physiology and pharmacology of the liver

Question 1

what are the metabolic functions of the liver

Answer 1

carbohydrate metabolism

fat metabolism

protein metabolism

Question 2

what comprises of carbohydrate metabolism

Answer 2

*is hormonally regulated
>gluconeogenesis - to produce glucose from amino acids
>glycolysis - to form pyruvate thence lactate or ACh
>glycogenesis - to store polymerised glucose as glycogen
>glycogenolysis - to release glucose

Question 3

what does fat metabolism consist of

Answer 3

processing of chylomicron remnants
synthesis of lipoproteins and cholesterol
ketogenesis (in starvation)

Question 4

what does protein metabolism consist of

Answer 4

synthesis of plasma proteins
transamination and deamination of amino acids
conversion of ammonia to urea

Question 5

what hormones are deactivated by the liver

Answer 5

insulin
glucagon
anti-diuretic hormone (vasopressin)
steroid hormone

Question 6

what hormones are activated by the liver

Answer 6

conversion of thyroid hormone

conversion of vitamin D to 25-hydroxyvitamin D2

Question 7

what are the major functions of the liver

Answer 7

storage
synthesis of proteins
protection
detoxification

Question 8

what does the liver store

Answer 8

• fat soluble vitamins A D E K in hepatocytes
• water soluble vitamin B12
• iron, copper
• glycogen

Question 9

what proteins does the liver synthesise for export

Answer 9

• coagulation factors II VII IX and X
• proteins C and S
• albumin
• complement proteins
• apolipoproteins
• carrier proteins

Question 10

what is the role of Kupffer cells

Answer 10

> they are liver phagocytes that digest particulate matter and old erythrocytes

Question 11

other than Kupffer cells what the protective function does the liver confer

Answer 11

the production of immune factors

-host defence proteins

Question 12

how is the liver involved in detoxification

Answer 12

> it has many endogenous substances ie bilirubin as a metabolite of haemoglobin breakdown
and has many exogenous substances ie xenobiotics (drugs and alcohol)

Question 13

what is bile

Answer 13

it participates in the digestion and absorption of fats and the excretion of products of metabolism
>produced continuously by hepatocytes and bile duct cells

Question 14

secretion of bile with regards to food intake

Answer 14

> between meals bile is stored and concentrated in the gall bladder as the sphincter of Oddi is closed
during a meal chyme in the duodenum stimulates gall bladder smooth muscle to contract (via CCK and vagal impulses)
-the sphincter of Oddi opens via CCK
-bile spurts into the duodenum via cystic and common bile ducts

Question 15

what does neutral / slightly alkaline bile assist with

Answer 15

micelle formation
neutralisation of chyme
pH adjustment for digestive enzyme action
protection of the mucosa

Question 16

what do hepatocytes mainly secrete and where

Answer 16

primary juice into canaliculi which drain into biliary ductules and ducts

Question 17

what does the primary bile acid contains

Answer 17

> contain mainly cholic and chenodeoxycholic acids
- which can be dehydroxylated by bacteria to form the secondary bile acids, deoxycholic acid and lithocolic acid
water and electrolytes including sodium, chloride and bicarbonate
lipids and phospholipids
cholesterol
-excess cholesterol relative to bile acids may precipitate microcrystals the can become gall stones (cholelithiasis)
IgA
bilirubin
metabolic wastes and conjugated drug metabolites

Question 18

what is cholelithiasis

Answer 18

*most common pathology of the biliary tract

when there is excess cholesterol relative to bile salts and lecithin that may precipitate and form microcrytsals that may aggregate and form gall stones

Question 19

how to treat symptomatic stones

Answer 19

laparoscopic cholecystectomy

eg stones causing cholangitis and pancreatitis

Question 20

how to treat patients with unimpaired gall bladder function who have small/medium sized stones (CH stones)

Answer 20

ursodeoxycholic acid dissolves these stones

> may cause diarrhoea

Question 21

analgesia for biliary colic

Answer 21

morphine is contraindicated - the pain may worsen due to constriction of the sphincter of Oddi and increase intrabiliary pressure
»buprenorphine and pethidine are alternatives

Question 22

how may biliary spasms be relieved

Answer 22

atropine and GTN

Question 23

bile salts and enterohepatic recycling

Answer 23

only a small fraction of bile salts entering the duodenum is lost in the faeces
most is reabsorbed by active transport in the terminal ileum and undergoes enterohepatic recycling

> secondary bile acids upon returning to the liver are conjugated with glycine or taurine and recycle as bile salts

Question 24

what are resins

Answer 24

bile salt sequestrants
ie colveselam colestipol colestyramine

> they are neither digested not absorbed by the gut
act by binding to bile acids preventing their reabsorption

Question 25

how do resins lower plasma LDL-cholesterol indirectly ?

Answer 25

> they promote hepatic conversion of cholesterol to bile acids
increase cell surface expression of LDL-receptor in hepatocytes
increase clearance of LDL cholesterol from plasma

Question 26

what are the clinical uses of resins

Answer 26

for hyperlipidaemia
cholestatic jaundice (itch)
bile acid diarrhoea

Question 27

side effects and limitations resins

Answer 27

unpalatable, inconvenient
frequently cause diarrhoea
reduced absorption of fat-soluble vitamins and some drugs ie thiazide diuretics

Question 28

what are drugs

Answer 28

xenobiotics

Question 29

functions of drug metabolism

Answer 29

• convert parent drugs to more polar metabolites that are not readily reabsorbed by the kidney facilitating excretion
• convert drugs to metabolites that are usually pharmacological less active than the parent compound

Question 30

unusual actions of metabolites

Answer 30

• can be converted from inactive prodrugs to active compounds or gain activity
• have unchanged activity
• possess a different type or spectrum of action

Question 31

what is the main organ of drug metabolism

Answer 31

the liver

Question 32

what is the function of haem proteins

Answer 32

-they are located in the endoplasmic reticule of the liver hepatocytes mediating oxidation reactions (phase 1) of many lipid soluble drugs

Question 33

what are the cytochrome P450 (CYP) family of monooxygenases ?

Answer 33

haem proteins

Question 34

CYP 3A4

Answer 34

3 = gene family 
A =  gene subfamily 
4 = individual gene

Question 35

what are the main families in human liver

Answer 35

CYP1
CYP2
CYP3

Question 36

what are phase 2 reactions involved in

Answer 36

conjugation of chemically reactive groups ie OH SH NH2 with glucuronyl, sulphate, methyl or acetyl groups

> > glucuronidation is a common reaction involving the transfer of glucuronic acid to electron-rich atoms of the substrate N O S forming amide ester or thiol bonds

> many endogenous substances are subject to glucuonidation ie bilirubin and adrenal corticosteroids

Question 37

what is hepatic encephalopathy HE

Answer 37

in severe hepatic failure - detoxification of ammonia via the urea cycle to urea fails

> blood ammonia levels rise (hyperammonemia) exerting a toxic effect upon the CNS that causes incoordination, drowsiness, coma and death due to cerebral oedema

Question 38

how to treat HE

Answer 38

> lactulose - a disaccharide of fructose and lactose

which:
- is not digested or absorbed in the small intestine
- when broken down in the colon acidifies the stool (reduces pH)
- converts ammonia to ammonium which is not absorbed

> antibiotics - neomycin rifamixin
-suppress colonic flora and this inhibit ammonia generation