Viral Hepatitis and Vaccinology Flashcards
What is hepatitis?
Inflammation of the liver (varying causes)
Causes:
- Trauma
- Alcohol abuse
- Drug-induced toxicity
- Viral infection (main cause)
What is liver cirrhosis?
- Advanced consequence of chronic liver disease (years)
- Characterised by fibrosis; liver tissue replacement by collagenous scars with no function, and regenerative nodules; attempts to repair damaged tissue
Why do the ‘regenerative nodules’ seen in liver cirrhosis not work?
- They are not hepatocytes any more
- They are fibroblasts, producing collagen
- Results in scarring (collagenous scars w/no function)
- Collagen has no function; hepatocytes have been replaced w/collagen
What is a common complication of cirrhosis? How can cirrhosis be treated?
- Ascites; fluid retention in the abdominal cavity ‘big belly’
- Cirrhosis is irreversible; liver transplant is the only therapeutic option
What causes viral hepatitis? List.
- Hepatitis A (HepA; HAV; naked; IV)
- Hepatitis B (HepB; HBV; enveloped; VII)
- Hepatitis C (HepC; HCV; enveloped; IV)
- Hepatitis D (HepD; HDV; enveloped; V)
- Hepatitis E (HepE; HEV; naked; IV)
- Can also be caused by other viruses e.g. Adenovirus, SARS, Ebola, Influenza etc.; but these mainly cause other symptoms (uncommon to result in hepatitis)
How do the differences in HepA - E impact on the type of infection they cause?
- Naked hepatitis viruses (Hep A, E) tend to cause acute infections
- Enveloped hepatitis viruses (Hep B, C, D) tend to cause persistent and chronic infections; have developed ways of evading immunity
How do the differences in HepA - E influence routes of transmission?
Naked (Hep A, E):
- Non-enveloped
- Oral-faecal transmission e.g. unwashed food
- Resistant to dryness, acids etc, can survive outside the body
- Cause acute hepatitis
Enveloped:
- Blood and other bodily fluids (contaminated blood transfusion, needle-stick injury, unprotected sexual intercourse)
- Envelope = sensitive to dryness and will not survive outside the body; transfer via bodily fluids
- Cause chronic disease
What is the characteristic symptom of hepatitis?
Jaundice (jaune; French for yellow) AKA icterus:
- Yellowing of the skin and eyes
- Due to increased levels of bilirubin (a haemoglobin breakdown product) in the blood
Describe how bilirubin is rid of in the healthy liver, and the precursors which contribute to jaundice.
- Heme is broken down in the liver to Biliverdin (non-soluble) via Heme oxygenase first
- Non-soluble biliverdin then reduced to bilirubin (via biliverdin reductase); but still not soluble
- These insoluble compounds build-up in the body w/poo liver function as the liver can’t keep up with degradation of RBCs
> > > In healthy liver, biliverdin is then conjugated with glucuronic acid to form the water-soluble product, bilirubin diglucuronide, which is then excreted.
Describe what other symptoms can arise from hepatitis infection aside from jaundice.
Jaundice in 70-80% of people 14+ y/o (but only 10% in children).
Other symptoms:
- Fatigue
- Abdominal pain
- Loss of appetite
- N&V
- Dark urine (more characteristic, above more non-specific)
What are the other causes of jaundice aside from hepatitis?
- Gilbert syndrome (mild hereditary hyperbilirubinemia)
- And other shit
What is the difference/purpose between pre-exposure immunisation and post-exposure immunisation?
Pre-exposure:
- To protect HCP against needlestick injury etc. (have antibodies)
Post-exposure:
- Vaccination given ASAP after being pricked
Describe the Hepatitis A virus; severity of infection, immunity, transmission etc.
- Self-limiting; HAV does not lead to chronic/persistent hepatitis (immune response sufficient)
- CAN result in fulminant (lightning/v. quick) hepatitis and death in small proportion; not reversible thus ICU/transplant required
- HAV induces lifelong protection against reinfection
- Transmission: mainly oral-faecal
- Occurs worldwide; risk of infection inversely proportion to levels of sanitation and personal hygiene
Describe the structure of the Hepatitis A virus.
Capsid:
- Densely packed icosahedral (20 faces) arrangement
- Consists of 60 promoters, each consisting of 3 polypeptides; VP1, VP2 and VP3 (Viral Protein 1…)
- VP4 not incorporated into outer capsid (inner capsid?)
- Non-enveloped
- Spherical (pseudo icosahedral)
- 30 nm positive ss(+)RNA virus; Group IV (4)
- Genus; hepatovirus, of the picornavirus family
Describe the Hepatitis B virus; severity of infection, complications, transmission etc.
- In most cases; HBV only stays in the body for 1 - 3 months (Acute Hep B)
- 1 in 20 cases; virus stays for 6 months+; usually w/o causing any noticeable symptoms (Chronic Hep B)
»> 20-25% of Chronic Hep B have progressive liver disease (degeneration), leading to cirrhosis
»»> Around 10% of Chronic Hep B w/cirrhosis etc. will develop liver cancer (0.1% of everyone developing Hep B)
Transmission:
• Sexual transmission (STI)
• Blood-to-blood contact; needle-sharing etc, needle-stick injuries
• Perinatal transmission from mother to child
Describe the structure of the Hepatitis B virus.
- Enveloped (stolen from host cell)
- Spherical
- Diameter; 42mn (smallish)
- Icosahedric capsid (within envelope)
- dsDNA, Baltimore VII (mix of dsDNA and sDNA w/RNA primer; exception to I - VI)
> > > Reverse transcriptase activity; HBV one of few non-retroviral viruses which use reverse transcription as part of its replication process
HBsAg (HepB Surface Antigens); 3 sub-units (Large S, Middle S, Small S) of different lengths on envelope
HBcAg (HepB Capsid Antigen)
Describe the Hepatitis C virus; epidemiology, symptoms, immunity, transmission etc.
Epidemiology:
- 170 million infected w/Hep C worldwide (loads more than HIV)
- 216,000 in UK have chronic hepatitis C
- 87% are current/past drug users (needle sharing)
Symptoms:
- No noticeable symptoms in most cases until liver has already become significantly damaged
- HCV infection progresses to chronic liver disease in 70-75% of cases; 3x more than HepB, resulting in liver failure, cancer
Immunity:
- There is no vaccine of HCV
Transmission:
- HCV concentrated in blood; transmitted through blood-to-blood contact (e.g. needle-sharing by IVDUs)
- Via saliva, semen or vaginal fluid (latter mostly in HepB)
to a much lesser extent
Describe the structure of HCV.
- Enveloped, spherical
- Icosahedral capsid
- 50nm diameter
- Mature virions contain two virus-encoded membrane proteins (E1, E2; form dimer), as well as capsid protein (within envelope)
- Baltimore IV; ssRNA(+)
- Genus: Hepacivirus, of the Flaviviridae family
Why is the genotype of HCV important?
- Dictates type of therapy to be used
- At least 11 genotypes (strains)
- Genotypes 1, 2 and 3 most widespread in Europe and North America
- Genotype 4 in AFrica
How is Hepatitis C infection treated?
- Combination therapy of Ribavirin (oral guanosine nucleoside analogue) and PEGylated IFN-α (cytokine peptide)
- Treatment duration; 6-12 months, BUT only 20-40% cure rate
What cautions are there with Ribavirin (+ PEGylated IFN-α) therapy of HCV? What influences outcome?
- Teratogenic; not to be given to pregnant women
- HCV Genotype affects treatment success; 2 or 3 and three times more likely to respond to therapy than Genotype 1 (dickhead ting)
»> Different strategies for different genotypes
What newer therapies have been devised for HCV treatment?
HCV protease inhibitors:
- Boceprevir and Telaprevir (UK)
- For HepC Genotype 1 in combination w/ribavirin (OG)
HCV Polymerase inhibitors:
- Sofosbuvir (Sovaldi)
- HepC Genotypes 2 & 3 as combination therapy with ribavirin (OG)
- HepC Genotypes 1 & 4 as triple therapy with ribavirin and PEGylated IFN-α (BUT; long + expensive treatment, w/low success)
Describe the Hepatitis D virus. Why is it peculiar?
- Defective, ‘satellite’ virus; cannot exist on its own
- Requires co-infection w/HBV; provides the antigens needed for cell host cell attachment and infection
- HDV does not have surface antigens required for infection
- But once inside cell, HDV can replicate independently
- Uses HBV surface antigens (HBsAg) as its own virion coat
Describe the structure of HDV, and how its boiz w/HBV.
- Enveloped
- Spherical
- 22nm diameter (small)
- Membrane proteins (M-glycoprotein, S-glycoprotein, L-glycoprotein) originate from HBV helper virus
- Delta antigen (HDAg) stabilises RNA genome within viral envelope; HDV has NO capsid, just the envelope
What is the significance of HDV infection (co-infection w/HBV)?
- Virus-like (no capsid) delta agent associated w/most severe forms of acute and chronic hepatitis in many HBsAg-positive patients
- Disease = Type D/Delta hepatitis
- Chronic hepatitis D may also lead to development of hepatocellular carcinoma (liver cancer)
»> WORST hepatitis.
What is passive immunisation? Adv vs. disadv?
- Injection of pathogen-specific pooled human Igs (antibodies)
- Used when no time for active immunisation, or in post-exposure prophylaxis; offers immediate protection e.g. rabies
- But, does not confer long-term protection (no immunity, foreign antibodies are degraded)
What are the different types of active immunisation availible?
- Live attenuated vaccines (#1)
- Inactivated vaccines (#2)
- Subunit vaccines (#3)
What do live attenuated vaccines entail?
Best active immunisation:
- Viruses grown in cultures and repeatedly passaged through rounds of culture (less pathogenic after each round)
- Low virulence viruses selected; these attenuated strains then reproduced in large quantities for vaccination
- Full immune response; without causing full illness (mild symptoms possible)
- Immune memory of pathogen generated
»> AVOID in immunosuppressed (CAN/HIV)
What are inactivated vaccines?
- Viruses cultured as per Live Attenuated Vaccines, but then inactivated w/formaldehyde ‘killed’
- # 2 Active Vaccination
- Fewer S/Es (symptoms) than LAVs
»> But immune response is less vigorous
What are subunit vaccines?
3 Active Vaccines:
- Surface antigens produced by recombinant DNA technologies (e.g. yeast)
- Recombinant protein given as single protein alone, or up to 20 different proteins together w/adjuvant (e.g. aluminum hydroxide, strengthens immune response)
- Safe approach; pathogen is not present, and pose nor risk to immunocompromised patients either (unlike LAVs)
»> BUT, evoked immune response may be weaker, hence less protection
E.g. Influenza vaccines, HBV vaccines.
What does vaccination against Hep A entail?
- There is one HAV serotype, but at least 7 different genotypes
- Antibodies against just one genotype protects against all other genotypes!!!!
- No specific treatment
- Vaccination; inactivated whole viruses propagated in MRC-5 human lung fibroblast cell line
What are the three types of vaccine that protect against HAV infection?
- Monovalent vaccine; protection against HepA
- Combined HepA and HepB vaccine (useful for HCPs)
- Combined HepA and typhoid fever vaccine (typhoid fever serious bacterial infection; useful for travellers)
What does HepB vaccination consist of?
- Subunit vaccine consisting of HBsAg (surface antigen) absorbed onto aluminium hydroxide adjuvant, prepared from yeast cells via recombinant DNA technology
- Combined vaccine containing purified inactivated HAV and purified recombinant HBsAg also availible
- Usually 3 doses, with a potential 4th booster after checking Ab level
- HepB vaccine highly effective at preventing infection if given shortly after exposure; needle-stick injuries
- 10-15% adults fail to respond to 3 doses of vaccine, or respond poorly (>40 y/o)
E.g.:
• Monovalent: Hep B
• Combined: HepA + Hep B
