Liver & friends (summary sheets) Flashcards
What is a xenobiotic?
A foreign chemical substance not normally found or produced in the body which cannot be used for energy requirements
How can xenobiotics be absorbed?
Across lungs, skin or ingested
How are xenobiotics excreted?
In bile, urine, sweat and breath
Define lipophilic
Able to pass through plasma membranes to reach metabolising enzymes
Name 3 features of pharmacologically active compounds?
- Lipophilic
- Non-ionised at pH 7.4
- Bound to plasma proteins to be transported in blood
Define microsome
A small particle consisting of a piece of endoplasmic reticulum to which ribosomes are attached
What is a microsomal enzyme?
An enzyme which is found in a microsome
What is a phase I reaction?
Modification - where there may be oxidation, reduction, hydrolysis etc
What is a phase II reaction?
Conjugation - when charged species are added to the compounds
In what reactions are microsomal enzymes involved in?
Mainly phase I, but may also be phase II
Where are microsomal enzymes located in the cell?
On the smooth endoplasmic reticulum
Where are microsomal enzymes located in general?
Mainly in the liver hepatocytes, but may be found in the kidneys and lungs too
What is a phase I reaction which is done by microsomal enzymes?
Biotransform substances (transformed from one chemical to another)
What is a phase II reaction which is done by microsomal enzymes?
Glucuronidation (the addition of glucuronic acid to a substance)
Name 5 things which may induce or inhibit microsomal enzymes
- Drugs
- Food
- Age
- Bacteria
- Alcohol
Name 3 types of reactions which microsomal enzymes are involved in
- Oxidation
- Reduction
- Hydrolytic
In what reactions are non-microsomal enzymes featured in?
Mainly phase II reactions
Where are non-microsomal enzymes located?
Mainly in the cytoplasm & mitochondria of hepatocytes in the liver, but may be in other tissues
Name 2 features of non-microsomal enzymes
- They are non-specific
- They are non-inducible
What reactions are non-microsomal enzymes involved in?
All conjugation reactions except glucuronidation
How are most drugs excreted?
By the kidneys
Why is the removal of lipophilic drugs less effective?
- They are passively absorbed
- This is due to the fact they can diffuse through cell membranes with ease
What is the aim of drug metabolism?
To make drugs more polar so they can’t get across lipid membranes
Where is the main site of drug metabolism?
The liver via Phase I & II reactions, which is sequentially
What is the aim of a phase I reaction?
To make the drug more hydrophilic so it can be excreted by kidneys (adding OH group). This means it can be used for conjugation reactions
Define non-synthetic catabolic
Chemical decomposition of complex substances by the body to form simpler ones, accompanied by the release of energy
Why do hydrophilic molecules not tend to reach the metabolising enzymes?
Since hydrophilic molecules are excreted easily
Name 4 types of oxidation
- Hydroxylation (add OH)
- Dealkylation (remove CH side chains)
- Deamination (remove NH)
- Hydrogen removal
What is reduction?
Adding hydrogen (to saturate unsaturated bonds)
What is hydrolysis?
To split a molecule into two or more molecules
What is functionalisation?
- Introducing a reactive group to a drug
- Product tends to be more reactive
- Small increase in hydrophilicity
What are some functions of cytochrome P450 enzymes?
- Type of microsomal enzyme
- Involved in phase I reactions
How do cytochrome P450 enzymes work?
Uses the heme group to oxidise substances
What is significant bout products of P450 enzymes?
They are more water soluble
What is the overall reaction of cytochrome P450 reductase?
NADPH + H+ + O2 + RH –> NADP + H2O + R-OH
Name 4 things what phase I reactions can do
- Inactivate drugs
- Further activate drugs
- Activate drug from pro-drug (inactive form of drug)
- Make a drug into a reactive intermediate (could be carcinogenic or toxic)
Define synthetic anabolic
The synthesis of complex molecules such as proteins & fats, from simpler ones
What is a conjugation reaction?
- Attachment of substituent groups (from molecules of the body)
- Usually inactive products
- Catalysed by transferases
What is the purpose of conjugation reactions
Significantly increases hydrophilicity for renal excretion
Where do conjugation reactions tend to occur?
Mainly in the liver but can occur in other tissues like the lungs and kidneys
What is a glucuronidation reaction?
Adding a glucuronic acid group to the drug to make it more hydrophilic
Why might a drug be excreted straight away?
Due to it being a polar drug and it usually being excreted unchanged
Define analgesic
Used for pain relief
Name 3 things in which iron is essential for
- Haemoglobin
- Myoglobin
- Bone marrow
Name 3 sources of iron in the diet
- Beans
- Meat
- Egg yolk
Where does the homeostatic control of iron occur?
- In the intestinal epithelium, in the duodenum
- Actively absorbs iron from digested food
How can the fraction of iron absorbed in the duodenum be altered?
By a negative feedback mechanism depending on the state of the bodies iron balance
What percentage of ingested iron is absorbed into the blood each day?
10%
How are iron ions transported into the blood?
- Actively transported
- Transported into the duodenal intestinal epithelial cells
What is the intracellular store of iron?
Ferritin, which is a protein-iron complex
What happens to iron once it has been absorbed into the intestinal epithelial cells of the duodenum?
- Released back into the intestinal lumen
- At the tips of the villi the ferritin disintegrates into iron
- Iron is excreted in the faeces
What happens when the bodies store of iron is enough?
- Increased conc. of free iron in plasma and intestinal epithelial cells lead to increased transcription of gene for ferritin
- Gives an increased synthesis of ferritin
- Increased binding of Fe
- Reduction of normal iron in blood
What happens when the bodies store of iron are too little?
- Production of intestinal ferritin decreases
- Decrease in the amount of iron bound to ferritin
- Increase in number of unbound iron in blood
What happens to absorbed iron that doesn’t bind to ferritin?
Released into blood, where it is able to circulate, bound to the plasma protein transferrin
What is the function of transferrin?
Transports iron into the blood plasma to the bone marrow to be incorporated into new erythrocytes
What happens to excess iron once it is in the blood
- Accumulates in tissues
- Most is stored in the Kupffer cells of the liver, in the form of liver ferritin
How is the bodies store of iron divided?
- 50% in haemoglobin
- 25% in heme containing proteins
- 25% in liver ferritin
Name 3 types of proteins the liver makes
- Plasma proteins
- Clotting factors
- Complement factors
Name 2 plasma proteins
Albumin and globulins
What is the most abundant plasma protein?
Albumin
What is the function of albumin?
Binding and transport of large, hydrophobic compounds
What is colloid osmotic pressure?
The effective osmotic pressure across blood vessel walls which are permeable to electrolytes but NOT large molecules
What is colloid osmotic pressure due to?
Plasma proteins
How does albumin maintain osmotic pressure?
- It’s presence in plasma means that water concentration of the blood plasma is slightly lower than that of the interstitial fluid
- Means there is a net flow of water OUT OF the interstitial fluid into the blood plasma
What are Starling forces?
Opposing forces which act to move fluid across the capillary wall
Name the 4 Starling forces
- Capillary hydrostatic pressure
- Interstitial hydrostatic pressure
- Osmotic force due to plasma protein concentration
- Osmotic force due to interstitial fluid protein concentration
Name the 2 Starling forces which favour fluid movement OUT of the capillary
- Capillary hydrostatic pressure
- Osmotic force due to the interstitial fluid protein
Name the 2 Starling forces which favour fluid movement INTO the capillary
- Interstitial hydrostatic pressure
- Osmotic force due to plasma protein concentration
How does bulk filtration of fluid out of the capillary at the arterial end occur?
- Hydrostatic pressure from capillary is greater than that from interstitial fluid
- Interstitial fluid protein concentration is smaller than osmotic pressure due to plasma proteins
- Outward pressure exceeds the net inward pressure
How does bulk filtration of fluid in the capillary at the venous end occur?
- Capillary hydrostatic pressure has reduced due to resistance encountered as the blood flows through the capillary
- Net inward pressure exceeds the net outward pressure
How does oedema occur with liver failure?
- Reduction in albumin in blood
- A decrease in capillary oncotic pressure
- Less of a difference in water conc. between plasma and interstitial fluid
- Accumulation of water in interstitial fluid –> oedema
Name 4 conditions which can cause albumin decrease
- Nephrotic syndrome
- Haemorrhage
- Gut loss
- Burns
What is the main function of globulins?
Antibody functions
Which globulins are made in the liver?
Some alpha/beta globulins
Where are all clotting factors except IV and VIII made?
The liver
Where are clotting factors IV & VIII made?
Liver sinusoidal endothelial cells. IV is calcium and VIII is von Willebrand factor
Name one function of absorption linked to liver function
The liver produces bile salts which are essential for vitamin K absorption (fat soluble)
What is one of vitamin K’s functions, linked to the blood?
It is essential to the synthesis of numerous clotting factors (2, 7, 9, 10)
What is a complement factor?
A plasma protein which sticks to pathogens and is recognised by neutrophils
What is the function of a complement factor?
- Help mark pathogens to kill
- Plays an important role in the immune response to pathogens
What is protein turnover?
The continuous degradation and re-synthesis of all cellular proteins
Give examples of when the rate of protein turn over increases
- When tissue is undergoing structural re-arrangement e.g. gluconeogenesis, severe burns
What are the 2 primary methods of protein breakdown?
Lysosomal and ubiquitin-proteasome pathway
Where does lysosomal protein breakdown occur?
In the reticulo-endothelial system of the liver
What does the reticule-endothelial system of the liver compromise of?
Sinusoidal endothelial cells, Kupffer cells and pit cells
What is the function of sinusoidal endothelial cells in lysosomal protein break down?
Remove soluble proteins and fragments from the blood through fenestrations known as sieve plates on their luminal surface
What are sinusoidal endothelial cells important for removing in lysosomal protein break down?
Fibrin, fibrin degradation products, collagen and IgG complexes
What happens to proteins once they are in the liver from the sinusoidal endothelial cells in lysosomal protein breakdown?
- The proteins are fused into lysosomes containing lysozyme (hydrolytic enzymes)
- Broke down into amino acids
What are the functions of Kupffer cells in lysosomal protein breakdown?
- Resident macrophages
- Phagocytose matter by packaging them into phagosomes in the cell, which contain hydrolytic enzymes
- Protein broke down into amino acids
Where does the ubiquitin-proteasome pathway occur?
Cytoplasm of cells
What is significant about degradation in the ubiquitin-proteasome pathway?
It is a selective process
Which proteins are rapidly degraded in the ubiquitin-proteasome pathway?
- Those that are defective because of incorrect AA sequences
- Those which are damaged to normal function
How come different proteins are degraded at different rates in the ubiquitin-proteasome pathway?
Depends on the structure of the protein - if it is denatured it is more readily digested
How can proteins be targeted for degradation in the ubiquitin-proteasome pathway?
- Attachment of a small peptide (ubiquitin)
- This directs the protein to a protein complex (proteasome)
- This unfolds the protein and breaks it down into small peptides
Where does amino acid degradation and catabolism occur?
Hepatocytes of the liver
What happens to amino acids which aren’t require as building blocks for proteins?
Must undergo degradation (degraded into specific proteins)
What is catabolism?
The breakdown of complex substances to simpler ones accompanied by the release of energy
What does amino acid catabolism require?
The alpha amino group (nitrogen containing) to be removed
What is produced from amino acid catabolism?
- Nitrogen (incorporated into other compounds or excreted)
- Carbon skeleton (can then be metabolised and used in Kreb’s cycle)
What are the 2 main catabolism processes?
Oxidative deamination and transamination
What is the main goal of oxidative deamination?
Results in liberation of an amino group as free ammonia
What is the only amino acid which undergoes rapid oxidative deamination?
Glutamate
What is the mechanism of oxidative deamination?
- AA gives rise to a molecule of ammonia and is replaced by an oxygen atom from water to form a alpha-keto acid
- The alpha-keto acid can be used in Kreb’s cycle for gluconeogenesis
What are the co-enzymes used in oxidative deamination?
- NAD+ (forward)
- NADPH (backwards)
What enzymes catalyses the reaction in oxidative deamination?
Glutamate dehydrogenase
What is the basic principle of transamination?
Transfer of an alpha-amino group from amino acid to a keto-acid to form a alpha-keto-acid
What enzyme is used in transamination?
Aminotransferase
Where is aminotransferase found?
In the cytosol of the mitochondria, mainly in the kidneys and liver
What is the measurement of nitrogen balance used for?
A measure of the equilibrium of protein turnover
What is anabolic in terms of nitrogen balance?
- Positive balance (net gain of amino acids)
- Nitrogen intake > nitrogen loss
What is catabolic in terms of nitrogen balance?
- Negative balance (net loss of amino acids)
- Nitrogen intake < nitrogen loss
What is a healthy nitrogen balance?
When it is equilibrium
How can a negative nitrogen balance occur?
If any of the essential amino acids are missing from the diet
What is the most common cause of positive nitrogen balance?
Pregnancy
Give two causes of negative nitrogen balance
- Malnutrition (most common)
- Multiple trauma/extensive trauma
What is the purpose of the glucose alanine cycle?
To produce a source of carbons for gluconeogenesis
Where are the enzymes of the urea cycle found?
In the liver, in the mitochondria of cytosol of hepatocytes
What is the mechanism of the urea cycle?
- Arginine (from the diet or protein breakdown) is cleaved by arginase generating urea & ornithine
- Ammonia and carbon dioxide is added to ornithine to create citrulline
- Another molecule of ammonia is then added to citrulline to regenerate arginine
- Cycle starts again
What does one turn of the urea cycle consume?
- 3 ATP equivalents
- 4 high energy nucleotides (PO4-)
What compound is generated by the urea cycle?
Only urea, all other components are recycled
What is an effect of a deficiency of an enzyme which is used in the urea cycle?
Higher levels of ammonia in the blood
Why is high levels of ammonia associated with neurotoxicity?
- Crosses blood-brain barrier easily
- Once inside, it is converted to glutamate by glutamate dehydrogenase
- Depletion in alpha-ketoglutarate
- Fall of alpha-ketoglutarate causes fall of oxaloacetate so halts Kreb’s
- Irreplaceable cell damage & neural cell death
What happens during the absorptive state of glucose regulation?
- Ingested nutrients are absorbed from the GI tract into the blood
- A proportion of nutrients are catabolised and used
- The remainder are converted and stored for future use
What happens to the macronutrients during the absorptive state of glucose regulation?
- Glucose is used to generate ATP
- Amino acids are converted to proteins
- Glycerol and fatty acids are converted to lipids
- Glucose is converted to glycogen
What happens during the post-absorptive state of glucose regulation?
- Nutrients are no longer absorbed from the GI tract
- Nutrient stores must supply the energy requirements of the body
What is the glucose regulation in the post-absorptive state?
- Glucose is no longer being absorbed from the GI tract
- Essential to maintain the plasma glucose concentration due to the fact that the CNS is dependent
- There is 3 sources at this point.
What are the three main sources of glucose in the post-absorptive state?
- Glycogenlysis
- Lipolysis
- Protein
Where does the hydrolysis of glycogen to monomers of glucose-6-phospate occur?
In liver and skeletal muscle
What is the process of glycogenolysis in the liver?
- Glycogen is hydrolysed to monomers of glucose-6-phosphate
- Glucose-6-phosphate is enzymatically converted to glucose which enters the blood
How quick does hepatic glycogenolysis occur?
- Within seconds of the right stimulus e.g. sympathetic nerves system stimulation
- It is the first line of defence in maintaining plasma glucose conc.
How long does the hepatic supply of glucose last?
Only several hours before they are depleted
What is the process of glycogenolysis in skeletal muscle?
- Glycogen is hydrolysed into glucose-6-phosphate
- Glucose-6-phosphate undergoes glycolysis to yield ATP, pyruvate and lactate
- ATP and pyruvate are used directly by muscle
- Some of the lactate enters the blood, circulates to liver and is converted to glucose, which can reenter to blood
What is the mechanism of lipolysis in the post-absorptive state?
- Triglycerides are catabolised in adipose via hydrolysis to produce glycerol and fatty acids
- Glycerol and fatty acids enter the blood by diffusion
- Glycerol enter the liver which enzymatically converts it into glucose
What is the mechanism of using protein for energy in the post-absorptive state?
- Large quantities of protein are catabolised without significant cellular malfunction
- Proteins supply AA’s, which enter the blood and are taken up by the liver
- They are converted via the alpha-keto acid pathway to glucose, where they are revealed into blood
What is gluconeogenesis?
The synthesis of glucose from precursors such as amino acids and glycerol
How many molecules of ATP are consumed per molecule of glucose formed?
6
How is most of the bodies fat stored?
- In adipocytes which form tissues called adipose tissues
- Some is stored in hepatocytes
What is the structure of a triglyceride?
3 fatty acids bound to a glycerol molecule
What are lipids?
Esters of fatty acids and certain alcohol compounds
Name 3 functions of lipids
- Energy reserves
- Structural part of cell membrane
- Hormone metabolism
What is the function of lipoproteins?
Used to transport cholesterol in the blood
Where are HDL’s formed?
In the liver
What are the two types of lipoproteins?
HDL and LDL
What is the function of HDL?
- Remove excess cholesterol from blood and tissue
- Deliver cholesterol to the liver which secretes it into bile or converts it into bile salts
- ‘Good’ cholesterol
Where is LDL formed?
In the plasma
What is the function of LDL?
Main cholesterol carriers and they deliver cholesterol to cells throughout the body
What is the mechanism of LDL transport in the body?
LDLs bind to plasma membrane receptors specific for a protein component of the LDLs and are then taken up by the cells via endocytosis
Why are LDLs considered ‘bad’ cholesterol?
Due to high plasma concentrations being associated with increased deposition of cholesterol in arterial walls and a higher incidence of heart attacks
What is the function of cholesterol in the body?
- Synthesis of cell membranes
- Steroid hormone production in the gonads and adrenal glands + aldosterone + cortisol
Where is VLDL synthesised?
Hepatocytes
What is the function of VLDL?
Carries triglycerides from glucose in liver to adipocytes
Under resting conditions, what percent of the energy used in the body is derived from the catabolism of fatty acids?
50%
What is the structure of an adipocyte in regards to fat?
Almost the entire cytoplasm of each adipocyte is filled with a single large fat droplet
What is the larger structure of adipocytes?
Clusters of adipocytes form adipose tissue, most which is in deposits underlying the skin or surrounding internal organs
What is the function of adipocytes?
- Synthesise and store triglycerides
- To release fatty acids & glycerol into blood to provide energy required for ATP formation
What is the process for ATP formation from fatty acids?
- Coenzyme A linked to carbonyl end of a fatty acid
- ATP –> AMP & 2Pi
- The coenzyme A derivative of fatty acid then proceeds through beta-oxidation reactions
- Acetyl coenzyme A split off from FA & 2 pairs of hydrogen atoms are transferred to coenzymes (1 to FAD & 1 to NAD+)
- Hydrogen ions from coenzymes enter oxidative phosphorylation to form ATP
- Cycle repeats
- Each cycle shortens the chain by 2 carbons
What is the hepatic metabolism of lipids?
Lipoprotein lipase hydrolyses triglycerides into lipoproteins (chylomicrons and VLDLs) into 2 free fatty acids and 1 glycerol molecule
Where is hepatic lipase expressed?
Liver and adrenal glands
What is the function of hepatic lipase?
Converts IDL (intermediate density lipoprotein) into LDL thereby packaging it with more triglycerides to be released in the body
Where is bile secreted from?
The hepatocytes in the liver, pretty much continuous
What is bile used for?
- To emulsify fats
- As an excretory pathway for most steroid hormones, many drugs and some toxins
Where is bile stored and concentrated?
In the gallbladder, as some NaCl and water are reabsorbed back into the blood
Where does the gall bladder lie anatomically?
At the junction of the right-mid-clavicular line & costal margin
What is the livers connection with the GI tract?
By the portal vein, which connects blood from the superior mesenteric vein (which in turn is effectively the venous drainage of both the small and large intestines)
What is the functional unit of the liver?
Hepatic lobules (formed by hepatic plates stacked on top of each other)
What is the structure of hepatic lobules?
- Hexagonal in cross-section with a portal triad at each corner
- Portal triad: hepatic portal vein, hepatic artery and bile duct
- In the centre of each lobule is the central vein, which soon becomes the hepatic vein
What is the structure of a hepatic sinusoid?
Blood vessel with fenestrated, discontinuous epithelium
How are hepatocytes separated from the sinusoids?
The space of Disse
What happens to substances which are absorbed from the small intestine?
Get into the hepatic sinusoid then go to the vena cava via the central vein or are took up by hepatocytes in which they can be modified
What is significant about the blood in the hepatic artery?
It is oxygen rich
What is significant about the blood in the portal vein?
It is nutrient rich
What are the blood sources for the hepatic sinusoid?
- Oxygen-rich from hepatic artery
- Nutrient-rich from the portal vein
What is the larger structure of the hepatic lobules?
- Wedge-like arrangements
- Around 1-2 cells deep
- Surrounded by sinusoids (containing mixed portal/hepatic artery blood)
What is unique about the liver’s major blood supply?
It comes from a vein - the portal vein (80%). The rest comes from the hepatic artery
How does the different types of blood get mixed in the hepatic sinusoids?
- Branches of artery and vein leave the portal triad
- They join and blood is mixed as it enter through the sinusoids
- It flows through centre and exits via the central vein
- Bile flows in the opposite direction to blood
What cells are the sinusoids of the liver lined with?
A continuous layer of specialised endothelial cells interspersed with Kupffer cells
What cells are on the undersurface of the sinusoids of the liver?
Stellate cells
What is the function of stellate cells?
Producing the extracellular matrix in the Space of Disse in the liver
What is present between adjacent hepatocytes?
Bile canaliculi
Why are bile canaliculi’s not true vessels?
As they don’t have specialised walls
What is the structure of bile canaliculi’s?
- Groove running alongside the side of the hepatocytes
- Bound together by tight junctions, gap junctions and desmosomes which cross both cell membranes
- Actin filaments are found in the areas surrounding
What is the function of bile canaliculi’s?
Serve to pump the formed bile towards the bile ducts
What is the bile pathways to the GI tract?
- Bile ducts in hepatic lobules lead to either left or right hepatic ducts
- Left/right hepatic ducts join to form the common hepatic duct
- Cystic duct joins the common hepatic duct to collect in gallbladder
- Cystic duct + common hepatic duct = common bile duct
- The pancreatic duct joins common bile duct at the point known as the Ampulla of Vater
- These 2 ducts enter the duodenum at the major duodenal papilla (2nd part of duodenum)
- Regulation of bile is done by the sphincter of Oddi (around both ducts)
What are the 6 major components of bile?
- Bile salts
- Lectithin (phospholipid)
- HCO3- and other salts
- Cholesterol
- Bile pigments
- Trace metals
What are bile salts manufactured by?
Hepatocytes
What are present in the micelles in bile?
Bile salts, cholesterol and lecithin
What is the purpose for micelles in bile?
- Maintained even when concentrated
- Due to bile salts being powerful detergents (needed for emulsification function)
- Bile salts are also capable of damaging cells membrane, so kept in micelles to reduce damage until needed
What is the function of HCO3- in bile?
Helps neutralise the acids in the duodenum
What is the most important digestive component?
Bile salts
What are the two different cell types which secrete the components of bile?
Hepatocytes and epithelial cells lining the bile ducts
What do hepatocytes secrete in relation to bile?
Bile salts, cholesterol, lectithin and bile pigments
What do epithelial cells lining the bile ducts secrete in relation to bile?
Most of the HCO3- rich solution
What stimulates the secretion of HCO3- rich solution in the bile ducts?
By secretin in response to the presence of acid in the stomach
What stimulates secretion by the pancreas?
Secretin in response to the presence of acid in the stomach
Where does the gallbladder receive its bile from?
The common hepatic duct, which is formed by the left and right hepatic ducts
How does hepatic bile enter the gallbladder?
By the cystic duct
What happens to the bile in the gallbladder?
- It is stored and concentrated
- Hepatic bile is relatively dilute
What causes the contraction of the gallbladder?
The action of cholecystokinin
What causes the release of cholecystokinin?
Due to fatty acid and amino acids in the duodenum
What is significant about the vasculature of the gallbladder?
- Cystic artery supplies oxygenated blood to gallbladder
- Has no venous drainage
- Gallbladder is stuck to the liver bed, so blood drains directly into the liver
Summarise the enterohepatic circulation
- Bile salts enter the intestinal tract via bile. They are absorbed by Na-coupled transporters in jejunum and terminal ileum (most here)
- Absorbed bile salts are returned via portal vein to the liver
- Uptake of bile salts into hepatocytes is driven by secondary active transport coupled to Na+
- A small amount of bile salts escape this cycle
What is bile synthesised from?
Cholesterol
Where can the liver also secrete cholesterol from?
From when it is extracted from the blood, into the bile
What is the mechanism for cholesterol homeostasis in the blood?
Bile secretion & excretion of cholesterol in the faeces
Is cholesterol soluble in water?
No, as it is a lipid
What is the differences between how cholesterol is stored in bile and the blood?
- In bile, it is stored in micelles
- In blood, it is incorporated into lipoproteins
What surrounds the common bile duct at the Ampulla of Vater?
The sphincter of Oddi
What happens when the sphincter of Oddi is closed?
The dilute bile secreted by the liver is shunted into the gallbladder, where it is concentrated due to NaCl and water being absorbed into the blood
What gets removed from bile in the gallbladder to concentrate it?
NaCl & water
What is the pressure like the in the bile duct system?
It is low pressure
What must the gallbladder do when it fills with bile?
Adaptive relaxation - when the size increases but the pressure doesn’t
What is the function of choleosystokinin?
- Causes the gallbladder to contract
- Causes sphincter of Oddi to relax
- Bile flows down cystic duct into common bile duct into duodenum, where it mixes with food & lipid digestion occurs
What are bile pigments?
Substances formed from the harm portion of haemoglobin when old/damaged erythrocytes are broken down in the spleen and liver
What is the predominant bile pigment and how is it extracted from blood?
- Bilirubin
- Extracted by hepatocytes
- Actively secreted into bile
What colour is bilirubin?
Yellow - it contributes to the colour of bile
What happens to erythrocytes when they are old/damaged?
They are broke down by macrophages
Where are erythrocytes broke down by macrophages?
- In spleen/bone marrow
- Can also happen in the Kupffer cells of the liver
Briefly outline the process of bilirubin metabolism
- Erythrocytes are ingested into macrophages
- Haemoglobin is broke down into haem & globin
- Globin is broke down into amino acids which can be used for new erythrocytes in bone marrow
- Haem is broke down into biliverdin, Fe2+ and CO by hemoxygenase
- The Fe2+ is bound to transferrin, where it is shuttled to bone marrow to make new RBC’s
- Biliverdin is reduced to unconjugated bilirubin by biliverdin reductase
- Unconjugated bilirubin must be excreted. It is lipid soluble and insoluble in blood
- Unconjugated bilirubin is bound to albumin and transported to liver
- Glucuronic acid is added to unconjugated bilirubin by UDP glucuronyl transferase to make it conjugated, so it is soluble to be excreted
- The conjugated bilirubin can then be stored in gallbladder, so it can enter the duodenum
- Conjugated bilirubin travels to ileum/beginning of large intestine where it is reduced by hydrolysis by intestinal bacteria, forming urobilinogen
- 10% of urobilinogen is transported back to the liver via albumin where it is oxidised to urobilin. Excreted in urine to give yellow colour
- 90% is oxidised by intestinal bacteria to make stercobilin
- Stercobilin is excreted into faeces (forms stercobilin)
What is jaundice?
A yellow discolouration of the skin caused by high serum bilirubin level
What are the 3 main types of jaundice?
Pre-hepatic, hepatic and post-hepatic/obstructive
What is the physiology behind pre-hepatic jaundice?
- Increased breakdown of erythrocytes resulting in increased levels of unconjugated bilirubin
- Causes an increased serum unconjugated bilirubin without excess bilirubin in urine
- Will have raised serum unconjugated bilirubin
What are some signs/symptoms of pre-hepatic jaundice?
- Yellow skin
- Enlarged spleen (due to excess breakdown)
- Stools brown and urine normal
Give 4 causes of pre-hepatic jaundice
- Malaria
- Sickle cell anaemia
- Thalassameia
- Physiological jaundice of the newborn
What is the physiology behind hepatic jaundice?
- Result of hepatocellular swelling
- Impaired cellular uptake, defect conjugation or abnormal secretion of bilirubin by the hepatocytes
- Liver is damaged so is unable to metabolise unconjugated bilirubin resulting in a buildup ins serum uncojugtaed bilirubin
- Increased conjugated and unconjugated bilirubin
- Decreased urobilinogen
What are some signs/symptoms of hepatic jaundice?
- Urine will be dark
- Stools can be pale or normal
- Enlargement of the spleen
- Yellow skin
Give 5 causes of hepatic jaundice
- Viral hepatitis
- Drugs
- Alcohol hepatitis
- Cirrhosis
- Jaundice of the newborn
What is the physiology behind post-hepatic jaundice?
- Occurs when the biliary system is damaged, inflamed or obstructed
- Elevated serum conjugated bilirubin
- Decreased urobilinogen
What are some signs/symptoms of post-hepatic/obstructive jaundice?
- Dark urine
- Pale stools
- No enlargement of the spleen
- Yellow skin
Give 5 causes of post-hepatic/obstructive jaundice
- Gallstones
- Pancreatic cancer
- Gallbladder cancer
- Bile duct cancer
- Pancreatitis
How can cancer/inflammation of the pancreas cause jaundice?
Due to the head of the pancreas being situated in the duodenal loop, near the common bile duct, so any inflammation will cause obstruction of the duct, therefore jaundice
Where does acute pancreatitis pain radiate from?
The back
What is Gilbert’s syndrome and what would it prevent with?
- A shortage of UDP glycerol transferase
- Normal conjugated bilirubin but a raised unconjuagted bilirubin
What is inside the micelles of the bile and why?
Cholesterol and phospholipids, as they are water-insoluble
How do gallstones form?
When the concentration of cholesterol in bile becomes high in relation to phospholipids and bile salts, the cholesterol will crystallise out of solution to form gallstones
What happens if a gallstone is small?
May be able to pass freely through the common bile duct into the intestine
What happens to the movement of a larger gallstone?
It may become lodged in the opening of the gallbladder, causing painful contractile spasms of the smooth muscle
What is the more serious problem of a larger gallstone?
May become lodged in the common bile duct, thereby preventing the bile from entering the intestines
What can happen if there is a significant decrease in bile (physiologically)?
- Can decrease fat digestion and absorption
- This can result in an impaired absorption of fat-soluble vitamins, resulting in clotting problems and calcium malabsorption
What can happen to stools if there is a significant decrease in bile?
- The fat isn’t absorbed, so enters large intestine and appears in the faeces
- Bacteria in the large intestine will convert some of the fat into FA derivatives, which alter salt and water movement so a net flow of water into large intestine - diarrhoea & fluid & nutrient loss
What can happen if a gall stone becomes lodged at a point the prevents bile & pancreatic secretions?
Results in failure to both neutralise acid and adequately digest most organic nutrients - may result in severe nutritional deficiencies
What is the positioning of the pancreas?
Completely retroperitoneal except from the tail
Where is the tail of the pancreas located?
Attached to the spleen and is intraperitoneal
What is the relevance of the head of the pancreas being closely related to the common bile duct?
A carcinoma or inflammation of the head of the pancreas can block the bile duct resulting in post-hepatic/obstructive jaundice
Where does the uncinate process of the pancreas come from and what is the relevance?
- Comes from the ventral bud (the rest of the pancreas comes from the dorsal bud)
- The superior mesenteric vein and artery are enthralled between the head and the process
How can disruption of the superior gasproduodenal artery eventually lead to haemorrhage and haematemesis?
A duodenal ulcer can eventually erode into the artery, causing the damage
Describe how the pancreas develops as two separate outgrowths embryologically
- The ventral and dorsal pancreas
- During development of the embryo the ventral bud rotates around and fuses with the dorsal pancreas - in effect becoming the head of the pancreas
Where does the pancreas receive its main blood supply from?
The coeliac trunk, which arises directly from the aorta and divides at the coeliac axis to form the gastric arteries, the hepatic artery and the splenic artery
Why does the superior mesenteric artery run ‘through’ the head of the pancreas?
Due it being enveloped during the rotation of the dorsal and ventral pancreas when they fuse. It provides some supply to the head of the pancreas
What is the venous drainage of the pancreas?
Mainly by the splenic vein, which then joins the superior mesenteric vein to form the portal vein
Name two things what the exocrine pancreas secretes
- Bicarbonate
- Digestive enzymes
Where do exocrine secretions of the pancreas occur?
From the acinar tissue
How are exocrine secretions secreted out of the pancreas?
- Secreted into bile ducts which converge into the pancreatic duct
- Joins the common bile duct just before it enters the duodenum at the ampulla of Vater
What is the sphincter of Oddi?
A separates bundle of circular muscle which regulates flow into the duodenum and may serve also to prevent mixing of bile & pancreatic juice within the pancreatic duct
What will reflux of bile down the pancreatic duct cause?
Acute inflammation due it the biles detergent properties
Where does the accessory pancreatic duct usually emerge?
Above the ampulla of Vater
Where is bicarbonate secreted from in the pancreas?
Epithelial cells lining the ducts (duct cells)
What are the functions of pancreas bicarbonate?
- In order to protect the duodenal mucosa from gastric acid
- Also buffers the material entering the duodenum to a pH suitable for enzyme action
What mechanism does acid in the duodenum cause?
- The release of the hormone secretin
- This stimulates the secretion of bicarbonate from the pancreas and liver
- Also potentiates the action of CCK which stimulates enzyme secretion
Where is secretin produced?
The small intestine
Name 3 things what secretin does
- Stimulates the secretion of bicarbonate from pancreas and liver
- Inhibits acid secretion
- Inhibits gastric motility
How do pancreatic duct cells secrete bicarbonate into the duct lumen?
By an apical membrane chloride/bicarbonate exchanger
What is the mechanism of secretion of bicarbonate into the duct lumen of the pancreas?
- Carbon dioxide and water form carbonic acid by the enzyme carbonic anhyrdrase
- Carbonic acid dissociates
- The H ion is pumped into the capillary by the Na/H exchanger
- There is a Na/K ATPase pump to return Na to capillary
- Also a potassium channel for the diffusion of K
- The bicarbonate is pumped into the duct lumen by the Cl/HCO3- exchanger
- Cl ions are recycled back into the lumen by the CFRT channel
How can digestive enzymes be secreted?
Either in active form or as precursors e.g. pepsinogen
Where are digestive enzymes secreted from?
By gland cells at the pancreatic end of the duct system
What do the enzymes of the pancreas digest?
- Triglycerides to fatty acids & monoglycerides
- Polysaccharides to sugar
- Proteins to amino acids
- Nucleic acids to nucleotides
Give 2 examples of active enzymes from the pancreas
- Alpha-amylase (starch to maltose)
- Lipase (triglycerides to monoglyceride & fatty acids)
Why are some enzymes from the pancreas released as precursors?
To protect pancreatic cells from autodigestion
What is enterokinase?
A proteolytic enzyme that splits off a peptide from pancreatic trypsinogen froming the active enzyme trypsin
Where is enterokinase found?
Embedded in the lumina plasma membranes of intestinal epithelial cells
What is the function of trypsin and chymotrypsin?
Enzymes used to break peptide bonds in proteins to form peptide fragments
Where is somatostatin produced?
By the D cells in the pancreatic islets.
What is the function of somatostatin?
It is a powerful inhibitor of pancreatic exocrine secretion
What are the 4 cell types of the Islets of Langerhans and what are their functions?
- Alpha cells produce glucagon
- Beta cells produce insulin & amylin
- Delta/D cells produce somatostatin
- PP cells produce pancreatic polypeptide
What is the physiology of type I diabetes?
Pancreas failure to produce enough insulin
What is the physiology of type II diabetes?
Cells fail to respond to insulin properly
What controls most of the pancreatic exocrine secretions?
By stimuli arising from the intestinal phase of digestion
Name two other phases which contribute to pancreatic exocrine secretions
Cephalic and gastric
What happens in the cephalic phase of digestion related to pancreatic secretion?
- Sensory experience of seeing & eating food
- Parasympathetic vagus nerve stimulation of acinar cells to produce digestive enzymes
What happens in the gastric phase of digestion related to pancreatic secretion?
Initiated by presence of food in the stomach and parasympathetic vagus nerve stimulation of acinar cells to produce digestive enzymes
What has happened by the end of the cephalic and gastric phases in relation to pancreatic secretion?
- Pancreatic ducts are filled with inactive digestive zymogens, ready for release into the intestinal lumen with bicarbonate via sphincter of Oddi
- Once FA & AA are present into the duodenum, CCK is release and the gallbladder contracts inducing enzyme secretion
What are the two sources of blood for the liver and what are the proportions?
- 25% from hepatic artery (oxygenated)
- 75% from hepatic portal vein (deoxygenated and nutrient rich)
How is blood drained into the sinusoids in the liver?
- The terminal branches of the portal vein and hepatic artery empty together in sinusoids surrounding hepatic cells
- Blood leaves the liver via the hepatic vein which drains into the inferior vena cava.
What is present in the blood which has just joined the inferior vena cava from the liver?
- Deoxygenated
- Detoxified
- Contains the normal homeostatic nutrient levels
Embryologically, what is the primitive gut made from and what structures does it provide?
- Endoderm (epithelial lining, hepatocytes of liver & endocrine and exocrine cells of pancreas)
- Visceral mesoderm (muscle & connective tissue)
What are the components of the foregut?
- Oral pharyngeal membrane (liver bud)
- Coeliac artery
- Oesophagus
- Stomach
- Liver
- Biliary apparatus
- 1/2 of duodenum
What are the components of the midgut?
- Liver bud (2/3rds transverse colon)
- Superior mesenteric artery
- Distal 1/2 of duodenum
- Jejunum
- Ileum
- Appendix
- Ascending colon
- Right 2/3rds of transverse colon
What are the components of the hindgut?
- Inferior mesenteric artery
- Left 1/3rd of transverse membrane
- Sigmoid colon
- Rectum
- Anal canal
What is the hepatic diverticulum?
A cellular expansion of the foregut which gives rise to the parenchyma (function part) of the liver
Where does the hepatic diverticulum appear?
In the middle of the 3rd week as an outgrowth of the endodermal epithelium at the distal end of the foregut (duodenum)
What does the liver bud contain (embryology)?
Rapidly proliferating cells that penetrate the septum transverse (thick mass formed in the embryo that gives rise to parts of the thoracic diaphragm and ventral mesentery)
When does the bile duct form in embryology?
When the connection between the liver diverticulum and the foregut narrows
How is the gallbladder and cystic duct formed embryologically?
From a small ventral outgrowth which develops from the bile duct
How do the hepatic sinusoids form embryologically?
By further growth of the liver bud which allows epithelial liver cords to intermingle with umbilical and vitellien veins
What do the liver cords of embryology develop into?
Hepatocytes (liver parenchyma) and form the lining of the biliary ducts
What happens to the mesoderm of the ventral mesentery in the 6th week?
Gives rise to haematopoietic cells, Kupffer cells and connective tissue cells
Where does haemotopoiesis happen in the embryo?
The liver
At the 10th week, what percentage of the body weight is liver and why?
- About 10%
- Due to the presence of large number of sinusoids and involvement of the liver in haemopoietic function
At birth, what percentage of the body weight is liver and why?
- About 5%
- Due to the existence of small number of haematopoietic islands in the liver and reduced haematopoietic function
When does bile production start?
At the 12th week, by the hepatic cells
When does the haematopoietic function of the liver subside?
During the last 2 months of intrauterine life
Name two things which happen to the liver after birth
- The left umbilical vein obliterates to form the ligamentum teres
- The ductus venous undergoes fibrosis leaving a remnant called the ligamentum venosus
What is a mesentery?
A fold of tissue that attaches the organs to the body wall
What is intraperitoneal mesentery?
Double layer of the peritoneum that completely surrounds the organ
What is retroperitoneal mesentery?
The organ is only covered by the peritoneum on its anterior side
Where does ventral mesentery occur?
Only in the foregut
What is the ventral mesentery derived from?
The septum transversum (also gives rise to the thoracic diaphragm)
What mesenteries does the foregut have?
Dorsal and ventral
What mesenteries does the midgut and hindgut have?
Dorsal
What divides the ventral mesentery?
The liver
How does the falciform ligament arise?
From the liver, attaches to anterior abdominal well (free edge contains the umbilical vein which becomes the ligament teres/round ligament after birth)
How does the lesser omentum? arise?
From the liver, gives it to the ventral borders of the stomach and duodenum (free edge contains the hepatic artery, portal vein and bile duct)
What is significant about the bare areas of the liver?
They aren’t covered by mesentery
How come the abdominal organs are placed where they are?
Due to rotation of the stomach
Briefly describe the formation of the lesser omentum
- Stomach rotates 90 digress along a longitudinal axis (left now becomes anterior
- The posterior wall grows quicker (now on right side) this gives the greater curvature
- Stomach rotates around the anterior posterior axis, the pyloric region of the stomach moves right and up and the cardiac region of the stomach moves left and down
Where is the pancreas located?
Retroperitoneally across the posterior abdominal wall, it sits behind the stomach across the back of the abdomen
What does the exocrine part of the pancreas do?
Secretes digestive enzymes and bicarbonate into the duodenum
What does the endocrine part of the pancreas do?
- Secrete hormones into the bloodstream
- The cells are alpha, beta, delta and PP cells
How does the pancreas develop embryologically?
From the endodermal lining of the duodenum as dorsal and ventral buds
Where is the dorsal bud found?
The dorsal mesentery
Where is the ventral bud found?
The ventral mesentery - close to the bile duct
What happens when the duodenum rotates and becomes C-shaped?
The ventral bud and the entrance to the common bile duct in the duodenum are shifted dorsally
Where does the ventral bud come to lie?
Immediately below and behind the dorsal bud, the parenchyma and duct systems of both buds fuse together
What does the ventral pancreatic bud form?
The uncinate process and inferior part of the head of the pancreas
What part of the pancreas does the dorsal bud form?
All except from the uncinate process and inferior part of the head of the pancreas
How does the pancreatic duct develop?
- Formed by the union of the ventral pancreatic duct with the distal part of the duct of dorsal bud
- The main pancreatic duct & common bile duct enter the ampulla of Vater which enters the wall of the duodenum at the site of the major duodenal papilla
How do the Islets of Langerhans develop?
From the parenchyma of the pancreas at the third month of fatal life
When does insulin secretion begin?
At the fifth month
How does pancreatic connective tissue develop?
From the visceral surround mesoderm
