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Chronic Viral Hepatitis:

Chronic Viral Hepatitis:. Associate Prof Dr Meltem Ergun Yeditepe University Department of Gastroenterology. Objective. To i dentify the etiologic agents of chronic viral hepatitis To understand the Pathophysiology , Clinical presentation D iagnosis , Evaluation and

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Chronic Viral Hepatitis:

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  1. Chronic Viral Hepatitis: AssociateProfDr Meltem Ergun Yeditepe University Department of Gastroenterology

  2. Objective • To identify the etiologicagents of chronicviralhepatitis • Tounderstandthe Pathophysiology, Clinicalpresentation Diagnosis, Evaluation and Management of chronicviralhepatitis

  3. Clinical Terms • Hepatitis: inflammation of liver; presence of inflammatory cells in the liver • Acute Viral Hepatitis: symptoms last less than 6 months • Chronic Hepatitis: Inflammation of liver for at least 6 months • Cirrhosis: a late stage of progressive hepatic fibrosis characterized by distortion of the hepatic architecture and the formation of regenerative nodules. • Fulminant Hepatitis: severe impairment of hepatic functions or severe necrosis of hepatocytes in the absence of preexisting liver disease

  4. Acute viral hepatitisetiologic agents

  5. Acute viral hepatitis • Hepatitis A • Hepatitis B • Hepatitis C • Hepatitis D • Hepatitis E

  6. Hepatitis A • Common cause of acute hepatitis • Single-stranded, positive-sense, linear RNA enterovirus (Picornaviridae) • Transmission fecal-oral route; Contaminated water and food • The incubation period of hepatitis A virus is 2-7 weeks, • AST & ALT levels usually return to reference ranges over 5-20 weeks. • High risk  Travellers: vaccinations; passive immunoglobins given to those exposed • Mild self-limited disease and confers lifelong immunity to hepatitis A virus. Chronic infection with hepatitis A virus does not occur. • HAV: IgM anti-HAV: positive at the time of onset of symptoms; results remain positive for 3-6 months after the primary infection • Treatment: supportive

  7. Hepatitis E • Hepatitis E virus (HEV) RNA virus of the genus Hepevirus • Enterically transmitted infection; fecal-oral route, typically self-limited • Most outbreaks occur in developing countries. • Symptoms of acute hepatitis • Incubation period of hepatitis E virus is 2-9 weeks • Case fatality rate is 4%Pregnancymortality ↑

  8. Clinical Evaluation: Acute Viral Hepatitis 1. Prodromal phase: • Patients experience anorexia, nausea, vomiting, alterations in taste, arthralgias, malaise, fatigue, urticaria, and pruritus. Some develop an aversion to cigarette smoke. • When seen by a health care provider during this phase, patients are often diagnosed as having gastroenteritis or a viral syndrome. 2. Icteric Phase • Jaundice, Patients may note dark urine, followed by pale-colored stools. • In addition to the predominant gastrointestinal symptoms and malaise, patients become icteric and may develop right upper quadrant pain with hepatomegaly. • Severe cases may result in Fulminant Hepatitis: • Hepatic Encephalopathy: B/L asterixis, palmar erythema • Hepatorenal syndrome • Bleeding diathesis

  9. Chronic Hepatitis • HBV • HCV • HDV

  10. Hepatitis: B & D

  11. Hepatitis B(HBV)--EPIDEMIOLOGY • HBV is a DNA virus that belongs to the hepadnavirus family. • 1/3 of population of the World has had hepatitis B infection. • 400 million people are chronic  HBV carriers. • HBV is the cause of 60% to 80% of worldwide Hepatocellular Carcinoma(HCC). • 500,000 to 1 million deaths worldwide are attributed to it. • 5% to 10% of all liver transplants are attributed to HBV. • InTurkey %80 transplants are attributed to HBV.

  12. Risk Groups • IV drug users • People receiving multiple blood transfusions • Sexual promiscuity • People in contact with HBV carriers • Travelers to endemic areas of South America, Southern Asia, and Africa • Resident and employees of residential care facilities • Health Care Workers

  13. Pathophysiology Transmission 3 main ways: • Parenterally/percutaneous route----IV Drug Users, needle sticks, Hemodialysis patients • Sexually • Vertical/ Perinatal route (TURKEY)

  14. Serology HBsAgsurfaceantigen • Present in acute or chronic infection • Detectable 1 to 2 weeks after infection HBeAg • Appears shortly after HBsAg • Indicates viral Replication and Infectivity HBsAB(Anti-HBS) • Present after vaccination or clearance of HBsAg(Usually 1 to 3 months) • Indicates immunity to HBV Hb core Antibody  (IgM anti-Hbc or IgG anti-HBc) • Only Serological marker of HBV during "Window Period"

  15. Inactivecarrierevery 6 months ALT AFP USG HBV DNA HBV DNA <2000 Hbsag+ HBV DNA >2000 Chronic hepatitis B bxandtreatment Hbe ag - HBV DNA >2000 Immune tolerant phase Hbe ag +

  16. Clinical Presentation Acute Hepatitis B - less than 6 months; Based on significant aminotransferase activity due to necro inflammatory injury •  Symptoms are often non-specific symptoms such as myalgia, malaise , nausea, fatigue , pruritus, abdominal pain, RUQ, jaundice •  Fulminant Hepatitis--Acute HBV results in Liver Failure Chronic Hepatitis B - greater than 6 months; Based  on grade, stage, and etiology. Fibrosis and Necroinflammatory processes; can last for  decades • Immune tolerant--High viral replication, NL liver enzymes, low inflammation and fibrosis. Seen in children or those affected early in life. • Immune active--High Liver enzymes and High HBV DNA and HBeAg, Active Replication • Carrier State with low replication • Seroconversion from HBeAg to HBeAB • Low HBV levels, NL liver enzymes, Reduced Liver inflammation • Low risk for developing of HCC

  17. Clinical Presentation cont. Chronic HbeAg negative • HBV DNA high, Liver enzymes high, No HbeAg • Seen in late phase of HBV Resolution • Viral clearance of HBV DNA

  18. Diagnosis • Serology • Liver Chemistry tests • AST, ALT, ALP, and total Bilirubin • Histology--Immunoperoxidase staining • HBV Viral DNA--Most accurate marker of viral REPLICATION • Liver Biopsy--to determine grade(Inflammation) and stage(Fibrosis) in chronic Hepatitis

  19. Progression • Incubation Period:  30-180 days • Acute HBV Infection:  90% resolve by themselves; less than 1% develop fulminant hepatitic failure • Chronic HBV Infection: 2-10% progress to chronic state • 90% in children less than five progress to chronic state • Risk of Liver  Cirrhosis:  5 year accumulation risk of 8% to 20% • 5% to 10% of people progress to HCC with or without preceding cirrhosis; less than 5%  achieve  a chronic carrier state

  20. Treatment • StrongAgents: • Entecavir – 1st line • 0.5 to 1mg PO • very effective; low resistance and greater than 90%  HBV DNA clearance rate in HBeAG positive Px's. • more effective than lamivudine • Tenofovir: • Dose: 300mg qd • Highly effective with low resistance • Well tolerated Nucleoside Analogues -- Lamivudine, Entecavir, Telbivudine Method of action is the inhibition of viral reverse transcriptase • WEAK AGENTS: • Lamivudine • Dose :  100 mg PO q daily • Good for reducing the risk of progression to hepatic decompensation in patients with cirrhosis or advanced fibrosis • Pregnancy category B--Not teratogenic in animal studies and successful use with pregnant women • Problem: High rates of resistant mutations • Telbivudine • Dose: 600mg q daily • Worse resistant profile than Entecavir Interferon: Not very effective in Genotype B

  21. Prophylaxis HBV Vaccine • Indicated for everyone and especially those in high risk groups • IM injection at 0,1,6 months in infants and adults • Response greater than 90% after 3rd dose HBV Pregnant Mothers • Give 1st dose of Hip B vaccine and Hip B Immunoglobulin(HBIG)  o.5 ml within 12 hours of birth. • 2nd dose at 1 month, 3rd at 6 months • Recheck at 12 months for active infection • 95% lifetime immunity • Not Done---leads to 90% chronic HBV • Transmitted through birth canal  during birth or through umbilical cord. Others i.e. those receiving a needle stick • Should receive 0.04 to 0.7 ml/kg  of HBIG and 1st dose vaccine within 48  and no later than a week.

  22. Transplant • Last resort for  those with advanced Liver Disease and HCC due to infection 

  23. HEPATITIS D Transmission • Only as co-infection with acute HBV or with superinfection in chronic HBV carrier • Requires outer envelope of HBsAGfor replication and transmission • Can progress to chronic disease • Incubation Period 30to 150 days Serology • Hepatitis D antibody  (Anti-HDV) • Indicates HDV superinfection • Ab not always present in acute infection---requires repeat testing

  24. HEPATITIS D Risk Factors - Same high risk groups as those for Hip B Prevention - Avoidance of Hip B and/or Hip B vaccine DX - HDV antigen in serum or finding Ab to HDV antigen Clinical • Coinfection-self limited • Superinfection-acute HBV carriers present with severe acute hepatitis infection  w/ increased risk for HDV infection. Fatality Rate - 2% to 10% Cirrhosis – Fast TX:IFN-alpha

  25. A hepatitis panel is ordered for a 27 year old female as part of a routine workup for abdominal pain. Results of serological testing a negative for HBeAg - and HBsAg -, HBsAb + and IgG HBcAb +. The patient has been exposed to Hep B. • Patient has recovered • Patient is in acute infective disease state • Window period • Chronically infected • Patient was never infected

  26. Imaging Studies • No specific imaging studies needed for diagnosis • Obtain the appropriate diagnostic imaging studies (eg, ultrasound, CT) if the differential diagnosis favors gallbladder disease, biliary obstruction, or liver abscess. Liver biopsy usually in cases of: o The diagnosis is uncertain. o Other coinfections or disease may be present. o The patient is immunocompromised. o Asses severity of chronic hepatitis B or chronic hepatitis C. Histologic Findings Lymphocytic infiltration, moderate degrees of inflammation and necrosis, and portal or bridging fibrosis are noted. Regenerative nodules are seen in patients with cirrhosis.

  27. LFT: Elevation of serum transaminases not diagnostic, but useful • ALT elevated more than AST • Acute Hepatitis: ALT > 1000 • Chronic HCV: ALT is generally x1,5-2 ULN • * Urine analysis: presence of bilirubin. • * Serum bilirubin: Total bilirubin may be elevated in infectious hepatitis. Bilirubin levels higher than 30 mg/dL indicate more severe disease. • * Alkaline phosphatase: if elevated significantly, consider abscess or biliary obstruction. • * Prothrombin time (PT) if prolonged  impaired synthetic function of the liver. • * BUN & serum creatinine  decreased renal function suggests fulminant hepatic disease. • * Serum ammonia in patients with AMS or other evidence of hepatic encephalopathy. • * CBC: lymphocytosis Lab Studies:

  28. Hepatitis C • Spherical, enveloped, single-stranded RNA virus (Flavivirus genus) • Incubation period: 7-8 wks • 170 million infected worldwide • Major cause of chronic hepatitis in U.S. • More common in Hispanic, AA population; females have better outcome • Parenteral Transmission: IV drug users • Most common indication for liver transplantation

  29. Clinical Evaluation: Chronic Hepatitis C • Occurs after acute Hepatitis in >80% of people with HCV • Some are asymptomatic, or have mild symptoms; others may only present with late complications (cirrhosis/HCC) • Categorized based on grade of inflammation, stage of fibrosis, and etiology of disease

  30. Hepatitis C • Usually clinically mild, does not cause significant acute illness • Fluctuating elevations of AST & ALT • 20% likelihood of developing cirrhosis • 50% likelihood of developing chronic hepatitis • Incubation period: 15-150 days, with symptoms developing anywhere from 5-12 weeks after exposure.

  31. Diagnosis: HCV • HCV: Anti-HCV; cannot distinguish acute from chronic infection • may appear 3 – 5 months after infection PCR: used to detect viral RNA  HCV 80% of cases: patients are asymptomatic and do not develop icterus. Treatment: Interferon alpha, Ribavirin; PEG-IFNs (better sustained absorption, a slower rate of clearance, and a longer half-life than those of unmodified IFN) +protease± polymerase inhibitors (sofosbuvir+simeprevir)

  32. A 61 yo F is brought to the ER, drowsy and disoriented, only able to follow simple commands. On PE, her abdomen is distended and non-tender and she is jaundiced. In her purse, the physician finds prescriptions for peginterferon and ribavirin. When asked to raise her hands, the physician notes a coarse tremor. Lab values show ALT = 93U/L, AST = 89U/L, total bilirubin = 3.1 mg/dL, and ammonia = 124microg/dL. What is the most likely diagnosis? A. Bleeding esophageal varices B. Hepatic encephalopathy C. Hepatocellular carcinoma D. Hepatorenal syndrome E. Spontaneous bacterial peritonitis

  33. Other Causes of Hepatitis • Alcoholic Hepatitis • Drug induced Hepatitis • Autoimmune Hepatitis • Ischemic Hepatitis

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