Viral Hepatitis

Medicine Student Lecture

David R Nelson, M.D.

Associate Professor of Medicine
Director, Hepatology and Liver Transplantation
University of Florida
Case 1:
29 y/o female came to your clinic with:
• Jaundice, Abdominal pain, Nausea / Vomiting
• AST-2,000 ALT- 2,500, Total bili 1.8
• She denies IVDA or any recent drug/medicine exposure, but
had unprotected sex about 6 weeks ago
• Ultrasound shows normal appearing liver and blood flow

• Her diagnosis is……

 Causes of Acute Hepatitis

Acute Hepatitis

Viral Hepatitis Drugs

Toxins Vascular Autoimmune
Metabolic
A, B/D, C, E Ethanol
Jamaica Bush Tea Hypotension Wilson's Disease
EBV Tylenol Hepatitis
Mushrooms Budd-Chiari A1AT
CMV & HSV Halothane
Case:
• 38 y/o male with past medical history of abnormal ALT for
past 4 years. He had a blood tx as a child due to MVA.
Patient came to your clinic with:
– ALT 150, AST 100
– HBsAb +, HBcAb +
– HCV Ab +
– HAV IgG +
• What is your dx?
 Causes of Chronic Hepatitis

Chronic Hepatitis

Drugs Autoimmune Metabolic

Viral Hepatitis
MTX AIH A1AT
Hep B Alcohol NAFLD
INH PBC HHC
Hep C
Amiodarone PSC Wilson's

Abbreviations:
NAFLD: nonalcoholic fatty liver disease; AIH: autoimmune hepatitis; PBC: primary biliary cirrhosis
PSC: primary sclerosing cholangitis, A1AT: alpha-1 antitrypsin deficiency, HHC:hereditary hemochromotosis
Acute Viral Hepatitis by Type, USA: 1982-1993

34%

47%
16%
Hepatitis A
3% Hepatitis B
Hepatitis C
Hepatitis
Non-ABC

Source: CDC Sentinel Counties Study on Viral Hepatitis

 Hepatitis A Virus
• Transmission route: fecal-oral
27 nm • Clinical presentation
- Jaundice: Adults- 30%, Children- <5%
- Fulminant: <1%
• Diagnostic tests
- Acute infection: IgM anti-HAV
- Chronic infection: Not applicable
• Immunity: IgG anti-HAV
• Case-fatality rate: 0.1 – 2.7%
• Chronic infection: None

Nucleic Acid: 7.5 kb ssRNA

 Global Prevalence of Hepatitis A Infection

HAV Prevalence
High
Intermediate
Low
Very Low
 Hepatitis A Virus Infection
Typical Serologic Course
Symptoms Total anti-HAV

ALT
Titer

Fecal
HAV
IgM anti-HAV

0 1 2 3 4 5 6 12 24
Months after Exposure
Hepatitis A Prevention - Immune Globulin

Preexposure
• Travelers to high HAV-prevalence regions

Postexposure (within 14 days)

• Routine
• Household and other intimate contacts

• Selected situations
• Institutions (e.g. daycare centers)
• Common source exposure (e.g. food prepared
by infected food handler)
 Hepatitis A: Pre-exposure Vaccination
Persons at increased risk or danger of infection
• Travelers to intermediate and high
HAV prevalence areas
• Men having sex with men
• Injecting drug users
• Persons with chronic liver disease

Communities with high rates of hepatitis A

(e.g., Alaskan Natives, Native-Americans)
Routine pre-school childhood vaccination

ACIP Recommendations MMWR 1999; 48(RR12):1

 Hepatitis E Virus
• Fecal-oral transmission (human to human)
• Contaminated water supplies in tropical
or subtropical developing countries
32 nm • Mainly young adults
• Can infect primates, swine, sheep, rats
• Swine may be reservoir of infection in
North America
• Maternal-infant transmission occurs and
is often fatal

Nucleic Acid: 7.5 kb ssRNA

Hepatitis E

Clinical Characteristics
• Similar to hepatitis A
• Dx: IgG anti-HEV (seroconversion)
• Can cause severe acute hepatitis
• Subclinical infection is common
• Attenuated virus from animal reservoirs
• Low-dose infections often asymptomatic
• No chronic infection
• Up to 20% mortality among pregnant women (esp. third
trimester)
 Hepatitis B Virus

HBsAg

42 nm HBcAg

HBV DNA

• Hepadnaviridae member that primarily infects liver cells

• 50 to 100 times more infective than HIV
• Multiple genotypes exist (A-H)
• DNA virus found in blood and body fluids
– Able to survive in dried blood for longer than 1 week
 > 350 million carriers (HBsAg + > 6 months)
Geographic Distribution of Chronic HBV
Infection

10th cause of death

(1 million / year)

Cirrhosis in 20% HBsAg Prevalence

(75 - 100 million) ≥8% - High
HCC in 5 - 10% 2-7% - Intermediate
(20 - 40 million) <2% - Low
 Hepatitis B Prevalence
• Overall U.S. prevalence: 0.3%
• Asian Americans: ~10-13%

Laotians

Vietnamese

Korean

Japanese

Filipino

Chinese

0%
Son D, Asian Am Pac Isl J Health 2001
2% 4% 6% 8% 10% 12% 14%
Slide courtesy of Robert Gish, MD
 HBV Sources of Infection
Household, 3%
MSM, 23%

Other, 23%
Sex
contact, 23%

Multiple sex IDU, 20%

partners, 24%

Many patients do not reveal IDU as source of infection

Centers for Disease Control and Prevention. Hepatitis B.

In: Atkinson W et al, eds. Epidemiology & Prevention of
Vaccine-Preventable Diseases. 8th ed Washington DC:
Public Health Foundation; 2005:191-212.
Signs and Symptoms of Acute Hepatitis B

• About 30% of persons have no signs or symptoms

• If symptoms are present, generally nonspecific including:

• Jaundice • Nausea, vomiting

• Fatigue • Joint pain
• Abdominal Pain • Dark Urine
• Loss of Appetite • Clay-colored bowel
movements
 Hepatitis B - Clinical Features
Incubation period
Clinical illness (jaundice)
Acute case-fatality rate
Chronic infection
Mortality from chronic liver disease
Average: 60 – 90 days
Range: 45 – 180 days
< 5 yrs of age: <10%
≥ 5 yrs of age: 30 – 50%
0.5 – 1%
< 5 yrs of age: 30 – 90%
≥ 5 yrs of age: 2 – 10%
15 – 25%
Progression to Chronic Hepatitis B Virus
Infection
Typical Serologic Course
Acute Chronic
(6 months) (Years)
HBeAg anti-HBe
HBsAg
Total anti-HBc
Titer

HBV DNA
IgM anti-HBc

0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after Exposure
 Interpretation of Serologic Markers
Recovery Chronic Chronic Resistance
Acute from acute HBeAg + HBeAG – Successful to antiviral
hepatitis B hepatitis B disease disease Vaccination agents

HBsAg  
(may clear)
Anti-HBs  
Anti-HBc

IgM

Anti-HBc    

HBeAg  

Anti-HBe (in some 
cases)

(may be
only 
DNA (PCR
marker   (sequence
if required)
during pol region)
window
period)
 Hepatitis B: Disease Progression

Liver Cancer
(HCC)
5%-10% 1

2-6%

Acute Chronic Liver

Infection Infection Cirrhosis Transplantation
Death
10-30% 1
90% in perinatal
30-90% in children<5yrs old
5% in healthy adults
Chronic HBV is the 6th
Higher in HIV, immune suppressed
Liver Failure leading cause of liver
(Decompensation) transplantation in the US4

23% within 5 years

1. Torresi J et al. Gastroenterology. 2000.
2. Fattovich G et al. Hepatology. 1995.
3. Moyer LA et al. Am J Prev Med. 1994.
4. Perrillo R et al. Hepatology. 2001.
 Targeted Surveillance for HCC

Hepatitis B Carriers Non-hepatitis B Cirrhosis

• Hepatitis C
• Asian males > age 40
• Alcoholic cirrhosis
• Asian females > age 50
• Genetic hemochromatosis
• All cirrhotic HBV carriers
• Primary biliary cirrhosis
• Family history of HCC
• Other (? efficacy)
• Africans > age 20
• A1AT deficiency
• High HBV DNA
• NAFLD
• Autoimmune hepatitis
 Surveillance for HCC should be with ultrasound at
6 to 12 month intervals; AFP is not adequate
Bruix J and Sherman M. Hepatology 2005;42:1208
 Prevention of Transmission of Hepatitis B
Vaccination
1. Vaccinate Sexual and household contacts
2. Newborns of HBV-infected mothers
• HBIG and
• hepatitis B vaccine at delivery
3. Test for response to vaccination
• infants of HBsAg-positive mothers (9 to 15 months )
• health care workers,
• dialysis patients, and
1-2 months
• sexual partners
4. Follow-up testing of vaccine responders
• Annually for chronic hemodialysis patients
 Goals of Treatment in HBV
• Reduce the risk of disease progression
• Reduce the risk of hepatocellular carcinoma

• Loss of HBeAg, HBeAg  HBeAb

• Undetectable HBV-DNA
Virologic Response
• (<105 copies/ml = 20,000IU/mL)
• Normalization of ALT
• Histologic Response
• HBsAg  HBsAb
Approved Treatments

Lok AND McMahon. .Hepatology, Vol. 45, No. 2, 2007

Hepatitis D Virus: Morphology and
Characteristics
• Nucleic Acid: 1.7 kb ssRNA

• Classification: unclassified,
related to viroids; deltavirus

• Transmission: sex, IVDA

• Clinical features
- Fulminant: 2 – 7.5%
35-37nm - Chronic infection
Superinfection: 80%
Coinfection: < 5%

• Diagnostic tests
-Acute infection: IgM anti-HDV
-Chronic infection:IgG anti-HDV, HBsAg +
 Modes of HDV infection
Coinfection

D
Superinfection

B
D
 HCV Life-Cycle and Pathogenesis

Immune Immune
Recognition Response
Cell Binding
and Infection CD4
CD8
NK
Replication
Effector DC
HCV Cytokines

HSC
Viral Packaging
and Release
Fibrosis
 Course of Acute HCV Infection

1000 HCV RNA positive

Anti-HCV
800 Symptoms
ALT (IU/L)

600

400

200
Normal ALT
0
0 2 4 6 8 10 12 24 1 2 3 4 5 6 7
Weeks Months
Time After Exposure
Hoofnagle JH. Hepatology. 1997;26:15S. Carithers RL Jr, et al. Semin Liver Dis.
2000;20:159-171. Pawlosky JM. Hepatology. 2002;36(suppl 1):S65-S73. NIH Management
of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at:
http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.
 Symptoms, or Lack of, in Chronic
HCV Infection

Symptomatic
37% 100
Cirrhosis 80
80
7%

Patients (%)
60

40

20

0
56% Fatigue
Asymptomatic
 ALT Elevations Are Not Indicative of
Chronic HCV Infection
100
Patients* With HCV infection (%)

80

60
42 43
40

20 15

0
Persistently Intermittently Persistently
Normal ALT Elevated ALT Elevated ALT

Inglesby TV, et al. Hepatology. 1999;29:590-596.

 Diagnostic Tests for HCV Infection
Diagnostic Test Type
Specifications Serologic Virologic
Mode of detection Antibodies Virus
Sensitivity > 95% > 98%
Specificity Variable > 98%
Detection postexposure 2-6 mos 2-6 wks
Use Screening Confirmation
CDC Morbidity Mortality Weekly Report. 1998;16(RR-19):1-33. NIH Management of
Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at:
http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.
 Molecular Virologic Assays

Qualitative assays Quantitative assays

High sensitivity Detection cutoff > qualitative
(≤ 50 IU/mL)
How much HCV is present?
Is HCV present?

Genotype
assays

What type of HCV is present?

 Clinical Significance of HCV Genotypes

• Great genetic diversity: 2 genotypes (1 through 6)

• Multiple subtypes: a, b, c, etc
• Genotype is best pretreatment predictor of response
• Genotype 1: least responsive to therapy
• Determines dose and duration of therapy
• Genotype 1: 48 weeks of peg-IFN alfa + RBV 1000-1200
mg
• Genotype 2/3: 24 weeks of peg-IFN alfa + RBV 800 mg
• All patients should have genotype determined prior to
initiating therapy
Choo QL, et al. Science. 1989;244:359-62. NIH Consensus Development
Conference Statement. Bethesda, Md: National Institutes of Health;
June 10-12, 2002. Hadziyannis SJ. Ann Intern Med. 2004;140:346-355.
Prevalence of HCV Dependant on Risk Factors

• Hemophilia 74-90%
• IVDA 72-89%
• Prison 40%
• HIV 30-40%
• Blood transfusion prior to 90 5-9%
• Infants to HCV+ Mothers 5%
• Sexual Partner 0.5-3%
• General Population 1.8%

Adapted from MMWR.1998;47:5.

 Prevalence of HCV Infection:
United States
7

6 Mexican
African American
Anti-HCV+ (%)

5
American 3.5%
4 3.2%
3
Caucasian
2
1.1%
1

0
6–11 12–19 20–29 30–39 40–49 50–59 60–69 70+
Age (yr)

Alter et al. N Engl J Med. 1999;341:556-562.

 HCV: Disease Progression
Time: 20-30 years

HCV infection

60-85%1

Chronic HCV Cirrhosis Hepatic Failure

20%-50%2 ~ 20%3
~20%4

Liver Transplant
Liver Cancer
Candidates
1. NIH Consensus Development Conference Statement; March 24-26, 1997.
2. Davis GL et al. Gastroenterol Clin North Am. 1994;23:603-613.
3. Koretz RL et al. Ann Intern Med. 1993;119:110-115.
4. Takahashi M et al. Am J Gastroenterol. 1993;88:240-243.
 Histologic Progression of HCV
Monitored by Liver Biopsy
Inflammation Grade No fibrosis
• Measure of severity and ongoing disease activity
• 0-4 (METAVIR)
• Inflammation leads to scarring/fibrosis

Fibrosis Stage
• Amount of fibrous scar tissue
• 0-4 (METAVIR)
• Stage 4 = cirrhosis
• Indicates long-term disease progression

Cirrhosis
Brunt EM. Hepatology. 2000;31:241-246.
 Common Schedule and Type of HCV Testing

Decision to Treat

Identification
Identification
and Planning
and Planning Treatment

Stage Diagnosis Prognosis Treatment Assess Response

Duration and Resistance
• Serological • Liver biopsy • Genotyping • Quant HCV RNA
Assay • Qual HCV • Quant HCV
RNA RNA
 Improvements in Therapy of HCV
100
1991 1998 2001 2002

80
Sustained Virologic
Response (%)

60 54-56%

42%
39%
40 34%

20 16%
6%
0
IFN IFN IFN/RBV IFN/RBV Peg-IFN Peg-IFN/
6m 12m 6m 12m 12m RBV 12m

Strader DB et al. Hepatology 2004;39:1147-1171

 Current standard treatment duration is
48 or 24 weeks according to genotype
HCV genotyping

HCV-1 (4,5,6) HCV-2,3

Quantitative HCV RNA

Peg-IFN+ RBV Peg-IFN +

1000/1200 mg/day RBV 800 mg/day
for 24 weeks
Quantitative HCV RNA at week 12

<2 log decline ≥ 2 log decline or HCV RNA (–)

Stop or re-evaluate 48 weeks

therapy
 The Burden of Liver Disease Associated
with HCV is Increasing
An estimated 5 million Americans have been infected with HCV, of
whom 4 million are chronically infected

Approximately 30,000 people in the US are infected with hepatitis C

each year

Hepatitis C is the leading causes of liver disease and cirrhosis in US

12,000 - 15,000 people die of hepatitis C each year in the US

The CDC estimate that the number of annual deaths from hepatitis C
will triple in the next 10 - 20 years

The estimated medical and work loss costs per year of hepatitis C is
over $600 million

Source: American Liver Foundation