WHAT IS HEPATITIS VIRAL AND AUTOIMMUNE HEPATITIS ?
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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 Human Hepatitis Viruses Human Hepatitis Viruses CAUSES OF ACUTE HEPATITIS • • • • • • Viral hepatitis Other infectious etiologies e.g. CMV, EBV, TB Alcoholic hepatitis Drug hepatitis Ischemic hepatitis Choledocholithiasis Virus Genome HAV RNA 7.5 - Picornaviridae hepatovirus HBV DNA 3.2 + Hepadnaviridae HCV RNA 9.6 + Flaviviridae hepacivirus HDV RNA positive sense, single stranded, linear RNA positive sense, single stranded, linear 1.7 + Unclassified 7.5 - Unclassified, HEV OTHER INFECTIOUS ETIOLOGIES OF ACUTE HEPATITIS • CMV - cytomegalovirus; immunocompromised host • EPSTEIN-BARR – mononuclesosis; lymphadenopathy; splenomegaly • TB and M. avium intracellurare (MAI) positive sense, single stranded, linear partially double stranded, circular positive sense, single stranded, linear Genome Envelope size (kb) Family / genus (viroid), delta virus togavirus and alpha virus-like SYMPTOMS OF ACUTE VIRAL HEPATITIS • Fatigue, nausea, anorexia • Jaundice • Low-grade fever, abdominal pain • Arthralgia, myalgia, headache 1 SIGNS OF ACUTE VIRAL HEPATITIS • • • • 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 He p a t i t i s A Vi ru s : Mo rp h o l o g y a n d Ch a ra c t e ri s t i c s OUTCOMES OF VIRAL HEPATITIS Hepatitis A Virus · Nucleic Acid: 7.5 kb ssRNA ACUTE ILLNESS 27 nm · Classification: Picornaviridae, Hepatovirus · One serotype and multiple genotypes · Nonenveloped, acid and heat stable · In vitro model: monkey and human cell cultures CHRONIC HEPATITIS CURE FULMINANT HEPATITIS · In vivo replication: in cytoplasm of hepatocyte; human and other higher primates Global Prevalence of Hepatitis A HAV - Epidemiology Global Prevalence of Hepatitis A Infection HAV Prevalence High Intermediate Low Very Low 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 2 Serological Course of Acute Hepatitis A HEPATITIS A PREVENTION AND TREATMENT HAV Typical Serologic Course of Acute Hepatitis A Virus Infection • No treatment of infection available • Passive immunity with gamma globulin can ameliorate disease in early stages of the infection • Gamma globulin can prevent disease preexposure • Vaccine available to induce active immunity Symptoms ALT Total anti-HAV Fecal HAV 0 IgM anti-HAV 1 2 4 3 5 6 12 24 Months after exposure Hepatitis B Virus: Morphology and Characteristics Hepatitis B Virus: Viral Replication. Pt. 1 Hepatitis B Virus - Replication Hepatitis B Virus Viral entry · Nucleic Acid: 3.2 kb DNA · Classification: Hepadnaviridae · Multiple serotypes and genotypes A-F 42 nm · Enveloped 22 nm · In vitro model: primary hepatocyte culture and transfection of cloned HBV DNA HBsAg 42 nm Nucleus · In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyte and other tissues, human and other primates HBcAg HBV DNA 4 Hepatitis B Virus: Viral Replication. Pt. 2 Hepatitis B Virus: Viral Replication. Pt. 3 Hepatitis B Virus - Replication Hepatitis B Virus - Replication Viral entry Viral entry Uncoating Uncoating Positive strand synthesis Nuclear import Nuclear import cccDNA Repair Repair Transcription 5’ 5’ 3’ 3.5 kb RNA Removal of pregenome cccDNA Transcription 2.4/2.1 kb RNA Negative strand synthesis Translation Encapsidation 5’ 3’ 5’ 3’ 3.5 kb RNA 3’ 2.4/2.1 kb RNA 3 Hepatitis B Virus: Viral Replication. Pt. 4 Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 1 Hepatitis B Virus - Replication Hepatitis B Virus - Immunopathogenesis Export Viral entry HBV Uncoating Assembly & budding ER Positive strand synthesis HBsAg Nuclear import Removal of pregenome cccDNA Repair HBV Transcription 5’ 5’ 3’ 3.5 kb RNA Negative strand synthesis 3’ 2.4/2.1 kb RNA Hepatocytes Translation Encapsidation Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 2 Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 3 Hepatitis B Virus - Immunopathogenesis HBV Hepatitis B Virus - Immunopathogenesis TH Ig HBV CD4 Class II Antigen presenting cells B cell TH CD4 Class II Ig B cell CD8 Class I Antigen presenting cells Cytokines CD8 Class I CTL CTL HBV HBV Cytokines Hepatocytes Hepatocytes Direct cytotoxicity ? NK, NKT cells Nonspecific inflammatory cells Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 4 HEPATITIS B VIRUS NATURAL HISTORY Hepatitis B Virus - Immunopathogenesis HBV TH CD4 Class II Ig Antigen presenting cells Cytokines B cell CD8 Class I CTL Apoptosis HBV Cytokines Hepatocytes Clearance Direct cytotoxicity ? NK, NKT cells • 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 Nonspecific inflammatory cells 4 Clinical Significance of Serological Markers for HBV Infection HBV - Diagnosis Serological Markers of Acute HBV Infection HBV - Diagnosis Serological Markers Acute HBV Infection Clinical Significance HBsAg Acute/Chronic infection Anti-HBc IgM Acute infection HBeAg High infectivity Anti-HBe Low infectivity Anti-HBs Immunity Anti-HBc IgG and HBsAg Chronic infection Anti-HBc IgG and anti-HBs Resolved infection HBV DNA HBeAg Anti-HBe Anti-HBs Anti-HBc HBsAg 0 Anti-HBc IgM 2 Months Hepatitis C Virus: Morphology and Characteristics 4 6 Years Hepatitis C Virus: Genome and Gene Products, pt.2 Hepatitis C Virus Hepatitis C Virus Genome and Gene Products · Nucleic Acid: 9.6 kb ssRNA · Classification: Flaviviridae, Hepacivirus · Genotypes: 1 to 6 40-60 nm C E1 E2 5’ UTR NS2 NS3 NS4B P7 NS5A NS5B NS4A 3’ UTR Nonstructural protein coding region Structural protein coding region · Enveloped · In vitro model: primary hepatocyte and T cell cultures; replicon system C · In vivo replication: in cytoplasm, hepatocyte and lymphocyte; human and other primates Hepatitis C Virus: The Functions of Gene Products Hepatitis C Virus Nucleocapsid E1 and E2 Envelope proteins hypervariable region in E2 p7 Nonstructural, ion channel (?) NS 2 NS 2-3 protease NS 3 Protease, nucleotide triphosphatase, and RNA helicase NS 4 Cofactor for NS 3 protease activity NS 4B Formation of membranous web NS 5A Interferon sensitivity sequence NS 5B RNA-dependent RNA polymerase E2 Envelope NS2 NS3 Protease Serine protease A NS4 B NS5A NS5B Protease Cofactor Helicase RNA polymerase Hepatitis C Virus: Viral Replication, pt. 1 Hepatitis C Virus - Replication Gene Products and Functions Core (C) E1 Core Lipoproteins Entry 5 Hepatitis C Virus: Viral Replication, pt. 2 Hepatitis C Virus: Viral Replication, pt. 3 Hepatitis C Virus - Replication Hepatitis C Virus - Replication Lipoproteins Lipoproteins Entry Progeny genome Entry Replication + NS5B NS5B NS4B NS4B NS5A NS3/4A Uncoating C ER NS2 E1 Uncoating E2 Translation Hepatitis C Virus: Viral Replication, pt. 4 E2 E1-E2 Translation Nucleus E1 Chaperones ER E1-E2 C ER NS2 Chaperones ER NS5A NS3/4A Nucleus Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 1 Hepatitis C Virus - Replication Hepatitis C Virus - Immunopathogenesis Lipoproteins Export Progeny genome Entry Assembly Replication + HCV E1-E2 NS5B Golgi NS4B NS5A NS3/4A NS2 Uncoating C ER E1 E2 HCV Chaperones ER E1-E2 Translation Nucleus Hepatocytes Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 2 Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 3 Hepatitis C Virus - Immunopathogenesis Hepatitis C Virus - Immunopathogenesis Antigen presenting cells Antigen presenting cells Ig Ig CD4 Class II TH HCV B cell HCV Cytokines CTL HCV CD4 Class II TH B cell Cytokines CD8 Class I CTL CD8 Class I HCV Cytokines Hepatocytes Nonspecific inflammatory cells Hepatocytes 6 Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 4 Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 5 Hepatitis C Virus - Immunopathogenesis Hepatitis C Virus - Immunopathogenesis Antigen presenting cells Lymphoproliferative disorders Lymphoid Ig CD4 Class II TH HCV Ig cells CD4 Class II TH B cell Cytokines Cytokines CD8 Class I CTL HCV Steatosis Cytokines Viral Clearance Immune modulation HCV B cell Apoptosis or cytopathic replication Antigen presenting cells Autoimmunity Cryoglobulins Nonspecific inflammatory cells CD8 Class I CTL HCV Apoptosis or cytopathic replication Steatosis Cytokines Viral Clearance Hepatocytes Hepatocytes NK, NKT cells Nonspecific inflammatory cells Acute hepatitis C infection HCV - Diagnosis 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 HCV Infection 1000 HCV RNA positive 800 Anti-HCV ALT 600 (IU/L) Symptoms 400 200 0 0 2 4 6 8 Weeks 10 12 24 1 2 3 Time After Exposure 4 5 Months 6 7 Normal ALT Hoofnagle JH, Hepatology 1997; 26:15S Outcome Following Hepatitis C Infection HCV - Natural History Outcome Following Hepatitis C Infection Acute hepatitis C • HEPATITIS D 80% – Also known as delta agent – Uses the HBsAg protein coat – Hepatitis B must be present – coinfection or preexist Chronic infection 70% Chronic hepatitis 20% 1 - 4%/yr HCC Cirrhosis Time (yr) 4 - 5%/yr 10 HEPATITIS D AND E 20 Decompensation • HEPATITIS E – Water borne virus resembling hepatitis A – Rarely seen in USA 30 7 CHRONIC HEPATITIS B AND C CHRONIC HEPATITIS • • • • • • • Fatty liver Viral – B and C Autoimmune Drugs Alcohol Metabolic Others – CHF, hemochromatosis, vasculitis, IBD, celiac disease, neoplasia, etc. • 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 Serological Markers of Chronic HBV Infection HBV - Diagnosis Chronic HBV Infection Serologic events in HBV infection HBV DNA HBeAg HBsAg antiHBs HBeAg AntiHBe Anti-HBc IgG anti-HBc IgM HBV DNA Acute HBV Infection + - + - + + + ↑↑ Vaccine Responder - + - - - - - Normal Exposure with Immunity - + - +/- + - - Normal Chronic HBV (Wild Type) + - + - + - + ↑/N Chronic HBV (Precore Mutant) + - - + + - + ↑ /N Inactive Carrier + - - + + - -/+ Normal Anti-HBe HBsAg Anti-HBc IgG Anti-HBc IgM Months Years ALT Acute hepatitis C infection HCV - Diagnosis 1000 AUTOIMMUNE HEPATITIS Chronic HCV Infection • Genetically predisposed host exposed to an environmental agent triggering an autoimmune response directed at liver antigens leading to a necroinflammatory response HCV RNA positive 800 Anti-HCV ALT 600 (IU/L) Symptoms 400 200 0 0 2 4 6 8 Weeks 10 12 24 1 2 3 Time After Exposure 4 5 Years 6 7 Normal ALT • Associated with other autoimmune diseases thyroid disease, colitis, hemolytic anemia, ITP, diabetes, celiac disease, polymyositis, pericarditis, SLE, MCTD Hoofnagle JH, Hepatology 1997; 26:15S 8 AUTOIMMUNE HEPATITIS • Clinical presentation – generally female, fatigue, jaundice, hypergammaglobulinemia, elevated AST and ALT • Lab - presence of associated autoantibodies – ANA, thyroid antibodies, LKM, smooth muscle • Diagnostic liver biopsy – interface hepatitis and plasma cell infiltration • Treatment - steroids and immunosuppressants END 9
