Liver Biochemistry

Question 1

Liver blood supply

Answer 1

75% by portal vein

25% by hepatic artery

Question 2

Hepatic circulation

Answer 2

Blood flows out via 3 hepatic veins into inferior vena cava
Oxygen rich blood flows through hepatic artery (peripheral circulation)
Nutrient rich blood from bowel flows through the portal vein (enteric circulation)

Question 3

Hepatocytes

Answer 3

Carry out most metabolic functions of liver, capable of regeneration

Question 4

Kupffer cells

Answer 4

Present in lining of sinusoids
Are macrophages of liver and secrete cytokines
Lots of lysosomes

Question 5

Stellate cells

Answer 5

Storage site for vitamin A and other lipids

Question 6

Pit cells

Answer 6

Lymphocytes- natural killer cells protecting liver against viruses/tumor cells

Question 7

Cholangiocytes

Answer 7

Line bile ducts, control bile flow rate and bile pH

Question 8

Functions of liver

Answer 8

Carb/lipid metabolism
Nucleotide biosynthesis
Removal of nitrogen via urea cycle
Synthesis of blood proteins (albumin, IgGs, fibrinogen, clotting factors V, VII, IX and X)
Bilirubin metabolism

Question 9

Structural adaptations of liver

Answer 9

Lack of basement membrane and absence of tight junctions b/w hepatocytes and endothelial cells
Allow greater access and increased contact b/w liver and blood

Question 10

Bile acids and salts help with

Answer 10

Emulsification of fats
Absorption of fat soluble vitamins
Digestion and absorption of fats
Prevention of cholesterol precipitation
Elimination of cholesterol

Question 11

Bile acids/salts synthesized from and by who

Answer 11

Hepatic cholesterol
Made in hepatocytes, released into bile canaliculi, stored and concentrated in gallbladder
Released into duodenum

Question 12

How do bile acids/salts work to break down fatty acids

Answer 12

Bile acids ionize to conjugate bile salts
Hydrophobic and hydrophilic surfaces of the salts form micelles around the fatty acids and pancreatic lipase sits outside of the micelle but is able to reach through to fatty acid
Lipase frees small bits of the fatty acid within a smaller micelle

Question 13

Rate limiting step in synthesis of bile acids

Answer 13

Cholesterol–> 7a-Hydroxycholesterol

Catalyzed by 7a hydroxylase in ER of hepatocytes

Question 14

Conjugation of bile acids

Answer 14

Bile acids are conjugated by either taurine or glycine - 3/4ths with glycine
Taurine conjugated has pKa of 2, glycine conjugated has pKa of 4- making taurine a better emulsifier

Question 15

Primary bile salts –> primary/secondary bile acids

Answer 15

Used in duodenum to emulsify dietary lipids to aid in their digestion and absorption
Deconjugated by bacteria into primary/secondary bile acids which are absorbed by ileum and then excreted in feces (5%) or recycled to liver via enterohepatic circulation (95%)

Question 16

Cholesterol lowering drugs: bile acid-binding resins

Answer 16

Non-absorbable bile acid binding resins such as cholestyramine cause large increase in excretion of bile acids
Rate of bile acid synthesis is increased by induction of 7a-hydroxylase - which uses cholesterol as substrate
Hepatic uptake of LDL cholesterol is increased, lowering plasma cholesterol levels

Question 17

Gallstones

Answer 17

Crystals made of bile supersaturated with cholesterol
Cholelithiasis- insufficient secretion of bile salts or phospholipids into gallbladder or excess cholesterol secretion into bile

Question 18

Chronic disturbance in bile salt metabolism leads to

Answer 18

Malabsorption syndromes (steatorrhea)
Deficiency in fat soluble vitamins

Question 19

Inactivation and detoxification of Xenobiotics

Answer 19

Phase I - polarity is increased - catalyzed by cytochrome P450 (CYP) enzymes
Phase II- functional groups conjugated to make molecule more amenable for safe excretion

Question 20

Drug metabolism- cytochrome P450 enzymes

Answer 20

Hepatic metabolism increases the hydrophilicity and hence their ability to be excreted
Enzymes catalyzing these reactions are all part of the cytochrome P450 (CYP) superfamily
CYPs are heme containing proteins

Question 21

Cytochrome P450 reductase

Answer 21

Required for Cytochrome P450 enzyme activity - reduces the ferric form of heme to ferrous
P450 is bound to drug, Ferric reduced to ferrous, eventually hydroxylation of the drug occurs so it can be excreted

Question 22

CYPs and drug interactions

Answer 22

Agents that inhibit CYP will cause increase in drug levels in plasma
Agents that stimulate CYP will cause decrease in drug levels in plasma
Many different things can modify CYP actions

Question 23

CYP inhibitors

Answer 23

Grapefruit juice, citrus juices

If patient takes statins with grapefruit juice, there will be in increase in statin levels

Question 24

CYP inducers

Answer 24

St Johns Wort

Will cause decrease in plasma statin levels if taken while on a statin

Question 25

Drug hepatotoxicity

Answer 25

Capacity for normal conjugation of drug is overwhelmed Can caused oxidization of the drug which creates free radicals Anti-oxidant can help

Question 26

Common major change in many diseases of the liver

Answer 26

Normally leaky basement membrane b/w endothelial cells and hepatocytes are replaced by high density membrane rich in fibrillar collagen Spaces b/w endothelial cells and fenestrations in plasma membrane are lost- impaired free exchange b/w hepatocytes and blood Increased stiffness of hepatic vascular channels offers resistance to free flow of blow through liver Elevated intra-sinusoidal fluid pressure and portal hypertension can result

Question 27

Liver function tests

Answer 27

``` Albumin Transaminases ALT/AST Alkaline phosphatase Prothrombin time Bilirubin unconjugated/conjugated BUN (Urea) Glucose TAGs Cholesterol ```