Excessive healing in the liver

Question 1

What is the result of end stage liver fibrosis?

Answer 1

Cirrhotic liver

Question 2

What is fibrosis?

Answer 2

Formation of excess fibrous connective tissue in an organ

Marked by quantitative and qualitative changes in the composition of hepatic ECM

Question 3

What are liver diseases associated with hepatic fibrosis?

Answer 3

Chronic viral hepatitis

Early alcoholic disease

Portal hypertension

Steatohepatitis

Question 4

How does hepatic fibrosis develop?

Answer 4

With different morphological and spatial patterns

Different etiologies cause different patterns of fibrosis

Liver lobule contains centrilobular vein and portal tract

Question 5

What is pericentral disease?

Answer 5

Caused by chronic alcohol hepatitis and steatohepatitis

Fibrosis accumulates in the centrilobular vein and makes contaft with the portal tract

Question 6

What is portal to central disease?

Answer 6

Caused by primary cirrhosis and chronic viral hepatitis

Formed at the portal tract and damage spreads to the center

Question 7

What is common in both pericentral disease and portal to central disease?

Answer 7

There is progressive sinusoidal arterialization leading to cirrhosis

Question 8

What are key components of the ECM in liver fibrosis?

Answer 8

Kupffer cells

Hepatocytes

Stellate cells

Sinusoidal epithelial cells

Question 9

What are the different stages of chronic liver disease?

Answer 9

Patients with different stages of cirrhosis are staged by a system to investigate progression of CLD

F0 = no fibrosis 
F1 = fibrosis withour septa 
F2 = few septa 
F3 = numerous septa without cirrhosis 
F4 = numerous septa with cirrhosis

Question 10

What is a septum?

Answer 10

A wall made of ECM that divides a tissue into smaller compartments

Question 11

What is the definition of cirrhosis?

Answer 11

Advanted stage of fibrosis

CHaracterised by the formation of regenerative nodules of liver parenchyma

Separated by and encapsulated in fibrotic septa

Question 12

What changes to the ECM leads to fibrosis?

Answer 12

Marked accumulation of high amounts of collagen and ECM

Qualitative change in ECM

MMPs production is decreased

Elastin and acellular fibrosis

Thick ECM septa with no space for cells

Question 13

What is the basal lamina?

Answer 13

Layer of low-density matrix

Allows for perdusion between blood and cells for nutrients, hromones and metabolites

Question 14

WHat type of ECM forms the liver?

Answer 14

Type IV matrix

Contains collagen type IV, Heparan sulphate, Proteoglycans, Enctactin and Laminin

Question 15

Structure of laminin

Answer 15

A chain - binds to proteoglycan

B1 chain - binds to collagen type IV

B2 chain - binds to enctactin

Question 16

WHat happens to laminin during fibrosis?

Answer 16

Increased laminin expression

Basal lamina will become fibrillar matrix and more dense than healthy basal lamina

Question 17

What are the major proteins in ECM?

Answer 17

Collagens

Question 18

Structure of collagens

Answer 18

Polypeptide with repeating sequence

Glycine, proline and hydroxyproline

Use repeating sequences to measure the accumulation of collagens

Question 19

Formation of a collagen fibril

Answer 19

1. Pro-a chain is synthesised in the RER
2. Pro-a chain assembles into 3 pro-a chains
3. Form triple helix
4. Secreted in the process of exocytosis
5. In the ECM propeptides will be cleaved and allow fibril formation
6. Self-assembly into a collagen fibril
7. A lot of fibrils to form one fiber

Question 20

What will the stimulus which causes liver fibrosis induce?

Answer 20

Inflammation

Oxidative stress

Apoptosis

Cytokine secretion

Question 21

What is the key cell that leads to hepatic fibrosis?

Answer 21

Hepatic stellate cell

95-97% of cells responsible for fibrosis

Produce GF and chemokines

Question 22

Which other cells are responsible for hepatic fibrosis?

Answer 22

Portal fibroblasts, hepatocytes, mesenchymal stem cells, circulating fibrocytes and hepatic stellate cells differentiate into myofibroblasts

Can lead to fibrosis

Apoptosis of these MFs leads to fibrosis regression

Question 23

How are hepatic stellate cells activated?

Answer 23

Upon liver damage

Produce collagen type IV

MMPs still working, but GF receptors are expressed

They then transition into myofibroblast-like cells

Question 24

What happens when stellate cells transition into myofibroblast-like cells?

Answer 24

Less ECM degradation

Large amount of fibrillar ECM

Key collagen produced - collagen I

Glycoproteins produced (Proteoglycans and lamina)

Autocrine loops of PDGF, TGF-b and ET-1

Question 25

Benefits of activated hepatic stellate cells

Answer 25

Production of new blood vessels

Question 26

What is the purpose of the contractile phenotype during portal hypertension development?

Answer 26

Important

MCP-1 = chemotactic protein that recruits monocytes and neutrophils to the site of damage

Question 27

Role of ROS in the development of excessive liver healing

Answer 27

Oxidative stress induced by an increased generation of ROS released by damaged or activated neighboring cells can directly affect the behavior of hepatocytes

Injured hepatocytes release ROS

Activate Kupffer cells and sinusoidal endothelial cells

Produce PDGF, TGF b and GFs

Activate stellate cells

Produce free radicals and TGFb, procollagen alpha 1 and MCP-1

Recruitment of WBCs

Question 28

What are ROSs?

Answer 28

Chemically reactive molecuels containing oxygen

Formed as natural byproducts of the normal metabolism of oxygen

Excessive production of ROS is associate with lipid peroxidation and cell injury