Liver symposium Flashcards
How does viral hepatitis affect the liver?
Indirect, immune mechanism of damage to hepatocytes
- Not the virus itself that causes the hepatitis
- It is not host response that gives rise to the disease
Clinical features of acute hepatitis: often so similar as to be indistinguishable- so can’t tell which virus it is
Onset is insidious - long prodrome syndrome where various symptoms displaying themselves
Many non-specific symptoms
Jaundice (more specific) can last few days to months, or may not occur at all
Itching (bile salts in skin) and pale stools, weight loss
Fatigue - may persist for months
5 hepatitis viruses?
Infectious hepatitis = hep A
- Spread by faeces- causes acute hepatitis (get it and it goes away)
Serum hepatitis = hep B
- Blood contact
Parenterally transmitted - nonA, non B = hep C
- Blood contact
Delta agent = hep D
Enterically transmitted, nonA, nonB =hep E
- acute
Viral hepatitis - acute or chronic?
Acute:
- diffuse inflammation of liver
- no prior symptoms
- viruses A, B, C and E
Chronic hepatitis:
- inflammation of the liver that has persisted for 6 months without improvement
- viruses B, C and D
What is hepatitis A?
Picornavirus
- pico = very small RNA virus
- Non enveloped 27nm particle
- +ve strand RNA genome
- single sense
- only one serotype worldwide
- transmitted by the faecal-oral route
Clinical disease is uncommon in infants and young children
- they get infected but don’t usually show signs of clinical disease
Rare in developed world - most recent UK outbreak in Portsmouth (2014)
Very good vaccine to control hep A
How to prove hepatitis is hep A?
About a month after infection, start showing signs of jaundice/other symptoms
Liver enzyme goes right up because liver damage - then goes down again
- Then make IgM: anti-HAV - primary antibody response to virus activity - then they get better
- Very simple diagnostic test to exclude all other viruses and prove that its hepatitis A
What is hepatitis B?
Acquired through contact with blood
- not infectious in the sense that hep A is
- lots of outbreaks in the past - usually due to contamination in vaccines
Primary infection self limiting (grades of infection)
- BUT 5-10% don’t resolve
- they carry the infection and are responsible for its spread
200 million HBV carrier act as reservoir for spread (vertical and horizontal transmission)
- vertical = mother to child
- horizontal = out in community by sharing blood products/needles
Chronic disease responsible for mortality
- 100x risk for liver cancer
- postal workers in Taiwan where infection endemic- first proof that virus has causal link with cancer
Treated by nucleoside analogues
- very good - block replication
- but mutants
- whole new generation of drugs called protease inhibitors for Hep C - very expensive, available on NHS, course lasts 40 days (12-40,000 for one course of treatment)
What are the parts of the hepatitis virus?
Dane particle = bigger infectious unit, about 42nm in diameter (made up of shell or surface antigen - inside there is a core)
Two protein coats - shell and core
Inside core - virus genomic material - piece of semiclosed circular DNA - tiny genome
The other two structures - the particle and the filament
(made exclusively from OUTER coat of virus)
- noninfectious
- do not contain the DNA as only made up from coat
How to prove hep B?
- 4-6 weeks post infection - virus causing disease (jaundice and other non-specific symptoms)
- Liver enzymes going up
- Can detect surface antigen (in outer coat - filaments and spheres), virus DNA, and polymerase in sera of patients
- Can also detect HBeAg
- HBsAg (Hep B surface antigen)
- HBcAg - the core - gets processed during infection to make another confirmation of the antigen - HBeAg
In acute infection - antibodies to surface antigen made quite a lot later in infection
- If you make these - clear the virus away - good chance - immune due to antibodies
- Antibodies to E antigen - start to come quite early then drop down again
- Diagnostic lab uses response to E antigen to determine if you are going to get better
- Can make a response to the core antigen but critical you make response to variant version of E antigen - marker for getting better (usually do if produce the response)
- used by GPs and diagnostic laboratories
- People who don’t make response to E antigen - become chronically ill
Hep D?
Only found in association with HBV
Transmission by parenteral routes
- can’t get infected by Hep D (delta agent) by itself
- much more severe hepatitis - discovered hepatitis virus was carrying satellite (delta agent)
Genome unique: 1679nt circular RNA molecule - resembles plant viroids (little circular pieces of RNA, devastating for some plant populations (potatoes, coconuts) - little circles of 250-500 nucleic acids of RNA - don’t code for any proteins
- viroid-like delta agent is very similar but codes for its own protein - the delta antigen
Genome is coated by hepatitis delta antigen
Delta agent protein in serum and antibodies to it
- Cannot get infected by delta antigen itself - satellite to the B antigen
- Can only replicate in presence of B virus
- Catch it with Hep B in first instance - or already chronically/persistently infected with B virus (so surface antigen in blood) and then exposed to delta agent so delta agent can take off and cause another episode of hepatitis
Hep C?
Some similarity with flavivirus (yellow fever), cannot be routinely grown in cell culture
6 types (1-6) each further divided into sub-types (a,b,c)
approximately 3% world’s population infected
Incubation period before onset of clinical symptoms:
- 15-150 days
- 60-70% asymptomatic
- 80% newly infected progress to develop chronic infection
- or at least was the case until quite recently
- leads to death
Over 20-30 years CIRRHOSIS develops in 10-20% and liver CANCER 1-5%
No vaccine for Hep C but excellent vaccines for A and B
Hep C can in most cases be treated now - antiviral treatments
Hep E?
- Transmitted by faecal oral route
- Outbreaks 10,000s cases: Indian subcontinent, central Asia, Mexico
- not endemic in population - found all over the world
- Highest attack rates 15-40 years
- High mortality (~20%) in infected pregnant women
- Mortality 2x high as Ebola
- Associated with men/middle age/swine in UK
Prevention of hepatitis viruses?
A:
- administration of pooled immune serum globulin
- achilles heel of Hep A = one serotype
- now there is a vaccine - that is efficacious and 100% safe
- once vaccinated protected for about 10 years as no variants
B:
- genetically engineered vaccine
- very efficacious - must have this before seeing patients
- protein engineered in yeast (before main donors were MSM who are high risk of HIV - so this is safer)
- retesting after shots - HBV surface antigen expressed in yeast
C:
- no vaccine
- prevention by screening blood products by RT-PCR
- looking for RNA of virus - really sensitive
Serological diagnosis hepatitis?
A: IgM to capsid protein of A virus: anti HAV antibodies present by the time symptoms occur
B: surface antigen is detected for several weeks during acute infection
- HBV: DNA
- antibodies to core antigen and ‘e’ antigen
C: presence of antibodies to envelope of virus- direct diagnosis by RT-PCR
D: presence of antibodies to single protein that coats the RNA genome
- IgM and IgG to delta antigen- increase briskly
E: - no diagnostic kit
- have to look at outbreak and ask questions - in house tests to look for viral RNA in stool samples
- For chronic, persistent infections - enormous eradication required - vaccine programme to eradicate not possible (so even though Hep B has a vaccine)
- could work for hep A as acute
Major risk factors chronic liver disease?
Hep C
Alcohol
Obesity
Alcoholic liver disease:
- ~20% of heavy drinkers progress to cirrhosis
- Complicated also by acute alcoholic hepatitis (mortality rate untreated 40-50%)
Risk factors for progression:
- female-more susceptible to toxic effects of alcohol
- consumption patterns
- binge
- eating - not with meals:increase risk 2.7*
- alcohol type?
- obese
- viral infection… hep B/C
- genes
- nutrition
What is NAFLD?
Non-alcoholic fatty liver disease
Steatosis –> progresses to NASH - non-alcoholic steatose hepatitis (an inflammatory disease)
NASH can progress to cirrhosis
Categories of liver disease?
Fatty liver disease
- whether alcoholic/non-alcoholic/metabolic syndrome related - still very common reason for biopsy
Chronic hepatitis
- Viral (B and especially C)
- Autoimmune
- Drugs
- all have similar pathological appearance in liver
Biliary disease
- chronic
Iron overload
Metabolic disease
What is steatohepatitis?
Means fatty liver disease + fibrosis and death of hepatocytes
- important as when people move on to steatohepatitis, risk of fibrosis and cirrhosis increases significantly
- ballooned cells (degenerate hepatocytes) - mallory bodies (degenerate cytoskeletal elements) - neutrophils (macrophages containing cellular debris)
Biliary tract diseases?
Primary sclerosing cholangitis
- used to be called primary biliary cirrhosis
- then people realised that indolent disease thats slowly progressive, does end up with cirrhosis in many patients, but for many don’t have cirrhosis
Primary biliary cholangitis
Both chronic and characterised by:
- Portal tract inflammation and expansion- expansion of portal tracts by inflammation
- Bile duct damage and loss
In PBC
- Granulomas (PBC)
- Collections of macrophages
How does iron overload occur?
Genetic haemochromatosis (genetic inability to regulate iron absorption from gut)
- Common, under diagnosed, can be asymptomatic until present with advance liver disease (cirrhosis)
- often diagnosed incidentally
- characteristic skin changes
- can become diabetic because affects pancreas
- very treatable via venesection
- genetically predetermined inability to regulate iron absorption from the gut
- regular venesection reduces Hb a bit without them getting anaemic
- gets rid of excess iron in body to prevent scarring and cirrhosis
- cirrhosis if untreated
Haemosiderosis
- transfusion related
- patients who have leukaemia ca have iron build up in liver
Metabolic diseases causing liver disease?
Alpha-1-antitrypsin deficiency
- sometimes make up this diagnosis if unexplained hepatitis/cirrhosis
Wilson’s disease
- not very common, most commonly in children
- copper deposition in liver causing hepatitis and cirrhosis
- CNS - copper despoiled in basal ganglia so get movement disorders
- eyes - specialist eye examination
Signs of chronic liver disease?
Chronic signs - not portal hypertension
- Jaundice
- Palmar erythema
- Spider naevi
- Xanethlasma
- Gynaecomastia
- Loss of axillary hair
Signs of portal hypertension
- SPLENOMEGALY
What occurs in hepatitis?
Cell death
Inflammation and release of enzymes from dying cells
Reduced functional capacity:
- raised transaminases - ALT, AST - unable to handle bilirubin - unable to make proteins
Causes of liver decompensation?
GI bleeding (variceal and non-variceal)
Infection
Alcoholic hepatitis
Acute portal vein thrombosis
HCC (hepatocellular carcinoma)
- if unknown cirrhosis consider a cancer that you haven’t found yet
- alpha-beta protein doesn’t go up in all hepatocellular carcinomas - there is a subset where it remains normal
Drugs
Ischaemia
Dehydration
Constipation
Causes of ascites that isn’t liver cirrhosis?
- Peritoneal carcinomatosis
- CCF (congestive cardiac failure)
- Non cirrhotic portal hypertension
- Renal failure
- TB
- Pancreatitis
- Myxoedema
Only scenario where you should use tumour markers is if they had a previous cancer and that cancer was producing the tumour marker before
Ascites treatment?
Salt and water restriction Diuretics Drainage - large volume paracentesis, needs plasma expanders Treat precipitants
What is spontaneous bacterial peritonitis?
Change in ratio of good/bad bacteria
Cytokine, vasoactive mediator release, splanchnic vasodilation, changes in portal flow –> ascites and HRS, vatical bleeding
Gut ‘leaky’ - bacteria leak out into mesenteric / hepatic system- then peritoneal cavity
Treatment SBP:
Prevention of renal failure:
- infusion: 1.5Kg 20% salt poor albumin on day 1 - infuse: 1g/Kg 20% salt poor albumin on day 3
Treat with SBP with broad spectrum with i.v. Cefotoxime or Ciprfloxacin
- or cephalosporins - but increases C. diff - hospital fined for C diff
Terlipressin?
V1 agonist smooth muscle vascular cells
Can cause peripheral and organ ischaemia
- Complications in 10-12%
Contraindicated in
- IHD, cerebrovascular disease, PVD - can get toes falling off! gangrene
- so be extremely careful in ischeamic heart disease
Terlipressin and albumin
- improve renal function in 40-50% patients with type 1 HRS
Reponse
- decrease Creat, increase urine volume and serum sodium
- increase MAP
- median response time 14 days
- Withdrawal of treatment - HRS recurs in 20%
- retreatment generally effective
Renal replacement therapy?
- Correct specific complications of renal failure
- hyperkalaemia
- acidosis
- volume overload
- uraemic symptoms
Haemofiltration rather than dialysis
- less hypotension
- avoid if no reversible component, or no intention to pursue transplantation
Hepatic encephalopathy?
Ammonia
CNS GABA receptors
Central neurotransmitters and circulating amino acids
Blood flow and cell swelling
Clinical spectrum of related conditions - not a single entity
Ammonia
- Produced by gut and kidney
- Removed by liver (conversion to urea and glutamine)
- Muscles tend to act as ‘buffer’ and take up excess ammonia
- NB malnourished cirrhotics
Management: exclude: DM, alcohol related (withdrawal, WKE), Hyponatraemia, Drugs, head injury
Modify microbiota
- Lactulose - Rifaxamin - Probiotics
- Laxatives
- Nutrition (muscles metabolise ammonia)
- If persistent- look for shunts
