Physiology/pharmacology of liver

Question 1

what are the metabolic functions of the liver?

Answer 1

regulation of carbohydrate, lipid and amino acid metabolism

Question 2

describe the processes in carbohydrate metabolism

Answer 2

hormonally regulated
gluconeogenesis (glucose from amino acids)
glycolysis (form pyruvate/lactate/acetyl CoA)
glycogenesis (store glucose as glycogen)
glycogenolysis (release glucose as needed)

Question 3

what are the processes in fat metabolism?

Answer 3

processing of chylomicron remnants
synthesis of lipoproteins (VLDLs, HDLs) and cholesterol (for steroid hormone/bile synthesis)
Ketogenesis (temp energy source in starvation) - important for neural function

Question 4

what are the processes in protein metabolism?

Answer 4

synthesis of plasma proteins
transamination and deamination of amino acids
conversion of ammonia to urea (urea cycle - detoxify)

Question 5

what is the role of the liver in hormone metabolism?

Answer 5

inactivates/degrades many hormones and activates others

Question 6

what hormones does the liver deactivate?

Answer 6

insulin
glucagon
ADH/vasopressin
steroid hormone

Question 7

what hormones does the liver activate?

Answer 7

conversion of thyroid hormone (TH) by deiodini.
.
.
.

Question 8

what substances are stored in the liver?

Answer 8

fat soluble vitamins (A (in Ito cells), D, E, K (in hepatocytes))
Vit B12 (long term - 3-5 years)
Iron, copper
Glycogen

Question 9

what is involved in the liver’s synthesis of proteins?

Answer 9

for export:

• coagulation factors II, VII, IX and X and proteins C and S
• albumin
• complement proteins
• apolipoproteins
• carrier proteins (secreted into blood and carries other substances eg. thyroid hormone)

Question 10

what are Kupffer cells?

Answer 10

like resident macrophages

liver phagocytes that digest/destroy particulate matter (eg bacteria) and senescent (old) erythrocytes

Question 11

How is the liver involved in protection?

Answer 11

Kupffer cells
production of immune factors
- host defence proteins (acute phase proteins)

Question 12

how is the liver involved in detoxification?

Answer 12

detoxifies many…
.
.

Question 13

what does bile do?

Answer 13

participates in digestion and absorption of fats and the excretion products of metabolism (including drug metabolites)

Question 14

how is bile produced?

Answer 14

0.6-1.2L per day by combined secretion from hepatocytes and bile duct cells (cholangiocytes)

Question 15

where happens to bile between meals?

Answer 15

stored and concentrated (removes bile and water) in the gall bladder (sphincter of oddi closed)

Question 16

what are the risks of concentrating bile?

Answer 16

components can precipitate out (e.g cholesterol) triggering formation of gall stones

Question 17

what happens to bile during a meal?

Answer 17

chime in duodenum stimulaes gall bladder smooth muscle to contract and sphincter of oddi to open (via CCK and vagal impulses)
Bile spurts into duodenum via cystic and common bile ducts and mixes with bile from liver

Question 18

what are the functions of bile?

Answer 18

micelles formation
neutralization of chime
pH adjustment for digestive enzyme action
protection of mucosa

Question 19

how do hepatocytes secrete primary juice?

Answer 19

secrete juice into canaliculi which drain into biliary ductules and ducts
materials removed from sinusoidal capillary into space of disse, across a membrane?

Question 20

what blood is in the sinusoidal capillaries?

Answer 20

hepatic portal vein and hepatic artery blood

Question 21

what is contained in secretion from hepatocytes?

Answer 21

primary bile acids, mainly cholic and chenodeoxycholic acids (a fraction of which are dehydroxylated by bacteria in the gut to form the secondary bile acids, deoxycholic acid and lithocholic acids)
Both the primary and secondary acids are then absorbed and taken back via the hepatic portal vein and can be reused and resecreted into the duodenum
Water and electrolytes (incuding Na, K, Cl, Ca2+ and HCO3)
Lipids and phospholipids
Cholesterol
IgA
Billirubin (renders urine yellow and faeces brown)
Metabolic waste and drug metabolites

Question 22

what is cholelithiasis?

Answer 22

excess cholesterol relative to bile acids and lecithin may precipitate into microcrystals that aggregate into gall stones

Question 23

what does dark urine and pale stool indicate?

Answer 23

bilirubin problem

Question 24

what is the most common pathology of the biliary tract?

Answer 24

cholelithiasis

Question 25

what is the best treatment for large symptomatic stones?

Answer 25

laproscopic cholecystectomy

Question 26

when is ursodeoxycholic acid useful?

Answer 26

unimpaired gall bladder function with small/medium sized radiolucent stones (CH stones) which it dissolves
causes diarrhoea

Question 27

what drugs are used in bilary colic pain?

Answer 27

Not morphine as may constrict sphincter of oddi and increase pressure and worsen pain
- may be used with atropine
Buprenorphine and Pethidine are better alternatives

Question 28

what does atropine do?

Answer 28

relives bilary spasm

as does GTN

Question 29

Most bile salts are lost in the faeces, true or false?

Answer 29

false

only 5% lost, most are reabsorbed via active transport in terminal ileum

Question 30

what are the 2 paths for bile after it has been pumped out of liver?

Answer 30

into gall bladder

into duodenum

Question 31

what is ASBT?

Answer 31

along with passive transport, brings bile acids (primary and secondary) back into hepatocytes where they can be recycled

Question 32

what happens to secondary bile acids on returning to the liver?

Answer 32

……..

Question 33

what are the major bile acid sequestrants (resins)?

Answer 33

colveselam
colestipol
colestyramine

Question 34

how do resins work?

Answer 34

neither absorbed or digested by gut
bind to bile acids preventing their reabsorption
lower plasma LDL-cholesterol indirectly
- promote hepatic conversion of cholesterol to bile acids
- increase cell curface expression of LDL receptors in hepatocytes
- increase clearance of LDL cholesterol from plasma

Question 35

what are the clinical uses of resins?

Answer 35

hyperlipidaemia (limited effect)
Cholestatic jaundice (itch)
Bile acid diarrhoea (bile acid overload)

Question 36

what are the limitations and side effects of resins?

Answer 36

taste bad and require large doses
frequently cause diarrhoea
reduce absorption of fat soluble vitamins

Question 37

what are the major phases of drug metabolism?

Answer 37

phase 1:
- mediated mainly by cytochrome p450 enzymes
- add polar group to parent drug compound either by oxidation (p450), reduction, hydrolysis
If a drug is lipophilic it is filtered by kidney then reabsorbed as cant be excreted, adding a polar group makes it easier for the kidney to excrete
functionalization = adding chemically active group that can be attacked by phase 2 reaction
Phase 2:
- products of phase 1 are conjugated, usually by glucuronyl, sulphate, methyl, actyl, ………….

Question 38

what are prodrugs?

Answer 38

need metabolic activation to activate the drug to work (eg. codeine)

Question 39

explain the 2 phases of metabolism of aspirin

Answer 39

phase 1:
- catabolic conversion of drug to derivative (……)
phase 2:
- anabolic conversion of derivative to……….

Question 40

what happens when detoxification of ammonia goes wrong?

Answer 40

blood ammonia levels rise causing hepatic encephalopathy which affects CNS

• drowsiness
• incoordination
• coma
• death

Question 41

how is hepatic encephalopathy treated?

Answer 41

lactulose (acidifies stool reducing pH and converts ammonia to ammonium which is not absorbed)
Antibiotics (neomycin, rifamixin) - suppress colonic flora and inhibit ammonia generation