Hepatitis Flashcards
What is viral hepatitis?
Inflammation of the liver
What are the symptoms acute of hepatitis?
Non-specific flu like symptoms
JAUNDICE, dark urine, pale faeces
What are the symptoms of chronic hepatitis?
General malaise, cirrhosis, primary hepatocellular carcinoma (after 10-30y)
What does fulminant mean?
is any event or process that occurs suddenly and quickly, and is intense and severe to the point of lethality, i.e., it has an explosive character.
What is it that causes damage in hepatitis?
The immune response to hepatitis viruses causes liver damage (i.e. it disrupts the normal architecture of the liver - lobules)
What is jaundice?
It is the result of liver damage/failure it is essentially hyperbilirubinemia
What type of infection is observed when one is exposed to a hepatitis virus early in life?
There is initially a less severe acute disease (i.e. less death of hepatocytes), however higher rates of chronic infection are observed
What are the different types of hepatitis?
Hep A-E A "infectious hepatitis" B "serum hepatitis" C serum non-A, non-B D dependant on HBV E enteric non-A, non-B
can hepatitis result from one virus or is it the product of many?
Hepatitis is one disease but there are many viruses which cause it, there is no cross over protection if infected by one
Hep A Source of virus? How is it transmitted? Incubation period? Infection type? Prevention? Symptoms by age group?
- Faeces
- Faecal-oral
- 2–6 weeks
- ACUTE
- Pre/post-exposure immunization
- Less then 6 = less then 10% 6-14 = 40-50% Older then 14 yrs = 70%-80%
Hep B Source of virus? Incubation period? Infection type? Prevention? Clinical illness (jaundice)? Chronic infection numbers? Perinatal transmission?
• Blood/blood-derived body fluids • Percutaneous, Permucosal • 4–26 weeks • Chronic • Pre/post-exposure immunization •
Hep C Source of virus? Incubation period? Infection type? Prevention? Immunity?
- Blood/blood-derived body fluids
- Percutaneous, Permucosal
- 2–26 weeks (ave 6-7 weeks)
- Chronic
- Blood donor screening; risk behaviour modification
- No protective antibody response identified
Hep D Source of virus? How is it transmitted? Incubation period? Infection type? Prevention?
- Blood/blood-derived body fluids
- Percutaneous, Permucosal
- Same as for HBV
- Chronic
- Pre/post exposure immunization; risk behaviour modification
Hep E Source of virus? How is it transmitted? Incubation period? Infection type? Prevention? Fatality?
- Faeces
- Faecal-oral
- 2–10 weeks (ave 40 days)
- ACUTE
- Ensure safe drinking water
- 1-3% overall but 15-25% in pregnant women
Where are Hep A rates the highest in Aus?
Higher prevalence in indigenous communities - NT
Hep A What virus family is it from? What kind of virus is it? How many serotypes worldwide? Does it infect other species?
- Picornaviridae family - Hepatovirus – (other relatives = polio, rhinoviruses)
- Non-enveloped (+) ssRNA virus
- Single serotype worldwide (useful for vaccine)
- Infects man, many higher primates
What is the life cycle of the HAV?
It is in contaminated water/food Ingested REPLICATES in intestinal epithelia Travels through the blood Replicates in the liver Excreted via the bile into the faeces Enters water/food
How are HAV and HEV transmitted?
Mainly through contaminated water/food
Also through Sexual intercourse and intravenous drug users
How is HBV transmitted?
Through sexual intercourse
Mostly between intravenous drug users
Need to look up prenatal (no Rx and Rx)
How is HCV transmitted?
Mainly through intravenous drug users
Some evidence that it can be transmitted sexually
Need to look up prenatal (no Rx and Rx)
How can we determine if the hepatitis is acute/chronic?
Serological tests - ELISAs etc. – IgM antibody to viral proteins (acute) • Reactive at 1-2 wks • Sensitivity >90%, Specificity >99% – IgG antibody to viral proteins • Rising titre confirms acute infection
Also Nucleic acid tests
– PCR from blood/faeces, but inferior to ELISA
What are the potential complications and chronic sequelae of Hep A
Complications: Fulminant hepatitis (rare), Cholestatic hepatitis
Chronic sequelae: None
Is Hep A cleared, how long do symptoms last?
Immune mediated cytopathology and viral clearance • Symptoms last 2-3 weeks
What is the principle way to prevent HAV?
Sanitation
If not Immune globulin can be used both pre exposure (in travellers) and post exposure
What is the Hep A vaccine?
It is an inactivated virus, grown on culture, it is highly effective (almost 100% effectiveness after 2 doses) , but is expensive to produce and test
Hep E
What virus family is it from?
What kind of virus is it?
Does it infect other species?
Hepeviridae family •Hepevirus
Non-enveloped •But more fragile than Hep A
(+) ssRNA
It is closely related to a virus which infects pig herds
What are the clinical signs of Hep E in adults?
– Jaundice 100% – Malaise >95% – Anorexia >65% – Abdominal pain 30-80% – Hepatomegaly 10-80% – Nausea & Vomiting 30-100% – Fever 20-90% – Pruritus 15-60%
Hep E pathogenesis?
Outbreaks typically occur in association with feacally contaminated drinking water
Pathogenesis
• Poorly understood
• Entry across intestinal mucosa (unknown)
• Secreted in faeces – 2 weeks before and 1 week after symptoms
• Detected in serum for two weeks after onset
• Affects liver Kupffer cells and hepatocytes
• Cholestasis is a feature in 50% of cases
• Injury appears immune mediated
Is there a vaccine for Hep E?
No but there are candidate vaccines (probably one that already works in China)
How many carries of the HBV are there worldwide?
350 million
What percentage of regular intravenous drug users have HCV and HBV?
HCV - 50-60%
HBV - 2%
HIV - 1%
Hep is approx 18x more prevalent than HIV
What are the two forms that the Hep B virus can be in?
- Virus particles have double walled structure with outer envelope and inner capsid
- Incomplete particles containing only envelope proteins, this is a non-infectious virus particle. As they have surface antigens they are though to act as decoys fro the immune system
Hep B
What virus family is it from?
What kind of virus is it?
- Hepadnavirus
* dsDNA
Mechanism of Hep B replication
Pregenomic RNA undergoes reverse transcription to make the dsDNA genome of HBV virion
DNA -> RNA -> DNA
- Virus enters cell
- →Releases capsid and genome into cytoplasm
- →Goes to nucleus
- →Relaxed circle of DNA repaired in nucleus
- →Forms covalently closed circular DNA episome (CCCDE)
- →becomes complete double strand DNA
- →serves as template for transcription of viral RNA to make proteins
- →Pregenomic RNA goes to cytoplasm
- →becomes core + precore protein & polymerase
- →polymerase then reverse transcriptases on pregenomic template into copy of dsDNA **unique enzymatic reaction in cells – good for antivirals).
What does the Hep B genome contain?
- dsDNA genome
- relaxed circle [area of ssDNA] of
- 3kb bound with viral polymerase (very small)
- short direct repeats (DR)
- RNA Primer
- Several RNA transcription start sites but only one termination (polyA) site
- DNA polymerase
- Overlapping translation reading frames within each RNA → allows production of different proteins:
- (C) = core protein
- The core gene consists of the precore and core regions, which give rise to the hepatitis B e antigen (HBeAg) and core protein
- **Pregenomic RNA goes >1 circle around DNA episome (drug implications)
- (P) = polymerase protein
- (S) = surface protein
• Produces DNA from RNA template
What is the life cycle of HBV, HDV and HCV?
Sex/close contact or injection
Virus PENETRATES (i.e. does replicate in) the mucosal epithilia
Virus enters the Sex/close contact or injection blood
Virus enters and replicates in the liver
Virus enters into blood, semen, secretions
Sex/close contact or injection
Concentration of Hepatitis B Virus in Various Body Fluids?
High:
Blood, Serum, Wound exudates
Moderate
Semen, vaginal fluid, Saliva
Low/Not detectable:
Urine, faeces, sweat, tears, breast-milk
What are the differences in the titre between chronic and acute Hep B infections?
In an acute infection HbsAg rises and then falls IgM anti-HBc rises and falls Anti-HBs rise when IgM is almost at 0 Total anti-HBc rises and then maintains a stable titre
In chronic hepatitis
IgM rises and falls
HBsAG rise and then maintain the same titre
Total anti-HBc rise and then maintain a titre
A CHRONIC CARRIER WILL BE HBsAG+
Strategies used by HBV to ensure persistence?
- HBeAg
- HBsAg
- HBV cccDNA
How is Hep B daignosed?
- HBsAg - used as a general marker of infection.
- Anti-HBs Ig - used to document recovery and/or immunity to HBV infection, but also successful vaccination.
- anti-HBc IgM - marker of acute infection.
- anti-HBc IgG - past or chronic infection.
- HBeAg - indicates active replication of virus and therefore effectiveness of therapy.
- Anti-HBe Ig - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV
- HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.
What does pegylated mean?
Sustains long acting release
What are the current anitviral drugs for HBV?
Interferon alpha
Nucleoside analogues
New generation drugs in development
How does interferon alpha work?
- Initiates host antiviral mechanisms [used in HBeAg +ve carriers with chronic hepatitis]
- Significant response rate (30-40%)
What are the nucleoside analogues and how do they work?
Lamivudine (3TC)
= nucleoSIDE: lacks hydroxyl in 3’ position -> prevents elongation
Adefovir = nucleoTIDE:
already added one phosphate group -> prevents elongation
Hep B vaccine?
- from yeast + alum adjuvant + 2-3 doses –
- (also protects against HDV)
- Cases of Hep B have ↓ed markedly once vaccination amongst infants, adolescents etc
What is Hep D?
- Hepatitis D particle contains self-complementary ssRNA
- Expresses 1 protein: Delta antigen
- transmitted by being packaged into hepatitis B surface antigen particle
- Requires the presence of hepatitis B virus in order to gain infectivity [hep B vaccination therefore protective]
What is superinfection with Hep D?
- ie already been infected with Hep B and now reinfected by Hep B & Hep D again)
- Usually develop chronic HDV infection
- High risk of severe chronic liver disease
Where are most hep C infections contracted from?
80% of infections occur through injecting drug use, IDU’s have HCV prevalence rates between 50-80%
What percentage of infections result in chronic infection?
Initial HCV infection may be asymptomatic but results in a lifelong chronic infection in 70% of people (30% of infected people clear the virus)
What kind of virus is Hep C
Flavivirus family = Single stranded, linear (+) RNA
Why is Hep C hard to treat?
High mutation rate -> enormous genetic diversity (in community and in patients) ii. International genotype diversity: mainly genotypes 3a, 1a, 1b and 2 in Australia
What is the structure of the HCV?
Enveloped virus with two proteins on the outer surface – envelope glycoprotein 1 + 2 ii. Associated with lipid droplets (virus particle seems to associate with lipid) iii. Inside the lipid bilayer = core made from nucleocapsid which encase single stranded RNA genome
What are some features of the mRNA genome of HCV?
Uses IRES (internal ribosome entry site) to initiated translation + Poly-U tail rather than poly-A tail
What are some features of the Hep C region which codes for one long polyprotein?
- Can then be processed into smaller individual units by proteolytic cleavage
- Structural protein (5’ end) = nucleocapsid + envelope glycoproteins
- Non-structural proteins (3’ end) = NS1, 2, 3, 4A, 4B, 5A, 5B
- Ones that are the most important are NS3 (serine protease activity); acts as an enzyme to facilitate the proteolytic cleavage of the polyproteins + NS5B is also important
How does HCV replicate?
i. Virus infects hepatocytes which have a collection of different receptors; hepatitis C uncoats
ii. E1 and E2 in conjunction with lipid bind and release +ve sense RNA genome into the cytoplasm of cells
iii. +ve sense RNA translated to produce the viral polyproteins -> processed into functional proteins
iv. Negative sense copy is used as a template to make lots of copies of new positive sense RNA
v. NS5B viral RNA polymerase (RNA-dep. RNA polymerase) mediated replication of viral (+) ssRNA to (-) sense ssRNA is HIGHLY ERROR PRONE leading to a high degree of genome diversity 1. NS3 is also involved in unwinding the RNA (helicase activity) 2. At threshold of maximal mutation rate before it leads to non-functional entity
How often is a clinical illness and jaundice seen in patients with Hep C?
30-40%
20-30% jaundice
What are the sequele of jaundice?
i. 70-90% become chronic carriers; ongoing replication of virus drives fibrosis
ii. Liver fibrosis
iii. Cirrhosis, liver failure (no. 1 presenters for liver transplantation)
iv. Primary hepatocellular carcinoma (?? With hepatitis B)
v. 170-300 million carriers; 5% lifetime mortality
What were the first available antiviral drugs for Hep C?
Pegylated Interferon alpha and ribavirin (nuceloside analogue)
Not effective for all and have significant side effects in some patients
Where do HCV life cycle inhibitors act?
i. Viral entry inhibitors
ii. HCV RNA translation inhibitors
iii. Post-translational processing inhibitors = NS3-4A protease inhibitors
iv. HCV replication inhibitors = NS5B polymerase inhibitors, Cyclophilin B inhibitors (essential host cofactor), NS5A inhibitors, Helicase inhibitors
v. Viral assembly and release inhibitors
What are the new HCV drugs called?
How effective are they?
Directly acting antivirals (DAA)
i. New drugs are known as direct acting antivirals (for Hep C) ii. Response rate = sustained virological response (essentially clearance of detectable virus) iii. Combination with IFN + ribavirin + protease inhibitor (targets NS3) increases the sustained irological response up to 85% iv. Many new drugs coming through 1. First two licensed = telaprevir and boceprevir (protease inhibitors) v. IFN-free combination DAA phase II studies = goal is to eliminate interferon from therapy; due to significant side effects -> shown to be efficacious (clearance >90%)
What are the advantages of DAA?
Treat primarily as infectious disease (rather than liver disease) 2. Treat all stages of disease 3. Major involvement of primary care, with advanced diease in liver 4. Potential role for treatment as prevention, but need DAA price reduction, only daily regimen 6-12 weeks therapy, IDU treatment infrastructure a. Still some toxicity with DAA + adherence is a big issue
