سيمنارات

45 yr-old-male Asymptomatic Abnormal liver enzymes ALT 55 (<40) AST 42 (<40) Bili, Alk, GGTP WNL

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Risk factors for hepatitis ?

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What do you want to know ?

Risk factors for hepatitis ?

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More detailed history Recent viral infection Co-morbid conditions Recent surgeries Family history Medications Recreational drugs ETOH use Occupation

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Sources of Infection
Sexual 15%
Other 1%*
Unknown 10%
Injecting drug use 60%
Transfusion 10% (before screening)
* Nosocomial; iatrogenic; perinatal
Occupational 4%
Source: Centers for Disease Control and Prevention

Modes of Transmission

Blood Transfusion prior to 1995 Blood transfusion after 1995 Tattooing Hemodialysis IVDA Unknown
4%
2%
4%
42%
8%
40%
Khatib et al, Unpublished data 2004

Modes of transmission

24%
33%
24%
19%
No risk factors
Circumcision at
home
Minor Surgical
procedure
Dental procedure
Khatib et al, Unpublished data 2004
Patients with unknown risk factors

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Risk factors for hepatitis ?

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HBsAg HCV ab RUQ ultrasound
ANA ASMA Anti LKM ab Lipid profile Fasting blood sugar
Complete physical examination

HBsAg + HBeAg - Anti-HBe + Anti-HBc +

HCV ab - RUQ US WNL

HBV Distribution

Chronic infection prevalence
 8% – High 2–7% – Intermediate < 2% – Low Predominant age at infection
Early childhood
Perinatal and early childhood
Adult
Past infection prevalence
40– 90% 16– 55% 4– 15% CDC, 1991

HBsAg Prevalence in Arab Countries

Bahrain
0.9-1.3%
Tunisia
7%
UAE
2-5%
Kuwait
2%
Oman
2-10%
Morocco
6%
Jordan
3-10%
Palestine
5-6%
Iraq
4-5%
S. Arabia
6-8%
Egypt
3-11%
Yemen
12-18%

preS2

Pol
(+)
(-)
DR1
DR2
POL
1621
2309
833
2850
3174
157
preS1
S
X
Pre-core
Core
2452
1816
1838
1376
1903
The HBV Genome
The HBV genome contains only four potential genes (S, C, P, and X), which overlap S: surface : envelope (HBsAg) C: core: nucleocapsid (HBcAg) Pre-core: HBeAg P: polymerase X: transcription activator
Lee WM. N. Engl. J. Med. 1997; 337:1733–45


Hepatitis BMutations
Precore mutation (G1896A) Abolishes HBeAg production Core promotor mutation (A1762T, G1764A) Down-regulates HBeAg production Treatment-induced mutations YMDD: Induced by Lamivudine (20%/year)1 N236T: Induced by Adefovir (1.7%/year)2
1 Lai C. Clin Infec Dis 2003;36;687-696 2 Xiang S. et al. J Hepatol 2003;38(2);102

Hepatitis BPrevalence of HBeAg-Negative 

Funk ML, et al. J. Viral Hep. 2002; 9:52–61 0
5
10
15
20
25
30
35
Mediterranean
Asia Pacific
USA and Northern
Europe
Percent of CHB patients
HBeAg-negative CHB
Pre-core stop variant

Age Factor in Acute HBV Infection

The Clinical Outcomes of HBV Infection
Adapted from EASL Consensus Statement. J. Hepatol. 2003; 39 (S1):S3–25 Chronic infection
Cirrhosis
HCC
Decompensation
Inactive carrier state
Adult acute infection
Recovery
Fulminant hepatitis
95%
< 1%
30–90% 5–50 years Transplant or Death
Perinatal/childhood acute infection
Recovery
10–70% < 5%
Mild, moderate or severe chronic hepatitis
 1*  0.1*  2–10*  4*  3* 2–8* * per 100 patient-years

Weeks after exposure

Titer
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
Serologic Course of Chronic HBV Infection


Phases of Chronic HBV Infection
Replicative Phase (Immunoactive):Immune Tolerance Phase: only in perinatally acquired disease, lasts 10-30 years. No active liver disease.HBeAg+ve, high HBV DNA, but normal ALT and biopsyImmune Clearance Phase: Chronic hepatitis B. Active liver disease present.HBV DNA in serum, high ALT, abnormal biopsy(HBeAg positive/ HBeAg negative)Non-replicative Phase HBeAg –ve, anti-Hbe +ve, undetectable HBV DNA

Replicative Phase

HBeAg positive and anti-HBe negative (wild Type) HBeAg negative and anti-HBe positive (precore or core promotor mutants) HBV DNA high: 104-108 copies/ml ALT persistently or intermittently elevated Symptoms presents or absent

Non-replicative Phase

HBeAg negative and anti-HBe positive HBV DNA low 102-104 copies/ml ALT persistently normal

HBsAg may later become negative (with development of anti-HBs)

HBsAg - Anti-HBs + Anti-HBc + HBeAg -
Previous Infection

HBsAg - Anti-HBs + Anti-HBc - HBeAg -

Vaccinated


A 19 year-old University student, presented with flu-like symptoms of 1 week duration, followed by lethargy and confusion. Clinically, she appeared jaundiced, with decreased level of consciousness, but did not have stigmata of chronic liver disease.

HBsAg Anti-HBc IgM HCV ab HAV IgM ANA Ceruplasmin RUQ U/S

PT/INR 2.2 Albumin 3.9 HBsAg Negative HCV ab Negative HAV IgM Positive
Diagnosis Fulminant Liver Failure Acute Hepatitis A
Case 1
Labs showed: AST 1198 ALT 1400 ALK 1189 T. Bili 16 Ammonia 225

Questions

Is Hepatitis A a fatal disease ? Do we need to get Vaccinated ? What kind of immunization do we have and is it effective?

Questions

Is Hepatitis A a fatal disease ? Do we need to get Vaccinated ? What kind of immunization do we have and is it effective?

Hepatitis AAge – specific fatality CDC Viral Hepatitis Surveillance Program, 1983-1989

Questions
Is Hepatitis A a fatal disease ? Do we need to get Vaccinated ? What kind of immunization do we have and is it effective?

Endemicity

Peak Age
Transmission Pattern
High
Early Childhood
Person to person, Outbreaks uncommon
Intermediate
Late childhood/ young adults
Person to person Food and water outbreaks
Low
Adults
Travelers, Outbreaks uncommon
Hepatitis ATransmission and Epidemics


0
10
20
30
40
50
60
70
80
90
100
0-1
1-2
2-3
3-4
4-5
5-10
10-
15
15-
20
20-
30
30-
40
40-
50
50-
60
>60
Age (years)
Proportion (%)
1988
1996
Hepatitis A Age-Prevalence Shift in Hepatitis A
Now !!!


Improvements in socio-economic & sanitary conditions

HIGH INTERMEDIATE LOW

increased subjects' susceptibility increased risk of outbreak increased severity of hepatitis A

Need for prevention measures

Hepatitis A Changing Epidemiology in Jordan

Questions

Is Hepatitis A a fatal disease ? Do we need to get Vaccinated ? What kind of immunization do we have, and is it effective?

Hepatitis APrevention

Few
Few
Systemic
Several
2
number of injections
Mild
Mild
Local
Side effects
Day 1
<14 days
Onset of protection
3-5 months
10 years
Duration
85%
97%
Efficacy
Immunoglobulin
Vaccination



A 35 year-old male gentleman presented to the clinic after a pre-employment test. He was found to be HBsAg positive. He is asymptomatic and his physical exam is normal. Labs ALT 65 AST 48 ALK 88 T.Bili 1.0 INR 1.1 Albumin 4.2
Case 2

HCV RNA PCR Positive Liver Biopsy Grade II stage III

Diagnosis Chronic Hepatitis C
Case 3

Questions

What are risk factors for Hepatitis C transmission? Did he acquire the infection from blood transfusion? Is hepatitis C a treatable disease?

Hepatitis CModes of Transmission

Blood Transfusion prior to 1995 Blood transfusion after 1995 Tattooing Hemodialysis IVDA Unknown
4%
2%
4%
42%
8%
40%
Khatib et al, Unpublished data 2004

Hepatitis CModes of Transmission

24%
33%
24%
19%
No risk factors
Circumcision at
home
Minor Surgical
procedure
Dental procedure
Khatib et al, Unpublished data 2004
Patients with unknown risk factors

Hepatitis CAdditional Sources of Infection

Traditional practices using unsterilized tools: Barbering Tattooing Circumcision Body piercing Dental procedures Hejama Use of unsterilized injection equipment

Questions

What are risk factors for Hepatitis C transmission in Jordan ? Did he acquire the infection from blood transfusion? Is hepatitis C a treatable disease?

All volunteer donors

HBsAg
Donor Screening for HIV Risk Factors
Anti-HIV
ALT/Anti-HBc
Anti-HCV
Improved HCV Tests
Adapted from HJ Alter and Tobler and Busch, Clin Chem 1997
Post-transfusion Hepatitis

Questions

What are risk factors for Hepatitis C transmission in Jordan ? Did he acquire the infection from blood transfusion? Is hepatitis C a treatable disease?

Hepatitis CGenotypes

Genotype 4
66%
Genotype 4+
1b
16%
Genotype 1a
4%
Genotypes 2
and 3
4%
Genotype 4+
2a/c
4%
Un-typable
4%
Genotype
1b+3a
2%
Genotype 4 – 66%Genotype 4 +1b – 16%Genotype 4+ 2a/c- 4%Genotype 2,3 – 4%Genotype 1b – 4% Khatib et al, Unpublished data 2004

Hepatitis CGenotypes

Genotype 4
66%
Genotype 4+
1b
16%
Genotype 1a
4%
Genotypes 2
and 3
4%
Genotype 4+
2a/c
4%
Untypable
4%
Genotype
1b+3a
2%
Genotype 4 – 66%Genotype 4 +1b – 16%Genotype 4+ 2a/c- 4%Genotype 2,3 – 4%Genotype 1b – 4% Khatib et al, Unpublished data 2004



At Wks 12 & 24 = HCV RNA negative or drop of 2 log10 PCR Hepatitis CCombination Therapy for Genotype 4
Interferon/Ribavirin (N = 49)
PEG Interferon+ Ribavirin (N = 51)
0
Thakeb F, et al. 2003.
10
20
30
40
50
60
70
80
90
100
Virological Response (% of Patients)
Wk 12
Wk 24
Wk 48 (EOT)
Wk 72 (SVR)
16.4
20.4
12.3
70.6
70.6
68.6
62.7
16.4
N = 8
N = 8
N = 6
N = 10
N = 36
N = 36
N = 35
N = 32


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