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PATH30001 - Mechanisms of Disease > Lecture 17 - Liver Pathology 2 > Flashcards

Lecture 17 - Liver Pathology 2 Flashcards

1
Q

What are some examples of liver disease associated with metabolic syndrome?

A
  • 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

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2
Q

Which people are most commonly affected by non-alcoholic liver disease?
Which other disorders are associated with it?

A

Middle aged women

Associations:
• Obesity
• Hypertension
• Diabetes

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3
Q

What is the underlying cause of non-alcoholic, metabolic liver disease?

A

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)
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4
Q

Describe the metabolic and inflammatory cascade of Central Obesity

A

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

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5
Q

What are the different categories of metabolic liver disease?

A
  • Acquired: NAFLD, NASH

* Genetic: hereditary storage diseases

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6
Q

What are liver ‘storage diseases’?

Give some examples

A

Genetic metabolic liver diseases

  • Genetic haemochromatosis
  • Wilson’s disease
  • α1-antitrypsindeficiency
  • Tyrosinaemia
  • Glycogen storage disease
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7
Q

What is genetic Haemochromatosis?

A

Hereditary iron overload

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8
Q

What is Wilson’s disease?

A

Copper overload

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9
Q

What is alpha-1-antitrypsin?

What is it needed for?

A

A protease inhibitor

Needed to inhibit all the proteases released by neutrophils in inflammation

→ If this isn’t controlled more inflammation and fibrosis

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10
Q

Compare most common cause of hereditary storage disease cirrhosis in:
• Adults
• Children

A

Adults: Haemochromatosis
• Because adults are using less iron
• More is accumulating

Children: α1-antitrypsin deficiency

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11
Q

What are the categories of hepatitic liver injury?

A

Infectious
• Viral hepatitis
Immunological
• Autoimmune hepatitis

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12
Q

What is the definition of the ‘Hepatitic histological pattern’?

What are the causes of Hepatitic histological pattern?

Describe the morphology

A

“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

  1. Cell death
    • Apoptosis
    • Necrosis
  2. Inflammatory reaction
    • Mononuclear inflammatory cell infiltration
    • Hyperplasia of Kupffer cells
    • Macrophages
  3. Mesenchymal reaction
    • This is HSCs
  4. Regeneration of hepatocytes
    • Hypertrophy
    • Mitosis
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13
Q

Describe the changes to the following in acute viral hepatitis:
• Liver lobules
• Hepatocytes

A

Liver lobules:
• Complete disarray; loss of order
• Inflammatory infiltrate: pigmented macrophages
• Sinusoids are hard to see

Hepatocytes:
• Apoptosis
• Necrosis
• Ballooning degeneration
• Regeneration
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14
Q

What are the features of resolving hepatitis?

How long does the acute stage last?

How long until it is completely resolved?

A

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

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15
Q

Describe the evolution of Acute Viral Hepatitis

A
  1. Early stage
  2. Fully developed stage
    • Parenchymal damage
    • Necrosis
  3. Later stage
    • Still have Pigmented macrophages
  4. Residual changes
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16
Q

What are pigmented macrophages and when are they seen?

What does this indicate

A

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

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17
Q

Which types of necrosis are seen in Hepatitic pattern in viral hepatitis?

Describe them

A

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

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18
Q

What are the three grades of increasing severity of confluent necrosis seen in viral hepatitis?

A

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

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19
Q

What is the parenchyma of the liver?

A

The hepatocytes

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20
Q

What is pan lobular necrosis?

A

Many or all lobules undergoing necrosis

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21
Q

Describe the order of events that can occur after BHN

A
  1. BHN
  2. Passive septum
  3. Active septum
  4. Bridging fibrosis

and if inflammation continues:

  1. Cirrhosis
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22
Q

Which malignancies are seen in the liver?

A

Hepatocellular carcinoma

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23
Q

Compare progression to cirrhosis in NAFLD & NASH with alcoholic FLD and SH

A

Alcoholic fatty liver disease and hepatosteatosis more likely to develop into cirrhosis:
• Only 3-4% get cirrhosis

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24
Q

What percent of sufferers of NAFLD progress to HCC?

A

less than 0.5% go on to get HCC

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25
Q

What is the end stage of hereditary storage diseases?

A

Cirrhosis

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26
Q

Which inflammatory cells infiltrate in non-alcoholic hepatitis?

A

Mononuclear cells

Hardly ever neutrophils (as is seen in alcoholic hepatitis)

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27
Q

Where is inflammation seen in hepatitis?

A
  • Portal tracts

* Lobules

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28
Q

What leads to cell death in viral hepatitis?

A

Not the virus that kills hepatocytes

It is the immune cells that are responsible

29
Q

What happens to bile in acute viral hepatitis

A

Ballooned cells are unable to secrete bile
Bile remains in the cytoplasm

→ Bile pigment in liver cells

30
Q

What happens in chronic viral hepatitis?

A

Lasts more than 3 months

• Virus persists
→ Persistent inflammation and hepatocellular injury

Most important feature: fibrosis (periportal and bridging)

Eventually:
→ Cirrhosis

31
Q

What is cholestasis?

When is it observed?

A

Bile plugs

Observed in acute hepatitis

32
Q

What are passive septa?

A

Collapsing of septa

Seen in lobular lesions in more severe cases

33
Q

What is piecemeal necrosis?

Where is the necrosis occurring?

A

Immune mediated cell death
• Lymphocytes reacting against liver cells

‘Interface necrosis’:
• Necrosis occurs at the interface of hepatocytes w/ connective tissue

34
Q

Where are stem cells seen in viral hepatitis?

A

Around portal tracts

Attempting to regenerate tissue

35
Q

Describe what happens to blood flow in BHN

A

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

36
Q

What are the differentiating factors in acute and chronic hepatitis?

A 
Acute:
• Ballooning degeneration of hepatocytes
• Bridging necrosis
• Steatosis
• Inflammatory cell infiltrates (macrophages)
• Apoptosis
Chronic:
• Bridging fibrosis
• Steatosis
• Lymphocyte aggregates
• Macrophage aggregates
37
Q

What is seen macroscopically in cirrhosis?

A

Macronodules all over the liver

• all nodules are within centrimetes in length

38
Q

What is seen macroscopically in HCC?

A

Green patches

• Bile unable to escape the cancerous cells, because they aren’t connected to anything

39
Q

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?

A

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%

40
Q

Why can’t an individual get rid of Hep B infection?

A

dsDNA genome of the virus is incorporated into the genome of the host

Cannot be cured, but can be controlled with drugs

41
Q

How are Hep A & E transmitted?

A

Faecal-oral route

42
Q

Can Hep C be treated?

A

Yes

Since about 5 years we have very good treatments that can cure the infection

43
Q

How are Hep B & C transmitted?

A

Blood (parenteral)
IVDU: Intravenous drug users

Hep B:
• often sexually transmitted

44
Q

Which viruses do we have a vaccine for?

A

HBV

Don’t have a vaccine for HCV

45
Q

What is the prognosis for Hep A & E?

What about Hep B?

What about Hep C?

A

Hep A & E: 99% recovery

Hep B: 95% recovery

Hep C: 15-20%
(80% chronic infection)

46
Q

What are the risk factors for Hep B infection?

A 
In order of risk:
• Heterosexual intercourse
• Injecting drug use
• Homosexual activity
• Health care workers
47
Q

Describe the structural features of the Hep B virus

A

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

48
Q

Describe the features of HBcAg

Why do neonates predominantly get chronic hepatitis?

A

‘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
49
Q

Compare acute vs. chronic viral hepatitis frequency in neonates and adults

A

Acute
• Adults: 90%
• Neonates: 2%

Chronic:
• Adults: 10%
• Neonates: 98%

50
Q

Describe global prevalence of HBV carrier infection

A

Highest:
• Africa
• SE Asia
• China

Middle:
• South America
• Russia
• Australia

Low:
• Europe
• USA

51
Q

Describe the potential outcomes for HBV infection in adults

A

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

52
Q

What is the major histological sign of HBV infection?

A

Ground glass hepatocytes

53
Q

Where are HBsAg and HBcAg kept in cells?

A

HBsAg: cytoplasmic inclusions
HBcAg: nucleus

54
Q

Describe reactivation of Hep B in children who got it from their mothers

A

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

55
Q

Describe the mechanism of hepatocyte necrosis in HBV infection

A
  1. HBV infected hepatocyte
  2. HBcAg presented on HLA class I
  3. CD8+ T cell recognises peptide on HLA-1 as foreign
  4. CD8+ T cell releases perforins and kills the cell
56
Q

Describe worldwide prevalence of Hep C

A

High:
• Egypt, Africa in general
• South America
• China

57
Q

What are the sequelae of Hep C infection?

A

Chronic infection
→ 30% cirrhosis (20 years)
→ 15% HCC (30 years)

58
Q

What is METAVIR?

A

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

59
Q

Which drugs can reverse fibrosis?

A

Anti-fibrotic agents

60
Q

What is autoimmune hepatitis?

A

Mainly in females

HLA-A1
HLA-B8
HLA-DR3
HLA-DR4

High Ig levels

Circulating auto antibodies
• to smooth muscle
• to nuclear antigens

61
Q

How can autoimmune hepatitis be treated?

A

Patients respond very well to corticosteroids

62
Q

What type of necrosis is seen as a hallmark of autoimmune hepatitis?

A

Piecemeal necrosis
• Lymphocytes
• Plasma cell infiltrate

Lymphocytes have lost tolerance to liver cells

63
Q

List some of the acquired aetiologies of cirrhosis

A 
• 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)
64
Q

List some risk factors for HCV

A
  • Male gender
  • IVDU
  • Heterosexual and homosexual contact
65
Q

When do most deaths due to HCV occur?

A

Around the ages of 50-80

This is 30 years after exposure, because the infection has been chronic for all this time

66
Q

Describe the changes in prevalence of HCV in Australia over the last 30 years

A

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

67
Q

What is the hallmark of chronic hepatitis?

A

Fibrosis:
• Bridging fibrosis (between portal tracts and central veins)
• Periportal fibrosis

68
Q

If hepatitis isn’t resolved and becomes chronic, what happens to bridging necrosis?

A

Becomes bridging fibrosis

69
Q

Which Hepatitis viruses are transmitted by the faecal-oral route?
How are the other transmitted?

A

Faceal-oral: HAV and HEV

The others are transmitted parenterally

PATH30001 - Mechanisms of Disease (34 decks)

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