Case 5 Flashcards

Question

what is ascites?

Answer 1

this is when high hepatic vascular pressures cause fluid transudation into the abdominal cavity from the liver and portal capillaries.

Answer 2

• 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.

Answer 3

* 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.

Answer 4

• 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)

Answer 5

* 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.

Answer 6

• 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.

Answer 7

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.

Answer 8

1. Storage of large amounts of glycogen (glucose buffer function) 2. Conversion of galactose and fructose to glucose 3. Gluconeogenesis 4. Formation of chemical compounds from intermediate products of carbohydrate metabolism

Answer 9

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.

Answer 10

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.

Answer 11

Although most cells of the body metabolize fat, certain aspects of fat metabolism occur mainly in the liver.

Answer 12

1. Oxidation of fatty acids to supply energy for other body functions 2. Synthesis of large quantities of cholesterol, phospholipids, and lipoproteins (HDL/VDL) 3. Synthesis of fat from proteins and carbohydrates

Answer 13

 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.

Answer 14

can take place in all cells of the body, but it occurs especially rapidly in the hepatic cells.

Answer 15

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.

Answer 16

 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.

Answer 17

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.

Answer 18

• 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

Answer 19

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.

Answer 20

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.

Answer 21

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.

Answer 22

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.

Answer 23

* 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.

Answer 24

* 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.

Answer 25

 Fibrinogen  Prothrombin  Accelerator globulin  Factor VII

Answer 26

* 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.

Answer 27

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.

Answer 28

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.

Answer 29

oval cells

Answer 30

erythrocytes

Answer 31

hepatocytes

Answer 32

bone marrow cells

Answer 33

foetal precursors of hepatocytes

Answer 34

the major cell type involved in liver fibrosis

Answer 35

• 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.

Answer 36

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

Answer 37

• 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.

Answer 38

* 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

Answer 39

• 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.

Answer 40

• 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

Answer 41

• 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

Answer 42

• 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)

Answer 43

• 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

Answer 44

* 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.

Answer 45

 Secondary active transport of Cl- and HCO3 –  Paracellular Na+ transport  Isosmotic water flow

Answer 46

* Stimulated by CCK, secretin, VIP, glucagon. | * Inhibited by somatostatin.

Answer 47

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.

Answer 48

- 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

Answer 49

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”

Answer 50

* 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.

Answer 51

* 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.

Answer 52

* 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.

Answer 53

* 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).

Answer 54

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”).

Answer 55

transaminase reaction

Answer 56

• 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.

Answer 57

• 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.

Answer 58

* 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

Answer 59

* 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.

Answer 60

* 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).

Answer 61

- 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

Answer 62

* 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.

Answer 63

• 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.

Answer 64

18 - glucose | 19 - fatty acids

Answer 65

• 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.

Answer 66

• 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.

Answer 67

• 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.

Answer 68

• 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.

Answer 69

• Oestrogen, the principal female sex hormone, also causes some deposition of protein, but its effect is relatively insignificant in comparison with that of testosterone.

Answer 70

* 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.

Answer 71

- 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

Answer 72

this is the term used for the absorption, metabolism, and excretion of a drug that has been administered.

Answer 73

* Pharmacokinetics – what the body does to the drug (metabolism). * Pharmacodynamics – what the drug does to the body (effect of drug).

Answer 74

* Stomach (small surface area) | * Small Intestine (large surface area)

Answer 75

* 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’.

Answer 76

are portal/systemic anastomoses

Answer 77

* Lipid-soluble drugs pass through the cell membrane. | * Water-soluble drugs cannot pass through the cell membrane.

Answer 78

its lipid solubility

Answer 79

1. Lipid solubility of the drug  Lipid-soluble can diffuse across cell membrane 2. Blood flow to the tissue/organ 3. 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.

Answer 80

Vd = dose administered / plasma concentration of drug

Answer 81

Drug elimination = metabolism + excretion

Answer 82

* 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

Answer 83

the enzyme-mediated conversion of a lipid-soluble drug into a more water-soluble one, so that it may be excreted.

Answer 84

- 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)

Answer 85

- 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 1. 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. - Usually this would reduce the activity of the drug. - But, for some drugs, their activity is increased – PRODRUGS. 2. 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.

Answer 86

decrease the duration of drug action (e.g. alcohol can cause this/ smoking induces CYP1A2)

Answer 87

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.

Answer 88

CYP3A4 - metabolises 30% of all drugs

Answer 89

1. Pharmacological Activation, e.g. pro-drugs – the drug has increased effect. - levodopa -> dopamine - azathioprine -> 6-metcaptopurine - enalapril -> enalaprilate 2. Pharmacological Inactivation, e.g. paracetamol – the drug has a reduced effect. 3. Change in Type of Pharmacological Response, e.g. diazepam → oxazepam 4. No Change in Pharmacological Activity, e.g. lidocaine → monoethylglycylxylidide 5. 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)

Answer 90

• 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

Answer 91

- 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

Answer 92

- 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

Answer 93

the removal of a drug (drug metabolites (phase 1 and phase 2 products) and water-soluble drugs) from the body.

Answer 94

urine, bile, faeces, lungs and skin.

Answer 95

1. Increase blood flow to the kidneys. | 2. Decrease plasma protein binding.

Answer 96

* 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.

Answer 97

• 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

Answer 98

polymorphisms (due to mutations)

Answer 99

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

Answer 100

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

Answer 101

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.

Answer 102

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]

Answer 103

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

Answer 104

 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.

Answer 105

 AST and ALT will be elevated in a hepatitis infection.  If AST > ALT = alcoholic hepatitis.  If ALT > AST = other causes (mainly viral)

Answer 106

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

Answer 107

* Acute infection = this can be resolved by the body and the symptoms aren’t severe. An acute infection can develop into a chronic infection. * Chronic infection = symptoms are more severe than an acute infection and can develop into cirrhosis/ hepatocellular carcinoma. * Fulminant infection

Answer 108

hep A: enteral (faecal/oral) (contaminated water, food) hep B: parenteral (IVDU, blood trasnfusions, sex, vertical) (blood and body fluids) hep C: parenteral (IVDU, blood transfusions, sex, vertical) hep D: parenteral (IVDU, blood transfusions, sex, vertical) hep E: enteral (faecal/oral) (and via blood and body fluids??)  ENTERAL = this involves the GI tract. The route of transmission can either be ‘oral’ or ‘faecal’.  PARENTERAL = this involves areas other than the GI tract.  Hepatitis A and E viruses have an enteral route of transmission.  Hepatitis B, C and D viruses have a parenteral route of transmission.

Answer 109

hep A: picornavirus hep B: hepadnavirus (DNA) (with multiple ‘subtypes’) hep C: flavivirus hep D: deltavirus (this virus isn't really classified and so is called 'delta'..) hep E: hepevirus (Herpesvirus?)

Answer 110

hep A: RNA (single stranded), no envelope hep B: DNA (double stranded), envelope hep C: RNA (single stranded), envelope hep D: RNA (single stranded), envelope hep E: RNA (single stranded), no envelope  Hepatitis A, C, D and E viruses are RNA. This means that they are single-stranded.  Hepatitis B virus is DNA. This means that it is double-stranded.  Hepatitis A and E viruses don’t have an envelope.  Hepatitis B, C and D viruses have an envelope.  Usually, a virus with doesn’t have an envelope, it will be acquired from the environment (enteral route of transmission).

Answer 111

hep A: yes 'self-limited' hep B: yes hep C: yes hep D: yes (must be coinfected with hep B) hep E: yes 'self-limited' - fulminant in pregnancy  All the hepatitis viruses can infect acutely.  For hepatitis D to infect a person, the person must first be infected by hepatitis B. HEPATITIS D REQUIRES COINFECTION WITH HEPATITIS B!! (HBsAg will be present).  Hepatitis A and E are “self-limiting”.  This means that the colony of these viral cells self-regulate their growth.  For the patient, this means that a hepatitis A/ E acute infection will resolve itself.

Answer 112

hep A: no hep B: yes (can develop into cirrhosis and hepatocellular carcinoma) hep C: yes (can develop into cirrhosis and hepatocellular carcinoma) hep D: yes (can develop into cirrhosis and hepatocellular carcinoma) hep E: no (it can but generally no)  Hepatitis B, C and D can cause chronic infections.  This means that the infection can lead to other pathology, such as cirrhosis and hepatocellular carcinoma. All except Hepatitis A can lead to chronic infection (persistence of infection > 6 months)

Answer 113

 Surface antigens (sAg) = the presence of these indicates the presence of the virus in the body.  Core antigens (cAg) = indicates that the body is producing antibodies against the virus.  Modified core antigens (eAg) = the presence of these indicates the viral cell is actively replicating. This means the person has higher infectability.

Answer 114

 IgM – this is the iMMediate response |  IgG – this is the chronic response

Answer 115

 HBsAg = this is the surface antigen found on the envelope of HBV.  HBcAg = this is the core antigen found around the nucleus of HBV.  HBeAg = this is the modified c antigen that appears when the viral cell is actively replicating.  Anti-HBs antibody = the presence of this would give the person immunity against HBV  Anti-HBc antibody = this can be HBc IgM (immediate) or HBc IgG (chronic)  Anti-HBe antibody = the presence of this would reduce infectability.

Answer 116

• The hepatitis A virus (HAV) belongs to the picornavirus group of enteroviruses. • HAV is highly infectious and is spread by the faecal-oral route. • Hepatitis A infection is usually asymptomatic because the virus remains in the faeces for about 2-3 weeks before the onset of symptoms for a further 2 weeks or so. - incubation periods = 30 days (4-6 weeks) (2-6 weeks = relatively short) • Infection is common in children, in areas of overcrowding, and areas of poor sanitation/ underdeveloped areas. • HEPATITIS A INFECTION IS ALWAYS ACUTE!!!

Answer 117

* High prevalence areas include: Africa, Asia, Central & S. America – high risk to travellers to these areas. * This virus can be found in raw shellfish, if the fish was found in a river that is contaminated, and the fish itself hasn’t been cooked properly. * Decreasing incidence in UK, now uncommon. Faecal oral transmission, associated with poor sanitation: Endemic in developing world - Infection in childhood - Mild or subclinical (>90% if < 5yrs) In developed world - Disease of adults - Contaminated food/water, travel to endemic countries, MSM (men who have sex with men), IVDU (intravenous drug user), occupational

Answer 118

* Travel to endemic areas * Household contact * Contaminated food (Salads/ Berries/ Tomatoes – sundried) * Sex risk (especially male homosexuals)

Answer 119

* The HAV carries a HAV antigen. * Individuals infected by HAV make an antibody against the HAV antigen (anti-HAV). * Anti-HAV of the IgM type = indicates a primary immune response (diagnostic of an acute HAV infection). * Anti-HAV of the IgG type = this antibody persists for years after infection (no diagnostic value), but it can be used as a marker of previous HAV infections. Its presence indicates immunity to HAV. Diagnosis - Acute infection HAV IgM (comes first) - Recovery (or vaccinated) HAV IgG (comes later, in the recovery stage) ACUTE HEPATITIS A (AND E) TYPICAL SEROLOGICAL COURSE - IgG remains – can see if someone’s previously had hep A because IgG will remain in the serum - Hepatitis A doesn’t become chronic, just E

Answer 120

• Human normal immunoglobulin (immunoglobulin/antibody replacement therapy)  After contact with case. • Hepatitis A vaccination (e.g. Harvix)  After contact  Before travel to endemic areas  Higher risk groups - Occupational (e.g. sewage workers, primate handlers) - Drug users, prisoners - MSMs • Infection is best prevented by improving social conditions, especially overcrowding and poor sanitation. ``` Prevention - Vaccine (given at 0, 6-12 months) - Immunoglobulin - Improvement in sanitation Declining incidence in UK since 2005 (330 cases in 2015) ```

Answer 121

• Incubation Period – 2-6 weeks • Normally:  ACUTE, self-limited, mild  NEVER CHRONIC  Jaundice about 1 week, LFTs up for 3 weeks  Often asymptomatic, especially children • Cholestatic:  <10%, LFTs (liver function tests) up to 3-4 months, pale stools, dark urine, itch • Relapsing:  <10%, illness and virus reappear at 10-20 weeks

Answer 122

* Incubation Period = 4-20 weeks (75 days - 6 weeks to 6 months = longer) * Many people have no symptoms during the initial infection but some develop a rapid onset of sickness with vomiting, yellow skin, feeling tired, dark urine and abdominal pain. * Often these symptoms last a few weeks and rarely does the initial infection result in death. * It may take 30 to 180 days for symptoms to begin.

Answer 123

* Working in healthcare * Blood transfusions * Dialysis * Living with an infected person * Travel in countries where the infection rate is high * Sex * Mother with Hep B

Answer 124

• >2000 million have had infection • 367 million carriers (WHO estimate) • 177 countries universal vaccination • In Europe:  1 million new cases per year  40000 at risk of progression to cirrhosis  20000 at risk of primary liver cancer • Universal vaccination - except UK, Scandinavia - Approx. 350 million infected, (180,000 in UK), > 0.6 million deaths/year from end stage liver disease and liver cancer 45% of the global population lives in areas with a high prevalence of HBV infection - High = > 8% of population being infected

Answer 125

* A current infection is indicated by the presence of HBsAg (antigens on the Hep B virus) in the blood. * A past infection is indicated by the presence of anti-HBs antibodies in the blood. ``` • N.Europe, USA, Australasia  HBsAg 0.2-0.5%  anti-HBs antibody 4-6% • E.Europe, S.Europe, USSR, S.America  HBsAg 2-7 %  anti-HBs 20-50% • China, S.East Asia, sub-Saharan Africa  HBsAg 8-20%  anti-HBs 70-95% ```

Answer 126

first IgM anti-HBc and then IgG anti-HBc

Answer 127

• Blood – form mother in utero (perinatal) • Intravenous drug users (IVDU), transfusions • Body fluids –genital secretions (heterosexual, male homosexual • Vertical – birth  HBsAg Positive HBeAg Positive mother - >90% chance of transmission  HBsAg Positive HBeAg negative mother - <10% transmission rate (Unless HBV DNA >1 million copies/ml) • Breast milk (?) • Percutaneous/ permucosal ``` Contact with infected blood: - IVDU - Unsterile tattooing - Piercing - Shaving equipment - Contaminated blood products - Non-sterile medical equipment Sexual: (sexually-transmitted disease) - Unprotected sex - Multiple partners Mother to baby: - Most important route globally (high risk of chronicity – baby -> chronic) ``` - Usually spread from infected pregnant women to their babies, or from child-to-child contact - In rare cases, can be spread through unprotected sex and injecting drugs

Answer 128

- the younger you are the less symptoms - at birth never symptomatic infection - 7-12 months some are symptomatic and increases from here - 90% chronic infection at birth - 10% chronic infection children older than 4 - Infected at birth – infection asymptomatic but 90% likely to be chronic - As you get older more likely to have a symptomatic infection and more likely to clear the infection and not have it as chronic - Children over 4 years and adults have very low risk of chronic infection

Answer 129

1. HBV binds to the NTCP bile receptor on hepatocytes. This allows the virus to enter the cell. 2. The HBV DNA is partially double stranded. 3. The viral DNA enters the host cell nucleus and uses the host cell’s DNA to complete its DNA from partially double-stranded to a ‘covalently closed circular DNA’ (cccDNA). 4. The viral DNA is now transcribed into viral RNA. 5. This is then translated to produce viral antigens and other viral proteins. 6. The viral RNA undergoes reverse transcription in the viral nucleocapsid to form its partially double stranded DNA once again. 7. This is now packaged within the viral antigens. 8. This is then exocytosed and infects other cells.

Answer 130

1. Is the person currently infected with hepatitis B? Hepatitis B surface antigen (HBsAg) POSITIVE – refer these people to secondary care. Vaccinate their contacts. Hepatitis B surface antigen (HBsAg) NEGATIVE – not currently infected but may have been exposed to infection. 2. Has the person ever been exposed to hepatitis B? Total antibody to hepatitis B core antigen (anit-HBc)

Answer 131

1. Whether this is an acute infection o Indicated by IgM antibody to core antigen (anti-HBc IgM) 2. How infectious the patient is to their contacts o Positive for e antigen (HBeAg) and/or high levels of HBV DNA

Answer 132

1. Whether the person has ever been exposed to hepatitis B o Indicated by total antibody to core antigen (anti-HBc) 2. Whether the person is immune to hepatitis B o Indicated by being positive for antibody to HBsAg (anti-HBs). o If not known, or low levels, complete vaccination course.

Answer 133

Anti-HBc IgG + HBsAg

Answer 134

Anti-HBc IgG + Anti-HBsAg

Answer 135

- HBsAg + = current infection (acute or chronic) - anti-HBc + = infection at some time (current or past) - anti-BHc IgM+ = recent (acute) infection - anti-HBs + = past infection: anti-HBc +, vaccination: if no other HBV markers also HBeAg+ HBV DNA - infectivity

Answer 136

1) Immune tolerance 2) Immune clearance 3) Low replication inactive carrier 4) Reactivation

Answer 137

- HBeAg+ - HBV DNA high + - ALT normal - low - mild liver inflammation, little fibrosis - Immune tolerant (this is more for neonates or babies than adults)

Answer 138

- HBeAg + (but decreasing) with appearance of anti-HBe - HBV DNA high + - ALT raised, fluctuating - moderate to severe liver inflammation, progressive fibrosis - Immune clearance (HBeAg-positive chronic hepatitis)

Answer 139

- anti-HBe+ - HBV DNA - or low+ - ALT normal - possible HBsAg loss

Answer 140

- HBeAg - but mutant viruses - HBV DNA and ALT raised intermittently - inflammation in liver - Reactivation (HBeAg-negative chronic hepatitis)

Answer 141

• To convert HBV from High replication phase to a Low replication phase  HBeAg + to anti-HBe  ALT normalization  Reduced hepatic inflammation • Prevent histological progression – Decrease risk of progression to cirrhosis and HCC • 20-40% cases seroconvert to anti-HBe

Answer 142

• Interferon  If HBeAg+ low HBV DNA  more chance of losing HBsAg but side effects • Nucleoside analogues (NUCs) - Fall to <15 IU/mL HBV DNA by 48 weeks • Lamivudine (3 TC) – Adefovir + Entecavir + Tenofovir (these are same as lamivudine) - these are all nucleoside reverse transcriptase inhibitors (NRTIs)

Answer 143

• Vaccination is recommended by the World Health Organization in the first day of life if possible. • Two or three more doses are required at a later time for full effect (0 months, 1 month, 6 months). • This vaccine works about 95% of the time. • Use in UK for people at high risk including:  Close family members & sexual partners of carriers  Healthcare workers  Drug users, prisoners  Male homosexuals  Babies born to HBV carrier mothers • It is also recommended that all blood be tested for hepatitis B before transfusion and condoms be used to prevent infection. - Prevention: vaccine (3 doses at 0, 6 weeks, 6 months – 2018 introduced) - Hepatitis B vaccination is routinely available as part of the NHS vaccination schedule – it’s offered to all babies at 8, 12 and 16 weeks of age

Answer 144

• Antenatal screening - HBsAg positive woman:  If HBeAg positive mother - Active infection, High HBV viral load - Hepatitis B immunoglobulin plus - Hepatitis B vaccine o Accelerated schedule (0, 1m, 2m, 12m)  If anti-HBe positive mother - Hepatitis B vaccine only o Accelerated schedule (0, 1m, 2m, 12m)

Answer 145

• Non-A, Non-B (NANB) Hepatitis. • Flavivirus (six major subtypes (genotype 1-6))  RNA virus 1989  Hepacivirus genus • Incubation period:  Average 6-7 weeks  Range 2-26 weeks (2 weeks - 6 months)(even then symptoms can be very mild and then go and then they come back in years when it turns chronic) • Acute illness (jaundice) Mild (≤20%) - Acute infection often asymptomatic • Case fatality rate Low • Chronic infection - 60%-85% (75% develop chronic infection irrespective of age, immune status) - No vaccine available – virus mutates – quasispecies – many forms of virus in body – difficult to pick out one single antigen that you can make the antibodies against

Answer 146

• Blood transfusion pre-1991 (blood < 1991, clotting factors < 1986) • IVDU 50-70% seropositive (shared needles is a big one) - Non-sterile tattoos, body piercing, shaving • Dialysis esp. abroad • HCW 3% risk from needle stick • Sex low risk - Rare in heterosexuals - Reported in HIV MSM (‘chemsex’ – consumption of drugs to facilitated sexual activity) • Vertical: 3-5% risk from HCV PCR+, 17% if HIV+

Answer 147

• HCV antibody  Total antibody  Slow response : 8-12 weeks  No IgM assay • HCV PCR  Appears early  Marker of infectivity and active infection  Monitor HCV RNA viral load for treatment response HCV antibody (AB) -> - HCV AB negative = no exposure - HCV AB positive, check HCV RNA if negative = prior exposure - HCV AB positive, HCV RNA positive = chronic infection (could be acute, depends on context) • Hepatitis C RNA test for active hepatitis C and genotyping (if this has not been requested already).

Answer 148

``` • Combination therapy 24-48 weeks • Pegylated interferon-α weekly • Ribavirin  RNA-dependent RNA polymerase inhibitor  Reduces GTP pool  RNA mutagen giving defective HCV (“error catastrophe”)  Immunomodulator ```

Answer 149

• Sustained Viral Response  Undetectable HCV RNA 6months post-treatment  40-80% of cases with IFN/ribavirin • Important to test:  Ever injected illegal drugs  Received clotting factors made before 1987  Received blood/organs before July 1992  Ever on chronic haemodialysis  Evidence of liver disease • Early treatment  Blood exposure eg Health Care Workers, baby ‘life cycle takes place in cytoplasm, no viral ‘reservoir’ = chronic infection is curable - Unlike hep B, which is uncurable, due to the fact that there is a step in the nucleus – not all in the cytoplasm

Answer 150

``` • Telaprevir, Bocepravir  Protease inhibitors  >70% response at 12 weeks genotype 1 - Cf 40% G1 IFN/ribavirin • Simeprevir  good response G1 if Q80K negative • Polymerase inhibitors  Sofusbuvir • Interferon-free treatments  daclatasvir + asunaprevir  ombitasvir–ABT-450/r and dasabuvir with ribavirin  sofosbuvir + simepravir ```

Answer 151

• Can only occur in presence of hepatitis B. - Defective RNA virus needs Hep B machinery to replicate (uses surface antigen for envelope) (dependent on another virus as well as humans) • Transmission by blood, especially IVDU, sex • Two forms of infection:  Coinfection with HBV - HDV acquired at same time as HBV. - Increase in fulminant hepatitis.  Superinfection - HDV acquired by hepatitis B carrier. - High risk of progression to cirrhosis - 70% - High risk of hepatocellular carcinoma - 16% (Lifetime risk of HCC (hepatocellular carcinoma) doubled) - 5-20 million cases globally (5% of HBV) - ‘pockets’ in Mediterranean basin, Turkey, Russia, Central Asia, Africa, S America - Don’t see much in UK

Answer 152

• Hepatitis E is caused by an RNA virus which is endemic in India and the Middle East.  20 million infections per year  3 million acute cases  57000 HEV-related deaths – principally due to genotypes 1,2 • Incubation period 15-60 days (mean 40 days). - Faeco-oral transmission - HEV contaminant of blood supply in many countries ``` • Symptoms  Jaundice  Abdominal pain  Nausea and vomiting  Anorexia • Commonly anicteric in children • High death rate in pregnant women  Overall death rate 1-2 % (cf hepatitis A <0.4%)  Death rate in pregnancy 15-25% • May become chronic in immunocompromised. HEPATITIS E INFECTION IS ALWAYS ACUTE!!! ```

Answer 153

• Endemic areas - 3.4 million acute cases globally (Pakistan, India, Mexico)  India, Pakistan, Nepal, China, Central Asia, Mexico (High seroprevalence to anti-HEV 11-25%) • Non-endemic areas  Western Europe, USA

Answer 154

• 11-25% seropositive in endemic areas • Commonest cause of sporadic hepatitis in adults in endemic areas. • Faecal-oral transmission:  70% infections in childhood  70% waterborne, 20% food • Outbreaks – waterborne  Faecal contamination of water • The prevalence rates are on the increase in UK. - Now most common cause of acute Viral Hepatitis in the UK (eclipsed hep A)

Answer 155

• Sanitation and clean water • (Immunoglobulin) – Little evidence of benefit • Vaccination (HEV 239 ‘Hecolin’) • NIAID/Novavax recombinant vaccine  Baculovirus expressed capsid antigens (HEV ORF-2)  Human Phase II trials in Nepal : 87% effective - Prevention: improvements in sanitation - Vaccine: Hecolin® (China only), recombinant vaccine

Answer 156

• Jaundice - refers to a yellowish tint to the body tissues, including a yellowness of the skin as well as the deep tissues. • It is caused by large quantities of bilirubin (free or conjugated) in the extracellular fluids: I. Pre-hepatic Jaundice II. Intra-hepatic Jaundice III. Post-hepatic Jaundice

Answer 157

* The normal plasma concentration of bilirubin, which is almost entirely the free form, averages 0.5 mg/dl of plasma. * In certain abnormal conditions, this can rise to as high as 40 mg/dl, and much of it can become the conjugated type. * The skin usually begins to appear jaundiced when the concentration rises to about three times normal—that is, above 1.5 mg/dl.

Answer 158

• This is caused either by haemolysis or by congenital hyperbilirubinaemia, and is characterised by an isolated raised bilirubin level (other liver biochemistry remains normal). • Haemolysis:  This is the destruction of RBCs or their precursors in the bone marrow.  This causes increased bilirubin production.  Therefore, the plasma concentration of unconjugated bilirubin rises to above normal levels.  Likewise, the rate of formation of urobilinogen in the intestine is greatly increased, and much of this is absorbed into the blood and later excreted in the urine. • Jaundice due to haemolysis is usually mild because a healthy liver can excrete a bilirubin load six times greater than normal before unconjugated bilirubin accumulates in the plasma.

Answer 159

Intra-hepatic Jaundice/ Hepatocellular Jaundice • This is caused by impaired cellular uptake, defective conjugation or abnormal secretion of bilirubin by hepatocytes, occurring as a consequence of parenchymal liver disease. • Bilirubin transport across the hepatocytes may be impaired at any point between uptake of unconjugated bilirubin into the cells and transport of conjugated bilirubin into the canaliculi. • In hepatocellular jaundice the concentrations of both unconjugated and conjugated bilirubin in the blood increase. • Hepatocellular jaundice can be due to acute or chronic liver injury and clinical features of acute or chronic liver disease may be detected clinically. * Characteristically, jaundice due to parenchymal liver disease is associated with increases in transaminases (AST, ALT), but increases in other LFTs, including GGT and ALP may occur, and suggest specific aetiologies. * Acute jaundice in the presence of raised AST is highly suggestive of an infectious cause (e.g. hepatitis A, B), drugs (e.g. paracetamol) or hepatic ischaemia.

Answer 160

Post-hepatic Jaundice/Obstructive (Cholestatic) Jaundice • Obstructive jaundice is caused by:  Failure of hepatocytes to initiate bile flow.  Obstruction of bile flow in the bile ducts or portal tracts.  Obstruction of bile flow in the extrahepatic bile ducts between the porta hepatis and the papilla of Vater.

Answer 161

• In obstructive jaundice, caused either by obstruction of the bile ducts (e.g. gallstone/ cancer blocking the common bile duct) or by damage to the hepatic cells (which occurs in hepatitis), the rate of bilirubin formation is normal, but the bilirubin formed cannot pass into the intestines. • The unconjugated bilirubin still enters the liver cells and becomes conjugated in the usual way. • This conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood.  Thus, most of the bilirubin in the plasma becomes the conjugated type rather than the unconjugated type. • Essentially, in cholestatic jaundice occurs because:  The conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood.  There is a failure of clearance of unconjugated bilirubin arriving at the liver.

Answer 162

* When there is total obstruction of bile flow, no bilirubin can reach the intestines to be converted into urobilinogen by bacteria. * Therefore, no urobilinogen is reabsorbed into the blood, and none can be excreted by the kidneys into the urine (urobilin). * Consequently, in total obstructive jaundice, tests for urobilinogen in the urine are completely negative. * Also, the stools become clay (pale) coloured owing to a lack of stercobilin.

Answer 163

pre-hepatic: isolated unconjugated bilirubin intra-hepatic jaundice: unconjugated bilirubin, conjugated bilirubin post-hepatic: conjugated bilirubin

Answer 164

Intra-hepatic: - transaminases (ALT and AST) - Gamma-glutamyl transpeptidase (GGT) - alkaline phosphatase (ALP)

Answer 165

pre-hepatic: - normal stool colour - normal urine colour - no itchy skin Intra-hepatic: - normal stool colour - dark urine (lack or urobilin) - no itchy skin Post-hepatic: - pale stool (lack of stercobilin) - dark urine (lack of urobilin) - itchy skin (pruritus)

Answer 166

• Hepatic cirrhosis is a common disease characterised by diffuse hepatic fibrosis and nodule formation. • It can occur at any age, has significant morbidity and is an important cause of premature death. • Worldwide, the most common causes of cirrhosis are:  Chronic viral hepatitis (B or C)  Prolonged excessive alcohol consumption  Chronic use of alcohol raises the mean corpuscular volume (MCV) and the enzyme GGT. • Cirrhosis is the most common cause of portal hypertension and its associated complications. • Any condition leading to persistent or recurrent hepatocyte death, such as chronic hepatitis C infection, may lead to cirrhosis.

Answer 167

 An increase in fibrous tissue  Progressive and widespread death of liver cells  Inflammation leading to loss of normal liver architecture

Answer 168

* Following liver injury, stellate cells in the space of Disse are activated by cytokines produced by Kupffer cells and hepatocytes. * This transforms the stellate cell into a myofibroblast-like cell, capable of producing collagen, pro-inflammatory cytokines and other mediators which promote hepatocyte damage and cause tissue fibrosis. * Destruction of liver architecture causes distortion and loss of normal hepatic vasculature with the development of portosystemic vascular shunts and the formation of nodules. * Cirrhosis evolves slowly over years to decades, and normally continues to progress even after the removal of the aetiology agent (e.g. abstinence of alcohol).

Answer 169

* Cirrhosis is a histological diagnosis characterised by diffuse hepatic fibrosis and nodule formation. * These changes usually affect the whole liver.

Answer 170

hepatitis or autoimmune liver disease.

Answer 171

• The symptoms are often non-specific and include: ```  Weakness and fatigue  Muscle cramps  Weight loss  Anorexia  Nausea and vomiting  Upper abdominal discomfort ```

Answer 172

``` include the measurement of serum:  Bilirubin  Aminotransferases  Alkaline phosphatase  Gamma-glutamyl transferase  Albumin ```

Answer 173

These tests do not assess the functioning of the liver, but rather provide biochemical markers of liver cell damage.

Answer 174

Bilirubin (<17μmol/L) • The degree of elevation of bilirubin reflects the degree of severity of liver damage. • A raised bilirubin often occurs earlier in the natural history of biliary disease (e.g. primary biliary cirrhosis) than in disease of the liver parenchyma (e.g. cirrhosis) where the hepatocytes are primarily involved.

Answer 175

* Serum albumin levels are reduced in patients with liver disease. * This is due to the change in the volume of distribution of albumin, as well as reduction in synthesis. * Since the plasma half-life of albumin is about 2 weeks, serum albumin levels may be normal in acute liver failure but are almost always reduced in chronic liver failure.

Answer 176

Alanine Aminotransferase, ALT (<40 U/L) and Asparate Aminotransferase, AST (<35 U/L) • Alanine aminotransferase (ALT) and Asparate aminotransferase (AST) normally transfer the amino group from an amino acid – alanine in the case of ALT and asparate in the case of AST – to a ketoacid, producing pyruvate and oxaloacetate respectively. • Both ALT and AST are located in the cytoplasm of the hepatocyte. • AST is also located in the cytoplasm of the mitochondria. • Although both transaminase enzymes are widely distributed, expression of ALT outside the liver is relatively low and therefore this enzyme is considered more specific for hepatocellular damage. • Large increases (>300 U/L) of aminotransferase activity favour hepatocellular damage, and this pattern of LFT abnormality is known as ‘hepatitic’.

Answer 177

* Alkaline Phosphatase (ALP) is the collective name given to the several different enzymes that are capable of hydrolysing phosphate esters at alkaline pH. * These enzymes are widely distributed around the body, but the main sites of production are the liver, GI tract, bone, placenta and kidney. * ALP enzymes in the liver are located in cell membranes of hepatic sinusoids and the biliary canaliculi/ducts. * ALP rise in plasma concentration is indicative of intrahepatic and extrahepatic biliary obstruction and with sinusoidal obstruction, as occurs in infiltrative liver disease.

Answer 178

* Gamma-Glutamyl Transferase (GGT) is a microsomal enzyme produced in high concentrations by hepatocytes and by the epithelium lining of the small bile ducts. * The function of GGT is to transfer glutamyl groups from gamma-glutamyl peptides to other peptides and amino acids. * The pattern of a modest increase in aminotransferase activity and large increases in ALP and GGT activity favours biliary obstruction and is commonly described as ‘cholestatic’ or ‘obstructive’.

Answer 179

hepatitic: big increase in AST/ALT, small increase GGT and ALP cholestatic/obstructive: small increase AST/ALT, moderate increase GGT, big increase ALP

Answer 180

Hepatitis viruses: non-cytopathic (what causes the damage is the immune response) Hepatocyte damage is immune-mediated (damage depends on how strong your immune response is) Antigen recognition by cytotoxic T cells: apoptosis Chemokine driven recruitment of Ag-nonspecific cells Depending on strength of immune response Mild inflammation to massive necrosis of liver (‘fulminant’ hepatitis, acute liver failure)

Answer 181

Injury to hepatocytes -> necrosis (release contents into the blood stream) - Alanine transaminase ALT >35 U/L - Aspartate transaminase AST > 40 U/L Injury to bile canaliculi (Cholestasis) - Alkaline phosphatase ALP >150 U/L - Bilirubin Bili >21 umol/L Assess synthetic function with INR (prothrombin time – blood test that measures how long it takes blood to clot), Albumin (measure these values everyday)

Answer 182

you shouldn’t measure ALT or AST to measure it, as once you destroy your liver cells, there isn’t much ALT or AST to go into the bloodstream – therefore you assess synthetic function

Answer 183

Sequelae of ongoing inflammation -> liver fibrosis Progression of fibrosis to cirrhosis (20-30 years) accelerated by co-factors - Alcohol, HIV, diabetes, steatohepatitis (liver stores fat, but if you lay down too much fat in the liver it becomes to become an irritant – so the inflammation can lead to fibrosis) Asymptomatic, until liver decompensation Liver biopsy - Can also diagnose fibrosis/cirrhosis with non-invasive methods, e.g. elastrography, Fibrotest™ - The fibroscan has pretty much replaced biopsies - These tests don’t show the aetiology however

Answer 184

Spectrum of presentation: depends on age and immune status (all of the viruses present quite similarly) - Asymptomatic vs. mild, non-specific v. ‘fulminant’ (severe and sudden in onset) - Prodrome (early symptom indicating onset of a disease) of nausea, fatigue, malaise, fever - Jaundice, dark urine, pale stools - RUQ (right upper quadrant) tenderness, hepatomegaly

Answer 185

Investigations: - Elevated ALT, AST (can be > 1000U/L) - Bilirubin, ALP less marked - Full blood count, INR - Liver ultrasound to rule out obstruction ‘viral screen’: - Hepatitis A antibody (IgM) - Hepatitis B surface (Ag) - Hepatitis C antibody - Consider Hep E IgM

Answer 186

- Prolonged cholestasis (cholestasis = reduction or stoppage of bile flow) - Liver failure Rare but more likely in older adults, pre-existing liver disease

Answer 187

- Epidemiology is genotype specific - Genotype 1,2 large ‘water borne’ outbreaks - Genotype 3,4 (seeing more of these cases in UK) zoonotic, sporadic cases associated with undercooked pork, wild boar, deer

Answer 188

HEV IgM (hepatitis E IgG (recovery), HEV RNA blood, stool)

Answer 189

- Higher mortality in cirrhotics, pregnant women (30% in 3rd trimester) - Linked to range of acute neurological syndromes - Genotypes 3,4 can become ‘chronic’ in immunosuppressed - At risk: solid organ and stem cell transplant patients, neonates, age <1, HIV with CD4 < 250

Answer 190

maturity of immune system and effectiveness of response

Answer 191

- UK prevalence 0.3% - Most new infections occur in adults, by sexual or parenteral route (intravenous drug use) - Screening programmes: identify non-immune, and chronic infections -antenatal clinics (mother HBV sAg +ve, vaccination of baby +/- Ig – prevent the baby getting virus) -prisons -GUM (genitourinary medicine) clinics, Community Drugs Services 95% of ‘new’ cases of chronic infection are immigrants from high prevalence areas

Answer 192

Surface Ag > 6 months defines chronic infection Prior vaccination – Hepatitis B surface antibody only – what the vaccination makes you produce - Hepatitis B surface Antigen HBsAg (this is the hallmark of the infection – if you don’t have the antigen then you don’t have an ongoing infection – whether you have acute or chronic)

Answer 193

- HBsAg antigen first in blood – four weeks after exposure - Then HBeAg antigen - If you’re clearing the virus, then both of these antigens drop and then you’re making the antibodies - IgM anti-HBc first, then goes away - Then IgG comes up later - Anti-HBe - Anti-HBs

Answer 194

HBV surface Ag, Core Antibody (IgM, IgG) -> - HBV sAg Negative, Core Ab Negative = no exposure, may need vaccine - HBV sAg Negative, Core Ab Positive = previous exposure, but did not become chronic (if recent exposure, IgM will be detectable, if exposed years ago you will only have IgG and not Igm) - HBV sAg Positive, Core Ab Positive = active infection, put into context to know if acute or chronic – if no jaundice or raised ALT, most likely chronic

Answer 195

The two blood tests to diagnose if got hep B and whether acute or chronic = surface antigen and core antibody

Answer 196

if no jaundice or raised ALT, most likely chronic | so more likely acute

Answer 197

Complex interaction between virus and immune response - Fluctuating ALT and level of virus (HBV DNA) - When immune system active: hepatocyte destruction - Cycles of inflammation and repair -> fibrosis Fibrosis can progress to cirrhosis 2-10% per year - At times immune system will have the upper hand and the destruction of liver cells will go up and the ALT level will increase and the virus level will be low – if you’re lucky you will clear the virus, if not you will stay in this phase for years which is the most dangerous stage as it will lead to cycles of inflammation - And there will be times when the virus will have the upper hand, so it’ll be replicating a lot but the immune system will be ignoring it, so the ALT will be low

Answer 198

- Covalently closed circular DNA (cccDNA) Tenofovir, Entecavir = good at preventing inflammation and stopping progressing, but not good at getting rid of the virus Interferon = stimulates immune response - When works, works really well - It makes immune system attack the infected hepatocyte and destroy it – get rid of the cccDNA - Only works in less than 1/3 patients

Answer 199

- Prevention Clearance of HBV sAg -> eradication of Delta - PEG IFN for > 48 weeks - Not antiviral drugs for this – so you have to try and get rid of the hep B surface antigen – use interferon but not very good - Hepatitis B vaccine

Answer 200

Hepatits Delta IgM, IgG, HDV RNA

Answer 201

For every 100 people infected with Hepatitis C virus: - 75-85 will develop chronic infection - 60-70 will develop chronic liver disease - 5-20 will develop cirrhosis - 1-5 will die of cirrhosis or liver cancer

Answer 202

- Globally 180 million infected > 350,000 deaths/year (UK estimates 214,000) GLOBAL PREVALENCE OF HCV - Egypt has highest prevalence - Pakistan has high prevalence HCV: UK EPIDEMIOLOGY - Overall UK prevalence Hep C antibody 0.44% - Acute infections occur mainly in IVDU - Anonymous monitoring survey 2015 52% IVDU Hep C antibody positive - ‘new’ cases of chronic infections immigrant populations from high prevalence areas (Pakistan, Bangladesh) - HCV often acquired in childhood associated with poor sterilisation practices

Answer 203

- Designed to block certain enzymes in the virus life cycle - Block NS3 helicase/protease - Block NS5B RNA polymersase

Answer 204

Progression to decompensated liver disease and hepatocellular carcinoma - With hep B you don’t need to be cirrhotic to have a risk of liver cancer, you can get liver cancer at any time along your natural history – it’s a oncogenic virus - Complications of portal hypertension Decompensated liver disease: 50% 5 years survival - Need to screen and diagnose before onset of irreversible liver damage

Answer 205

- Ascites - Variceal bleeding - Encephalopathy - Subacute bacterial peritonitis - Acute on chronic liver failure

Answer 206

compensated cirrhosis = you won’t have any symptoms – your liver can still do its job because here are enough healthy cells to make up for the damaged cells and scar tissue caused by cirrhosis decompensated cirrhosis = your liver has too much scarring and you develop complications

Answer 207

- Via portal vein, receives blood (and nutrients) from spleen and from most of the GI tract, esp. stomach, pancreas, duodenum and mesentery - Responds to insulin and glucagon - Processing of carbohydrates, lipids and amino acids depending on physiological condition - Goes to liver first before going to heart and lungs

Answer 208

``` glycolysis = happens everywhere gluconeogenesis = almost exclusive to the liver ```

Answer 209

- hepatic glucose production (HGP): glycogenolysis and gluconeogenesis - high blood glucose normally supresses HGP via insulin – failure to regulate HGP is the main reason for hyperglycaemia in type II diabetes mellitus

Answer 210

- Glycolysis - Synthesis of glycogen and fatty acids - Absorptive state

Answer 211

- Gluconeogenesis - Degradation of glycogen and fatty acids - Fasting state

Answer 212

- Glucose goes into liver through GLUT-2 (doesn’t normally take up glucose unless there is plenty around - Glucose turned into glucose-6-P (by glucokinase) (central hub – can make many different things from it)  Glycogen (glycogenesis)  Pyruvate -> acetyl-CoA -> fatty acids -> TAG (triacylglycerol)  PPP (pentose phosphate pathways) -> NADPH – this is needed to make fatty acids (liver uses excess glucose to make storage forms – glycogen or TAG)

Answer 213

- Glycogen –> glucose-6-P (glycogenolysis) -> glucose (by glucose-6-phosphatase – unique to the liver) (glycogen stores don’t last very long – can just about tie you over at night) - Hydrolysis of TAGs (if use up glycogen supplies I think) -> fatty acids -> acetyl-CoA (you can never turn fatty acids back into sugar – only sugar into fatty acids) -> pyruvate (via Krebs cycle or something complicated – through ketogenic pathway) - Acetyl-CoA -> ketone bodies (ketogenesis) (emergency fuel – if fasting for several days) - Lactate, amino acids -> pyruvate (TCA/Krebs cycle) -> glucose-6-P -> glucose (do this step before producing ketone bodies)

Answer 214

- Catabolism (breaking down) of glucose (and most other carbohydrates via glucose) in all tissues - Generation of intermediates for other pathways - Generation of energy and (in aerobic conditions) reducing equivalents - End product depends on O2 – pyruvate under aerobic conditions, lactate under anaerobic conditions

Answer 215

- A family of glucose transporters (GLUT) facilitates diffusion of glucose into cells - Many are tissue-specific: GLUT-4 (sensitive to insulin) in adipose tissue; GLUT-2 in liver - GLUT-2 (not regulated (by insulin), it’s there all the time) can facilitate both glucose entry into liver cells and exit (liver can’t take up glucose unless there’s a lot of it around after a meal)

Answer 216

- Phosphorylation traps glucose in the cell, because the ionic phosphate cannot cross the membrane spontaneously (glucose -> glucose-6-P (using 1 ATP)) - The reaction is catalysed by the enzyme hexokinase – enzyme variants in most tissues (hexokinase I-III) are relatively slow but are fully active at very low concentrations of glucose - Hexokinase-IV, or glucokinase, in the liver has a much higher capacity to trap glucose in the liver, but only when glucose concentrations are high – e.g. after a meal

Answer 217

- Hexokinase I-III – constant enzyme activity at all glucose levels - Hexokinase IV – little activity at low glucose concentrations but increases a lot, higher than the other enzymes, when glucose concentration increases - Therefore liver is able to trap a lot more glucose than other tissues, if you have an abundance of glucose around

Answer 218

- Glucose-6-P is isomerised to fructose-6-P - F-6-P is phosphorylated again to yield F-1, 6-BP in the most critical regulated step (after this step there is no return to glucose – only do it if there is enough glucose around) - The C6 molecule F-1, 6-BP is cleaved into two C3 molecules - In the only oxidative step of glycolysis, GA-3P is converted to 1,3-BPG - NADH + H+ generated in this oxidative step can be regenerated under anaerobic conditions by reducing pyruvate to lactate - This happens in exercising skeletal muscle and poorly vascularised and/or mitochondria-free tissues - The liver can re-oxidase lactate to pyruvate

Answer 219

- 1,3-BPG and PEP are high-energy compounds that can transfer phosphate to ADP (substrate level phosphorylation) – that way, 4 ATP are generated from each molecule of F-1,6 - Accounting for the “investment” of 2 ATP per molecule glucose early on, there is a net generation of 2ATP per glucose in glycolysis - Pyruvate kinase, the last enzyme of glycolysis, is activated by Fructose-1,6-bisphosphate (feed forward activation!) and repressed by glucagon (because they reload glucose levels – don’t want to burn sugar, want to make it available to the body)

Answer 220

by brain and nervous tissue, and essential for the adrenal medulla, testes and mature erythrocytes

Answer 221

performing these two maintenance mechanisms: glycogenesis, glycogenolysis & gluconeogenesis (almost reverse of glycolysis but not quite)

Answer 222

- Is a highly branched, all-glucose poly-saccharide with an α-1,4-linked backbone and α-1,6-linked branches - Resembles the amylopectin component of plant starch but is more highly branched - Is the storage form of glucose, mainly in skeletal muscle (1-2% by weight, total ~400g) and liver (up to 10% by weight, total ~100g) - Synthesis after a meal and degradation during an overnight fast are key mechanisms that maintain blood glucose levels and are regulated by glucagon Glucose -> glucose-6-P glucose-1-P

Answer 223

during an overnight fast, but not much longer

Answer 224

- Glycogen stores in the liver can supply glucose-dependent tissues with most of the fuel during an overnight fast, but not much longer - Gluconeogenesis is a pathway active in the liver (and after prolonged fasting, the kidney) that regenerates glucose from non-carbohydrate precursors: - lactate from skeletal muscle is re-oxidised to pyruvate – this liver-muscle cycle is called Cori Cycle - glycerol is released by the hydrolysis of fat (TAGs) in adipocytes - amino acids from tissue protein are metabolised to alpha-keto acids like oxaloacetate and alpha-ketoglutarate (transamination – getting rid of nitrogen atom) – feed into TCA cycle

Answer 225

- Increase glucose uptake (more in peripheral tissues) - Increase protein synthesis - Increase glycogen synthesis - Increase fat synthesis - Decrease ketogenesis - Decrease lipolysis - Decrease gluconeogenesis - Decrease glycogenolysis (above usually signal starvation when not decreased)

Answer 226

- Decrease glycogen synthesis - Decrease fat synthesis - Increase ketogenesis - Increase lipolysis - Increase gluconeogenesis - Increase glycogenolysis - Increase amino acid uptake

Answer 227

- Availability of substrates: e.g. glucokinase (first enzyme of liver that uses glucose) - Allosteric control (regulatory metabolites bind outside of the active site of enzymes and modulate activity): e.g. PFK1 regulation by F-2,6-BP - Regulatory phosphorylation: e.g. phosphorylation of glycogen synthase and phosphorylase kinase by PKA (protein kinase A) – glucagon controls glycogen breakdown via PKA - Changes in transcription: e.g. increase in expression of glycolytic enzymes triggered by insulin; suppression of gluconeogenesis in the liver

Answer 228

PHOSPHOFRUCTOKINASE-1 (PFK-1) PFK1 acts after isomerisation of glucose-6-P to fructose-6-P and catalyses the most important regulated step of glycolysis: - It is the rate-limiting (slowest) step in glycolysis - Glucose-6-P fructose-6-P -> fructose-1,6-bis-P (ATP, PFK-1)

Answer 229

- PFK-1 is allosterically activated by AMP (if you use up all your ATP) (activation by low energy levels in the cell) and repressed by ATP and citrate (signals high energy levels) (citrate is further down the TCA cycle – it backs up if you don’t use what the TCA cycle produces) - PFK-1 is activated by fructose-2,6-bisphosphate (produced by PFK-2) whose biosynthesis in turn is regulated by insulin (increase) and glucagon (decrease) (PFK-2 regulated by insulin and glucagon) High insulin suppresses glucagon production - High glucagon – PFK-2 is phosphorylated = inactive - Low glucagon – PFK-2 is not phosphorylated = active – favours formation of fructose-2,6-bisphophate -> activates PFK-1 -> increase glycolysis

Answer 230

- Glucagon is the main regulator of gluconeogenesis - It acts by repressing pyruvate kinase, thus increasing the availability of PEP (phosphoenolpyruvate) for gluconeogenesis - Glucagon also increases the expression of PEP carboxykinase (oxaloacetate -> phosphoenolpyruvate) - Finally, glucagon represses the formation of F-2,6-BP, which is a repressor of fructose-1,6-bisphosphatase in gluconeogenesis (while it is an activator of PFK-1 in glycolysis) (fructose-1,6-bis-P -> fructose-6-P)

Answer 231

- Glycogen metabolism is controlled hormonally by glucagon and insulin - Glucagon triggers the production of cAMP in cells, which in turn activates protein kinase A (PKA) - PKA phosphorylates (inactivates – so when low glucose, glycogen synthase doesn’t produce glycogen) glycogen synthase directly, and glycogen phosphorylase (breaks down glycogen) via phosphorylase kinase - Phosphorylation has opposite effects on the two enzymes: glycogen synthase becomes inactive, while glycogen phosphorylase is activated by phosphorylation - As a result, glucagon promotes glycogenolysis and inhibits glycogenesis

Answer 232

- End product of glycolysis is pyruvate - Pyruvate shuttled into mitochondria - Huge enzyme turns pyruvate into acetyl-CoA - The TCA cycle (or Krebs cycle, or citric cycle) is a central ‘metabolic roundabout’ with multiple entry and exit points – several of the intermediates are involved in gluconeogenesis, amino acid and heme metabolism - The oxidative catabolism of carbohydrates, lipids and amino acids comes together here - Acetyl-CoA goes into the roundabout - Cycle breaks down (oxidises) acetyl-CoA eventually to carbon dioxide - Generate a lot of ATP – 28 ATP per glucose molecule - Generate a lot of NADH - Four intermediates of the TCA cycle are amino acid metabolites – this allows their conversion to glucose by gluconeogenesis

Answer 233

can be converted to fatty acids by the liver and ultimately stored as fats (triacylglycerols, TAGs) in adipocytes (fat is the most efficient way of storing calories)

Answer 234

- The process starts with cytoplasmic acetyl-CoA | - Since most acetyl-CoA is generated in mitochondria and cannot cross the membrane, a shuttle is needed

Answer 235

TAGs and fatty acids can be used by most tissues, but de novo synthesis (synthesis of complex molecules from simple molecules) is mainly in the liver

Answer 236

- Regulated by availability of substrate: carbohydrate-rich meals provide carbon (pyruvate/acetyl-CoA) and NADPH (different to NADH – NADPH is specially used to produce stuff like fatty acids) via the pentose phosphate pathway - Insulin stimulates lipogenesis via transcriptional activation of L-PK, ACC and other enzymes leading to TAG

Answer 237

- The next step, catalysed by acetyl-CoA carboxylase (ACC) is rate-limiting and regulated - It is activated by citrate - The enzyme is active as a multi-subunit polymer stabilised by citrate - ACC is inactivated directly by fatty acyl-CoA and by phosphorylation by AMPK - Via regulation of ACC phosphorylation, insulin indirectly activates ACC; glucagon and AMP inactivate ACC

Answer 238

- beta-oxidation - large amounts of energy - The B-oxidation of fatty acids produces large amounts of energy - Per 2-carbon unit, one FADH2, one NADH and one acetyl-CoA are produced – ultimately, these produce 2, 3, and 12 ATP, respectively – per 16-carbon (palmitoyl-) CoA, that’s 129 ATP! - Triacylglycerol -> fatty acids -> fatty acyl-CoA -> acetyl-CoA

Answer 239

synthesis: - after carbohydrate-rich meal - high insulin/glucagon ration - primarily liver - cytosol - NADPH - palmitate (C16) degradation: - in starvation - low insulin/glucagon ration - muscle, liver - primary mitochondria - NAD+, FADH2 - acetyl-CoA

Answer 240

- They are an ‘emergency fuel’ that the liver can produce to preserve glucose – the liver itself cannot use ketone bodies, though! - During starvation, the ability of the liver to oxidise fatty acids released from adipocytes may be limited - The liver produces ketone bodies and releasees them into the blood for peripheral tissues - Ketone bodies are acids – so if you produce lots of them your blood becomes a bit acidic - Can also form acetone from these ketone bodies - Ketone bodies e.g. acetoacetate, 3-hydroxybutyrate - Ketone bodies are highly soluble and unlike lipids can be transported without carriers

Answer 241

- Increased levels of ketone bodies in blood (ketonaemia) and urine (ketonuria) are observed in uncontrolled type 1 diabetes mellitus – the acidity of ketone bodies lowers blood pH (ketoacidosis – clinical crisis) - Side product of diabetes is the production of ketone bodies even when you’re not starving - This is because there’s a lack of insulin production, which means you are not supressing ketogenesis, so you are making ketone bodies even if you’re not starving

Answer 242

- Unlike carbohydrates and fatty acids, amino acids have no storage form - All must be taken up with the diet or recycled via regular turnover of body proteins (about 400g/day) - Excess amino acids are degraded, and the generated nitrogen excreted largely as urea - Most amino acids can be used in gluconeogenesis (they are glucogenic), but some are partially or fully ketogenic: they only form acetyl-CoA or acetoacetate

Answer 243

- The catabolism of most amino acids begins with the removal of the alpha-amino group - The amino group is transferred to alpha-ketoglutarate (alpha-keto acid) in a transaminase reaction (start with one alpha-amino acid and one alpha-keto acid and end of with one of each still but different types of each)

Answer 244

- Most transaminases are quite specific for one or few amino acids and transfer their amino group to alpha-ketoglutarate - Alanine transaminase (ALT) is a typical enzyme in that is fully reversible and does not strongly favour one direction - Alanine & alpha-KG (alpha-ketoglutarate) pyruvate & glutamate - Alanine is turned into pyruvate - Alpha-KG is turned into glutamate - Aspartate transaminase (AST) is an exception – the alpha-amino group of glutamate that has come from many other amino acids is passed on to oxaloacetate to form aspartate, and from there is fed into the urea cycle - Aminotransferases are cytoplasmic enzymes - 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 - Often measure both, both tell you slightly different things

Answer 245

- In peripheral tissues, excess ammonia is converted to glutamine and shuttled to the liver - Glutamate -> glutamine (NH3 + ATP, glutamine synthetase -> ADP + Pi)

Answer 246

In the liver, two molecules NH3 can be released from glutamine by glutaminase and then glutamate dehydrogenase

Answer 247

- A second route for delivering ammonia to the liver is via the alanine-glucose shuttle: alanine from muscle delivers NH3 via ALT; resulting pyruvate goes into gluconeogenesis; glucose is returned to muscle - Ammonia can also be transferred to oxaloacetate by aspartate transaminase – the resulting aspartate feeds into the urea cycle

Answer 248

- In 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 4 ATP - Urea is shuttled from the liver to the kidney for excretion

Answer 249

- Although the liver normally produces glucose rather than consume it, after a meal the low-affinity GLUT2 transporter takes up glucose from the blood - The low-affinity, high-capacity glucokinase can channel glucose into glycolysis only when glucose is abundant - High levels of glucose-6-phosphate promote glycogenesis - High levels of glucose-6-phosphate promote NADPH production in the pentose phosphate pathway - Glycolysis is promoted and gluconeogenesis suppressed by a high insulin/glucagon ratio: PFK-1 activation by F-2,6-BP; dephosphorylation (=activation) of pyruvate kinase and PDH

Answer 250

- Surplus carbohydrates from a meal are converted to acetyl-CoA and then mainly channelled into fatty acid synthesis: high ATP inhibits isocitrate dehydrogenase, leading to an accumulation of citrate in mitochondria and export to the cytoplasm 0 ATP-citrate lyase restores acetyl-CoA in the cytoplasm, and ACC is activated by dephosphorylation and by citrate - TAG synthesis is promoted by the high availability of fatty acyl-CoA both from de novo fatty acid biosynthesis and form dietary fats - Surplus amino acids are recycled, redistributed or degraded into pyruvate, TCA cycle intermediates or acetyl-CoA – branched-chain amino acids are only used by muscle

Answer 251

- The number 1 priority for the liver during a fast is to maintain blood glucose levels for the glucose-dependent tissues - Glucagon stimulates the activation of glycogen phosphorylase via PKA-mediated activation of phosphorylase kinase - The liver-specific enzyme glucose-6-phosphatase produces glucose from G-6-P – glucose is released into the bloodstream - Glucagon also triggers a reduction in the concentration of fructose-2,6-bisphosphate by shifting PFK-2 towards phosphatase activity - The reduction in F-2,6-BP means that gluconeogenesis is favoured over glycolysis: the key enzyme fructose-1,6-bisphosphatase is no longer inhibited by F-2,6-BP

Answer 252

- The main sources of carbon for gluconeogenesis are lactate from muscle and glucogenic amino acids - Hydrolysis of TAGs in adipose tissues supplies the liver with fatty acids - The key enzyme of fatty acid biosynthesis, ACC, is inhibited directly by abundant fatty acyl CoA and indirectly by phosphorylation (mediated by AMPKK and glucagon) – ACC inhibition lowers malonyl-CoA, which in turn activates B-oxidation - Abundant acetyl-CoA activates pyruvate carboxylase (for gluco-neogenesis) and inhibits degradation of pyruvate (inhibition of PDH) - During prolonged fasting, the liver produces the ketone bodies acetoacetate and 3-hydroxybutyrate that can be used as emergency fuel by all tissues, even the brain

Answer 253

- 75% from portal vein - rich in absorbed nutrients - recycled bile acids/salts - lower in oxygen - 25% from hepatic artery - regular systemic arterial blood - high concentration of oxygen - Both feed into hepatic sinusoids - Single venous drainage pathway Hepatic portal vein delivers about 1.3L/min of blood Cardiac output about 5L/min

Answer 254

- They have a basolateral (sinusoidal) membrane, which is bathed in interstitial fluid, coming from the sinusoids - Sinusoid contains the mixed portal & arterial blood - Sinusoid has fenestrations/windows between certain endothelial cells (fenestrated endothelium), allowing substances to move quite freely from the blood into the space of Disse (the interstitial area) - Stuff coming from your gut bathes in the sinusoidal side of the epithelial cell/hepatocyte, and will be transported into the hepatocytes so that they can deal with it - Many transporters in these membranes - There are other groups of transporters in the apical (canalicular) membrane, which move things into the bile from the cell - The bile is then transported to the intestine and then you lose these substances from your body in the faeces - There are tight junctions (junctional complexes) either side of the bile canaliculus, between two hepatocytes, which separate the canalicular membrane form the basolateral membrane

Answer 255

- Bile acids/salts (+ phospholipids & cholesterol – particularly important in production of mixed micelles) - Bilirubin (conjugated form – water-soluble substance is attached by covalent bond to substance that you want to get rid of (i.e. bilirubin) – breakdown product of haemoglobin) - Metabolites of hormones & drugs - Heavy metal ions – very toxic to the kidney, but not so bad if excreted by body in the bile - Electrolytes (HCO3- neutralise acid found in duodenum) and water (as a ‘vehicle’ – carries all the above – allows substances to flow from the hepatocytes into the duodenum) The rest, in between meals, isn’t secreted into the duodenum, it goes into the gallbladder, which reabsorbs water, so the volume goes down to about half the total amount produced

Answer 256

About 1000 ml.day^-1 secreted by liver | About 500 ml.day^-1 reaches duodenum (only secreted into the duodenum during the absorptive state)

Answer 257

Uptake of recycled bile salts via… - Simple diffusion of unconjugated, neutral BAH - Cotransport with Na+ via Na+-taurocholate cotransporting peptide (NTCP) - Exchange with Cl- via organic anion transporting peptide (OATP) NB – don’t worry about names just recognise diversity! NB – don’t worry about names just recognise diversity!

Answer 258

e.g. thyroid & steroid hormones, prostaglandins, drugs (statins), toxins - Basolateral uptake by exchange with Cl- via OATP (large family) - Conjugation with glucuronate or sulphate (Y) - Apical secretion via MRP2 - Sulphated (make bit more soluble) sex steroids (St-Y) via another ABC transporter ABCG2 Transporters take the above substances from the blood into the hepatocytes and then other transporters which secrete the substances into the bile so they can be excreted from the body in the faeces NB transporter diversity – also seen in kidney and BBB

Answer 259

(cytotoxic drugs, local anaesthetics, antibiotics) - Bulky molecules via OATP (into cell) and multidrug resistance transporter 1 (MDR1) (into bile) - Amines by facilitated diffusion via organic cation transporters (OCT1/3) (into cell) or by exchange with H+ (MATE1) (into bile) - Cholesterol via ABCG5/8 (into bile) - Phospholipids via a flippase (MDR3) (into bile)

Answer 260

- Ductal (cholangiocyte) secretion - Secretion into canaliculi - Converge to form larger canaliculi - End up in perilobular bile ducts - Which drain into (larger) interlobular bile ducts - And out to the kidney

Answer 261

- Cystic duct joins gall bladder to common hepatic duct - Gall bladder stores about 50ml of bile - So, if you produce about 500ml bile overnight, you don’t have the capacity to store that – so it concentrates the bile - When you eat a meal, the gallbladder contracts, sphincter of Oddi relaxes and the bile is released into the duodenum

Answer 262

- Wide range of waste products, lipids, drugs and other xenobiotics excreted via organic anion and cation transporters and ABC pumps - Bile acids synthesised, conjugated, secreted and recycled to aid fat digestion - Fluid and electrolytes secreted by hepatocytes and cholangiocytes (epithelial cells of the bile duct) as vehicle - Hepatic bile concentrated by reabsorption of electrolyte and water by gall bladder epithelium

Answer 263

ADME (pharmacokinetics) - Absorption (into blood) - Distribution (blood to tissues and vice versa) - Metabolism (blood to elimination) - Excretion/elimination (blood to urine) Liver is the main site of drug metabolism

Answer 264

- Free drug can bind to proteins in the plasma, e.g. 99% of warfarin is bound to albumin - Only free or unbound drugs can have an effect (because once bound it’s too big to be lipid-soluble and pass into the tissue) - Decrease plasma albumin and increase bilirubin -> drug displacement - What can happen in liver disease is that we get a reduction in production of albumin – so more drug in free state - In liver disease we also see an increase in bilirubin levels, what we see is that it starts to displace some of the drug molecules from the proteins – so more increase in free drug present – also see this in renal failure

Answer 265

- Decrease plasma albumin and increase bilirubin -> drug displacement - Diazepam: 2% -> 6% (change in the amount of free drug) (small change) - Theophylline: 35% -> 71% (significant increase) - Increased Vd (volume of distribution) - the Vd represents the fluid volume that would be required to contain the total amount of absorbed drug in the body at a uniform concentration equivalent to that in the plasma at steady state - relates the amount of drug in the body to the blood concentration - if we gave a drug dose and we measure how much in the blood stream, and there’s less than we gave, what Vd tells us is where in the body has that drug gone to - if a drug has a very low Vd, it’s telling us that the drug is mainly staying in the blood stream - if it’s got high Vd, it’s telling us that it’s really widely distributed around the body - so, the way we can calculate Vd, is knowing what dose is being given to the individual and dividing that by the concentration in the blood – so small concentration in the blood would give a high Vd - drugs with high lipid-solubility have a really high Vd, drugs with poor lipid-solubility will have a lower Vd - drug like warfarin would have a small Vd, because highly bound to albumin - so if we have a decrease in plasma albumin, Vd for a drug would then increase

Answer 266

Lipid-solubility and whether drug is bound to plasma proteins both affects the volume of distribution

Answer 267

Most drugs are lipophilic -> re-circulate

Answer 268

the enzyme-mediated conversion of a lipid-soluble compound into a more water-soluble one - If we’ve got a water-soluble drug, then it’s just going to be excreted in the urine - However if we got a lipid-soluble drug, it’s going to tend to be reabsorbed by the kidney, into the peritubular vessels and be recirculated in the bloodstream to then by delivered back to the kidneys to be reabsorbed – so we need a way to get of drug by making it able to be excreted = drug enzymes

Answer 269

- Won’t be able to metabolise drugs as effectively, therefore half-life for that drug will increase - If there’s lack of functioning drug metabolising enzymes, may be very difficult for that patient for to metabolise prodrug into active form – e.g. codeine may not be able to metabolise into morphine

Answer 270

Conjugation reactions: (sticking together drug molecule/metabolite with a much bigger molecule) - Glucuronidation (e.g. with paracetamol) – most widespread - Sulphation – also common - Methylation - Acetylation - Amino acid – damage to hepatocytes can deplete the pool of these – impact on metabolism of those drugs - Glutathione - Fatty acid Products generally: - Water-soluble (large molecule) and easily excreted - Increased MW - Inactive: - ‘pharmacological inactivation’ - decrease receptor affinity (large molecule now) - enhance excretion

Answer 271

- Drug - oral administration - > absorbed in Gi tract - > blood - > liver (glucuronyl transferase) - > drug-glucuronide - > bile - > GI tract - > faces OR > (B-glucuronidase (hydrolysis)) drug > absorbed in GI tract Particularly glucuronides (affected by this pathway?) e.g. oestrogens, rifampicin, chloramphenicol, morphine if we have poor glucuronidation due to liver disease then that’s going to impact on that step glucuronide = any substance produced by linking glucuronic acid to another substance via a glycosidic bond

Answer 272

- Drug metabolising enzymes are present at birth but not fully functional – difficult for babies/infants to metabolise certain drugs – can be fatal - After a few weeks of life, enzymes become fully functional – may even be more active than later in life – may need to adjust dose - Increase in expression of certain drug metabolising enzymes during pregnancy – drug during pregnancy may start to seem less beneficial and that’s because they’re metabolising it more quickly - Also increase blood flow to liver and kidneys during pregnancy – speed up elimination of drugs - Placenta also important in terms of this

Answer 273

- Inability to hydrolyse succinylcholine (used as muscle relaxant in surgery) - aspartic acid change to glycine at position 70 - about 1:3,500 Caucasians are homozygous - t1/2 is increased from 2 minutes to 2-3 hours - prolonged muscle paralysis and apnoea - phenotypic observation - Genotypic observations: - DNA insertions, deletions, disparity in the number of repeated sequences and SNPs (single nucleotide polymorphisms – change in DNA has to be present in 1% of population for it to be classed as a SNP) (e.g. TAGC- TACC) all lead to polymorphisms (if gene coding for an enzyme) - Can now do genetic profiling to predict how a patient might respond to a drug – individualised therapies

Answer 274

Ultrarapid metabolisers: - Increase metabolism and decrease plasma [drug] - Occurs by gene amplification: up to 13 copies of the gene Dosing disparity: - Poor metabolisers = 10-20 mg nortriptyline/day - Ultra-rapid metabolisers = 500 mg/day

Answer 275

- Immunosuppressants, e.g. tacrolimus (disrupts signalling in T lymphocytes) (used following transplants) - narrow therapeutic window (need to get conc. Just right), variable pharmacokinetics, nephrotoxicity - CYP3A4 and CYP3A5 major enzymes responsible for metabolising tacrolimus - SNPs in both enzymes -> lack of functional enzyme - SNP in CYP3A5: increase risk of nephrotoxicity - Screen for allele before transplantation to ensure correct dose

Answer 276

- Normally metabolised by phase 2 reactions – conjugation reaction - Glucuronide & sulphate conjugates of -OH group - Goes to inactive metabolite - Urinary excretion - If the dose is increased, these pathways become overwhelmed by the amount of paracetamol that’s present, and it starts to build up toxic effects - There is a plan B for paracetamol metabolism: - N-hydroxylation pathway involving CYP450 - This produces N-acetyl-p-benzoquinone imine (toxic – but conjugated so its fine) - Glutathione conjugation -> inactive metabolite -> urinary excretion - If the dose is too high and plan A and B are both saturated, you get a build up of the toxin (N-acetyl-p-benzoquinone imine) -> hepatoxicity and cell death = irreversible damage to liver

Answer 277

- Licensed, e.g. co-amoxiclav, isoniazid, methyldopa, halothane, rifampicin, paracetamol - Unlicensed herbal remedies, e.g. black cohosh, comfrey, kava (patients may be taking without telling anyone) Adverse drug reactions (ADRs): type A-E reactions - Type A: ‘augmented’ reactions, exaggerated response to drug’s normal actions when give at usual dose; normally dose-dependent - Type B: ‘bizarre’ reactions, novel response to drug that was not expected based upon known pharmacological actions of the drug - Account for 1 in 16 hospital admissions; > 2% of patients with ADR die; annual cost to NHS > £1 billion

Answer 278

1. Hepatocellular (e.g. paracetamol, isoniazid, green tea) - hepatocyte necrosis & inflammation - big increase in alanine and aspartate transferase - increase y-glutamyl transpeptidase 2. Cholestatic (e.g. co-amoxiclav, sulphonylureas) - resembles bile duct obstruction - big increase in alkaline phosphatase & y-glutamyl transpeptidase - increase alanine and aspartate transferase 3. Mixed hepatocellular-cholestatic (e.g. phenytoin, enalapril) - most characteristic pattern seen - (medium?) increase in alkaline phosphatase & alanine transferase

Answer 279

Inducers: - E.g. carbamazepine, alcohol, St. John’s wort Inhibitors: - E.g. fluoxetine, erythromycin, ketoconazole - Grapefruit juice inhibits CYP3A4 -metabolises about 30% of all drugs (statins, verapamil, nifedipine…) -increase in plasma levels -> prolonged effect (and toxic effects if we remain dosing at the same level)

Answer 280

- Right upper quadrant of abdomen - 1200-1500 g in adult - Peritoneal covering - 4 anatomical lobes (right, left, caudate, quadrate) - Hepatic artery from coeliac axis - Portal vein from gut - Venous outflow via hepatic veins to inferior vena cava - 2 functional lobes (right, left) in 8 segments - Related to afferent blood supply

Answer 281

- Infectious mononucleosis | - Can occasionally cause liver disease but more a virus that makes you feel grotty and gives you lymph nodes problems

Answer 282

- Immunosuppressed patients | - Gives problems with any organs in those patients

Answer 283

- Asymptomatic subclinical disease - Acute clinical jaundice - Acute massive necrosis (< 2%) (liver undergoes huge inflammatory process and becomes non-functional very quickly) - Chronic hepatitis - Chronic hepatitis > 6 months (especially hepatitis B and C) - Grade of disease = portal and lobular inflammation, interface hepatitis (where portal tract meets hepatocellular plates?) - Stage of disease = fibrosis (portal, bridging, nodules) and cirrhosis - May lead to cirrhosis and ultimately hepatocellular carcinoma

Answer 284

- Alcohol absorbed from upper small intestine, then via portal vein to liver - Some metabolism in stomach by alcohol dehydrogenase - Alcohol converted to acetaldehyde and excreted by conversion to carbon dioxide in citric acid cycle - Cytochrome p4502E1 involved - Rate of metabolism variable – related to weight, gender and body fat (takes it out of circulation – keeps circulating alcohol volume down) - Can be induced, so tolerance increases

Answer 285

- Fatty change – reversible - Alcoholic hepatitis – reversible - Mallory’s hyaline – reversible - Fibrosis – reversible, up to a point - Cirrhosis – irreversible ALCOHOLIC LIVER DISEASE - Fatty change - reversible - every hepatocyte is full of fat - because it’s full of fat, it doesn’t do other things very well - also get it with obesity - Alcoholic hepatitis - reversible - Mallory’s hyaline – an indication of major internal damage to hepatocyte - Pericellular fibrosis (around hepatocyte) - reversible - means you don’t get toxic substances into the hepatocyte but you don’t get metabolites out of hepatocyte - Cirrhosis - irreversible - nodules of hepatocytes are surrounded entirely by fibrous tissue - leads to major change in way venous blood is delivered from the portal vein into the hepatocytes and into the way the hepatocytes get rid of toxic substances that they’ve detoxified

Answer 286

- Illegal intoxication is 0.08 g/dL = driving limit - 0.2 g/dL is drunk, 0.3 is smashed, 0.4 is out cold - Lethal toxicity: > 0.4 g/dL in alcohol naïve > 0.5 g/dL in anyone But very variable - But some have survived far higher levels than these potentially fatal values, up to 1.4 g/dL - Death due to respiratory depression - Synergy with other respiratory depressants – such as opiates and opioids Elimination: - Average elimination rate 0.015 g/dL/hr - From legal intoxication to undetectable takes about 5 hours - Alcoholics may eliminate up to 0.05 g/dL/hr - Post mortem production of alcohol up to 0.05 g/dL

Answer 287

- Fatty change - Non-alcoholic steatohepatitis (NASH) - Fibrosis - Cirrhosis - Changes identical to alcohol - Associated with obesity, diabetes, hyperlipidaemia, some drugs

Answer 288

Disease of all of the liver with parenchymal nodules and surrounding fibrosis - Green nodules because not getting rid of bile as well as they should Causes: - Alcohol – tend to be small nodules (micronodular cirrhosis) - Viruses – big nodules (micronodule cirrhosis) -especially HBV and HCV - Metabolic diseases -iron, copper (in inappropriate storage of this and iron because people don’t have the appropriate enzymes), glycogen storage disease, lipid disorders, alpha-1 antitrypsin deficiency (can’t be exported from hepatocyte – damages it) - Autoimmune -autoimmune hepatitis: (‘lupoid’), young women: anti-nuclear and anti-smooth muscle antibodies -primary biliary cirrhosis (primary biliary cholangitis): middle aged women, anti-mitochondrial antibodies (autoimmune diseases of any kind are almost always more common in women than men)

Answer 289

- Liver failure - protein synthesis: low albumin (can’t maintain fluid in bloodstream) - coagulation factors: bleeding - jaundice - encephalopathy: confusion (because not detoxifying things that gut absorbs) - Portal hypertension (because blood can’t flow forward) - ascites - varies – dilated veins when blood is bypassed from liver through veins that go around lower third of the oesophagus – major cause of internal bleeding - splenomegaly – blood gets diverted through the spleen - Hepatocellular carcinoma - very common carcinoma where HBV endemic (SE Asia, Africa) - very poor prognosis, about 6-9 months - possibly the biggest killing cancer of all (first or second – small cell carcinoma of the lung) - raised serum alpha-fetoprotein levels

Answer 290

many different tissues If you have a liver problem, both of them will be elevated ALT is more specific for liver disease than AST If AST is high, while ALT is normal –> think extrahepatic

Answer 291

* Drug treatment is available and has recently improved, with a better success rate and fewer side effects * 90-95% of people can be cured by the new medications, known as DAAs * These are taken in tablet form once or twice a day, typically for 12 weeks * Current hep C treatments made up of combinations of DAAs * They directly target the virus in different ways * DAAs promise treatments with shorter treatment times, much higher cure rates, and fewer side effects * Four classes of DAAs that combine in different way to make up the different hep C DAA treatments

Answer 292

- Infections due to beta-lactamase-producing strains (where amoxicillin alone not appropriate) - Contraindications = history of co-amoxiclav-associated jaundice or hepatic dysfunction - Can cause hepatitis

Answer 293

- Some ‘all-natural’ herbal products, like green tea extract and comfrey tea, can cause injury to your liver - Drug-induced liver injury, a form of liver disease, is on the rise as herbal and dietary supplements have become more popular over the last decade - St john’s wort (for mental health problems) should be avoided by anyone taking the newer hepatitis C medications

Answer 294

- Scarring of liver caused by long-term liver damage - Scar tissue prevents liver working properly - Can eventually lead to liver failure, which can be fatal - Currently no cure but possible to manage symptoms and any complications, and slow its progression - Treating the underlying cause, such as using anti-viral medication to treat hepatitis C infection, can also stop cirrhosis getting worse - Most common causes in the UK: - drinking too much alcohol over many years - being infected with hepatitis for a long time, particularly hep C - non-alcohol steatohepatitis – a more severe form of non-alcoholic fatty liver disease, where the liver becomes inflamed as the result of a build up of excess fat

Answer 295

Liver one of main sources of ALP, but some also made in bones, intestines, pancreas, and kidneys

Answer 296

- blood test that helps doctors diagnose hep C - used to measure level of hep C virus in blood - looks for genetic material of hep C virus (RNA) and uses a PCR - this test often given early on, as they can detect the virus itself rather than antibodies to it that the body creates - can take an average of 6 to 8 weeks after a hep C infection for antibodies to be detected, it may only take 1 week to detect the virus directly by using PCR or other means of direct virus detection • Hepatitis B virus-DNA (HBV DNA) present at low levels - viral load test - performed using PCR technique

Answer 297

- once you’ve received diagnosis, before you start treatment, you need to determine genotype of virus - 6 well-established genotypes (strains) of hep C, plus more than 75 subtypes - uncommon but possible to be infected with more than one genotype - in US, about 13-15% have genotype 2, genotype 1 is most common and affects up to 75% - knowing genotype impacts treatment recommendations - genotype 2 – often combination of two antiviral drugs for 8 weeks or longer - genotypes 4 and 6 are less common, and genotypes 5 and 6 are rare

Answer 298

- HBeAg = different to the above, it’s a protein that the virus manufactures and secretes – it it’s circulating while attached to the virus but instead is free in your bloodstream and tissues - some strains don’t produce HBeAg, so a negative test has little meaning in those cases – strains in Middle East and Asia

Answer 299

- appears at the onset of symptoms in acute hep B and persists for life - presence indicated previous or ongoing infection in an undefined time frame

Answer 300

Sofosbuvir: • Nucleoside and nucleotide NS5B polymerase inhibitors • They directly target the hep C virus to stop it from making copies of itself in the liver • They attach themselves onto the RNA to block the virus from multiplying

Answer 301

``` i. Pegylated IFNs • PEG-INF -pegylated interferon-alpha-2a -pegylated interferon-alpha-2b -pegylated interferon-beta-1a • In these formulations, PEG is added to make interferon last longer in the body ``` ii. Ribavirin * Used in combination with other antiviral medications (such as interferon, sofosbuvir) to treat chronic hep C * Synthetic antiviral nucleoside analogue * Combination of interferon and ribavirin is now no longer used as safer, shorter highly effective and more tolerable tablet-only treatments are available

Answer 302

- In the UK, it’s most commonly spread through sharing needles used to inject drugs - Poor healthcare practices and unsafe medical injections are the main way it’s spread outside the UK - Causes no noticeable symptoms, or only flu-like symptoms, so many people are unaware they’re infected - Around 1 in 4 people will fight off the infection and be free of the virus (hep E - Number of cases in Europe has increased in recent years and is now the most common cause of acute hepatitis in the UK)

Case 5 Flashcards

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