GI Pathophysiology: ALD

Question 1

functions of the liver not related to digestion:

• ____
• ____
• ____
• ____
• ____
• ____
• ____

Answer 1

• metabolic processing of the major categories of nutrients
• detoxifying or degrading body wastes and hormones, drugs and other foreign compounds
• synthesizing plasma proteins
• stores glycogen, fats, iron, copper, and many vitamins
• activates vitamin D
• removes bacteria and worn-out RBCs
• excretes cholesterol and bilirubin

Question 2

major cells of the liver:

Answer 2

• hepatocytes - basically polarized epithelial cells
• kupffer cells - resident macrophages
• stellate cells - special cells that wrap around endothelial cells

Question 3

major and minor ethanol-oxidizing pathways in the liver

Answer 3

• Major pathway: cytosol; ethanol —> acetylaldehyde via ADH and reduction of NAD+ to NADH.
• Major inducible pathway: Endoplasmic Reticulum; ethanol –> acetylaldehyde via CYP2E1 enzyme converting NADPH to NADP+
• Accessory pathways: peroxisomes; ethanol —> acetylaldehyde via catalase converting H2O2 to H20
• IN ALL PATHWAYS, ACETYLALDEHYDE THEN GOES TO MITOCHONDRIA LEADING TO FORMATION OF ACETATE (LESS DAMAGING THAN ACETYLALDEHYDE)

Question 4

map out the molecular pathway that leads to steatosis

Answer 4

EtOH —–> acetylaldehyde via with ADH or CYP2E1. Acetyaldehyde then enhances Egr-1 gene transcription by activating the Egr-1 gene promoter —–> increasing the levels of Egr-1 mRNA —-> increasing Egr-1 nuclear protein —-> increase in transcription of TNF and SREBP-1c —> initiation of ethanol-induced lipogenesis and fatty liver (steatosis)

Question 5

describe the gut liver axis of habitual alcohol drinker

Answer 5

• In chronic drinker, gram (-) bacteria overtake gram (+) in the gut lumen
• LPS endotoxin translocates to the liver via the portal circulation
• In liver, LPS activates Kupffer cells and hepatic stellate cells via TLR4.
• These cells produce ROS and pro inflammatory cytokines that contribute to hepatocyte damage.
• The ROS and cytokines can also interact with alcohol to cause activation of various immune cells including neutrophils that leads to further hepatocyte damage.
• Alcohol also directly acts on adipose tissue, leading to production of DAMPs, leading to further hepatocyte damage.

Question 6

3 key roles stellate cells play in liver fibrosis

Answer 6

1) secrete great amounts of scar-forming extracellular matrix proteins
2) loss of hepatocyte microvilli
3) loss of sinusoidal endothelial fenestrae

Question 7

4 pathways that lead to the development of ascites with cirrhosis and liver damage.

Answer 7

1) blocked lymphatics –> increased fluid in the peritoneal cavity —> ascites
2) portal hypertension –> increased hydrostatic pressure in portal circulation –>fluid shift out of portal circulation in to peritoneal cavity –> ascites
3) decreased synthesis of albumin –> decreased plasma osmotic pressure –> fluid shifts out of portal circulation and into peritoneal cavity –> ascites
4) decreased blood volume plus reduced inactivation of aldosterone and ADH –> increased serum aldosterone and ADH –> increased water and sodium retention –> fluid shifts from portal circulation into peritoneal cavity –> ascites