Liver Physiology

By Jonathan Tsun & Ilona Blee

List the SEVEN main functions of the liver.

1.Metabolism – carbohydrates, proteins & lipids

2.Excretion – bilirubin

3.Synthesis – albumin/plasma proteins, cholesterol, bile

4.Storage – glycogen

5.Detoxification – drugs

6.Destruction of RBC’s and bacteria

7.Immune function - ?Which cells Kupffer cells!

Think: MESSDDI

The liver is made up of hepatocytes which are arranged into lobules; how are lobules functionally classified?

Zone 1 periportal hepatocytes are the most oxygenated; carry out oxidative metabolism, gluconeogenesis & urea synthesis

Zone 2 = middle

Zone 3 pericentral hepatocytes are the least oxygenated; carry out drug metabolism, glycolysis & lipogenesis

Could think of this like a Bull's-eye where number three is in the middle so it’s the highest number

What is the blood supply to the liver? 70% Hepatic portal vein

30% Hepatic artery

What vasculature does the hepatic artery originate from?

Coeliac trunk – can work backwards logically to remember this the liver is a foregut structure therefore is likely to have a foregut blood supply

What is the venous drainage of the liver?

Hepatic veins

Where do the hepatic veins drain into?

Inferior vena cava

Picture from sketchy medicine

You cannot just say “Portal vein”, as

there are other portal veins in the body!

What are the FOUR major cell types in the liver?

1. Hepatocytes

2. Endothelial cells which line the sinusoid walls

3. Kupffer cells (modified macrophages)

4. Lipocytes (or stellate cells) for fat storage

Where is bile produced and stored? How much is produced per day?

Bile is produced in the liver

Bile is stored and concentrated in the gall bladder

0.7-1.2 litres is produced per day

HORMONES

Where are these hormones secreted?

Small intestine (duodenum)

Secretin Bile production in the liver Bicarbonate secretion from the pancreas

Cholecystokinin Gall bladder contraction to release bileEnzyme secretion from the pancreas

*SAQ exam style question: Which hormones control the pancreas and biliary tree and what are their physiological effects?

LIVER FUNCTION TESTS what FOUR enzymes are included in this?

1. Aspartate transaminase (AST)

2. Alanine transaminase (ALT)

3. *Alkaline phsophatase

4. Gamma-glutamyl transferase (GGT)

Transaminases are released by hepatocytes

Alkaline phosphatase is found on the luminal surface of bile duct cells

TRUE or FALSE: LFT’s measure liver function. FALSE!

So what does LFT really measure? It indicates hepatocyte/biliary

damage

Picture from sketchy medicine

TRUE test of liver function – what parameters are measured and why?

1.Albumin levels Liver’s ability to synthesise proteins (e.g.

albumin)

2.Prothrombin time (clotting screen) Liver’s ability to synthesise clotting

factors

3.Urea levels Liver’s ability to convert ammonia into

urea

4.Bilirubin levels Liver’s ability to conjugate bilirubin

Remember this using “A PUB” Liver function is probably not so good

after being at the pub ..

What are the SIX components of bile?

1. Bile salts

2. Lecithin phospholipid

3. HCO3- (Bicarbonate)

4. Cholesterol

5. Bile pigments

6. Trace metals

What are bile acids derived from? Cholesterol

Describe how bile acids are recycled (location/route)

1. Reabsorbed in the terminal ileum

2. Go via the enterohepatic circulation

3. Back to the liver, to be used again or re-conjugated

Some

Little

Hepatocytes

Can’t

Produce

Trace metals

What are the FOUR functions of bile salts?

1. Emulsification of lipids to be broken down by pancreatic lipases

2. Elimination of cholesterol

3. Prevents cholesterol precipitation in the gall bladder

4. Facilitates absorption of fat-soluble vitamins Vitamins A, D, E & K

Name an example of a bile pigment Bilirubin

How is bilirubin formed? Formed from the breakdown of haem in the

spleen and bone marrow

ON EXAMINATION: What are FIVE signs of chronic liver disease? This is an example of a question you might be

expected to say in an OSCE for an abdominal examination but they can easily ask you about OSCE things in written examinations!

1. Palmar erythema

2. Liver/metabolic flap

3. Leuconychia think leukocytes/white cells = white nails

4. Yellowing of the skin or sclera (jaundice)

5. Dilated umbilical veins caput medusae

6. Abdominal distension ascites

7. Umbilical herniation

Be careful – if you want to mention a sign, make sure you have an understanding (even a brief one) of what is causing these signs – you may be asked.

For example:

• Yellowing of the skin/sclera – hyperbilirubinaemia due to liver’s inability to metabolise bilirubin for excretion

• Dilated umbilical veins – built up back-pressure due to hepatic portal vein hypertension blood travels to the route of least resistance (which is reopening umbilical veins)

• Ascites – combination of increased hydrostatic pressure (due to hepatic portal vein hypertension) and reduced oncotic pressure (due to liver’s failure to produce adequate proteins) fluid escapes into the abdominal cavity

Drug metabolism what are the THREE phases?

Phase I: addition of a functional group to a drug to activate it. This increases the polarity of the drug and makes it able to undergo phase II reactions

Phase II: addition of a large/bulky chemical group to inactivate the drug. This makes the drug more hydrophilic, which will mean it is easier to excrete

Phase III: transport either into circulation for renal elimination or into bile for excretion in feces

Define: Bioavailability The proportion of a drug that enters the

circulation unchanged and is available to go to its site of action.

List FIVE factors affecting drug metabolism.

1.Liver disease

2.Age

3.Drug interactions

4.Genetics

5.Environmental influences

Statins! Can you name an example of a statin?

Simvastatin

Atorvastatin lipitor

What is the mechanism of action of statins?

HMG CoA reductase inhibitors; this enzyme is basically the terminal step in the sequence of cholesterol metabolism so by stopping it you are lowering cholesterol

With cholesterol levels think: keep the lows “low” and the highs “high” keep low density lipoproteins low and high density lipoproteins high

MCQ Which one of these is an example of a phase II metabolism reaction?

A. Oxidation

B. Reduction

C.Conjugation

D.Hydrolysis

Can you name a conjugation reaction?

Glucuronidation

Some drug interactions can inhibit drug metabolism, which one of these listed below is an example of this, a cytochrome P450 inhibitor?

A. St. John’s Wort

B. Carbamazepine

C.Grapefruit juice

D.Rifampicin

E. Ritonavir

If you have a patient who strictly must have grapefruit juice as part of her diet, what changes must you make to the doses of her medications? • You must reduce the doses of medications that are cytochrome

P450-dependent

• Reduced metabolism by cytochrome P450 reduced drug clearance increased drug levels in body!

THANK-YOU!

Any questions?