Hepatitis C

Hepatitis C

Cengiz Pata

Gastroenterology Department, Yeditepe University

clinicaloptions.com/hep

Hepatitis C: Epidemiology, Diagnosis, and Treatment

Hepatitis C Virus InfectionMagnitude of the Problem Nearly 4 million persons in United States infected

Approximately 35,000 new cases yearly

85% of new cases become chronic

Leading cause of

Chronic liver disease

Cirrhosis

Liver cancer

Liver transplantation

Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.



Hepatitis C VirusFate of Acute Infection

15%

Chronic85%

Spontaneousresolution

Alter MJ, et al. N Eng J Med. 1999;341:556-562.



0

50

100

150

200

0 6 12 18 24

Month

AL

T (

IU/l)

Resolution

Chronic

HCV RNA+/- + -

Hepatitis C VirusResponse to Acute Infection

Illustration by Mitchell L. Shiffman, MD.



Hepatitis C Virus InfectionNatural History

Stable80% (68%)

HCCLiver failure25% (4%)

Slowlyprogressive75% (13%)

Resolved15% (15%)

Acute HCV

Cirrhosis20% (17%)

Chronic HCV85% (85%)

HCC, hepatocellular carcinoma



Hepatitis C Virus InfectionPopulation at Risk Transfusion of blood products before 1992

Intravenous drug use

Nasal inhalation of cocaine

Chronic renal failure on dialysis

Incarceration

Occupational exposure to blood products

Transplantation of an organ/tissue graft from an HCV-positive donor

Body piercing and potentially tattoo

Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.



Hepatitis C Virus InfectionPrevalence

Sex

B, Blacks; F, female; H, Hispanic; M, male; W, Whites.

0

1.0

2.0

3.0

4.0

All W B H M FRace

An

ti-H

CV

Po

siti

ve (

%)


1.8%



Hepatitis C Virus Infection Prevalence by Age

0

1.0

2.0

3.0

4.0

5.0

< 11 11-19 20-29 30-39 40-49 50-59 60-69 ≥ 70

Age Group

An

ti-H

CV

Po

siti

ve (

%)


Hepatitis C:Diagnosis and Management



Management of Chronic HCVTests Utilized

Disease Severity Response to Therapy

AST/ALT

Bilirubin

Albumin

Pro-time (INR)

Platelet count

Liver histology

ALT

HCV RNA

HCV genotype

Liver histology

LFTs



Viral HepatitisRole of Diagnostic Testing Identify patients with viral hepatitis infection

– Previous exposure to hepatitis virus

– Active infection

– Inactive infection

– Resolved infection

Assess response to therapy

– Prior to onset of treatment

– During and following treatment



Hepatitis C VirusHost Production of HCV Antibodies

HCV infects cell

HCV proteins expressed on surface of hepatocytes

Antibodies to HCV proteins produced by host

HCV antibodies DO NOT convey immunity YY YYY YYY




False positives

– Autoimmune disorders

– Spontaneous resolution of viral infection

False negatives

– Chronically immune suppressed

– Transplant recipients

– Chronic renal failure on dialysis

– HIV positive

HCV Antibody TestingLimitations



Hepatitis C VirusGenotypes in the USA

All others1%

Type 310%

Type 217%

Type 172%

McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.



Hepatitis C Virus InfectionLiver Biopsy Only test that can accurately assess

– Severity of inflammation

– Degree of fibrosis

Determines the following

– Risk for developing cirrhosis in future

– Need for therapy

– Need for ongoing therapy when initial treatment has failed



Assessment of Liver HistologyNoninvasive Serum Tests

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4

Fibrosis Stage

FIB

RO

TE

ST

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3

Activity Grade

AC

TIT

ES

T

Poynard T, et al. Hepatology. 2003;38:481-492.



Chronic HCV With Normal Serum ALTALT Patterns and Flares

ULN

0

20

40

60

80

100

120

0 3 6 9 12 15 18 21 24

Month

AL

T (

IU/l)

Single elevationsPeriodic elevationsAlways normal




Chronic HCV InfectionSymptoms

Asymptomatic

Symptomatic

Cirrhosis

0

20

40

60

80

100

Fatigue

Per

cen

tag

e o

f P

atie

nts

37%

7%

56%

Unpublished data from MCV Hepatitis Program, 1995.



Chronic HCV InfectionProgression to Cirrhosis

0

20

40

60

80

100

0 5 10 15 20Time (Years)

Bridging

Portal

None

Ap

pro

xim

ate

Pe

rce

nta

ge

of

Pa

tie

nts

Wit

h C

irrh

osi

s

Yano M, et al. Hepatology. 1996;23:1334-1340.

Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis



Hepatitis C Virus InfectionIdentification of Patients Found to have elevated serum ALT during

– Routine physical examination

– Routine blood testing after starting certain medications

Test positive for anti-HCV during

– Volunteer blood donation

– Health or life insurance applications

Physician

– Inquires about previous risk behaviors

Hepatitis C:Extrahepatic Manifestations



Chronic Hepatitis C VirusExtrahepatic Manifestations Nonspecific antibodies Essential mixed cryoglobulinemia Glomerulonephritis Porphyria cutanea tarda Leukocytoclastic vasculitis Mooren’s corneal ulcer Non-Hodgkin’s lymphoma Autoimmune thyroiditis Diabetes mellitus Sjögren’s syndrome



Pawlotsky JM, et al. Hepatology. 1994;19:841-848.

Chronic Hepatitis C VirusAutoantibodies

HCV, % Control, %

Rheumatoid factor 70 8

Cryoglobulins 36 < 1

ANA > 1:40 > 1:180

21

13

10

2

Antismooth muscle > 1:40 > 1:180

21

7

2

< 1

Anti–liver-kidney microsome 5 < 1

Antithyroid 7 2



Cacoub P, et al. Curr Opin Rheumatol. 2002;14:29-35.

CryoglobulinemiaClassification

Immunoglobulin Classification

IMonoclonal

No rheumatoid factorPrimary

II

Polyclonal IgG

Monoclonal IgM

Rheumatoid factor

Secondary mixed

HCV infection

IIIPolyclonal IgG

Polyclonal IgM

Secondary mixed

Infections

Autoimmune disorders

Lymphoproliferative diseases



Immune Manifestations of HCVPathogenesis

Monoclonal IgM rheumatoid factor

Cryoglobulin traps HCV

HCV evades theimmune response

Chronic immune stimulation by

single HCV antigen

Polyclonal IgG YGenetic and

environmentalfactors

Illustration by Mitchell L. Shiffman, MD



HCV and CryoglobulinemiaDermatitis

Occurs in dependent areas

Deposition of cryoglobulins in small capillaries

Ulcerations may develop

Pruritic



HCV and CryoglobulinemiaManifestations Dermatitis (dependent areas)

Vasculitis

Myalgias (fibromyalgia?)

Arthralgias (RA and/or ANA positive)

Membranoproliferative glomerulonephritis

Neuropathy

Chronic fatigue syndrome (?)

Hepatitis C:Treatment



Treatment of Chronic HCVPeginterferon and Ribavirin

0

20

40

60

80

100

1 2-3

Genotype

Su

stai

ned

Vir

olo

gic

Res

po

nse

(%

)

PegIFN-2a/RBVPegIFN-2b/RBV

Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.



Nishiguchi S, et al. Lancet. 1995;346:1051-1055.

Treatment of Chronic HCVEffect on Development of HCC Interferon treatment reduces the risk of developing

hepatocellular carcinoma among patients with chronic HCV (P = .002)

Hepatocellular carcinoma incidence

– Untreated controls: 38% (24%-58%)

– Interferon-treated patients: 4% (1%-15%)

HCC risk ratio: 0.067 (0.009-0.530; P = .01)

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