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Flashcards in GI X & XI Deck (44):
1

Describe the liver.

From where does it receive blood? Describe its supply.

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.

2

What are the major functions of the liver?

Major functions of the liver are in:
Metabolism
Detoxification
Excretion

3

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

Slide 3

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?

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

5

Blood drains from liver into what?

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

6

What is the hepatic triad?

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

7

Describe zone 1, zone 2 and zone 3 cells.

Which are periportal? Which are pericentral?

What happens in liver diseases?

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.

8

What are the origination point of bilary system?

What is canaliculus? What do they do?

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.

9

What are cholangiocytes?

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.

10

Describe the action of the following:

classic hepatic lobule
portal lobule
portal acinus


Which zone is most oxygenated? Least?

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

11

Describe pathway of bile after bilary ductules.

Which 2 places might bile end up?

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

12

What do hepatocytes do?

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

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?

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.

14

Describe the lipid metabolism of the liver.

(3 things)


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.

15

Describe protein metabolism of the liver.

What does the liver synthesize?

What does it convert?


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).

16

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

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

17

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

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

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.

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).

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.?


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.

20

Where is bile synthesized and what is it synthesized into?

Bile is synthesized and secreted by hepatocytes into bile canaliculi.

21

Bile is a micellar solution containing what?

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

22

What 2 primary bile acids do hepatocytes synthesize?

Hepatocytes synthesize two primary bile acids:
Cholic acid
Chenodeoxycholic acid

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.

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

24

How are bile acids conjugated or deconjugated?


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.

25

What is enterohepatic circulation?

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

26

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

(Draw)

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

27

What can modify bile?

How is bile modified?

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

28

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

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

29

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

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.

30

What are gallstones? Where do they accumulate?

What are they composed of?

What do they do?

What can contribute/cause gallstones?

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.

31

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

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.

32

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

When this molecule have fatal consequences? Why?

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.

33

What might help detect liver disease clinically?

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

34

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

How does this differ from conjugated bilirubinemia?

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.

35

What is jaundice? What causes it?

Describe clinical symptoms.

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

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.

36

What are causes of hyperbilirubinemia?

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).

37

Describe ammonia handling by the liver.

Slide 36

38

What is hepatic encephalopathy? What can lead to this?

What clinical manifestations indicate significant disease progression?

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.

39

Describe liver cirrhosis. What is it?

What is a consequence of?

What are clinical signed derived from?

Major causes?

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.

40

What causes portal hypertension?

What is happening in this condition?

What results?

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.

41

What is caput medusae?

What might it indicate?

Slide 40

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

42

What are esophageal varices?

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

Clinical consequences?

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.

43

What is spider naevus?

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

44

What is the purpose of hepatic skellate cells?

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.