THE ABCS OF HEPATITIS

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THE ABCS OF HEPATITIS
Michael E. Hagensee, M.D., Ph.D. Louisiana State
University Associate Professor of Clinical
Medicine Department of Medicine Section of
Infectious Disease Division of HIV
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OBJECTIVES

• To understand the natural history and clinical
  manifestations of viruses that cause hepatitis
• To know the basic virology of the viruses that
  cause hepatitis
• To know how to treat or prevent viral hepatitis

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VIRAL HEPATITIS
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HEPATITIS A

• ssRNA in the picornavirus family
• 27 nm particle, icosahedral, non-enveloped
• with an incubation period of 15-45 days
• Virus can be grown in-vitro

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HEPATITIS A VIRUS
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HEPATITIS A

• Mode of Transmission Fecal oral
• Risk Factors Personal contact
• Poor hygiene
• Overcrowding
• Contaminated food
• shellfish, milk, water
• Day care, nursing homes
• IVDU
• International Travel
• Gay men

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HEPATITIS A
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HEPATITIS A
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HEPATITIS A

• Symptoms and Signs
• Prodrome 1-2 weeks prior, fatigue, malaise,
  anorexia, nausea, vomiting
• Icteric phase jaundice yellow eyes, skin,
  mucous membranes
• Pruritis - itching
• Enlarged and tender liver - lasts 3-4 weeks
• Many do not become icteric
• Fulminant Rare 0.1

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HEPATITIS A

• Symptoms and Signs

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HEPATITIS A
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EVENTS IN HEPATITIS A VIRUS INFECTION
Clinical illness
Infection
ALT
IgM
IgG
Viremia
Response
HAV in stool
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Week
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HEPATITIS A

• Serology
• Acute IgM lasts 3-6 months
• Chronic IgG lifetime
• Liver enzymes increases in ALT, AST, bilirubin

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HEPATITIS A

• Differential Diagnosis
• Other viral hepatitis
• including CMV, HSV, coxsackievirus
• Other infections toxoplasmosis and others
• Drugs, alcohol
• Gall bladder disease cholescystitis
• Pancreatitis
• Autoimmune liver disease ascending cholangitis
• Obtain hepatitis viral serologies, and liver
  ultrasound

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HEPATITIS A

• Treatment
• Supportive anti-itch meds
• anti-emetics
• Isolate patient if uncontrolled diarrhea

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HEPATITIS A

• Prophylaxis
• Improve Hygiene
• Post-exposure Passive immunity
• Immunoglobulin Ig
• 0.02 ml/kg IM
• Works as late as 2 weeks after exposure

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HEPATITIS A VACCINE-(HAVRIX)
MOA Inactivated virus Indications
Travelers to endemic areas, military
personnel Native Alaskans, Native Americans,
Gay males, drug users, outbreaks
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HEPATITIS A VACCINE-(HAVRIX)
Dose gt18 years old - 1 ml (1440 units), and
6-12 months later (43/dose) 2-18 years old -
0.5 ml (360 units), and 6-12 months later
(15/dose) Side effects Pain at injection
site, fever, headache
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HEPATITIS A VACCINE EFFICACY
Cases of Hepatitis A
Werzberger et al, NEJM 327453, 1992
plt0.001
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HEPATITIS B

• DNA virus hepadnavirus 3200 bp
• Compact - uses overlapping genes
• Complicated replication has a ssDNA
• component to RNA to DNA
• Difficult to grow
• Liver damage may be due
• to host immunity

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HEPATITIS B

• Structure and major antigens
• 22 nm most abundant extra viral envelope
  protein
• - spheres and tubes
• 42 nm double-shelled intact virus
• Both covered by HBsAg see in blood
• Disrupt 42 nm with mild detergent get 27nm core
  particle covered by HBcAg never see in blood
• HBeAg soluble binds to the smooth ER and gets
  exported into the circulation see in blood

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HEPATITIS B
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HEPATITIS B

• Mode of Transmission Blood and sexual contact
• Perinatal at delivery
• Risk Factors Blood Transfusion
• IVDU shared needles
• Unprotected Sex
• Gay men
• Birth from a mom who is HBeAg
• positive

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HEPATITIS B
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HEPATITIS B
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HEPATITIS B

• Incubation period 10-12-weeks
• Signs and symptoms
• Acute As above
• Fulminant 0.1
• Chronic HBsAg - leads to cirrhosis and cancer
• Weight loss, fatigue, malaise
• Liver failure ascites, edema, bleeding

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HEP B LIVER CANCER

• Hepatitis B surface antigen positivity
• Increases risk of liver cancer 100X
• Supported by over 80 studies
• Takes gt 30 years for cancer
• Find DNA in 85 of cases, most integrated (gt75)

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HEP B LIVER CANCER MOA
Two main theories 1. HepB causes chronic
inflammation and cell regeneration 2. X-gene
- activates other genes in the cell - can
increase liver cell proliferation
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HEPATITIS B
Serologic Markers During Acute HBV Hepatitis and
Recovery
Anti-HBcAb
Titer
HBsAg
Anti-HBsAb
Window
Anti-HBeAb
HBeAg
Months after exposure
Jaundice
Incubation
Recovery
IMMUNE
Elevated ALT
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HEPATITIS B

• Serology - acute
• HBsAg (HBsAb-) acute infection or chronic
  carrier
• HBeAg highly infectious
• HBsAb immune naturally or vaccine
• Window HBsAg- and HBsAb-
• will be HBcAb (IgM acute)

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Progression to Chronic Hepatitis B Virus
Infection Typical Serologic Course
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HEPATITIS B

• Serology Chronic
• HBsAg and HBsAb- chronic carrier

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HEPATITIS B

• Treatment
• Acute
• Supportive anti-itch meds
• anti-emetics
• Blood-borne pathogen procedures
• Chronic
• Interferon alpha (pegylated)
• - 24 weeks 75 effective
• Lamividine
• Adefovir
• Tenofovir

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INTERFERON- ALPHA

• Intron A, Roferon A
• Pegylated PEG Intron
• Indications Hepatitis B and C, HPV-warts
• Dose 3 million units t.i.w. (3 x per week)
• Peg - 1-3 million units q week (1x per week)
• Side effects Flu-like, increases depression,
  may increase cardiac conditions
• Cost 35/dose

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HEPATITIS B VACCINE
RECOMBINIVAX-HB or ENERGERIX-B Composition
- Recombinant yeast HepB surface
antigen Schedule - Birth, 2, 6
months Effectiveness - USA - No large impact
yet Universal vaccination commenced in
1991 Taiwan - Decrease by 50 - 75 of HCC cases
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HEPATITIS B Post-exposure Prophylaxis
HBIG infants 0.5 ml, adults 0.06 ml/kg IM x 1
and follow up with full 3 dose
vaccination
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HEPATITIS C

• ss RNA Flavivirus (former non-A, non-B)
• Marked genetic heterogeneity due to hypervariable
  region
• Major neutralization epitope of HCV
• Mutates under immunologic pressure and becomes
  chronic
• Vaccines are difficult to develop
• Immunoglobulin not effective

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HEPATITIS C

• 6 major genotypes (1-6)
• 80 in U.S. are genotype 1a or 1b
• Genotype dictates length of therapy and predicts
  therapeutic response
• Genotype 1 requires longer therapy and has lower
  response

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HEPATITIS C

• Prevalence
• 4 million Americans infected
• 3.2 of African - Americans
• 2.1 of Mexican - Americans
• 1.5 of non Hispanic whites
• 8,000- 10,000 deaths per year
• Leading cause of liver transplants

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HEPATITIS C

• Transmission
• Blood, rarely sexual
• Increasing number of sexual partners is
  associated with higher rates of infection
• Monogamous couples at low risk
• Signs and Symptoms
• Rarely acute symptoms
• Most asymptomatic until liver failure
• 50 of those infected progress
• Fulminant 0.1

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HEPATITIS C

• Serology
• Screen by antibodies
• PCR for viral DNA may be more sensitive

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Serologic Pattern of Acute HCV Infection with
Recovery
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
0
1
2
3
4
5
6
1
2
3
4
Years
Months
Time after Exposure
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Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
0
1
2
3
4
5
6
1
2
3
4
Years
Months
Time after Exposure
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HEPATITIS C - Fibrosis
3
2.5
gt40 Years lt40 Years
2
1.5
1
lt5
6-10
11-15
16-20
gt20
4
3
gt50 g Alcohol/Day lt50 g Alcohol/Day
Fibrosis Stage
2
1
lt10
11-20
21-30
31-40
gt40
4
3
Men Women
2
1
lt10
11-20
21-30
31-40
41-50
Duration of Infection (Years)
Poynard T et al. Lancet. 1997349825.
II-11
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HEPATITIS C - Fibrosis
Normal
Mild Chronic Hepatitis
Moderate Chronic Hepatitis
Cirrhosis
II-8
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HEPATITIS C - Fibrosis

• Treatment
• Pegylated interferon alfa plus ribavirin
• Treatment for 24-48 weeks
• Overall success rates of 50
• Decreased by genotype 1, HIV, older
• Can try longer treatments 48 weeks
• Follow by serum HepC viral load, liver biopsy

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INTERFERON ALPHA TREATMENT OF HEPATITIS C-RESPONSE
Shindo et al, Ann Intern Med 117700, 1991
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HEPATITIS D (delta)

• Virus incomplete -ssRNA virus, needs a HBsAg to
  replicate
• 35 nm virus encapsidated by HBsAg
• Incubation Period - 2- 4 weeks
• Mode of Transmission - Blood and Secretions

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HEPATITIS D (delta)
d antigen
HBsAg
RNA
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HEPATITIS D (delta)

Coinfection - Acute HDV and HBV severe acute
disease low risk of chronic infection Superinfect
ion Acute HDV superimposed upon chronic
HBV usually develop chronic HDV infection high
risk of severe chronic liver dz Fulminant 5-20
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HEPATITIS D (delta) co-infection
Symptoms
ALT Elevated
anti-HBs
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV
Time after Exposure
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HEPATITIS D (delta) - superinfection
Jaundice
Symptoms
Total anti-HDV
ALT
HDV RNA
HBsAg
IgM anti-HDV
Time after Exposure
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HEPATITIS D (delta)

Serology Acute IgM Chronic
IgG Treatment HBV-HDV Coinfection Pre or
postexposure prophylaxis to prevent HBV
infection HBV-HDV Superinfection Education to
reduce risk behaviors among persons with chronic
HBV infection
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HEPATITIS E

• Virus
• ssRNA calcivirus
• 32 nm non-enveloped
• Incubation Period
• Average 40 days
• Range 15-60 days
• Mode of Transmission Fecal oral

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HEPATITIS E

Most outbreaks associated withfecally
contaminated drinking water Minimal
person-to-person transmission U.S. cases usually
have history of travel to HEV-endemic areas
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HEPATITIS E

Case-fatality rate Overall, 1-3(fulminant)
Pregnant women, 15-25 Illness
severity Increased with age Chronic
sequelae None identified Diagnosis
History, serology not routinely
available
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HEPATITIS E
Symptoms
ALT
IgG anti-HEV
IgM anti-HEV
Virus in stool
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Weeks after Exposure
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HEPATITIS E

Prevention Avoid drinking water of unknown
purity, uncooked shellfish, and uncooked
fruit/vegetables not peeled or prepared by
traveler
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HEPATITIS G (GB)

• Blood borne flavivirus, related to HCV
• Benign clinical course
• No treatment required
• No vaccines available
• Diagnose with HGV RNA
• Appears to benefit HIV patients???

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Question Which virus(es) are sexually spread

• HAV
• HBV
• HCV
• All the above

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A Chinese family is moving back to China. What
vaccines should the 2 yr old receive?

• HAV
• HBV
• BOTH OF THE ABOVE
• NONE OF THE ABOVE

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Which newborn is at greatest risk for
contracting HBV

• Mother is HBsAg , HBeAg -
• Mother is HBsAg -, HBeAg -
• Mother is HBsAg , HBeAg

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A 10 year old child has acute hepatitis, which
diagnostic panel is the best?

• HAV Ab, HBcIgM, HCV Ab
• HAV IgM, HBsAg, HCV Ab
• HAV IgM, HBsAg, HCV IgM
• HAV IgM, HBcIgM, HCV Ab

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Which Panel Below is Best to Detect Chronic Viral
Hepatitis

• HAV Ab, HBsAg, HCV Ab
• HBsAg, HCV Ab
• HAV IgM, HBsAg
• HAV IgM, HCV Ab

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