Liver and Gallbladder Flashcards
where is the liver
- Liver is in the right upper quadrant of the abdomen
what is the blood supply to the liver
- ¾ of the blood supply of the liver is from the portal system
- The rest of the blood supply of the liver is arterial, carries oxygen supplied blood from the celiac axis which is a branch of the aorta
- All of the portal blood drains into the liver
where does the portal system come from
- Portal system comes from the gut, this means that if you eat anything it goes through the digestive system and is absorbed through the liver
what do the sinusoids carry
- Sinusoids carry a mixture of oxygen and nutrient rich blood
where do the sinusoids go
the drain into the central vein, this goes into the hepatic veins which drain back into the IVC
what lines the sinusoids
- They pass the hepatocytes which line the sinusoids, the hepatocytes take out what they need and put back in what they want to excrete
what organ also drains into the liver
the spleen
what are kupffer cells
these are macrophage like cells that are part of the overall immune function of the liver
what are cholangiocytes lined cells
- There are cholangiocytes lined cells that line into bile ducts and this makes bile
what vessels include the portal tract
biliary ductile, portal venule and hepatic arterial
almost all carbohydrate ..
reaches the liver as glucose
- All carbohydrates needs to be changed to glucose
what makes up sucrose
fructose + glucose
what makes up lactose
galactose + glucose
what makes up starches
maltose + glucose
what does glycogensis mean
storing glucose as glycogen
what does glycolysis mean
breakdown of glycogen into glucose
what happens if there is too much glucose
- If there is too much glucose the liver can store it as glycogen, when it is needed glycogen can be converted back to glucose and be converted to glycogen
what happens if there is not enough glucose
- If there isn’t enough glucose around, gluconeogenesis (production of new glucose from things such as amino acids and glycerol) takes place
what is the effect of insulin on the liver
- Signals the fed state
- It promotes glycogen synthesis
- Supresses gluconeogenesis
- Accelerates glycolysis – increases fatty acid synthesis
- Reduces blood sugar levels
where does insulin primarily act
- Insulin acts primarily on the liver
what are amino acids
- Amino acids are the building block of proteins
what is amino acid metabolism
it is a bidirectional process
what are the two different types of amino acids
essential and non essential
what are essential amino acids
mino acids need to have in our diet as we cannot synthesis them our selves
how can we make new Amino acids from ones that we already have
transamination
what is transamination
Non-essential fatty acids can be made by the liver form other amino acids = transamination (transfer of amino group to a keto-acid) by transaminase enzymes
what is transamination catalysed by
aminotransferases (alanine and aspartate aminotransferases
what happens if alanine and aspartate aminotransferases are detected in the blood
if these are detected in the blood then there is damage to the hepatocytes
what is deamination
deamination of the amino acid, this is when you need to get rid of the amino acid as it is in excess
- therefore you remove the amine group and turn it into an ammonium ion
what happens if the ammonium ions are not removed
- Produces ammonia and this ammonium this pushes the equilibrium back the opposite way towards more proteins causing the cells to be depleted of ketoglutarate (important in Krebs cycle)
what does excess ammonia lead to
deplete cell of ketoglutarate
what happens if you have a depleted storage of ketoglutarate
- this impairs energy producing activity
- The ammonia in astrocytes leads to increased osmotic pressure and astrocyte swelling – increasing the volume of the cells in the skull this creates pressure in the brain and leads to herniation, and problems of neural exchange
how is the ammonium ion reduced
- Ammonia is produced by deamination and gut bacteria
- Ammonia is reduced to the ammonium ion and the ammonium ion is converted to urea
describe how the urea cycle works
- Ammonium ions and carbon dioxide go into the urea cycle and makes urea
- Urea removed by urine
what does a raised serum level indicate
- Kidneys are not working therefore they are unable to absorbed and excrete the urea and therefore it builds up in the blood
- Or the patient has a high protein in the blood this is caused by an internal bleed, leads to lots of albumin in the blood
what does a low serum level indicate
- has no effect on liver disease
- enzymes won’t work leads to low serum urea urine
what is plasma
is the cell free component of the blood (has no red and white blood cells)
what is serum
is plasma without clotting factors (important as clotting factors can get in the way of some testing)
what does plasma contain
- Albumin – reduced albumin liver failure
- Globulin
- Clotting factors – reduced clotting factors liver failure
- Water/glucose/electrolytes
- 90% of plasma proteins are form the liver
what is the benefits of protein in the blood
- Protein in the blood makes sure that the blood stays in the vascular space
- If liver fails less protein in the blood vessels meaning that the osmotic pressure is low meaning that the blood vessels leak water out into the tissue this is called oedema
lipids are not
water soluble
what do triglycerides breakdown into
fatty acids and glycerol
why are lipids energy rich
- Energy rich molecule triglycerides are, lots of carbon-carbon bonds which release energy when they are broken down
what is it called when fats are synthesised in the liver
de novo lipogenesis
what inhibits the breakdown of lipids
insulin
how are free fatty acids metabolised
- Free fatty acids can be used for beta oxidation in the mitochondria and this feeds into the krebes ccycle
in what form are fatty acids shuttled around the Body
these can be formed from dietary chylomicrons, these can be shuttled around the body
what happens if the liver is resistance to insulin
if the liver is resistance to insulin this means that insulin is ineffective therefore there is high blood glucose level, therefore you activate de novo lipogenesis, this is the starting point of non-alcoholic liver disease
what does liver insulin resistance lead to
- increased glucose
- inappropriate gluconeogensis
- imparted glycogen synthesis
- impaired suppression of lipolysis in adipocytes such as glycerol and FFA
what causes increases glucose in liver insulin resistance
(activates ChREBP)
– De novo lipogenesis (SREBP1)
– Activates PKCe (inhibits IR tyrosine kinase
what causes Inappropriate gluconeogenesis in liver insulin resistance
– Abnormal as high glucose level in the blood, make new glucose from lots of different sources when you don’t need to be this is caused by FOXO-1
what causes increases glucose in liver insulin resistance
– Akt2-mediated
– Glycogen is not made from the glucose
what converts excess glucose to fatty acids
– SREBP-1c
– ChREBP
what is ketogensis
- In the absence of glucose (starvation) there needs to be blood supply and energy supply to the brain, therefore ether Brian uses ketogensis
what switches off ketogenesis
switched off by insulin
describe how ketogensis takes place
- Brains supply called ketones that go into the body, these are the breakdowns of lipids and proteins
- The acytyle CoA produces ketone bodies Acetoacetate, D-β-Hydroxybutyrate
- Turned back into Acetyl CoA in brain and this feeds the krebs ccyle
what happens if inulin is missing
- If insulin is missing that you are unable to turn off glycolysis and therefore you end up doing ketogenesis
- These ketones eventually acidify the blood and cause confusion in the brain
- This is diabetic ketoacidosis
describe the billiard
- Made out of the cystic duct, the gall bladder and hepatic ducts
- Stuff from the liver drains into the biliary from the hepatic duct
- Bile flows up the cystic duct into the gallbladder
- The common bile duct drains into the duodenum
what is bile
- Bile is an emulsifier breaks down large fat molecules into smaller molecules
where is bile secreted
- Secreted by hepatocytes in canaliculi
how much bile does the liver make
- Liver makes Up to 800ml bile daily
what is bile modified by
- Modified by cholangiocytes – addition of HCO3
what hormones control bile production
- Cholecystokinin (CCK)
* Secretin
when is CCK released
– Signal made in response of Fatty acids in lumen of duodenum
– Gall bladder contraction
– Sphincter of Oddi relaxation, this is so you get a squeeze at top and relaxation at bottom so it goes into the duodenum
when is secretin released
– Made when Acid chyme that comes out of the stomach goes in duodenum
– Stimulates biliary ductal cells to make more bile
what is the composition of bile
- Water (>90%)
- Bile Salts
- Bilirubin
- Cholesterol
- Fatty acids
- Lecithin
- Na+ / K+ / Ca2+ / Cl- / HCO3- - some patients have biliary diversions that drain, patients are high risk of being dehydrated as they lose the electrolytes
what are bile salts
- These are breakdown products of cholesterol or they are synthesised from cholesterol
what are the Amin bile salts
- The main ones are Cholate or Chenodeoxycholate
what are bile salts conjugated to and then secreted as
- Conjugated to glycine or taurine
- They are then Secreted as sodium salts
what is the action of bile salts
- They act as Detergents this allows things that are fat soluble to be absorbed
what are the substances that are absorbed when bile acts as a detergent
- Fatty acids
- Monoglycerides
- Cholesterol
- Fat soluble vitamins (A,D,E & K)
what is the Enteroheptiatc circulation of bile
- The important parts of the bile are reabsorbed once there function is done, this happens at the terminal ileum
- This then goes back to the liver and is involved in making more bile
what happens if you interpret the enterohepatic circulation of bile
- If you interrupt this then you loose a lot of bile salts and this causes water to be drawn into the colon and produces watery diarrhoea
describe how the FXR signalling pathway works
Nuclear receptor for bile salts
The bile salts which are agonists are brought in to the terminal ileum cells where they act of the FXR receptor
They make FGF19
This inhibits the synthesis of more bile salts in the liver
This is the feedback mechanism
works directly in the hepatocytes
what reduces the bile effect on the FXR receptor
The of bile effect on the FXR receptor is reduced by Acid synthesis, Reduced lipiogenesis, glyconeognesis and more liver cell regeneration this can be used clinically
what is obeticholic acid
semi-synthetic bile acid
what can semi-synthetic bile acids be used to treat
• Semi-synthetic bile acid that selectively activates FXR – this can cause much more activity of the FXR and drugs that can be used to treat patients with issues with their billary
where can you get cholesterol from
- Exogenous – diet
- Endogenous- liver
what is the use of cholesterol
- Cell membrane
- Steroid hormones
- Skin
- Bile salts 80%
what is the one step in cholesterol synthesis that you need to know
- HMG-CoA is converted to mevalonate
- This is done by HMG-CoA reductase
what inhibits HMG-CoA reductase
– statins inhibit this enzyme
- Statins are used to lower the cholesterol by stopping the production of cholesterol
what Is bilirubin
• Bilirubin is made by the breakdown of RBC in spleen
how is bilirubin excreted
- Haem component is broken down it is converted to bilirubin
- Bilirubin bound to albumin
- Conjugated to glucuronate in the liver and secreted to the bile
What happens if the flow of bile is obstructed
- Less fat absorption
- Less absorption of fat dependent vitamins as well
- Less bile in the intestine and therefore the stool has a high content of fat but a low content of bile therefore you have pale stool
- At the other end there is a build up of bilirubin this causes jaundice
what is jaundice
- Yellowing of skin and sclera due to excess bilirubin
what are the causes of jaundice
- Can be broken down into pre-hepatic, hepatic or post hepatic
- Might be breaking down too much of there blood (pre hepatic)
- The liver is unable to conjugate the bilirubin and excrete it (hepatic)
- Might have a blockage in the gall bladder (post hepatic)
describe how the liver acts as a storage
• Vitamins – A, D, B12 • Iron – Apoferritin to ferritin (reversible) – Haemosiderin (insoluble)
describe how the liver acts as drug metabolism
• Phase I – Modification – e.g. hydroxylation by cytochrome P450 Phase II – Conjugation – e.g. glutathione • Phase III - Further Modification / Excretion
describe the steps of how paracetamol metabolism works
- Acetaminophen (paracetamol) conjugated into sulphates or glucoconirde – renders it non-toxic in the liver
- P450 system metabolises the drug into the toxic intermediate NAPQI, this is quickly converted in to glutathione rendering it non-toxic
- If there is a large amount of paracetamol then NAPQI builds up which is toxic
- Overdoses can lead to acute liver failure
- In order to treat this
- Give cysteine and mercapturic
what happens in liver failure
- Hypoglycemia
- Reduced albumin
- Impaired clotting
- Jaundice
- Hyperammonaemia (encephalopathy)
