Liver Flashcards

Question

Is the absorption of carbohydrates energy dependent?

Answer 1

◦ Glucose absorption into hepatic cells - non energy dependent, concentration gradient driven, non insulin regulated - via GLUT2 transporter

Answer 2

rapidly phosphorylated (Hexokinase) into glucose 6 phosphate (insulin upregulated) trapping in liver --> biotransformation This also maintains a constant concentration gradient

Answer 3

Fat Carbohydrates are processed for the benefit of the rest of the body

Answer 4

‣ Post prandial glycogen synthesis ‣ Post prandial fatty acid synthesis and TG synthesis (for storage of energy - <5% liver mass) from glucose ‣ Fasting glycogenolysis - main mechanism pre meals of maintaining BSL * Other tissues store glucose as glycogen but can only use it themselves as they do not possess glucose 6 phosphatase to recreate glucose for systemic release ‣ Gluconeogenesis

Answer 5

* Other tissues store glucose as glycogen but can only use it themselves as they do not possess glucose 6 phosphatase to recreate glucose for systemic release

Answer 6

* Other tissues store glucose as glycogen but can only use it themselves as they do not possess glucose 6 phosphatase to recreate glucose for systemic release

Answer 7

◦ Lactate ◦ Lesser extent ‣ Pyruvate ‣ Glycerol ‣ Gluconeogenic amino acids ◦ Rarely ‣ Fructose - via triode phosphates ‣ Glucose - 10% of dietary glucose converted to glycogen

Answer 8

◦ Glycogenlysis - phosphorylase converts glycogen to glucose-6-phosphate ‣ Theorised that perivenous hepatocytes are primarily responsible for glycolysis, periportal cells for gluconeogenesis

Answer 9

◦ Glycogenlysis - phosphorylase converts glycogen to glucose-6-phosphate ‣ Theorised that perivenous hepatocytes are primarily responsible for glycolysis, periportal cells for gluconeogenesis

Answer 10

◦ Gluconeogenesis - newly synthesised glucose from lactate, pyruvate, amino acids (alanine, glutamine from muscles), and glycerol (lypolysis of fat stores)

Answer 11

◦ Gluconeogenesis - newly synthesised glucose from lactate, pyruvate, amino acids (alanine, glutamine from muscles), and glycerol (lypolysis of fat stores)

Answer 12

‣ Facilitated by glucagon * Enhances alanine transport across hepatocytes membrane * Enhances pyruvate transport across mitochondrial membrane ‣ Cortisol * Increased peripheral proteolysis —> increased plasma concentrations of amino acids —> promoting gluconeogenesis

Answer 13

‣ Facilitated by glucagon * Enhances alanine transport across hepatocytes membrane * Enhances pyruvate transport across mitochondrial membrane ‣ Cortisol * Increased peripheral proteolysis —> increased plasma concentrations of amino acids —> promoting gluconeogenesis

Answer 14

‣ Facilitated by glucagon * Enhances alanine transport across hepatocytes membrane * Enhances pyruvate transport across mitochondrial membrane ‣ Cortisol * Increased peripheral proteolysis —> increased plasma concentrations of amino acids —> promoting gluconeogenesis

Answer 15

breakdown of glucose to carbon dioxide and water with production of energy

Answer 16

◦ Cleavage of glucose to trioses —> pyruvic acid + lactic acid (Embden-Meyerhof pathway)

Answer 17

‣ Pyruvic acid —> citric acid cycle by conversion to acetic acid via loss of one molecule of CO2

Answer 18

‣ Citric acid cycle generates 12 molecules of ATP for every molecule of acetic acid

Answer 19

‣ 38 molecules of ATP

Answer 20

Acetyl CoA can be used for TG and lipogesis

Answer 21

◦ Oxidation and decarboxylation of glucose—> pentose (hexose monophosphate shunt) ‣ Pentose phosphate pathway involves production of NADPH (nicotinamide adenine dinucleotide phosphate) ‣ 2 NADPHmolecules and ribose-5-phosphate are produced from 1 glucose molecule ‣ NADPH required for microsomal and mitochondrial hydroxylation fo steroid hormones and bio transformation of drugs

Answer 22

NADPH required for hydroxylation and biotransformation of drugs

Answer 23

3 molecules

Answer 24

7kcal per gram

Answer 25

4 kcal per gram Then stored in a hydrated form making it less energy efficient than fat for storage

Answer 26

‣ Not especially water soluble, bound to albumin, short half life <5 minutes

Answer 27

producing oxidative stress and interfere with biosynthesis in endoplasmic reticulum of cells --> therefore not the ideal substrate to transport in large quantities

Answer 28

Immediately usable metabolic fuel

Answer 29

◦ Packaged as triglycerides to allow transport - 3 FFA and a glycerol backbone, similar energy density to FFA ‣ Insoluble, packaged in VLDLs and chylomicrons ‣ Endothelial lipases release FFA locally

Answer 30

◦ Packaged as triglycerides to allow transport - 3 FFA and a glycerol backbone, similar energy density to FFA ‣ Insoluble, packaged in VLDLs and chylomicrons ‣ Endothelial lipases release FFA locally

Answer 31

◦ Packaged as triglycerides to allow transport - 3 FFA and a glycerol backbone, similar energy density to FFA ‣ Insoluble, packaged in VLDLs and chylomicrons ‣ Endothelial lipases release FFA locally

Answer 32

◦ Packaged as triglycerides to allow transport - 3 FFA and a glycerol backbone, similar energy density to FFA ‣ Insoluble, packaged in VLDLs and chylomicrons ‣ Endothelial lipases release FFA locally

Answer 33

Lipid breakdown for energy Lipid synthesis for fat storage Lipid processing

Answer 34

FFA i.e. fat

Answer 35

‣ Beta oxidation * Free fatty acid conversion to acetyl CoA occurs rapidly in the liver (hepatocytes mitochondria) * Excess acetyl CoA is converted to ace to acetic acid - highly soluble and transportable to other tissues —> converted back to acetyl CoA peripherally for energy ‣ Partial oxidation of fatty acids to ketone bodies which is alternative ot TG production providing metabolic fuel between meals

Answer 36

‣ Beta oxidation * Free fatty acid conversion to acetyl CoA occurs rapidly in the liver (hepatocytes mitochondria) * Excess acetyl CoA is converted to ace to acetic acid - highly soluble and transportable to other tissues —> converted back to acetyl CoA peripherally for energy ‣ Partial oxidation of fatty acids to ketone bodies which is alternative ot TG production providing metabolic fuel between meals

Answer 37

‣ Partial oxidation of fatty acids to ketone bodies which is alternative ot TG production providing metabolic fuel between meals

Answer 38

Esterification

Answer 39

‣ Synthesis of fatty acids from excess glucose —> converted to triacylglycerol and very low density lipoproteins (VLDL) * Triglyceride storage in fat deposits is the most efficient method of energy storage ◦ Either in the liver itself (can lead to pathological changes) or transported as VLDL to peripheral sites

Answer 40

* Origin - from diet, also synthesised in the liver, adrenal cortex and skin from Acetyl CoA

Answer 41

* Origin - from diet, also synthesised in the liver, adrenal cortex and skin from Acetyl CoA

Answer 42

◦ Hydroxymethylglutaryl CoA ◦ 80% of cholesterol synthesised in the liver is converted to bile ◦ Remainder of cholesterol is ‣ Transported in blood by lipoproteins —>used by cells to form membranes and intracellular structures ‣ Precursor to steroid hormones

Answer 43

◦ Hydroxymethylglutaryl CoA ◦ 80% of cholesterol synthesised in the liver is converted to bile ◦ Remainder of cholesterol is ‣ Transported in blood by lipoproteins —>used by cells to form membranes and intracellular structures ‣ Precursor to steroid hormones

Answer 44

Apoliproteins

Answer 45

‣ Apoliproteins synthesised in the liver involved in packaging cholesterol and TG as low density lipoprotein, VLDL and HDL * Phospholipids transported by lipoproteins —> used to form cell membranes and intracellular structures

Answer 46

‣ Lipoprotein fragments return to liver post peripheral degredation of VLDL by lipoprotein lipases at adipocytes and tissue surfaces where they are absorbed by endocytosis then either * Hydrolysed into FFA and released unchanged or as ketones * Hydrolysed into free fatty acids and burned by hepatocytes as metabolic fuel sources * Hepatic fat storage as TG

Answer 47

‣ Lipoprotein fragments return to liver post peripheral degredation of VLDL by lipoprotein lipases at adipocytes and tissue surfaces where they are absorbed by endocytosis then either * Hydrolysed into FFA and released unchanged or as ketones * Hydrolysed into free fatty acids and burned by hepatocytes as metabolic fuel sources * Hepatic fat storage as TG

Answer 48

* Triglycerides absorbed from the diet ◦ 50% hydrolysed to glycerol and fatty acids ◦ 40% partially hydrolysed to monoglycerides * Fate after absorption ◦ Short chain fatty acids (<12 carbon atoms) transported directly to the liver via portal vein without re-esterification ◦ Longer chain fatty acids are re-esteritifed after absorption, then covered with phospholipid and protein layers to form chylomicrons ‣ Lipoprotein lipases hydrolyse the chylomicrons —>free fatty acids —> adipocyte storeage or metabolised within body tissues for energy ◦ Absorption into the liver via receptor mediated endocytosis

Answer 49

* Triglycerides absorbed from the diet ◦ 50% hydrolysed to glycerol and fatty acids ◦ 40% partially hydrolysed to monoglycerides * Fate after absorption ◦ Short chain fatty acids (<12 carbon atoms) transported directly to the liver via portal vein without re-esterification ◦ Longer chain fatty acids are re-esteritifed after absorption, then covered with phospholipid and protein layers to form chylomicrons ‣ Lipoprotein lipases hydrolyse the chylomicrons —>free fatty acids —> adipocyte storeage or metabolised within body tissues for energy ◦ Absorption into the liver via receptor mediated endocytosis

Answer 50

* Triglycerides absorbed from the diet ◦ 50% hydrolysed to glycerol and fatty acids ◦ 40% partially hydrolysed to monoglycerides * Fate after absorption ◦ Short chain fatty acids (<12 carbon atoms) transported directly to the liver via portal vein without re-esterification ◦ Longer chain fatty acids are re-esteritifed after absorption, then covered with phospholipid and protein layers to form chylomicrons ‣ Lipoprotein lipases hydrolyse the chylomicrons —>free fatty acids —> adipocyte storeage or metabolised within body tissues for energy ◦ Absorption into the liver via receptor mediated endocytosis

Answer 51

◦ Absorption into the liver via receptor mediated endocytosis

Answer 52

* Lipid breakdown for energy extraction ◦ Beta oxidation - free fatty acid conversion to acetyl CoA which proceed through the Kreb’s cycle; or alternatively stored as acetic acid to transport energy to peripheral tissues to undergo conversion back to Acetyl CoA for energy utilisation * Lipid synthesis ◦ Synthesis of fatty acids from excess glucose —> conversion to triglycerides integrated into VLDL for peripheral fat storage ◦ Cholesterol synthesis - either cholesterol ingested or synthesised in the liver or adrenal cortex from acetyl CoA is converted to bile, used as a precursor for hormones or transported to peripheral tissues in lipoproteins for use in cell membranes or intracellular structure * Lipid processing ◦ Apoliprotein synthesis to facilitate transport and redistribution of body lipid

Answer 53

Catrabolism Amino acid metabolism and storage Urea synthesis

Answer 54

Amines Nucleic acids (proteins) Amino acids Glutamate

Answer 55

A product from ammonia

Answer 56

Gluconeogenesis Protein synthesis Interconversion of amino acids for re-release for utilisation by peripheral tissues Breaking down for removal of nitrogen as urea via deamination or oxidation into metabolic fuel and ammonia

Answer 57

◦ endocytosis of large circulating proteins into Kupffer cells (macrophages of reticuloendothelial system) --> degraded into amino acids and peptides by lyososomes and re-released ◦ Hepatocyte uptake of released amino acids and direct uptake of some proteins e.g. lipoproteins via receptor mediated endocytosis

Answer 58

Albumin Globulins including complement Clottign factors

Answer 59

120-300mg/kg per day

Answer 60

◦ Regulated by nutritional status, endocrine balance, plasma oncotic pressure

Answer 61

20 days Poor marker of acute processes

Answer 62

‣ Haptoglobin ‣ Alpha 1 anti trypsin - serine protease inhibitor protecting the body from damaging enzymes released by activated inflammatory cells e.g. neutrophil elastase ‣ Alpha 2 macroglobulin ‣ Antithrombin 3 ‣ Ceruloplasmin transporting copper ‣ Thyroxin binding globulin

Answer 63

transferrin binding iron in its ferric form,sex hormone binding globulin binding androgen ad oestrogen

Answer 64

Alpha 1 acid glycoprotein

Answer 65

◦ Vitamin K dependent clotting factors - 2, 7, 9,10 - vitamin K cofactor catalysed gamma carboxylation required for synthesis ◦ Vitamin K independent factors - 5, 8, 11, 12, 13 ◦ Fibrinogen ◦ Protein C, S antithrombin 3

Answer 66

Oxoacid carbon skeleton

Answer 67

Energy in citric acid cycle Transformed into another maino acid Substrate for gluconeogenesis

Answer 68

glutamate oxidation to alpha ketoglutarate whcih directly enters citric acid cycle glycine oxidation to glyoxylate serine deaminiation to pyruvate

Answer 69

TransaminationD

Answer 70

When no dedicated deamination to usable substrate amino group transfered to a keto acid leaving behind an oxoacid and creating a new amino acid that is amenable to deaminiation (usually glutamate)

Answer 71

‣ Keto acids can be transformed into non essential amino acids by transaminaation taking amino groups from one amino acid transferring it to a keto acid to form anew amino acid

Answer 72

‣ Producing acetyl CoA, oxoglutarate, succinyl COA, oxaloacetate and fumurate —> all which enter the citric acid cycle ‣ This gets rids of lots of unwanted amino acids, but generates lots of ammonia, and ammonium

Answer 73

* Amino acid path ◦ Arginine,histidine, lysine, methionine, threonine, tryptophan, phenylalanine degraded in the liver primarily ◦ Aspartic acid, glutamic acid, glycine, proline, alanine metabolised in BOTH hepatic and muscle tissue * Oxidative deamination of amino acids that are no longer required liberating energy —> produces urea

Answer 74

* Syntheised in the liver from methionine, glycine and arginine * Muscles phosphorylation creating to form phosphocreatine —> backup energy store for ATP production * Creatinine is formed from phosphocreatine and is excreted at a relatively constant rate

Answer 75

* Syntheised in the liver from methionine, glycine and arginine * Muscles phosphorylation creating to form phosphocreatine —> backup energy store for ATP production * Creatinine is formed from phosphocreatine and is excreted at a relatively constant rate

Answer 76

* Syntheised in the liver from methionine, glycine and arginine * Muscles phosphorylation creating to form phosphocreatine —> backup energy store for ATP production * Creatinine is formed from phosphocreatine and is excreted at a relatively constant rate

Answer 77

* Filter for bacterial and other antigens from the GIT via the portal system ◦ Kupffer cells (macrophages) attached tot eh endothelium in the liver phagocytoses substances mediating infection, inflammation e.g.bacteria, viruses, endotoxins, immune complexes, denatured albumin, thrombin, fibrin-fibrinogen complexes ◦ Antigens degraded without antibodies as little lymphoid tissue - prevents adverse immune reactions as antigens never reach antibody producing sites * Kupffer cells secrete interleukins, tumour necrosis factor, collagenases, lysosomal hydrolases ◦ This can be prompted by endotoxin exposure * Plasma proteins such as complement are produced in the liver

Answer 78

Kupffer cells

Answer 79

* Filter for bacterial and other antigens from the GIT via the portal system ◦ Kupffer cells (macrophages) attached tot eh endothelium in the liver phagocytoses substances mediating infection, inflammation e.g.bacteria, viruses, endotoxins, immune complexes, denatured albumin, thrombin, fibrin-fibrinogen complexes ◦ Antigens degraded without antibodies as little lymphoid tissue - prevents adverse immune reactions as antigens never reach antibody producing sites * Kupffer cells secrete interleukins, tumour necrosis factor, collagenases, lysosomal hydrolases ◦ This can be prompted by endotoxin exposure * Plasma proteins such as complement are produced in the liver

Answer 80

Tissue macrophages and monocytes distributed in areas of high blood vessel permeability allow for significant filtering of blood to occur

Answer 81

* Tissue macrophages in this system include ◦ Kuppfer cells lining hepatic sinusoids ◦ Macrophages lining sinusoids of the bone marrow and spleen ◦ Pulmonary alveolar macrophages ◦ Macrophages in lymph nodes ◦ Microglial cells in CNS ◦ Osteoclasts in bone

Answer 82

◦ Antigen prcessing and presentation via Class 2 MHC proteins ◦ Phagocytosis of bacteria, cellular debris ◦ Removal of bacteria, old RBC, other debri ◦ Secretions of cytokines

Answer 83

* Glycogen * Triglycerides * Vitamins A, D E, K, riboflavin, nicotinamide, pyridoxine, folic acid, B12 ◦ Vitamin D storage sufficient for 4 months ◦ Vitamin A storage for 10 months ◦ B12 for 1 year * Iron - excess iron take up with apoferritin to form ferritin * Copper - Blood

Answer 84

* Glycogen * Triglycerides * Vitamins A, D E, K, riboflavin, nicotinamide, pyridoxine, folic acid, B12 ◦ Vitamin D storage sufficient for 4 months ◦ Vitamin A storage for 10 months ◦ B12 for 1 year * Iron - excess iron take up with apoferritin to form ferritin * Copper

Answer 85

* BV 450mL-500mLs (30mL per 100g of liver tissue) half (250-350mLs) of which can be mobilised * Portal blood can bypass sinusoids as blood shunted from portal venules to hepatic venules by relaxation of hepatic venules sphincters * Catecholamines mobilise blood from sinusoids * Hepatic o pliable is higher at high venous pressures than low venous pressures buffering against high volumes

Answer 86

* Can be either a signficant net producer or consumer of hydrogen ions * Carbon doxide production from complete oxidation of substrates ◦ Liver uses 20% of the bodies oxygen consumption ◦ Produces 20% of the bodies CO2 * Metabolism of acid anions ◦ Endogenous - lactate and ketoacids ‣ Metabolism consumes the H+ produced when lactate was originally produced in muscles or other locations ◦ Exogenous - citrate, acetate, gluconate ‣ Metabolism of these where a H+ was not adminsitered with them results in H+ consumption resulting in net proudction of a bicarbonate anion * Amino acid metabolism ◦ Incomplete metabolism --> net fixed acid production ‣ E.g. sulphuric acid from metabolism of methionine, cysteine ◦ Overally amino acid metabolism results in average net production of 50mmol/day of fixed acid which is 70% of daily net fixed acid production * Metabolism of ammonium ◦ Conversion of NH4+ to urea results in equivalent production of H+

Answer 87

* Can be either a signficant net producer or consumer of hydrogen ions * Carbon doxide production from complete oxidation of substrates ◦ Liver uses 20% of the bodies oxygen consumption ◦ Produces 20% of the bodies CO2 * Metabolism of acid anions ◦ Endogenous - lactate and ketoacids ‣ Metabolism consumes the H+ produced when lactate was originally produced in muscles or other locations ◦ Exogenous - citrate, acetate, gluconate ‣ Metabolism of these where a H+ was not adminsitered with them results in H+ consumption resulting in net proudction of a bicarbonate anion * Amino acid metabolism ◦ Incomplete metabolism --> net fixed acid production ‣ E.g. sulphuric acid from metabolism of methionine, cysteine ◦ Overally amino acid metabolism results in average net production of 50mmol/day of fixed acid which is 70% of daily net fixed acid production * Metabolism of ammonium ◦ Conversion of NH4+ to urea results in equivalent production of H+

Answer 88

* Can be either a signficant net producer or consumer of hydrogen ions * Carbon doxide production from complete oxidation of substrates ◦ Liver uses 20% of the bodies oxygen consumption ◦ Produces 20% of the bodies CO2 * Metabolism of acid anions ◦ Endogenous - lactate and ketoacids ‣ Metabolism consumes the H+ produced when lactate was originally produced in muscles or other locations ◦ Exogenous - citrate, acetate, gluconate ‣ Metabolism of these where a H+ was not adminsitered with them results in H+ consumption resulting in net proudction of a bicarbonate anion * Amino acid metabolism ◦ Incomplete metabolism --> net fixed acid production ‣ E.g. sulphuric acid from metabolism of methionine, cysteine ◦ Overally amino acid metabolism results in average net production of 50mmol/day of fixed acid which is 70% of daily net fixed acid production * Metabolism of ammonium ◦ Conversion of NH4+ to urea results in equivalent production of H+

Answer 89

Carbohydrate metabolism summary * Blood glucose level regulation ◦ Energy storage - up to 100g of glucose can be stored through glycogen formation and storage of glucose which is stimulated by insulin in response to elevated portal blood sugar levels. ◦ Glycogenlysis + gluconeogenesis in response to low BSL levels - glucose released from glycogen breakdown but also glucose is synthesised from muscle derived amino acids (alanine,glutamine) and glycerol from lypolsyis of peripheral fat stores * Energy production ◦ Catabolism via glycolysis with net energy gain of 38 ATP from aerobic breakdown of glucose to pyruvate and subsequent citric acid cycle processsing * Oxidation and decarboxylation of glucose to pentose producing NADPH for steroid hormone processing and bio transformation of drugs Lipid summary * Lipid breakdown for energy extraction ◦ Beta oxidation - free fatty acid conversion to acetyl CoA which proceed through the Kreb’s cycle; or alternatively stored as acetic acid to transport energy to peripheral tissues to undergo conversion back to Acetyl CoA for energy utilisation * Lipid synthesis ◦ Synthesis of fatty acids from excess glucose —> conversion to triglycerides integrated into VLDL for peripheral fat storage ◦ Cholesterol synthesis - either cholesterol ingested or synthesised in the liver or adrenal cortex from acetyl CoA is converted to bile, used as a precursor for hormones or transported to peripheral tissues in lipoproteins for use in cell membranes or intracellular structure * Lipid processing ◦ Apoliprotein synthesis to facilitate transport and redistribution of body lipid Protein metabolism summary * Protein synthesis - the dominant site of protein synthesis for all major protein groups aside from immunoglobulins ◦ Albumin synthesis - key transport protein for acidic drugs and intrinsic hormones + electrolytes; the dominant source of intravascular plasma oncotic pressure ◦ Globulin protein synthesis ‣ Alpha globulins including haptoglobin for plasma free haemoglobin binding, serine protease inhibitors e.g. alpha 1 anti trypsin ‣ Beta globulins - transferrin binding and transferring iron in its ferric form ‣ Complement synthesis ◦ Clotting factors - vitaminK dependent clotting factors + independent factors * Amino acid synthesis and metabolism ◦ Oxidative deamination forming energy and urea from surplus amino acids - remaining keto acid can be transformed by transamination to another amino acid, used as a substrate for gluconeogenesis or utilised in the citric acid cycle * Nitrogenous waste excretion from protein degredation i.e. urea ◦ Surplus ammonia is toxic thus converted to urea for kidney excretion

Answer 90

Note that the reverse reaction to produce glutamine can be performed consuming 2 NH4+

Answer 91

* a toxic metabolite of protein and purine synthesis which mainly causes neurological dysfunction and cerebral oedema

Answer 92

Non polar Therefore abel to diffuse through lipid bilayers

Answer 93

* Ammonia, NH3 is non-polar and can diffuse through lipid bilayers ◦ It has a pungent/sharp odour ◦ In low concentrations has high toxicity when inhaled causes pulmonary oedmea/ARDS ◦ Immediate blistering contact with skin ◦ Supports combustion by donation hydrgoen to oxygen

Answer 94

* Ammonia, NH3 is non-polar and can diffuse through lipid bilayers ◦ It has a pungent/sharp odour ◦ In low concentrations has high toxicity when inhaled causes pulmonary oedmea/ARDS ◦ Immediate blistering contact with skin ◦ Supports combustion by donation hydrgoen to oxygen

Answer 95

* 98% exists in ionised form (ammonium, NH4+) at physiological pH, which is less lipid-soluble and is trapped in water compartments ◦ NH3 (gas) + H+ ⇌ NH4+ ◦ pKa 9, confined to extracellualr body water with a Vd 0.4L/kg

Answer 96

* 98% exists in ionised form (ammonium, NH4+) at physiological pH, which is less lipid-soluble and is trapped in water compartments ◦ NH3 (gas) + H+ ⇌ NH4+ ◦ pKa 9, confined to extracellualr body water with a Vd 0.4L/kg

Answer 97

1-4 minutes

Answer 98

Liver and skeletal muscle mainlyW

Answer 99

11-30 micromol/L

Answer 100

* Intestine ◦ Primarily from gut bacteria urea hydrolysis/urea splitting in colon --> main source for the liver ◦ Metabolism of glutamine by enterocytes leading to recirculation ◦ Dietary sources - miniscule * Amino acid metabolism in the liver and skeletal muscle ◦ Glutamine from peripheral tissues is exported to the liver via circulation where metabolism releases ammonia ◦ Skeletal muscle when resting is a net absorbed of ammonia but exercising muscle produce ammonia ◦ The liver itself deamination of amino acids - dietary or endogenous in origin * Purine nucleotide cycle in skeletal muscle and brain * Renal tubular synthesis (from glutamine) - small percentage of ammonia release - 70% of ammonia produced in kidney is returned to blod stream * Liver - deaminiation of amino acids (mainly glutamine)

Answer 101

Metabolised of glutamine in the liver --> deamination Glutamine is released from peripheral tissues for liver and renal processing

Answer 102

* Renal tubular synthesis (from glutamine) - small percentage of ammonia release - 70% of ammonia produced in kidney is returned to blod stream * Liver - deaminiation of amino acids (mainly glutamine)

Answer 103

* Intestine ◦ Primarily from gut bacteria urea hydrolysis/urea splitting in colon --> main source for the liver ◦ Metabolism of glutamine by enterocytes leading to recirculation ◦ Dietary sources - miniscule

Answer 104

◦ Skeletal muscle when resting is a net absorbed of ammonia but exercising muscle produce ammonia * Purine nucleotide cycle in skeletal muscle and brain

Answer 105

* Circulating pure ammonia * Circulating glutamine as a form of interorgan ammonia transport (by far the most important, quantitatively) - and represents 50% of circulating amino acids. Alanine is a less important circulating ammonia pathway

Answer 106

* Circulating pure ammonia * Circulating glutamine as a form of interorgan ammonia transport (by far the most important, quantitatively) - and represents 50% of circulating amino acids. Alanine is a less important circulating ammonia pathway

Answer 107

* Ammonia and CO2 are combined to form urea, (NH2)2CO, in an enzyme cycle which recycles ornithine

Answer 108

92% first pass extraction ratio

Answer 109

* Only hepatocytes possess the full set of enzymes to complete these reactions - in particular oxidative deamination requring glutamate and water as substrates (glutamate dehydrogenase can transform glutamate into alpha ketoglutarate releasing ammonia)

Answer 110

the kidneys mostly 13-30% enterohepatic recirculation

Answer 111

* Some (~13-30%) undergoes enterohepatic recirculation where urea is excreted into the gut, hydrolysed back into ammonia by gut organisms, is reabsorbed into the portal blood and returns to the liver.

Answer 112

* Some tiny fraction of ammonia 10-100mmol is eliminated as ammonium ions, and some as gaseous ammonia ◦ glutamine enters peritubular cells of PCT --> 80% from peritubular capillaries, 20% from filtrate reabsorbed. Deaminated via glutaminase which has increased activity in acidosis. HCO3 reabsorbed, NH4 excreted. ◦ Ammonium cycling with 80% reabsorbed TAL of LOH but then diffuses down concentration gradient into collecting duct

Answer 113

* Some tiny fraction of ammonia 10-100mmol is eliminated as ammonium ions, and some as gaseous ammonia ◦ glutamine enters peritubular cells of PCT --> 80% from peritubular capillaries, 20% from filtrate reabsorbed. Deaminated via glutaminase which has increased activity in acidosis. HCO3 reabsorbed, NH4 excreted. ◦ Ammonium cycling with 80% reabsorbed TAL of LOH but then diffuses down concentration gradient into collecting duct

Answer 114

* Brain, skeletal and cardiac muscle non hepatic amino acid metabolism - transamination ◦ Amino acids transminated into carbon skeletons to feed TCA cycle producing alpha ketoglutarate and glutamine/alanine which the muscle exports back to the liver ◦ This consumes ammonia in vast quantities so muscle becomes an ammonia clearance organ

Answer 115

* Brain, skeletal and cardiac muscle non hepatic amino acid metabolism - transamination ◦ Amino acids transminated into carbon skeletons to feed TCA cycle producing alpha ketoglutarate and glutamine/alanine which the muscle exports back to the liver ◦ This consumes ammonia in vast quantities so muscle becomes an ammonia clearance organ

Answer 116

◦ Make amino acids back out of ammonia reversing deaminiation usually happens thorugh glutamate dehydrogenase adn glutamine synthase ‣ Glutamate dehydrogenase catalyses the pathway in both direction ◦ Glutamine is the most abundant amino acid in the body - 1/3 of glutamine syntheiss is extrahepatic ‣ And this is the main form in which ammonium is usually transported in the body ◦ This does not however excrete the ammonia, and is not a source of fuel without the re-release of ammonia ◦ It does however allow transport of ammonia in non toxic form back to the lvier for processing

Answer 117

◦ Make amino acids back out of ammonia reversing deaminiation usually happens thorugh glutamate dehydrogenase adn glutamine synthase ‣ Glutamate dehydrogenase catalyses the pathway in both direction ◦ Glutamine is the most abundant amino acid in the body - 1/3 of glutamine syntheiss is extrahepatic ‣ And this is the main form in which ammonium is usually transported in the body ◦ This does not however excrete the ammonia, and is not a source of fuel without the re-release of ammonia ◦ It does however allow transport of ammonia in non toxic form back to the lvier for processing

Answer 118

Fumarate and malate metabolic substrates produced and plugged into citric acid cycle * Many tissues have necessary enzymes but brain and muscle most important

Answer 119

Deamination Transamination

Answer 120

◦ oxidative deaminiation in liver removing amino group to create a ketoacid and ammonia which enters the urea cycle (requiring 3 ATP

Answer 121

◦ transamination where amino group transferred by aminotransferases to another amino acid or ketoacid to produce ‣ ketoacids (enter citric acid cycle producing ATP or get converted to glucose or fatty acids) ‣ amino groups entering the urea cycle

Answer 122

>`1microg/mL

Answer 123

‣ Nitrogenous end of ammonia (2x ammonia) combines with carbon dioxide in liver cell mitochondria forming carbomoyl phosphate (NH2)2-CO

Answer 124

Carbamoyl phosphate

Answer 125

Urea cycle an energy dependent process utilising 3 ATP molecules per urea molecule synthesised

Answer 126

‣ Nitrogenous end of ammonia (2x ammonia) combines with carbon dioxide in liver cell mitochondria forming carbomoyl phosphate (NH2)2-CO

Answer 127

Ornithine to produce citrulline

Answer 128

Ornithine and carbamyl phosphate

Answer 129

‣ Citrulline reacts with aspartate —>arginine

Answer 130

‣ Arginine hydrolysed —> ornithine, water, urea

Answer 131

Combines with carbamyl phosphate to produce citrulline

Answer 132

combines with citrulline to form arginosuccinate

Answer 133

10-30% - 15% on average

Answer 134

Passive diffusino down concentration gradient

Answer 135

◦ Urease splitting organisms (E.coli, Clostridium, Klebsiella, Proteus, Providencia and Morganella ) then produce ammonia and CO2 --> reabsorption fo ammonia intop splanchnic circulation and transport back to the lvier with 90% clearance

Answer 136

◦ 50% is then reabsorbed in the proximal tubule ‣ This is a passive process (solute drag) - 40% - paracellualrly ‣ More water is reabsorbed than urea --> As the result, urea is concentrated by about 50% (7.5mmol/L)

Answer 137

◦ 50% is then reabsorbed in the proximal tubule ‣ This is a passive process (solute drag) - 40% - paracellualrly ‣ More water is reabsorbed than urea --> As the result, urea is concentrated by about 50% (7.5mmol/L)

Answer 138

◦ In the thin descending limb, urea is concentrated signficantly ‣ Some urea is added to the fluid by UT-A2 transport proteins from ascending vasa recta; urea permeability out is low and water permeability high resulting in water reabsorption and urea concentration by 30-40 times --> 150-200mmol/L

Answer 139

‣ Thin ascending - urea permeability higher,. water permeability low, urea therefore diffuses out into the medullary intersitium, where it is captured by the vasa recta and recirculates; however even more enters the thin ascending limb from the collecting duct increasing concentration by 20-25% between the bend and the ned of the thin ascneding limb. ‣ In the thick ascending limb, some urea may diffuse back out into the medullary interstitium ‣ In the inner medulla, urea is recycled by countercurrent exchange and a high urea concentration is maintained to facilitate osmotic recovery of water from the tubular fluid

Answer 140

‣ The recovery of water via aquaporins in the collecting duct further concentrates the urea in the lumen ‣ Terminal collecting duct *(deep medullary interstitium) urea concentration can be up to 100 times greater than plasma ‣ Here, urea permeability is increased, allowing urea diffusion into the inner medulla --> via UTA transporters ‣ Reuptake of urea from the terminal collecting duct is a part of urea recycling and helps maintain high urea concentration in the renal medulla driving reabsorption of water elsewhere in the tubule

Answer 141

‣ The recovery of water via aquaporins in the collecting duct further concentrates the urea in the lumen ‣ Terminal collecting duct *(deep medullary interstitium) urea concentration can be up to 100 times greater than plasma ‣ Here, urea permeability is increased, allowing urea diffusion into the inner medulla --> via UTA transporters ‣ Reuptake of urea from the terminal collecting duct is a part of urea recycling and helps maintain high urea concentration in the renal medulla driving reabsorption of water elsewhere in the tubule

Answer 142

Metabolised by gut bacteria and increases osmolality of the tool and water content preventing reabsotion Also a metabolic substrate for bacteria diverting metabolism to production of non nitrgoenous metabolites

Answer 143

2 hours Duration of effect 4-8 hours

Answer 144

Disaccharide of glucose and fructose Cannot be absorbed

Answer 145

Increased exogenous administration Increased urea synthesis Increased catabolism Decreased clearance due to either increased reabsorption or decreased renal clearance

Answer 146

◦ High protein diet ◦ GI haemorrhage - as enteric organisms break down proteins in blood into amino acids which are reasborbed with a large protein load processed by the liver ◦ Paraenteral oversupplementation of amino acids - TPN ◦ Glycine intoxication in TURP syndrome ◦ Gastric bypass ◦ Multiple myeloma

Answer 147

◦ Corticosteriods ◦ Trauma ◦ Burns ◦ Major surgery ◦ Starvation

Answer 148

‣ Hypovolaemia - CCF, renal artery stenosis ‣ actual hypovolaemia ‣ Tetracyclkine therapy ‣ Post renal obstruction

Answer 149

In liver impairment urea may fail to be produced from ammonia resulting in ammonia accumulation * Liver failure - acute, chronic, portosystemic shunt * Drugs and toxins - valproate, carbamazapine, topiramate, salicylates, rifampicin, hepatotoxic drugs * Metabolic errors

Answer 150

* Inhibits Na/K/2Cl cotransporter in red blood cells at levels 45mmol/L and above ◦ Involved in regulation of cell volume and K levels ' * Inhibition of enzyme function ◦ Xanthine oxidase directly involved in reducing intracellular macromolecular crowding * Nitric oxide synthase inhibition opposing vasodilation * Carbamoylation of proteins - changing their function

Answer 151

* Cardiovascular - pericardial rub, pericardial effusion * Neuro - encephalopathy, peripheral neuropathy * Endocrine - improved glycaemic control * GI - nausea and vomiting * Platelet dysfunction * Misc ◦ Mixed metabolic acidosis ◦ Uraemic foetor, frost, pruritis, nail atrophy and sallow skin

Answer 152

* Haemoglobin broken down in reticuloendothelial system (spleen) ◦ 85% of bilirubin comes from haemoglobin, 15% from other haem containing compounds e.g. myoglobin * Haem broken down into ◦ Haem ◦ Globin —> broken down into constituent amino acids * Haem unit broken down via haem oxygenase and NADPH-cytochrome P450 ◦ Iron—> re-utilised and bound to transferrin for transfer to bone marrow ◦ Small amounts of carbon monoxide excreted via lungs ◦ Porphyrin ring —> Biliverdin via oxidation in macrophages of the spleen * Biliverdin reductase converts (reduces) this to unconjugated (indirect) bilirubin (insoluble)

Answer 153

* Bilirubin bound to serum albumin and transported to the liver * Hepatocytes uptake bilirubin - 2 binding proteins involved * Conjugation inside hepatocytes via UDP (uridine disphosphate)-glucoronosyl transferase with glucoronides —> water soluble conjugated bilirubin * Conjugate bilirubin secreted in bile into the small intestine

Answer 154

* Conjugated bilirubin reabsorbed in the small intestine - enterohepatic recycling as resecreted by the liver into the intestine * Conjugated bilirubin broken down by bacteria to ◦ Urobilinogen —> enters enterohepatic circulation but its reuptake is not as complete as conjugated bilirubin and excreted in urine ◦ Urobilinogen may be converted further by oxidation to urobilin and stercobilin which are excreted in faeces

Answer 155

* Failure of bilirubin conjugation due to intrahepatic disease —> blood unconjugated bilirubin levels high * Because it is unconjugated none is filtered by the glomerulus * The degree of hepatocellular dysfunction and the aetiology may effect the degree to which pure hepatocytes dysfunction occurs or some biliary duct disruption leading to a mixed picture of conjugated and unconjugated

Answer 156

* Obstruction of bile drainage results in back pressure on hepatocytes and release of conjugated bilirubin into systemic circulation * High conjugated levels peripherally in blood —> as it’s water soluble it is found in the urine with a ositive dipstick * Faeces becomes pale in colour due to failure of bilirubin and its metabolites to reach the intestine

Answer 157

exocrine secretion of hepatocytes into the gut lumen via hepatic and bile ducts

Answer 158

* Bile is created at the tiny apical membrane of the hepatocytes that forms the biliary canaliculi.

Answer 159

◦ Bile then undergoes extensive modification in the bile ducts. ◦ About 90% of the bile produced during the day comes to rest in the gallbladder before being released to work its magic on some ingested fats, and while it waits the gallbladder also slowly works to modify its composition

Answer 160

cholesterol

Answer 161

Carboxylic acid incorporated inot a sterol ring

Answer 162

◦ Cholesterol is converted to cholic acid and chenodeoxycholic acid by oxidation and excreted into canaliculi by hepatocytes (primary bile salts) ◦ Passes into the gallbladder where it s concentrated to 1/5 of its volume ◦ In the gut bacterial action result in secondary bile acids —> deoxycholic acid and lithocholic acid ◦ These conjugate with taurine and glycine to form bile salts with Na and K ◦ Bile salts are more water soluble and less lipid soluble limiting passive absorption

Answer 163

◦ Cholesterol is converted to cholic acid and chenodeoxycholic acid by oxidation and excreted into canaliculi by hepatocytes (primary bile salts) ◦ Passes into the gallbladder where it s concentrated to 1/5 of its volume ◦ In the gut bacterial action result in secondary bile acids —> deoxycholic acid and lithocholic acid ◦ These conjugate with taurine and glycine to form bile salts with Na and K ◦ Bile salts are more water soluble and less lipid soluble limiting passive absorption

Answer 164

◦ Cholesterol is converted to cholic acid and chenodeoxycholic acid by oxidation and excreted into canaliculi by hepatocytes (primary bile salts) ◦ Passes into the gallbladder where it s concentrated to 1/5 of its volume ◦ In the gut bacterial action result in secondary bile acids —> deoxycholic acid and lithocholic acid ◦ These conjugate with taurine and glycine to form bile salts with Na and K ◦ Bile salts are more water soluble and less lipid soluble limiting passive absorption

Answer 165

1/5 of volume 5-10x concentration Although lots of ions are also reclaimed

Answer 166

0.5g per day

Answer 167

2-3x per meal for 3x meals per day

Answer 168

95% in terminal ileum

Answer 169

Apical sodium dependent bile transporter

Answer 170

* 95% reabsorbed at terminal ileum by apical sodium dependent bile transporter ◦ Carried to the liver in portal circulation bound to plasma proteins —> reabsorbed into hepatocytes ◦ Recirculation called enterohepatic recirculation —> re-secreted into bile ducts via active transport ◦ Enterohepatic recirculation important in maintaining a low hepatic bile acid production requirement - production is subject to feedback inhibition by reabsorbed bile acids

Answer 171

Due to osmotic effects of bile salts on water it moves out into the canaliculi post secretion

Answer 172

is due to the osmotic effects of other organic molecules such as glutathione, bilirubin, bicarbonate and organic conjugates

Answer 173

Bile salt dependent bile secretion - osmotic effects of bile salts Bile salt INDEPENDENT bile secretion due to the osmotic effects of other organic molecules such as glutathione, bilirubin, bicarbonate and organic conjugates Transported via aquaporins via osmotic forces and through tight junctions

Answer 174

* In the bile ducts, more fluid (~40%) is added and the bile is alkalinised

Answer 175

* Water 95% - transported into bile via aquarporins via mostly osmotic forces as well as thorugh tight junctions * 5% organic and inorganic solutes ◦ Electrolytes - similar to plasma, more alkaline (pH 8) --> becomes more acidic (pH5-6) and concentrated in gallbladder ◦ Protein <1g/L - ‣ Passively filtered - albumin, apoliproteins, Haptoglobin, ceruloplasmin ‣ Secreted - cholecystokinin, amylase, epidermal growth factor, IgA, IgG, IgM ◦ Bilirubin - otherwise known as bile pigment 1-2mmol/L ‣ bilirubin content of bile is therefore high (1000-2000 μmol/L), usually at least ten times higher (and up to a hundred times higher) than in blood ◦ Bile salts - bile acids are steriod compounds produced in the liver from cholesterol ‣ 3-45mmol/L - total pool 3g ◦ Lipids - cholesterol and phospholipids ‣ Cholesterol 2.5-8mmol/L and lipids 20g/L

Answer 176

* 5% organic and inorganic solutes ◦ Electrolytes - similar to plasma, more alkaline (pH 8) --> becomes more acidic (pH5-6) and concentrated in gallbladder

Answer 177

◦ Electrolytes - similar to plasma, more alkaline (pH 8) --> becomes more acidic (pH5-6) and concentrated in gallbladder

Answer 178

◦ Protein <1g/L - ‣ Passively filtered - albumin, apoliproteins, Haptoglobin, ceruloplasmin ‣ Secreted - cholecystokinin, amylase, epidermal growth factor, IgA, IgG, IgM ◦ Bilirubin - otherwise known as bile pigment 1-2mmol/L ‣ bilirubin content of bile is therefore high (1000-2000 μmol/L), usually at least ten times higher (and up to a hundred times higher) than in blood ◦ Bile salts - bile acids are steriod compounds produced in the liver from cholesterol ‣ 3-45mmol/L - total pool 3g ◦ Lipids - cholesterol and phospholipids ‣ Cholesterol 2.5-8mmol/L and lipids 20g/L

Answer 179

◦ Protein <1g/L - ‣ Passively filtered - albumin, apoliproteins, Haptoglobin, ceruloplasmin ‣ Secreted - cholecystokinin, amylase, epidermal growth factor, IgA, IgG, IgM ◦ Bilirubin - otherwise known as bile pigment 1-2mmol/L ‣ bilirubin content of bile is therefore high (1000-2000 μmol/L), usually at least ten times higher (and up to a hundred times higher) than in blood ◦ Bile salts - bile acids are steriod compounds produced in the liver from cholesterol ‣ 3-45mmol/L - total pool 3g ◦ Lipids - cholesterol and phospholipids ‣ Cholesterol 2.5-8mmol/L and lipids 20g/L

Answer 180

Emulsificatino of fat for lipase action and absorption * The micelles make contact with enterocytes which absorb the lipid contents including fat soluble vitamins ◦ Absorption of fat soluble vitamins A, D, E, K * Excretory function ◦ Excreting cholesterol and bilirubin - main mechanism ◦ Lipid soluble xenobiotic secretino * Immune function - IgA and IgG * Growth stimulus - trophic stimuli to enterocytes

Answer 181

◦ Bile salts are amphipathic - hydrophobic on one end and hydrophilic on the other, enabling them to surround dietary lipid breaking large globules into a suspension of multiple small fat droplets called micelles

Answer 182

◦ Bile salts are amphipathic - hydrophobic on one end and hydrophilic on the other, enabling them to surround dietary lipid breaking large globules into a suspension of multiple small fat droplets called micelles ‣ Bile salts act with monoglycerides and phospholipids to do this ‣ This action occurs becasue there is a decrease in surface tension in the fat particles caused by these substances

Answer 183

◦ These micelles enable pancreatic lipase to act on the dietary lipid in the core, and micelles transported to the brush border where lipids diffuse out of the micelle and across the lipid membrane of the enterocytes ◦ Absorption of dietary fat is reduced to 50% with excess lost in stools in absence of bile salts

Answer 184

◦ These micelles enable pancreatic lipase to act on the dietary lipid in the core, and micelles transported to the brush border where lipids diffuse out of the micelle and across the lipid membrane of the enterocytes ◦ Absorption of dietary fat is reduced to 50% with excess lost in stools in absence of bile salts

Answer 185

* The micelles make contact with enterocytes which absorb the lipid contents including fat soluble vitamins ◦ Absorption of fat soluble vitamins A, D, E, K * Excretory function ◦ Excreting cholesterol and bilirubin - main mechanism ◦ Lipid soluble xenobiotic secretino * Immune function - IgA and IgG * Growth stimulus - trophic stimuli to enterocytes

Answer 186

Bile acids are insoluble fatty (sterol) acids Bile salts are soluble ionised fatty (sterol) acids

Answer 187

* Decreased first pass metabolism as discussed under metabolism will also be reflected in increased oral bioavailability of drugs especially those with high hepatic clearance - this occurs due to both increased intrahepatic shunting with disease as well as reduced intrinsic metabolic potential and therefore reduced hepatic extraction

Answer 188

* Drug transport ◦ High bilirubin levels may displace drugs from albumin resulting in lower total drug levels altering drug monitoring mechanisms ◦ Low drug transport proteins due to failure of transport protein synthesis e.g. albumin will increase free fraction and reduce total drug levels * Increased total body water as part of chronic liver disease ◦ Increased volume of distribution

Answer 189

The liver is one of the primary sites of drug metabolism and clearance and like any organ its clearance is a manifestation of both the blood flow to the organ and the efficiency of irreversible drug extraction (hepatic extraction ratio) * Drug metabolism occurs via 3 phases and its compromise reduces hepatic extraction ratio and therefore clearance ◦ Phase 1 reactions - Non synthetic, non specific reactions converting parent drug to a more polar metabolite by introducing or unmasking a functional group. Involve largely cytochrome p450 enzyme reactions within the hepatocyte’s endoplasmic reticulum e.g. oxidation, reduction and hydrolysis. These reactions often inactivate drugs, but may also activate or enhance their action and by increasing their polarisation they are more likely to be renally cleared ‣ Liver failure will reduce this process resulting in prolongation of drugs inactivated by this process, or failure of action of drugs which require activation via this process ◦ Phase 2 reactions - Conjugation reactions the most common of which is glucoronidation e.g. of morphine orpropofol ‣ Many phase 1 metabolites go on to have phase 2 reactions which generally inactivate them a major exception being morphine 6 gluronide; although some phase 2 reactions have no preceding phase 1 reaction ‣ Liver failure reduces this process leading to prolongationof mechanism of action or longer half lives of drugs with reduced clearance ◦ Drug metabolism also occurs via plasma esterases and peptidases that are live rproudced prolonging the clearance of suxamethonium and other drugs metabolised in plasma * Synergistic mechanism with reduced liver blood flow and increased intrahepatic shunting will reduce hepatic clearance ◦ This will also reduce first pass metabolism therefore for orally administered medications with high hepatic clearance there will be a proportional significant increase in bioavailability * Phase 3 - ATP dependent drug excretion into bile often against a concentration gradient ◦ Reduction in this process will prolong half life by reducing clearance e.g. steroid based muscle relaxants ◦ Enterohepatic recirculation of drugs will be decreased

Answer 190

◦ Phase 1 reactions - Non synthetic, non specific reactions converting parent drug to a more polar metabolite by introducing or unmasking a functional group. Involve largely cytochrome p450 enzyme reactions within the hepatocyte’s endoplasmic reticulum e.g. oxidation, reduction and hydrolysis. These reactions often inactivate drugs, but may also activate or enhance their action and by increasing their polarisation they are more likely to be renally cleared ‣ Liver failure will reduce this process resulting in prolongation of drugs inactivated by this process, or failure of action of drugs which require activation via this process

Answer 191

◦ Phase 2 reactions - Conjugation reactions the most common of which is glucoronidation e.g. of morphine orpropofol ‣ Many phase 1 metabolites go on to have phase 2 reactions which generally inactivate them a major exception being morphine 6 gluronide; although some phase 2 reactions have no preceding phase 1 reaction ‣ Liver failure reduces this process leading to prolongationof mechanism of action or longer half lives of drugs with reduced clearance ◦ Drug metabolism also occurs via plasma esterases and peptidases that are live rproudced prolonging the clearance of suxamethonium and other drugs metabolised in plasma

Answer 192

* Synergistic mechanism with reduced liver blood flow and increased intrahepatic shunting will reduce hepatic clearance ◦ This will also reduce first pass metabolism therefore for orally administered medications with high hepatic clearance there will be a proportional significant increase in bioavailability

Answer 193

1500-1800g

Answer 194

◦ 2 surfaces the diaphragmatic and the visceral ‣ Diaphragmatic - convex and smooth, covered in peritoneum, everywhere realted to the diaphragm lungs and pleura. Superiorly also related to the pericardium ‣ Visceral surface * Concave, irregular, impressed with shapes of organs beneat * H shaped patter of structures ◦ Porta hepatis is the cross bar of the H - it is the right a left hepatic ducts, the right and left branches of the hepatic artery and portal vein * Gallbladder and IVC on the right of the H * Lesser omentuand ligamentum teres on the left of the H

Answer 195

◦ 2 surfaces the diaphragmatic and the visceral ‣ Diaphragmatic - convex and smooth, covered in peritoneum, everywhere realted to the diaphragm lungs and pleura. Superiorly also related to the pericardium ‣ Visceral surface * Concave, irregular, impressed with shapes of organs beneat * H shaped patter of structures ◦ Porta hepatis is the cross bar of the H - it is the right a left hepatic ducts, the right and left branches of the hepatic artery and portal vein * Gallbladder and IVC on the right of the H * Lesser omentuand ligamentum teres on the left of the H

Answer 196

◦ 2 surfaces the diaphragmatic and the visceral ‣ Diaphragmatic - convex and smooth, covered in peritoneum, everywhere realted to the diaphragm lungs and pleura. Superiorly also related to the pericardium ‣ Visceral surface * Concave, irregular, impressed with shapes of organs beneat * H shaped patter of structures ◦ Porta hepatis is the cross bar of the H - it is the right a left hepatic ducts, the right and left branches of the hepatic artery and portal vein * Gallbladder and IVC on the right of the H * Lesser omentuand ligamentum teres on the left of the H

Answer 197

* Consists of hepatocytes (70%), cholangiocytes (15%) and Kupffer cells (15%)

Answer 198

1-2mm units called hepatic lobules

Answer 199

* Each lobule has a central hepatic vein and peripheral portal tracts (portal vein, biliary ductule, hepatic arteriole), connected by hepatic sinusoids. * A lump of tissue, hexagonal in cross-section, filled with hepatocytes * Terminal vein, running down the centre * Portal tracts, running along the corners, which contain: ◦ Interlobular hepatic artery, around the corners ◦ Interlobular portal veins, around the corners ◦ Biliary ductules ◦ Lymphatic vessels ◦ Nerves

Answer 200

◦ Interlobular hepatic artery, around the corners ◦ Interlobular portal veins, around the corners ◦ Biliary ductules ◦ Lymphatic vessels ◦ Nerves

Answer 201

‣ near absent discontinuous basement membrane with multiple endothelial fenestrations - only prevents cells from entering space of disse ‣ slightly larger diametre than most cpaillaries ‣ hepatocyte microvilli - on the basal surface, apical surface onto canaliculi ‣ Space of Disse - perisinusoidal space between endothelial layer of sinusoid and hepatocytes filled with blood plasma and microvilli ‣ Lined with Kupffer cells descended from monocytes in the lumen of sinusoids - * phagocytosing bacteria translocating into circulation, foreign particles, sensecent blood cells, heparin, blood proteins, immune complexes * Metabolism of iron, bilirubin * Secretion and synthesis of complement, pyrogens, lymphokines, LK and interferon ‣ Hepatic stellate cells - regulatory proteins and can function as APC, storage of vitamin A and TG storage, contractile functions and fibroblast like functions

Answer 202

‣ Hepatic stellate cells - regulatory proteins and can function as APC, storage of vitamin A and TG storage, contractile functions and fibroblast like functions

Answer 203

‣ near absent discontinuous basement membrane with multiple endothelial fenestrations - only prevents cells from entering space of disse

Answer 204

‣ Lined with Kupffer cells descended from monocytes in the lumen of sinusoids - * phagocytosing bacteria translocating into circulation, foreign particles, sensecent blood cells, heparin, blood proteins, immune complexes * Metabolism of iron, bilirubin * Secretion and synthesis of complement, pyrogens, lymphokines, LK and interferon

Answer 205

‣ Space of Disse - perisinusoidal space between endothelial layer of sinusoid and hepatocytes filled with blood plasma and microvilli * Space of Disse is the narrow (500-1000nm) space that contains hepatocyte microvilli, hepatocyte precursor stem cells and hepatic stellate cells. ◦ From the space of Disse, filtered blood plasma flows through interstitial lymphatic channels into the thoracic duct, where hepatic lymph contributes ~50% of the total flow

Answer 206

Within the hepatic sinsuoids

Answer 207

Within the space of Disse facing the sinusoid

Answer 208

* Periportal limiting plate, the ring of connective tissue and the adjacent row of hepatocytes that surround each portal tract.

Answer 209

* Space of Mall, a space between the other wall of the portal tract and the hepatocytes, where the formation of hepatic lymph occurs

Answer 210

* Space of Mall, a space between the other wall of the portal tract and the hepatocytes, where the formation of hepatic lymph occurs * Space of Disse is the narrow (500-1000nm) space that contains hepatocyte microvilli, hepatocyte precursor stem cells and hepatic stellate cells. ◦ From the space of Disse, filtered blood plasma flows through interstitial lymphatic channels into the thoracic duct, where hepatic lymph contributes ~50% of the total flow

Answer 211

* Zones - dividing the liver into elliptical acinus with a terminal branch of the hepatic vein at either end with two portal triads at the midpoint of the gflattenedsides. Blood flows from the portal triad towards the terminal vein - the further the hepatocyte is from the portal triad the lower the O2 tension ◦ Zone 1 - closest to portal triads, best oxygenated. Does energy consuming processes e.g. gluconeogenesis and beta oxygenation of fatty acids ◦ Zone 2 - intermediate areas ◦ Zone 3 - closest to terminal vein, lowest O2 tension, least energy consuming processes e.g. drug metabolism and glycolysis. Centrilobular necrosis refers to this zone owing to the distance from the triad and most susceptable to hypoxic injury as well as the site affected by drug toxic metabolites

Answer 212

Canaliculi

Answer 213

◦ Narrow channels between hepatocytes (i.e. walls consist of hepatocytes) - basically just clefts in the adjacent walls of hepatocytes, like gutters running between neighbouring houses ◦ Normally 1-2 μ in width; also occasionally referred to as "bile capillaries"

Answer 214

* Canals of Hering: ◦ Short channels between biliary canaliculi and biliary ductules, lined by a combination of hepatocytes and cholangiocytes

Answer 215

* Terminal cholangioles, occasionally called "bile ductules" ◦ The first tubular structure entirely lined by cholangiocytes ◦ The finest ramification of the biliary tree, less than 15 μm in diameter

Answer 216

* Interlobular ducts ◦ Cholangiocyte-lined tubes, 15–100 μm in diameter ◦ Run along portal tracts

Answer 217

* Septal ducts ◦ Originate from the confluence of interlobular ducts ◦ 100–300 μm in diameter * Area ducts ◦ 300–400 μm in diameter; structurally just a larger version of septal ducts * Segmental ducts ◦ 400–800 μm in diameter, draining a segment of the liver * Hepatic ducts ◦ Larger than 800 μm; regarded as being a part of the extrahepatic biliary tree

Answer 218

* Cuboidal (in small ducts) or columnal (in large ones) * Smaller than hepatocytes, 6 to 15 μm in diameter * Distinct apical and basal membrane properties * Joined by tight junctions * Apical membrane possesses microvilli

Answer 219

* Apical membrane secretes bile * Modification of secreted bile takes place: ◦ Alkalinisation of bile by exchanging chloride for bicarbonate ◦ Concentration of bile by reabsorbing water * The reabsorption of other organic molecules (glucose, amino acids, etc) takes place here mainly to reclaim nutrients that would otherwise be lost

Answer 220

Altered liver function * Disturbed carbohydrate metabolism ◦ Hyperglycaemia chronically ◦ Hypoglycaemia acutely * Decreased protein synthesis ◦ Clotting abnormalities ◦ Hypoalbuminaemia - altered protein binding and fluid redistribution * Altered drug metabolism ◦ Slower clearance systemically ◦ Higher amounts of systemic drug delivery if high first pass metabolism usually from oral route ◦ Reduced delivery of prodrug active metabolites if dependent on same * Inadequate clearance of ammonia and nitrogenous waste

Answer 221

* Increased resistance to flow due to fibrosis obstructing sinusoids increasing portal vein pressure (normally 5-10mmHg) and hypertension is when >12mmHg * Portal vein hypertension causes ◦ Ascites - transudative fluid loss into peritoneal cavity which poses infection risk ◦ Splenomegaly - backflow into splenic vein with increased platelet and red cell removal ◦ Portocaval anastomoses - high portal veinous pressure opens collateral vessels with systemic circulation causing dilation and engorgement leading to varices(oesophageal/rectal/caput medusae)

Answer 222

◦ Failure of synthetic function - and has prognostic relevance in liver disease (Child Pugh score) ◦ Starvation, protein malnutrition - preserve scarce amino acids ◦ Stress and critical illness - as other protein production is prioritised ◦ Protein loss via nephrotic syndrome ◦ In the context of dehydration albumin level may appear normal

Answer 223

Factor 3 - tissue factor Factor 4 - calcium Factor 8 - antihaemophilic factor from vascular endothelium Platelets vWF

Answer 224

11-15 seconds

Answer 225

30-40 seconds

Answer 226

◦ Decreased clotting function by decreased synthesis of clotting factors and decreased clearance of tPA ◦ Increased clotting function by decreased synthesis of antithrombotic factors (eg. proteins C and S)

Answer 227

2, 5, 7, 10 all <24 hours

Answer 228

* Acute liver failure typically results in the loss of clotting protein synthesis and as 2/5/7/10 have half lives <24 hours demonstrate acute changes ◦ Normal - 8, 11, tPA (increased because of reduced hepatic clearance) ◦ Reduced in early liver failure - Vitamin K factors (2/7/9/10), 5, platelets with increased destruction in spleen and reduced thrombopoetin ◦ Reduced in severe end stage/fulminant liver failure - fibrinogen, protein C and S, antithrombin,

Answer 229

* Acute liver failure typically results in the loss of clotting protein synthesis and as 2/5/7/10 have half lives <24 hours demonstrate acute changes ◦ Normal - 8, 11, tPA (increased because of reduced hepatic clearance) ◦ Reduced in early liver failure - Vitamin K factors (2/7/9/10), 5, platelets with increased destruction in spleen and reduced thrombopoetin ◦ Reduced in severe end stage/fulminant liver failure - fibrinogen, protein C and S, antithrombin,

Answer 230

* Glucose is the dominant form of metabolic fuel in human cellular energy production ◦ Normal value is 5mmol/L, up to 10 following a meal ◦ The liver stores glucose as glycogen and triglycerides, and is able to mobilise glucose into the bloodstream as needed * Hypoglycaemia is often associated with acute liver failure - blood glucose can drop over hours or minutes * In chronic liver failure, hyperglycaemia is often seen, due to decreased hepatic insulin clearance and increased peripheral insulin resistance * Extrahepatic influences on glucose include nutrition (eg. glucagon depleted in starvation), diabetes, medications (eg. insulin, exogenous IV glucose), skeletal muscle glycogen and renal gluconeogenesis.

Answer 231

11-32 micromol/L

Answer 232

* A raised ammonia level suggests poor metabolic liver function, a dysfunction of urea cycle enzymes, altered gut organisms, or increased protein turnover/catabolism/uptake

Answer 233

* Aspartate aminotransferase (AST) ◦ Ubiquitous enzyme which converts oxaloacetate into aspartate. ◦ Found in many extrahepatic tissues, including cardiac and skeletal muscle ◦ An early but nonspecific biomarker of hepatocellular injury

Answer 234

◦ Kreb cycle enzyme found in hepatocytes cytosol ; half life 50 hrs ◦ Released later, after AST, in hepatocellular injury

Answer 235

◦ Induceable microsomal enzyme; transfers γ-glutamyl off glutathione ◦ Found in numerous tissues (renal tubules, liver, biliary tract, pancreas (minimal in bone)) - in hepatocytes surrounding biliary canaliculi ◦ Disproportionate rise in comparison to ALP suggests ETOH ◦ A highly non-specific marker of biliary tract disease

Answer 236

* Alkaline phosphatase (ALP) ◦ A hydrolase which removes the phosphate group from various molecules ◦ Found in all tissues (eg. kidney, bone, small intestine, leukocytes and the placenta) as well as biliary canalicular membrane of hepatocyte ◦ A non-specific marker of biliary tract stress when >3x ULN

Answer 237

* Lactate dehydrogenase (LDH) ◦ Catalyses the conversion of lactate acid to pyruvate ◦ Found in essentially all cells ◦ A non-specific marker of liver damage

Liver Flashcards

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