1.Chronic hepatitis Hepatic inflammation and necrosis for more than 6 monthswww.medicinemcq.com1

2. Chronic HBV infection Hepatitis B surface antigenemia for six months or more.www.medicinemcq.com2 3. Risk of chronic infection Related to two major factors Age at which infection is acquired Immune state of the host.www.medicinemcq.com3 4. Piecemeal necrosis Also called interface hepatitis disruption of the limiting plate of periportal hepatocytes by inflammatory cells. Progression to cirrhosis is not common. www.medicinemcq.com4 5. Bridging necrosismay progress to cirrhosis.www.medicinemcq.com5 6. Classification of chronic hepatitis depends on three features. (1) cause (2) grade ( histologic activity) (3) stage ( degree of progression). www.medicinemcq.com6 7. Grading of chronic hepatitis Portal tract inflammation 0 = none. 4 = severe limiting plate necrosis Hepatic lobule inflammation 0 = none 4 = bridging necrosis www.medicinemcq.com7 8. Staging based on the degree of fibrosis. 0 - no fibrosis. 1 - mild fibrosis. 2 - moderate fibrosis. 3 - severe fibrosis, including bridging fibrosis. 4 cirrhosis. www.medicinemcq.com8 9. Piecemeal necrosis Also called interface hepatitis erosion of the limiting plate of hepatocytes surrounding the portal triads. www.medicinemcq.com9 10. Chronic active hepatitis Piecemeal necrosis is always present dense mononuclear infiltrate of the portal tracts. Portal inflammation extends beyond the limiting plate into the hepatic parenchyma. destruction of the hepatocytes at the periphery of the lobule. www.medicinemcq.com10 11. Bridging hepatic necrosis severe and progressive form of chronic active hepatitis. Collapse of the reticulin network is the hallmark of bridging necrosis. www.medicinemcq.com11 12. Chronic persistent hepatitis Mononuclear inflammatory infiltrate is contained within portal tracts. no extension of the necroinflammatory process into the liver lobule. no piecemeal or bridging necrosis Cirrhosis does not develop. www.medicinemcq.com12 13. Chronic active hepatitis Piecemeal necrosis is always present dense mononuclear infiltrate of the portal tracts. Portal inflammation extends beyond the limiting plate into the hepatic parenchyma. destruction of the hepatocytes at the periphery of the lobule. www.medicinemcq.com13 14. Chronic active hepatitis Bridging hepatic necrosis is a severe and progressive form of chronic active hepatitis. Collapse of the reticulin network is the hallmark of bridging necrosis. www.medicinemcq.com14 15. Fibrosis common and progressive. continuing hepatic necrosis. leads to cirrhosis, liver failure, and death. Physical findings of chronic liver disease and portal hypertension are common www.medicinemcq.com15 16. Histologic hallmarks of chronic active hepatitis 1. Portal and periportal infiltrate of lymphocytes, plasma cells, and macrophages 2. piecemeal necrosis 3. Bridging necrosis 4. may progress to cirrhosis. www.medicinemcq.com16 17. Ground glass hepatocytes Seen in Chronic Hepatitis B best seen by aldehyde fuschin or orcein stain. www.medicinemcq.com17 18. neonatally acquired infection risk of chronicity is very high (up to 90%). neonates have an immature immune system. transplacental passage of viral proteins. fetus becomes tolerant to HBV in utero. www.medicinemcq.com18 19. Risk of chronicity after acute HBV infection about 1%. Most cases of chronic hepatitis B in adults occur in patients who never had a clinically apparent acute viral hepatitis. Chronic disease only rarely present as nonresolution of acute hepatitis B. www.medicinemcq.com19 20. Risk of chronicity increased in chronic hemodialysis exogenous immunosuppression following solid organ transplantation cancer chemotherapy www.medicinemcq.com20 21. concomitant HIV infection.20% 30% remain HBsAg positive after acute infection. www.medicinemcq.com21 22. Children < 6 years significant risk of chronic infection (approximately 30%). www.medicinemcq.com22 23. Lysis of liver cells depends on the host immune response. good immune response clears the virus (acute hepatitis). poor immune response - healthy carrier state slightly better response insufficient to clear the virus but cause continuing necrosis. www.medicinemcq.com23 24. very aggressive immune response Fulminant hepatitis HBV infected hepatocytes are destroyed HBV is completely cleared from the body High mortality no future risk of cirrhosis in survivors. www.medicinemcq.com24 25. healthy carriers normal serum aminotransferase normal or near-normal liver histologic findings no symptoms immunologically tolerant of the virus prognosis is excellent www.medicinemcq.com25 26. Symptom Chronic hepatitis Fatigue - common symptom. Persistent or intermittent jaundice is a common feature in severe or advanced cases. Exacerbations occur spontaneously. associated with evidence of virologic reactivation. www.medicinemcq.com26 27. end-stage chronic hepatitis. Complications of cirrhosis 1. 2. 3. 4. 5.Ascites Bleeding varices Hepatic encephalopathy Coagulopathy Hypersplenism. www.medicinemcq.com27 28. extrahepatic complications of chronic HBV Arthralgias - due to deposition of circulating hepatitis B antigenantibody immune complexes Purpuric cutaneous lesions - due to leukocytoclastic vasculitis Glomerulonephritis - Immunecomplex PAN - result of generalized vasculitis www.medicinemcq.com28 29. Hyperglobulinemia and circulating autoantibodies uncommon in chronic hepatitis B. This is in contrast to autoimmune hepatitis. www.medicinemcq.com29 30. ALT more elevated than aspartate aminotransferase ( as in acute viral hepatitis B) Once cirrhosis is established, AST tends to exceed ALT. Alkaline phosphatase - normal or only marginally elevated. www.medicinemcq.com30 31. IFN All human cells can synthesize IFN-a or -b in response to viral infection. IFN-g is produced mainly by NK cells and by T lymphocytes responding to IL-12. www.medicinemcq.com31 32. IFN response induced by the presence of double-strand viral RNA, which can be made by both RNA and DNA viruses. IFN receptors signal through receptor-associated JAK kinases and "STAT" proteins. www.medicinemcq.com32 33. IFN - 3 antiviral effects Induction of 1.oligo(A) synthetases 2.PKR. 3.Mx proteins. www.medicinemcq.com33 34. Induction of oligo(A) synthetases result in the activation of RNAse L. RNAse L degrades single-strand RNA. www.medicinemcq.com34 35. Induction of PKR PKR negatively regulates the translational initiation factor eIF2a. This stops protein synthesis in the infected cell. IFN effects are not virus specific. Infected-cell RNA and protein synthesis are globally inhibited. IFN may contribute to the death of the infected cell. www.medicinemcq.com35 36. Induction of Mx proteins Mx proteins are particularly important in inhibiting influenza virus and vesicular stomatitis virus replication. www.medicinemcq.com36 37. Lamivudine directly block HBV replication converted intracellularly into its active triphosphorylated form. potent inhibitor of the HBV reverse transcriptase. www.medicinemcq.com37 38. Lamivudine 5triphosphate causes chain termination of the elongating nucleic acid strand. poor substrate for both nuclear and mitochondrial DNA polymerases. Therefore, lamivudine has a good safety profile. www.medicinemcq.com38 39. HIV and HBV Lamivudine inhibits reverse transcriptase activity of both HIV and HBV. Anti-Hbe seroconversion occur in up to 20 %. Histological improvement is seen in up to 50%. www.medicinemcq.com39 40. Interferon and lamivudine are equally effective. Interferon requires requires subcutaneous injections for 4 months. Interferon is not tolerated well. www.medicinemcq.com40 41. Lamivudine is preferred as first-line therapy. Side effects of lamivudine are negligible. Lamivudine is given orally very well tolerated. www.medicinemcq.com41 42. Resistance is the major problem HBV has a high rate of viral turnover. HBV reverse transcriptase very much error prone www.medicinemcq.com42 43. Adefovir inhibitor of the viral polymerase. inhibits the replication of lamivudine-resistant HBV mutants. www.medicinemcq.com43 44. HBV - NEW ANTIVIRAL DRUGS Tenofovir adenine nucleotide analogue has activity against the HBV polymerase. Entecavir guanosine analogue highly selective for the HBV polymerase no activity against HIV. active against lamivudine-resistant HBV. www.medicinemcq.com44 45. L-deoxythymidine thymidine analogue selectively inhibits the HBV polymerase active against lamivudine-resistant virus. www.medicinemcq.com45 46. Emtricitabine and Clevudine nucleoside analogues not reliably active against all lamivudineresistant variants.www.medicinemcq.com46 47. HCV major cause of chronic hepatitis Cirrhosis HCC Most common indication for liver transplantation. www.medicinemcq.com47 48. chronic infection HCV produce chronic infection in 90 % of infected persons despite a vigorous humoral and cellular host immune response. www.medicinemcq.com48 49. 2 different cellular receptors for HCV 1. low-density lipoproteins 2. CD81 cell surface protein called tetraspanin expressed on most human cells, except red blood cells and platelets. www.medicinemcq.com49 50. The two main risk factors.1.Blood transfusion from unscreened donors 2.injection drug use www.medicinemcq.com50 51. Liver histology Best prognostic indicator in chronic hepatitis C www.medicinemcq.com51 52. excellent prognosis.Mild necrosis, inflam mation, and limited fibrosis www.medicinemcq.com52 53. septal or bridging fibrosisWhen present, progressi on to cirrhosis is highly likely over 20 years. www.medicinemcq.com53 54. Long-term prognosis for chronic hepatitis C is good. 60% = asymptomatic. very slowly progressive, if at all, in the vast majority 25 % = progress to endstage cirrhosis. www.medicinemcq.com54 55. not predictive of prognosis. Level of HCV RNA Severity of acute hepatitis level of aminotransferase activity presence or absence of jaundice www.medicinemcq.com55 56. Hepatic iron Progression is more likely when hepatic iron is increased. www.medicinemcq.com56 57. Duration of infectionProgression is more likely . www.medicinemcq.com57 58. Factors that accelerate clinical progression alcohol intake - pronounced effect coinfection with HIV-1 or HBV male sex older age at infection. www.medicinemcq.com58 59. Fatigue Most common symptom of chronic hepatitis C www.medicinemcq.com59 60. Other nonspecific symptoms Depression Nausea Anorexia Abdominal discomfort Difficulty with concentration. www.medicinemcq.com60 61. chronic hepatitis in 85% majority of these will have elevated or fluctuating serum ALT levels one third has persistently normal ALT values, despite continued liver injury and detectable viremia. www.medicinemcq.com61 62. HCV infection is selflimiting in only 15%. In these patients HCV RNA in serum becomes undetectable and ALT levels return to normal.www.medicinemcq.com62 63. Jaundice rarely seen in chronic HCV infection until hepatic decompensation has occurred. Acute infection is only rarely seen vast majority of patients have no clinical symptoms. Fulminant hepatitis is rare. www.medicinemcq.com63 64. HCV RNA appears in the blood within 2 weeks of exposure followed by an increase in serum aminotransferase levels several weeks later. www.medicinemcq.com64 65. Essential mixed cryoglobulinemia most common immune-complex mediated extrahepatic complication. www.medicinemcq.com65 66. Cryoglobulins found in 50% of patients infected with HCV. www.medicinemcq.com66 67. Clinical symptoms develop in only 25% Arthritis Purpura Raynauds phenomenon Vasculitis Peripheral neuropathies Glomerulonephritis. www.medicinemcq.com67 68. Extrahepatic manifestations 1. membranoproliferative glomerulonephritis 2. porphyria cutanea tarda 3. leukocytoclastic vasculitis 4. focal lymphocytic sialadenitis www.medicinemcq.com68 69. Extrahepatic manifestations 5.Mooren corneal ulcers 6.lichen planus 7.rheumatoid arthritis 8.non-Hodgkins lymphoma www.medicinemcq.com69 70. Membranoproliferative glomerulonephritis frequent extrahepatic disease Most affected patients also have essential mixed cryoglobulinemia. www.medicinemcq.com70 71. present with nephrotic syndrome nonnephrotic-range proteinuria renal insufficiency. Hypocomplementemia is frequent Positive rheumatoid factor common 10% - progress to end-stage renal failure www.medicinemcq.com71 72. PCR confirmatory test of choice. to monitor the effects of therapy. www.medicinemcq.com72 73. Serologic assays used for screening indicates exposure to the virus Does not differente between acute, chronic, and resolved infection.www.medicinemcq.com73 74. RIBA test two serologic tests enzyme immunoassay (EIA) recombinant immunoblot assay (RIBA). sensitivity of RIBA test is lower than that of EIAs, but their specificity is superior. www.medicinemcq.com74 75. Liver biopsy gold standard for determining the activity of HCVrelated liver disease. www.medicinemcq.com75 76. Histologic staging only reliable predictor of prognosis and the likelihood of disease progression. Liver biopsy is not mandatory before the initiation of treatment. www.medicinemcq.com76 77. Pegylated interferons interferon bound to polyethylene glycol. increases the half-life reduces the volume of distribution. www.medicinemcq.com77 78. Interferon indication detectable levels of HCV RNA who have persistently elevated alanine aminotransferase levels and a liver biopsy showing at least moderate fibrosis, necrosis and inflammation. www.medicinemcq.com78 79. excellent prognosis without therapy persistently normal alanine aminotransferase levels and only minimal histologic evidence of necrotic and inflammatory changes or changes. www.medicinemcq.com79 80. Pegylated interferons allows once-weekly dosing. sustain more uniform plasma levels. Therefore, there is enhanced viral suppression. www.medicinemcq.com80 81. Ribavirin causes hemolysis. Fall in hemoglobin of 3 gm occur in 5 to 10%. small percentage gets severe hemolysis. close monitoring of blood counts is important. www.medicinemcq.com81 82. Contraindication history of myocardial infarction or cardiac arrhythmia Because of the potential to cause a sudden fall in hemoglobin www.medicinemcq.com82 83. half-life long cumulative half-life. excreted by the kidney should not be used by patients with renal insufficiency severe side effects, particularly hemolysis, can occur www.medicinemcq.com83 84. Teratogenic Avoid pregnancy during therapy and for 6 months after cessation of treatment. Use contraception during therapy. pregnancy test is needed before initiating ribavirin therapy in women. www.medicinemcq.com84 85. Vaccination HCV-infected patients arevaccinated against HAV and HBV. high risk of severe liver disease if superinfection with these viruses occurs. www.medicinemcq.com85 86. HCV - prevention no effective vaccine no effective postexposure prophylaxis. www.medicinemcq.com86 87. pregnancy not contraindicated low rate of vertical transmission Breast-feeding is not contraindicated. www.medicinemcq.com87