Structure and Function of Liver Flashcards
Describe the blood supply to the liver
75% is venous blood via the hepatic portal vein –> blood from SI, stomach, pancreas and spleen
25% is arterial blood via the hepatic artery –> oxygenated blood
Where do most substances absorbed by the GI tract pass before going to the rest of the body?
Liver
Describe the output of blood from the liver
Hepatic vein –> into the vena cava
Describe the internal structure of the liver
Lobules separated by connective tissue (hexagonal structure)
What is located at the corners of liver lobules?
Portal triad
What does the portal triad contain?
Bile duct, branch of hepatic artery, hepatic portal vein
Where does blood from the hepatic artery and hepatic portal vein flow together into?
Blood filled cavities called sinusoids –> these run into the hepatic vein
Allow blood to enter liver tissue
What forms part of the lining of sinusoids?
Kupffe cells
How are the plates of hepatocytes arranged?
Each cell has access to blood supply on one face and to bile canaliculi on the other
What runs along the face of the sinusoid facing side (of the plates of hepatocytes)?
A layer of endothelial cells
Describe this layer of endothelial cells of the sinusoid facing side
Forms an incomplete barrier between blood and hepatocytes –> pores and fenestra
What is purpose of these pores and fenestra?
Material can flow through
What runs between the hepatocytes and endothelial cells?
Space of Disse
What does the Space of Disse contain?
Stellate cells and collagen fibres
What are bile cannaliculi?
Tiny ducts into which bile is actively excreted
What are the 5 cell types that make up the liver?
- Hepatocytes
- Endothelial cells
- Kupffer cells
- Pit cels
- Hepatic stellate cells
What is the most common cell type?
60% are hepatocytes (parenchymal cells)
What is function of hepatocytes?
Carry out most metabolic functions
What is function of endothelial cells?
- Lining cells of sinusoids
- Contain pores and fenestra so don’t form barrier for small molecules entering hepatocytes
What cells are associated with the immune system?
Kupffer cells and Pit cells
Where are Kupffer cells located?
Within sinusoidal lining
What is function of Kupffer cells?
Macrophages –> phagocytose bacteria, old erythrocytes, protect liver from gut derived bacteria
As there is very little lymphoid tissue present , Kupffer cells remove antigens without much antibody production, so preventing a more general systemic response to antigens
What is function of Pit cells?
Natural killer cells –> help protect liver from viruses / tumour cells
When stimulated, what do Kupffer cells produce?
Cytokines e.g. IL-6, IL-8 and TNF-a
What are hepatic stellate cells also called?
Ito cells or lipocytes
Where are hepatic stellate cells found?
In space of Disse
What is function of stellate cells?
Lipid-filled cells. Primary site of vitamin A storage. Also control turnover of connective tissue, synthesise collagen & regulate contractility of sinusoids
What reaches the liver via the hepatic portal vein / hepatic artery?
Almost everything absorbed from the GI tract – via the hepatic portal vein, and also has access to metabolites produced in other parts of the body via the hepatic artery.
What are the main functions of the liver?
- Synthesis – proteins, nucleotides, cholesterol
- Recycle compounds from other parts of the body
- Control blood levels of substances e.g. glucose
- Storage e.g. glycogen, vitamins
- Carbohydrate, lipid & protein metabolism
- Waste management
How is the liver involved in waste management?
- Detoxification of xenobiotics
- Removal of internal waste e.g. degradation of bilirubin
How is liver involved in storage?
Glucose (as glycogen), vitamin A, D, K (fat soluble), B12, iron, copper
How is liver involved in maintaining blood glucose?
Gluconeogenesis, glycogen synthesis/breakdown)
How is liver involved in nitrogen metabolism?
Amino acid synthesis, breakdown, urea cycle
How is liver involved in lipid metabolism?
Cholesterol synthesis, lipid transport, bile formation
How is liver involved in synthesis of blood components?
Albumin, clotting factors (red blood cell synthesis in the foetus), lipoproteins
What are the constituents of bile?
Water, bicarbonate, bile salts, free cholesterol, phospholipids
How are bile salts formed?
In the liver (hepatocytes) from cholesterol
What is function of bile salts?
Emulsify fats
What happens to 95% of bile salts?
Recirculated
What is cholesterol breakdown inhibited by?
Bile salts –> if you can increase bile salt loss, more cholesterol can be metabolised
What is cholestyramine (Questran)?
Drug used for high cholesterol
How does cholestyramine work?
- Binds bile acids and salts in the gut to prevent recirculation of bile (increases excretion)
- Increases bile acid synthesis
- Decreases blood cholesterol
What is a natural method of decreasing cholesterol levels?
Increasing dietary fibre (bile salts tend to bind to dietary fibre so will be excreted)
If too much cholesterol enters the bile than can be solubilised by bile salts, what happens?
Precipitation of cholesterol –> gallstones (can get stuck in common bile duct)
What are xenobiotics?
A chemical substance found within an organism that is not naturally produced or expected to be present within the organism
Potentially toxic and of no nutritional value
What are examples of xenobiotics?
- Drugs (pharmacologic or recreational)
- Food additives or toxins present in food
What is bilirubin?
From breakdown of erythrocytes
What normal waste products of metabolism is the liver involved in the removal of?
- Hormones e.g. insulin, growth hormone, oestrogen
- Bilirubin – from breakdown of erythrocytes
- Urea – removal of NH4+ ions - mainly from metabolism of protein, but also that produced by gut bacteria
What are the 2 basic steps in the removal of a xenobiotic compound?
Phase 1 and phase 2 reactions
Xenobiotic compound –> primary metabolite –> secondary metabolite
What are phase 1 reactions?
Oxidation, hydroxylation, hydrolysis, reduction
What are phase 2 reactions?
Conjugation e.g. sulphation
What is purpose of turning compound into metabolite?
Metabolites are usually pharmacologically inactive and more hydrophilic
More easily excreted in urine or bile
What is phase 1 performed by?
Cytochrome P450 enzymes (CYP)
What are CYP enzymes?
Large family of haem proteins –> mono-oxygenases found in smooth endoplasmic reticulum
How is the individual variation in P450 enzymes important?
Important in therapeutics and how effective drug is for individual person
How are P450 enzymes inducible?
Synthesis of them can be increased by certain compounds (drugs, alcohol)
What are detoxification reactions important for?
Protection from ingested toxins
Why can detoxification reactions be a problem?
When drugs are given orally –> first pass metabolism (drug can’t make it past liver)
What is a prodrug?
A prodrug is an inactive (or less active) compound which is metabolised to produce the therapeutically active form in the body
Why are prodrugs used?
- To improve absorption of drug in gut
- To allow alternative route of administration (e.g. skin patch)
What is Tamoxifen?
A prodrug used in treatment of hormone-sensitive breast cancer
How is Tamoxifen activated?
It is activated by cytochrome P450 enzymes to produce endoxifen, 100 x more potent than tamoxifen
How is paracetamol primarily metabolised?
Via phase 2 pathways
What happens during a paracetamol overdose?
Depletion of glutathione allows free NAPQI to react with cell membranes
Hepatic necrosis –> liver failure (see pharmacology)
How is the majority of alcohol metabolised?
Ethanol –> acetaldehyde –> acetate
How is alcohol metabolised when alcohol levels are high?
Some is also metabolised by the cytochrome P450 enzymes
What is effect of chronic alcohol use?
Induces synthesis of cytochrome P450 enzymes –> affects interaction between drugs and alcohol (drug may be broken down too quickly)
How long do erythrocytes last before needing replacement?
About 120 days
How are old RBCs taken up?
Phagocytosed by Kupffer cells in liver, spleen and bone marrow
What happens to haemoglobin?
- Globin protein degraded
- Haem broken down into bilirubin
What does the breakdown of haem require?
NADPH and H+
How is bilirubin transported to the liver?
Attached to albumin (as not very soluble)
What happens once bilirubin reaches liver?
Is conjugated (mainly with glucuronic acid) and secreted into biliary canalicula (an active process)
Where does bilirubin go after the liver?
Into the gut
What happens to bilirubin in the gut?
Further metabolised by bacteria in the gut to urobilinogen
What can urobilinogen then be converted into?
- Urobilin
- Stercobilin
How is urobilin excreted?
In urine
How is stercobilin excreted?
In faeces
What is result of problems with haem degradation (and liver function)?
Jaundice
What is jaundice?
Bilirubin (insoluble) builds up and deposits in tissues (mainly seen in whites of eyes, sometimes skin)
What is the removal of bilirubin pathway?
Haem –> bilirubin –> conjugated bilirubin –> bile secretion
What is prehepatic jaundice?
Increase in rate of breakdown of RBCs (too much haem for liver to cope)
e.g. Haemolytic anaemia (sickle cell)
What is intrahepatic jaundice?
Problems with liver itself conjugating bilirubin
Liver damage - infection, inflammation, cirrhosis
Inherited - Gilbert’s syndrome (individual doesn’t produce enough conjugating enzyme)
What is extrahepatic jaundice?
Problems with bile secretion
Blockage –> gallstones, pancreatic carcinoma
