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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:
      • 29 y/o female came to your clinic with:
      • Jaundice, Abdominal pain, Nausea / Vomiting
      • AST-2,000 ALT- 2,500, Total bili 1.8
      • She denies IVDA or any recent drug/medicine exposure, but had unprotected sex about 6 weeks ago
      • Ultrasound shows normal appearing liver and blood flow
      • Her diagnosis is……
    • 3. Causes of Acute Hepatitis Acute Hepatitis Viral Hepatitis A, B/D, C, E EBV CMV & HSV Drugs Ethanol Tylenol Halothane Toxins Jamaica Bush Tea Mushrooms Vascular Hypotension Budd-Chiari Autoimmune Hepatitis Metabolic Wilson's Disease A1AT
    • 4. Case:
      • 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:
            • ALT 150, AST 100
            • HBsAb +, HBcAb +
            • HCV Ab +
            • HAV IgG +
      • What is your dx?
    • 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'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
      • Transmission route: fecal-oral
      • Clinical presentation
      • - Jaundice: Adults- 30%, Children- <5%
      • - Fulminant: <1%
      • Diagnostic tests
      • - Acute infection: IgM anti-HAV
      • - Chronic infection: Not applicable
      • Immunity: IgG anti-HAV
      • Case-fatality rate: 0.1 – 2.7%
      • Chronic infection: None
    • 8. HAV Prevalence High Intermediate Low Very Low Global Prevalence of Hepatitis A Infection
    • 9.  
    • 10. Hepatitis A Prevention - Immune Globulin
      • Preexposure
        • Travelers to high HAV-prevalence regions
      • Postexposure (within 14 days)
        • Routine
          • Household and other intimate contacts
        • Selected situations
          • Institutions (e.g. daycare centers)
          • Common source exposure (e.g. food prepared by infected food handler)
    • 11. ACIP Recommendations MMWR 1999; 48(RR12):1 Hepatitis A: Pre-exposure Vaccination
      • Persons at increased risk or danger of infection
        • Travelers to intermediate and high HAV prevalence areas
        • Men having sex with men
        • Injecting drug users
        • Persons with chronic liver disease
      • Communities with high rates of hepatitis A (e.g., Alaskan Natives, Native-Americans)
        • Routine pre-school childhood vaccination
    • 12. Hepatitis E Virus Nucleic Acid: 7.5 kb ssRNA
      • Fecal-oral transmission (human to human)
      • Contaminated water supplies in tropical or subtropical developing countries
      • Mainly young adults
      • Can infect primates, swine, sheep, rats
      • Swine may be reservoir of infection in North America
      • Maternal-infant transmission occurs and is often fatal
      32 nm
    • 13. Clinical Characteristics Hepatitis E
      • Similar to hepatitis A
      • Dx: IgG anti-HEV (seroconversion)
      • Can cause severe acute hepatitis
      • Subclinical infection is common
        • Attenuated virus from animal reservoirs
        • Low-dose infections often asymptomatic
      • No chronic infection
      • Up to 20% mortality among pregnant women (esp. third trimester)
    • 14. Hepatitis B Virus
      • Hepadnaviridae member that primarily infects liver cells
      • 50 to 100 times more infective than HIV
      • Multiple genotypes exist (A-H)
      • DNA virus found in blood and body fluids
        • Able to survive in dried blood for longer than 1 week
      HBsAg HBV DNA HBcAg 42 nm
    • 15. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence  8% - High 2-7% - Intermediate <2% - Low > 350 million carriers (HBsAg + > 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
      • Overall U.S. prevalence: 0.3%
      • Asian Americans: ~10-13%
      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 & 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
      • About 30% of persons have no signs or symptoms
      • If symptoms are present, generally nonspecific including:
      • Nausea, vomiting
      • Joint pain
      • Dark Urine
      • Clay-colored bowel movements
      • Jaundice
      • Fatigue
      • Abdominal Pain
      • Loss of Appetite
    • 19. Hepatitis B - Clinical Features Incubation period Average: 60 – 90 days Range: 45 – 180 days Clinical illness (jaundice) < 5 yrs of age: <10%  5 yrs of age: 30 – 50% Acute case-fatality rate 0.5 – 1% Chronic infection < 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<5yrs old 5% in healthy adults Higher in HIV, immune suppressed
    • 23. Targeted Surveillance for HCC
      • Asian males > age 40
      • Asian females > age 50
      • All cirrhotic HBV carriers
      • Family history of HCC
      • Africans > age 20
      • High HBV DNA
      • Hepatitis C
      • Alcoholic cirrhosis
      • Genetic hemochromatosis
      • Primary biliary cirrhosis
      • Other (? efficacy)
        • A1AT deficiency
        • NAFLD
        • Autoimmune hepatitis
      Hepatitis B Carriers Non-hepatitis B Cirrhosis Bruix J and Sherman M. Hepatology 2005;42:1208
      • Surveillance for HCC should be with ultrasound at
      • 6 to 12 month intervals; AFP is not adequate
    • 24. Prevention of Transmission of Hepatitis B Vaccination
      • Vaccinate Sexual and household contacts
      • Newborns of HBV-infected mothers
        • HBIG and
        • hepatitis B vaccine at delivery
      • 3. Test for response to vaccination
        • infants of HBsAg-positive mothers (9 to 15 months )
        • health care workers,
        • dialysis patients, and
        • sexual partners
      • 4. Follow-up testing of vaccine responders
        • Annually for chronic hemodialysis patients
      1-2 months
    • 25. Goals of Treatment in HBV
      • Reduce the risk of disease progression
      • Reduce the risk of hepatocellular carcinoma
      • Loss of HBeAg, HBeAg  HBeAb
      • Undetectable HBV-DNA
        • (<10 5 copies/ml = 20,000IU/mL)
      • Normalization of ALT
      • Histologic Response
      • HBsAg  HBsAb
      Virologic Response
    • 26. Approved Treatments Lok AND McMahon. .Hepatology , Vol. 45, No. 2, 2007
    • 27. Hepatitis D Virus: Morphology and Characteristics
      • Nucleic Acid: 1.7 kb ssRNA
      • Classification: unclassified, related to viroids; deltavirus
      • Transmission: sex, IVDA
      • Clinical features
      • - Fulminant: 2 – 7.5%
      • - Chronic infection Superinfection: 80% Coinfection: < 5%
      • Diagnostic tests
      • -Acute infection: IgM anti-HDV
      • -Chronic infection:IgG anti-HDV, HBsAg +
      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 > 95% > 98% Specificity Variable > 98% Detection postexposure 2-6 mos 2-6 wks Use Screening Confirmation
    • 34. Molecular Virologic Assays Quantitative assays Detection cutoff > 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
      • Great genetic diversity: 2 genotypes (1 through 6)
        • Multiple subtypes: a, b, c, etc
      • Genotype is best pretreatment predictor of response
        • Genotype 1: least responsive to therapy
      • Determines dose and duration of therapy
        • Genotype 1: 48 weeks of peg-IFN alfa + RBV 1000-1200 mg
        • Genotype 2/3: 24 weeks of peg-IFN alfa + RBV 800 mg
      • All patients should have genotype determined prior to initiating therapy
      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
      • Hemophilia 74-90%
      • IVDA 72-89%
      • Prison 40%
      • HIV 30-40%
      • Blood transfusion prior to 90 5-9%
      • Infants to HCV+ Mothers 5%
      • Sexual Partner 0.5-3%
      • General Population 1.8%
      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
      • Inflammation Grade
      • Measure of severity and ongoing disease activity
      • 0-4 (METAVIR)
      • Inflammation leads to scarring/fibrosis
      • Fibrosis Stage
      • Amount of fibrous scar tissue
      • 0-4 (METAVIR)
      • Stage 4 = cirrhosis
      • Indicates long-term disease progression
      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
      • Serological
      • Qual HCV RNA
      Prognosis
      • Liver biopsy
      Treatment Duration
      • Genotyping
      • Quant HCV RNA
      Assess Response and Resistance
      • Quant HCV RNA
    • 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 <2 log decline Stop or re-evaluate therapy  2 log decline or HCV RNA (–) 48 weeks
    • 43.
      • An estimated 5 million Americans have been infected with HCV, of whom 4 million are chronically infected
      • Approximately 30,000 people in the US are infected with hepatitis C each year
      • Hepatitis C is the leading causes of liver disease and cirrhosis in US
      • 12,000 - 15,000 people die of hepatitis C each year in the US
      • The CDC estimate that the number of annual deaths from hepatitis C will triple in the next 10 - 20 years
      • The estimated medical and work loss costs per year of hepatitis C is over $600 million
      The Burden of Liver Disease Associated with HCV is Increasing Source: American Liver Foundation

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