Lecture 17 - Liver Pathology 2 Flashcards
What are some examples of liver disease associated with metabolic syndrome?
- Non-alcoholic fatty liver disorder (NAFLD)
- Non-alcoholic steatohepatitis (NASH)
These look like Steatohepatitis and Steatosis under the microscope, but the sufferer is a non-drinker
Which people are most commonly affected by non-alcoholic liver disease?
Which other disorders are associated with it?
Middle aged women
Associations:
• Obesity
• Hypertension
• Diabetes
What is the underlying cause of non-alcoholic, metabolic liver disease?
Central obesity: aka big belly
Men: more than 94 cm
Women: more than 80 cm
In Asians it is even less, because they are often shorter
\+ two of the following features: • Raised serum Triglyceride (TG) level • Reduced serum HDL cholesterol • Raised BP • Raised fasting blood glucose (FBG)
Describe the metabolic and inflammatory cascade of Central Obesity
Dyslipidaemia
Systemic inflammation
Endothelial dysfunction → hypertension
Insulin Resistance
NASH / NAFLD
Polycystic ovary syndrome; infertility
Atherosclerosis
Obstructive sleep apnoea
Disordered fibrinolysis
Hypertension
Type 2 Diabetes Mellitus
What are the different categories of metabolic liver disease?
- Acquired: NAFLD, NASH
* Genetic: hereditary storage diseases
What are liver ‘storage diseases’?
Give some examples
Genetic metabolic liver diseases
- Genetic haemochromatosis
- Wilson’s disease
- α1-antitrypsindeficiency
- Tyrosinaemia
- Glycogen storage disease
What is genetic Haemochromatosis?
Hereditary iron overload
What is Wilson’s disease?
Copper overload
What is alpha-1-antitrypsin?
What is it needed for?
A protease inhibitor
Needed to inhibit all the proteases released by neutrophils in inflammation
→ If this isn’t controlled more inflammation and fibrosis
Compare most common cause of hereditary storage disease cirrhosis in:
• Adults
• Children
Adults: Haemochromatosis
• Because adults are using less iron
• More is accumulating
Children: α1-antitrypsin deficiency
What are the categories of hepatitic liver injury?
Infectious
• Viral hepatitis
Immunological
• Autoimmune hepatitis
What is the definition of the ‘Hepatitic histological pattern’?
What are the causes of Hepatitic histological pattern?
Describe the morphology
“Diffuse inflammation of the liver accompanied by features hepatocellular injury and regeneration”
Causes:
• Viral hepatitis
• Idiosyncratic reactions to therapeutic drugs
Morphology:
1. Parenchymal degeneration
• aka damage to liver cells:
• Ballooning hepatocytes
- Cell death
• Apoptosis
• Necrosis - Inflammatory reaction
• Mononuclear inflammatory cell infiltration
• Hyperplasia of Kupffer cells
• Macrophages - Mesenchymal reaction
• This is HSCs - Regeneration of hepatocytes
• Hypertrophy
• Mitosis
Describe the changes to the following in acute viral hepatitis:
• Liver lobules
• Hepatocytes
Liver lobules:
• Complete disarray; loss of order
• Inflammatory infiltrate: pigmented macrophages
• Sinusoids are hard to see
Hepatocytes: • Apoptosis • Necrosis • Ballooning degeneration • Regeneration
What are the features of resolving hepatitis?
How long does the acute stage last?
How long until it is completely resolved?
In most forms of viral hepatitis, it starts to resolve after 6 weeks
There will be residual cells for about 3 months
Inflammation remains in the portal tracts
Sinusoids are open again
Still some pigmented macrophages in zone 3
Describe the evolution of Acute Viral Hepatitis
- Early stage
- Fully developed stage
• Parenchymal damage
• Necrosis - Later stage
• Still have Pigmented macrophages - Residual changes
What are pigmented macrophages and when are they seen?
What does this indicate
Seen in viral hepatitis
Macrophages filled with ceroid & iron
Indicates that they are filled with lipids from the plasma membranes of the cells that have just undergone necrosis
Which types of necrosis are seen in Hepatitic pattern in viral hepatitis?
Describe them
Spotty (focal) necrosis
• 2-10 hepatocytes necrosis
• collections of lymphocytes and pigmented macrophages
Confluent necrosis
• en masse death of tracts hepatocytes
Piecemeal necrosis
• Hepatocyte death at interface of connective tissue & liver parenchyma
What are the three grades of increasing severity of confluent necrosis seen in viral hepatitis?
Zonal:
• just in one of the zones
BHN: Bridging hepatic necrosis
• Bridging between two vascular structures (i.e. portal tracts and central veins)
MLN: Multilobular hepatic necrosis
• Lots of neighbouring lobules disappear at once
What is the parenchyma of the liver?
The hepatocytes
What is pan lobular necrosis?
Many or all lobules undergoing necrosis
Describe the order of events that can occur after BHN
- BHN
- Passive septum
- Active septum
- Bridging fibrosis
and if inflammation continues:
- Cirrhosis
Which malignancies are seen in the liver?
Hepatocellular carcinoma
Compare progression to cirrhosis in NAFLD & NASH with alcoholic FLD and SH
Alcoholic fatty liver disease and hepatosteatosis more likely to develop into cirrhosis:
• Only 3-4% get cirrhosis
What percent of sufferers of NAFLD progress to HCC?
less than 0.5% go on to get HCC
What is the end stage of hereditary storage diseases?
Cirrhosis
Which inflammatory cells infiltrate in non-alcoholic hepatitis?
Mononuclear cells
Hardly ever neutrophils (as is seen in alcoholic hepatitis)
Where is inflammation seen in hepatitis?
- Portal tracts
* Lobules
What leads to cell death in viral hepatitis?
Not the virus that kills hepatocytes
It is the immune cells that are responsible
What happens to bile in acute viral hepatitis
Ballooned cells are unable to secrete bile
Bile remains in the cytoplasm
→ Bile pigment in liver cells
What happens in chronic viral hepatitis?
Lasts more than 3 months
• Virus persists
→ Persistent inflammation and hepatocellular injury
Most important feature: fibrosis (periportal and bridging)
Eventually:
→ Cirrhosis
What is cholestasis?
When is it observed?
Bile plugs
Observed in acute hepatitis
What are passive septa?
Collapsing of septa
Seen in lobular lesions in more severe cases
What is piecemeal necrosis?
Where is the necrosis occurring?
Immune mediated cell death
• Lymphocytes reacting against liver cells
‘Interface necrosis’:
• Necrosis occurs at the interface of hepatocytes w/ connective tissue
Where are stem cells seen in viral hepatitis?
Around portal tracts
Attempting to regenerate tissue
Describe what happens to blood flow in BHN
BHN: Bridging hepatic necrosis
• Occurs in viral hepatitis
Fibrosis bridges form between portal tracts and ventral veins
The blood now has a path go lower resistance between these two structures, and will flow through here.
The other regions will be prone to ischemia, because they are no longer getting adequate blood supply
What are the differentiating factors in acute and chronic hepatitis?
Acute: • Ballooning degeneration of hepatocytes • Bridging necrosis • Steatosis • Inflammatory cell infiltrates (macrophages) • Apoptosis
Chronic: • Bridging fibrosis • Steatosis • Lymphocyte aggregates • Macrophage aggregates
What is seen macroscopically in cirrhosis?
Macronodules all over the liver
• all nodules are within centrimetes in length
What is seen macroscopically in HCC?
Green patches
• Bile unable to escape the cancerous cells, because they aren’t connected to anything
What are the different viruses than can cause hepatitis?
Which are the most frequent causative agents of viral hepatitis?
Which virus most commonly causes chronic liver disease?
Hepatitis A-E
Causative agent of viral hepatitis in order of frequency: • HBV • HAV • HCV Very low: • HEV • HDV
Chronic infection: (in order of frequency)
• Hep C: 80%
• Hep B: 5%
• Hep D: 5%
Why can’t an individual get rid of Hep B infection?
dsDNA genome of the virus is incorporated into the genome of the host
Cannot be cured, but can be controlled with drugs
How are Hep A & E transmitted?
Faecal-oral route
Can Hep C be treated?
Yes
Since about 5 years we have very good treatments that can cure the infection
How are Hep B & C transmitted?
Blood (parenteral)
IVDU: Intravenous drug users
Hep B:
• often sexually transmitted
Which viruses do we have a vaccine for?
HBV
Don’t have a vaccine for HCV
What is the prognosis for Hep A & E?
What about Hep B?
What about Hep C?
Hep A & E: 99% recovery
Hep B: 95% recovery
Hep C: 15-20%
(80% chronic infection)
What are the risk factors for Hep B infection?
In order of risk: • Heterosexual intercourse • Injecting drug use • Homosexual activity • Health care workers
Describe the structural features of the Hep B virus
Genome: dsDNA
Envelope
HBsAg: Hep B surface antigen
HBcAg: Hep B core antigen
• aka ‘e’ antigen
• Can circulate in the blood stream
• Can cross the placenta
Describe the features of HBcAg
Why do neonates predominantly get chronic hepatitis?
‘e’ antigen
• Can cross the placenta
- Does not cause infection of the foetus
- Tolerises the child to the infection
- When the child is born, if they swallow some of the blood, they will be tolerant to the virus
→ Chronic hepatitis
- Virus is there, but at lower levels
- Not attacking anything
Compare acute vs. chronic viral hepatitis frequency in neonates and adults
Acute
• Adults: 90%
• Neonates: 2%
Chronic:
• Adults: 10%
• Neonates: 98%
Describe global prevalence of HBV carrier infection
Highest:
• Africa
• SE Asia
• China
Middle:
• South America
• Russia
• Australia
Low:
• Europe
• USA
Describe the potential outcomes for HBV infection in adults
90% Recovery
A large proportion are in a Healthy carrier state
• They do not know they are infected
• Transmitting the disease to many people unknowingly
What is the major histological sign of HBV infection?
Ground glass hepatocytes
Where are HBsAg and HBcAg kept in cells?
HBsAg: cytoplasmic inclusions
HBcAg: nucleus
Describe reactivation of Hep B in children who got it from their mothers
Reactivation of the virus around age of 25
Immune system has learnt to recognise the virus as foreign
The peptide is presented on the cell membrane to CTLs
Describe the mechanism of hepatocyte necrosis in HBV infection
- HBV infected hepatocyte
- HBcAg presented on HLA class I
- CD8+ T cell recognises peptide on HLA-1 as foreign
- CD8+ T cell releases perforins and kills the cell
Describe worldwide prevalence of Hep C
High:
• Egypt, Africa in general
• South America
• China
What are the sequelae of Hep C infection?
Chronic infection
→ 30% cirrhosis (20 years)
→ 15% HCC (30 years)
What is METAVIR?
Fibrosis scoring system
F0: no fibrosis
F1: Stellate enlargement of portal tracts w/o septa
F2: enlargement of portal tracts w/ rare septa
F3: numerous septa w/o cirrhosis
F4: cirrhosis
Which drugs can reverse fibrosis?
Anti-fibrotic agents
What is autoimmune hepatitis?
Mainly in females
HLA-A1
HLA-B8
HLA-DR3
HLA-DR4
High Ig levels
Circulating auto antibodies
• to smooth muscle
• to nuclear antigens
How can autoimmune hepatitis be treated?
Patients respond very well to corticosteroids
What type of necrosis is seen as a hallmark of autoimmune hepatitis?
Piecemeal necrosis
• Lymphocytes
• Plasma cell infiltrate
Lymphocytes have lost tolerance to liver cells
List some of the acquired aetiologies of cirrhosis
• Alcoholic • Viral hepatitis • Autoimmune hepatitis • Cryptogenic (don't know the cause) • Primary biliary cirrhosis • Secondary biliary cirrhosis • Drug induced • Toxins (e.g. fungal, alkaloids) • Venous outflow obstruction (obstruction in vena cavae, blood gets backed up to the liver)
List some risk factors for HCV
- Male gender
- IVDU
- Heterosexual and homosexual contact
When do most deaths due to HCV occur?
Around the ages of 50-80
This is 30 years after exposure, because the infection has been chronic for all this time
Describe the changes in prevalence of HCV in Australia over the last 30 years
Epidemic in the late 70’s
Peaked around 2014
We think it will now start to drop off, because we have a very good curative treatment
What is the hallmark of chronic hepatitis?
Fibrosis:
• Bridging fibrosis (between portal tracts and central veins)
• Periportal fibrosis
If hepatitis isn’t resolved and becomes chronic, what happens to bridging necrosis?
Becomes bridging fibrosis
Which Hepatitis viruses are transmitted by the faecal-oral route?
How are the other transmitted?
Faceal-oral: HAV and HEV
The others are transmitted parenterally
