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PATH30001 - Mechanisms of Disease > Lecture 16 - Liver Pathology 1 > Flashcards

Lecture 16 - Liver Pathology 1 Flashcards

1
Q

What are the various cell types in the liver?

A
  • Hepatocytes
  • Kupffer cells
  • Hepatic stellate cells (HSC)
  • Pit cells (NK cells of the liver)
  • Cholangiocytes
  • Endothelial cells
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2
Q

What are the NK cells of the liver?

A

Pit cells

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3
Q

What are the resident macrophages of the liver?

Where are these located?

A

Kupffer cells

Attached to the luminal wall of the endothelium

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4
Q

What are the stem cells of the liver?

Where are these located?

A

Hepatic stellate cells (HSC)

In the Space of Disse, surrounding the endothelium

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5
Q

What are the various categories of liver function?

A

Metabolic

Catabolic

Synthetic

Storage

Excretory

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6
Q

Describe glucose metabolism in the liver

A
  • Glucose formation: (glycogenolysis, gluconeogenesis)

* Glycogenesis & storage thereof

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7
Q

Describe lipid metabolism in the liver

A
  • TG synthesis
  • Lipoprotein synthesis
  • Uptake of FAs
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8
Q

List the various compounds that are synthesised in the liver

A
  • Albumin
  • Clotting factors
  • Complement
  • Cholesterol
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9
Q

List some examples of catabolic function in the liver

A
  • Ammonia conversion to urea
  • Break down of foreign toxic substances
  • Break down of endogenous toxic substances
  • Activation of drugs
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10
Q

Describe the excretory function of the liver

A

Bile formation, containing:

• many toxic break down products for excretion

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11
Q

Which compounds are stored in the liver?

A
  • Glycogen
  • Fat soluble vitamins (A, D, E & K)
  • Cu, Fe
  • Fatty acids
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12
Q

Describe the cellular architecture of the liver

A

Two models:
• Lobular
• Acinar

Liver lobule:
• Hepatocytes, forming plates
• Sinusoids (lined by fenestrated endothelium, Kupffer cells)
• Central vein
• Portal tract (HPV, H. artery, bile duct)
• Spaces of Disse (collagen forming reticulin framework, HSCs)
• Bile canaliculi (in between abutting hepatocytes)

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13
Q

What are liver cell plates?

A

Single cell thick layer of hepatocytes surrounding the sinusoids

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14
Q

What does the portal tract consist of?

A

Hepatic portal vein
Hepatic artery x2
Bile duct

Surrounded by some collagen

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15
Q

How much blood is delivered to the liver per minute?

A

1.5 L per minute
1L: hepatic portal veins
500 mL: hepatic arteries

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16
Q

Describe the functional unit of the liver

A

Acinus

Zone 1:
• Closest to the branches of the hepatic artery
•Rich oxygen supply

Zone 2

Zone 3:
• Furthest from the hepatic artery, near central vein
• Prone to anoxia
• Poor oxygen supply

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17
Q

Describe the old and the new lobule

A

Old - Lobule
• ‘Imaginary lobule’
• Three portal tracts make up to corners
• Not related to function

1950’s - acinus
• Funcitonal unit
• 3 zones, defined based on their oxygen supply from the terminal hepatic artery

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18
Q

Which part of the acinus will start to die off first when there is decreased blood flow?

A

Zone 3, furthest from the hepatic artery

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19
Q

What is special about the internal structure of hepatocytes?

A
  • Much ER (Endoplasmic reticulum)

* Many mitochondria

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20
Q

Compare the function of sER and rER

A
  • rER: protein synthesis

* sER: detoxification

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21
Q

Describe the location of the bile canaliculus

A

In between abutting hepatocytes

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22
Q

What happens upon injection of a drug such as Phenobarbital into liver hepatocytes

A
  • Proliferation of sER in hepatocytes

* Increased demand for drug detoxification

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23
Q

Compare the molecules present in hepatocytes in Zones 1 and 3, and the ramifications of this

A

Zone 1:
• High glutathione

Zone 3:
• High CYPs
• High ADH (alcohol dehydrogenase)

→ Zone 3 more prone to alcohol damage, since it have more enzymes that break it down into acetaldehyde, which is the toxic species

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24
Q

What type of injury are zone 3 hepatocytes prone to?

A
  • Toxic
  • Anoxic
  • Alcoholic
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25
Q

Describe liver regeneration

A

Liver has great capacity for regeneration
There will be regeneration with up to 2/3rds of the liver are resected

Due to:
• Stable cell population in the liver
• Cells can re-enter the cell cycle

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26
Q

How is microcirculation of the liver controlled?

A

Contraction of HSCs

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27
Q

What is the Reticulin framework?

A

Collagen fibres in the spaces of Disse

Normally very organised, but structure is lost in liver injury

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28
Q

What is the function of Kupffer cells?

Describe:
• How they become activated
• Molecules they produce when activated
• Effect of various molecules produced

A

Resident macrophages in the liver

Adhere to the luminal surface of the endothelial cells of the sinusoids

Function:
• Phagocytosis of particulate matter in the blood

Activation:
1. Resting

→ Experience cytokine / endotoxin

  1. Primed Kupffer cells
    • Hypertrophy
    • Extension of processes
  2. Activated Kupffer cell:
  • Phagocytosis
  • Eicosanoid production → inflammation
  • Cytokine production → inflammation
  • GF production → HSC proliferation and differentiation
  • Protease production → breakdown of ECM
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29
Q

Which inflammatory mediators do Kupffer cells produce?

A
  • Arachidonic acid metabolites (eicosanoids)
  • Cytokines
  • GFs
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30
Q

Describe the effect of the following molecules that activated Kupffer cells release:
• TNF
• PDGF
• ED-1 (Endothelin 1)
• MCP-1 (monocyte chemotactic protein-1)
• TGF-beta

A
  1. HSC proliferation
    • TNF
    • PDGF
  2. Contraction of HSCs
    • ED-1 (Endothelin 1)
  3. Fibrogenesis by activated HSCs
    • TGF-beta
  4. Chemotaxis
    • PDGF
    • MCP-1 (monocyte chemotactic protein-1)
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31
Q

Describe the change in phenotype of HSCs

A 
1. Quiescent:
 • Compact shape
 • Lipid vacuoles containing vitamin A
 • Not proliferating
 • Cells in contact with basement membrane
  1. Initiation of activation
    • Cytokine receptor expression
    • Matrix disruption via collagenase secretion
  2. Perpetuation of activation
    • Proliferation (PDGF)
    • Collagen synthesis (TGF-B)
    • Basement membrane replaced with type I collagen
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32
Q

Compare collagen production in quiescent and activated HSCs

A

Quiescent:
• Types III & IV

Activated
• Type I

33
Q

Which receptors are activated HSCs expressing?

A
  • PDGF-receptor

* ED-1 receptor

34
Q

What are the changes in actin in activated HSCs?

A
  1. ED-1 signalling
  2. Microfilaments (actin) arrange to form processes and cell contraction

→ Portal hypertension

35
Q

What is end stage liver disease?

A

Cirrhosis

+/- HCC: Hepatocellular carcinoma

36
Q

Define cirrhosis

A

Liver replacement by nodules

Nodules:
• Hepatocytes separated by anastomosing sheets of fibrous tissue (septa)

Loss of normal lobular architecture

37
Q

What happens to portal tracts and central veins in cirrhosis?

A

Irregularly spaced

Imbedded in fibrous septa

38
Q

What are the various classifications of cirrhosis?

A

Macronodular
• Nodules more than 3mm

Micronodular
• Nodules less than 3 mm

Mixed

39
Q

Which malignancy is seen as a result of cirrhosis?

A

HCC: Hepatocellular carcinoma

40
Q

What are the various clinical consequences of cirrhosis?

A

Portal hypertension
Hepatocellular failure
Hyperestrinism
HCC: Hepatocellular carcinoma

41
Q

What is hyperestrinism?

What can it lead to?

A

Males are unable to break down oestrogen

Normally both sexes secrete these hormones
Males break them down, and females don’t

Increased oestrogen levels

Leads to:
• Testicular atrophy
• Gynaecomastia (growth of breasts)
• Altered hair distribution

42
Q

Describe the sequelae of portal hypertension

A

Splenomegaly
• Because all the blood from the liver (as well as the gut) is going through the spleen

Oesophageal varices

Ascites

43
Q

What is hypersplenism?

A
  • Increased function of the spleen (due to splenomegaly)

* Increased break down of RBCs → anaemia

44
Q

What are some consequences of Hypersplenism?

A
  • Anaemia
  • Leukopaenia
  • Thrombocytopaenia (reduced platelets)
45
Q

Describe oesophageal varices

A
  1. Portal hypertension in the liver, blood can’t go through, and thus must find an alternate route
  2. Blood goes through oesophageal veins
  3. Varices form: increase in size of the veins to cope with increase in blood flow
46
Q

What are ascites?

A
  • Liver starts pouring out lymph

* Collection of hepatic lymph into peritoneal cavity

47
Q

What is caput medusae?

A

Opening up of veins around the umbilicus due to portal hypertension

48
Q

Why do males develop testicular atrophy?

A

Secondary to hepatocellular failure

Hepatocytes stop breaking down oestrogen

49
Q

Describe the processes that can no longer occur in hepatocellular failure
What are the clinical consequences of this?

A
  • Inability to excrete bilirubin → jaundice
  • Reduced albumin synthesis → peripheral oedema and ascites
  • Decrease synthesis of clotting factors → haemorrhagic tendency
  • Deficient ammonia metabolism → hepatic encephalopathy and coma
  • Renal failure
50
Q

What does an inability to excrete bilirubin lead to?

A

Jaundice

51
Q

What does reduced albumin synthesis lead to?

A

Decreased oncotic pressure

→ Peripheral oedema & ascites

52
Q

What does decreased synthesis of clotting factors lead to?

A

Haemorrhagic tendency

53
Q

Describe deficiency in ammonia metabolism

What does it lead to?

A

Normally:
• Ammonia enters liver in portal vein
• Ammonia converted to urea by hepatocytes
• Urea leaves liver via hepatic vein
• Urea filtered from blood at kidneys and excreted

Cirrhosis:
 • Ammonia arriving at the liver is not converted to urea
 • Ammonia leaves liver in veins
 • Ammonia goes to brain
→ Hepatic encephalopathy
→ Coma
54
Q

Is HCC often seen in cirrhosis?

What does the development of the malignancy depend on?

A

10-30% of heavy drinkers

Depends on cause of cirrhosis
Higher in:
 • Hep B & C
 • Haemochromatosis
 • Alpha-1-antitrypsin deficiency
55
Q

What is a critical factor influencing susceptibility to drug induced liver injury?

A

Genetic variability (of CYPs especially)

56
Q

What is ABCD of drug toxicity?

A

A: augmented, on-target, predictable
B: bizarre, idiosyncratic
C: chronic, long term use
D: delayed

57
Q

Which zone of the liver undergoes the most necrosis in toxic liver injury?
Why is this so?

A

Usually Zone 3
• CYPs in the highest concentration here
• Drug converted to a reactive metabolite in the highest concentrations in this zone

58
Q

What is zonal necrosis?

A

Specific zones of the liver undergoing necrosis

Normally is zone 3

59
Q

Which drugs when overused can cause zonal necrosis?

A

Paracetamol

60
Q

How much alcohol is safe?

A

80 mg / day ??

61
Q

Describe metabolism of ethanol

A
  1. CYPs in microsomes (sER)
  2. ADH in cytosol
  3. Catalase in peroxisomes

Converted to:
• Acetaldehyde
• NAPH also produced

62
Q

What is the effect on fatty acid metabolism of ethanol?

A
  • Increased lipolysis
  • Increased delivery of FFA to liver)
  • increased fatty acid synthesis in hepatocytes
  • Decreased mitochondrial oxidation of FAs
  • Increased production of TG
  • Decreased release of lipoproteins from liver cells
63
Q

Describe the alcoholic liver disease spectrum

A
  • Steatosis
  • Steatohepatitis
  • Cirrhosis
64
Q

Describe the histology of liver cells in severe steatosis

A

Liver cells are filled with fat, and there is not enough cell left for the liver to function properly

This does not normally progress to fibrosis

For fibrosis, you need to have necrosis and inflammation, so that HSC to lay down collagen

65
Q

What is steatohepatitis?

A

Alcohol hepatitis

66
Q

What are the histological characteristics of steatohepatitis?

A
  • Zone 3 ballooning
  • Zone 3 spotty necrosis
  • Zone 3 inflammation
  • Zone 3 activation of HSC
  • Micronodular cirrhosis
  • Obliteration of the central vein
67
Q

Describe ballooning hepatocytes

What is the cause?

A

• Hepatocytes increase in size by 5-20 times

Cause:
• Acetaldehyde causes the cytoskeleton to collapse to form Mallory bodies in the cell
• Cell loses its shape
• Other proteins associate in the Mallory bodies
• Cell stops secreting proteins, as the cytoskeleton track is missing
• Increase in intracellular osmotic pressure
• Swelling of cell

68
Q

What are some functions of the cell cytoskeleton?

A
  • Gives cell shape
  • Determines the location of the organelles within the cell
  • Contractility of the cell
  • Transport of proteins and fats around the cell
69
Q

What are the proteins involved in the Mallory bodes?

A

Keratin
Ubiquitin
Hsp62 (Heat shock protein)
Proteasome

70
Q

How do ballooning hepatocytes stain?

A

Very light, there is no cytoskeleton to be stained apart form the Mallory body aggregates

71
Q

What happens to the central vein in steatohepatitis?

A

The central vein is obliterated

Because
• The structure is dependent on the liver plate cells surrounding it
• These cells give structure to the sinusoids as well as the veins.

  • The wall of the sinusoids are the liver cell plates.
  • If they disappear, this framework collapses and the lumen disappears
72
Q

Describe the histology of micronodular cirrhosis

A
  • Obliteration of central veins
  • Complete disorganisation of vascular structure
  • Blood has difficulty flowing through the liver
  • Portal hypertension

Curvilinear fibrosis
• Surrounds and isolates nodules of regenerating liver
• Gives rise to micronodular cirrhosis

Hepatocytes are trying to regenerate and reform this liver mass
Nodules form

73
Q

What are curvilinear fibrous septa?

A

Fibrous tissue bridging the portal tracts and central zones

74
Q

What is Bilirubin?

A

Yellow break down product of haeme (from haemoglobin)

Excreted into bile & urine

75
Q

Describe what is happening in spotty necrosis?

When is this seen?

A

Seen in steatohepatitis, in zone 3

• Clusters of neutrophils

76
Q

What causes mallory body formation?

A

Acetaldehyde

77
Q

Where is vitamin A stored in the liver?

A

HSCs

78
Q

Characterise the endothelium lining the sinusoids in the liver

A

Sieve plates: fenestrated

Fenestrae allow only the movement of small compounds or plasma into the spaces of Disse (cells can’t move across)

79
Q

How do abutting hepatocytes join together?

A

Attached together with studs like lego

NB bile canaliculi running between abutting hepatocytes

PATH30001 - Mechanisms of Disease (34 decks)

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