Viral Hepatitis (Virus Hepatitis)

Viral HepatitisViral HepatitisMedicine Student LectureMedicine Student Lecture

David R Nelson, M.D.Associate Professor of Medicine

Director, Hepatology and Liver TransplantationUniversity of Florida

Case 1: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 HepatitisCauses of Acute Hepatitis

Acute Hepatitis

Viral HepatitisA, B/D, C, E

EBVCMV & HSV

DrugsEthanolTylenol

Halothane

ToxinsJamaica Bush Tea

Mushrooms

VascularHypotensionBudd-Chiari

AutoimmuneHepatitis

MetabolicWilson's Disease

A1AT

Case: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 HepatitisCauses of Chronic Hepatitis

Chronic Hepatitis

Viral HepatitisHep BHep C

DrugsMTXINH

Amiodarone

Alcohol NAFLD

AutoimmuneAIHPBCPSC

MetabolicA1ATHHC

Wilson's

Abbreviations: NAFLD: nonalcoholic fatty liver disease; AIH: autoimmune hepatitis; PBC: primary biliary cirrhosisPSC: primary sclerosing cholangitis, A1AT: alpha-1 antitrypsin deficiency, HHC:hereditary hemochromotosis

47%

34%

16%

3%Hepatitis AHepatitis BHepatitis CHepatitis Non-ABC

Source: CDC Sentinel Counties Study on Viral Hepatitis

Acute Viral Hepatitis by Type, USA: 1982-1993 Acute Viral Hepatitis by Type, USA: 1982-1993

27 nm27 nm

Transmission route: fecal-oralTransmission route: fecal-oral

Clinical presentationClinical presentation - Jaundice: Adults- 30%, Children- <5%- Jaundice: Adults- 30%, Children- <5% - Fulminant: <1%- Fulminant: <1%• Diagnostic testsDiagnostic tests - Acute infection: IgM anti-HAV- Acute infection: IgM anti-HAV - Chronic infection: Not applicable- Chronic infection: Not applicable• Immunity: IgG anti-HAVImmunity: IgG anti-HAV• Case-fatality rate: 0.1 – 2.7%Case-fatality rate: 0.1 – 2.7%• Chronic infection:Chronic infection: NoneNone

Transmission route: fecal-oralTransmission route: fecal-oral

Clinical presentationClinical presentation - Jaundice: Adults- 30%, Children- <5%- Jaundice: Adults- 30%, Children- <5% - Fulminant: <1%- Fulminant: <1%• Diagnostic testsDiagnostic tests - Acute infection: IgM anti-HAV- Acute infection: IgM anti-HAV - Chronic infection: Not applicable- Chronic infection: Not applicable• Immunity: IgG anti-HAVImmunity: IgG anti-HAV• Case-fatality rate: 0.1 – 2.7%Case-fatality rate: 0.1 – 2.7%• Chronic infection:Chronic infection: NoneNone

Hepatitis A VirusHepatitis A Virus

Nucleic Acid: 7.5 kb ssRNA

HAV PrevalenceHAV Prevalence

HighHigh

IntermediateIntermediate

LowLow

Very LowVery Low

Global Prevalence of Hepatitis A InfectionGlobal Prevalence of Hepatitis A Infection

FecalHAV

Symptoms

ALTALT

IgM anti-HAVIgM anti-HAV

Total anti-HAVTotal anti-HAV

Months after ExposureMonths after Exposure

Tit

erT

iter

Typical Serologic CourseTypical Serologic Course

0 1 2 3 4 5 6 12 24

Hepatitis A Virus InfectionHepatitis A Virus Infection

Hepatitis A Prevention - Immune GlobulinHepatitis A Prevention - Immune Globulin

PreexposurePreexposure

• Travelers to high HAV-prevalence regionsTravelers to high HAV-prevalence regions

Postexposure (within 14 days)Postexposure (within 14 days)

• RoutineRoutine• Household and other intimate contactsHousehold and other intimate contacts

• Selected situationsSelected situations• Institutions (e.g. daycare centers)Institutions (e.g. daycare centers)• Common source exposure (e.g. food prepared Common source exposure (e.g. food prepared

by infected food handler)by infected food handler)

PreexposurePreexposure

• Travelers to high HAV-prevalence regionsTravelers to high HAV-prevalence regions

Postexposure (within 14 days)Postexposure (within 14 days)

• RoutineRoutine• Household and other intimate contactsHousehold and other intimate contacts

• Selected situationsSelected situations• Institutions (e.g. daycare centers)Institutions (e.g. daycare centers)• Common source exposure (e.g. food prepared Common source exposure (e.g. food prepared

by infected food handler)by infected food handler)

ACIP Recommendations MMWR ACIP Recommendations MMWR 1999; 48(RR12):1

Hepatitis A: Pre-exposure VaccinationHepatitis A: Pre-exposure Vaccination

Persons at increased risk or danger of infectionPersons at increased risk or danger of infection

• Travelers to intermediate and high Travelers to intermediate and high HAV prevalence areasHAV prevalence areas

• Men having sex with menMen having sex with men• Injecting drug usersInjecting drug users• Persons with chronic liver diseasePersons with chronic liver disease

Communities with high rates of hepatitis ACommunities with high rates of hepatitis A(e.g., Alaskan Natives, Native-Americans)(e.g., Alaskan Natives, Native-Americans)Routine pre-school childhood vaccinationRoutine pre-school childhood vaccination

Persons at increased risk or danger of infectionPersons at increased risk or danger of infection

• Travelers to intermediate and high Travelers to intermediate and high HAV prevalence areasHAV prevalence areas

• Men having sex with menMen having sex with men• Injecting drug usersInjecting drug users• Persons with chronic liver diseasePersons with chronic liver disease

Communities with high rates of hepatitis ACommunities with high rates of hepatitis A(e.g., Alaskan Natives, Native-Americans)(e.g., Alaskan Natives, Native-Americans)Routine pre-school childhood vaccinationRoutine pre-school childhood vaccination

Fecal-oral transmission (human to Fecal-oral transmission (human to human)human)

• Contaminated water supplies in tropical Contaminated water supplies in tropical or subtropical developing countriesor subtropical developing countries

• Mainly young adultsMainly young adults• Can infect primates, swine, sheep, ratsCan infect primates, swine, sheep, rats• Swine may be reservoir of infection in Swine may be reservoir of infection in

North America North America • Maternal-infant transmission occurs and Maternal-infant transmission occurs and

is often fatalis often fatal

Fecal-oral transmission (human to Fecal-oral transmission (human to human)human)

• Contaminated water supplies in tropical Contaminated water supplies in tropical or subtropical developing countriesor subtropical developing countries

• Mainly young adultsMainly young adults• Can infect primates, swine, sheep, ratsCan infect primates, swine, sheep, rats• Swine may be reservoir of infection in Swine may be reservoir of infection in

North America North America • Maternal-infant transmission occurs and Maternal-infant transmission occurs and

is often fatalis often fatal

32 nm32 nm

Hepatitis E VirusHepatitis E Virus

Nucleic Acid: 7.5 kb ssRNANucleic Acid: 7.5 kb ssRNA

Hepatitis EHepatitis E

Similar to hepatitis ASimilar to hepatitis A

Dx: IgG anti-HEV (seroconversion)Dx: IgG anti-HEV (seroconversion)

Can cause severe acute hepatitisCan cause severe acute hepatitis

Subclinical infection is commonSubclinical infection is common Attenuated virus from animal reservoirsAttenuated virus from animal reservoirs Low-dose infections often asymptomaticLow-dose infections often asymptomatic

No chronic infectionNo chronic infection

Up to 20% mortality among pregnant women (esp. third Up to 20% mortality among pregnant women (esp. third trimester)trimester)

Similar to hepatitis ASimilar to hepatitis A

Dx: IgG anti-HEV (seroconversion)Dx: IgG anti-HEV (seroconversion)

Can cause severe acute hepatitisCan cause severe acute hepatitis

Subclinical infection is commonSubclinical infection is common Attenuated virus from animal reservoirsAttenuated virus from animal reservoirs Low-dose infections often asymptomaticLow-dose infections often asymptomatic

No chronic infectionNo chronic infection

Up to 20% mortality among pregnant women (esp. third Up to 20% mortality among pregnant women (esp. third trimester)trimester)

Clinical CharacteristicsClinical Characteristics

Hepatitis B VirusHepatitis B Virus

• 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

HBsAgHBsAg

HBV DNAHBV DNA

HBcAgHBcAg42 nm42 nm

Geographic Distribution of Chronic HBV Infection

Geographic Distribution of Chronic HBV Infection

HBsAg Prevalence

8% - High

2-7% - Intermediate

<2% - Low

> 350 million carriers (HBsAg + > 6 months)

10th cause of death(1 million / year)

Cirrhosis in 20% (75 - 100 million)

HCC in 5 - 10% (20 - 40 million)

Son D, Asian Am Pac Isl J Health 2001Slide courtesy of Robert Gish, MD

Hepatitis B PrevalenceHepatitis B Prevalence

• Overall U.S. prevalence: 0.3%

• Asian Americans: ~10-13%

0% 2% 4% 6% 8% 10% 12% 14%

Chinese

Filipino

Japanese

Korean

Vietnamese

Laotians

HBV Sources of InfectionHBV Sources of InfectionHousehold, 3%

Other, 23%

IDU, 20%Multiple sexpartners, 24%

Sexcontact, 23%

MSM, 23%

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.

Many patients do not reveal IDU as source of infection

Signs and Symptoms of Acute Hepatitis BSigns and Symptoms of Acute Hepatitis B

• About 30% of persons have no signs or symptoms

• If symptoms are present, generally nonspecific including:

• Nausea, vomiting• Joint pain• Dark Urine• Clay-colored bowel movements

• Jaundice• Fatigue• Abdominal Pain• Loss of Appetite

Hepatitis B - Clinical FeaturesHepatitis B - Clinical Features

Incubation periodAverage: 60 – 90 daysRange: 45 – 180 days

Clinical illness (jaundice)< 5 yrs of age: <10% 5 yrs of age: 30 – 50%

Acute case-fatality rate 0.5 – 1%

Chronic infection< 5 yrs of age: 30 – 90% 5 yrs of age: 2 – 10%

Mortality from chronic liver disease 15 – 25%

Progression to Chronic Hepatitis B Virus Infection

Progression to Chronic Hepatitis B Virus InfectionTypical Serologic CourseTypical Serologic Course

Weeks after ExposureWeeks after Exposure

TiterTiter

IgM anti-HBc

Total anti-HBc

HBsAg

Acute(6 months)

HBeAg

Chronic(Years)

anti-HBe

0 4 8 12 16 20 24 28 32 36 52 Years

HBV DNA

Acute Acute

hepatitis Bhepatitis B

Recovery Recovery from acute from acute hepatitis Bhepatitis B

Chronic Chronic HBeAg + HBeAg + diseasedisease

Chronic Chronic HBeAG – HBeAG – diseasedisease

Successful Successful VaccinationVaccination

Resistance Resistance to antiviral to antiviral

agentsagents

HBsAg

(may clear)

Anti-HBs

Anti-HBc IgM

Anti-HBc

HBeAg

Anti-HBe

(in some cases)

DNA (PCR if required)

(may be

only marker during

window period)

(sequence pol region)

Interpretation of Serologic MarkersInterpretation of Serologic Markers

Hepatitis B: Disease ProgressionHepatitis B: Disease Progression

Acute Infection

Chronic Infection Cirrhosis Death

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.

5%-10% 1

10-30% 1

23% within 5 years

Liver Cancer (HCC)

Chronic HBV is the 6th leading cause of liver transplantation in the US4

Liver Liver TransplantationTransplantation

Liver Failure (Decompensation)

2-6%2-6%

90% in perinatal90% in perinatal30-90% in children<5yrs old30-90% in children<5yrs old

5% in healthy adults5% in healthy adultsHigher in HIV, immune suppressedHigher in HIV, immune suppressed

Targeted Surveillance for HCCTargeted Surveillance for HCC

• Asian males > age 40• Asian females > age 50• All cirrhotic HBV carriers• Family history of HCC• Africans > age 20• High HBV DNA

• Hepatitis C• Alcoholic cirrhosis• Genetic hemochromatosis• Primary biliary cirrhosis• Other (? efficacy)

• A1AT deficiency• NAFLD• Autoimmune hepatitis

Hepatitis B Carriers Non-hepatitis B Cirrhosis

Bruix J and Sherman M. Hepatology 2005;42:1208

Surveillance for HCC should be with ultrasound at Surveillance for HCC should be with ultrasound at 6 to 12 month intervals; AFP is not adequate6 to 12 month intervals; AFP is not adequate

Prevention of Transmission of Hepatitis B Prevention of Transmission of Hepatitis B VaccinationVaccination

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 • sexual partners

4. Follow-up testing of vaccine responders • Annually for chronic hemodialysis patients

1-2 months

Goals of Treatment in HBVGoals of Treatment in HBV

• Reduce the risk of disease progression• Reduce the risk of hepatocellular carcinoma

• Loss of HBeAg, HBeAg HBeAb• Undetectable HBV-DNA

• (<105 copies/ml = 20,000IU/mL)• Normalization of ALT• Histologic Response• HBsAg HBsAb

Virologic Response

Approved TreatmentsApproved Treatments

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

Nucleic Acid: 1.7 kb ssRNANucleic Acid: 1.7 kb ssRNA

Classification: Classification: unclassified, unclassified, related to viroids; deltavirusrelated to viroids; deltavirus

Transmission: sex, IVDATransmission: sex, IVDA

Clinical featuresClinical features - Fulminant: 2 – 7.5%- Fulminant: 2 – 7.5% - Chronic infection- Chronic infection

Superinfection: 80%Superinfection: 80%Coinfection: < 5%Coinfection: < 5%

• Diagnostic testsDiagnostic tests -Acute infection: IgM anti-HDV-Acute infection: IgM anti-HDV -Chronic infection:IgG anti-HDV, HBsAg +-Chronic infection:IgG anti-HDV, HBsAg +

Nucleic Acid: 1.7 kb ssRNANucleic Acid: 1.7 kb ssRNA

Classification: Classification: unclassified, unclassified, related to viroids; deltavirusrelated to viroids; deltavirus

Transmission: sex, IVDATransmission: sex, IVDA

Clinical featuresClinical features - Fulminant: 2 – 7.5%- Fulminant: 2 – 7.5% - Chronic infection- Chronic infection

Superinfection: 80%Superinfection: 80%Coinfection: < 5%Coinfection: < 5%

• Diagnostic testsDiagnostic tests -Acute infection: IgM anti-HDV-Acute infection: IgM anti-HDV -Chronic infection:IgG anti-HDV, HBsAg +-Chronic infection:IgG anti-HDV, HBsAg +

35-37nm35-37nm

Hepatitis D Virus: Morphology and Hepatitis D Virus: Morphology and CharacteristicsCharacteristics

CoinfectionCoinfection

SuperinfectionSuperinfection

BB

BB

DD

DD

Modes of HDV infectionModes of HDV infection

HCV Life-Cycle and PathogenesisHCV Life-Cycle and PathogenesisHCV Life-Cycle and PathogenesisHCV Life-Cycle and Pathogenesis

Cell Binding Cell Binding and Infectionand InfectionCell Binding Cell Binding and Infectionand Infection

Replication

Immune Immune ResponseResponseImmune Immune

ResponseResponse

CD4CD4CD8CD8NKNKDCDC

CD4CD4CD8CD8NKNKDCDC

HSCHSC

FibrosisFibrosis

Immune Immune RecognitionRecognition

Immune Immune RecognitionRecognition

CytokinesCytokinesCytokinesCytokines

Viral Packaging Viral Packaging and Releaseand Release

Viral Packaging Viral Packaging and Releaseand Release

EffectorEffectorEffectorEffectorHCVHCVHCVHCV

Time After Exposure

Symptoms

0

400

600

800

1000

AL

T (

IU/L

)

0 2 4 6 8 10 12 24 1 2 3 4 5 6

Anti-HCVAnti-HCV

Weeks Months

HCV RNA positive

200

7

Normal ALT

Course of Acute HCV InfectionCourse of Acute HCV Infection

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 Symptoms, or Lack of, in Chronic HCV InfectionHCV Infection

Symptomatic37%

Cirrhosis7%

56%Asymptomatic

0

20

40

60

80

100

FatigueP

atie

nts

(%

)

80

ALT Elevations Are Not Indicative of ALT Elevations Are Not Indicative of Chronic HCV InfectionChronic HCV Infection

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

42 43

15

0

20

40

60

80

100

PersistentlyNormal ALT

IntermittentlyElevated ALT

Persistently Elevated ALT

Pat

ien

ts*

Wit

h H

CV

infe

ctio

n (

%)

Diagnostic Tests for HCV InfectionDiagnostic 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 AssaysMolecular Virologic Assays

Quantitative assaysQuantitative assaysDetection cutoff > qualitativeDetection cutoff > qualitative

How much HCV is present?

Qualitative assaysQualitative assaysHigh sensitivityHigh sensitivity

(( 50 IU/mL) 50 IU/mL)

Is HCV present?

GenotypeGenotypeassaysassays

What type of HCV is present?

Clinical Significance of HCV GenotypesClinical Significance of HCV Genotypes

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.

• 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

Prevalence of HCV Dependant on Risk FactorsPrevalence 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:Prevalence of HCV Infection: United States United States

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

An

ti-H

CV

+ (

%)

0

1

2

3

4

5

6

7

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

MexicanAmerican

Caucasian

3.5%

1.1%

African American

3.2%

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.

HCV infectionHCV infection

Chronic HCV Chronic HCV CirrhosisCirrhosis Hepatic FailureHepatic Failure

Liver CancerLiver Cancer Liver TransplantLiver TransplantCandidatesCandidates

60-85%60-85%11

~20%~20%44

~ 20%~ 20%3320%-50%20%-50%22

HCV: Disease ProgressionHCV: Disease Progression

Time: 20-30 yearsTime: 20-30 years

Histologic Progression of HCV Histologic Progression of HCV Monitored by Liver BiopsyMonitored by Liver Biopsy

Inflammation Grade• 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

No fibrosis

CirrhosisBrunt EM. Hepatology. 2000;31:241-246.

Identification and Planning

Common Schedule and Type of HCV TestingCommon Schedule and Type of HCV Testing

Identification and PlanningIdentification and Planning TreatmentTreatment

DiagnosisDiagnosis

• Serological • Qual HCV

RNA

PrognosisPrognosis

• Liver biopsy

Treatment Treatment DurationDuration

• Genotyping • Quant HCV

RNA

Assess Response and Resistance

• Quant HCV RNAQuant HCV RNA

Decision to Treat

Stage

Assay

39%42%

34%

16%

54-56%

6%

0

20

40

60

80

100

Sus

tain

ed V

irolo

gic

Sus

tain

ed V

irolo

gic

Res

pons

e (%

)R

espo

nse

(%)

IFNIFN6m6m

IFN/RBVIFN/RBV6m6m

Peg-IFN/ Peg-IFN/ RBV 12mRBV 12m

IFNIFN12m12m

IFN/RBVIFN/RBV12m12m

Peg-IFNPeg-IFN12m12m

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

Improvements in Therapy of HCVImprovements in Therapy of HCV

19911991 19981998 20012001 20022002

Current standard treatment duration is Current standard treatment duration is 48 or 24 weeks according to genotype48 or 24 weeks according to genotype

HCV genotypingHCV genotyping

HCV-1 (4,5,6)HCV-1 (4,5,6)Quantitative HCV RNAQuantitative HCV RNA

HCV-2,3HCV-2,3

Peg-IFN +Peg-IFN +RBV 800 mg/dayRBV 800 mg/day for for 24 weeks 24 weeks

Peg-IFN+ RBVPeg-IFN+ RBV1000/1200 mg/day1000/1200 mg/day

Quantitative HCV RNA at week 12Quantitative HCV RNA at week 12

<2 log decline<2 log decline

Stop or re-evaluate Stop or re-evaluate therapytherapy

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

48 weeks48 weeks

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

The Burden of Liver Disease Associated The Burden of Liver Disease Associated with HCV is Increasingwith HCV is Increasing

Source: American Liver Foundation