GI: Liver Function

Question 1

What are the major functions of the liver?

Answer 1

Metabolism
Detoxification
Excretion

Question 2

Define hepatocytes.

Answer 2

• main liver cell type
• arranged in plates
• receive high O2 and nutrients from portal vein and hepatic artery

Question 3

Define sinusoids.

Answer 3

• low-resistance cavities in between hepatocyte plates created by portal vein and hepatic artery branches
• drain into central veins in the hepatic lobules which eventually goes to the hepatic vein => IVC

Question 4

What makes up the hepatic triad?

Answer 4

• portal vein
• hepatic artery
• bile duct

Question 5

Describe the zones of the hepatic triad.

Answer 5

• Zone 1 = periportal cells; closest to the triad, largest supply of O2 and nutrients, hence sensitive to oxidative injuries,
• Zone 2 = intermediate
• Zone 3 = pericentral cells; close to the central vein; sensitive to ischemia;

Question 6

Which zone of cells is active in detoxificiation? bile synthesis?

Answer 6

Zone 1 = detox (periportal)

Zone 3 = bile synthesis (pericentral)

Question 7

What happens to zone cells during liver disease?

Answer 7

Zones 2 and 3 can compensate for Zone 1 cells (detox)

Question 8

Define the classic hepatic lobule.

Answer 8

extends from triad to central vein

drains blood from portal vein and hepatic artery to hepatic vein

Question 9

Define the portal lobule.

Answer 9

extends from the triad to surrounding central veins

drains bile from hepatocytes to the canaliculi and eventually to the bile duct

Question 10

Define the portal acinus.

Answer 10

extends around the triad

delivers oxygen to all hepatocytes

Question 11

Describe the biliary tree (starting with hepatocytes).

Answer 11

1. hepatocytes secrete bile into canaliculi => biliary ductules => large bile duct => right and left hepatic duct => common bile duct =>
2. either goes to the cystic duct => gallbladder
3. or goes down the common bile duct, joins the pancreatic duct, and empties into the duodenum via sphincter of Oddi

Question 12

What type of cells line the biliary ductules? What are they responsible for?

Answer 12

cholangiocytes

bile modification

Question 13

Describe carbohydrate metabolism function of the liver.

Answer 13

1. gluconeogenesis - converting other sugars to glucose

2. glucose stored as glycogen (glycogenolysis releases glucose when needed)

Question 14

Describe the effects of liver disease on carbohydrate metabolism

Answer 14

• hyperglycemia during and after meals

- hypoglycemia in between meals

Question 15

Describe lipid metabolism function of the liver.

Answer 15

• fatty acid oxidation
• converts CHO to lipids: lipoproteins, cholesterol, phospholipids
• converts cholesterol to bile acids

Question 16

Describe protein metabolism function of the liver.

Answer 16

1. synthesizes non-essential AAs
2. modifies AAs to enter biosynthetic pathways
3. synthesizes plasma proteins (albumin) and clotting factors
4. converts ammonia to urea

Question 17

What effects would liver failure have on protein metabolism?

Answer 17

• reduced synthesis of albumin => hypoalbuminemia => reduced oncotic pressure => peripheral edema
• clotting disorders

Question 18

Describe the mechanisms of first-pass metabolism.

Answer 18

1. Physical - Kupffer cells phagocytose toxins
2. Chemical - liver enzymes modify toxins to make them water soluble to ensure they are not absorbed by the intestine
   => Phase 1 = oxidation/hydroxylation via cytochrome P450
   => Phase 2 = conjugation
   => excreted in bile or enters bloodstream to be excreted in urine

Question 19

During first-pass metabolism, what molecules are conjugated with toxins in phase 2 chemical modification?

Answer 19

glutathione
sulfate
AAs
glucuronide

Question 20

Describe the excretion function of the liver.

Answer 20

Excretes all the large, protein-bound, steroid molecules that the kidney cannot through the bile or the feces

Question 21

List the components of bile.

Answer 21

• bile acids
• phospholipids
• proteins
• cholesterol
• bile pigments
• electrolytes

Question 22

Name the primary bile acids.

Answer 22

• cholic acid

- chenodeoxycholic acid.

Question 23

Name the secondary bile acids.

Answer 23

• lithocholic acid (cytotoxic)
• deoxycholic acid
• ursodeoxycholic acid

Question 24

Describe how primary and secondary bile acids are made.

Answer 24

primary bile acids are synthesized as end products of cholesterol metabolism in the hepatocytes.

secondary bile acids are the product of colonic bacterial enzymes acting on primary bile acids

Question 25

Describe bile acid conjugation in the hepatocyte. What is the purpose of conjugation?

Answer 25

in the hepatocyte, primary and secondary bile acids are conjugated with glycine or taurine to from bile salts. Conjugation makes bile acids much more water soluble, allowing them to be amphipathic and interact with the aqueous luminal solution and lipids. In acidic intestinal pH, they become fully ionized.

Question 26

Describe how synthesis rates of bile acids are affected.

Answer 26

1. if there is a decrease in plasma levels of bile, there will be an increase in synthesis (i.e. ileal resection terminating bile reabsorption => loss of bile) 2. if there is an increase in plasma levels of bile, there will be a decrease in synthesis (i.e. bile feeding)

Question 27

Describe the steps in enterohepatic circulation of bile acids.

Answer 27

1. unconjugated bile acids may be passively reabsorbed at the duodenum => portal vein => liver 2. conjugated bile acids are actively reabsorbed at the ileum via ASBT (apical Na-dependent bile acid transporters) 3. if conjugated bile acids remain in the colon after active reabsorption, colonic bacteria deconjugate the acids => passive reabsorption

Question 28

What is the main goal of bile modification by the cholangiocytes?

Answer 28

- dilution: secretin activates aquaporins for diffusion of water into the bile - glucose and AA are passively reabsorbed - alkalination: Cl/HCO3 exchanger on the apical membrane secretes HCO3 into the bile - glutathione is broken down to AA via apical GGT (AA is reabsorbed)

Question 29

What bile modifications occur in the gallbladder?

Answer 29

- concentration via water reabsorption and NaCl reabsorption (H+ secretion)

Question 30

When does bile release from the gallbladder occur?

Answer 30

- relaxed sphincter of Oddi | - 30 minutes after meal ingestion

Question 31

What hormone stimulates the release of bile from the gallbladder?

Answer 31

CCK (secreted in the presence of nutrients in the duodenum) - contraction of gallbladder - relaxation of sphincter of Oddi

Question 32

Describe neural stimulation of bile release from the gallbladder.

Answer 32

Vagal stimulation - CCK => afferents => efferents - ACh => contraction of gallbladder - NO/VIP => relaxation of sphincter of Oddi

Question 33

Define gallstones.

Answer 33

- precipitated bile constituents that accumulate in the gallbladder or bile ducts - mostly Ca-bilirubinate (pigment) stones

Question 34

Why do gallstones occur?

Answer 34

Typically, there is anti-nucleating protein that prevents accumulation of cholesterol. However, the longer the bile sits in the gallbladder, the higher the chance of nucleation

Question 35

What are the symptoms of obstruction of biliary flow by gallstones?

Answer 35

``` pain poor tolerance of fatty foods biliary injury cholecystitis pancreatitis jaundice ```

Question 36

What is a porcelain gallbladder?

Answer 36

calcification of the gallbladder wall

Question 37

List the steps for bilirubin synthesis and excretion.

Answer 37

1. in the reticuloendothelial system, hemoglobin is broken down to heme. From heme, you get biliverdin (green) => bilirubin (yellow) 2. bilirubin binds to albumin (becomes water soluble) and is absorbed by the hepatocytes via OATP transporter. 3. bilirubin + glucoronic acids => UDP-glucuronyl transferase => conjugated bilirubin-glucuronyl 4. Since conjugated bilirubin is water soluble, some of it is excreted in the urine.. The rest is sent to the bile => small intestine 5. colonic bacteria deconjugate bilirubin => urobilinogen 6. Some urobilinogen enters enterohepatic circulation and goes back to the liver. Some of it is further converted and is excreted in the feces.

Question 38

What can an increased level of unconjugated bilirubin in the plasma indicate?

Answer 38

- loss of UGT (can't conjugate it; builds up in the liver => enters blood) - oversupply of heme (increased RBC degradation, transfusion)

Question 39

What can an increased level of conjugated bilirubin in the urine indicate? (conjugated bilirubinemia)

Answer 39

- defective transporter blocks secretion of conjugated bilirubin into the bile (buildup in the liver => blood => urine) - obstructed biliary flow due to gallstones => backup of bile => buildup in the liver => blood => urine)

Question 40

Define jaundice.

Answer 40

yellowing of the skin, sclera, and mucous membranes due to bilirubin buildup in the blood (free or conjugated). Usually accompanied by pruritis (itchiness)

Question 41

What are relevant clinical values to define jaundice?

Answer 41

bilirubin > 2mg/dL | bilirubin > 34uM

Question 42

List causes for hyperbilirubinemia.

Answer 42

- excess heme production (hemolytic anemia) - defective OATP transporters block uptake of bilirubin into hepatocytes - defective conjugation (buildup of free bilirubin in liver) - defective secretion of conjugated bilirubin into bile canaliculi (buildup of conjugated bilirubin in liver) - bile duct obstruction (backup) - presurgical antibiotics (no colonic bacteria to produce urobilinogen) - newborns don't have UDP-GTase yet

Question 43

Describe how the liver handles NH3 from protein catabolism and colonic bacteria.

Answer 43

- protein catabolism => urea cycle | - colonic bacteria => acidified in lumen => ammonium => stool

Question 44

Name 2 molecules toxic to the CNS

Answer 44

bilirubin | NH3

Question 45

What are the causes and symptoms of hepatic encephalopathy?

Answer 45

- patients with liver disease can't detoxify => buildup of NH3 => CNS effects - confusion, dementia, coma, death

Question 46

What are the causes and symptoms of liver cirrhosis?

Answer 46

- drugs (alcohol), poisons, hepatitis | - fibrosis, dysfunctional hepatocytes, portal hypertension

Question 47

What are the causes and symptoms of portal hypertension?

Answer 47

- increased vascular resistance in the liver - increased sinusoidal BP => backflow into hepatic vein => IVC - splenomegaly, ascites, varices (esophageal, caput medusa, hemorrhoids), melena, hematemesis