L15 - Viral hepatitis Flashcards
1
Q
Hepatitis definition
A
A diffuse necroinflammatory disease of the liver
2
Q
Hepatitis clinical presentations
A
- pain over the R hypochondrium
- Fever
- Loss of appetite, nausea, vomiting
- Jaundice (sclera & skin), pale stools, dark urine.
- Elevated liver enzymes
- alanine aminotransferase
- aspartate aminotransferase
3
Q
Aetiology of acute hepatitis
A
1) Infections:
i) Viral infection
- Hepatitis A, B, C, D, E Viruses
- Epstein-Barr virus
- Cytomegalovirus
- Yellow fever virus (South America & Africa)
- Echovirus
- Ebola virus
- Varicella
ii) Bacterial Infection
- leptospirosis
- Q fever
iii) Parasitic Infection
2) Toxins and Drugs
- e.g. Alcoholism
3) Autoimmune diseases
- e.g. autoimmune hepatitis
4) Metabolic diseases
- e.g. Wilson’s disease
(5) Obeisity ?)
4
Q
Infectious hepatitis (viral)
A
An older terminology used to classify viral hepatitis transmitted via the faecal-oral route (i.e. HAV & HEV)
5
Q
serum hepatitis (viral)
A
An older terminology used to classify viral hepatitis transmitted via the blod-borne route
i.e. HBV (with HDV) & HCV
6
Q
Non-A non-B hepatitis
A
A dated terminology used to denote syndrome of acute viral hepatitis occurring without the serologic markers of hepatitis A or B
- includes hepatitis C and hepatitis E.
7
Q
Non-ABCDE hepatitis
A
- A syndrome of acute viral hepatitis occurring without the serologic markers of hepatitis A, B, C, D or E
- Also known as seronegative hepatitis
8
Q
Hepatitis B virology
A
- A hepadnavirus
- Causes hepatitis
- 8 genotypes (A to H)
Genome:
- Contains DNA genomes
- Small genome with 3200 nucleotides
- Utilizes limited genome to maximal effect - with overlapping Open Reading Frames (4 ORF that translate to 7 proteins)
- DNA genomes are replicated via an RNA intermediate. In other words, their replication involves reverse transcription
Structure:
(from innermost to outermost)
1) (+)-DNA & (-)-DNA encased
2) capsid
3) Outer envelope membrane
9
Q
HBV Replication
A
1.1) Attachment: virus attach to hepatocyte surface receptors
1.2) Entry:
- Virus is endocytosed then the nucleocapsid is released from the endosome.
- The nucleocapsid is shown entering the nucleus
- The viral DNA ligated to form covalently closed circular DNA (cccDNA)
2) Transcription
- cccDNA is the template for transcription
- transcripted to RNAs which are then exported out of the nucleus
3) Translation
- 7 types of viral proteins are translated with overlapping ORFs based on mRNAs
4) Genome synthesis
- The RNAs, through reverse transcription, produce (-)-DNA and (+)-DNA
5) Packing & Export
- Nucleocapsids & virus formed
10
Q
Serological markers of HBV
A
1) HBV antigens
i) HBsAg
ii) HBcAg
iii) HBeAg
2) Antibody against HBV antigens
i) Anti HBs
ii) Anti HBc
iii) Anti HBe
3) HBV DNA
11
Q
HBsAg & Anti HBs & Acute infection
A
HBsAg:
- the first serological marker detectable after a HBV infection
- remains detectable during the entire icteric or symptomatic phase in acute hepatitis B
- The prominence can be explained as there is an excess production of envelope protein, leading to non-infectious envelope protein aggregates in filamentous or spherical form, which are released and detected in blood
- becomes undetectable 1 to 2 months after the onset of jaundice and rarely persists beyond 6 months
Anti-HBs
- After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter. Level will gradually decrease
- occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti-HBs
12
Q
HBcAg & Anti HBc & Acute infection
A
HBcAg:
- Because HBcAg is sequestered within an HBsAg coat, HBcAg is not detectable routinely in HBV infection
Anti HBc:
- readily demonstrable in serum
- beginning within the first 1 to 2 weeks after the appearance of HBsAg and preceding detectable levels of anti- HBs
- IgM anti-HBc predominates during the first 6 months after acute infection, whereas IgG anti-HBc is the predominant class of anti-HBc beyond 6 months
13
Q
HBeAg & Anti HBe & Acute infection
A
HBeAg:
- appears shortly after appearance of HBsAg
- disappears shortly before disappearance of HBsAg
- Reflects high levels of virus replication and the presence of circulating intact virions and detectable HBV DNA
- Qualitative marker
Anti HBe:
- appears after appearance of HBeAg and persists
- indicates low level of viral replication
14
Q
HB DNA & acute infection
A
HBV DNA:
- a quantitative marker of the replicative phase of HBV
15
Q
Serological differentiation of recent or past HBV infection
A
In patients with current or recent acute hepatitis B (including those in the anti-HBc window) have IgM anti-HBc in their serum.
In patients who have recovered from hepatitis B in the remote past as well as those with chronic HBV infection, IgG anti-HBc is predominant
[Anti-HBc of the IgM class (IgM anti-HBc) predominates during the first 6 months after acute infection, whereas IgG anti-HBc is the predominant class of anti-HBc beyond 6 months]
16
Q
Serological appraisal of viral replication activity
A
HBeAg
- a qualitative marker for active replication phase of HBV
- HBeAg positive indicates high level of replication
Anti HBe
- a qualitative marker indicating nonreplicative phase of HBV
- low level of virus
HBV DNA
- a quantitative marker for active replication phase of HBV
17
Q
Serological differentiation between natural HBV infection & vaccination
A
Given the infection and vaccination are not recent:
Natural infection:
- Anti HBc positive
- Anti HBs positive (negative if infection very long past)
Vaccination immunity:
- Only Anti HBs positive
18
Q
Chronic hepatitis B infection overview
A
Defintion: HBsAg Positive > 6 months
- accounts for < 10% of adult infections
- accounts for > 90% of newborn infections
- common following infection of immunocompromised
19
Q
Chronic HBV carrier serology
A
- HBsAg remains detectable beyond 6 months
- anti-HBc is primarily of the IgG class
- anti-HBs is either undetectable or detectable at low levels (i.e. no seroconversion to anti HBs)
- HBeAg remains high in the replication stage of HBV
- Seroconversion to Anti HBe noted when HBV enters nonreplicative phase, indicating low level viral replication
- HBV DNA is a quantitative marker of HBV replicative phase
[- nonreplicative HBV infection may convert back to replicative infection. Such spontaneous reactivations are accompanied by reexpression of HBeAg and HBV DNA, and sometimes of IgM anti- HBc]
20
Q
Chronic HBV carrier epidemiology
A
- 350 million chronic carriers (5% of world population)
- Genotype A represents pandemic
- Genotype B and C predominant in Asia
- Not strongly related to treatment response
21
Q
Immunity to hepatitis B
A
Prevent infection: antibody to HBs (anti HBs)
• Recover from infection: cell mediated immunity
– CD8 T cells: Cytotoxic T cells, cytokines • Virus escape from immune response:
– Virus down regulation of Major Histocompatibility antigen (MHC) on cell surface.
– Immune tolerance generated by HBeAg
22
Q
Adult HBV infection prognosis
A
- After acute HBV infection, 95% of adult will undergo virus clearance and be completely recovered
- In cases where viruses persist (i.e. no Anti HBs seroconversion), will lead to chronic infection
- up to 25-40% of chronic carriers succumb to HBV related illness, e.g. chronic hepatitis, cirrhosis, hepatocellular carcinoma
- In 0.1 – 1% of cases, fulminant hepatitis occurs
- Cross infection may occur
23
Q
Neonate HBV infection prognosis
A
- Usually starts with asymptomatic infection.
- In rare cases, naturally progress to viral clearance and complete recovery
- in 90% of cases, viruses persist (i.e. no Anti HBs seroconversion), will lead to chronic infection
- up to 25-40% of chronic carriers succumb to HBV related illness, e.g. chronic hepatitis, cirrhosis, hepatocellular carcinoma
- In 0.1 – 1% of cases, fulminant hepatitis occurs
- Cross infection may occur
24
Q
HBV infection prognosis in immunocomprimised
A
- starts with asymptomatic infection.
- In rare cases, naturally progress to viral clearance and complete recovery
- in 90% of cases, viruses persist (i.e. no Anti HBs seroconversion), will lead to chronic infection
- up to 25-40% of chronic carriers succumb to HBV related illness, e.g. chronic hepatitis, cirrhosis, hepatocellular carcinoma
- In 0.1 – 1% of cases, fulminant hepatitis occurs
- Cross infection may occur
25
HBV damage mechanism
- Virus does not directly kill the liver cells, i.e. is not cytopathic
- In acute infections, through strong cell mediated immunity, cytotoxic CD8 cells will release IFN gamma / TNF-alph targeted at virus infected cell, Destroying these infected liver cells and thus clearing virus. This results in acute hepatitis & recovery
- In chronic cases, cell mediated immunity is poor, thus virus infection persists. Such chronic infection will lead to chronic hepatitis B. Sequelae such as chronic liver disease, cirrhosis and Hepatocellular carcinoma follows.
26
Hepatitis B and primary hepatocellular carcinoma (PHC)
- 300,000 cases of PHC globally, is due to HBV
- 80-90% of PHC is associated with HBV in Hong Kong (\> 80% of PHC tumors in HBV carriers have virus DNA in tumor cells)
- Risk of PHC is increased x 217 in HBV carriers.
**Pathogenesis:**
- The virus DNA is integrated into the host DNA (site of viral DNA integration for all tumor cells a given patient is the same i.e. monoclonal), leading to insertional mutagenesis
- Cirrhosis leads to recurring damage, cell death and regeneration of hepatocytes. This increased turnover rate will increase chance of oncogenesis.
- HBV might be an oncogene
27
Treatment of HBV chronic carrier
**1) Immunomodulation**
- Interferon alfa (not so effective in Asian patients)
**2) Viral suppression**
- Lamivudine, adefovir dipivoxil, tenofovir
- Combination therapy
28
Management of occupational exposure to HBV and HCV
[Occupational exposure] -\>
[First Aid] -\>
[Report to Infection Control] -\>
[Risk assessment] -\>
[Exposure evaluation] & [Source and exposed person evaluation] -\>
[If risk is established, do baseline blood testing for HBV, HCV for exposed and source] -\>
[Post exposure prophylaxis: HB vaccination / HBIG; in cases of HCV Follow up and early Rx if infected] -\>
[Follow up lab tests and clinical assessment]
29
Vertical transmission defintion
A kind of parenteral transmission.
Occurs at the time of birth when materal and placental blood mix together (NOT in utero)
30
Transmission and epidemiology of HBV
**Transmission:**
- Parenteral route
- Vertical (mother-baby) transmission in perinatal period
- intimate physical contact esp. sexual
- Blood transfusion/ blood products/ needle contamination/ tattooing
- Carrier state exists
**Epidemiology**
- extremely common in Hong Kong and Southern China
- Every 5 of 10 ppl have been infected by HBV in Hong Kong (1 in 10 is carrier)
- Its incidence varies greatly in different parts of the world (HBsAg is present in 5 - 20% of apparently healthy persons in Southeast Asia and tropical Africa but in only 0.1 - 0.6% in Western Europe and America)
- Globally 350 million chronic HBV carriers (75% are Chinese)
- High risk groups: family members of HBV carrier, harmophiliacs, chronic liver disease patients
31
Clinical presentation and prognosis of HBV
**_Clinical presentation:_**
- The usual clinical attack of acute hepatitis B tends to be more severe than hepatitis A or C
- Incubation period 2-6 months
- 50% of infected adults are symptomatic
- Infected neonates usually asymptomatic, much higher risk of chronicity (up to 95%)
- Acute or insidious onset
**_Prognosis:_**
- 95% will recover from acute HBV hepatitis
- subclinical infection is also frequent especially in infants and children
- A proportion of otherwise normal adult patients will not clear HBV from the serum. They become persistent chronic carriers or develop chronic hepatitis
- up to 25-40% of chronic carriers succumb to HBV related illness
- Chronic hepatitis may lead to cirrhosis,
- Chronic hepatitis may progress to develop hepatocellular carcinoma (HCC) – 80%-90% of HCC associated with HBV in Hong Kong (i.e. HBsAg carriers have a much higher risk of HCC than non-carriers)
- In 0.1 – 1% of cases, fulminant hepatitis occurs
- Cross infection may occur
32
Lab diagnosis and prevention of HBV
**_Lab diagnosis:_**
- Serology: HBsAg positive; HBeAg indicates high infectivity; HBV DNA quantitatively indicates viral replication and activity
**_Prevention_**
- Vaccination (Active immunity) – based on genetically engineered analogues of HBsAg, leading to production of Anti-HBs
- Passive immunisation: Hyperimmune Hep B Immune globulin (HBIG)
- All infants in HK are immunised
; All health care workers should be immunised
33
HCV Virology
- Flaviviridae
- a single-stranded linear RNA virus
- enveloped
34
HCV transmission & epidemiology
**Transmission**:
- Parenteral route
- - Blood transfusion/ blood products(0.02% of HK blood donors)/ needle contamination/ tattooing
(? Vertical (mother-baby) transmission in perinatal period)
(? intimate physical contact esp. sexual)
- carrier state exist in \>90% of patients
**Epidemiology:**
- 170 million carriers worldwide
- 100,000 cases of hepato-cellular carcinoma annually, worldwide
- Greatest incidence rate in Egypt, due to reuse of injection needles in the past
- Carrier state occurs in \>90% of patients
- uncommon in Hong Kong, with \<1% population infected (Carrier rate of HK blood donors ~ 0.02%)
- High risk groups include IV drug users, haemophiliacs, chronic dialysis patients, patients with liver disease
35
HCV clinical presentation and prognosis
Clinical presentation:
**Clinical Presentation:**
- Usually asymptomatic, lead to chronic carrier state in \>90% of patients
- Long incubation period (7-8 weeks)
- insidious onset
**Prognosis:**
- very rarely leads to fulminant hepatitis
- About 50% of patients with acute hepatitis C progress to chronic hepatitis, leading to cirrhosis with or without development of hepatocellular carcinoma
- Acute hepatitis C tends to be mild clinically. It is associated with a wide spectrum of disease outcome, similar to the pattern of HBV infection
- Cross infection may occur
36
HCV Lab diagnosis & prevention
**Lab diagnosis:**
- Serology: HCV infection is recognised by positive anti-HCV antibodies
- PCR: HCV RNA is detectable early, preceding the appearance of anti- HCV by several weeks; quantitatively represent viral load
- No viral culture
**Prevention:**
- None
- passive anti-HCV is NOT protective
- No vaccination
37
HCV Infection Treatment
* **Pegylated inferferon + ribavirin**: \>50% viral clearance, reduce liver fibrosis and reverse cirrhosis
* Virus genotype predicts response to treatment
– Genotypes 2 and 3: _88% response_
– Genotypes 1, 4, 5, 6 : _48% response_
* Duration (24-48 weeks) of treatment depends on genotype and clinical assessment.
* New antiviral drugs licenced: Protease inhibitors: Telapravir, Bocepravir (need to be used in combination with interferon+ribavirin)
38
HAV virology
- Picornavirus
- RNA
- unenveloped
39
HAV transmission & epidemiology
**Transmission**:
- faeco-oral route; spreads by ingestion of contaminated water and foods especially shell fish
- Shed in the stool for 2–3 weeks before and 1 week after the onset of jaundice
- Transmission often seasonal from December to May
- Faecal virus titres falling by the time jaundice appears
- No carrier state
**Epidemiology:**
- occurs throughout the world and is endemic in countries with substandard hygiene and sanitation.
40
HAV clinical presentation and prognosis
**Clinical presentation:**
- 2-6 weeks incubation period
- direct cytopathic effect
- 10% symptomatic in children; 50% symptomatic in adult
- acute onset, no chronic carrier state
**Prognosis:**
- Type A hepatitis is an acute self-limiting disease
- does not become chronic.
- Mild disease will 99% full recovery
- May lead to protracted hepatitis, cholestatic hepatitis, relapsing hepatitis; these will all recover
- Very rarely fatal, e.g in the case of developing fulminant hepatitis (0.1%)
- No cross infection
41
HAV lab diagnosis & prevention
**Lab diagnosis:**
- Serology: Anti-HAV (IgM antibody) appears during the attack and persists
- no virus culture
**Prevention**
- Passive immunity: normal human immunoglobulin
- Active immunity: HAV vaccine
42
HEV virology
- Calicivirus
- RNA
- Unenveloped
43
HEV Transmission
**Transmission**:
- faecal-oral route; has caused massive outbreaks of water-borne hepatitis
- No chronic carrier state
- Convalescent patients will shed HEV for weeks
44
HEV clinical presentation & prognosis
**Clinical Presntation:**
- 2-9 weeks incubation period
- Acute onset; no chronic carrier state
**Prognosis:**
- low risk of chronicity
- Full recovery is expected
- No cross infection
- Low risk of chronicity
- Fulminant hepatitis in 1-2% patients; 10-20% in Pregnant
- It may cause severe disease especially in pregnant women
45
HEV Lab diagnosis & prevention
**Lab diagnosis:**
- Serology: rising IgG antibody and IgM antibody against HEV antigen
- No viral culture
**Prevention**: none
46
HDV Virology
- Defective/ incomplete RNA virus
**Special note:**
- under natural conditions replicates only in hosts who are HBs-antigenaemic. This is because HDV requires surface antigen of hepatitis B (HBsAg)
- HDV infection is therefore either an acute HBV/HDV coinfection or a superinfection on chronic HBV infection
47
HDV Clinical Presentation & Prognosis
- Acute HBV/HDV coinfection may be indistinguishable from hepatitis B, though it is associated with a relatively high rate of fulminant hepatitis.
- HDV can transform mild chronic hepatitis B into severe chronic hepatitis & cirrhosis.
48
Cross infection of hepatitis viruses
Cross infection occurs in HBV, HCV, HDV, but not in HAV & HEV
