus. Test results for anti-hepatitis A virus IgM are positive at the time of onset of symptoms and usually accompany the first rise in alanine aminotransferase (ALT) level. This test is sensitive and specific, and the results remain positive for 3-6 months after the primary infection and for as long as 12 months in 25% of patients. </li></ul>
  17. 17. Diagnosis <ul><li>Anti-hepatitis A virus immunoglobulin G. </li></ul><ul><li>Anti-hepatitis A virus IgG appears soon after IgM and generally persists for many years. </li></ul><ul><li>The presence of anti-hepatitis A virus IgG in the absence of IgM indicates past infection or vaccination rather than acute infection. </li></ul><ul><li>IgG provides protective immunity. </li></ul>
  18. 18. Diagnosis <ul><li>Liver enzymes. </li></ul><ul><li>Rises of levels in ALT and aspartate aminotransferase (AST) assays are sensitive for this disease. Levels may exceed values of 10,000 mIU/mL, with ALT levels generally greater than AST levels. Levels usually return to reference ranges over 5-20 weeks. </li></ul><ul><li>Rises in alkaline phosphatase accompany the acute disease and may progress during the cholestatic phase of the illness following the rises in transaminase levels. </li></ul>
  19. 19. Diagnosis <ul><li>Hepatic synthetic function. </li></ul><ul><li>Bilirubin level rises soon after the onset of bilirubinuria and follows rises in ALT and AST levels. Levels may be impressively high and can remain elevated for several months; persistence beyond 3 months indicates cholestatic hepatitis A virus infection. </li></ul><ul><li>Older individuals have higher bilirubin levels. </li></ul><ul><li>Both direct and indirect fractions increase because of hemolysis, which often occurs in acute hepatitis A virus infection. </li></ul><ul><li>Modest falls in serum albumin level may accompany the illness. </li></ul>
  20. 20. Diagnosis <ul><li>Prothrombin time. </li></ul><ul><li>Prothrombin time usually remains within or near the reference range. Significant rises should raise concern and support closer monitoring. </li></ul><ul><li>In the presence of encephalopathy, an elevated prothrombin time has ominous implications (eg, fulminant hepatic failure). </li></ul>
  21. 21. Treatment <ul><li>For acute cases of hepatitis A virus infection, therapy is generally supportive, with no specific treatment of acute uncomplicated illness. Initial therapy often consists of bed rest. The patient should probably not work during the acute phase of the illness. </li></ul><ul><li>Nausea and vomiting are treated with antiemetics. </li></ul><ul><li>Dehydration may require hospital admission and intravenous fluids. </li></ul>
  22. 22. Prevention. <ul><li>People with chronic liver disease of any cause should consider hepatitis A vaccination. Hepatitis A vaccine is used for active immunization against disease caused by hepatitis A virus. </li></ul><ul><li>Hepatitis A vaccine, inactivated, and hepatitis B vaccine (Twinrix) - for active immunization of persons >18 years against disease caused by hepatitis A virus and infection by all known subtypes of hepatitis B virus. Adult dose: 0.5 mL IM; repeat at 1 and 6 mo. </li></ul><ul><li>Hepatitis A vaccine, inactivated (Havrix, Vaqta) - may be administered with immunoglobulin injections without affecting efficacy. Adult dose: Havrix: 1440 U IM once; booster dose at 6-12 mo. Vaqta: 50 U IM once; booster dose at 6 mo. </li></ul>
  23. 23. Prevention. <ul><li>Postexposure prophylaxis is recommended for nonimmunized close contacts of those recently diagnosed with acute hepatitis A virus infection. </li></ul><ul><li>Immune globulins </li></ul><ul><li>Immune globulin, intramuscular - adult dose: 0.02-0.06 mL/kg IM for exposed contacts or individuals traveling to areas for up to 6 mo; use higher dose if subject will be in the area for up to 6 mo (ie, where hepatitis A is common). 0.06 mL/kg IM q4-6mo for travelers staying > 3 mo. </li></ul>
  24. 24. Complications <ul><li>Generally, hepatitis A virus infection elicits no lasting sequelae. Death is rare, occurring in fewer than 0.2% of cases. Death is more frequent in elderly patients and in those with underlying liver disease. </li></ul>
  25. 25. Prognosis <ul><li>Prognosis is excellent. Long-term immunity accompanies hepatitis A virus infection. Recurrence and chronic hepatitis do not usually occur. </li></ul>
  26. 26. Hepatitis E <ul><li>Definition </li></ul><ul><li>Hepatitis E virus (HEV) is an enterically transmitted self-limited infection. It has many similarities with hepatitis A. </li></ul><ul><li>Etiology </li></ul><ul><li>HEV is icosahedral and nonenveloped. It has a diameter of approximately 34 nanometers and contains a single strand of RNA approximately 7.5 kilobases long. </li></ul>
  27. 27. Hepatitis E
  28. 28. Epidemiology <ul><li>Hepatitis E is spread by fecally contaminated water within endemic areas. Outbreaks can be epidemic and individual. It has worldwide distribution, but predominating factors include tropical climates, inadequate sanitation, and poor personal hygiene. It is found most often in developing countries near the equator, in both the Eastern and Western hemispheres. Outbreaks are associated with rainy seasons, floods, and overcrowding. It predominantly affects those aged 15-40 years. It may affect younger age groups but generally is not recognized and may be subclinical. Although predilection is unknown, pregnant women are prone to complications. No chronic cases have been described. </li></ul>
  29. 29. Patho genesis <ul><li>The HEV genome contains 3 open reading frames (ORFs). The largest, ORF-1, codes for the nonstructural proteins responsible for viral replication. ORF-2 contains genes encoding the capsid. The function of ORF-3 is unknown, but the antibodies directed against ORF-3 epitopes have been identified. </li></ul>
  30. 30. Patho genesis
  31. 31. Pathology <ul><li>The pathology picture is cholestatic, with stasis of canalicular bile and marked proliferation of intralobular bile ductules. The cholestasis is most notable within the centroacinar regions. Parenchymal changes are less severe and include swollen hepatocytes, foam cells, and acidophil bodies. Inflammatory infiltrate of mononuclear cells is present, resulting in expanded portal areas and possible piecemeal necrosis. </li></ul>
  32. 32. Signs and symptoms <ul><li>The incubation period ranges from 15 days to 60 days, and the course of infection has 2 phases termed prodromal and icteric. </li></ul><ul><li>Prodromal-phase symptoms include the following: </li></ul><ul><ul><li>Myalgia; </li></ul></ul><ul><ul><li>Arthralgia; </li></ul></ul><ul><ul><li>Fever with mild temperature elevations; </li></ul></ul><ul><ul><li>Anorexia; </li></ul></ul><ul><ul><li>Nausea/vomiting; </li></ul></ul><ul><ul><li>Weight loss; </li></ul></ul><ul><ul><li>Dehydration; </li></ul></ul><ul><ul><li>Right upper quadrant pain that increases with physical activity. </li></ul></ul>
  33. 33. Signs and symptoms <ul><li>Icteric-phase symptoms include the following: </li></ul><ul><ul><li>Jaundice - may be difficult to see with some patients’ natural skin color; serum bilirubin level is greater than 3 mg/dL; scleral icterus is present; </li></ul></ul><ul><ul><li>Dark urine; </li></ul></ul><ul><ul><li>Light-colored stools; </li></ul></ul><ul><ul><li>Pruritus. </li></ul></ul>Yellow discoloration of eyes
  34. 34. Signs and symptoms <ul><li>Other features include the following: </li></ul><ul><ul><li>Urticarial rash; </li></ul></ul><ul><ul><li>Diarrhea; </li></ul></ul><ul><ul><li>Rapidly increasing serum amino transferase (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) levels that peak within 4-6 weeks of onset and gradually decrease to normal within 1-2 months; </li></ul></ul><ul><ul><li>Viral excretion in stool persisting 14 days from onset. </li></ul></ul>
  35. 35. Signs and symptoms <ul><li>Symptoms of HEV are similar to other hepatitides and include the following: </li></ul><ul><ul><li>Abdominal pain; </li></ul></ul><ul><ul><li>Jaundice; </li></ul></ul><ul><ul><li>Anorexia; </li></ul></ul><ul><ul><li>Hepatomegaly; </li></ul></ul><ul><ul><li>Malaise; </li></ul></ul><ul><ul><li>Vomiting. </li></ul></ul><ul><ul><li>When or how long the patient is infectious cannot be determined, but infectivity may relate to the presence of the virus in the stool. </li></ul></ul>
  36. 36. Differential diagnoses <ul><li>The differential diagnoses for acute hepatitis E are viral hepatitis A, viral hepatitis B, viral hepatitis C, viral hepatitis D. Other problems to be considered: isoniazid hepatotoxicity, recurrent pyogenic cholangitis. </li></ul>
  37. 37. Laboratory Studies <ul><li>Western blot and enzyme immunoassays detect anti-HEV antibodies by using the antigenic domains from ORF-2 and ORF-3. Assays of ORF-2 are more sensitive. Testing to detect anti-HEV immunoglobulin M (IgM) and immunoglobulin G (IgG) differentiates acute and chronic infection. The IgM titer falls rapidly after infection, becoming virtually undetectable within 6 months. Anti-HEV IgG persists for longer than 6 months, although its actual duration of positivity is unknown. IgG anti-HEV appears to afford protection against reinfection. </li></ul>
  38. 38. Laboratory Studies <ul><li>Serum, liver, and stool samples can be tested for HEV RNA with a polymerase chain reaction assay. These tests are not available commercially. </li></ul><ul><li>Aminotransferase levels (AST, ALT) are elevated several days before the onset of symptoms but generally return to normal within 1-2 months after the peak severity of the disease has passed. Elevations can be associated with underlying liver disease or exposure to other hepatotoxins. Whether the magnitude of elevation correlates with the histological severity is not clear. </li></ul>
  39. 39. Laboratory Studies <ul><li>Serum bilirubin elevations occur in both the total and direct fractions. Hemolysis is unusual. In most cases, bilirubin levels take longer to return to normal than aminotransferase levels. </li></ul><ul><li>Many patients develop a mild leukocytosis. If associated with fever, bacteremia should be suspected. More commonly, WBC counts are decreased. Differential counts may show atypical cells and lymphocytosis. </li></ul>
  40. 40. Treatment . <ul><li>Therapy should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. </li></ul><ul><li>Once infection occurs, therapy is limited to support. Provide patients with adequate hydration and electrolyte repletion. Hospitalization is indicated only for patients unable to maintain oral intake. </li></ul>
  41. 41. Prevention. <ul><li>Travelers to endemic areas should avoid drinking water or other beverages that may be contaminated and should avoid eating uncooked shellfish. Care should be taken while preparing uncooked fruits or vegetables. Boiling water may prevent infection, but the effectiveness of chlorination is unknown. </li></ul><ul><li>No immunoprophylaxis is available. Immunoglobulin from infected patients is not effective in preventing outbreaks or sporadic cases. </li></ul>
  42. 42. Prognosis <ul><li>No chronic cases of acute hepatitis E have been reported. The infection is self-limited. Whether protective immunoglobulins develop against future reinfection remains unknown. </li></ul>
  43. 43. Thank you for your attention!