2. 2
Viral Hepatitis - Historical Perspective
A“Infectious”
“Serum”
Viral
hepatitis
Enterically
transmitted
Parenterally
transmitted
F, G,
? other
E
NANB
B D C
3. 3
Viral Hepatitis
A B C D E
Source of
virus
faeces blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
feces
Route of
transmission
fecal-oral percutaneous
permucosal
percutaneous
permucosal
percutaneous
permucosal
fecal-oral
Chronic
infection
no yes yes yes no
Prevention pre/post-
exposure
immunization
pre/post-
exposure
immunization
blood donor
screening;
risk behavior
modification
pre/post-
exposure
immunization;
risk behavior
modification
ensure safe
drinking
water
5. 5
HAV Transmission
Close personal contact
household contact, sex contact, child day
care centers
Contaminated food, water
infected food handlers, raw shellfish
Blood exposure (rare)
injecting drug use, transfusion
6. 6
Hepatitis A - Clinical Features
Incubation period: Mean 30 days
Range 15-50 days
Jaundice by <6 yrs, <10%
age group: 6-14 yrs 40%-50%
>14 yrs 70%-80%
Complications: Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
Chronic sequelae: None
7. 7
HAV - Typical Serologic Course
Fecal
HAV
Sympto
ms
ALT
IgM anti-HAV
Total anti-HAV
Months after Exposure
Titer
0 1 2 3 4 5 6 1
2
2
4
8. 8
Serological Testing
• HAV total Ab appears 4-5 weeks after infection and
remains positive for the patient’s lifetime
• HAV IgM is present at the onset of symptoms and
usually disappears after 4-6 months.
• The presence of total Ig without IgM indicates past
infection
9. 9
Hepatitis A Virus
• Highest virus concentrations occur in stool 1-2
weeks before the onset of illness. Transmission
is most likely at this time.
• Minimal virus present in stool 1 week after the
onset of jaundice.
• In neonates and young children, virus may be
detected in stool for months.
10. Treatment
• Treatment is supportive.
• Patients who develop fulminant infection require aggressive
supportive therapy, and should be transferred to a center capable of
performing liver transplantation
• Approximately 85 percent of HAV-infected individuals have full
clinical and biochemical recovery within three months, and nearly
all have complete recovery by six months.
• Passive immunization with intramuscular polyclonal serum
immune globulin as preexposure or postexposure prophylaxis
14. 14
Progression to Chronic HBV Infection
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
15. 15
HBV Transmission
• Parenteral
• Sexual
• Perinatal
• Risk of transmission increases
with the level of HBV DNA in
serum and HBeAg positive
16. 16
HBV Concentrations in Various
Body Fluids
High Moderate
Low/Not
Detectable
blood semen urine
serum vaginal fluid feces
wound exudates saliva sweat
tears
breast milk
17. 17
HBV DNA Testing
• Assess of viral replication in chronic HBsAg
carriers.
• Assess the risk of progression toward cirrhosis and
hepatocellular carcinoma.
• Decision to treat.
• Assess treatment efficacy and failure
18. 18
Approved Therapies for HBV Infection
• Interferons
– Interferon alpha 2b (5 million units qd or 10 million units
TIW for 12-24 weeks)
– Pegylated interferon alpha 2a (180 ug once/week for 48
weeks)
• Nucleoside analogues
– Lamivudine (100 mg qd)
– Entecavir (0.5 mg qd; 1 mg if lamivudine resistance)
• Nucleotide analogues
– Adefovir (10 mg qd)
19. 19
HCV - Sources of Infection
Sexual 15%
Other* 5%
Unknown 10%
Injecting drug use 60%
Transfusion 10%
(before screening)
*Nosocomial;
Health-care work;
Perinatal
Source: Centers for Disease Control and Prevention
20. 20
Other Transmission Issues
• HCV is not spread by kissing, hugging,
sneezing, coughing, food or water, sharing
eating utensils or drinking glasses, or
casual contact
• HCV infection status should not be used to
exclude patients from work, school, play,
child-care or other settings
21. 21
Acute Hepatitis C Clinical Presentation and
Natural History
• HCV RNA can be detected in blood within 1-3 weeks after
exposure
• Average time from exposure to seroconversion is 8-9 weeks
• Average time from exposure to symptoms period 6-7 weeks
• Liver injury (elevations in ALT) with 4-12 weeks
• Symptoms develop in only of 20% of patients
– Nonspecific 10%-20%
– Jaundice in only 20%-30%
CDC. MMWR. 1998; 47(No. RR-19):1-39.
Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S
NIH Consensus Development Conference Panel Statement Management of Hepatitis C, 2002
22. 22
Hepatitis C Infection
• Incubation period Average 6-7
weeks
Range 2-26
weeks
• Case fatality rate Low
• Chronic infection 75%-85%
• Chronic hepatitis 70% (most asx)
• Cirrhosis 10%-20%
• Mortality from CLD 1%-5%
23. 23
Acute Hepatitis C
Chronic Hepatitis
75%-85 %
Cirrhosis 20 %
10-20 years
Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S
Di Bisceglie, Hepatology, 2000
Natural History of Hepatitis C
24. 24
Acute HCV Infection with Recovery
Symptoms
+/-
Time after Exposure
Titer
HCV Ab
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
YearsMonths
HCV RNA
25. 25
Acute HCV Infection with Progression to
Chronic Infection
Symptoms
+/-
Time after Exposure
Titer
HCV Ab
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
YearsMonths
HCV
RNA
26. 26
Hepatitis C Complications
• Hepatitis encephalopathy – if untreated can lead
to:
Confusion
Disorientation
Hallucination
Stupor/Coma
• Jaundice
• Pruritus
• Renal damage/failure
• Hypo/Hyperthyroidism
• Varices of Esophagus, Stomach, Rectum
• Muscle Wasting
27. 27
Extrahepatic Manifestations of Hepatitis C
• Hematologic: Mixed
cryoglobulinemia
(10%–25% of HCV patients)*
• Renal: Glomerulonephritis
• Dermatologic:
– Porphyria cutanea tarda
– Cutaneous necrotizing vasculitis
– Lichen planus
Management of Hepatitis C. NIH Consensus Statement,
2002.
28. 28
Chronic Hepatitis C
Factors Promoting Progression or Severity
• Increased alcohol intake
• Age > 40 years at time of
infection
• HIV co-infection
• Other
– Male gender
– Chronic HBV co-infection
33. 33
Hepatitis D - Clinical Features
Coinfection
severe acute disease
low risk of chronic infection
Superinfection
usually develop chronic HDV infection
high risk of severe chronic liver
disease
34. HBV - HDV Coinfection
Time after Exposure
Titer
anti-
HBs
Symptoms
ALT
Elevated
Total anti-
HDV
IgM anti-HDV
HDV RNA
HBsAg
35. HBV - HDV Superinfection
Time after Exposure
Titer
Jaundice
Symptoms
ALT
Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
36. Treatment
• The only drug approved at present for
treatment of chronic hepatitis D is Interferon
Alfa (IFNa)
36
37. 37
Hepatitis E Virus
Most outbreaks associated with
fecally contaminated drinking water
Minimal person-to-person transmission
Most cases usually have history of travel
to HEV-endemic areas
38. 38
Hepatitis E Virus
Incubation period: Average 40 days
Range 15-60
days
Case-fatality rate: 1%-3% overall
15%-25% in
pregnancy
Illness severity: Increased with age
Chronic sequelae: None identified
39. 39
Typical Serological Course - HEV
Weeks after Exposure
Titer
Symptoms
ALT
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
anti-HEV
40. 40
Serological Profile
HEV IgM is usually present at the onset
of symptoms and persists for 3-4
months
HEV IgG is also present at the onset of
symptoms and persists for the patient’s
lifetime
41. 41
HEV Detection
Culture is worthless
PCR can detect HEV RNA in serum
and stool specimens from 2 weeks
before, to 2 weeks after, the onset of
symptoms
Nucleic acid sequencing is useful for
tracking HEV outbreaks
43. UNIVERSAL PRECAUTIONS !!!
When there is a risk of splashing, particularly with power tools
Use of a full face mask ideally, or protective spectacles;
Use of fully waterproof, disposable gowns and drapes, particularly during
seroconversion;
Boots to be worn, not clogs, to avoid injury from dropped sharps;
Double gloving needed (a larger size on the inside is more comfortable);
Allow only essential personnel in theatre;
Avoid unnecessary movement in theatre;
Respect is required for sharps, with passage in a kidney dish;
A slow meticulous operative technique is needed with minimised bleeding.
43
After initial exposure, HCV RNA can be detected in blood with 1 to 3 weeks and is present at the onset of symptoms. Antibodies to HCV are detected by enzyme immunoassay (EIA) in only 50 to 70 percent of patients at onset of symptoms, increasing to more than 90 percent after 3 months.
Acute infection can be severe but rarely is fulminant. Symptoms are uncommon but can include malaise, weakness, anorexia, and jaundice. Symptoms usually subside after several weeks as ALT levels decline.
Persons with acute HCV infection typically are either asymptomatic or have a mild clinical illness., 60%-70% have no discernible symptoms; 20%-30% might have jaundice; and 10% might have non-specific symptoms (eg, anorexia, malaise, or abdominal pain).
After acute infection, 15%-25% of persons appear to resolve their infection without sequelae as defined by sustained absence of HCV RNA in serum and normalization of ALT levels. Chronic HCV infection develops in most persons, with persistent or fluctuation in ALT elevations indicating active liver disease.
Based on studies conducted in the last decade since the publication by Kiyosawa et al., it has become possible to formulate an algorithm of the natural history of hepatitis C using data from a combination of prospective studies of posttransfusion and long-term follow-up of patients with established HCV infection.
75%-85% of patients will become chronically infected. Over a variable time period 10-20 years, 20% of patients will develop cirrhosis.
Extrahepatic Manifestations of HCV
Patients with chronic HCV can present with extrahepatic manifestations or syndromes considered to be of immunologic origin, such as rheumatoid symptoms, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, lymphoma, and essential mixed cryoglobulinemia. Cryoglobulins have been detected in the serum of up to one-half of patients with chronic hepatitis C, but the clinical features of mixed cryoglobulinemia are uncommon. Chronic hepatitis C is also related to porphyria cutanea tarda. Psychological disorders including depression have been associated with HCV infection in up to 20 to 30 percent of cases Management of Hepatitis C. NIH Consensus Statement, 2002. P 7-8 [Ref. 4.1]
