CAUSES OF ACUTE HEPATITIS
VIRAL AND AUTOIMMUNE HEPATITIS
Arthur M. Magun, M.D. Clinical Professor of Medicine
• • • • • •
Viral hepatitis Other infectious etiologies e.g. CMV, EBV, TB Alcoholic hepatitis Drug hepatitis Ischemic hepatitis Choledocholithiasis
Human Hepatitis Viruses
Human Hepatitis Viruses Virus
Genome
HAV
RNA
Genome Envelope size (kb)
-
Picornaviridae hepatovirus
3.2
+
Hepadnaviridae
9.6
+
Flaviviridae hepacivirus
1.7
+
Unclassified
7.5
-
Unclassified,
positive sense, single stranded, linear
HBV
DNA
Family / genus
7.5
partially double stranded, circular
HCV
RNA positive sense, single stranded, linear
HDV
HEV
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
RNA positive sense, single stranded, linear RNA positive sense, single stranded, linear
(viroid), delta virus togavirus and alpha virus-like
OTHER INFECTIOUS ETIOLOGIES OF ACUTE HEPATITIS • CMV - cytomegalovirus; immunocompromised host • EPSTEIN-BARR – mononuclesosis; lymphadenopathy; splenomegaly • TB and M. avium intracellurare (MAI)
1
SYMPTOMS OF ACUTE VIRAL HEPATITIS
OUTCOMES OF VIRAL HEPATITIS ACUTE ILLNESS
• Fatigue, nausea, anorexia • Jaundice • Low-grade fever, abdominal pain • Arthralgia, myalgia, headache
CHRONIC HEPATITIS
CURE
FULMINANT HEPATITIS
Hepatitis A Virus: Morphology and Characteristics
SIGNS OF ACUTE VIRAL HEPATITS
Hepatitis A Virus • Nucleic Acid: 7.5 kb ssRNA 27 nm
• • • •
Fever – low grade Jaundice Hepatomegaly with RUQ tenderness Splenomegaly - infrequent
• Classification: Picornaviridae, Hepatovirus • One serotype and multiple genotypes • Nonenveloped, acid and heat stable • In vitro model: monkey and human cell cultures • In vivo replication: in cytoplasm of hepatocyte; human and other higher primates
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
Global Prevalence of Hepatitis A
HAV - Epidemiology
Global Prevalence of Hepatitis A Infection
HAV Prevalence High Intermediate Low Very Low
2
Hepatitis B Virus: Morphology and Characteristics
HEPATITIS A
Hepatitis B Virus • Nucleic Acid: 3.2 kb DNA
• 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
• 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
• In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyte and other tissues, human and other primates
HBcAg
HBV DNA
4
Serological Course of Acute Hepatitis A
Hepatitis B Virus: Viral Replication. Pt. 1
HAV
Hepatitis B Virus - Replication
Typical Serologic Course of Acute Hepatitis A Virus Infection
Viral entry
Symptoms
ALT
Total anti-HAV
Fecal HAV
IgM anti-HAV Nucleus
0
1
2
3
4
5
6
12
24
Months after exposure
Hepatitis B Virus: Viral Replication. Pt. 2
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 preexposure • Vaccine available to induce active immunity
Hepatitis B Virus - Replication Viral entry
Uncoating
Nuclear import cccDNA
Repair
Transcription 5’
5’
3’
3’
2.4/2.1 kb RNA
3.5 kb RNA
3
Hepatitis B Virus: Viral Replication. Pt. 3
Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 2
Hepatitis B Virus - Replication
Hepatitis B Virus - Immunopathogenesis
Viral entry
HBV
TH Ig
CD4 Class II
Uncoating
Antigen presenting cells
Positive strand synthesis
B cell
CD8 Class I
Nuclear import Repair
CTL
Removal of pregenome
cccDNA
HBV
Transcription 5’
5’
3’
Negative strand synthesis
3’
2.4/2.1 kb RNA
Hepatocytes
Translation Encapsidation
3.5 kb RNA
Hepatitis B Virus: Viral Replication. Pt. 4
Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 3
Hepatitis B Virus - Replication
Hepatitis B Virus - Immunopathogenesis Export
Viral entry
HBV
TH
CD4 Class II
Ig
Uncoating
Assembly & budding
HBsAg
Nuclear import
Positive strand synthesis
Cytokines B cell
CD8 Class I
CTL
Removal of pregenome
cccDNA
Repair
Antigen presenting cells
ER
HBV
Transcription
Cytokines 5’ 5’
3’
3.5 kb RNA
3’
2.4/2.1 kb RNA
Negative strand synthesis
Hepatocytes
Translation Encapsidation
Direct cytotoxicity ?
Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 1
NK, NKT cells
Nonspecific inflammatory cells
Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 4
Hepatitis B Virus - Immunopathogenesis
Hepatitis B Virus - Immunopathogenesis
HBV
HBV
TH
CD4 Class II
Ig
Antigen presenting cells
Cytokines B cell
CD8 Class I
CTL HBV
Apoptosis
HBV Cytokines
Hepatocytes
Hepatocytes Clearance
Direct cytotoxicity ?
NK, NKT cells
Nonspecific inflammatory cells
4
Hepatitis C Virus: Morphology and Characteristics
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
Hepatitis C Virus • Nucleic Acid: 9.6 kb ssRNA • Classification: Flaviviridae, Hepacivirus • Genotypes: 1 to 6
40-60 nm
• Enveloped • In vitro model: primary hepatocyte and T cell cultures; replicon system • In vivo replication: in cytoplasm, hepatocyte and lymphocyte; human and other primates
Clinical Significance of Serological Markers for HBV Infection
Hepatitis C Virus: Genome and Gene Products, pt.2
HBV - Diagnosis
Hepatitis C Virus
Serological Markers
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
Genome and Gene Products C
E1
E2
5’ UTR
C
E1
E2
Core
0
Anti-HBe
4
3’ UTR
Nonstructural protein coding region
NS2
NS3
Serine protease
A
NS4
B
NS5A
NS5B
Protease Cofactor
Helicase
RNA polymerase
Gene Products and Functions
Anti-HBs
Anti-HBc IgM
2 Months
NS5B
Hepatitis C Virus: The Functions of Gene Products
HBV DNA
HBsAg
NS5A
Hepatitis C Virus
Acute HBV Infection
Anti-HBc
NS4B NS4A
Protease
Serological Markers of Acute HBV Infection
HBeAg
NS3
Structural protein coding region
Envelope
HBV - Diagnosis
NS2 P7
6 Years
Core (C)
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
5
Hepatitis C Virus: Viral Replication, pt. 1
Hepatitis C Virus: Viral Replication, pt. 4
Hepatitis C Virus - Replication
Hepatitis C Virus - Replication
Lipoproteins
Lipoproteins
Export
Progeny genome
Entry
Entry Assembly
Replication
+
E1-E2 NS5B
Golgi
NS4B NS5A
NS3/4A NS2
Uncoating
C
ER
E1 E2
Chaperones
ER
E1-E2
Translation
Hepatitis C Virus: Viral Replication, pt. 2
Nucleus
Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 1
Hepatitis C Virus - Replication
Hepatitis C Virus - Immunopathogenesis
Lipoproteins
Entry
HCV NS5B NS4B NS5A
NS3/4A NS2
Uncoating
C
ER
E1 E2
HCV
Chaperones
ER Translation
E1-E2
Nucleus
Hepatocytes
Hepatitis C Virus: Viral Replication, pt. 3
Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 2
Hepatitis C Virus - Replication
Hepatitis C Virus - Immunopathogenesis Antigen presenting cells
Lipoproteins
Ig
Progeny genome
CD4 Class II
Entry TH
Replication
HCV
+
B cell
Cytokines
NS5B CD8 Class I
NS4B NS3/4A
Uncoating
NS2
NS5A
ER
CTL
C E1 E2
HCV
Chaperones
ER Translation
E1-E2
Nucleus
Hepatocytes
6
Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 3
Hepatitis C Virus - Immunopathogenesis
HEPATITIS C CLINICAL
Antigen presenting cells
Ig CD4 Class II
TH
HCV
B cell
Cytokines CD8 Class I
CTL HCV Cytokines
Nonspecific inflammatory cells
• • • • • • • •
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
Hepatocytes
Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 4
Acute hepatitis C infection
Hepatitis C Virus - Immunopathogenesis
HCV - Diagnosis Antigen presenting cells
Acute HCV Infection
1000
Ig
HCV RNA positive CD4 Class II
TH
HCV
B cell
800
Anti-HCV ALT
Cytokines
600
(IU/L) CD8 Class I
Symptoms
400
CTL 200 HCV
Apoptosis or cytopathic replication
Cytokines
Viral Clearance
Normal ALT
0
Steatosis
0
Nonspecific inflammatory cells
Hepatocytes
2
4
1
2
3
4
5
6
7
Months
Time After Exposure
Outcome Following Hepatitis C Infection Acute hepatitis C
Ig
cells
CD4 Class II
TH
80%
Chronic infection B cell
70%
Cytokines CD8 Class I
Chronic hepatitis
CTL
Viral Clearance
24
Outcome Following Hepatitis C Infection
Antigen presenting cells
Immune modulation
Apoptosis or cytopathic replication
12
HCV - Natural History
Autoimmunity
HCV
10
Weeks
Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 5
Lymphoproliferative disorders Lymphoid
8
Hoofnagle JH, Hepatology 1997; 26:15S
Hepatitis C Virus - Immunopathogenesis Cryoglobulins
6
20%
1 - 4%/yr
Steatosis Cytokines
Hepatocytes
HCC
Cirrhosis
HCV
NK, NKT cells
Nonspecific inflammatory cells
Time (yr)
4 - 5%/yr 10
20
Decompensation
30
7
Serological Markers of Chronic HBV Infection
HBV - Diagnosis
HEPATITIS D AND E
Chronic HBV Infection HBV DNA
• HEPATITIS D Anti-HBe
HBeAg
– Also known as delta agent – Uses the HBsAg protein coat – Hepatitis B must be present – coinfection or preexist
HBsAg Anti-HBc IgG
• HEPATITIS E – Water borne virus resembling hepatitis A – Rarely seen in USA
Anti-HBc IgM
Months
CHRONIC HEPATITIS • • • • • • •
Fatty liver Viral – B and C Autoimmune Drugs Alcohol Metabolic Others – CHF, hemochromatosis, vasculitis, IBD, celiac disease, neoplasia, etc.
Years
Serologic events in HBV infection 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
ALT
Acute hepatitis C infection
CHRONIC HEPATITIS B AND C
HCV - Diagnosis
1000
• 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
Chronic HCV Infection HCV RNA positive
800
Anti-HCV ALT
600
(IU/L)
Symptoms
400 200
Normal ALT
0 0
2
4
6
8
10
12
24
1
2
3
Weeks
4
5
6
7
Years
Time After Exposure Hoofnagle JH, Hepatology 1997; 26:15S
8
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
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
END
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