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

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CAUSES OF ACUTE HEPATITIS • • • • • •

Viral hepatitis Other infectious etiologies e.g. CMV, EBV, TB Alcoholic hepatitis Drug hepatitis Ischemic hepatitis Choledocholithiasis

Human Hepatitis Viruses

Human Hepatitis Viruses Virus Virus

HAV

Genome Genome

RNA

Genome Genome Envelope Envelope size size (kb) (kb)

7.5

-

Picornaviridae hepatovirus

DNA

3.2

+

Hepadnaviridae

RNA

9.6

+

Flaviviridae hepacivirus

1.7 1.7

+

Unclassified Unclassified

positive positive sense, sense, single single stranded, stranded, linear linear

HBV HCV HDV HDV

HEV HEV

Family Family // genus genus

partially partially double double stranded, stranded, circular circular positive positive sense, sense, single single stranded, stranded, linear linear RNA RNA positive positive sense, sense, single single stranded, stranded, linear linear RNA RNA positive positive sense, sense, single single stranded, stranded, linear linear

(viroid), delta virus 7.5 7.5

-

Unclassified, Unclassified,

togavirus and alpha virus-like

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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

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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

Hepatitis A Virus • Nucleic Acid: 7.5 kb ssRNA 27 nm

• 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

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Global Prevalence of Hepatitis A

HAV - Epidemiology

Global Prevalence of Hepatitis A Infection

HAV HAV Prevalence Prevalence High High Intermediate Intermediate Low Low Very Very Low 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

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Serological Course of Acute Hepatitis A

HAV

Typical Serologic Course of Acute Hepatitis A Virus Infection Symptoms

ALT ALT

Total Total anti-HAV anti-HAV

Fecal Fecal HAV HAV

00

11

IgM IgM anti-HAV anti-HAV

22

33

44

55

66

12 12

24 24

Months Months after after exposure exposure

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

7

Hepatitis B Virus: Morphology and Characteristics

Hepatitis B Virus • 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

HBcAg

HBV DNA

• In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyte and other tissues, human and other primates 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 3’

5’

3.5 kb RNA

Hepatitis B Virus: Viral Replication. Pt. 3

Hepatitis B Virus - Replication Viral entry

Uncoating Positive strand synthesis Nuclear import

Removal of pregenome

cccDNA

Repair

Transcription 5’

3’

2.4/2.1 kb RNA 3’

5’

3.5 kb RNA

Negative strand synthesis

Translation Encapsidation

9

Hepatitis B Virus: Viral Replication. Pt. 4

Hepatitis B Virus - Replication Export Viral entry

Uncoating

Assembly & budding

ER

HBsAg

Nuclear import

Removal of pregenome

cccDNA

Repair

Positive strand synthesis

Transcription 5’

3’

2.4/2.1 kb RNA 3’

5’

3.5 kb RNA

Negative strand synthesis

Translation 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 Ig

CD4 Class II 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 Class II

Ig

Antigen presenting cells

Cytokines B cell

CD8 Class I

CTL HBV Cytokines

Hepatocytes Direct cytotoxicity ?

NK, NKT cells

Nonspecific inflammatory cells

11

Hepatitis B Virus: Immune Responses and Pathogenesis, pt. 4

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

Nonspecific inflammatory 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

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

Serological Markers of Acute HBV Infection

HBV - Diagnosis

Acute HBV Infection HBV DNA HBeAg

Anti-HBe Anti-HBe Anti-HBs Anti-HBs

Anti-HBc Anti-HBc

HBsAg

00

Anti-HBc Anti-HBc IgM IgM

22 Months Months

44

66 Years Years

13

Hepatitis C Virus: Morphology and Characteristics

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

Hepatitis C Virus: Genome and Gene Products, pt.2

Hepatitis C Virus

Genome and Gene Products C E1

E2

5’ 5’ UTR UTR

NS2

NS3

P7 P7

E1

E2

Core Core

Envelope Envelope

NS5A

NS5B

NS4A NS4A

3’ 3’ UTR UTR

Nonstructural Nonstructural protein protein coding coding region region

Structural Structural protein protein coding coding region region

C

NS4B

NS2

NS3

Protease Protease

Serine Serine protease protease

A A

NS4

B B

NS5A

NS5B

Protease Protease Cofactor Cofactor

Helicase Helicase

RNA RNA polymerase polymerase

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Hepatitis C Virus: The Functions of Gene Products

Hepatitis C Virus

Gene Products and Functions Core (C) E1 and E2 p7 NS 2 NS 3 NS 4 NS 4B NS 5A NS 5B

Nucleocapsid Envelope proteins hypervariable region in E2 Nonstructural, ion channel (?) NS 2-3 protease Protease, nucleotide triphosphatase, and RNA helicase Cofactor for NS 3 protease activity Formation of membranous web Interferon sensitivity sequence RNA-dependent RNA polymerase

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 NS2

Uncoating

C

ER

E1

E2

Chaperones

ER Translation

E1-E2

Nucleus

Hepatitis C Virus: Viral Replication, pt. 3

Hepatitis C Virus - Replication Lipoproteins

Progeny genome

Entry Replication

+ NS5B NS4B NS3/4A

Uncoating

NS2

NS5A

ER

C E1

E2

Chaperones

ER Translation

E1-E2

Nucleus

16

Hepatitis C Virus: Viral Replication, pt. 4

Hepatitis C Virus - Replication Lipoproteins

Export

Progeny genome

Entry Assembly

Replication

+

E1-E2 NS5B

Golgi

NS4B NS3/4A NS2

Uncoating

NS5A C

ER

E1

E2

Chaperones

ER Translation

E1-E2

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

CTL

CD8 Class I

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

CTL

CD8 Class I

HCV Cytokines

Nonspecific inflammatory 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

CTL

CD8 Class I

HCV

Apoptosis or cytopathic replication

Steatosis Cytokines

Viral Clearance

Nonspecific inflammatory cells

Hepatocytes

Hepatitis C Virus: Immune Responses and Pathogenesis, pt. 5

Hepatitis C Virus - Immunopathogenesis Antigen presenting cells

Autoimmunity

Cryoglobulins

Immune modulation Lymphoproliferative disorders Lymphoid

Ig

cells

CD4 Class II

TH

HCV

B cell

Cytokines

CTL

Apoptosis or cytopathic replication Viral Clearance

CD8 Class I

HCV Steatosis Cytokines

Hepatocytes

Nonspecific inflammatory cells

NK, NKT cells

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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

Acute HCV Infection

1000

HCV RNA positive 800

AntiAnti-HCV ALT

600

(IU/L) (IU/L)

Symptoms

400 200

Normal Normal ALT ALT

0 0

2

4

6

8

10

12

24

1

2

3

Weeks Weeks

4

5

6

7

Months Months

Time After Exposure Hoofnagle Hoofnagle JH, JH, Hepatology Hepatology 1997; 1997; 26:15S 26:15S

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Outcome Following Hepatitis C Infection

HCV - Natural History

Outcome Following Hepatitis C Infection Acute hepatitis C 80%

Chronic infection 70% Chronic hepatitis 20%

1 - 4%/yr

HCC

Cirrhosis 4 - 5%/yr

Time (yr)

10

Decompensation

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

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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

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Serological Markers of Chronic HBV Infection

HBV - Diagnosis

Chronic HBV Infection HBV DNA HBeAg

Anti-HBe Anti-HBe HBsAg HBsAg Anti-HBc IgG

Anti-HBc IgM

Months Months

Years Years

Serologic events in HBV infection HBsAg

antiHBs

HBeAg

AntiHbe

Anti-HBc IgG

anti-HBc IgM

HBV 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

1000

Chronic HCV Infection HCV RNA positive

800

AntiAnti-HCV ALT

600

(IU/L) (IU/L)

Symptoms

400 200

Normal Normal ALT ALT

0 0

2

4

6

8

10

12

24

1

2

3

Weeks Weeks

4

5

6

7

Years Years

Time After Exposure Hoofnagle Hoofnagle JH, JH, Hepatology Hepatology 1997; 1997; 26:15S 26:15S

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

END

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