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Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
Viral Hepatitis 	 Viral Hepatitis
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Viral Hepatitis Viral Hepatitis

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    • 1. Viral Hepatitis Medicine Student Lecture David R Nelson, M.D. Associate Professor of Medicine Director, Hepatology and Liver Transplantation University of Florida
    • 2. Case 1: <ul><li>29 y/o female came to your clinic with: </li></ul><ul><li>Jaundice, Abdominal pain, Nausea / Vomiting </li></ul><ul><li>AST-2,000 ALT- 2,500, Total bili 1.8 </li></ul><ul><li>She denies IVDA or any recent drug/medicine exposure, but had unprotected sex about 6 weeks ago </li></ul><ul><li>Ultrasound shows normal appearing liver and blood flow </li></ul><ul><li>Her diagnosis is…… </li></ul>
    • 3. Causes of Acute Hepatitis Acute Hepatitis Viral Hepatitis A, B/D, C, E EBV CMV &amp; HSV Drugs Ethanol Tylenol Halothane Toxins Jamaica Bush Tea Mushrooms Vascular Hypotension Budd-Chiari Autoimmune Hepatitis Metabolic Wilson&apos;s Disease A1AT
    • 4. Case: <ul><li>38 y/o male with past medical history of abnormal ALT for past 4 years. He had a blood tx as a child due to MVA. Patient came to your clinic with: </li></ul><ul><ul><ul><ul><li>ALT 150, AST 100 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>HBsAb +, HBcAb + </li></ul></ul></ul></ul><ul><ul><ul><ul><li>HCV Ab + </li></ul></ul></ul></ul><ul><ul><ul><ul><li>HAV IgG + </li></ul></ul></ul></ul><ul><li>What is your dx? </li></ul>
    • 5. Causes of Chronic Hepatitis Abbreviations: NAFLD: nonalcoholic fatty liver disease; AIH: autoimmune hepatitis; PBC: primary biliary cirrhosis PSC: primary sclerosing cholangitis, A1AT: alpha-1 antitrypsin deficiency, HHC:hereditary hemochromotosis Chronic Hepatitis Viral Hepatitis Hep B Hep C Drugs MTX INH Amiodarone Alcohol NAFLD Autoimmune AIH PBC PSC Metabolic A1AT HHC Wilson&apos;s
    • 6. 47% 34% 16% 3% Hepatitis A Hepatitis B Hepatitis C Hepatitis Non-ABC Source: CDC Sentinel Counties Study on Viral Hepatitis Acute Viral Hepatitis by Type, USA: 1982-1993
    • 7. Hepatitis A Virus Nucleic Acid: 7.5 kb ssRNA 27 nm <ul><li>Transmission route: fecal-oral </li></ul><ul><li>Clinical presentation </li></ul><ul><li>- Jaundice: Adults- 30%, Children- &lt;5% </li></ul><ul><li>- Fulminant: &lt;1% </li></ul><ul><li>Diagnostic tests </li></ul><ul><li>- Acute infection: IgM anti-HAV </li></ul><ul><li>- Chronic infection: Not applicable </li></ul><ul><li>Immunity: IgG anti-HAV </li></ul><ul><li>Case-fatality rate: 0.1 – 2.7% </li></ul><ul><li>Chronic infection: None </li></ul>
    • 8. HAV Prevalence High Intermediate Low Very Low Global Prevalence of Hepatitis A Infection
    • 9. &nbsp;
    • 10. Hepatitis A Prevention - Immune Globulin <ul><li>Preexposure </li></ul><ul><ul><li>Travelers to high HAV-prevalence regions </li></ul></ul><ul><li>Postexposure (within 14 days) </li></ul><ul><ul><li>Routine </li></ul></ul><ul><ul><ul><li>Household and other intimate contacts </li></ul></ul></ul><ul><ul><li>Selected situations </li></ul></ul><ul><ul><ul><li>Institutions (e.g. daycare centers) </li></ul></ul></ul><ul><ul><ul><li>Common source exposure (e.g. food prepared by infected food handler) </li></ul></ul></ul>
    • 11. ACIP Recommendations MMWR 1999; 48(RR12):1 Hepatitis A: Pre-exposure Vaccination <ul><li>Persons at increased risk or danger of infection </li></ul><ul><ul><li>Travelers to intermediate and high HAV prevalence areas </li></ul></ul><ul><ul><li>Men having sex with men </li></ul></ul><ul><ul><li>Injecting drug users </li></ul></ul><ul><ul><li>Persons with chronic liver disease </li></ul></ul><ul><li>Communities with high rates of hepatitis A (e.g., Alaskan Natives, Native-Americans) </li></ul><ul><ul><li>Routine pre-school childhood vaccination </li></ul></ul>
    • 12. Hepatitis E Virus Nucleic Acid: 7.5 kb ssRNA <ul><li>Fecal-oral transmission (human to human) </li></ul><ul><li>Contaminated water supplies in tropical or subtropical developing countries </li></ul><ul><li>Mainly young adults </li></ul><ul><li>Can infect primates, swine, sheep, rats </li></ul><ul><li>Swine may be reservoir of infection in North America </li></ul><ul><li>Maternal-infant transmission occurs and is often fatal </li></ul>32 nm
    • 13. Clinical Characteristics Hepatitis E <ul><li>Similar to hepatitis A </li></ul><ul><li>Dx: IgG anti-HEV (seroconversion) </li></ul><ul><li>Can cause severe acute hepatitis </li></ul><ul><li>Subclinical infection is common </li></ul><ul><ul><li>Attenuated virus from animal reservoirs </li></ul></ul><ul><ul><li>Low-dose infections often asymptomatic </li></ul></ul><ul><li>No chronic infection </li></ul><ul><li>Up to 20% mortality among pregnant women (esp. third trimester) </li></ul>
    • 14. Hepatitis B Virus <ul><li>Hepadnaviridae member that primarily infects liver cells </li></ul><ul><li>50 to 100 times more infective than HIV </li></ul><ul><li>Multiple genotypes exist (A-H) </li></ul><ul><li>DNA virus found in blood and body fluids </li></ul><ul><ul><li>Able to survive in dried blood for longer than 1 week </li></ul></ul>HBsAg HBV DNA HBcAg 42 nm
    • 15. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence  8% - High 2-7% - Intermediate &lt;2% - Low &gt; 350 million carriers (HBsAg + &gt; 6 months) 10th cause of death (1 million / year) Cirrhosis in 20% (75 - 100 million) HCC in 5 - 10% (20 - 40 million)
    • 16. Hepatitis B Prevalence <ul><li>Overall U.S. prevalence: 0.3% </li></ul><ul><li>Asian Americans: ~10-13% </li></ul>Son D, Asian Am Pac Isl J Health 2001 Slide courtesy of Robert Gish, MD
    • 17. HBV Sources of Infection Household, 3% Other, 23% IDU, 20% Multiple sex partners, 24% Sex contact, 23% MSM, 23% Centers for Disease Control and Prevention. Hepatitis B. In: Atkinson W et al, eds. Epidemiology &amp; Prevention of Vaccine-Preventable Diseases . 8th ed Washington DC: Public Health Foundation; 2005:191-212. Many patients do not reveal IDU as source of infection
    • 18. Signs and Symptoms of Acute Hepatitis B <ul><li>About 30% of persons have no signs or symptoms </li></ul><ul><li>If symptoms are present, generally nonspecific including: </li></ul><ul><li>Nausea, vomiting </li></ul><ul><li>Joint pain </li></ul><ul><li>Dark Urine </li></ul><ul><li>Clay-colored bowel movements </li></ul><ul><li>Jaundice </li></ul><ul><li>Fatigue </li></ul><ul><li>Abdominal Pain </li></ul><ul><li>Loss of Appetite </li></ul>
    • 19. Hepatitis B - Clinical Features Incubation period Average: 60 – 90 days Range: 45 – 180 days Clinical illness (jaundice) &lt; 5 yrs of age: &lt;10%  5 yrs of age: 30 – 50% Acute case-fatality rate 0.5 – 1% Chronic infection &lt; 5 yrs of age: 30 – 90%  5 yrs of age: 2 – 10% Mortality from chronic liver disease 15 – 25%
    • 20. Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course Weeks after Exposure Titer IgM anti-HBc Total anti-HBc HBsAg Acute (6 months) HBeAg Chronic (Years) anti-HBe 0 4 8 12 16 20 24 28 32 36 52 Years HBV DNA
    • 21. Interpretation of Serologic Markers Acute hepatitis B Recovery from acute hepatitis B Chronic HBeAg + disease Chronic HBeAG – disease Successful Vaccination Resistance to antiviral agents HBsAg  (may clear)   Anti-HBs   Anti-HBc IgM  Anti-HBc     HBeAg   Anti-HBe  (in some cases)  DNA (PCR if required)  (may be only marker during window period)    (sequence pol region)
    • 22. Hepatitis B: Disease Progression Acute Infection Chronic Infection Cirrhosis Death 1. Torresi J et al. Gastroenterology . 2000. 2. Fattovich G et al. Hepatology . 1995. 3. Moyer LA et al. Am J Prev Med . 1994. 4. Perrillo R et al. Hepatology . 2001. 5%-10% 1 10-30% 1 23% within 5 years Liver Cancer (HCC) Chronic HBV is the 6th leading cause of liver transplantation in the US 4 Liver Transplantation Liver Failure (Decompensation) 2-6% 90% in perinatal 30-90% in children&lt;5yrs old 5% in healthy adults Higher in HIV, immune suppressed
    • 23. Targeted Surveillance for HCC <ul><li>Asian males &gt; age 40 </li></ul><ul><li>Asian females &gt; age 50 </li></ul><ul><li>All cirrhotic HBV carriers </li></ul><ul><li>Family history of HCC </li></ul><ul><li>Africans &gt; age 20 </li></ul><ul><li>High HBV DNA </li></ul><ul><li>Hepatitis C </li></ul><ul><li>Alcoholic cirrhosis </li></ul><ul><li>Genetic hemochromatosis </li></ul><ul><li>Primary biliary cirrhosis </li></ul><ul><li>Other (? efficacy) </li></ul><ul><ul><li>A1AT deficiency </li></ul></ul><ul><ul><li>NAFLD </li></ul></ul><ul><ul><li>Autoimmune hepatitis </li></ul></ul>Hepatitis B Carriers Non-hepatitis B Cirrhosis Bruix J and Sherman M. Hepatology 2005;42:1208 <ul><li>Surveillance for HCC should be with ultrasound at </li></ul><ul><li>6 to 12 month intervals; AFP is not adequate </li></ul>
    • 24. Prevention of Transmission of Hepatitis B Vaccination <ul><li>Vaccinate Sexual and household contacts </li></ul><ul><li>Newborns of HBV-infected mothers </li></ul><ul><ul><li>HBIG and </li></ul></ul><ul><ul><li>hepatitis B vaccine at delivery </li></ul></ul><ul><li>3. Test for response to vaccination </li></ul><ul><ul><li>infants of HBsAg-positive mothers (9 to 15 months ) </li></ul></ul><ul><ul><li>health care workers, </li></ul></ul><ul><ul><li>dialysis patients, and </li></ul></ul><ul><ul><li>sexual partners </li></ul></ul><ul><li>4. Follow-up testing of vaccine responders </li></ul><ul><ul><li>Annually for chronic hemodialysis patients </li></ul></ul>1-2 months
    • 25. Goals of Treatment in HBV <ul><li>Reduce the risk of disease progression </li></ul><ul><li>Reduce the risk of hepatocellular carcinoma </li></ul><ul><li>Loss of HBeAg, HBeAg  HBeAb </li></ul><ul><li>Undetectable HBV-DNA </li></ul><ul><ul><li>(&lt;10 5 copies/ml = 20,000IU/mL) </li></ul></ul><ul><li>Normalization of ALT </li></ul><ul><li>Histologic Response </li></ul><ul><li>HBsAg  HBsAb </li></ul>Virologic Response
    • 26. Approved Treatments Lok AND McMahon. .Hepatology , Vol. 45, No. 2, 2007
    • 27. Hepatitis D Virus: Morphology and Characteristics <ul><li>Nucleic Acid: 1.7 kb ssRNA </li></ul><ul><li>Classification: unclassified, related to viroids; deltavirus </li></ul><ul><li>Transmission: sex, IVDA </li></ul><ul><li>Clinical features </li></ul><ul><li>- Fulminant: 2 – 7.5% </li></ul><ul><li>- Chronic infection Superinfection: 80% Coinfection: &lt; 5% </li></ul><ul><li>Diagnostic tests </li></ul><ul><li>-Acute infection: IgM anti-HDV </li></ul><ul><li>-Chronic infection:IgG anti-HDV, HBsAg + </li></ul>35-37nm
    • 28. Modes of HDV infection Coinfection Superinfection B B D D
    • 29. HCV Life-Cycle and Pathogenesis Cell Binding and Infection Replication Immune Response CD4 CD8 NK DC HSC Fibrosis Immune Recognition Cytokines Viral Packaging and Release Effector HCV
    • 30. Course of Acute HCV Infection Time After Exposure Symptoms 0 400 600 800 1000 ALT (IU/L) 0 2 4 6 8 10 12 24 1 2 3 4 5 6 Anti-HCV Weeks Months HCV RNA positive 200 7 Normal ALT Hoofnagle JH. Hepatology. 1997;26:15S. Carithers RL Jr, et al. Semin Liver Dis. 2000;20:159-171. Pawlosky JM. Hepatology. 2002;36(suppl 1):S65-S73. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.
    • 31. Symptoms, or Lack of, in Chronic HCV Infection Symptomatic 37% Cirrhosis 7% 56% Asymptomatic 0 20 40 60 80 100 Fatigue Patients (%) 80
    • 32. ALT Elevations Are Not Indicative of Chronic HCV Infection Inglesby TV, et al. Hepatology. 1999;29:590-596. 42 43 15 0 20 40 60 80 100 Persistently Normal ALT Intermittently Elevated ALT Persistently Elevated ALT Patients* With HCV infection (%)
    • 33. Diagnostic Tests for HCV Infection CDC Morbidity Mortality Weekly Report. 1998;16(RR-19):1-33. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007. Diagnostic Test Type Specifications Serologic Virologic Mode of detection Antibodies Virus Sensitivity &gt; 95% &gt; 98% Specificity Variable &gt; 98% Detection postexposure 2-6 mos 2-6 wks Use Screening Confirmation
    • 34. Molecular Virologic Assays Quantitative assays Detection cutoff &gt; qualitative How much HCV is present? Qualitative assays High sensitivity (  50 IU/mL) Is HCV present? Genotype assays What type of HCV is present?
    • 35. Clinical Significance of HCV Genotypes <ul><li>Great genetic diversity: 2 genotypes (1 through 6) </li></ul><ul><ul><li>Multiple subtypes: a, b, c, etc </li></ul></ul><ul><li>Genotype is best pretreatment predictor of response </li></ul><ul><ul><li>Genotype 1: least responsive to therapy </li></ul></ul><ul><li>Determines dose and duration of therapy </li></ul><ul><ul><li>Genotype 1: 48 weeks of peg-IFN alfa + RBV 1000-1200 mg </li></ul></ul><ul><ul><li>Genotype 2/3: 24 weeks of peg-IFN alfa + RBV 800 mg </li></ul></ul><ul><li>All patients should have genotype determined prior to initiating therapy </li></ul>Choo QL, et al. Science. 1989;244:359-62. NIH Consensus Development Conference Statement. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Hadziyannis SJ. Ann Intern Med. 2004;140:346-355.
    • 36. Prevalence of HCV Dependant on Risk Factors <ul><li>Hemophilia 74-90% </li></ul><ul><li>IVDA 72-89% </li></ul><ul><li>Prison 40% </li></ul><ul><li>HIV 30-40% </li></ul><ul><li>Blood transfusion prior to 90 5-9% </li></ul><ul><li>Infants to HCV+ Mothers 5% </li></ul><ul><li>Sexual Partner 0.5-3% </li></ul><ul><li>General Population 1.8% </li></ul>Adapted from MMWR .1998;47:5.
    • 37. Prevalence of HCV Infection: United States Alter et al. N Engl J Med . 1999;341:556-562. Anti-HCV+ (%) 0 1 2 3 4 5 6 7 Age (yr) Mexican American Caucasian 3.5% 1.1% African American 3.2% 6–11 12–19 20–29 30–39 40–49 50–59 70+ 60–69
    • 38. HCV: Disease Progression 1. NIH Consensus Development Conference Statement; March 24-26, 1997. 2. Davis GL et al. Gastroenterol Clin North Am . 1994;23:603-613. 3. Koretz RL et al. Ann Intern Med . 1993;119:110-115. 4. Takahashi M et al. Am J Gastroenterol . 1993;88:240-243. HCV infection Chronic HCV Cirrhosis Hepatic Failure Liver Cancer Liver Transplant Candidates 60-85% 1 ~20% 4 ~ 20% 3 20%-50% 2 Time: 20-30 years
    • 39. Histologic Progression of HCV Monitored by Liver Biopsy <ul><li>Inflammation Grade </li></ul><ul><li>Measure of severity and ongoing disease activity </li></ul><ul><li>0-4 (METAVIR) </li></ul><ul><li>Inflammation leads to scarring/fibrosis </li></ul><ul><li>Fibrosis Stage </li></ul><ul><li>Amount of fibrous scar tissue </li></ul><ul><li>0-4 (METAVIR) </li></ul><ul><li>Stage 4 = cirrhosis </li></ul><ul><li>Indicates long-term disease progression </li></ul>No fibrosis Cirrhosis Brunt EM. Hepatology . 2000;31:241-246.
    • 40. Common Schedule and Type of HCV Testing Identification and Planning Identification and Planning Treatment Decision to Treat Stage Assay Diagnosis <ul><li>Serological </li></ul><ul><li>Qual HCV RNA </li></ul>Prognosis <ul><li>Liver biopsy </li></ul>Treatment Duration <ul><li>Genotyping </li></ul><ul><li>Quant HCV RNA </li></ul>Assess Response and Resistance <ul><li>Quant HCV RNA </li></ul>
    • 41. Improvements in Therapy of HCV Sustained Virologic Response (%) IFN 6m IFN/RBV 6m Peg-IFN/ RBV 12m IFN 12m IFN/RBV 12m Peg-IFN 12m Strader DB et al. Hepatology 2004;39:1147-1171 1991 1998 2001 2002
    • 42. Current standard treatment duration is 48 or 24 weeks according to genotype HCV genotyping HCV-1 (4,5,6) Quantitative HCV RNA HCV-2,3 Peg-IFN + RBV 800 mg/day for 24 weeks Peg-IFN+ RBV 1000/1200 mg/day Quantitative HCV RNA at week 12 &lt;2 log decline Stop or re-evaluate therapy  2 log decline or HCV RNA (–) 48 weeks
    • 43. <ul><li>An estimated 5 million Americans have been infected with HCV, of whom 4 million are chronically infected </li></ul><ul><li>Approximately 30,000 people in the US are infected with hepatitis C each year </li></ul><ul><li>Hepatitis C is the leading causes of liver disease and cirrhosis in US </li></ul><ul><li>12,000 - 15,000 people die of hepatitis C each year in the US </li></ul><ul><li>The CDC estimate that the number of annual deaths from hepatitis C will triple in the next 10 - 20 years </li></ul><ul><li>The estimated medical and work loss costs per year of hepatitis C is over $600 million </li></ul>The Burden of Liver Disease Associated with HCV is Increasing Source: American Liver Foundation

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