Hepatitis .ppt - HEPATITIS Meral S\u00d6NMEZO\u011eLU MD Yeditepe University Hospital Department of Infectious Diseases and Microbiology Global perspective \u2022

Hepatitis .ppt - HEPATITIS Meral Su00d6NMEZOu011eLU MD...

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Unformatted text preview: HEPATITIS Meral SÖNMEZOĞLU, MD Yeditepe University Hospital Department of Infectious Diseases and Microbiology Global perspective • One in every 12 persons worldwide is living with viral • hepatitis; • approximately 350–370 million persons are infected with HBV, • • • • and another 130–170 million are living with HCV infection. In 2010 , globally, about 248 million individuals were HBsAg positive. Globally, an estimated 78% of primary liver cancer and 57% of liver cirrhosis cases are caused by viral hepatitis 1 million deaths from viral hepatitis occur each year . The proportion of persons living with viral hepatitis is greatest in Asia, sub-Saharan Africa, and Egypt. 2 Definition: • Diffuse liver inflammation lasting less than 6 months 3 Causes: Hepatitis A HAV Infective hepatitis Hepatitis B HBV serum hepatitis Hepatitis D HDV Hepatitis C HCV Post transfusion hepatitis Hepatitis E HEV Epidemic/ Entral virus 27 nm RNA 42 nm DNA Hepa virus 35 nm Incomplete RNA+HBsAg 30 – 60 nm RNA flavi firus 32 nm RNA transmission Feco-oral Paraentral and post transfusion Sexual low risk 1-5 % Intrauterine low risk <5% Incubation p. 2 – 6 weeks 2 – 6 months 2 – 6 months 2 – 6 months 2 – 6 weeks Chronicity &liver cancer no Yes Yes Yes No Immunization -passive Non specific Ig Specific Ig IgM -active HAV vaccine danger Heptavax HBV vaccine Heptavax HBV vaccine Feco-oral Non specific Ig 4 Global perspective 5 Characteristics of hepatitis 6 Reported Cases of Selected Notifiable Diseases Preventable by Vaccination, United States, 2001 Varicella 22,536 Hepatitis A 10,609 Hepatitis B 7,843 Pertussis 7,580 Meningococcal disease 2,326 H. influenzae, invasive 1,597 Mumps 266 Measles (total) 116 Rubella 23 7 Acute Viral Hepatitis A, B and C/NANB by Year, United States, 1952-2000 Total Hepatitis A Hepatitis B Hepatitis C/ NANB 8 Vaccine preventable diseases USA 9 10 11 12 13 Trends of hepatitis B notification rates in Turkey, 1990 to 2012 Eurosurveillance, Volume 18, Issue 47, 21 November 2013 14 Eurosurveillance, Volume 18, Issue 47, 21 November 2013 In a meta-analysis, evaluating seroprevalence studies published between 1999 and 2009, it was determined that the overall HBsAg positivity in Turkey was 4.6% 15 16 17 Turkey 18 19 A, B, Cs of Viral Hepatitis •A – fecal-oral spread: hygiene, drug use, men having sex with men, travelers, day care, food – vaccine-preventable •B – sexually transmitted – 100x more infectious than HIV – blood-borne (sex, injection drug use, mother-child, and health care) – vaccine-preventable •C – blood borne (injection drug use primarily) – 4-5 times more common than HIV – NOT vaccine-preventable! 20 Acute Hepatitis – Clinical Symptoms Asymptomatic > Symptomatic > Fulminant Liver Failure > Death Symptoms (if present) are the same, regardless of cause (e.g., A, B, C, other viruses, toxins) • Nausea, vomiting • Abdominal pain • Loss of appetite • Fever • Diarrhea • Light (clay) colored stools • Dark urine • Jaundice (yellowing of eyes, skin) 21 Hepatitis symptoms 22 Hepatitis B virus (HBV) • Hepadnaviridae member that primarily infects liver cells • 100 times more infective than HIV • Found in blood and body fluids – Able to survive in dried blood for > 1 week Ott MJ et al. J Pediatr Health Care 1999; 13(5):211–216 Ribeiro RM et al. Microbes Infect 2002; 4:829–835 CDC. MMWR 2003; 52:1–33 23 Hepatitis B virus (HBV) • Hepatitis B is a viral infection that attacks the liver and can cause both acute and chronic disease. • The virus is transmitted through contact with the blood or other body fluids of an infected person - not through casual contact. • About 2 billion people worldwide have been infected with the virus and about 350 million live with chronic infection. An estimated 600 000 persons die each year due to the acute or chronic consequences of hepatitis B. 24 Hepatitis B virus (HBV) • About 25% of adults who become chronically infected during childhood later die from liver cancer or cirrhosis (scarring of the liver) caused by the chronic infection. • The hepatitis B virus is 50 to 100 times more infectious than HIV. • Hepatitis B virus is an important occupational hazard for health workers. • Hepatitis B is preventable with a safe and effective vaccine. 25 Hepatitis B nomenclature Name Abbreviation Definition/Comment Hepatitis B Surface Antigen HBsAg Protein indicating infection Hepatitis B e Antigen HBeAg Antigen correlating with HBV replication and infectivity; levels lower in patients with precore and core mutations Hepatitis B Core Antigen HBcAg Detected in liver tissue Chronic Hepatitis B CHB Defined as the persistence of HBsAg for > 6 months HBV deoxyribonucleic acid HBV DNA Indicates active viral replication HBeAg-negative CHB e-CHB Chronic hepatitis B with active viral replication, but low or undetectable HBeAg CDC. MMWR 2003; 52:1–33 Mahoney FJ Clin Microbiol Rev 1999; 12:351–366 Funk ML et al. J Viral Hepat 2002; 9:52–61 26 Serologic testing of Hepatitis B 27 100 100 80 80 60 60 Chronic Infection 40 40 20 20 Older Children and Adults 1-4 yrs 7-12 mos 1-6 mos Birth 0 Symptomatic Infection Symptomatic Infection (%) Chronic Infection (%) Outcome of Hepatitis B Virus Infection by Age at Infection 0 28 Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Symptoms HBeAg anti-HBe Titer Total anti-HBc IgM anti-HBc anti-HBs HBsAg 0 4 8 12 16 20 24 28 32 36 Weeks after Exposure 52 100 29 Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course Acute Chronic (6 months) (Years) HBeAg anti-HBe Titer HBsAg Total anti-HBc IgM anti-HBc 0 4 8 12 16 20 24 28 32 36 52 Weeks after Exposure 30 Structure of HBV illustrating source and key antigen particles HBcAg HBeAg Partially double Stranded DNA DNA polymerase HBsAg ~41nm (smallest known DNA virus) Adapted from Ganem D et al. N Engl J Med 2004; 350:1118–1129 Adapted from Liang TJ et al. N Engl J Med 2002; 347:208–210 Fung SK et al. Hepatology 2004; 40:790–792 8 HBV genotypes (A-H) based on ≥8% divergence in sequence identity 31 • HBV proteins • Core: Significance Protein of core particle; kinase activity (role in replication?) • Pre-core (HBeAg) : Pre-core/core cleaves to HBeAg; good marker of • active replication. Surface (HBsAg) : Envelope protein of HBV; basis of current vaccine • Pre-S2 : HBV binding and entry into hepatocytes • Pre-S1 • Polymerase :Viral replication • X protein :Transcriptional and transactivator activity. 32 Hepatitis B virus (HBV) genome. 33 34 • • • • • • • • • • • Significance of viral markers in hepatitis B Antigens HBsAg :Acute or chronic infection HBeAg :Acute hepatitis B Persistence implies: continued infectious state ,increased severity of disease HBV DNA : Implies viral replication Found in serum and liver Antibodies Anti-HBs :Immunity to HBV; previous exposure ;vaccination Anti-HBe :Seroconversion Anti-HBc : IgM Acute hepatitis B (high titre) . IgG Past exposure to hepatitis B . 35 Interpretation 36 HBV mutants • Four relevant HBV mutants – Naturally occurring • Precore mutation – Abolished HBeAg production (e-CHB) • Core promoter mutation – Down-regulates HBeAg production (e-CHB) – Treatment-induced mutations • YMDD: induced by L-nucleoside analogue RT-inhibitors e.g. Lamivudine • N236T and A181V: induced by Adefovir 37 Epidemiology Global impact of hepatitis B 2 billion with evidence of HBV infection World population 7.3 billion 25–40% (75–160 million) die of cirrhosis or liver cancer 350–400 million with chronic hepatitis B (CHB) 39 World’s hepatitis B disease burden is high Past/present infection ~2 billion Chronically infected 350–400 million Deaths 0.5–1.2 million/year Ranked cause of death 10th worldwide Lavanchy D J Viral Hepat 2004; 11:97–107 40 Global prevalence of hepatitis B virus infection Cold Spring Harb Perspect Med 2015;5:a021410 41 Global, regional, and national age–sex specifi c all-cause and cause-specifi c mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 Lancet 2015; 385: 117–71 42 43 44 Turkey • In 2008 and 2012, notification rates for acute hepatitis B in Turkey were 8.0 and 3.6 per 100,000, respectively. • In Europe (among 27 European Union Member States and three European Economic Area countries), the notification rate of acute hepatitis B was 0.8 per 100,000 in 2010 45 Geographical distribution of HBV genotypes (1) Genotype Geographical Distribution A Northern Europe, Africa B and C Asia D Southern Europe, Middle East E Africa F and H Central and South America G Africa A, B, C, and D United States McMahon BJ Semin Liver Dis 2004; 24:17–21 Chu CJ et al. Gastroenterology 2003; 125:444–451 46 Geographical distribution of HBV genotypes (2) F D A D A,B,C,D C C D D E D Bj Ba F F A A,B,C,D • Over-simplification of distribution – populations are not static Fung SK, Lok AS. Hepatology 2004; 40:790–792. 47 Transmission of HBV Horizontal Transmission Host Vertical Transmission Recipient Mother Child-to-Child Contaminated Needles Sexual Health Care Worker Transfusion Perinatal Infant 90% infected infants become chronically infected 6% infected after age 5 years become chronically infected No clear risk factors in 2030% of patients CDC Fact Sheet Accessed July 26 2005 Lee WM N Engl J Med 1997; 337:1733–1745 Lavanchy D J Viral Hepat 2004; 11:97–107 48 Risk groups for hepatitis B • Children of immigrants from a country with high HBV prevalence • Intravenous drug users • History of a sexually transmitted disease/ multiple sex partners • Men who have sex with men • Household contact with • • • • chronically infected persons Infants born to infected mothers Healthcare workers Haemodialysis patients Sexual contact with infected persons CDC Fact Sheet Accessed July 26 2005 49 Hepatitis B disease burden in Europe/EMEA Modes of transmission (2) TURKEY Intrafamilial; also reports of transmission by dentists, health-care workers, barbers etc. Vertical transmission low BMS Colloquia 20034: Summary 51 Natural history of chronic hepatitis B Hepatitis B: a variable disease • Natural history influenced by: • Clinical spectrum varies – – – – – – – Age at infection Viral mutations Level of HBV replication Gender Host immune status Alcohol use Infection with other hepatotropic viruses Fattovich G Semin Liver Dis 2003; 23:47–58 – Acute hepatitis • Subclinical • Acute symptomatic • Fulminant – HBsAg carrier (low level replication) – Chronic hepatitis • Cirrhosis • HCC 53 Phases of chronic hepatitis B HBeAg Status HBV DNA Levels (copies/mL) Immune Tolerant Phase HBeAg High (> 10 ) Immune Active Phase (Chronic Hepatitis B) HBeAg or anti-HBe High (> 105) Non-replicative Phase (Inactive HBsAg Carrier) Anti-HBe McMahon BJ Semin Liver Dis 2004; 24:17–21 5 Low (< 105) ALT Levels Liver Histology Normal Normal or minimal inflammation Elevated Chronic inflammation Normal Normal or minimal inflammation 54 Dynamics of HBV replication and clinical disease Immune Tolerant Immune Active Non-replicative 55 Multiple outcomes of chronic hepatitis B (n = 283) Spontaneous seroconversion 33% ALT elevation (>2xULN) 24% e-CHB with detectable HBV DNA Hsu YS et al. Hepatology 2002; 35:1522–1527 67% Sustained remission 5% Undetermined causes 4% HBeAg reversion 56 Changing prevalence of HBeAg-negative CHB in Europe/EMEA GERMANY 1999 ~80% of CHB reported to be HBeAgFRANCE 1994 22% of cases reported to be HBeAg2004 Multicentre cohort study1 reported 57% of cases HBeAg- DENMARK ~50% of CHB reported to be HBeAg- POLAND Increased percentage of HBeAg- disease, especially in older patients ITALY 1975–1985 55.4% HBeAg- 2 1997 91% HBeAg- 3 More common in older patients SPAIN 1996 63% HBeAg- GREECE ~90% of CHB reported to be HBeAg- MOROCCO ~50% of CHB carriers are HBeAg- TURKEY ~66% of CHB reported to be HBeAg- EGYPT ~90–95% of CHB reported to be HBeAg- ISRAEL Varies with age Majority of patients 50 yrs HBeAgYounger patients tend to be HBeAg+ LEBANON and UAE HBeAg- CHB reported to be on the increase 1. Zoulim F et al. J Hepatol 2004; 40(suppl 1):134, Abstract 453; 2. Giusti G et al. Ital J Gastroenterol 1991; 23:111118; 3. Gaeta GB et al. J Hepatol 2003; 39:10361041; BMS Colloquia 20034: Summary 57 Long-term outcomes of chronic hepatitis B Pathogenesis of HBV infection Hepatocyte regeneration Uninfected hepatocyt es Infection Immune respons e Re-infection HBV production HBV-infected hepatocytes Coinfection Inflammation & cell death Clinical hepatitis Averett et al. Viral Hepatitis Reviews 1995; 1:129–142 Keeffe EB et al. Clin Gastroenterol Hepatol 2004; 2:87–106 59 Clinical course of acquired HBV infection in adults 60 Histopathologic features of HBV infection Healthy Liver Hepatic Fibrosis Cirrhosis Hepatocellular Carcinoma Images provided courtesy of Dr Z Goodman, Armed Forces Institute of Pathology, Washington DC 61 Significance of HBV DNA/viral replication Presence of HBV DNA/viral replication precedes Elevated ALT Worsening histology HCC 62 63 64 Risk factors for progression to cirrhosis • Older age • Ongoing HBV Replication – Persistent or intermittent non-PCR HBV DNA detection • Severity of fibrosis/necroinflammation stage at diagnosis • Concurrent clinical conditions – HBV, HCV, HIV, heavy alcohol consumption Fattovich G et al. Semin Liver Dis 2003; 23:47–58 65 Hepatocellular carcinoma • Primary liver carcinoma is the 5th most frequent cancer in the world • HCC is the major type of primary liver carcinoma • HCC is mainly associates with viral hepatitis – In many areas of the world > 85% of HCC retain markers of HBV and/or HCV Kim JW et al. Hepatology 2004; 39:518–527 66 Risk factors for HCC • • • • • • • • Cirrhosis Male gender Older age Viral replication HBeAg-positive or HBeAg-negative Alcohol consumption Concurrent infection with HCV Family history with HCC Fattovich G et al. Semin Liver Dis 2003; 23:47–58 67 “Approximately 15–40% of infected patients will develop cirrhosis, liver failure, or HCC” Lok AS N Engl J Med 2002; 346(22):1682–1683 69 Hepatitis B screening and vaccination HBV immunization • Two types of HBV immunization: – Passive immunization • Inject the individual with ready-made HBV-specific Immunoglobulin (HBIG) • Provides immediate short-term protection • Involves large injection volumes • Can be given at birth to reduce perinatal transmission – Active immunization • Currently HBV vaccines are based on recombinant HBsAg with or without preS • The aim of giving therapeutic vaccines to HBV-infected patients is to increase the efficiency of the natural immune response – in particular the T-helper or cytotoxic T lymphocyte response World Health Organisation, Hepatitis B – department of communicable diseases surveillance and response 71 HBV vaccination (1) • The HBV vaccine currently used is a synthetically prepared recombinant DNA vaccine, e.g. – – – – – – Engerix-B (GlaxoSmithKline) Recombivax HB (Merck) Genhevac B (Pasteur Merieux Connaught) Euvax B (LG Chemical) Heprecombe (Swiss Serum and Vaccines Institute) Hepavax-Gene (Korea Green Cross) • Recombinant DNA vaccines contain sections of HBV proteins (antigenic regions such as outer protein or surface antigen) to stimulate a natural immune response • All licensed vaccines (except Genehevac-B, Pasteur-Merieux) consist of the major S-gene product • Live virus not used – eliminates risk of vaccine-acquired infection Hollinger FB and Liang TJ. Fields Virology 2001 Chapter 87: Hepatitis B virus Lai CL et al. Hepatitis B Virus: Human virus guidelines 2002 IMP World Health Organization, Hepatitis B – department of communicable diseases surveillance and response 72 HBV vaccination (2) • Hepatitis D virus relies on Hepatitis B for productive infection, so the HBV vaccine also protects against HDV • The HBV vaccine can be given in combination with other vaccines, Hepatitis A for example • Vaccine efficacy is extremely high with 80–90% of recipients mounting a natural immune response • Protection is also long lasting but the exact time period of protection is unknown CDC Hepatitis B fact sheet, Accessed July 26 2005 Immunisation against infectious disease 1996 Department of Health Welsh Office, Scottish Office, Department of Health DHSS (Northern Ireland) Accessed August 2005 73 Selected screening and vaccination programmes (1) FRANCE ITALY Vaccination programme suspended in 1998 due to link to MS Vaccination programme started 1991; all newborns, followed up at 12 years Voluntary for young adults No systematic/military screening apart from during pregnancy Screening regarded as inefficient and public awareness low GREECE Vaccination programme started early 1990s, plus catch up programme Blood donor and employer screening Patients often picked up by chance or following diagnosis of CHB in family member CDC 1991 WHO World Health Report 2002 Diagnosis often follows incidental finding of elevated ALT or employer/blood donor screening 2/3 of infected people go undetected TURKEY Vaccination programme started 1997 All newborns; random follow up Adults, apart from high risk groups, have to pay Blood donors screened; compulsory military and premarital screening Optional for health-care workers 74 Endemicity change with vaccine 75 HBV vaccine: not always efficacious • Seroprotection: anti-HBs titre ≥10mIU/mL – Immunity inadequate <10mIU/mL • Protection rates after completion of 3 dose series: – >95% for infants of HBsAg-negative women and adolescents – 90% in adults <40 years • Risk factors for suboptimal response – Age >40 years – IVDU – Immunocompromised state – Obesity – Smoking Mahoney FJ Clin Microbiol Rev 1999; 12:351–366 76 Türkiye İstatistik Yıllığı 2013 77 Türkiye’e aşılama oranları 78 79 80 İnaktif hepatit B 81 Tedavi endikasyonu 82 83 • Hepatitis D • This is caused by the hepatitis D virus (HDV or delta virus). • It is an incomplete RNA particle enclosed in a shell of HBsAg. • • • • It is unable to replicate on its own but is activated by the presence of HBV. It is particularly seen in intravenous drug abusers but can affect all risk groups for HBV infection. Hepatitis D viral infection can occur either as a co-infection with HBV or as a superinfection in an HBsAg-positive patient.. Diagnosis is confirmed by finding serum IgM anti-delta. Superinfection results in an acute flare-up of previously quiescent chronic HBV infection. A rise in serum AST or ALT may indication of infection. Fulminant hepatitis can follow both types of infection but is more common after co-infection. 84 85 86 87 Hepatitis A Virus 88 Geographic Distribution of HAV Infection 89 Basics of Hepatitis A • RNA Picornavirus – Single serotype worldwide – Acute disease and asymptomatic infection • No chronic infection – Protective antibodies develop in response to infection - confers lifelong immunity 90 Hepatitis A – Clinical Features • Incubation period: • Jaundice by age group: < 6 yrs 6 – 14 yrs > 14 yrs • Rare Complications: • Chronic sequelae: Average 30 days Range 15-50 days <10% 40%-50% 70%-80% Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis None 91 Acute Hepatitis A Case Definition For Surveillance – Clinical criteria of an acute illness with: • discrete onset of symptoms (e.g. fatigue, abdominal pain, loss of appetite, intermittent nausea, vomiting), and • jaundice or elevated serum aminotransferase levels – Laboratory criteria • IgM antibody to hepatitis A virus (anti-HAV) positive – Case Classification • Confirmed. A case that meets the clinical case definition and is laboratory confirmed or a case that meets the clinical case definition and occurs in a person who has an epidemiologic link with a person who has laboratory-confirmed hepatitis A during the 15-50 days before the onset of symptoms. 92 Events In Hepatitis A Virus Infection Clinical illness Infection ALT Response IgM IgG Viremia HAV in stool 0 1 2 3 4 5 6 Week 7 8 9 10 11 12 13 93 Concentration of Hepatitis A Virus in Various Body Fluids Body Fluids Feces Serum Saliva Urine 100 102 104 106 108 1010 Infectious Doses per mL Source: Viral Hepatitis and Liver Disease...
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