VIRAL AND AUTOIMMUNE HEPATITIS Arthur M. Magun, M.D. Clinical Professor of Medicine WHAT IS HEPATITIS ? • Inflammation of the liver • Almost always, inflammation implies elevation in liver enzymes • AST and ALT are the key liver enzymes • Other Liver Function Tests (LFTs) which can be abnormal in hepatitis include: • Bilirubin, albumin, alkaline phosphatase, gamma glutamyl transpeptidase 1 CAUSES OF ACUTE HEPATITIS • Viral hepatitis • Other infectious etiologies e.g. CMV, EBV, TB • Alcoholic hepatitis • Drug hepatitis • Ischemic hepatitis • Choledocholithiasis Human Hepatitis Viruses HumanHuman HepatitisHepatitis VirusesViruses VirusVirus Genome Genome GenomeGenome EnvelopeEnvelope Family Family // genusgenus sizesize (kb)(kb) HAVHAV RNA RNA 7.5 7.5 - - Picornaviridae Picornaviridae positivepositive sense,sense, hepatovirushepatovirus singlesingle stranded,stranded, linearlinear HBVHBV DNA DNA 3.2 3.2 + + Hepadnaviridae Hepadnaviridae partiallypartially doubledouble stranded,stranded, circularcircular HCVHCV RNA RNA 9.6 9.6 + + Flaviviridae Flaviviridae positivepositive sense,sense, hepacivirushepacivirus singlesingle stranded,stranded, linearlinear HDVHDV RNA RNA 1.7 1.7 ++ UnclassifiedUnclassified positivepositive sense,sense, (viroid),(viroid), deltadelta virusvirus singlesingle stranded,stranded, linearlinear HEVHEV RNA RNA 7.5 7.5 -- Unclassified,Unclassified, positivepositive sense,sense, singlesingle togavirustogavirus andand stranded,stranded, linearlinear alphaalpha virus-likevirus-like 2 OTHER INFECTIOUS ETIOLOGIES OF ACUTE HEPATITIS • CMV - cytomegalovirus; immunocompromised host • EPSTEIN-BARR – mononuclesosis; lymphadenopathy; splenomegaly • TB and M. avium intracellurare (MAI) SYMPTOMS OF ACUTE VIRAL HEPATITIS • Fatigue, nausea, anorexia • Jaundice • Low-grade fever, abdominal pain • Arthralgia, myalgia, headache 3 SIGNS OF ACUTE VIRAL HEPATITS • Fever – low grade • Jaundice • Hepatomegaly with RUQ tenderness • Splenomegaly - infrequent LIVER BLOOD TEST ABNORMALITIES IN ACUTE VIRAL HEPATITIS • AST AND ALT - 1000-5000 IU • Bilirubin – generally elevated – both conjugated and unconjugated • Alkaline Phosphatase – minimally elevated • Bilirubin and urobilinogen increased in urine 4 OUTCOMES OF VIRAL HEPATITIS ACUTE ILLNESS CHRONIC HEPATITIS CURE FULMINANT HEPATITIS Hepatitis A Virus: Morphology and Characteristics HepatitisHepatitis AA VirusVirus •• NucleicNucleic Acid:Acid: 7.57.5 kbkb ssRNAssRNA 27 nm •• Classification:Classification: Picornaviridae,Picornaviridae, HepatovirusHepatovirus •• OneOne serotypeserotype andand multiplemultiple genotypesgenotypes •• Nonenveloped,Nonenveloped, acidacid andand heatheat stablestable •• InIn vitrovitro model:model: monkeymonkey andand humanhuman cellcell culturescultures •• InIn vivovivo replicatioreplication:n: inin cytoplasmcytoplasm ofof hepatocyte;hepatocyte; humanhuman andand otherother higherhigher primatesprimates 5 Global Prevalence of Hepatitis A HAV - Epidemiology GlobalGlobal PrevalencePrevalence ofof HepatitisHepatitis AA InfectionInfection HAVHAV PrevalencePrevalence HighHigh IntermediateIntermediate LowLow VeryVery LowLow HEPATITIS A • Oral fecal route of transmission • Excreted in stool about 2 weeks prior to clinical illness • 1 month incubation period • Children often asymptomatic • Never causes chronic hepatitis 6 Serological Course of Acute Hepatitis A HAV TypicalTypical SerologicSerologic CourseCourse ofof AcuteAcute HepatitisHepatitis AA VirusVirus InfectionInfection Symptoms ALT ALT TotalTotal anti-HAVanti-HAV FecalFecal HAVHAV IgMIgM anti-HAV anti-HAV 00 11 22 33 44 55 66 1212 2424 MonthsMonths afterafter exposureexposure HEPATITIS A PREVENTION AND TREATMENT • No treatment of infection available • Passive immunity with gamma globulin can ameliorate disease in early stages of the infection • Gamma globulin can prevent disease pre- exposure • Vaccine available to induce active immunity 7 Hepatitis B Virus: Morphology and Characteristics HepatitisHepatitis BB VirusVirus ••NucleicNucleic Acid:Acid: 3.23.2 kbkb DNADNA •• Classification:Classification: HepadnaviridaeHepadnaviridae • Multiple serotypes and genotypes 42 nm • Multiple serotypes and genotypes 42 nm A-FA-F •• EnvelopedEnveloped 22 nm 22 nm •• InIn vitrovitro model:model: primaryprimary hepatocytehepatocyte culture culture andand HBsAg transfectiontransfection of of clonedcloned HBVHBV DNADNA 42 nm HBcAg •• InIn vivovivo replication:replication: inin cytoplasm,cytoplasm, cccDNAcccDNA in in nucleus;nucleus; hepatocytehepatocyte andand otherother tissues,tissues, humanhuman andand HBV DNA otherother primatesprimates 4 Hepatitis B Virus: Viral Replication. Pt. 1 Hepatitis B Virus - Replication Viral entry Nucleus 8 Hepatitis B Virus: Viral Replication. Pt. 2 Hepatitis B Virus - Replication Viral entry Uncoating Nuclear import cccDNA Repair Transcription 5’ 3’ 2.4/2.1 kb RNA 5’ 3’ 3.5 kb RNA Hepatitis B Virus: Viral Replication. Pt. 3 Hepatitis B Virus - Replication Viral entry Uncoating Positive strand synthesis Nuclear import cccDNA Removal of pregenome Repair Transcription 5’ 3’ Negative 2.4/2.1 kb RNA strand 5’ 3’ Translation synthesis 3.5 kb RNA Encapsidation 9 Hepatitis B Virus: Viral Replication. Pt. 4 Hepatitis B Virus - Replication Export Viral entry Uncoating Uncoating Assembly ER & budding Positive strand synthesis Nuclear HBsAg import cccDNA Removal of pregenome Repair Transcription 5’ 3’ Negative 2.4/2.1 kb RNA strand 5’ 3’ Translation synthesis 3.5 kb RNA Encapsidation Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 1 Hepatitis B Virus - Immunopathogenesis HBV HBV Hepatocytes 10 Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 2 Hepatitis B Virus - Immunopathogenesis HBV TH CD4 Class II Ig Antigen presenting cells B cell CD8 Class I CTL HBV Hepatocytes Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 3 Hepatitis B Virus - Immunopathogenesis HBV TH CD4 Ig Class II Antigen presenting cells Cytokines B cell CD8 Class I CTL HBV Cytokines Hepatocytes Nonspecific inflammatoryinflammatory Direct cells cytotoxicity ? NK, NKT cells 11 Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 4 Hepatitis B Virus - Immunopathogenesis HBV TH CD4 Ig Class II Antigen presenting cells Cytokines B cell CD8 Class I CTL Apoptosis HBV Cytokines Hepatocytes Nonspecific inflammatoryinflammatory Clearance Direct cells cytotoxicity ? NK, NKT cells HEPATITIS B CLINICAL • Transmission – parenteral, secretions, sexual mother to child (vertical) • 6-8 week incubation • 20% pf patients have serum sickness prodrome • 4% of patients develop chronic hepatitis • Treatment and vaccine available 12 Clinical Significance of Serological Markers for HBV Infection HBV - Diagnosis SerologicalSerological ClinicalClinical MarkersMarkers SignificanceSignificance HBsAgHBsAg Acute/Chronic Acute/Chronic infectioninfection Anti-HBcAnti-HBc IgMIgM Acute Acute infectioninfection HBeAgHBeAg High High infectivityinfectivity Anti-HBeAnti-HBe LowLow infectivityinfectivity Anti-HBsAnti-HBs Immunity Immunity Anti-HBcAnti-HBc IgGIgG and and HBsAgHBsAg ChronicChronic infectioninfection Anti-HBcAnti-HBc IgGIgG and and anti-Hanti-HBsBs Resolved Resolved infectioninfection Serological Markers of Acute HBV Infection HBV - Diagnosis AcuteAcute HBVHBV InfectionInfection HBV DNA HBeAg Anti-HBeAnti-HBe Anti-HBsAnti-HBs Anti-HBcAnti-HBc HBsAg Anti-HBcAnti-HBc IgMIgM 00 22 44 66 MonthsMonths YearsYears 13 Hepatitis C Virus: Morphology and Characteristics HepatitisHepatitis CC VirusVirus ••NucleicNucleic Acid:Acid: 9.69.6 kbkb ssRNAssRNA •• Classification:Classification: Flaviviridae,Flaviviridae, HepacivirusHepacivirus 40-60 nm •• Genotypes:Genotypes: 11 toto 66 •• EnvelopedEnveloped •• InIn vitrovitro model:model: primaryprimary hepatocytehepatocyte and and TT cellcell cultures;cultures; repliconreplicon system system •• InIn vivovivo replicatioreplication:n: inin cytoplasm,cytoplasm, hepatocytehepatocyte and and lymphocyte;lymphocyte; humanhuman andand otherother primatesprimates Hepatitis C Virus: Genome and Gene Products, pt.2 Hepatitis C Virus GenomeGenome andand GeneGene ProductsProducts CC E1E1 E2E2 NS2NS2 NS3NS3 NS4BNS4B NS5ANS5A NS5BNS5B 5’ UTR 5’ UTR P7P7 NS4ANS4A 3’3’ UTRUTR StructuralStructural proteinprotein NonstructuralNonstructural proteinprotein codingcoding regionregion codingcoding regionregion CC E1E1 E2E2 NS2NS2 NS3NS3 AA NS4NS4 BB NS5ANS5A NS5BNS5B ProteaseProtease CoreCore ProteaseProtease CofactorCofactor Serine EnvelopeEnvelope Serine HelicaseHelicase RNARNA polymerasepolymerase proteaseprotease 14 Hepatitis C Virus: The Functions of Gene Products Hepatitis C Virus GeneGene ProductsProducts andand FunctionsFunctions CoreCore (C)(C)Nucleocapsid Nucleocapsid E1E1 andand E2E2Envelope Envelope proteinsproteins hypervariablehypervariable region region inin E2E2 p7p7Nonstructural, Nonstructural, ionion channelchannel (?)(?) NSNS 22NS NS 2-32-3 proteaseprotease NSNS 33Protease, Protease, nucleotidnucleotidee triphosphatase,triphosphatase, andand RNARNA helicasehelicase NSNS 44Cofactor Cofactor forfor NSNS 33 proteaseprotease activityactivity NSNS 4B4BFormation ofof membranousmembranous webweb NSNS 5A5AInterferon sensitivitysensitivity sequencesequence NSNS 5B5BRNA-dependent RNA-dependent RNARNA polymerasepolymerase Hepatitis C Virus: Viral Replication, pt. 1 Hepatitis C Virus - Replication Lipoproteins Entry 15 Hepatitis C Virus: Viral Replication, pt. 2 Hepatitis C Virus - Replication Lipoproteins Entry NS5B NS4B NS5A NS3/4A ER C NS2 E1 Uncoating E2 Chaperones ER E1-E2 Translation Nucleus Hepatitis