14. Viral hepatitis Flashcards
How is hepatitis A spread?
Via the faecal-oral route
Where does viral hepatitis tend to be more common?
Tends to be more common in countries in which access to clean water is poor. There are also occasionally outbreaks in schools and amongst MSM.
What is the incubation period of viral hepatitis?
Incubation period: 2-6 weeks
Who does Hep A cause clinical problems in?
Often subclinical (often people don’t realise that they have it). Tends to cause worse clinical problems in people with underlying liver disease e.g. Hep B, alcoholics (these people should be targeted for immunisation)
Is Hep A virus notifiable?
Yes
What are risks of contracting Hep A virus?
Occupational risks (sewage workers and plumbers are at risk, chefs not washing hands properly may spread it to others). GUM clinics. Low socioeconomic status
What outbreak occuredin Shanghai blood clams (1988) and New Zealand blueberries 2011?
Hep A outbreak
What is the natural history of Hep A?
2-6 weeks (15-50 days) after the infection
you get hepatitis (transaminitis i.e. rise in ALT) (lasts approx. 4 weeks)
What is the diagnostic test for Hep A?
IgM anti- hepatitis A virus (If you have had the vaccine, you will have a high IgM AND high IgG but WITHOUT the high ALT). HAV detectable in stool for several weeks.
Who is the vaccine recommended for in hep A?
Recommended for high risk populations e.g. occupational, those who travel often
Describe the features of HAV?
The family Picornaviridae, genus hepatovirus.
Single-stranded, positive sense RNA genome.
Quasi-enveloped virions
What are clinical manifestations of HAV?
Wide disease spectrum from asymptomatic to fulminant hepatitis. Strong correlation with age: <10% symptomatic among children <6 years old versus 70% in adults. Typical symptoms: fever, malaise, anorexia/nausea, abdominal discomfort, diarrhoea, jaundice. Extra-hepatic diseases. Acute presentation; 99% resolution.
HAV is an aetiology for chronic hepatitis true or false?
FALSE. HAV NOT an aetiology for chronic hepatitis
What does acute HAV infection show on serology?
IgM reactive; unlikely if bilirubin level < 30umol/L
What does past HAV infection show on serology?
IgM non-reactive, IgG reactive
How is Hep A managed?
Supportive Tx.
Pre-exposure immunisation among population at risk.
Post-exposure prophylaxis:
within 14 days of exposure to index case: HAV vaccine +/- HNIG (for 60 years and above, chronic liver diseases inc CHB/CHC, immunocompromised contact)
Over 14 days: HAV vaccine +/- HNIG (for chronic liver diseases inc CHB/CHC, immunocompromised contact)
What is the infectious period in HAV?
Infectious period of index case: two weeks before onset of first symptoms and until one week after the onset of jaundice
What are features of Hep B virus?
The family Hepadnaviridae.
Double-strained DNA with reverse transcriptase.
Enveloped virions.
10 genotypes (A-J) with distinctive geographic distribution.
How is Hep B transmitted?
Blood-borne transmission: horizontal & vertical i.e. sexually transmitted, blood products, mother-to-baby
What is the incubation period of HBV?
Incubation period of 40-160 days (2-6 months)
Is HBV infection acute or chronic?
BOTH
How can Hep B be transmitted in children?
Horizontal transmission – person to person. e.g. In sub-Saharan Africa this can be seen in children who catch it whilst playing in school etc
What chronic hep B infection?
Chronic: viraemia and hepatic inflammation 6 months or more OR persistence of HBsAg for 6 months or more after acute HBV infection
What percentage of people with acute Hep B infection develop a chronic infection?
Adults have a 5-10% chance of developing chronic infection (becoming a chronic carrier). Babies have a 95% chance of developing chronic infection (becoming a chronic
carrier)
What is the molecular organisation of HBV?
It is a DNA Virus. HBV proteins include: core antigen (HBcAg), surface antigen (HBsAg), E antigen (HbeAg) – marker of high infectivity. It has FOUR overlapping reading frames
What is on the surface of HBV?
On the surface, you have surface antigen (HBsAg) forming spears and tubules on surface. Surface antigen is used as a screening test
What drugs for another condition can be used in HBV?
It is a DNA virus, however, it uses reverse transcriptase to replicate so some HIV drugs are effective against HBV.
What happens as a result of the reading frames in HBV overlapping?
Because the reading frames overlap, you may get a mutation in the polymerase gene which may change the surface antigen. This can rarely cause patients to have HBV but not be positive in the surface antigen screening test
What antigen do some patients with HBV have?
Most people with HBV are e antigen positive (HBeAg) which is found in the pre-core part of the core reading frame. Some patients do NOT have HBeAg
What is the role of X antigen in HBV?
Unknown
Can Hep B affect animals?
Yes
What are clinical manifestations of acute hepatitis B in neonates and children?
Mostly asymptomatic or anicteric; 90% HBV-infected neonates develop CHB, and 30% among children age <5 years
What are clinical manifestations of acute hepatitis B in adults?
30-50% icteric hepatitis; 10% become CHB
What is the risk of fulminant hepatitis in HBV?
0.1-0.05% risk of fulminant hepatitis; related to co-infection with HCV/HDV
What are complications of chronic hepatitis B?
Cirrhosis: 8-20% untreated CHB in 5 years.
Hepatocellular carcinoma: the annual risk of 2-5% among CHB cirrhotic patients; affected by host (e.g. alcohol abuse) and viral factors (e.g. high HBV viral load & qHBsAg).
How many people are living with chronic Hep B?
296 million people
CHB-related mortality per year?
Roughly 820,000 people per year
How many cases of HAV infection worldwide?
Approx. 1.5 millions of cases worldwide annually. Developing countries with poor socio-economic conditions
How many cases of HAV per year in the UK?
300-500 cases annually in the UK. Mostly among age 15-34 and travellers. Outbreaks among MSM (2016/17) & IVDU (2001 & 2017).
What are the phases of chronic Hep B?
- HBeAg-positive chronic infection; 2. HBeAg-positive chronic hepatitis; 3. HBeAg-negative chronic infection; 4. HBeAg-negative chronic hepatitis.
In HBV serology, how do you interpret HBsAg, HBsAb, HBcAb, HbeAg, HBeAB?
HBsAg: infection; HBsAb: immunity through either immunisation or past infection; HBcAb: exposure -
IgM: acute infection; HbeAg: replication activity
HBeAB
What would HBV serology show in someone who is susceptible?
HBsAg (-); HBsAb (-); HBc IgM (-); HBcAb (-)
What would HBV serology show in someone who is immune due to past infection?
HBsAg (-); HBsAb (+); HBc IgM (-); HBcAb (+)
What would HBV serology show in someone who is immune due to immunisation?
HBsAg (-); HBsAb (+); HBc IgM (-); HBcAb (-)
What would HBV serology show in someone who has acute hepatitis B?
HBsAg (+); HBsAb (-); HBc IgM (+/-); HBcAb (-)
What would HBV serology show in someone who has chronic hepatitis B?
HBsAg (+); HBsAb (-); HBc IgM (-); HBcAb (+)
What are consequences of HBV?
Hepatocellular carcinoma (HCC) is the most common cancer associated with HBV. It tends to occur in diseased livers. Resection of the tumour alone is unlikely to be a feasible option, because the rest of the liver is likely to be damaged and not functioning very well (therefore transplantation may be considered)
What are three stages of HBV disease?
Immune tolerant, immune reactive, HBsAg negative phase
What is the immune tolerant stage of HBV?
Seen mainly in children infected at birth by mothers who are HBeAg positive. High viral replication but minimal liver inflammation and fibrosis (normal ALT). Low immune response
What is the immune reactive HBV disease stage?
Immune system recognises and starts to clear the virus. ALT high or fluctuating. Chronic active liver inflammation can occur.
In the immune reactive stage, at some point, most individuals with HBeAg positive
chronic hep B will
lose HBeAg and
seroconvert spontaneously to antibody to HBeAg (anti-HBe). What happens after this?
Most individuals enter the inactive HBV carrier state where there is normal ALT, low HBV DNA, improved in liver inflammation/fibrosis. However, some individuals may enter the HBeAg negative chronic HBV stage where raised ALT and HBV DNA is maintained. They will be HBeAg negative and anti-HBe positive. There is a high risk of progression to cirrhosis/HCC in chronic HBV stage individuals.
What is a strong indicator of the incidence of cirrhosis and
HCC and the need to treat
Baseline HBV DNA levels (copies/mL)
How is HBV infection prevented?
All pregnant women screened antenatally. Neonates born to HBsAg positive mothers should receive active hepatitis B
vaccination (recombinant HBsAg vaccine). If mother was also HBeAg positive, also give neonate passive immunisation via hep B immunoglobulin
What is the treatment for acute HBV?
Symptomatic treatment: antipyretics, antiemetics etc. Notifiable disease
Which treatments are given for which patients with chronic HBV?
Interferon Alpha: this is used in a subset of patients who look like they are more or less clearing the virus by themselves. Cytokine that augments natural antiviral mechanisms.
Nucleoside/ nucleotide analogues (usually on these for life) i.e. lamivudine, tenofovir, entecavir, emtricitabine.
GUIDELINES - NICE, EASL, AASLD
What is the route of administration of PegIFNalpha?
Subcutaneous injection
What is the route of administration of ETV (entecavir), TDF (tenofovir disoproxil fumarate), TAF (tenofovir alafenamide)?
Oral
How long is PegIFNalpha given for in CHB?
48 weeks
How long is ETV, TDF, TAF given for in CHB?
Long term until HBsAg loss (stopping nucleoside/nucleotide analogues after some years might be considered in selected cases)
What is the tolerability of PegIFNalpha?
Low
What is the tolerability of ETV, TAF, and TDF?
High
What are the long-term safety concerns of PegIFNalpha?
Very rarely persistence of on-treatment AEs (psych, neuro, endo)
What are the long-term safety concerns of ETV, TDF, TAF?
Probably not (uncertainties regarding kidney function, bone diseases for some NA)
What are the contraindications of PegIFNalpha?
Many (i.e. decompensated disease, co-morbidities etc.)
What are the contraindications of ETV, TAF, TDF?
None (dose adjustment according to eFFR^2)
What is the strategy of PegIFNalpha in CHB?
Induction of a long-term immune control by finite treatment
What is the strategy of ETV, TAF and TDF in CHB?
Stopping hepatitis and disease progression by inhibiting viral replication
What is the level of viral suppression of PegIFNalpha in CHB?
Moderate - variable response pattern
What is the level of viral suppression of ETV, TAF and TDF in CHB?
Universally high
What is the effect on HBeAG loss by PegIFNalpha in CHB?
Moderate depending on baseline characteristics
What is the effect on HBeAG loss by ETV, TDF and TAF in CHB?
Low in the first year, increase to moderate during long-term treatment
What is the effect on HBsAG levels by PegIFNalpha in CHB?
Variable depending on baseline characteristics (overall higher as compared to NA)
What is the effect on HBsAG levels by ETV, TAF, TDF in CHB?
Low, slowly increases with treatment time in HBeAG-positive patients. Very low in HBeAg-negative patients
What is the risk of relapse after Tx cessation of PegIFNx in CHB?
Low for those with sustained response 6-12 months after
What is the risk of relapse after Tx cessation of ETV, TAF, TDF in CHB?
Moderate if consolidation Tx provided after HBeAg seroconversion. High for HBeAg-negative disease
Is there a risk of viral resistance development in PegIFNalpha?
No
Is there a risk of viral resistance development in ETV, TAF, TDF?
Minimal to none
What is the public health implication of Hep B and how can we prevent it?
Acute hepatitis B: a notifiable disease.
Pre-exposure prophylaxis: routine childhood immunisation in the UK since 2017; high risk population.
Post-exposure prophylaxis:
neonate born to mother living with hepatitis B; sexual partner: HBV vaccine +/- HBIG (within one week from the contact); needle stick injury
What vaccines may babies at risk of HBV be given?
Hep B vaccine, HBIG (see slides for guidelines)
What are issues with liver transplantation in a CHB patient?
Can get graft reinfection; requires various other treatments (e.g.immunosuppression, nucleoside analogues, hepatitis B Ig) NOTE: interferon should NOT be used in transplants. Further complicated as they are immunosuppressed
What can be done in a CHB patient with liver failure?**
Someone may present with acute liver failure in a decompensated hep B state. Antivirals are very effective in treating the viral hepatitis -> work gradually ->
eventually can transfer them so that they do not need liver transplant. HBV vaccine may also be used. There are some non-responders who need novel vaccines
What are features of HDV?
Single-stranded, circular RNA genome. A defective virus that relies on HBV for propagation.
How is HDV transmitted?
Blood-borne transmission
What is the incubation period for HDV?
3-6 weeks
What is HDV co-infected with?
HBV/HDV simultaneous co-infection. Similar to classic acute hepatitis B; mostly self-limited. <5% chronic infection.
What are issues associated with HDV super-infection in CHB?
HDV super-infection in CHB.
80% chronic infection and increased risk of cirrhosis and HCC than CHB alone
How is HDV diagnosed?
Anti-HDV serology (other HDV investigations rarely used). Could also do PCR
How is HDV treated?
Self limited when acute. PEG-interferon alpha licensed for HDV superinfection in CHB. Pre-exposure HBV immunisation. Acute HDV infection: notifiable disease
What is anti-HDV total in acute HBV/HDV coinfection, acute HDV superinfection and chronic HDV infection?
Acute HBV/HDV coinfection = late, low titre; acute HDV superinfection = rapidly increasing titres; and chronic HDV infection = high titres
What is the smallest virus known to infect man?
Hepatitis D
In which countries is HDV seen?
Quite common in some areas of South America and the Middle-East
What are features of Hep C virus?
The family Flaviviridae, genus Hepacivirus. Single-stranded, positive sense RNA genome.
How is HCV transmitted?
Blood borne transmission. Big issue amongst MSM and IVDU. Very rarely, mother to baby transmission. Heterosexual transmission not common
What is the incubation period of HCV?
2-6 weeks
How many people live with chronic Hep C?
58 million people living with chronic hepatitis C worldwide
How many new cases a year of Hep C?
1.5 million new cases every year
What are the outcomes of acute hep C infection?
30% spontaneous clearance; 70% become chronic hepatitis C (CHC)
What are manifestations of Hep C?
Hepatic versus extra-hepatic manifestations. Lymphoma, cryoglobulinemic vasculitis, depression, fatigue, neurocognitive impairment, Sicca syndrome, hypothyroidism, increased risk of MACEs, T2DM, insulin resistance, CKD, glomerulonephritis, porphyria cutanea tarda, lichen planus, necrolytic acral erythema, autoimmune cytopenia (ITP, AIHA), MGUS, autoantibodies.
What are complications of HCV?
Cirrhosis (15-30% in 20 years) & HCC as complication of CHC
How does Hep C progress overtime?
Incubation: 2-7 weeks. Acute phase: 4-12 weeks. Cure: years. Might progress to chronicity
What is the treatment for HCV?
Direct-acting antivirals (DAA) including protease inhibitors, NS5A inhibitors, NS5B inhibitors. 8 or 12 weeks. Sustained virological response (SVR) at week 12. Pan-genotypic regimen. Single-tablet regimen. Drug-drug interaction.
What is the public health implication of HCV and how can we prevent HCV?
Acute hepatitis C: notifiable disease in the UK. Nil vaccine available. Nil post-prophylaxis available. Active HCV screening. Risk reduction (e.g. safe handling and disposal of sharps, protected sex).
Which has a higher rate of chronicity than other types of Hep?
Hep C - Higher rate of chronicity (60-80% progress to chronic carriage) than other types of hepatitis
Describe the virology of hep C
Small, enveloped, ssRNA virus. Consists of components for the Core, Envelope and Non-Structural components. Most antivirals are protease inhibitors and inhibitors
of non-structural components (NS5A and NS5B).
When did Hep C outbreaks occur?
Dodgy Spanish anaesthetist; Irish anti-D; HIV-positive MSM
How to diagnose hep C?
IgM and IgG anti-HCV antibodies. HCV RNA is the best way to check whether you have the virus in your blood (PCR)
What are features of Hep E virus?
The family Hepeviridae, genus Orthohepevirus; species A strains (8 genotypoes) infect humans.
G1 & G2: obligate human pathogens. G3 & G4: zoonotic; pigs & wild boar are natural hosts.
Single-stranded, positive sense RNA genome, quasi-enveloped HEV
How is HEV transmitted?
This is faecal-orally transmitted i.e. sewage-contaminated water
It is also a zoonosis - it can be transmitted from animals to humans (mainly pigs). Very little human to human spread. There have been some associations with shellfish consumption, blood transfusions, sausages and pig liver consumption
What has a high mortality rate in pregnant women?
HEV, mainly genotype 1
What is the incubation period of HEV?
15-60 days
How many new cases worldwide annually of HEV?
Approx 20 million
How many with symptomatic HEV?
3.3 million
Annual mortality due to HEV?
44000
Which genotype is endemic in UK?
UK is a HEV G3 endemic country
How to treat HEV?
Mostly self-limited; advised against alcohol during the course. Notifiable disease; HEV patient should avoid prepping food during the first 2 weeks. 3 month course of ribavarin monotherapy is only indicated in chronic hepatitis E (where there is no HEV clearance). If HEV is persistent, pegylated interferon for 3 months in liver-transplant patients. (See EASL guidelines). Immunocompromised and chronic liver disease patients should avoid consumption of undercooked meat (pork, wild boar and venison) and shellfish. HEV vaccination: only licensed in China
Who is at risk of HEV?
Pregnant women: G1; fulminant hepatic failure and obstetric complications (e.g. eclampsia and haemorrhage); 25% maternal mortality & high perinatal infant mortality.
Chronic liver disease patients.
Immunocompromised patients: may develop chronic hepatitis E (G3 & G4).
What are extrahepatic manifestations of HEV?
Neuro: Neuralgic amyotrophy, Guillan Barre syndrome, meningoencephalitis, mononeuritis multiplex, myositis, Bell’s palsy, vestibular neuritis and peripheral neuropathy. Renal: membranproliferative and membranous glomerulonephritis, IgA nephropathy. Haem: Thrombocytopaenia; monoclonal Ig, cryoglobulinaemia…
How is HEV diagnosed?
Immunocompetent: HEV serology. Immunocompromised: HEV PCR.
What is HGV?
This was shown to not cause much liver disease. Reclassified as Pegiviruses. This is thought to be more of a Simian virus. There has been some evidence to show that HIV-positive patients with HGV have higher
CD4 counts.
