Path Notes ***** Liver Cirrhosis and Alcohol induced cirrhosis

Question 1

What is Liver Cirrhosis and What are the three main changes that occur with it? (Ros*******)

Answer 1

Liver cirrhosis is an end-stage presentation of chronic liver diseased.

Three main characteristics:
1. Bridging Fibrous Septae - between portal tracts and/or between portal tracts and terminal hepatic veins. Irreversible fibrosis*

2. Formation of parenchymal nodules, when hepatocytes regenerate and proliferate, encircled by the surrounding fibrosis
3. Disturbances to normal liver architecture - chiefly re-organisation of the vascular architecture

Question 2

Describe the Pathogenesis of Liver CIrrhosis: (Ros *******)

Answer 2

1. In response to inflammation of the liver, Hepatic Stellate cells are converted to collagen-secreting fibroblasts. This occurs due to release of chemokines and cytokines by Kupffer cells, Lymphocytes, Hepatic and Biliary Duct Endothelial and epithelial cells, and hepatocytes.
2. Collagen is then deposited in abnormal places. I.e. excessive deposition in the Space of Disse and excessive deposition around portal tracts and terminal hepatic veins, which leads to formation of fibrous septae that eventually form bridges between these structures.
3. Collagen deposition in the Space of Disse results in loss of the normal fenestrations of the endothelial cells of the liver sinusoidal capillaries. This means that proteins (albumin, clotting factors, lipoproteins, etc.) cannot be effectively secreted into the blood plasma. (Thus why chronic liver disease often accompanied by oedema, presents with increased INR, low protein counts, etc).
4. New vasculature is formed within the fibrous septae that link portal tracts and terminal hepatic veins. This results in the shunting of blood around the parenchyma.
5. Hepatocytes regenerate and proliferate, forming spherical, parenchymal nodules completely surrounded by the fibrotic septae.
6. The ramifications of this fibrotic, nodular liver mean that the functioning hepatocyte’s blood supply is compromised - they are unable to secrete their synthesised products into the blood plasma and biliary ducts, due to shunting and loss of sinusoidal fenestrations. This results in jaundice.

Question 3

What are the three main pathologies involved with/included in Alcoholic Liver Disease? (***)

Answer 3

1. Hepatic Steatosis
2. Alcoholic Hepatitis
3. Cirrhosis (late stage, occurs in 10-15% of those with history of chronic alcohol intake, women>men)

Question 4

What is the Pathogenesis of Alcoholic Liver Disease - what type of alcoholic intake picture leads to it? (***)

Answer 4

Mild, reversible changes (acute changes), including hepatic steatosis, can occur after an episode of excessive alcohol intake - >8 standard drinks.

Chronic alcohol intake predisposes to liver cirrhosis (does not occur in everyone)

Question 5

What occurs in / causes Hepatic Steatosis - pathogenesis (***)

Answer 5

1. Enzymes involved in alcohol metabolism produce Reduced NADH (nicotinamide-adenine dinucleotide)
2. Reduced NADH reduces catabolism and increases lipid biosynthesis
3. There is associated impairment in lipoprotein assembly and secretion
4. Increased peripheral catabolism of fats

Question 6

What vascular alterations typically occur with Alcoholic Liver Disease (in terms of the hepatitis component)? (***)

Answer 6

1. Alcohol causes the release of potent vasocontricting endothelins from sinusoidal endothelial cells
2. These endothelins (released from sinusoidal endothelial cells) also cause stellate cells to contract. This decreases perfusion to hepatocytes, causing hypoxia.

Question 7

What causes the hepatocellular injury, which leads to inflammation (hepatitis component), in Alcoholic Liver Disease? (***)

Answer 7

1. Acetylaldehyde causes peroxidation (oxidative degradation of lipids), and binds to protein - this induces immune system reactivity
2. The induction of P-450. P-450 promotes the reactive oxygen species which reacts with cellular proteins, and dugs/toxin metabolites.
3. Alcohol causes impaired hepatocyte metabolism of anti-oxidants, including glutathione
4. Alcohol also causes direct toxicity of micro-tubular and mitochondrial function

Question 8

What are the clinical features of hepatic steatosis? (***)

Answer 8

Hepatic steatosis is reversible.

Associated with an elevated ALT.

Question 9

What are the microscopic features of hepatic steatosis? (***)

Answer 9

1. Accumulation of lipid-filled vacuoles (microvesicular lipid droplets) within the hepatocyte’s cytoplasm
2. Chronic alcohol intake is associated with formation of macrovesicular lipid droplets, which compress the nucleus to the periphery of the hepatocyte
3. Initially centrilobar (close to terminal hepatic veins), but can eventually involve the entire lobe.

Question 10

What are the macroscopic features of hepatic steatosis? (***)

Answer 10

1. Enlarged liver 4-6kg (normal 1.4-1.6kg)

2. Soft, yellow, greasy looking liver

Question 11

What are the clinical features of Alcoholic Hepatitis? (***)

Answer 11

Often occurs acutely, following an alcohol binge

Question 12

What are the microscopic features of Alcoholic Hepatitis? (***)

Answer 12

1. Hepatocyte swelling and necrosis. Secondary to accumulates of lipid droplets (hepatic steatosis), proteins and water that are normally exported
2. Presence of Mallory Bodies.
   - Aggregates of intermediate filaments, cytokeratin and other proteins. Form an eosinophilic “twised rope” shape within the cytoplasm.
3. Neutrophillic Infiltrate, centred around degrading/degraded hepatocytes
4. Fibrosis. Activated sinusoidal stellate cells and portal tract fibroblasts produce collagen leading to fibrosis. Initially enlarged portal tracts, then peri-portal septae form, and there is eventual bridging fibrosis which splits apart the hepatic parenchyma

Question 13

What are the microscopic features of alcohol-induced Cirrhosis? (***)

Answer 13

1. Initially, there will be enlargement of the liver (>2kg). This is associated with hepatic steatosis, so liver will tend to have a yellow / greasy appearance.
2. Eventually, there is shrinking of the liver, sometimes to <1kg
3. Areas of regenerative hepatocytes surrounded by fibrous bridges, together with the presence of shrinking liver, leads to the macroscopically nodular liver appearance. = Hobnail appearance

Question 14

What are the Clinical Features of Clinical Features? (***)

Answer 14

Typically presents with: anorexia, weight loss, weakness.

A variety of symptoms and signs of progressive liver failure or complications of cirrhosis: jaundice, cholestasis, coagulopathy, portal hypertension, hepatocellular carcinoma, hepatorenal syndrome

Question 15

What are the main aetiologies of Liver Cirrhosis? (*******)

Answer 15

1. Alcohol
2. Viral Hepatitis - HepB and HepC
3. Non-alcoholic steatohepatitis
4. Biliary disease: Primary and Secondary Cirrhosis, Primary sclerosing cholangitis, autoimmune hepatitis
5. Inherited Metabolic Disease: Haemochromatosis, Wilson’s disease, a1-antitrypsin deficiency
6. Idiopathic Cirrhosis