GI X & XI

Question 1

Describe the liver.

From where does it receive blood? Describe its supply.

Answer 1

Liver – a large, multilobed organ is located in the abdominal cavity.

It receives portal blood from all the GI organs – stomach, small and large intestines, pancreas and spleen.

The majority of liver’s blood supply is venous blood from the GI tract via portal vein.

Question 2

What are the major functions of the liver?

Answer 2

Major functions of the liver are in:
Metabolism
Detoxification
Excretion

Question 3

Draw out the functional structure of the liver (arteries, organs, veins…)

Answer 3

Slide 3

Question 4

What are the major cell types in the liver?

How are they arranged?

How do they receive nutrients? Which arteries are they supplied by?

Answer 4

Hepatocytes are the major cell types in the liver.

They are arranged in anastomising cords that form plates.

Liver receives a high blood flow –ensures that hepatocytes receive high quantities of both O2 and nutrients.

The plates of hepatocytes – supplied by sinusoids, which are low-resistance cavities – supplied by branches of both portal vein and hepatic artery.

Slide 4

Question 5

Blood drains from liver into what?

Answer 5

Blood drains from the liver into central branches of hepatic vein.

Question 6

What is the hepatic triad?

Answer 6

Hepatic Triad: Consists of the branches of the hepatic artery, portal vein and bile duct. Triad defines:

Question 7

Describe zone 1, zone 2 and zone 3 cells.

Which are periportal? Which are pericentral?

What happens in liver diseases?

Answer 7

Zone 1 or periportal cells – hepatocytes closest to triad- most sensitive to oxidative injury – have largest supply of nutrients and O2, most active in detoxification.

Zone 2 cells- intermediate between zones 1 and 2.

Zone 3 or pericentral cells-closest to the hepatic vein - most sensitive to ischemia - most active in bile synthesis.

Cells in zones 2 and 3 can function as zone 1 cells in liver diseases.

Question 8

What are the origination point of bilary system?

What is canaliculus? What do they do?

Answer 8

Hepatocytes are the origination point of biliary system.

Apical membranes of adjacent hepatocytes forms a channel called canaliculus.

These canaliculi drain bile from liver and transport to the biliary ductules- these ductules are lined by columnar epithelial cells – the cholangiocytes.

Question 9

What are cholangiocytes?

Answer 9

Hepatocytes are the origination point of biliary system.

Apical membranes of adjacent hepatocytes forms a channel called canaliculus.

These canaliculi drain bile from liver and transport to the biliary ductules- these ductules are lined by columnar epithelial cells – the cholangiocytes.

Question 10

Describe the action of the following:

classic hepatic lobule
portal lobule
portal acinus

Which zone is most oxygenated? Least?

Answer 10

classic hepatic lobule- drains blood from the portal vein and the hepatic artery to the heaptic or central vein

portal lobule- drains bile from hepatocytes to the bile duct

portal acinus -supplies oxygenated blood to hepatocytes

Zone III- least oxygenated
Zone I-most oxygenated

Slide 12

Question 11

Describe pathway of bile after bilary ductules.

Which 2 places might bile end up?

Answer 11

Biliary ductules drain into large bile ducts – coalesce into right and left hepatic ducts.

These then form the common hepatic duct.

Bile then flows either
to gall bladder via cystic duct
or to the intestine via common bile duct.

Slide 13

Question 12

What do hepatocytes do?

Answer 12

Hepatocytes participate in the metabolism of major nutrients – carbohydrates, lipids and proteins.

Question 13

Describe the carbohydrate metabolism of the liver.

What does the liver play an important role in?

Describe its glucose buffer function.

What will impaired liver function result in?

Answer 13

Liver plays an important role in gluconeogenesis – conversion of other sugars to glucose.

Glucose buffer function- liver stores excess glucose as glycogen and releases stored glucose in the bloodstream when needed.

Impaired liver function results in – hyperglycemia during/after meals and hypoglycemia between meals.

Question 14

Describe the lipid metabolism of the liver.

3 things

Answer 14

Hepatocytes are a rich store of enzymes for fatty acid oxidation – contributes to energy generation.

They also convert products of carbohydrate metabolism into lipids – synthesis of lipoproteins, cholesterol and phospholipids.

They also convert a significant portion of the cholesterol to bile acids.

Question 15

Describe protein metabolism of the liver.

What does the liver synthesize?

What does it convert?

Answer 15

Liver synthesizes all of the non-essential amino acids- also modifies amino acids so they can enter biosynthetic pathways for carbohydrate synthesis.

It synthesizes almost all plasma proteins- including albumin (determines plasma oncotic pressure) and the clotting factors.

Converts ammonia to urea (excreted in urine).

Question 16

What is hypoalbuminemia? What can this lead to? Why?

Answer 16

Patients with liver failure develop hypoalbuminemia – may lead to peripheral edema due to loss of plasma protein oncotic pressure and clotting disorders.

Question 17

What types of things does the liver protect the body from?

Answer 17

Liver protects the body from toxic substances
Endogenous or exogenous toxic molecules (including pharmaceutical drugs)
bacterial toxins

Question 18

Liver protects the body from toxic substances
Endogenous or exogenous toxic molecules (including pharmaceutical drugs)
bacterial toxins.

How does it do this?

Describe the process.

Answer 18

modifies them in “first pass metabolism” so little or none can enter systemic circulation.

This is achieved in two phases:
Phase I reactions – oxidation, hydroxylation etc. – catalyzed by cytochrome P-450 enzymes.

Phase II reactions – conjugate the substances with glucuronide, sulfate, amino acids or glutathione.

The products are excreted in feces (via bile) or in urine (via kidney).

Question 19

Kidneys play important role in excretion of small water-soluble catabolites.

What happens to large water-soluble catabolites and molecules bound to plasma proteins like steroid hormones, etc.?

Answer 19

Large water-soluble catabolites and molecules bound to plasma proteins, steroid hormones etc. – cannot be excreted through kidney.

Liver helps by excreting these in bile – they are ultimately excreted in feces.

Question 20

Where is bile synthesized and what is it synthesized into?

Answer 20

Bile is synthesized and secreted by hepatocytes into bile canaliculi.

Question 21

Bile is a micellar solution containing what?

Answer 21

Bile acids
Phospholipids (mainly lecithins - Phosphatidylcholine)
Proteins
Cholesterol
Bile pigments (bilirubin for example)
Electrolytes (similar and isotonic to plasma)

Question 22

What 2 primary bile acids do hepatocytes synthesize?

Answer 22

Hepatocytes synthesize two primary bile acids:
Cholic acid
Chenodeoxycholic acid

Question 23

Hepatocytes synthesize two primary bile acids:
Cholic acid
Chenodeoxycholic acid

What acts on these to yield secondary bile acids? Describe the secondary bile acids.

Answer 23

Colonic bacterial enzymes act on these to yield secondary bile acids:
Ursodeoxycholic acid
Deoxycholic acid
Lithocholic acid

Question 24

How are bile acids conjugated or deconjugated?

Answer 24

In hepatocytes, both primary and secondary bile acids are conjugated with glycine or taurine – produces conjugated bile acids or bile salts - more water soluble.

Conjugated bile acids are fully ionized in intestinal lumen - actively absorbed in terminal ileum via apical Na+ -dependent bile salt transporter (asbt).

Some (that escape) are deconjugated by colonic bacterial enzymes – unconjugated forms reabsorbed passively in colonic epithelium.

Question 25

What is enterohepatic circulation?

Answer 25

Majority of bile acid pool is recycled from the intestine back to the liver – via enterohepatic circulation.

Question 26

What happens to conjugated bile acids in the enterhepatic circulation process?

(Draw)

Answer 26

Conjugated bile acids are unable to passively cross the intestinal epithelial lining.

When chyme reaches the terminal ileum and lipid absorption is completed, conjugated bile acids are reabsorbed by a symporter known as apical Na+ -dependent bile acid transporter (asbt).

A minor fraction of bile acids enters the colon –become deconjugated and is reabsorbed passively.

Slide 22

Question 27

What can modify bile?

How is bile modified?

Answer 27

Cholangiocytes lining biliary ductules can modify bile.

Glucose, amino acids are reclaimed by specific transporters.

Cl- ions are exchanged for HCO3- - making bile slightly alkaline.

Glutathione - broken to amino acids by γ-glutamyl transpeptidase - absorbed.

Bile is diluted here –secretin stimulate aquaporin water channels.

Slide 23

Question 28

Where is bile stored? What happens to bile here? How?

Answer 28

Bile is stored in gallbladder.

In between meals, outflow of bile is blocked by constriction of sphincter of Oddi.

In the gallbladder, bile becomes more concentrated.

The mechanism is not very clear how it does concentrate. However, there is Na+ and H- exchanger which plays some role.

Sodium is absorbed which also brings water which can result concentrated bile salt

Slide 24

Question 29

When does ejection of bile from gallbladder begin? What is a major stimulus?

Answer 29

Ejection of bile from gall bladder begins within 30 minutes of meal ingestion.

Major stimulus for bile secretion is CCK – causes
contraction of gallbladder
relaxation of sphincter of Oddi.

Other internal neural reflexes and vagal pathways are also involved.

Question 30

What are gallstones? Where do they accumulate?

What are they composed of?

What do they do?

What can contribute/cause gallstones?

Answer 30

Gallstones – are precipitated bile constituents – accumulate in the gallbladder or elsewhere in the biliary tree.

Composed predominantly of cholesterol or Ca2+ bilirubinate (pigment) stones.

They obstruct biliary flow – pain, poor tolerance of fatty food, biliary injury.

Cholesterol is supersaturated in the bile of many adults – but precipitation is normally inhibited by anti-nucleating proteins.

Prolonged storage of bile increases the chance of nucleation – thus skipping breakfast might enhance this.

Question 31

Draw out bilirubin formation and excretion by the liver. starting with RBC.

Answer 31

Slide 31

Heme degradation in the RES – first forms pigment biliverdin (green) – this is then converted to bilirubin (yellow) which is insoluble in aqueous solution at neutral pH.

Bilirubin binds to albumin (increases solubility in aqueous solution)- transported via bloodstream to liver – it is taken up by hepatocytes via an an organic anion-transporting polypeptide (OATP) transporter.

In hepatic microsomes, bilirubin is conjugated with glucoronic acid by enzyme UDP glucuronyl transferase.

Some newborns develop jaundice, since this enzyme is synthesized slowly after birth.

Question 32

Where does conjugated bilirubin go/ describe its secretion or absorption.

When this molecule have fatal consequences? Why?

Answer 32

Conjugated bilirubin is water soluble – a portion is excreted in urine. The remaining is secreted in bile – travels to small intestine.

In terminal ileum and colon, it is deconjugated by bacterial enzymes – metabolized to urobilinogen.

A portion of urobilinogen is absorbed via enterohepatic circulation (to liver).

The remainder is converted to urobilin and stercobilin –excreted in feces.

Bilirubin can cross blood-brain barrier - can be fatal.

Question 33

What might help detect liver disease clinically?

Answer 33

Unconjugated or conjugated bilirubin levels in plasma - important tools for diagnosis of liver disease.

Question 34

What would increase of unconjugated bilirubin in the plasma imply clinically?

How does this differ from conjugated bilirubinemia?

Answer 34

Increase of unconjugated bilirubin in plasma reflects:
Loss or absence of UGT
Sudden oversupply of heme (e.g. in transfusion reactions)

In conjugated bilirubinemia there is high bilirubin in urine (dark color) due to:
Defect in the transporter that secretes conjugated bilirubin in bile
Blockage of bile flow – gallstone.

Question 35

What is jaundice? What causes it?

Describe clinical symptoms.

When does it clincally manifest? (At what levels) What is this called?

Answer 35

Jaundice: yellow color of the skin and conjunctiva - accumulation of bilirubin (hepatic dysfunction).

Yellowness of skin, scleras and mucous membranes due to accumulation of free and conjugated bilirubin in the blood.

Usually accompanied by pruritus (itching of the skin, increased levels of bile acids in serum leading to skin deposit).

Jaundice becomes clinically manifest when total plasma bilirubin is >2 mg/dl (> 34 µM) = hyperbilirubinemia.

Question 36

What are causes of hyperbilirubinemia?

Answer 36

Excess production of bilirubin (e.g. hemolytic anemia)

Decreased uptake of bilirubin into hepatic cells

Disturbed intracellular protein binding and conjugation

Disturbed secretion of conjugated bilirubin into bile canaliculi

Intrahepatic and extrahepatic bile duct obstruction

Pre-surgery use of potent antibiotics (lack of bacteria)

Newborns (lack of UDP glucuronyl transferase).

Question 37

Describe ammonia handling by the liver.

Answer 37

Slide 36

Question 38

What is hepatic encephalopathy? What can lead to this?

What clinical manifestations indicate significant disease progression?

Answer 38

Coma and death can result - if metabolic activity of liver is compromised acutely.

Patients with chronic liver disease – may have a gradual decline of mental function – ammonia and other toxins not cleared by liver – results in hepatic encephalopathy.

Development of confusion, dementia and coma – indicates significant disease progression – can be fatal if left untreated.

Question 39

Describe liver cirrhosis. What is it?

What is a consequence of?

What are clinical signed derived from?

Major causes?

Answer 39

An irreversible destruction of the functional anatomy of the liver

It is a consequence of hepatic injury, fibrosis and tissue degeneration.

The clinical signs derive from dysfunctional hepatocytes. Portal hypertension and other clinical signs are always present.

Drugs (alcohol), poisons, and hepatitis are the major causes of cirrhosis.

Question 40

What causes portal hypertension?

What is happening in this condition?

What results?

Answer 40

caused by increased vascular resistance in the liver.

Increased blood pressure in the sinusoids reflects back to the portal vein (portal vein does not have valves) and other vascular beds.

Results in enlargement of the spleen (splenomegaly), ascites and other complications.

Question 41

What is caput medusae?

What might it indicate?

Answer 41

Slide 40

Portal hypertension and portal-to-systemic shunting
Caput medusae: dilated abdominal veins

Question 42

What are esophageal varices?

What might lead to this? In what type of patients is this commonly seen?

Clinical consequences?

Answer 42

Esophageal varices is a condition in which there are extremely dilated sub-mucosal veins in the esophagus. They are most often a consequence of portal hypertension, commonly due to cirrhosis; patients with esophageal varices have a strong tendency to develop bleeding.

Question 43

What is spider naevus?

Answer 43

Spider naevus/nevus is condition in which minor thin walled blood vessels are visible under the skin.

Question 44

What is the purpose of hepatic skellate cells?

Answer 44

hepatic skeletal (skellate) cell- 1-2% fiber plastic cells, if liver injured then these will multiply and prod. collagen 
collagen prod. main prod. leading to fibrosis. over activation for long period is pathological problem bc leads fibrosis and cirrhosis.
cirrhotic liver lots of collagen deposition, see many of these hepatic cells lost.