viral hepatitis 1 Flashcards
what is hepatitis?
inflammation of the liver
what are the infectious causes of hepatitis?
viral, bacterial, fungal , parasitic
what are the non-infectious causes of hepatitis?
- alcohol — alcoholic liver disease
- drugs eg. paracetamol
- autoimmune eg. primary biliary cirrhosis, autoimmune hepatitis
- metabolic — fatty liver disease caused by metabolic syndrone, diabetes
- ischaemic
what hepatitis viruses are transmitted via the faecal-oral route?
A and E
what hepatitis viruses are transmitted via blood and body fluids?
E (transmitted both ways), B, Delta, C
all hepatitis viruses can lead to CHRONIC infection except what?
hepatitis A
what is chronic infection defined as?
> 6 months
why does hepatitis A not cause chronic liver disease?
because it never causes chronic infection
chronic viral hepatitis causes ___________, and subsequent healing with _____, which over time can progress to _______
- chronic liver inflammation
- fibrosis
- cirrhosis
describe viral hepatitis pathogenesis
- non-cytopathic — hepatitis viruses don’t cause damage themselves to hepatocytes, it is the immune response to the virus that gives rise to the damage
- hepatocyte damage is IMMUNE-MEDIATED
- eg. hep B enters hepatocyte, then the hepatocyte will express on its surface certain antigens recognised by cytotoxic T ells, which will then destroy the hepatocyte
- antigen recognition by cytotoxic T cells : apoptosis
- chemokine driven recruitment of Ag-nonspecific cells
- damage depends on strength of immune response
- mild inflammation to massive necrosis of liver (‘fulminant’ hepatitis, acute liver failure)
what does injury to hepatocytes lead to?
necrosis
what enzymes are released into the bloodstream from the breakdown of hepatocytes, and are indicative of liver inflammation and injury?
ALT and AST — both usually contained within hepatocytes
alkaline phosphatase (ALP) is indicative of what?
damage to bile canaliculi
ALP and bilirubin are elevated in what?
cholestasis
The liver cells synthesise clotting factors (measured by __, ___) and other proteins such as _____, and hence these tests are the best indicator of how the liver is functioning
- prothrombin time, INR
- albumin
how do you assess synthetic liver function?
INR, albumin
what does the presentation of acute viral hepatitis depend on?
age and immune status
what are the ranging presentations of acute viral hepatitis?
asymptomatic (childhood) vs mild, non-specific vs fulminant (adulthood)
what are the commonest symptoms of acute viral hepatitis?
prodrome of nausea, fatigue, malaise, fever
other symptoms of acute viral hepatitis?
jaundice (when fever settles), dark urine (due to conjugated bilirubin in urine), pale stools, RUQ tenderness, hepatomegaly
what are dark urine and pale stools due to?
cholestasis
what is pain felt in hepatomegaly?
pain felt because there are only pain receptors in the capsule of the liver. there are none in the actual substance. therefore if liver is enlarged, the patient may experience pain
what investigations are doing in acute viral hepatitis?
- elevated ALT/AST
- bilirubin, ALP less marked
- FBC, INR
- liver ultrasound to rule out obstruction of biliary tract
- viral screen — Hep A antibody (IgM), Hep B surface Ag, Hep C antibody, consider Hep E IgM
what is produced first out of IgG and IgM?
IgM
describe chronic viral hepatitis
ongoing inflammation in cycles with an immune response to the virus infection of the liver cells. liver tries to heal itself with fibrosis = connective tissue. as inflammation progresses with secondary fibrosis, get less and less of liver cells present as they are replaced with fibrotic tissue which cannot carry out the function of the liver.
- progression of fibrosis to cirrhosis (20-30 years)
- accerelated by co-factors eg. alcohol, HIV, diabetes, steatohepatitis
- asymptomatic, until liver decompensation (so little functioning liver left so patient develops complications such as ascites or jaundice)
what is the gold standard for diagnosing cirrhosis and fibrosis?
liver biopsy
what non invasive methods can be sued to diagnosis fibrosis/cirrhosis?
elastography, Fibrotest
what’s APRI score?
combination of blood tests - uses platelet count and the AST in a formulation
describe a fibroscan
- ultrasound elastography is performed by the fibroscan machine
- probe sounds out US waves which are reflected through the liver. they are reflected more quickly as the liver stiffness increases
- machine will tell you in real time a numerical score
- there are settings on the score on which above you would call someone cirrhotic
- can repeat and say there and then if they’re cirrhotic, unlike biopsy
WAVES REFLECTED MORE QUIUCKYL AS LIVER ‘STIFFNESS’ INCREASES IE. AS LIVER BECOMES MORE FIBROTIC
what are complications of cirrhosis?
progression to decompensation liver disease and hepatocellular carcinoma
the fibrous tissue laid down through the liver alters the blood flow and leads to _________
portal hypertension
what are complications of portal hypertension?
- ascites
- variceal bleeding
- encephalopathy
- subacute bacterial peritonitis = infection of ascites
- acute on chronic liver failure
what is the % 5 year survival for decompensated liver disease?
50%
what type of virus is hepatitis A?
RNA virus from picornavirus family
what is the incubation period for hep A?
30 days (4-6 weeks) = relatively short
how is hepatitis A transmitted?
faecal-oral transmission, associated with poor sanitation
hep A in developing vs developed world
- endemic in developing world — infection in childhood, mild or subclinical (>90% if <5 years)
- in developed world, hep A is a disease of adults, contaminated food/water, travel to endemic countries, IVDU, occupational
what does hepatitis A not lead to?
chronic infection
what are 2 complications of hepatitis A?
prolonged cholestasis, liver failure - RARE but more likely in adults and in pre-existing liver disease
how is Hep A diagnosed?
acute infection — HAV IgM
recovery or vaccinated — HAV IgG
how is Hep A prevented?
- vaccine (given at 0, 6-12 months)
- immunoglobulin given in outbreak as vaccine takes several weeks to work
- improvement in sanitation
DECLINING UK INCIDENCE since 2005
what type of virus is hepatitis E?
RNA virus from herpevirus family
what is average IP for hep E?
40 days (slightly longer than hep A)
how is Hep E transmitted?
faecal-oral transmission, HEV contaminant of blood supply in many countries
global HEV?
big problem globally — 3.4 million acute cases (Pakistan, India, Mexico)
what are the different HEV genotypes?
Genotype 1,2 — large ‘water borne’ outbreaks
Genotype 3,4 — zoonotic, sporadic cases — associated with undercooked pork, wild boar, deer
in who is there a higher mortality of hep E?
cirrhotics (underlying liver disease) and pregnant women (30% mortality in 3rd trimester)
what is hep E linked to?
a range of acute neurological syndromes eg. transverse myelitis
what hep E genotypes can become chronic in immunosuppressed? example?
3, 4
eg. solid organ and stem cell transplant patients, neonates, age <1, HIV with CD4 <250
how is HEV diagnosed?
HEV IgM (HEV IgG, HEV RNA blood, stool)
what do you check for in chronic HEV?
Hep E RNA in blood
hep E prevention?
improvements in sanitation
vaccine currently only in china
what is the most common cause of acute viral hepatitis in UK?
HEV
HEV neurological syndromes — dont often seen much in the way of raised _____. if someone comes in with _______ with transverse myelitis or ____________ — check for Hep E
dont often seen much in the way of raised ALT. if someone comes in with Guillain Barre with transverse myelitis or meningoencephaltiis — check for Hep E
what type of virus in HBV?
DNA virus from hepadnaviridae family - has multiple genotypes (subtypes)
what is the HBV IP?
75 days (6 weeks to 6 months)
what is the outcome of infection with HBV linked to?
maturity of immune system and effectiveness of response (linked to age)
HBV globally?
approx 350 million infected (180 000 in UK)
> 0,6 million deaths/year from end stage liver disease and liver cancer
HBV prevention?
vaccine - 3 doses at 0, 6 weeks, 6 months
link with HBV infection outcome and age at infection
what are the routes of transmission for HBV?
- contact with infected blood
- sexual
- mother to baby
what is the epidemiology of chronic HBV infection?
45% of the global population lives in areas with a high prevalence of HBV infection
UK HBV prevelance
0.3%
95% new cases of chronic infection are immigrants from high prevalence areas
most new HBV infections in the uk occur in who?
adults by sexual or parenteral (drug) route
Hep B serology : viral proteins
- Hepatitis B surface antigen HBsAg
- Hepatitis B e antigen HBeAg
Hep B serology : host antibodies
- hepatitis B e Antibody - Anti-Hbe — made in response to exposure to E antigen
- hepatitis B core antibody - Anti-HBc (IgM, IgG) — made in response to hepatitis B core antigen
- hepatitis B surface antibody - Anti-HBs
presence of what over 6 months defines chronic HBV infection?
surface Ag
what is seen in someone with a prior Hep B vaccination only?
Hep B surface antibody
if patient clears Hep B (which as an adult you have over a 95% chance of doing), left in blood after infection = what?
IgG antibodies to Hep B core antigen, and antibodies to surface antigen
what is the first then second thing to appear in blood after HBV exposure?
HBsAG, then HBeAg
what do you test for if screening someone for chronic HBV infection?
1) Hep B surface antigen
2) Hep B core antibody
what is seen in blood in someone with - HBV
- no exposure
- previous exposure
- chronic infection
- HBV sAg -ve, core Ab -ve
- HBV sAg -ve, Core Ab +ve
- HBV sAG +ve, Core Ab +ve
if infected with HBV at birth, what are the different phases you go through throughout life?
- immune tolerant
- immune clearance (HBeAg-positive chronic hepatitis)
- inactive carrier phase - at older age, can have acquired significant fibrosis or even cirrhosis by this stage
- reactivation (HBeAg-negative chronic hepatitis)
how can high dose steroids cause reactivation in hep B?
high dose steroids given in inactive carrier phase — these suppress immune system so virus becomes more active again - reactivation
what are the Hep B phases characterised by?
fluctuating levels of ALT and hep B virus DNA
how can some people with HBV lose the virus?
some people can lose virus — lose surface antigen and make surface antibody. however could have developed quite severe fibrosis by this time
what is seen in immature vs mature immune system in Hep B?
- immature immune system = high levels of Hep B DNA - virus replicating unchecked but immune system is not destroying virally infected hepatocytes so ALT levels are normal
- mature immune system (20+) - fluctuating ALT and virus level. see raised ALT when immune system is active and destroying the hepatocytes
what % per year does fibrosi progress to cirrhosis?
2-10%
describe tenofovir and entecavir treatment for chronic HBV
= nucleoside analogues
- block hepatitis B DNA polymerase - switch off replication in cell, but do not eradicate CCC DNA stored in hepatocyte nucleus. therefore if medication stopped the whole process starts up again
- LIFELONG MEDICAITON
describe interferon treatment for chronic HBV
injection given 1x week. stimulates our immune response to recognise that the hepatocytes are infected with a virus. immune system therefore destroys these cells.
HBV life cycle — part of it is in the _____. part involves _______ being inserted into host genome (our DNA) — sits like a viral reservoir and is hard to get rid of unless ______ is destroyed
- cytoplasm
- CCC DNA = covalently closed circular DNA
- hepatocyte
current HBV treatment clinical trial research involves what?
eradication CCC DNA
HDV vs HBV virus type
HDV = RNA VIRUS, HBV = DNA VIRUS
describe hepatitis delta virus
defective RNA virus — cannot replicate by itself — uses surface antigen of Hep B as its viral envelope
same routes of transmission as HBV
simultaneous vs superinfection
HDV epidemiology
- 5-20 million cases globally = 5% of HBV
- pockets in mediterranean basin, turkey, russia, central asia, africa, s america
- not as widespread as hep b
clinical features of HDV
- severe hepatitis, 70% progress to cirrhosis
- lifetime risk of hepatocellular carcinoma is doubled
HDV accelerates the progression of liver disease in chronic HBV (cirrhosis can occur up to 10 years earlier) and also increases the risk of liver cancer.
HDV diagnosis
hepatitis delta IgM, IgG, HDV RNA
hep delta treatment
clearance of HBV sAg —> eradication of delta
pegylated interferon for > 48 weeks
hep delta prevention
hepatitis B vaccine
why can tenofovir not be used to treat HDV?
tenofovir inhibits hepatitis B DNA polymerase, and has no effect on HDV replication. pegylated interferon is currently the only licensed treatment for HDV
Currently licenced treatments for chronic hepatitis B infection include _____ and ______ ( inhibitors of ________________ )and pegylated interferon. Interferon enhances the host immune response towards virally infected cells, and also inhibits various stages of viral replication.
Currently licenced treatments for chronic hepatitis B infection include Tenofovir and Entecavir ( inhibitors of Hepatitis B polymerase )and pegylated interferon. Interferon enhances the host immune response towards virally infected cells, and also inhibits various stages of viral replication.
what type of virus is hepatitis C?
RNA flavivirus, six major subtypes
HCV IP?
2 weeks to 6 months
how does acute infection of hepatitis C often present?
asymptomatic
hepatitis C — 75% develop chronic infection irrespective of what?
age and immune status
HCV epidemiology
- globally 180 million infected - UK 214 000
- > 350 000 deaths/year
- no vaccine available
progression of hepatitis C: for every 100 people infected, how many will:
- develop chronic infection
- develop chronic liver disease
- develop cirrhosis
- die or cirrhosis or liver cancer
- 75-85
- 60-70
- 5-20
- 1-5
how is hep C transmitted?
- contact with infected blood = most important
- sexual transmission
- mother to baby (<5%) — less than 5% babies born to hepatitis C infected mothers will develop infection — dependent on viral load. risk increases if mothers viral load is >1000000 units/ml
what country has the highest levels of HVC globally?
Egypt = 14-20%
UK HCV epidemiology
diagnosis of HCV — no vs prior vs chronic infection/exposure
what do pegylated interferon and ribavirin do in HCV treatment?
IFN — stimulates immune system , direct inhibitor of viral replication
RBV — mechanism unclear, induces viral mutations
what are poor prognostic indications in HCV?
cirrhosis, non caucasian, HIV co-infected, steatosis
unable to treat people with HCV in those with contraindications to IFN/RBV — example?
decompensated liver disease
in contrast to Hep B, the lifecycle of Hep C occurs entirely where?
in cytoplasm of hepatocyte
what are the different types of direct acting anti virals (DAA)? drug suffixes?
DAA drugs block each of the enzymes involved in Hep E viral replication
- NS3/4 protease inhibitors - translation and only protein processing = ‘previr’
- NS5B polymerase inhibitor - RNA replication - ‘buvir’
- NS5A inhibitors - transport and release - ‘asvir’
what is the current therapy for chronic HCV?
- combinations of DAAs in single tablet
- need to know genotype, if cirrhosis
‘ one pill a day (+ ribavirin if cirrhosis present)
- average treatment length 8-12 weeks
HCV pan genotyping 98% cure medications
Velpatasvir/Sofosbuvir (Epclusa)
HCV genotype 1,4 90% cure medications
Elbasvir/Grazoprevir (Zepatier)
