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 Genome Genome Envelope Envelope 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 Chronic Chronic 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 6 6 MonthsMonths Years Years
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 C Virus: Viral Replication, pt. 3 Hepatitis C Virus - Replication
Lipoproteins
Progeny genome Entry Replication +
NS5B NS4B NS5A NS3/4A ER C NS2 E1 Uncoating E2 Chaperones ER E1-E2 Translation Nucleus
16 Hepatitis C Virus: Viral Replication, pt. 4 Hepatitis C Virus - Replication
Lipoproteins
Export Progeny genome Entry Replication Assembly + E1-E2
NS5B NS4B Golgi NS5A NS3/4A ER C NS2 E1 Uncoating E2 Chaperones ER E1-E2 Translation Nucleus
Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 1 Hepatitis C Virus - Immunopathogenesis
HCV
HCV
Hepatocytes
17 Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 2 Hepatitis C Virus - Immunopathogenesis Antigen presenting cells
Ig CD4 Class II TH HCV B cell Cytokines CD8 Class I CTL
HCV
Hepatocytes
Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 3 Hepatitis C Virus - Immunopathogenesis Antigen presenting cells
Ig CD4 Class II TH HCV B cell Cytokines CD8 Class I CTL
HCV
Cytokines Nonspecific inflammatoryinflammatory cells Hepatocytes
18 Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 4 Hepatitis C Virus - Immunopathogenesis Antigen presenting cells
Ig CD4 Class II TH HCV B cell Cytokines CD8 Class I CTL
Apoptosis HCV or cytopathic Steatosis replication Cytokines Nonspecific inflammatoryinflammatory Viral cells Clearance Hepatocytes
Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 5 Hepatitis C Virus - Immunopathogenesis
Cryoglobulins Autoimmunity Antigen presenting ImmuneImmune cells Lympho- modulation proliferative Ig disorders Lymphoid CD4 Class II cells TH HCV B cell Cytokines CD8 Class I CTL
Apoptosis HCV or cytopathic Steatosis replication Cytokines Nonspecific inflammatoryinflammatory Viral cells Clearance NK, Hepatocytes NKT cells
19 HEPATITIS C CLINICAL
• Most common cause of chronic hepatitis in USA • 1.5% of population in USA carries the virus • Parenteral transmission – blood, sexual • 6-8 week incubation period • Acute infection generally mild • 80% of acute develop chronic disease • No vaccine available • Treatment – 40-80% cure rate
Acute hepatitis C infection HCV - Diagnosis AcuteAcute HCVHCV InfectionInfection 1000 HCV RNA positive 800 Anti-HCV 600 ALTALT 600 (IU/L) (IU/L) Symptoms 400
200
NormalNormal 0 ALTALT 0 2 4 6 8 10 12 24 1 2 3 4 5 6 7 WeeksWeeks MonthsMonths TimeTime AfterAfter ExposureExposure
HoofnagleHoofnagleJH, JH, HepatologyHepatology 1997;1997; 26:15S26:15S
20 Outcome Following Hepatitis C Infection HCV - Natural History OutcomeOutcome FollowingFollowing HepatitisHepatitis CC InfectionInfection Acute hepatitis C 80%80% Chronic infection
70%70% Chronic hepatitis 11 - 4%/yr 20%20% HCC Cirrhosis Decompensation 4 - 5%/yr TimeTime 4 - 5%/yr (yr)(yr) 10 20 30
HEPATITIS D AND E
• HEPATITIS D – Also known as delta agent – Uses the HBsAg protein coat – Hepatitis B must be present – coinfection or preexist
• HEPATITIS E – Water borne virus resembling hepatitis A – Rarely seen in USA
21 CHRONIC HEPATITIS
• Fatty liver • Viral – B and C • Autoimmune •Drugs • Alcohol • Metabolic • Others – CHF, hemochromatosis, vasculitis, IBD, celiac disease, neoplasia, etc.
CHRONIC HEPATITIS B AND C
• Cirrhosis develops in 20% of patients • Liver failure and hepatoma develop in about ½ of cirrhotics • Diagnosis of chronic hepatitis made on basis of: – chronic AST and ALT elevations – positive serology – positive DNA or RNA in blood – some patients have normal liver enzymes • Treatment available with varying success rates
22 Serological Markers of Chronic HBV Infection HBV - Diagnosis ChronicChronic HBVHBV InfectionInfection HBV DNA
HBeAg Anti-HBeAnti-HBe
HBsAgHBsAg
Anti-HBc IgG
Anti-HBc IgM
MonthsMonths YearsYears
Serologic events in HBV infection
anti- Anti- Anti-HBc anti-HBc HBV HBsAg HBs HBeAg Hbe IgG IgM DNA ALT
Acute HBV Infection + - + - + + + ↑↑
Vaccine Responder - + - - - - - Normal Exposure with Immunity - + - +/- + - - Normal Chronic HBV (Wild Type) + - + - + - + ↑ / N Chronic HBV (Precore Mutant) + - - + + - + ↑ /N
Inactive Carrier + - - + + - -/+ Normal
23 Acute hepatitis C infection HCV - Diagnosis ChronicChronic HCVHCV InfectionInfection 1000 HCV RNA positive 800 Anti-HCV 600 ALTALT 600 (IU/L) (IU/L) Symptoms 400
200
NormalNormal 0 ALTALT 0 2 4 6 8 10 12 24 1 2 3 4 5 6 7 WeeksWeeks YearsYears TimeTime AfterAfter ExposureExposure
HoofnagleHoofnagleJH, JH, HepatologyHepatology 1997;1997; 26:15S26:15S
AUTOIMMUNE HEPATITIS
• Genetically predisposed host exposed to an environmental agent triggering an autoimmune response directed at liver antigens leading to a necroinflammatory response
• Associated with other autoimmune diseases - thyroid disease, colitis, hemolytic anemia, ITP, diabetes, celiac disease, polymyositis, pericarditis, SLE, MCTD
24 AUTOIMMUNE HEPATITIS
• Clinical presentation – generally female, fatigue, jaundice, hypergammaglobulinemia, elevated AST and ALT • Presence of associated autoantibodies – ANA, thyroid antiboides, LKM, smooth muscle • Diagnostic liver biopsy – interface hepatitis and plasma cell infiltration • Treatment - steroids and immunosuppressants
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