Case 5 Flashcards
what is innate immunity?
- This is the pre-existing immunity (naturally present).
- It does not amplify with repeated attacks by the same pathogen.
- It has no memory.
- It is non-specific.
what are the cells of the innate immune system?
• Mast Cells • Phagocytes: 1. Macrophage 2. Neutrophil 3. Dendritic Cells • Basophils • Eosinophils • Natural Killer cells
what are the four elements of the innate immune system?
- Physical barriers
- Antimicrobial factors
- Phagocytes and natural killer cells
- Inflammation and fever
Physical Barriers:
- Skin: barrier, sweat, sebum.
- Respiratory tract: mucus, cilia.
- GI tract: stomach acid
- Eyes: tears
what are antimicrobial factors?
- Complement
- Cytokines (e.g. interferons – released by activated macrophages and lymphocytes and virally affected cells. Interferon act internally in these cells and they also bind to receptor on normal cells, causing them to produce antiviral proteins. These proteins don’t interfere with the entry of the virus but they interfere with viral replication inside the cell.
- Iron-binding proteins (e.g. lactoferrin – bind to iron, and in doing so remove essential substrate required for bacterial growth).
- Anti-microbial peptides (AMPs)(e.g. defensins – found in phagocytes)
what is adaptive immunity? what are its 3 cardinal characteristics? what are the cellular vectors of adaptive immune response?
• Innate immunity provides vital early response but it is often not enough. This is why the adaptive immune system is required. The adaptive immune system is a dedicated system of tissues, cells and molecules that act in concert to provide specific immune responses.
• The adaptive immune system has 3 cardinal characteristics of adaptive immune responses which the innate immune system doesn’t:
1. Memory
2. Specificity
3. Discrimination between “self” (host cells) and “non-self” (foreign cells)
• Lymphocytes are the cellular vectors of adaptive immune response.
what are the three types of lymphocytes? where matured?
- T Lymphocytes
- B lymphocytes:
• Humoral immunity involves resistance against extracellular pathogens and the production of specific antibodies to combat these pathogens. - Natural killer cytotoxic cells
Derivation of Lymphocytes:
• Both are made initially in the bone marrow.
• B-lymphocytes are educated and matured in the bone marrow.
• T-lymphocytes are educated and matured in the thymus gland.
what are the stages of adaptive immunity?
- Inflammation
- Phagocytosis
• Neutrophils: leading to B-lymphocyte activation.
• Macrophages: leading to T-helper cell (CD4) activation.
• Dendritic Cells: leading to T-lymphocyte (CD4) activation. - T-helper cell activation and clonal expansion
- B-lymphocyte activation, clonal expansion and clonal differentiation into plasma cells (antibody production).
what are the two major classes of MHC proteins?
Two major classes of MHC proteins are known: Class I and Class II.
1. Class I:
• Present in the membranes of all nucleated cells.
• Via the endogenous pathway, these proteins pick up intracellular peptides and present them on its surface.
• If the cell is healthy and the peptides are normal, the T cells will ignore the cell.
• If the cytoplasm contains abnormal (non-self) peptides or viral proteins, these will be presented instead by the MHC-I proteins.
• These activate CD8 cells.
- Class II:
• Present only in the membranes of macrophages and dendritic cells (antigen presenting cells (A.P.C)).
• Via the exogenous pathway, these proteins pick up extracellular protein (e.g. antigens from engulfed bacteria) and present them on its surface.
• This is known as antigen processing followed by antigen presentation.
• The A.P.C will now travel to the lymph nodes, where they will activate CD4 cells.
what are some of the functions of the liver?
1) Metabolism of carbohydrates, proteins, fats, hormones, foreign chemicals (xenobiotics), drugs
2) Filtration (kupffer cells) of blood
3) Formation of bile and coagulation factors
4) Synthesis of plasma proteins, glucose, ketone bodies, cholesterol, fatty acids, amino acids
5) Storage of vitamins, iron, glycogen and blood
- Storage of carbohydrates, lipids, vitamins
- Phagocytosis of particulates (Kupffer cells) (for bacteria and viruses that have escaped through the mucosal layer of the intestine – the normal protection system)
- Degradation of endogenous compounds and xenobiotics (NH3 – liver disease -> can lead to increase in ammonia = hyperammonemia-induced encephalopathy), drugs and toxins)
- Manufacture of plasma proteins – people with liver disease lack albumin and the blood clotting factors
- Inactivation (& activation) of hormones (e.g. activation of vitamin D)
- Excretion of lipophilic waste products
- Secretion of emulsifiers
what is the basic functional unit of the liver? what size?
• The basic functional unit of the liver is the liver lobule, which is a cylindrical structure several millimeters in length and 0.8 to 2 millimeters in diameter.
The human liver contains 50,000 to 100,000 individual lobules.
liver lobule
- describe it
- what drains into what
- how many cells thick are the hepatic plates
- The liver lobule is constructed around a central vein that empties into the hepatic veins and then into the vena cava.
- The liver lobule itself is composed principally of many liver cellular plates that radiate from the central vein like spokes in a wheel.
- Each hepatic plate is usually two cells thick, and between the adjacent cells lie small bile canaliculi that empty into bile ducts in the fibrous septa separating the adjacent liver lobules.
- In the septa are small portal venules that receive their blood mainly from the venous outflow of the gastrointestinal tract by way of the hepatic portal vein.
- From these venules blood flows into flat, branching hepatic sinusoids that lie between the hepatic plates and then into the central vein.
- Thus, the hepatic cells are exposed continuously to portal venous blood.
- Hepatic arterioles are also present in the interlobular septa. These arterioles supply arterial blood to the septal tissues between the adjacent lobules, and many of the small arterioles also empty directly into the hepatic sinusoids, most frequently emptying into those located about one third the distance from the interlobular septa.
in addition to hepatocytes, what are the venous sinusoids lined by?
1) Typical endothelial cells
2) Large Kupffer cells, which are resident macrophages that line the sinusoids and are capable of phagocytizing bacteria and other foreign matter in the hepatic sinus blood.
what are the pores in the endothelial lining of the sinusoids like?
endothelial lining of the sinusoids has extremely large pores.
what is beneath the endothelial lining of the sinusoids? what happens here?
• Beneath this lining, lying between the endothelial cells and the hepatic cells, are narrow tissue spaces called the spaces of Disse, also known as the perisinusoidal spaces.
The millions of spaces of Disse connect with lymphatic vessels in the interlobular septa.
Therefore, excess fluid in these spaces is removed through the lymphatics.
Because of the large pores in the endothelium, substances in the plasma move freely into the spaces of Disse.
Even large portions of the plasma proteins diffuse freely into these spaces.
what are the different zones of the liver? where? what happens at each? where does fibrosis generally originate?
- As the blood near the beginning of the sinusoids contains most oxygen, as the blood moves through to the central vein, the amount of oxygen available to those hepatocytes decreases
- Zones I – III, going from nearest the beginning of the sinusoid to the central vein
- Zone II is like a mix of the two functions/regions below
Zone I (periportal) (nearer portal triad)
- amino acid catabolism
- gluconeogenesis
- cholesterol synthesis..etc.
Zone III (pericentral) (nearer central vein)
- lipid synthesis
- ketogenesis
- glutamine synthesis
- drug metabolism …etc
- Fibrosis generally originates in this zone, which impairs the movement of blood through the liver
Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between.
- Zone 2 is an intermediate zone between zones 1 and 3.
- Zone 3 is the main zone for detoxification of drugs etc.
- Bile production takes place in all zones.
what is blood flow and vascular resistance like in the liver?
high blood flow and low vascular resistance
how much blood flows from portal vein into the liver sinusoids each minute and how much from hepatic artery? total?
- About 1050ml of blood flows from the portal vein into the liver sinusoids each minute
- an additional 300ml flows into the sinusoids from the hepatic artery
- the total averaging about 1350 ml/min.
what is the pressure in the portal vein and hepatic vein? what does this show?
The pressure in the portal vein leading into the liver averages about 9 mm Hg.
The pressure in the hepatic vein leading from the liver into the vena cava normally averages almost exactly 0 mm Hg.
This small pressure difference, only 9 mm Hg, shows that the resistance to blood flow through the hepatic sinusoids is normally very low, especially when one considers that about 1350 milliliters of blood flows by this route each minute.
what does cirrhosis of the liver increase?
resistance of blood flow
what is cirrhosis of the liver?
this is when liver parenchymal cells (functional cells) are destroyed, they are replaced with fibrous tissue that eventually contracts around the blood vessels, thereby greatly impeding the flow of portal blood through the liver.
what are the causes of the cirrhosis?
1) Alcoholism
2) Ingestion of poisons such as carbon tetrachloride
3) Viral diseases such as infectious hepatitis
4) Obstruction of the bile ducts
5) Infectious processes in the bile ducts
what is and what leads to portal hypertension?
- The portal system is also occasionally blocked by a large clot that develops in the portal vein or its major branches.
- When the portal system is suddenly blocked, the return of blood from the intestines and spleen through the liver portal blood flow system to the systemic circulation is tremendously impeded, resulting in portal hypertension and increasing the capillary pressure in the intestinal wall to 15 to 20 mm Hg above normal.
- The patient often dies within a few hours because of excessive loss of fluid from the capillaries into the lumens and walls of the intestines.
can the liver act as a store of blood, why?
what is normal blood volume?
what can happen?
Liver Function as a Blood Reservoir
• Because the liver is an expandable organ, large quantities of blood can be stored in its blood vessels.
• Its normal blood volume, including both that in the hepatic veins and that in the hepatic sinuses, is about 450ml, or almost 10% of the body’s total blood volume.
• When high pressure in the right atrium causes backpressure in the liver, the liver expands, and 0.5 to 1 litre of extra blood is occasionally stored in the hepatic veins and sinuses.
This occurs especially in cardiac failure with peripheral congestion.
• Thus, in effect, the liver is a large, expandable, venous organ capable of acting as a valuable blood reservoir in times of excess blood volume and capable of supplying extra blood in times of diminished blood volume.
how much lymph arises from the liver and why?
- Because the pores in the hepatic sinusoids are very permeable and allow ready passage of both fluid and proteins into the spaces of Disse, the lymph draining from the liver usually has a protein concentration of about 6 g/dl, which is only slightly less than the protein concentration of plasma.
- Also, the extreme permeability of the liver sinusoid epithelium allows large quantities of lymph to form.
- Therefore, about half of all the lymph formed in the body under resting conditions arises in the liver.
what is ascites?
this is when high hepatic vascular pressures cause fluid transudation into the abdominal cavity from the liver and portal capillaries.
what causes ascites?
• When the pressure in the hepatic veins rises greatly, excessive amounts of fluid begin to transude into the lymph and leak through the outer surface of the liver capsule directly into the abdominal cavity.
This fluid is pure plasma.
It lacks plasma proteins (usually there is a decrease in the levels of albumin too, which encourages more fluid out of the vessels and into the abdomen)
• Blockage of portal flow through the liver also causes high capillary pressures in the entire portal vascular system of the gastrointestinal tract, resulting in oedema of the gut wall and transudation of fluid through the serosa of the gut into the abdominal cavity – lead to ascites.
can the live restore itself? when?
- The liver can restore itself after significant hepatic tissue loss from either partial hepatectomy or acute liver injury, as long as the injury is uncomplicated by viral infection or inflammation.
- Partial hepatectomy, in which up to 70% of the liver is removed, causes the remaining lobes to enlarge and restore the liver to its original size.
what happens during liver regeneration? what produced from where?
• Factors promoting liver regeneration:
Hepatocyte Growth Factor (HGF)
- Promotes cell growth of hepatic progenitor cells into hepatocytes.
- Produced by mesenchymal cells in the liver, but not by hepatocytes.
- Levels of HGF rise more than 20-fold after a partial hepatectomy.
Epidermal Growth Factor (EGF) and Cytokines (e.g. TNF and IL-6)
what happens when the liver has returned to its original size? what produced?
- After the liver has returned to its original size, the process of hepatic cell division is terminated.
- Transforming growth factor-β (TGF-β), a cytokine secreted by hepatic cells, is a potent inhibitor of liver cell proliferation and is the main terminator of liver regeneration.
describe and explain the blood-cleansing function of the liver
• Blood flowing through the intestinal capillaries picks up many bacteria from the intestines.
• Blood in portal veins before it enters the liver almost always grows colon bacilli when cultured, whereas growth of colon bacilli from blood in the systemic circulation is extremely rare.
• Kupffer cells, that line the hepatic sinuses, are the hepatic macrophages that help clean this blood.
When a bacterium comes into momentary contact with a Kupffer cell, it takes less than 0.1s for the bacterium to be engulfed for phagocytosis.
Less than 1% of the bacteria entering the portal blood from the intestines succeeds in passing through the liver into the systemic circulation.
summarise the metabolic function of the liver
The liver is a large, chemically reactant pool of cells that have a high rate of metabolism, sharing substrates and energy from one metabolic system to another, processing and synthesizing multiple substances that are transported to other areas of the body, and performing myriad other metabolic functions.
what functions does the liver perform in carbohydrate metabolism?
- Storage of large amounts of glycogen (glucose buffer function)
- Conversion of galactose and fructose to glucose
- Gluconeogenesis
- Formation of chemical compounds from intermediate products of carbohydrate metabolism
what is the glucose buffer function of the liver? how important is this?
The liver is especially important for maintaining a normal blood glucose concentration.
Storage of glycogen allows the liver to remove excess glucose from the blood, store it, and then return it to the blood when the blood glucose concentration begins to fall too low.
This is called the glucose buffer function of the liver.
what is gluconeogenesis also important for? when does it take place? what happens?
Gluconeogenesis in the liver is also important in maintaining a normal blood glucose concentration, because gluconeogenesis occurs to a significant extent only when the glucose concentration falls below normal.
• In such a case, large amounts of amino acids and glycerol from triglycerides are converted into glucose, thereby helping to maintain a relatively normal blood glucose concentration.
which cells metabolise fats?
Although most cells of the body metabolize fat, certain aspects of fat metabolism occur mainly in the liver.
what are the specific functions of the liver in fat metabolism?
- Oxidation of fatty acids to supply energy for other body functions
- Synthesis of large quantities of cholesterol, phospholipids, and lipoproteins (HDL/VDL)
- Synthesis of fat from proteins and carbohydrates
how is energy derived from neutral fats?
The fat is split into glycerol and fatty acids.
Then the fatty acids are split by ‘beta-oxidation’ into two-carbon acetyl radicals that form acetyl coenzyme A (acetyl-CoA).
Acetyl-CoA can enter the citric acid cycle and be oxidized to liberate tremendous amounts of energy.
where does beta-oxidation take place?
can take place in all cells of the body, but it occurs especially rapidly in the hepatic cells.
does the liver use all the acetyl-CoA that is formed? what happens to it?
liver itself cannot use all the acetyl-CoA that is formed; instead, it is converted by the condensation of two molecules of acetyl-CoA into acetoacetic acid, a highly soluble acid that passes from the hepatic cells into the extracellular fluid and is then transported throughout the body to be absorbed by other tissues.
These tissues reconvert the acetoacetic acid into acetyl-CoA and then oxidize it in the usual manner.
liver synthesis cholesterol and phospholipids
- what happens to the them
- what used for
About 80%of the cholesterol synthesized in the liver is converted into bile salts, which are secreted into the bile.
The remainder is transported in the lipoproteins and carried by the blood to the tissue cells everywhere in the body.
Phospholipids are also transported principally in the lipoproteins.
Both cholesterol and phospholipids are used by the cells to form membranes, intracellular structures, and multiple chemical substances that are important to cellular function.
what happens to fat synthesised from carbohydrates and proteins?
Almost all the fat synthesis in the body from carbohydrates and proteins also occurs in the liver.
After fat is synthesised in the liver, it is transported in the lipoproteins to the adipose tissue to be stored.
how important is protein metabolism in the liver? what are the most important functions of the liver in protein metabolism?
• The body cannot dispense with the liver’s contribution to protein metabolism for more than a few days without death ensuing.
• The most important functions of the liver in protein metabolism, are the following:
1. Deamination of amino acids
2. Formation of urea for removal of ammonia from the body fluids
3. Formation of plasma proteins
4. Transamination to form non-essential amino acids
why is deamination of amino acids important?
Deamination of amino acids is required before they can be used for energy or converted into carbohydrates or fats.
A small amount of deamination can occur in the other tissues of the body, especially in the kidneys, but this is much less important than the deamination of amino acids by the liver.
why is the formation of urea by the liver important?
Formation of urea by the liver removes ammonia from the body fluids.
• Large amounts of ammonia are formed by the deamination process, and additional amounts are continually formed in the gut by bacteria and then absorbed into the blood.
• If the liver doesn’t produce urea, the plasma ammonia concentration rises rapidly and results in hepatic coma and death.
• Even greatly decreased blood flow through the liver - as occurs occasionally when a shunt develops between the portal vein and the vena cava - can cause excessive ammonia in the blood, an extremely toxic condition.
which plasma proteins are made by the which cells in the liver? where are others made? what happens when there is plasma protein depletion? what happens with chronic liver disease?
Essentially all the plasma proteins, with the exception of part of the gamma globulins, are formed by the hepatic cells.
This accounts for about 90%of all the plasma proteins.
• The remaining gamma globulins are the antibodies formed by plasma cells in the lymph tissue.
• It is particularly interesting that plasma protein depletion causes rapid mitosis of the hepatic cells and growth of the liver to a larger size; these effects are coupled with rapid output of plasma proteins until the plasma concentration returns to normal.
• With chronic liver disease (e.g., cirrhosis), plasma proteins (e.g. albumin), may fall to very low levels, causing generalized oedema and ascites.
describe the formation of non-essential amino acids
4) An important function of the liver is its ability to synthesize certain amino acids and to synthesize other important chemical compounds from amino acids.
For instance, the so-called nonessential amino acids can all be synthesized in the liver.
To do this, a keto-acid having the same chemical composition (except at the keto oxygen) as that of the amino acid to be formed is synthesized.
Then an amino radical is transferred through several stages of transamination from an available amino acid to the keto-acid to take the place of the keto oxygen.
liver as a storage site for vitamins
- how good is it
- which vitamin is stored in greatest quantities, which other
- how much stored/to last you for how long
- The liver is good at storing vitamins.
- It is an excellent source of certain vitamins in the treatment of patients.
- The vitamin stored in greatest quantity in the liver is vitamin A, but large quantities of vitamin D and vitamin B12 are normally stored as well.
- Sufficient vitamin A can be stored to prevent vitamin A deficiency for as long as 10 months.
- Sufficient vitamin D can be stored to prevent deficiency for 3 to 4 months.
- Sufficient vitamin B12 can be stored to last for at least 1 year and maybe several years.
liver as a store for iron
- how much iron stored here
- in what form
- how stored
- what happens when iron in the circulating body fluids reaches a low level
- what system acts as what
- Except for the iron in the haemoglobin of the blood, by far the greatest proportion of iron in the body is stored in the liver in the form of ferritin.
- The hepatic cells contain large amounts of a protein called apoferritin, which is capable of combining reversibly with iron.
- Therefore, when iron is available in the body fluids in extra quantities, it combines with apoferritin to form ferritin and is stored in this form in the hepatic cells until needed elsewhere.
- When the iron in the circulating body fluids reaches a low level, the ferritin releases the iron.
- The apoferritin-ferritin system of the liver acts as a blood iron buffer, as well as an iron storage medium.
which coagulation factors are produced by the liver?
Fibrinogen
Prothrombin
Accelerator globulin
Factor VII
what is required for the formation for several of these coagulation factors, which in particular?
- Vitamin K is required by the metabolic processes of the liver for the formation of several of these coagulation factors, especially prothrombin and Factors VII, IX, and X.
- In the absence of vitamin K, the concentrations of all these decrease markedly and this almost prevents blood coagulation.
what is removed by the liver?
The active chemical medium of the liver is well known for its ability to detoxify or excrete into the bile many:
Drugs - including sulphonamides, penicillin, ampicillin, and erythromycin.
Hormones - hormones secreted by the endocrine glands are either chemically altered or excreted by the liver, including thyroxine and essentially all the steroid hormones, such as oestrogen, cortisol, and aldosterone.
• Finally, one of the major routes for excreting calcium from the body is secretion by the liver into the bile, which then passes into the gut and is lost in the faeces.
what can liver damage lead to in terms of hormones?
excess accumulation of one or more of these hormones in the body fluids and therefore cause over activity of the hormonal systems.
For example, an increase in oestrogen can cause men to develop gynecomastia.
which cells are activated if hepatocyte proliferation is severely impaired?
oval cells
what is produced by the liver but only in the foetus?
erythrocytes
which cells converts haem to bilirubin?
hepatocytes
which cells are exogenous stem cells for liver regeneration?
bone marrow cells
what are hepatoblasts?
foetal precursors of hepatocytes
what are hepatic stellate cells (Ito cells)?
the major cell type involved in liver fibrosis
what percentage of liver mass/volume do hepatocytes represent?
70-80%
how are many substances excreted? what is one example? what is this?
• Many substances are excreted in the bile and then eliminated in the faeces.
• One of these is the greenish yellow pigment bilirubin.
This is a major end product of haemoglobin degradation.
describe the process by which bilirubin is formed and reaches the intestine
1) When the red blood cells have lived out their life span (on average, 120 days) and have become too fragile to exist in the circulatory system, their cell membranes rupture, and the released haemoglobin is phagocytized by tissue macrophages (also called the reticuloendothelial system) throughout the body.
2) The haemoglobin is first split into globin and heme, and the heme ring is opened to give:
Free iron, which is transported in the blood by transferrin
A straight chain of four pyrrole nuclei, which is the substrate from which bilirubin will eventually be formed.
3) The first substance formed is biliverdin, but this is rapidly reduced to free bilirubin, which is gradually released from the macrophages into the plasma.
4) The free bilirubin immediately combines strongly with plasma albumin and is transported in this combination throughout the blood and interstitial fluids.
Even when bound with plasma protein, this bilirubin is still called “free bilirubin” to distinguish it from “conjugated bilirubin”.
5) Within hours, the0@@@. free bilirubin is absorbed through the hepatic cell membrane.
In passing to the inside of the liver cells, it is released from the plasma albumin and soon thereafter conjugated about:
80% with glucuronic acid to form bilirubin glucuronide
10% with sulfate to form bilirubin sulfate
10% with a multitude of other substances.
6) In these forms, the bilirubin is excreted from the hepatocytes by an active transport process into the bile canaliculi and then into the intestines.
EXCRETION – BILIRUBIN
- Breakdown of haem to bilirubin following phagocytosis
- Carried by albumin to liver and taken up via OATP and ??
- Conjugation with glucuronate in ER and secretion via MRP2 (into bile from hepatocyte)
- Globin part can be recycled – amino acids
- Haem part can’t be broken down
- Fe2+ recycled but the biliverdin part can’t be
- Biliverdin reduced to bilirubin
- Bilirubin attached to albumin etc…..
- Conjugated and actively secreted by the liver (bilirubin-glucuronide)
- Stored in gallbladder and gets into small intestine
- Bacteria (in terminal ileum, colon) deconjugate some of the bilirubin and it is converted to urobilinogen (colourless)
- Most then further converted to stercobilin (brown) in colon -> excretion in faeces
- Some urobilinogen reabsorbed and excreted as urobilin (yellow) via kidney
Lighter colour poo means not delivering bile correctly into the intestine
Bilirubin leads to colour of poo and wee
what happens once bilirubin reaches the intestine?
• Once in the intestine, about half of the conjugated bilirubin is converted by bacterial action into the substance urobilinogen, which is highly soluble.
• 90% of this urobilinogen is broken down further into stercobilinogen and stercobilin and excreted in faeces.
• 10% of this urobilinogen is absorbed through the intestinal mucosa back into the blood.
Most of this absorbed urobilinogen is re-excreted by the liver back into the gut.
About 5% of this absorbed urobilinogen is excreted by the kidneys into the urine.
After exposure to air in the urine, the urobilinogen becomes oxidized to urobilin.
what are the functions of bile?
- Excretion of waste products (those that are not easily excreted by the kidney – kidney is good at getting rid of water-soluble substances but not very good at getting rid of lipid-soluble substances)
- Excretion of hormones (lipid-soluble hormones – thyroxin and steroid hormones)
- Excretion of drugs and other xenobiotics
- Secretion of bile acids/salts to aid intestinal lipid digestion and absorption
- Secretion of electrolytes and water as a vehicle
electrolyte secretion into the bile canaliculi - how and why does this happen? which transporters?
• There is polarised distribution of ‘housekeeping’ transporters e.g. Na,K-ATPase, Ca-ATPase, NHE, NBC, AE, etc.
This means that the normal charges and ion concentrations are maintained in the hepatocytes.
• Consequently there is some net fluid & electrolyte secretion:
Secondary active transport of Cl- and HCO3 –
Paracellular Na+ transport
Isosmotic water flow
• Many other solute transporters for metabolic substrates/products e.g. GLUT2, amino acid transporters etc.
describe the synthesis of bile acids/salts
• Liver synthesises cholesterol.
• Bile acids and salts are derived from cholesterol.
• In the liver, cholesterol is converted into primary bile acids.
Primary bile acids are weakly ionised, hence ‘bile acids’. (BAH = undissociated – proton remains bound to the anion of the bile substance)
• Primary bile acids are released by the liver into bile and are carried to the intestine.
• In the intestine, the bacteria convert these into secondary bile acids.
• Conjugation of primary and secondary bile acids with taurine, glycine, sulphate, glucuronate makes them more water soluble and charged, hence ‘bile salts’. (BA-X^- = dissociated acid – bile anion and the conjugate) (thought to be less toxic in the gut)
- ‘secondary’ = bacterial modification in terminal ileum and colon – these are conjugated
describe the apical secretion of bile acids/salts
• Unconjugated (BA− ) and conjugated bile salts (BA-Z − & BA-Y − ) secreted via:
Bile salt export pump (BSEP) (BA-Y-)
Multidrug resistance associated protein 2 (MRP2) (BA-Z-)
• Both these are ABC transporters with wide substrate specificities (LEARN THIS!)
Z: taurine, glycine Y: sulphate, glucuronate
ABC transporters
- what does ABC stand for
- what are they
- what is common structure
- examples
• ABC stands for ‘ATP Binding Cassette’ Transporters.
• Huge family of ‘pumps’ using ATP hydrolysis to import or export a wide range of substrates. (including lots of lipid-soluble substances)
• Common structure:
2 transmembrane domains (TMDs)
2 nucleotide-binding domains (NBDs)
• Alternating access mechanism powered by ATP hydrolysis.
Examples:
- ABCA
- ABCA1 (cholesterol transporter)
- ABCB
- MDR1 (P-glycoprotein) – can be overexpressed in cancer cells
- bile salt export pump (SBEP)
- ABCC
- MRP2
- CFTR
- sulphonylurea receptor (SUR1)
- ABCG
- ABCG2 (sulphated steroids)
- ABCG5/8 (cholesterol)
describe the enterohepatic circulation of bile acids - where and how taken up by intestines
- how many bile acids/salts in body and how much needed
- what does this mean
- where absorption
- how absorbed
- synthesis of how many primary bile acids per day
- what is bile acid production regulated by
• Some unconjugated bile acids are passively reabsorbed across the proximal intestinal wall.
This is becasuse they are lipid soluble and so can pass throught the lipid cell membranes of the intestinal cells.
• Active uptake of conjugated bile salts occurs in the terminal ileum via Na+ -bile salt (co)transporter [ASBT] and organic solute transporter [OST].
- 3 g in body BUT >15g required to digest a fat-rich meal
- You don’t have enough bile salts in your body to digest meal without the recycling of the bile salts
- All fats been digested and absorbed by time get to terminal ileum, so the bile salts are absorbed here
- Some of the bile salts will be damaged in this process, and they can be absorbed by passive diffusion – small amount of bile acids absorbed like this along the length of the small intestine
- Passive reabsorption of unconjugated BAH along intestine = slow
- Active uptake of conjugated bile salt in terminal ileum via Na+-bile salt cotransporter (ASBT) (takes into cell) and organic solute transporter (OST) (in basolateral membrane – bile salts out of cell into portal blood – portal blood goes back to the liver, so you get recycling)
- Not all absorbed, about 600mg bile acids lost daily in faeces
- Therefore, synthesis of about 600mg/day of ‘primary bile acids’
- Bile acid production is regulated by the amount of bile salts coming back to the liver – feedback mechanism
biliary tree
- what lines with
- what secretes hepatic bile
- what is bile
- The biliary tree/duct is lined with epithelial cells called cholangiocytes.
- 30-50% of hepatic bile is secreted by cholangiocytes.
- The bile secreted is a HCO3- -rich, isosmotic fluid.
what is the mechanism of secretion of bile?
Secondary active transport of Cl- and HCO3 –
Paracellular Na+ transport
Isosmotic water flow
what is bile production stimulated/inhibited by?
- Stimulated by CCK, secretin, VIP, glucagon.
* Inhibited by somatostatin.
how is ACh involved in bile secretion?
ACh causes contraction of the gall bladder and NO causes the relaxation of the sphincter of Oddi, therefore promoting the entry of bile into duodenum.
describe the concentration of bile in the gall bladder
- what happens
- how
- oncentrations of solids & solutes, bile acids, pH
- Different composition to that of hepatic bile
• Half of secreted bile is diverted to gall bladder between meals.
• Gall bladder reabsorbs electrolytes and water.
• Other solutes are concentrated 10- to 20-fold.
Reabsorption by Gall Bladder Epithelium
• Na+ reabsorbed via apical NHE (sodium-hydrogen exchanger - proton into lumen) and basolateral Na+ ,K+ -ATPase. (sodium out, potassium in)
• Some (not quite equivalent) Cl- reabsorbed in exchange for HCO3 - (into bile), but net acid secretion into lumen (therefore slight accumulation of protons into the gall bladder fluid – which is why there is a decrease in pH in gall bladder bile)
• Isosmotic water reabsorption - due to movement of sodium and chloride ions
- As sodium is reabsorbed, bicarbonate is excreted into the bile – causes the change in pH ??
Hepatic bile:
- solids & solutes = 2-4%
- bile acids = 10-20 mM
- pH = 7.5
Gall bladder bile:
- solids & solutes = 10-12%
- bile acids = 50-200 mM
- pH = 6.0
how many amino acids present in body proteins?
how many essential and non-essential?
20
• Out of the 20 amino acids in the body:
10 of them can be synthesised in the cells of the body – “nonessential amino acids”
10 of them cannot be synthesised in the body or are synthesised in quantities too small to supply the bosy’s needs (acquired in diet) – “essential amino acids”
what are the major types of proteins present in the plasma? function?
- Albumin - major function of albumin is to provide colloid osmotic pressure in the plasma, which prevents plasma loss from the capillaries.
- Globulin - perform a number of enzymatic functions in the plasma, but equally important, they are principally responsible for the body’s both natural and acquired immunity against invading organisms (immunoglobulins – antibodies).
- Fibrinogen - polymerizes into long fibrin threads during blood coagulation, thereby forming blood clots that help repair leaks in the circulatory system.
where are albumin, fibrogen and globulin produced? what happens in liver conditions? what does this lead to?
- All of albumin, fibrogen, and 50-80% of globulin is produced in the liver.
- 20-50% of the globulin is produced in lymphoid tissues.
- In liver conditions, such as in cirrhosis, the ability of the liver to produce plasma proteins decreases greatly.
- This leads to decreased colloid osmoic pressre, which causes generalised oedema.
what do plasma proteins act as? how?
- When tissues become depleted of proteins, the plasma proteins can act as a source of rapid replacement.
- These proteins are taken up by macrophages by pinocytosis; once these plasma proteins enter these cells, they split into amino acids that are transported back into the blood and used throughout the body to build cellular proteins wherever needed.
- In this way, the plasma proteins function as a protein storage medum and represent a readily available source of amino acids wherever a particular tissue requires them.
what is the storage form of amino acids? what happens to them?
- Unlike carbohydrates and fatty acids, amino acids have no storage form (except plasma proteins).
- All must be taken up with the diet or recycled via regular turnover of body proteins (about 400g/ day).
what happens to excess amino acids?
1) Degraded, and the generated nitrogen excreted largely as urea (Ornithine cycle)
2) Most are used for gluconeogenesis (“glucogenic”).
3) Some are used for ketogenesis – making acetyl-CoA or acetoacetate - (“partially/fully ketogenic”).
the catabolism of most amino acids is carried out via what type of reaction?
transaminase reaction
describe the transaminase reaction
• This reaction depends mainly on the formation of appropriate α-keto acids, which are precursors of the respective amino acids.
• Then the process of transamination takes place as follows:
1. An amino radical is transferred to the a-keto acid
2. The keto oxygen is transferred to the donor of the amino radical
• This reaction is promoted by transaminase enzymes.
give an example of the transaminase reaction
• Pryuvic acid, which is formed in large quantitites during the glycolytic breakdown of glucose, is the α-keto acid precursor to alanine.
• Transamination process:
Amino radical group is transferred from glutamine (amino acid) to pyruvic acid, forming alanine (amino acid)
Keto oxygen is transferred from pyruvic acid to glutamine, forming α-ketoglutamic acid
• This reaction is reversible:
Alanine and α-ketoglutamic acid swap the amino radical and keto oxygen groups to form pyruvate and glutamine.
- Glutamate and Pyruvate can be transaminated into alanine.
- Glutamine and Pyruvic acid can be transaminated into alanine.
- Glutamate is converted to α-ketoglutarate acid
- Glutamine is converted to α-ketoglutamic acid
- Pyruvic acid and Pyruvate are both converted to alanine.
transaminase enzymes
- what are they mostly
- how specific
- give examples
- how reversible and why
- Most transaminases are cytoplasmic enzymes that are quite specific for one or few amino acids.
- Alanine transaminase (ALT) is a typical enzyme in that is fully reversible and does not strongly favor one direction:
- Aspartate transaminase (AST) is an exception because the product of this reaction enters the ornitihine cycle.
- The α-amino group of glutamate that has come from many other amino acids is transferred to oxaloacetate to form aspartate, and from there is fed into the urea cycle (ornitihine cycle - learn this?).
- Therefore, the forward reaction (producing asparate) is favoured in the attempt to remove excess NH2 from the body via the ornithine cycle. This is why this reaction isn’t fully reversible.
pyruvate + glutamate -(ALT)-> alanine + A-KG
oxaloacetate + glutamate -(AST)-> aspartate + A-KG
increased levels of which enzymes is diagnostic of what? which more specific and sensitive?
- Increased levels of these enzymes in blood plasma, especially of ALT and AST, are diagnostic of cell/ tissue damage.
- ALT is more specifically indicative of liver damage, but serum AST is more sensitive because the liver contains larger amounts of AST than ALT.
deamination
- what is this
- what generally happens
- what happens to products
- This is the removal of amino groups from the amino acids.
- The greatest amount of deamination occurs by the following schema:
- The amino acid (which contains an amine group [-NH2]) reacts with water and NAD+.
- This forms NADH, H+ and NH3.
- NH3 can now travel to the liver.
- NH3 cannot frrely travel in the blood and so is converted to glutamine (in peripheral tissue) or alanine (in muscles), which can then travel to the liver for the removal of NH3 in the ornithine cycle. (see below).
delivery of ammonia to the liver for removal as urea - describe this (urea cycle)
- how much ATP used up
- in peripheral tissues, excess ammonia is converted to glutamine and shuttled to the liver
- in the liver, two molecules NH3 can be released from glutamine by glutaminase and then glutamate dehydrogenase
- ammonia can also be transferred to oxaloacetate by aspartate transaminase - the resulting aspartate feeds into the urea cycle
- a second route for delivering ammonia to the liver is via the alanine-gluose shuttle: alanine from muscle delivers NH3 via ALT; resulting pyruvate goes into gluconeogenesis; glucose is returned to muscle
- in the liver mitochondria, ammonia and CO2 are joined by carbamoyl phosphate synthetase I - two molecules of ATP are required to drive the process
- in the urea cycle, a total two molecules ammonia and one bicarbonate are converted to urea, the major nitrogen waste product
- the total cost of one round of the urea cycle is 4ATP
- urea is shuttled from the liver to the kidney for excretion
when is ammonia released? what converted to? through what? what happens in liver pathology? what leads to?
- The ammonia released during deamination of amino acids is removed form the blood almost entirely by conversion to urea.
- The urea is synthesised in the liver (ornitihine cycle).
- In liver pathology, ammonia accumulates in the blood, which is extremely toxic, especially to the brain, often leading to a state called hepatic enencephalopathy/ coma.
what can certain deaminated amino acids be used to synthesise? example? what is this called?
• Certain deaminated amino acids can be used to synthesize glucose or fatty acids in hepatocytes.
• For example, deaminated alanine and pyruvic acid can be converted into:
Either glucose or glycogen
Acetyl-CoA, which can then be:
- Polymerized into fatty acids
- Condensed to form acetoacetic acid which is one of the ketone bodies.
- The conversion of amino acids into glucose or glycogen is called gluconeogenesis.
- The conversion of amino acids into keto acids or fatty acids is called ketogenesis.
out of the 20 deaminated amino acids, how many have chemical structures that allow them to be converted into glucose or fatty acids?
18 - glucose
19 - fatty acids
growth hormone
- affects on protein metabolism
- how
• Growth Hormone increases the synthesis of cellular proteins.
• Growth hormone causes the tissue proteins to increase.
• This results from:
Increased transport of amino acids through the cell membranes.
Acceleration of the DNA and RNA transcription and translation processes for protein synthesis.
insulin
- affect on protein metabolism
- what happens with total lack of insulin
- how work
• Insulin is necessary for protein synthesis and storage.
• Total lack of insulin reduces protein synthesis to almost zero.
• Insulin:
Accelerates the transport of some amino acids into cells, which acts as a stimulus for protein synthesis.
Increases the availability of glucose to the cells (gluconeogenesis), so that the need for amino acids for energy is correspondingly reduced.
glucocorticoids
- affect on protein metabolism
- how
• Glucocorticoids increase breakdown of most tissue proteins.
• The glucocorticoids secreted by the adrenal cortex:
Decrease the quantity of protein in most tissues while increasing the amino acid concentration in the plasma.
Increase both liver proteins and plasma proteins.
- Glucocorticoids act by increasing the rate of breakdown of extrahepatic proteins, thereby making increased quantities of amino acids available in the body fluids.
- This allows the liver to synthesize increased quantities of hepatic cellular proteins and plasma proteins.
testosterone
- affects on protein metabolism
- how effect different to that of growth hormone
• Testosterone increases protein deposition in tissues.
• Testosterone, the male sex hormone, causes increased deposition of protein in tissues throughout the body, especially the contractile proteins of the muscles (30-50% increase).
• The mechanism of testosterone is different from the effect of growth hormone, in the following way:
Growth hormone causes tissues to continue growing almost indefinitely, whereas testosterone causes the muscles and, to a much lesser extent, some other protein tissues to enlarge for only several months.
Once the muscles and other protein tissues have reached a maximum, despite continued administration of testosterone, further protein deposition ceases.
oestrogen
- affect on protein metabolism
- how significant effect
• Oestrogen, the principal female sex hormone, also causes some deposition of protein, but its effect is relatively insignificant in comparison with that of testosterone.
thyroxine
- how affects protein metabolism
- what happens if deficiency of thyroxine
- Thyroxine increases the rate of metabolism of all cells and, as a result, indirectly affects protein metabolism.
- If insufficient carbohydrates and fats are available for energy, thyroxine causes rapid degradation of proteins and uses them for energy.
- Conversely, if adequate quantities of carbohydrates and fats are available and excess amino acids are also available in the extracellular fluid, thyroxine can actually increase the rate of protein synthesis.
- In growing animals or human beings, deficiency of thyroxine causes growth to be greatly inhibited because of lack of protein synthesis.
summary of hormones and their effect in regulation of protein metabolism
- growth hormone: increases the synthesis of cellular proteins
- insulin: necessary for protein synthesis and storage
- glucocorticoids: increase breakdown of tissue proteins, thus increasing the amount of amino acid concentration in plasma
- testosterone: increases protein deposition in tissues until the maximum limit is reached
- oestrogen: some deposition of protein
- thyroxine: increases the rate of metabolism of all cells: 1. can degrade proteins in times of insufficient fats and carbohydrates as sources of energy 2. can increase protein synthesis if sufficient energy sources available
what is drug deposition?
this is the term used for the absorption, metabolism, and excretion of a drug that has been administered.
what is pharmacokinetics and pharmacodynamics?
- Pharmacokinetics – what the body does to the drug (metabolism).
- Pharmacodynamics – what the drug does to the body (effect of drug).
where are sites of absorption?
- Stomach (small surface area)
* Small Intestine (large surface area)
oral administration
- what happens if administered orally
- whole journey
- bio-availability - greater if what
- If the drug is administered orally, it must first undergo dissolution (disolving of the solid tablet); then it undergoes absorption (stomach/ small intestine) into the bloodstream (hepatic portal vein).
- Once in the bloodstream, it travels to the liver, where it undergoes first-pass metabolism, before entering the systemic circulation to have its effect.
- The greater the concentration of the drug that enters the systemic circulation, the greater its ‘bio-availability’.
what allow bypassing of presystemic metabolism?
are portal/systemic anastomoses
which drugs can pass through the cell membrane?
- Lipid-soluble drugs pass through the cell membrane.
* Water-soluble drugs cannot pass through the cell membrane.
the distribution of a drug is dependent on what?
its lipid solubility
what factors affect the extent of distribution?
- Lipid solubility of the drug
Lipid-soluble can diffuse across cell membrane - Blood flow to the tissue/organ
- Protein Binding of the drug to proteins
Free drug can bind to carrier proteins in the plasma, e.g. albumin
Only free or unbound drug can diffuse across membranes and have an affect
Decrease in the levels of albumin will lead to more free drug (increased volume of distribution [Vd]) in the blood, thus a greater affect caused by the drug – this is problematic with drugs with a narrow therapeutic window.
An increase in bilirubin can cause displacement of drugs from albumin.
equation for volume of distribution
Vd = dose administered / plasma concentration of drug
what causes drug elimination?
Drug elimination = metabolism + excretion
are most drugs lipid or water soluble? what does this mean in terms of elimination?
- Most drugs are lipophilic. Therefore, it is hard for the body to excrete them.
- In order for the body to excrete the drug, it must convert it into a water-soluble substance.
lipid-soluble drug -> water-soluble drug -> water-soluble drug excreted
what is drug metabolism?
the enzyme-mediated conversion of a lipid-soluble drug into a more water-soluble one, so that it may be excreted.
where are sites of drug metabolism?
- Mainly in the liver
- SER (smooth endoplasmic reticulum) (& cytosol & mitochondria)
- Kidney
- Lung
- GI tract (enterocytes contain a number of enzymes)
- Brain
- Plasma
- Skin (low expression of drug metabolising enzymes – but contributes to about 10% of metabolism because large organ)
liver metabolism (detoxification) - what are the phases?
- Phase 1 – drug metabolised to produce metabolite
- Phase 2 – metabolite then goes through phase 2 reaction to produce metabolite that is excreted
- Usually occur sequentially – don’t need to know the exceptions
- Phase 1:
FUNCTIONALISATION- Addition/uncovering of functional (chemically reactive) groups, e.g. C-H to C-OH.
- Produce/uncover chemically reactive functional groups -> ‘functionalisation’ (uncover or add in particular functional groups that are going to help with excretion of that drug)
-e.g. -OH, -NH2, -SH or -COOH - This prepares the molecule for the next phase by making it slightly polar (slightly more water-soluble).
Oxidation (number of different types of phase 1 reactions – most important one is oxidation)- This occurs via enzymes such as alcohol dehydrogenase, MAO, and mainly by CYP450 and CYP3A4 (cytochrome family of enzymes).
-57 CYP genes divided into 18 families: CYP1-3 (a lot of genetic variation – explains why certain patients have different responses to a drug?)
- Products slightly more polar -> water-soluble (small change) (this may change their reactivity as well)
- Preparation for phase 2
PHARMACOLOGICAL ACTIVATION
- The inactive compound has now become chemically active.
- This occurs via enzymes such as alcohol dehydrogenase, MAO, and mainly by CYP450 and CYP3A4 (cytochrome family of enzymes).
- Usually this would reduce the activity of the drug.
- But, for some drugs, their activity is increased – PRODRUGS.
- Addition/uncovering of functional (chemically reactive) groups, e.g. C-H to C-OH.
- Phase 2:
Conjugation with charged species.
Conjugation reactions: (sticking together drug molecule/metabolite with a much bigger molecule)
Active compounds become less active because now the molecule is bigger and more water soluble and so can no longer bind to its receptor (decreased receptor affinity) in tissues, but instead can be excreted in urine (enhanced excretion) – PHARMACOLOGICAL INACTIVATION.
what happens if drug metabolising enzymes are induced? what can do this?
decrease the duration of drug action (e.g. alcohol can cause this/ smoking induces CYP1A2)
what happens if drug metabolising enzymes are inhibited? what can do this?
increase the duration of drug action (e.g. grapefruit juice can cause this by inhibiting CYP3A4 – this enzyme metabolises 30% of all drugs)
• These effects occur due to drug interactions with certain substances.
what is an important enzyme for drug metabolism?
CYP3A4 - metabolises 30% of all drugs
what are the outcomes of drug metabolism?
- Pharmacological Activation, e.g. pro-drugs – the drug has increased effect.
- levodopa -> dopamine
- azathioprine -> 6-metcaptopurine
- enalapril -> enalaprilate - Pharmacological Inactivation, e.g. paracetamol – the drug has a reduced effect.
- Change in Type of Pharmacological Response, e.g. diazepam → oxazepam
- No Change in Pharmacological Activity, e.g. lidocaine → monoethylglycylxylidide
- Change in Drug Distribution (e.g. if produce more water-soluble drugs they’re more likely to be excreted than remain in the blood stream)
what are factors affecting metabolism?
• Age
-reduced as liver mass and blood flow decrease
-drug inactivation is slower (mostly phase 1 oxidation)
-decrease first-pass metabolism
• Gender (to a lesser extent)
• Pregnancy – increased hepatic metabolism
• Genetic
• Disease – this damages the metabolic enzymes, therefore reducing metabolism
what are external factors affecting metabolism?
- Drug-induced
• Lifestyle- cigarette smoking induces metabolism of by inducing CYP1A2:
theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, estradiol
• Environment (pollutants) e.g. arsenic, toluene, fluorine
• Diet (BBQed meat – carbon and other molecules can induce metabolism, brussel sprouts ↑(increase expression of drug metabolising enzymes), grapefruit juice ↓by inhibiting CYP3A4)
• These factors can be inducers or inhibitorsof enzymes
what is the effect of liver disease outcomes on metabolism?
- what is used as a marker of liver pathology
- Liver function tests: serum albumin (change in production in liver – albumin good guide for severity of damage - marker of liver pathology), (prothrombin time) – these are probably both the most important in measuring liver function
- Liver biochemistry (serum)
-aspartate aminotransferase (AST) (less specific because also present in other tissues), alanine aminotransferase (ALT) (specific to the liver) – these both present in hepatocytes and get released into bloodstream when damaged
-alkaline phosphatase, Y-glutamyl transpeptidase - Reduced hepatocyte function
-CYP450 reduced in severe disease - Decrease blood flow through the liver (reduced delivery of drugs to liver, so reducing ability of liver to metabolise drugs)
- Decrease first-pass metabolism (due to decreasing metabolising enzymes) -> increase [plasma] of metoprolol, labetalol and clomethiazole (these drugs normally susceptible to first-pass metabolism)
- Increase t1/2 (half-life) and decrease CL (clearance) (e.g. diazepam, tolbutamide, rifampicin)
= increase likelihood of side effects
what is excretion?
the removal of a drug (drug metabolites (phase 1 and phase 2 products) and water-soluble drugs) from the body.
what are sites of excretion?
urine, bile, faeces, lungs and skin.
how do you increase drug excretion?
- Increase blood flow to the kidneys.
2. Decrease plasma protein binding.
what do you have to consider/do when prescribing for patients with liver disease?
- Risk/benefit analysis
- Select alternative drugs eliminated by routes other than liver.
- Monitoring of drugs with narrow therapeutic windows, e.g. warfarin.
- Drugs with known hepatotoxicity (e.g. cytotoxic drug) should only be used for strongest of indications.
adverse drug reactions
- what is the aim
- why do people exhibit variable responses
• Aim - desired effect with minimum toxicity.
• People exhibit variable responses:
This is due to a genetic or heritable component.
The genetic variability can have an effect on:
Transport – uptake and efflux (e.g. P-gp)
Cellular targets and signalling pathways (e.g. B2-adrenorecptors and salbutamol)
Metabolism (changes in enzymes)
variations in DNA sequences -> altered expression or function of proteins -> variation in drug response
what have been identified in every pathway of drug metabolism?
polymorphisms (due to mutations)
what enzyme is really important and in which phase of metabolism?
- family and specific examples
- what problem could they face
CYP450 family (cytochrome P450)
POLYMORPHISMS
- SNPs present in virtually every pathway of drug metabolism
- CYP2C9, CYP2C19 & CYP2D6 (enzymes) metabolise about 40% of drugs
- So, if have a SNP in one coding region for one of these you may have problems with a lot of drugs
what is P-gp? where expressed? what can a mutation lead to? what does this mean?
P-glycoprotein
• P-gp - protects cells from toxic substances or metabolites by preventing their absorption in the duodenum, e.g. anticancer drugs and digoxin.
• Expressed in liver, kidney, GI tract & BBB.
• A mutation (SNP in C3435T) can lead to decreased amounts of P-gp in the intestine.
• This means that more toxic substances can be absorbed, leading to side effects
the more severe the mutation, the what in terms of metabolism of drug? however, genetic variability can also lead to?
Genetic Variablity and Effect on Clearance
• The more severe the mutation, the longer it takes to clear the drug after metabolism.
• However, this genetic variablility can lead to a variety of proteins which cause metabolisation at different rates.
E.g. Ultrarapid Metabolisers
These increase metabolism and decrease the concentration of plasma drug concentration.
These ultrarapid metabolisers form because there are extra copies of genes that encode these proteins.
poor metaboliser -> ultra-rapid metaboliser - what type of genes is this due to?
- what gene is this important for
- what do you want to be
poor metaboliser = homozygous for defective gene (decrease metabolites, increase drug)
intermediate metaboliser = heterozygous for defective gene
extensive metaboliser = homozygous for functional gene
ultra-rapid metaboliser = extra copies of functional gene (increase metabolites, decrease drug)
CYP POLYMORPHISMS
Poor metaboliser = homozygous for defective gene (not good – concentration of drug too high which can lead to side effects)
Intermediate metaboliser = heterozygous for defective gene
Extensive metaboliser = homozygous for functional gene (this is what you want to be)
Ultra-rapid metaboliser = extra copies of functional gene (not good – concentration of drug going to be lower – below threshold for seeing therapeutic effect)
- From top to bottom of list above, increase [drug] and decrease [metabolites] goes to increase [metabolites] and decrease [drug]
what are causes of hepatitis?
INFECTIOUS
Viral infection - e.g. hepatitis A, hepatitis B
Bacterial infection - e.g. leptospirosis
Parasite infection - e.g. hydatid, clonorchiasis
- fungal
NON-INFECTIOUS
Immunological - e.g. AUTOIMMUNE, graft v host disease
Toxins - e.g. carbon tetrachloride, ALCOHOL
Drugs - e.g. paracetamol, rifampicin
Vascular congestion (ischaemic) - e.g. portal vein thrombosis
- metabolic
what are symptoms of hepatitis?
The symptoms are non-specific and include fatigue, lethargy, itching.
It may also lead to some specific symptoms, for example: jaundice, right upper quadrant pain.
what are diagnostic markers of hepatitis?
AST and ALT will be elevated in a hepatitis infection.
If AST > ALT = alcoholic hepatitis.
If ALT > AST = other causes (mainly viral)
what are causes of viral hepatitis?
Common Causes:
- Hepatitis A Virus (HAV)
- Hepatitis B Virus (HBV)
- Hepatitis C Virus (HCV)
- Hepatitis D Virus (HDV) – hepatitis delta
- Hepatitis E Virus (HEV)
Less Common Causes:
• Cytomegalovirus (congenital and perinatal infection)
• Epstein-Barr virus (adolescence)
Rare Causes:
• Herpes simplex (congenital and perinatal infection)
• Yellow fever
