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

3. What do you want to know ?
Risk factors for hepatitis ?
What do you do next ?

4. Risk factors for hepatitis ?
What do you want to know ?
Risk factors for hepatitis ?
What do you do next ?
More detailed history
Recent viral infection
Co-morbid conditions
Recent surgeries
Family history
Medications
Recreational drugs
ETOH use
Occupation

5. What do you want to know ?
Risk factors for hepatitis ?
What do you do next ?

6. Sources of Infection
Sexual 15%
Other 1%*
Unknown 10%
Injecting drug use 60%
Transfusion 10%
(before screening)
* Nosocomial; iatrogenic; perinatal
Occupational 4%
This pie chart reflects the main sources of HCV infection in the US. Parenteral transmission comprises most of the cases, with drug use being the major source (about 60%). Other methods of transmission include sexual (15%), Occupational (4%). Perinatal, nosocomial or household transmission may also occur. The 10% for transfusion reflects the rate prior to screening blood products for HCV. In about 10% of patients, no source is found.
Source: Centers for Disease Control and Prevention

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Khatib et al, Unpublished data 2004

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Khatib et al, Unpublished data 2004

9. What do you want to know ?
Risk factors for hepatitis ?
What do you do next ?

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

11. HBsAg +
HBeAg
Anti-HBe +
Anti-HBc +
HCV ab -
RUQ US WNL

12. HBV Distribution Chronic infection prevalence  8% – High
Hepatitis B is a major public health problem globally, but the prevalence varies between different regions of the world. Shown in red are the high prevalence areas. Intermediate prevalence is shown in orange, and low prevalence in yellow. The middle East and Africa are among the intermediate to high prevalence regions. The distribution has probably changed somewhat since 1991, by population movements from high prevalence areas to other areas.
Chronic infection
prevalence
 8% – High
2–7% – Intermediate
< 2% – Low
Predominant age at infection
Early childhood
Perinatal and early childhood
Adult
Past infection
40– 90%
16– 55%
4– 15%
CDC, 1991

13. HBsAg Prevalence in Arab Countries
Jordan
3-10%
Palestine
5-6%
Iraq
4-5%
S. Arabia
6-8%
Egypt
3-11%
Yemen
12-18%
Bahrain %
Tunisia 7%
UAE
2-5%
Kuwait 2%
Oman
2-10%
Morocco 6%
WHO data show the prevalence of Hepatitis B in Jordan to be between 3-10%. This is similar to Egypt and Oman. Other Arab countries have somewhat lower prevalence, except for Yemen where it ranges between 12-18%.

14. The HBV Genome
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 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
The HBV genome is circular, and partly double-stranded DNA molecule of about 3200 nucleotide subunits. The HBV genome contains only four potential genes (S, C, P, and X), which overlap as shown in the figure. The surface (S) gene encodes for the major envelope protein (hepatitis B surface antigen 'HBsAg') . The C (core) gene encodes the protein of the nucleocapsid (HBcAg) and is preceded by a short Pre-C region that with the core region forms a large protein that is eventually degraded and secreted into the serum (HBeAg). The P gene encodes enzymes (DNA polymerase) required for viral replication. Finally, the X gene protein product regulates the transcription of all viral genes by interacting with a DNA sequence in the genome(Transcriptional trans-activator).
Lee WM. N. Engl. J. Med. 1997; 337:1733–45

15. Hepatitis B Mutations 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
The 2 types of e-antigen negative chronic hepatitis B are the precore mutation and the core promoter mutation.
27% of the US chronic hepatitis B population has precore mutation -- where there is abolition of e-antigen production -- and 44% are the e-antigen negative type chronic hepatitis B, which is associated with a core promoter mutation. There also are treatment-induced mutations.
1 Lai C. Clin Infec Dis 2003;36;
2 Xiang S. et al. J Hepatol 2003;38(2);102

16. Hepatitis B Prevalence of HBeAg-Negative5 10 15 20 25 30 35
Mediterranean
Asia Pacific
USA and Northern
Europe
Percent of CHB patients
HBeAg-negative CHB
Pre-core stop variant
Funk ML, et al. J. Viral Hep. 2002; 9:52–61

17. Age Factor in Acute HBV Infection
This chart just shows that the younger the patient is at the time of initial infection, the less frequent are the initial symptoms, but at the same time more likelihood of developing chronic disease.The rate of progression from acute to chronic infection is almost 90% for perinatally acquired infection, 20-50% between the age of 1 to 5, and less than 5% for adult acquired infection.

18. The Clinical Outcomes of HBV Infection
10–70%
95%
Perinatal/childhood
acute infection
Adult
acute infection
Recovery
Recovery
< 1%
30–90%
< 5%
Fulminant
hepatitis
Chronic infection
 1*
Inactive carrier state
Mild, moderate or severe chronic hepatitis
 2–10*
5–50
years
The natural course of chronic HBV depends on the interplay between viral replication and the host immune response.
Other factors include gender, alcohol consumption, and concomitant infection with other viruses. With treatment, outcome depends on severity of liver disease at the time HBV replication is arrested.
Cirrhosis
 0.1*
 4*
 3*
2–8*
Decompensation
Transplant
or Death
HCC
Adapted from EASL Consensus Statement. J. Hepatol. 2003; 39 (S1):S3–25
* per 100 patient-years

19. Serologic Course of Chronic HBV Infection
Weeks after exposure
Titer
IgM anti-HBc
Total anti-HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(years)
anti-HBe 4 8 12 16 20 24 28 32 36 52
Years

20. Phases of Chronic HBV Infection
Replicative Phase (Immunoactive):
Immune Tolerance Phase: only in perinatally acquired disease, lasts years. No active liver disease.
HBeAg+ve, high HBV DNA, but normal ALT and biopsy
Immune 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
Chronic HBV infection generally consists of two phases: early replicative phase with liver disease, and a late or nonreplicative phase with remission of liver disease.
In patients with perinatally acquired HBV, there is an additional immune tolerence phase, in which replication is not accompanied by active liver disease.(Ineffective cytotoxic T cell lysis of infected hepatocytes). Slow clearnce of HBeAg

21. Replicative Phase HBeAg positive and anti-HBe negative (wild Type)
HBeAg negative and anti-HBe positive (precore or core promotor mutants)
HBV DNA high: copies/ml
ALT persistently or intermittently elevated
Symptoms presents or absent
What do we see in the consultation practice is mainly patients in the immunoactive phase, or what we currently call chronic hepatitis B. It is recognized now that there are 2 main variants. There are the e-antigen positive chronic hepatitis B patients who have a negative e-antibody due to the wild-type virus. Also relatively common in different populations are the e-antigen negative chronic hepatitis B patients who have a positive e-antibody. These individuals do not have the wild-type virus, but have transitioned to a precore or a core promoter mutant of variant virus. Their DNA levels are high, but a little lower than in the immune tolerant phase. The ALT levels may be persistently elevated or intermittently elevated. It is that intermittent elevation that mandates that we check the ALT frequently to help properly classify patients. They often are asymptomatic, but they may have mild symptoms of fatigue or malaise.

22. Non-replicative Phase
HBeAg negative and anti-HBe positive
HBV DNA low copies/ml
ALT persistently normal
HBsAg may later become negative (with development of anti-HBs)
Finally, the inactive or nonreplicative phase describes the individual who is now e-antigen negative and e-antibody positive and who has low DNA levels by PCR. These are individuals who are wild type, have seroconverted, and now have inactive disease. Their ALT is persistently normal. Good data from Alaska from McMahon, and from several investigators from Taiwan and China, show that a small percentage of patients will actually lose surface antigen over long-term follow-up.

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

25. HBsAg -
Anti-HBs +
Anti-HBc -
HBeAg -
Vaccinated

27. 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.

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

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

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

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

32. Hepatitis A Age – specific fatality
CDC Viral Hepatitis Surveillance Program,

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

34. Hepatitis A Transmission and Epidemics
02/20/02
Hepatitis A Transmission and Epidemics
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 13

35. Hepatitis A Age-Prevalence Shift in Hepatitis A
02/20/02
Hepatitis A Age-Prevalence Shift in Hepatitis A
1988
1996
100 90
Now !!! 80 70
Proportion (%) 60 50 40 30 20 10
0-1
1-2
2-3
3-4
4-5
5-10
10-
15-
20-
30-
40-
50-
>60 15 20 30 40 50 60
Age (years) 22

36. Hepatitis A Changing Epidemiology in Jordan increased risk of outbreak
02/20/02
Hepatitis A
Changing Epidemiology in Jordan
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 14

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

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

39. He is asymptomatic and his physical exam is normal. Labs
Case 2
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

40. Liver Biopsy Grade II stage III
Case 3
HCV RNA PCR Positive
Liver Biopsy Grade II stage III
Diagnosis Chronic Hepatitis C

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

42. Hepatitis C Modes of Transmission4% 2%
42% 8%
40%
Blood Transfusion prior to 1995
Blood transfusion after 1995
Tattooing
Hemodialysis
IVDA
Unknown
Khatib et al, Unpublished data 2004

43. Hepatitis C Modes of Transmission
Patients with unknown risk factors
24%
33%
19%
No risk factors
Circumcision at
home
Minor Surgical
procedure
Dental procedure
Khatib et al, Unpublished data 2004

44. Hepatitis C Additional Sources of Infection
Traditional practices using unsterilized tools:
Barbering
Tattooing
Circumcision
Body piercing
Dental procedures
Hejama
Use of unsterilized injection equipment
In the developing countries the use of unsterilized injection equipment, unscreened transfusions and the performance of traditional practices (such as barbering, tattooing, circumcision) using unsterilized tools are additional sources of infection.

45. 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?

46. Post-transfusion Hepatitis
All volunteer donors
HBsAg
Donor Screening for HIV Risk Factors
Anti-HIV
ALT/Anti-HBc
Anti-HCV
This slide shows the drop in the incidence of post-transfusion hepatitis with the introduction of screening tests, initially to hepatitis B around 1970, and hepatitis C early 1990s. At present the incidence is lower than one per 100,000 units transfused.
Improved
HCV Tests
Adapted from HJ Alter and Tobler and Busch, Clin Chem 1997

47. 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?

48. Hepatitis C Genotypes Genotype 4 66% Genotype 4+ 1b 16% Genotype 1a 4%
and 3
2a/c
Un-typable
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

49. Hepatitis C Genotypes Genotype 4 66% Genotype 4+ 1b 16% Genotype 1a 4%
and 3
2a/c
Untypable
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

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

51. Thank You