Liver and Friends Flashcards
What are xenobiotics?
- foreign chemical substances not normally found or produced in the body
- cannot be used for energy requirements
- can be absorbed across lungs, skin or ingested
- excited in bile, grin, sweat and breath
What are pharmacologically active compounds?
- lipophilic: can pass through PM to reach metabolising membranes
- non-ionised at pH 7.4
- bound to plasma proteins to be transported in the blood
What are microsomal enzymes?
enzymes that can be found in microsomes
What are microsomal enzymes?
- mainly phase 1 reactions (can be phase 2)
- located on SER
- mainly found in liver hepatocytes
Give some examples of microsomal enzymes…
Cytochrome P450 (CYP's) Flavin monooxygenase (FMO's) and UDP glucoronosyltransferase (UGT)
Name two major detoxification pathways in the liver
Phase 1 and phase 2 reactions
What are non-microsomal enzymes?
- located in the cytoplasm and mitochondria of hepatocytes in the liver (but also other tissues)
- non-specific (can be used in phase 1 and 2)
- involved in ALL conjugation reactions except GLUCORONIDATION
What is the aim of drug metabolism?
to make drugs more polar so they cannot get across the membrane
what drugs are not excreted by the kidney?
lipophilic drugs as they are passively absorbed because they can diffuse through membranes easily
What is the aim of the Phase 1 reaction?
To make the drug more hydrophilic so it can be excreted by the kidneys.
Introduces reactive group to the group (-OH group) which is an attack point for conjugation
What are the 3 stages of phase 1?
Oxidation, Reduction and Hyrdrolysis
What are the stages of Phase 1 oxidation?
- Hyrdroxylation (add -OH)
- Dealkylation (remove -CH side chain)
- Deamination (remove -NH)
- Hyrdogen removal
What are the stages of Phase 1 reduction?
Add a hydrogen to saturate unsaturated bonds
What are the stages of Phase 1 hydrolysis?
add water to break the bond between the amide and ester
What is functionalisation?
Introduction of reactive group to drug by adding or exposing -OH, -SH, -NH2, -COOH
What is the main catalyst for phase 1 reaction?
Cytochrome p450 enzymes
What are cytochrome P450 enzymes?
microsomal enzyme which uses its heme group to oxidise substances
What is important about the products of P450 enzymes?
They are more water soluble
What happens to phase 1 enzymes with age?
Their activity decreases and blood flow through the liver is decreased which further aggravates the problem
Name an enzyme that inhibits phase 1 but promotes phase 2…
Curcumin
What is the phase 1 overall reaction equation?
NAPDH + H+ + O2 + RH > NADP +H20 + R-OH
Name 4 things that phase 1 reactions can do to a drug
- inactivate drugs
- further activate drug
- activate drug from pro-drug
- make a drug into a reactive intermediate (could be carcinogenic or toxic)
Describe what happens in Phase 1 reaction
Enzyme cytochrome P450 required to transfer electrons from NADPH to CYP450.
This contains flavoprotein (consisting of FAD and FMN)
- FAD accepts electrons from NADPH
- FMN donates electrons to CYP’s
Name 6 detoxification Phase 2 pathways
- Glucoronidation
- Sulfation
- Glutathione conjugation
- AA conjugation
- Acetylation
- Methylation
What is Gilberts Syndrome?
inherited impairment of glucoronidation pathway. Characterised by jaundice and elevated levels of bilirubin
What is the conjugation reaction?
Liver cells add another substance to a toxic chemical/ drug to make it less harmful, making it water soluble so it can be excreted
What does glucuronidation require?
Magnesium and B-vitamins
What enzyme is required for glucuronidation?
glucuronysyltransferase
Which coenzyme is required in glucuronidation?
UDPGA (uridine diphospho-glucuronic acid)
What substances are produced by glucuronidation?
glucuronides
Glucuronidation forms what type of bonds?
covalent bonds
Phase 2 reactions require what type of enzymes?
non-microsomal enzymes found mostly in the cytoplasm or mitochondria of hepatocytes
Draw the glucuronidation pathway…
UDPGA + drug > uridine diphosphate + drug (+glucuronide)
What happens if Phase 1 and 2 pathways become overloaded?
build up of toxins in the body, many of these toxins are fat soluble and incorporated into fatty parts of body, most common sites are brain and endocrine organs»_space; brain dysfunction and hormonal imbalances
What s the action of aspirin?
irreversibly inhibits cyclooxyrgenase (COX), suppressing the production of prostaglandins and thromboxanes
What is the hydrolysis reaction of aspirin?
Aspirin + H20»_space; Salcylic acid + ethnic acid
How is aspirin metabolised?
is a pro-drug and activated upon metabolism and follows Phase 1 and 2.
Phase 2 it is conjugated with glucuronic acid
How is paracetamol metabolised?
predominantly via Phase 2: conjugated with glucuronic acid and sulfuric acid
What is the alternative name for paracetamol?
acetaminophen
Will paracetamol undergo Phase 1 reaction?
Not usually. If stores of glucuronic acid and sulphate are running low it undergoes Phase 1 metabolism via oxidation to produce toxic NAPQI- removed by conjugation with glutathione
What happens in an overdose of paracetamol?
Stores of glutathione can run low resulting in toxicity- reactive metabolite begins to react with -SH groups present on hepatic and renal proteins
What is an overdose of paracetamol treated with?
N-Acetyl Cysteine
What is the equation for alcohol metabolism?
Ethanol- (ADH) > acetaldehyde - (ALDH) > acetate > CO2 + H20
Which two enzymes help break apart the alcohol molecule to allow excretion?
ADH (alcohol dehydrogenase) and ALDH (aldehyde dehydrogenase)
Give some sources of iron?
meat, liver, beans, nuts, cereal
Where in the GI tract is iron absorbed?
Duodenum
How is the amount of iron absorbed increased or decreased
in a negative feedback manner depending not eh state of the bodies iron balance
How much of the iron ingested is absorbed into the blood each day?
10%
How are iron ions transported into the duodenal intestinal epithelial cells?
active transport
Once in the epithelial cells what are iron ions incorporated into?
ferritin which acts as an intracellular store for iron
When is most of the iron bound to ferritin released BACK into the intestinal lumen?
when the cells at the tips of the villi disintegrate, and iron is excreted in the faeces
What happens when the body has enough iron?
increased conc of free iron in plasma and interstitial epithelial cells»_space; increased transcription of the gene encoding for ferritin»_space; increased synthesis of ferritin protein»_space; increased binding of Fe in intestinal epithelial cells»_space; reduction in the amount of iron released into the blood
What happens when body stores of iron are low? e.g. after blood loss.
the production of intestinal ferritin decreases»_space; decrease in amount of iron bound to ferritin»_space; increase in the unbound iron released into the blood
What happens to iron that is not bound to ferritin
It is released into the blood where is is able to circulate around the body bound to the plasma protein TRANSFERRIN
Where does transferrin transport the iron in the blood?
to the bone marrow to be incorporated into new erythrocytes
Once iron has entered the blood the body has little way of excreting it. Where does it accumulate and where is it stored?
Accumulates in tissues, MOST of the iron is stored in the LIVER in liver ferritin within Kupffer cells
How is iron used/stores in the body? (percentages)
50% of total iron is in haemoglobin
25% is in heme containing proteins (mainly cytochromes)
25% is in liver ferritin
Name a protein not made in the liver?
Von Willebrand Factor
What is oncotic pressure?
a form of osmotic pressure exerted by proteins, notably albumin, in a blood vessel’s plasma (blood/liquid) that usually tends to pull water into the circulatory system. It is the opposing force to hydrostatic pressure.
Define hydrostatic pressure
the pressure of any fluid enclosed in a space
What is capillary hydrostatic pressure (CHP)?
the pressure exerted by blood against the wall of a capillary
What is the effect of liver failure on albumin and net flow of water in the capillaries?
liver failure = reduction in album > less album in blood (hypoalbuminaemia) > decrease in capillary oncotic pressure > accumulation of water in interstitial fluid > oedema
What also conditions can lead to a decrease in albumin?
- Nephrotic syndrome
- Haemorrhage
- Gut loss
- Burns
How does nephrotic syndrome lead to decreased albumin?
there is an increased glomerular permeability which allows proteins to filter through he basement membrane (loss of several grams of protein a day)
How can gut loss lead to decreased albumin?
a rare syndrome in which the wall of the gut is unusually permeable to large molecules resulting in albumin loss
Define osmotic pressure
the P. that must be applied in a solution to stop the inflow of water through a partially permeable membrane
What are the functions of globulin?
- antibody functions
- blood transport of:
- lipids by lipoproteins
- iron by transferrin
- copper by caeruloplasmin
What is the function of clotting factors?
convert fibrinogen to fibrin in the clotting cascade
Which clotting factors are not produced by the liver?
VWF and calcium
Which vitamin is essential for the synthesis of clotting factors 1972?
Vitamin K
Which clotting factors are vitamin K dependent?
1972
What is the role of complement factors?
important role in the immune response: its is a plasma protein that sticks to pathogens, that is recognised by neutrophils and marks pathogens to kill.
Summary = ozonisation and killing of bacteria
What are the two primary methods of protein breakdown in the liver?
Lysosomal and Ubiquitin-Proteasome Pathway
What is protein turnover?
the continuous degradation and resynthesis of proteins
When would you see an increase in protein turnover?
when tissue is damaged due to trauma, uterine tissue damage during pregnancy in skeletal muscle starvation
Where does the Ubiquitin-Proteasome Pathway take place?
in the cytoplasm of cells
Which proteins are degraded quickest?
a denatured protein
Describe the Ubiquitin-Proteasome Pathway of protein degradation…
a small peptide called ubiquitin attaches to the protein and directs the protein to a protein complex called a proteasome- “the cellular executioner” which unfolds the protein and breaks it down into smaller peptides
Which proteins are degraded?
degradation = selective process therefore defective proteins due to incorrect AA sequencing or because of damage to normal function (denatured)
Where is lysosomal degradation carried out?
in the reticula-endothelial system of the liver
Describe lysosomal degradation…
sinusoidal endothelial cells remove soluble proteins and fragments from the blood. Once in the liver these proteins are then fused into lysosomes containing lysozyme which are hydrolytic enzymes that break down the protein into AA’s.
What is the role of Kupffer cells in lysosomal degradation?
Kupffer cells - resident macrophages which phagocytose particulate matter»_space; package them into phagosomes in the cell which contain hydrolytic enzymes which break down the protein into AA’’s
Where does amino acid degradation and catabolism take place?
In hepatocytes of the liver
Which amino acids must undergo degradation?
any not required as building blocks for protein synthesis
Define catabolism…
The breakdown of complex substances to simpler ones, accompany by the release of energy
What are the two main catabolism processes?
Oxidative deamination and transamination
What does amino acid catabolism require?
The alpha amino group (nitrogen containing) to be removed
What two products does amino acid catabolism produce?
nitrogen (which is then incorporated into other compounds or excreted)
carbon skeleton- can be metabolised and used in the krebs cycle
Which is the only amino acid to undergo rapid oxidative deamination?
glutamate
Which amino acid is the most abundant in the body?
glutamate
What can happen in oxidative deamination when there is excess ammonia (NH3+)?
It can easily cross the BBB and react with alpha-ketoglutarate»_space; decrease in ATP = dangerous in the brain
Which enzyme catalyses the reaction in oxidative transamination?
glutamate dehydrogenase
What is oxidative deamination?
The removal of NH4+ and addition of an oxygen molecule from water to convert glutamate into alpha-ketoglutarate
What is transamination?
The transfer of an alpha-amino group from amino acid to a keto-acid to form an alpha-kets-acid
Which enzyme is involved in transamination
amino transferase enzyme
What does the transamination of alanine produce?
formation of pyruvate (for use in the krebs cycle) and glutamate (AA which can then be oxidatively deaminated)
Where are aminotransferases found?
in the cytosol of the mitochondria throughout the body and particularly in the liver and kidneys
Define nitrogen balance
a measure of the equilibrium of protein turnover
What is anabolic nitrogen balance?
positive balance i.e. net GAIN in amino acids
What is catabolic nitrogen balance?
negative balance i.e. a net LOSS in amino acids
When does a negative nitrogen balance occur?
When any of the essential AA’s are missing from our diet
What are essential amino acids?
ones the body cannot synthesise
What is the most common use of positive nitrogen balance (anabolic)?
pregnancy
What is the most common cause of negative nitrogen balance (catabolic)?
malnutrition or multiple trauma or excessive trauma
What is the recommended daily intake of amino acids to remain in nitrogen balance?
0.8g/kg of body weight
What percentage of energy stored in the body do fats account for?
78%
What percentage of energy stored in the body do proteins account for?
21%
What percentage of energy stored in the body do carbs account for?
1%
What percentage of dietary lipids are triglycerides?
95%
What are lipids?
Esters of fatty acids that contain certain alcohol compounds
What are the 3 functions of lipids?
Energy reserves
Structural part of cell membrane
Hormone metabolism
What are lipoproteins used for?
transport cholesterol in the blood
Name the 5 types of lipoproteins…
- chylomicrons
- VLDL’s
- LDL’s
- Intermediate density lipoproteins
- HDL’s
What is the function of HDL’s?
- remove excess cholesterol from blood and tissue
- deliver this cholesterol to the liver which secretes it into bile
- or converts it to bile salts
Where are HDLs formed?
in the liver
Why are HDL’s referred to as “good” cholesterol?
removes cholesterol from plasma
Where are LDL’s formed?
in the plasma
What is the function of LDL’s
- main cholesterol carrier
- deliver cholesterol to cells throughout the body
How do LDL’s work?
They bind to plasma membrane receptors and then are taken up by the cells via endocytosis
Why is LDL cholesterol said to be ‘bad’?
high plasma concentrations can be associated with increased deposition of cholesterol in arterial walls and a higher incidence of heart attacks
Why are LDL’s useful?
- essential in supplying cells with the cholesterol they require to synthesis cells membranes and for steroid hormone production, aldosterone and cortisol
Where are VLDL’s synthesised?
hepatocytes
What do VLDL’s do?
carry triglycerides from glucose in the liver to adipocytes
What is the function of adipocytes during periods of food uptake?
synthesis and store triglycerides
What is the function of adipocytes post-absorption?
release fatty acids and glycerol into the blood for uptake and use by other cells in order to provide the energy required for ATP formation
Name the functional unit of the liver
The hepatic lobule
What cells are responsible for producing the extra-cellular matrix in the space of disse?
stellate cells on the undersurface of sinusoids
Where is bile secreted?
In the liver by hepatocytes
Where are actin filaments found in the liver and what is their purpose?
found in the areas around the canaliculi and serve to pump the formed bile towards the bile ducts
What forms the Ampulla of Vater?
The common bile duct and pancreatic duct
Where does the Ampulla of Vater open into the duodenum?
The major duodenal papilla
What spinster regulates the release of bile into the duodenum?
The sphincter of Oddi
What 6 things does bile contain?
- bile salts
- bile pigment
- lecithin
- HCO3- and other salts
- cholesterol
- trace metals
What controls the secretion of the HCO3- rich solution by the bile ducts?
Secretin in response to the presence of acid in the duodenum
How are bile salts stored?
in mixed micelles (bile salts are powerful detergents capable of damaging cell membranes so separated in micelles to reduce damage until they are required)
Which two cell types secrete bile salts?
- hepatocytes- bile salts, cholesterol, lecithin and bile pigments)
- epithelial cells lining the bile ducts (HCO3- rich solution)
What does the gall bladder receive its bile from?
The common hepatic duct (formed by left and right hepatic duct)
What is different about the vasculature of the gall bladder?
It has no venous drainage (blood drains from the gallbladder directly into the liver)
What is the enter-hepatic circulation?
a continuous process of bile salts secreted into bile, entering duodenum, reabsorption in the jejunum and terminal ileum, returned via portal vein (attached to albumin), back to the liver
Cycle = REPEATED
When would absorption of bile salts in the GI tract be highest?
After a fatty meal
Bile is synthesised from what?
cholesterol
How is cholesterol homeostasis maintained in the blood?
bile secretion followed by excretion of cholesterol in the faeces
How is cholesterol soluble in bile?
it is incorporated into micelles (whereas in the blood cholesterol is incorporated into lipoproteins).
What type of pressure system is the bile duct system?
a low pressure system- so when the gallbladder fills with bile is must exhibit adaptive relaxation (size increases but pressure doesn’t)
What is adaptive relaxation?
Where the size of the gallbladder increased but the pressure doesn’t
What are the 3 types of Jaundice?
Pre-hepatic, hepatic and post-hepatic
Why can cancer or inflammation of the pancreas cause jaundice?
The head of the pancreas s situated in the duodenal loop, near to the common bile duct, thus cancer/inflammation can eventually cause obstruction to the duct»_space; jaundice
With acute pancreatitis where will pain radiate from?
The back
In Gilbert syndrome what till happen to the conjugated and unconjugated bilirubin levels?
conjugated bilirubin = normal
unconjugated bilirubin = raised
When does pre-hepatic jaundice occur?
increased breakdown of erythocytes
What causes jaundice of the newborn?
excess breakdown of foetal haemoglobin since its no longer required»_space; increase in unconjugated bilirubin and liver cannot conjugate it fast enough since its not developed properly yet»_space; jaundice
What diseases lead to pre-hepatic jaundice?
malaria, sickle cell anaemia, thalassaemia
What is jaundice?
A yellow discolouration of the skin caused by a high serum bilirubin level (detectable when bilirubin >50micromol/L)
When does hepatic jaundice occur?
result of hepatocellular swelling
When does post-hepatic jaundice occur?
when the biliary system is damaged, inflamed or obstructed
How are gallstones formed?
increased concentration of cholesterol in relation to phospholipids and bile salts»_space; cholesterol will crystallise out of the solution forming gall stones
What happens if the gallstone is small?
it may pass freely through the common bile duct not the intestine with no complications
What happens if the gallstone is large?
may become lodged in the opening of the gallbladder leading to painful contractile spasms of the SM
A decrease in fat digestion and absorption can result in impaired absorption of what?
Vitamins ADEK»_space; clotting problems (Vit K) and calcium malabsorption (Vit D)
What happens when fat is not absorbed in the GI tract?
It will enter the large intestine and appear in the faeces
What is fat in the faeces called?
steatorrhea
If a gall stone becomes lodged at a point that prevents both bile and pancreatic secretions from entering the intestine what will this result in?
failure to neutralise acid and inadequately digest most organic nutrients not just fat»_space; sever nutritional deficiencies
Is pancreas retro or intra peritoneal?
retroperitoneal apart from tail
tail = attached to spleen and intraperitoneal
What part of the liver comes from the ventral bud?
the ucinate process (the rest of the pancreas comes from the dorsal bud)
What two structures are entrapped between the head of the pancreas and the ucinate process?
the superior mesenteric vein and artery
What is the venous drainage of the pancreas?
superior mesenteric vein to form the portal vein
Where does the pancreas receive its blood supply from?
The coeliac trunk (T12)and head supplied partly by superior mesenteric artery
How does the pancreas develop embryologically?
develops as two separate outgrowths- the dorsal and ventral 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)
What does the exocrine pancreas secrete?
HCO3- and digestive enzymes
What will reflux of bile does the pancreatic duct result in?
acute inflammation because of its detergent properties
What cells secrete HCO3-?
duct cells = epithelial cells lining the ducts
What stimulates the secretion of HCO3- from the pancreas and liver?
secretin in response to presence of acid in the duodenum
What is normal bilirubin level?
3-20umol/L
How much blood can the liver hold at any given moment?
1 pint (13% of the bodies blood
