Alimentary System Flashcards

Question

What is the most common large bowel disease?

Answer 1

IBS | 1/3 population

Answer 2

Faecal incontinence (soiling) may affect 1/20 people By age 50, about 1/2 population have haemorrhoids Over half of the >70yr old population have diverticula of the large intestine

Answer 3

``` HEALTHCARE COSTS In-patients 6.1% GI Out-patients 6.9% GI Primary care 3.9% GI Community health and social care 3% GI ``` COSTS Not-working= early death, short-term sick, long-term sick NHS costs= healthcare and drugs >3 billion

Answer 4

40% adults suffer with dyspepsia, of which 2% consult their GP £600 million for endoscopies and prescribed drugs £100 million for OTC drugs

Answer 5

``` Antacids Antispasmodics Ulcer-healing Chronic diarrhoeal agents Laxatives Haemorrhoid treatment Stoma care Intestinal secretion drugs ``` Total cost to NHS in 1995/6 was £0.83 billion

Answer 6

NHS bowel cancer screening (BCSP) programme

Answer 7

DIETARY LIMITATION Lactose intolerance, diabetes, cholecystitis, coeliac, alcohol FLATULENCE Sound and smell INCONTINENCE AND SOILING TREATMENT Smell and sight E.g. stoma bag

Answer 8

Mucosa= epithelium, lamina propria, LCT and muscularis mucosae Submucosa= connective tissue, nerve plexuses Muscularis= smooth muscle, nerve plexuses Serous/adventitia= connective tissue +/- more epithelium

Answer 9

Colonic epithelium Stomach epithelium Small intestinal epithelium

Answer 10

Submucosa Ganglion cells and nerves (also muscularis) Submucosal gland

Answer 11

Longitudinal muscle Circular muscle Ganglion cells and nerves (also submucosa)

Answer 12

Seroa (external)

Answer 13

C5 (where pharynx becomes oesophagus) | T10 (pierces into the diaphragm)

Answer 14

Gets food from the mouth to the stomach Important in control of swallowing Food comes in through the mouth-> the tongue forces food posteriorly to the pharynx (soft palette raised to close nasal cavity) into the pharynx (under neural control) The oesophagus passes very close to the recurrent laryngeal nerves and the pericardium These may be damaged in excessive oesophagus extension

Answer 15

Designed for 'wear and tear' Stratified squamous epithelium Non-keratinising-> moist Lubricated by mucus secreting gland Many layers act as protective layer if surface layer damaged 2 sphincters (prevent backflow of food) Tonically active

Answer 16

Swallowing centre within the medulla | Under parasympathetic control via vagus

Answer 17

Lots in upper oesophagus (some voluntary control in upper half) Decreases as it descends (Smooth muscle increases as it descends)

Answer 18

Bolus of food moved down by peristalsis (purely under muscular control, gravity has no effect)

Answer 19

Circular muscle is major driver Assisted by longitudinal muscle Muscle just superior to bolus contracts One in front/inferior relaxes If food gets stuck, swallowing centre can start a wave of 2nd peristalsis

Answer 20

``` Upper= skeletal muscle Lower= skeletal and smooth ```

Answer 21

Negative pressure | But sphincter prevents this (sealed off)

Answer 22

``` Upper= only open to let food in, can't breathe when it's open Lower= open until food passes down ```

Answer 23

Where the oesophagus and stomach are joined At the Z-line, stratified squamous lining of the oesophagus gives way to the simple columnar epithelium of the stomach

Answer 24

At the gastro-oesophageal junction

Answer 25

The pressure difference between the abdominal oesophagus and stomach Contraction of the diaphragm As the stomach expands, it compresses the Z-line

Answer 26

Acid reflux

Answer 27

Acidic content is ejected into the oesophagus Lower sphincter not working properly Common in pregnancy because stomach is forced upwards so lower oesophagus is forced back into thorax -> Loss of pressure difference and contractile element of diaphragm Also after large meal

Answer 28

``` Gastric folds (present when stomach is empty) As stomach distends-> rugae expand ``` Allow for huge changes in surface area Allows stomach to expand after meal

Answer 29

Break food down into smaller particles stored (due to acid & pepsin) Hold food and release at a controlled steady rate into duodenum Kill parasites and certain bacteria

Answer 30

``` Cardia Fundus Body Antrum Pyloris ```

Answer 31

Sphincters of the stomach are closed post-eating for about 4 hours before release into duodenum Bolus churned steadily during this time

Answer 32

Cardia and pyloric region= mucus only Body and fundus= mucus, HCl, pepsinogen Antrum= gastrin

Answer 33

Slight variation due to different secretory functions Simple columnar Invaginates into mucosa- tubular glands

Answer 34

All regions | Mucin 'mops up' excess acid

Answer 35

Parietal cells

Answer 36

Endocrine cells

Answer 37

2L per day | 150mM [H+]

Answer 38

Epithelial surface= pH 6-7 Neutralised by bicarbonate ions trapped in mucus gel (mucins= gel coating) Lumen= pH 1-2

Answer 39

Pepsinogen secreting cell Protein-secreting epithelial cell Abundant RER Golgi packaging and modifying for export Masses of apical secretion granules (Pepsinogen passes through gastric pit into stomach)

Answer 40

``` RESTING Many mitochondria (requires lots of ATP) Cytoplasmic tubulovesicles (contain H+/K+ ATPase) Internal canaliculi (extend to apical surface) ``` SECRETING (active state) Tubovesicles fuse with membrane and microvilli project into canaliculi (which also fuse to form large open reservoir extending to apical surface-> H+ diffuse out through stomach lumen)

Answer 41

On BL membrane= Na/K pump (K in, passive diffusion into lumen) H+ ions generated by carbonic anhydrase (and bicarbonate ions) from CO2 and H2O H+ ions are acively secreted into the reservoir in exchange for K All bicarbonate ions are exchanged out of the cell for Cl entry (also diffuses into reservoir) H+ and Cl- ions bond-> HCl (Need high H/K ATPase and carbonic anhydrase)

Answer 42

Interacts with HCl-> pepsin (via autocatalytic process) The pepsinogen on its own has conformation with internal active site which is protected Acidic environment of the stomach exposes the active site Pepsin itself then further catalyses its own production once the active site is exposed (positive feedback) Pepsin is a protease

Answer 43

Endocrine product of the stomach (predominant) Produced predominantly in the pyloric antrum One of its major actions is to stimulate histamine release from the chromafin cells within the lamina propria Together, these then increase acid production in the stomach There is a sort of negative feedback system, as the stomach gets more acidic – gastrin secretion is inhibited A protein rich meal acts against this, as proteins make very good buffers for acid

Answer 44

Together-> increase acid production

Answer 45

Cephalic phase Gastric phase Intestinal phase

Answer 46

Thought/sight/smell and taste of food- central effect Central effect mediated by efferent vagus nerve-> ACh production ACh acts directly of parietal cells (to increase acid) or indirectly on chromaffin cells (increase histamine) Prepares for arrival of food HCl pepsin and gastrin present

Answer 47

Distension when food enters stomach-> activates stretch receptors Contents activatate chemoreceptors (local enteric phase) ACh and gastrin release (more than during cephalic) HCl pepsin present

Answer 48

Largely inhibitory effect on acid secretion Food leaves stomach and enters small intestine (pH must be increased, acid secretion reduced) = Chyme ( Protein concentration in duodenum stimulates gastrin secretion Gastric inhibitory peptide Cholecystokinin Secretin Enterogastrones-> enterogastric effect

Answer 49

Affect H/K ATPase (omeprazole) Affect histamine receptor (-> cAMP and Ca) (ranitidine)

Answer 50

Protein (high content in meal)

Answer 51

Semifluid mass of partly digested food that is expelled by the stomach into the duodenum via pyloric sphincter

Answer 52

To absorb nutrients, salt and water (from the lumen to the blood)

Answer 53

6m long, 3.5cm diameter ``` Duodenum= 25cm Jejunum= 2.5m Ileum= 3.75m ```

Answer 54

Fan shaped mesentery Throws the small intestine into folds Large blood supply to support the metabolic functions of the cells and aid absorption

Answer 55

No sudden transition between duodenum, jejunum and ileum All have same basic histological organisation (differences are slight) External wall has longitudinal and circular muscles (important for motility) Internal mucosa arranged in circular folds and covered in villi (1mm tall) Invaginations known as Crypts of Lieberkühn

Answer 56

1mm tall Simple epithelium= 1 cell thick (like rest of intestine), dominated by enterocytes Have good innervation from the submucosal plexus Motile, have a rich blood supply and lymph drainage for absorption of digested nutrients Increase surface area for absorption (most nutrients absorbed in small intestine) Villi only occur in the small intestine

Answer 57

Crypts of lieberkuhn | Epithelium which include paneth cells and stem cells

Answer 58

``` LINE MUCOSA (simple columnar epithelium consisting of:) Enterocytes= absorptive Goblet cells= mucous secreting Enteroendocrine cells= hormone secreting ``` IN CRYPTS OF LIEBERKUHN (epithelium includes:) Paneth cells= antibacterial, protect stem cells Stem cells= migrate up villus 'escalator', pluripotent

Answer 59

Cylindrical internal surface area of the small intestine increased by 500x 0.4-> 200m2 Maximum opportunity for nutrient absorption

Answer 60

Columnar absorptive cells with microvilli and a basal nucleus Cells of intestinal lining Most abundant cells in small intestine Specialised for absorption and transport of substances Lifespan 1-6 days Tight junctions between cells are important for intercellular communication and to maintain polarity (stop proteins moving between surfaces)

Answer 61

0.5-1.5um high Make up brush border Several thousand microvilli per cell-> increased surface area Surface covered with glycocalyx

Answer 62

Rich carbohydrate layer on apical membrane that serves as protection from the digestional lumen But allows for absorption Traps a layer of water and mucous known as the “unstirred layer” -> regulates rate of absorption from intestinal lumen

Answer 63

2nd most abundant epithelial cell type (between enterocytes) Goblet shape because mucous containing granules accumulate at the apical end of the cell (where brush border is) Increasing goblet cells along the entire length of the bowel (few in duodenum, many in colon)

Answer 64

Large glycoprotein that facilitates passage of material through the bowel

Answer 65

Columnar epithelial cells scattered among absorptive cells Mostly in lower part of crypts in intestine Hormone secreting (influence gut motility

Answer 66

Found only in bases of the crypts Contain large, acidophilic granules containing: - Lysozyme (antibacterial enzyme, protects stem cells) - Glycoproteins and zinc (essential trace metal for number of enzymes) Engulf some bacteria and protozoa May have a role in regulating intestinal flora

Answer 67

Most cells are constantly proliferating Enterocytes and goblet cells of the small intestine have a short life span (36 hours) Continually replaced by dividing stem cells in the crypts

Answer 68

Undifferentiated cells which remain capable of cell division to replace cells which die Epithelial stem cells are essential in the GI tract to continually replenish the surface epithelium Continually divide by mitosis Migrate up to tip of villus, replacing older cells that die by apoptosis Differentiate into various cell types (pluripotent)

Answer 69

Paneth cells Stem cells Crypt enterocytes Escalator of epithelial migration

Answer 70

Dividing stem cells in the crypts -> surface and tips of villi At villus tips, cells become senescent -> sloughed into the lumen of the intestin-> digested and reabsorbed For rapid turnover of enteroctyes

Answer 71

Rapid turnover (compared with lifespan of weeks/months for other epithelial cell types e.g. lung, blood vessels) Because enterocytes are are the first line of defence against GI pathogens/toxic substances in the diet Effects of agents which interfere with cell function, metabolic rate etc will be diminished Any lesions will be short-lived If escalator-like transit of enterocytes is interrupted through impaired production of new cells (e.g. radiation) severe intestinal dysfunction will occur

Answer 72

London physician | Proved water bourne transmission of cholera in 1849

Answer 73

Causes prolonged opening of the chloride channels in the small intestine-> uncontrolled secretion of water Causes rapid, massive dehydration-> death (unless treated with rehydration, cholera bacteria will clear and epithelium will be replaced)

Answer 74

Brunner's glands Submucosal coiled tubular mucous glands secreting alkaline fluid Open into base of crypts Alkaline secretions of Brunner's glands-> neutralises acidic chyme from stomach (protects proximal small intestine) and helps optimise pH for pancreatic digestive enzymes)

Answer 75

``` Plicae circulares (valves of Kerchring) Numerous, large fold in the submucosa ``` Present in duodenum and ileum too but in jejunum= taller, thinner and more frequent Frilling interior (formed of circular folds in mucosa)

Answer 76

Some features shared with large intestine Lots of Peyer's patches (large clusters of lymph nodules in submucosa) Prime immune system against intestinal bacteria (other mechanisms for defence= bactericidal Paneth cells, rapid cell turnover) Well positioned to prevent bacteria from colon migrating up into small intestine

Answer 77

To mix ingested food with digestive secretions and enzymes To facilitate contact between contents of intestine and the intestinal mucosa To propel intestinal contents along alimentary tract

Answer 78

Mixes the contents of the lumen Segmentation by stationary contraction of circular muscles at intervals (breaks big bolus into smaller segments) More frequent contractions in duodenum compared to ileum-> allow pancreatic enzymes and bile to mix with chyme General movement DOWN

Answer 79

Sequential contraction of adjacent rings of smooth muscle Propels chyme towards the colon Most waves travel about 10cm

Answer 80

Chyme being segmented, mixed and propelled towards the colon

Answer 81

Sweeping wave of contraction helps propel down cut In fasting= cycles of smooth muscle contractions Each cycle= contraction of adjacent segments of small intestine Begins in stomach-> through small intestine-> terminal ileum-> duodenum Prevents migration of colonic bacteria into the ileum (may clean intestine of residual food) Less ordered and less frequent in fed state

Answer 82

Segmentation= mixing Peristalsis= propelling Migratory motor complex= sweeps through gut, prevents accumulation of residue

Answer 83

In an alkaline environment Involves digestive enzymes (from pancreatic duct) and bile (from bile duct) Duodenal epithelium also produces digestive enzymes (in contact with brush border) Digestion in lumen and unstirred layer of the membrane

Answer 84

PASSIVE DIFFUSION No carrier proteins With gradient No energy required ``` FACILITATED DIFFUSION Carrier proteins With gradient No energy required Tends to equilibrate substance across the membrane E.g. GLUT-5, GLUT-2 ``` ``` PRIMARY ACTIVE TRANSPORT Carrier proteins Against gradient Energy required (hydrolysis of ATP) E.g. Na+/K+ ATPase, H+/K+ ATPase ``` SECONDARY ACTIVE TRANSPORT Carrier proteins Against gradient Energy required (electrochemical gradient) E.g. SGLT-1 co-transport, HCO3-/Cl- counter transport, Na+/H+ counter transport

Answer 85

Digestion begins in the mouth by salivary -amylase, but is destroyed in the stomach (acid pH) Most of the digestion of carbohydrates occurs in the small intestine

Answer 86

Monosaccharides e.g. glucose and fructose Disaccharides e.g. maltose and sucrose

Answer 87

Sugars bonded together to form a chain E.g. starch, cellulose (amylose), pectins (amylopectin)

Answer 88

Secreted into duodenum in response to a meal Continues digestion of starch and glycogen into small intestine (started by salivary amylase) Needs Cl- for optimum activity and neutral/slightly alkaline pH (Brunner's glands in duodenum-> alkaline secretion) Acts mainly in lumen (some absorbs to brush border)

Answer 89

LUMEN= pancreatic a-amylase MEMBRANE= digestion of amylase products and simple carbohydrates (glucoamylase, sucrase, isomaltase, trehalase, lactase)

Answer 90

Glucose | Galactose

Answer 91

Glucose | Fructose

Answer 92

Starch glycogen - > Amylase - > a-Dextrins, maltotriose, maltose - > glucose (with enzymes) Lactose -> glucose and galactose (with lactase) Sucrose-> glucose and fructose (with sucrase) Trehalose-> glucose (with trehalase)

Answer 93

Maltase Lactase Sucrase Trehalase On enterocyte apical membrane

Answer 94

SGLT-1 Absorption of glucose and galactose is by secondary active transport = Carrier protein SGLT-1 on apical membrane (Effective when glucose levels lower in lumen than enterocytes) GLUT5 Absorption of fructose is by facilitated diffusion = Carrier protein GLUT-5 on apical membrane (Effective at relatively low concs of fructose in lumen as tissue and plasma levels are low) GLUT-2 Facilitates exit of glucose at the basolateral membrane = Carrier protein GLUT-2 (high capacity, low affinity facilitative transporter) (Glucose between plasma and tissue/enterocyte generally equilibrated)

Answer 95

Protein digestion begins in the stomach by pepsin, but pepsin is inactivated in the alkaline duodenum Pancreatic proteases are secreted as precursors Trypsinogen-> (with enterokinase)-> trypsin Enterokinase= enzyme located on the duodenal brush border Trypsin then activates the other proteases

Answer 96

Trypsinogen-> trypsin Chemyotrrypsinogen-> chymotrypsin Proelastase-> elastase Procarboxypeptidase A-> carboxypeptidase A Procarboxypeptidase B-> carboxypeptidase B

Answer 97

Brush border peptidases break down the larger peptides prior to absorption AAs are absorbed by facilitated diffusion and secondary active transport (similar to sugars) Di- and tri-peptides are absorbed using carrier proteins distinct from single amino acids Cytoplasmic peptidases break down most of the di- and tri-peptides before they cross the basolateral membrane

Answer 98

Lipids are poorly soluble in water so complicated to digest 1. Secretion of bile and lipases 2. Emulsification - Bile salts facilitate the emulsification of a fat into a suspension of lipid droplets, increasing the surface area for digestion 3. Enzymatic hydrolysis of ester linkages - Pancreatic lipase then splits the triglycerides into 2 fatty acids and a monoglyceride at a fat/water interface - Lipases complexes with colipase preventing the bile salts from displacing the lipase from the fat droplet 4. Solubilization of lipolytic products in bile salt micelles - Bile salts form micelles with the released fatty acids and glycerol

Answer 99

Water and fat don’t mix Bile and lipases are secreted into the duodenum Bile salts facilitate the emulsification of fat into a suspension of lipid droplets (1um diameter) Increases the surface area for digestion Allows pancreatic lipase to split triglycerides A triglyceride is broken down into two fatty acids and a monoglyceride at fat/water interface

Answer 100

Steroid nucleus planar Two faces= amphipathic Hydrophobic face (nucleus and methyl) dissolves in fat Hydrophilic face (hydroxyl and carboxyl) dissolves in water

Answer 101

Micelles = hydrophilic "head" regions in contact with surrounding solvent, hydrophobic tail regions in the micelle centre with lipid core (free fatty acids and cholesterol inside bile salts) Mixed micelles in small intestine= water insoluble monoglycerides from lipolysis are solubilised by forming a core, stabilised by bile salts - Transported to GI epithelial cells for absorption HYDROPHILIC DOMAINS FACE OUT HYDROPHOBIC DOMAINS FACE IN (i->o, o->i)

Answer 102

Lipase breaks down triglycerides into monoglycerides and free fatty acids Pancreatic lipase complexes with colipase Colipase prevents bile salts from displacing lipase from the fat droplet Also important= phospholipase A1 and pancreatic cholesterol esterase

Answer 103

Hydrolyses fatty acids at the 2 position in many phospholipids -> lysophospholipids and free fatty acids

Answer 104

Hydrolyses cholesterol ester to free cholesterol and fatty acid

Answer 105

Micelles are important in absorption (absorbed much quicker than emulsion) Micelles allow transport across the unstirred layer, and present the fatty acids and monoglycerides to the brush border The whole micelle is not absorbed together - Bile salts are absorbed in the ileum - Lipid absorption is usually complete by the middle of the jejunum Bile salts are transported back to the liver for recycling (enterohepatic circulation)

Answer 106

``` Monoglyceride acylation (major) Phosphatidic acid pathway (minor) ```

Answer 107

Fatty acids bind to the apical membrane Fatty acid binding proteins (FABP) facilitate transfer of fatty acids from apical membrane to the smooth ER In the smooth ER - fatty acids esterified into diglycerides and triglycerides

Answer 108

Triglycerides are synthesised from CoA fatty acid and a-glycerophosphate

Answer 109

Lipoprotein particles synthesised in enterocytes as an emulsion Chylomicrons are transported to the Golgi and secreted across the basement membrane by exocytosis Too big to enter blood capillaries of villi Enter lacteals (lymph channels) instead

Answer 110

``` 80-90% triglycerides 8-9% phospholipids 2% cholesterol 2% protein Trace carbohydrate ```

Answer 111

Ileocaecal sphincter

Answer 112

Ileocaecal sphincter Relaxation and contraction Also prevents back flow of bacteria into the ileum

Answer 113

CARBOHYDRATE Pancreatic a-amylase and brush border enzymes PROTEIN Trypsin, which activates other proteases LIPID Emulsification by bile, hydrolysis and solubilisation into bile salt micelles

Answer 114

2 million Incidence is rising >1 million hospital admissions a year 1 in 10 deaths of people in their 40s are due to liver disease

Answer 115

Predominantly in right upper quadrant (apex into LUQ) Superior border at the level of the 5th costal cartilage Protected mainly by ribcage, superiorly by the diaphragm and interiorly by abdominal muscles and organs Surface anatomy important in biopsy to avoid damaging other organs Dull region= liver (percussion) Large inspiration then expiration prior to insertion of needle

Answer 116

4 lobes= right, left, caudate, quadrate Caudate above quadrate and both between L and R (behind falciform ligament) R and L lobes separated by the falciform ligament Right lobe is much larger (60% mass) ``` Coronary ligament (above R lobe) and left triangular ligament (above L lobe) connect the liver to the abdominal wall and diaphragm -> Falciform ligament-> Ligamentum teres (round ligament) connects to front of abdomen ```

Answer 117

Gall bladder lies inferiorly in the arch of the liver (under R lobe) Shouldn't be palpable unless enlarged

Answer 118

Bound by vystic duct, bile duct and cytic artery Triangular space (dissected in cholecystectomy to ID window to safely expose gallbladder)

Answer 119

Liver and biliary system share a common origin with the ventral part of the pancreas Secretory cells derived from endoderm (parenchymal cells) -> Embedded in mesoderm At junction between foregut and midgut Arises from the septum transversum- point at which the ectoderm of the amnion meets endoderm of the yolk sac Mesenchymal structure of the septum provides a framework on which the parenchymal (hepatocyte) cells and bile ducts with associated blood supply can develop ENDODERM= parenchymal cells, flattened cells become columnar and become epithelial lining MESODERM= forms connective tissue, differentiates from rest of embryos through IC signalling-> polarisation Somites form skin and musculoskeletal parts of body SEE CARNEGIE STAGING

Answer 120

Carnegie staging= 23 stages, during first 60 days of development STAGE 1-10 Fertilisation-> blastocyst-> primary yolk sac-> septum traversum (stage 9) STAGE 11 (29 days) Hepatic diverticulum or liver bud development (Diverticulum invades septum transversum) Cell differentiation STAGE 12 (30 days) Septum transversum forming liver stroma Hepatic diverticulum forming hepatic trabeculae ``` STAGE 13 (32 days) Epithelial cord proliferation enmeshing stromal capillaries ``` ``` STAGE 14 (33 days) Enlargement of the liver bud Haematopoietic function appears ``` ``` STAGE 18 (44 days) Bile ducts become reorganised (continuity between liver cells and gut) ``` STAGE 18-23 (44-56 days) Cell differentiation Early structural organisation Biliary ductules developed in periportal connective tissue and ductal plates form that receive biliary canaliculi

Answer 121

Thick mass of cranial mesenchyme-> gives rise to parts of throacic diaphragm and ventral mesentry of the foregut in the developed human being Arises from the mesoderm

Answer 122

The liver bud (first apparent around 29 days, stage 11)

Answer 123

Stage 11 29 days Grows into transverse septum

Answer 124

Pancrease migrates to posterior, left portion of the abdominal cavity/coelom

Answer 125

Liver rotates to the right

Answer 126

25% of resting cardiac output (rich blood supply) DUAL BLOOD SUPPLY= direct and indirect 1. Hepatic artery (L and R branches) - 20% arterial blood from - T o bring oxygen 2. Hepatic portal vein (HPV) - 80% venous blood draining from the gut - Brings everything from gut (before it can get into systemic circulation)

Answer 127

Inferior vena cava via the hepatic vein

Answer 128

Couinaud classification 8 functionally independent segments (can resect a segment without bleeding and damaging the sounding) ``` Centrally= portal vein, hepatic artery, bile duct Peripherally= hepatic vein ``` Determined by blood supply Each segment can be resected without damaging those remaining

Answer 129

Numbered clockwise from the posterior central caudate lobe 1. Caudate lobe 2. Lateral to falciform ligament and superior to portal venous supply 3. Lateral to falciform ligament and inferior to portal venous supply 4. Medial to falciform ligament 5. Medial and inferior right hemisphere 6. Posterior portion of right hemisphere 7. Above 6 8. Above 5 (medial and superior right hemisphere)

Answer 130

Hepatocytes (80%)= large cells with pale and rounded nuclei Endothelial cells= lining blood vessels and sinusoids, fenestrated (allows lipids and other large molecules to move to and from hepatocytes) Cholangiocytes (aka bile duct epithelial cells)= lining biliary structures Kupffer cells= fixed phagocytes (liver macrophages), phagocytosis and secretion of cytokines that promote HSC activation (proliferation, contraction and fibrogenesis) Hepatic stellate cells= Vitamin A storage cells (Ito cells), may be activated to a fibrogenic myofibroblastic phenotype and produce collagen, important in liver disease

Answer 131

Units known as lobules Classical lobule is hexagonal and divided in concentric centrilobular, midzonal and periportal parts Lobules consist of a central vein (which drains into hepatic veins- IVC) with radiating hepatocyte sheets Round the edges of adjoining lobules are portal triads - Hepatic arteriole - Branch of hepatic portal vein - Bile duct Capillary sinusoids eventually drain into central vein Between sheets of hepatocytes and capillary sinusoids are bile canaliculi (drain bile produced in hepatocytes into ductules which flow outwards into the portal triad)

Answer 132

LOBULES Lobules are HISTOLOGICAL units within the liver Easily identified and are centred around central veins which drain into the hepatic veins ACINI Acini are FUNCTIONAL units which are aligned around the portal triad, and divided into zones dependent on their proximity to arterial blood supply These are less easy to visualise Unit of hepatocytes divided into zones dependent on proximity to arterial blood supply

Answer 133

Kupffer cells or hepatic stellate cells

Answer 134

Hepatic arteriole Branch of hepatic portal vein Bile duct

Answer 135

Hepatic portal vein

Answer 136

Hepatic artery

Answer 137

The central vein

Answer 138

Unit of hepatocytes divided into zones dependent on proximity to arterial blood supply Cluster of cells like a 'berry' Demarcated by zone: - Periportal - Transition zone - Pericentral The terminal acinus is centred on the the portal tract and each hepatic acinusis centred on the line connecting two portal triads

Answer 139

Periportal zone 1 is nearest to the entering vascular supply and receives the most oxygenated blood Makes it least susceptible to ischaemic injury but most susceptible to viral hepatitis or hemosiderin deposition in haemachromatosis Involved in gluconeogenesis, oxidation of fatty acids and cholesterol synthesis

Answer 140

Zone 3 (pericentral) is least susceptible to ischaemic injury Furthest from entering vascular supply Involved in glycolysis, lipogenesis and P450 based drug detoxification

Answer 141

Sinusoids (sinusoidal faces) and hepatocytes (lateral faces)

Answer 142

Hepatocytes

Answer 143

Secreted in bile canaliculi Drain into ductules-> intralobular bile ducts-> right/left hepatic ducts-> join outside liver to form common hepatic duct THEN EITHER... -> Cystic duct drains the gall bladder OR -> Common bile duct unites with common hepatic duct-> forms COMMON BILE DUCT (joined by pancreatic duct before entering duodenal papilla) Opposite direction to blood flow

Answer 144

Bile production and excretion Excretion of bilirubin, cholesterol, hormones, and drugs Metabolism of fats, proteins, and carbohydrates Enzyme activation Storage of glycogen, vitamins, and minerals Synthesis of plasma proteins, such as albumin, and clotting factors

Answer 145

SER Mitochondria Cytoplasmic enzymes Glycolysis = Glucose oxidation to form ATP and pyruvate Pyruvate-> Krebs cycle-> more ATP Glycogenesis = Storage of excess glucose as glycogen Glycogenolysis =Breakdown of glycogen to glucose Gluconeogenesis = De novo synthesis of glucose

Answer 146

Lysosomes SER Metabolise, modify/detoxify exogenous compounds, e.g. drugs

Answer 147

Liver bud gives rise to gall bladder bud Eventually hepatic diverticulum/bud divides in the pars hepatic and pars cystica around 4 weeks -> forms liver sites and necessary structures (particularly those that connect liver to gall bladder) Cystic diverticulum (pars cystica)-> cystic duct and gallbladder by around 8 weeks

Answer 148

Important in excretion of toxins and secretion of fats Bile neutralises chyme and aids digestion of fats

Answer 149

STORES Serves as a reservoir of bile between meals Stores 50ml-> released after meal for fat digestion ACIDIFIES BILE CONCENTRATES BILE By H2O diffusion following net absorption of Na, Cl, Ca, HCO3 -> decreased intra-cystic pH -> reduced volume of stored bile by 80-90%

Answer 150

Cystic duct fuses gall bladder to the hepatic duct-> common bile duct The common bile duct has a spiral muscular structure which twists/untwists -On untwisting of the duct and sphincter of Oddi, it becomes patent and secretes bile into the ampulla (in the 2nd part of the duodenum) At the ampulla, the CBD may also join the pancreatic duct

Answer 151

Bile neutralises chyme and aids digestion of fats

Answer 152

ERCP (endoscopic retrograde choliographic pancreatography) - A wire is passed through the spinchter of Oddi (along with a scope), and dye is injected to the see the branches of the bile ducts - This can be used to see any obstructions, e.g. gall stones or tumours - Is also good because as it is invasive, provides opportunity to solve problem found, e.g. removing the obstruction MRI - Can also be used to observe the effects of gall stones or tumours on the biliary tree, e.g. dilation due to accumulation of bile, or constriction of the distal end of the bile duct

Answer 153

It is important to control blood glucose After a meal, blood glucose increases and must be taken up into tissues -> stored mainly as glycogen in muscle and liver Between meals, liver glycogen breakdown (glycogenolysis) maintains blood glucose concentration However a 24hr fast will deplete the glycogen store (only 80g), then blood glucose must then be increased by another pathway

Answer 154

The process of synthesising glucose from non-carbohydrate sources CORI CYCLE Glucose is broken down anaerobically in muscles into lactate Lactate can be used by the liver to synthesise glucose (via pyruvate) Requires 6 ATP and LDH (lactate dehydrogenase) ``` From lactate (rbc metabolism anaerobic, also muscle) Lactate-> pyruvate -> glucose ``` VIA DEAMINATION OR FROM TRIGLYCERIDES Synthesised from AAs via deamination or from triglycerides Alanine-> pyruvate-> glucose Triglycerides-> glycerol-> glucose

Answer 155

Synthesis 90% plasma proteins (remainder are -globulins) Makes 15-50 g/day Importance of plasma proteins -binding/carrier function, plasma COP - oedema Synthesis of blood clotting factors and dietary “non-essential” AAs by transamination

Answer 156

Transamination= synthesis of dietary non-essential AAs from an alpha-keto acid precursor Involves exchange of amino group (NH2) on an acid with a ketone group (=O) on another acid E.g. pyruvic acid (keto acid) + glutamic acid (aa)-> alanine (AA) + a-ketoglutaric acid

Answer 157

Essential AAs

Answer 158

Deaminate AAs prior to use as an energy source Deamination is the conversion of an AA into the corresponding keto acid = Remove amine group as ammonia = Replaced with a ketone group Deamination occurs primarily on glutamic acid because glutamic acid is the end product of many transamination reactions -> NH3 (needs to be converted)

Answer 159

NH3 highly toxic – particularly to CNS Liver converts NH3 to urea Urea very water soluble, metabolically inert, non-toxic Excreted in urine

Answer 160

Fat is the main energy store in body (100x glycogen) -> Stored in adipose and liver When glycogen stores full, liver can convert excess glucose and AAs to fat for storage Metabolises fats as energy source (converts FA’s to AcetylCoA, by Krebs/TCA cycle in liver) OR Produces ketone bodies Synthesise lipoproteins, cholesterol, phospholipids

Answer 161

Ketone bodies produced in the liver Transported to other tissues and used as energy Water soluble (no need for carriers) Liver can convert 2 AcetylCoA -> acetoacetatic acid for transport in blood -> other tissues -> acetyl CoA -> energy Ketone bodies= cetoacetate, beta-hydroxybutyrate and acetone (their spontaneous breakdown product)

Answer 162

Synthesis of lipoproteins required for lipid transport in aqueous environment Contain triglycerides and cholesterol core, with a phospholipid and protein coat (stabilising the lipid)

Answer 163

There are various types of lipoproteins depending on their composition: ``` VLDL = lots of triglycerides (IDL = intermediate density lipoprotein) LDL = high cholesterol and phospholipids (bad cholesterol) HDL = high protein coat (good cholesterol) ``` In decreasing density= HDL > LDL > IDL > VLDL The lower the density, the larger the diameter

Answer 164

LDL delivers cholesterol to tissues | HDL can transport it back to the liver for re-processing and/or disposal as bile salts

Answer 165

Shuttles cholesterol from HDL to LDLs | So inhibiting it-> good for drugs to prevent atherosclerosis (but side effects in current attempts)

Answer 166

Cholesterol= sterol nucleus synthesised from acetyl CoA (and dietary intake)

Answer 167

Used in the synthesis of various compounds including steroid hormones and bile salts Important in cell/organelle membrane structure

Answer 168

Compound containing fatty acid, phosphoric acid and nitrogen containing base Important in cell/organelle membrane structure

Answer 169

Continually secreted by liver | Stored and concentrated in gall bladder

Answer 170

Holds 15-60ml | Concentrates bile salts

Answer 171

``` Bile salts (50% dry weight) Cholesterol Phospholipids (lecithin) Bile pigments (bilirubin, biliverdin) Bicarbonate ions and water ``` Separately, some components would be insoluble, but together, bile is stable solution

Answer 172

IN LIVER Addition of carboxyl and hydroxyl groups to cholesterol (increases water solubility) ->Primary bile acids (from oxidation of cholesterol into cholic and chenodeoxycholic acids) Conjugated with taurine or glycine -> bile acid conjugated in liver (->taurocholic and glycocholic acids) This increases the water solubility further IN GALL BLADDER Bile acid conjugates stored/concentrated Primary bile acids are de-conjugated and de-hydroxylated to form bile salt (ionised) conjugates (secondary bile salts)– involves bacteria in ileum

Answer 173

Digestion/absorption fats (4 stage process) Excretion variety substances via GI tract Neutralise acid chyme from stomach

Answer 174

Released into duodenum during digestion Small amounts during cephalic and gastric phases due to vagal nerve and gastrin In intestinal phase, CCK causes contraction of the gall bladder and relaxation of sphincter of Oddi

Answer 175

Active reabsorption of bile salts in terminal ileum In addition, de-conjugatation and de-hydroxylation by bacteria make bile salt lipid soluble (Lose

Answer 176

Liver breaks down/inactivates steroid and peptide hormones Secreted into bile for excretion Also performs similar role with variety of “foreign” compounds- usually drugs Excretory route for excess cholesterol (lecithin allows more cholesterol in micelles) Too much-> gall stones or lost in salts EXCRETION OF BILE PIGMENTS Bilirubin from breakdown of haem from old red blood cells (15% from other proteins) Iron from haem removed in spleen and conserved Porphyrin group reduced to bilirubin and conjugated to glucoronic acid in liver.

Answer 177

Bile pigment gallstones

Answer 178

Storage of fat soluble vitamins (A,D,E,K). - Stores sufficient 6-12 month except Vit K where store is small. - Vit K is essential for blood clotting Storage of iron as ferritin - Available for erythropoeisis Storage Vit B12 - Pernicious (megaloblastic) anaemia, nerve demyelination Glycogen and fat store

Answer 179

Liver sinusoids contain tissue macrophages (Kupffer cells) Bacteria may cross from gut lumen into blood Kupffer cells destroy these and prevent bacteria entering the rest of the body

Answer 180

UV light converts cholesterol to Vitamin D precursor, which requires a double hydroxylation (to convert it to the active form) First hydroxylation is in the liver (second in the kidneys) Can lead to rickets if this fails

Answer 181

A foregut derivative arising at the foregut-midgut junction Dorsal and ventral buds Duodenum rotates to form a C shape - > Ventral bud (part of hepatobiliary bud) swings round to lie adjacent to the dorsal bud - > Both buds fuse Ventral bud duct becomes main pancreatic duct

Answer 182

Subdivided into head, neck, body, tail and uncinate process

Answer 183

Islet tissue most abundant in tail

Answer 184

5 regions Lies mainly on the posterior abdominal wall extending from the C-shaped duodenum to the hilum of the spleen Pancreatic juice reaches duodenum via main (and accessory) pancreatic ducts

Answer 185

Via main (and accessory) pancreatic ducts The branches of the duct system of both the ventral and dorsal buds give rise to both exocrine (acinar) and exocrine (islets) tissue

Answer 186

Main posterior relations are IVC, abdominal aorta and left kidney Spleen lies supralaterally to the left, with left and right kidneys posterolaterally on either side (each associated with their own adrenal gland) Close relations with (and supply from) coeliac and superior mesenteric arteries

Answer 187

MRI To image pancreatic tumour Angiography For assessing pancreatic disease Contrast agent into blood supply (tumour needs blood supply to grow)

Answer 188

Secretion into the blood stream to have effect on distant target organ (Autocrine/Paracrine) Ductless glands 2% of gland Islets of Langerhans Secretes insulin and glucagon (and somatostatin and pancreatic polypeptide) -> Regulates blood glucose, metabolism and growth effects

Answer 189

Secretion into a duct to have direct local effect 98% of gland Secretion of pancreatic juice into duodenum via pancreatic duct/common bile duct Digestive function

Answer 190

Anabolic hormone Promotes glucose transport into cells and storage as glycogen Reduces blood glucose Promotes protein synthesis and lipogenesis

Answer 191

Increases gluconeogenesis and glycogenolysis | -> increased blood glucose

Answer 192

Hormone that inhibits growth hormone | 'Endocrine cyanide'

Answer 193

``` Endocrine= 2% Exocrine= 98% ```

Answer 194

May involve endocrine AND exocrine effects e.g. cystic fibrosis

Answer 195

EXOCRINE Ducts Acini are grape-like clusters of secretory units Acinar cells secrete pro-enzymes into ducts ``` ENDOCRINE Derived from the branching duct Lose contact with ducts- become islets Differentiate into alpha and beta cells secreting into blood Tail>head ```

Answer 196

IN ENDOCRINE TISSUE α-cells (A) Form about 15-20% of islet tissue Secrete glucagon β-cells (B) Form about 60-70% of islet tissue Secrete insulin δ-cells (D) Form about 5-10% of islet tissue Secrete somatostatin The islets are highly vascular, ensuring that all endocrine cells have close access to a site for secretion

Answer 197

Acinar cells= low volume, viscous, enzyme-rich Duct and centroacinar cells= high volume, watery, bicarbonate-rich (so quite alkaline)

Answer 198

Connective tissue with columnar epithelium lining the interspersed minor pancreatic duct (which fuse to form the major pancreatic duct)

Answer 199

Duct and centroacinar cells Pancreatic juice is rich in bicarbonate - 120 mM (mmol/L) - pH 7.5-8.0 Neutralises acid chyme from the stomach - > Prevents damage to duodenal mucosa - > Raises pH to optimum range for pancreatic enzymes to work Washes low volume enzyme secretion out of pancreas into duodenum

Answer 200

Large with apical secretory granules Store inactive precursors in order to protect the tissue from auto-digestion

Answer 201

Small, pale with few granules

Answer 202

More stomach contents squirted into it-> increased rate of bicarbonate Pancreas working as much as possible around pH 3 Duodenal pH

Answer 203

Bile also contains bicarbonate and helps neutralise the acid chyme Brunner's glands secrete alkaline fluid

Answer 204

1. SEPARATION OF H+ AND HCO3- Catalysed by carbonic anhydrase CO2 diffuses into the duct cell from the blood, reacting with H2O to form H+ and HCO3 CO2 AND H2O HCO3 Simultaneously, Na+ moves down a concentration gradient between tight junctions (paracellular transport) H2O follows ``` 2. TRANSPORT OF H+ AND HCO3- OUT OF THE DUCT CELL Coupled exchange driven by electrochemical gradients (secondary active transport) The HCO3- is exchanged with Cl- ``` (Cl has a high lumen concentration compared to IC duct cell concentration so bicarbonate is transported into the lumen with Cl going into the cell) H+ is exchanged with Na+, which has a higher blood conc compared with the cell conc so flows into the cell and H+ is transported into the blood 3. MAINTENANCE OF NA+ GRADIENT Primary active transport using ATP For step 2 (done using the Na/K exchange pump) 4. RETURNING OF THE K+ TO THE BLOOD AND CL- TO THE DUCT CELL Via protein channels K via K channel Cl via Cl channel (CFTR)

Answer 205

The same reaction CO2 and H2O H+ and HCO3 Occurs in gastric parietal cells and pancreatic duct cells In the stomach, the hydrogen goes into gastric juice and the bicarbonate into blood In the pancreas, the bicarbonate is secreted into the juice and the hydrogen into the blood

Answer 206

ACINAR CELL ENZYME SECRETION Enzymes for digestion of fat (lipases), protein (proteases) and carbohydrates (amylase) are synthesised and stored in zymogen granules Zymogens= pro-enzymes

Answer 207

Proteases are released as inactive pro-enzymes-> protects acini and ducts from auto-digestion Pancreas also contains a trypsin inhibitor to prevent trypsin activation Enzymes become activated ONLY in duodenum

Answer 208

Blockage of pancreatic duct may overload protection and result in auto-digestion (= acute pancreatitis)

Answer 209

Protein digestion is started in the stomach by pepsin, which acts in acid conditions When the chyme enters the duodenum, the pepsin is soon inactivated by the alkaline conditions The pancreas produces a cocktail of proteases, all released as precursors The duodenal brush border produces enterokinases-> cleaves trypsinogen between a valine and an isoleucine-> active form of trypsin-> can activate other proteases All the proteases are fairly short lived as they are digested themselves

Answer 210

Lipase secreted in active form but requires colipase, which is secreted as precursor (Lipases require presence of bile salts for effective action) Trypsin converts all other proteolytic and some lipolytic enzymes

Answer 211

Pancreatic secretions adapt to diet e.g. high protein, low carbs, increases proportion of proteases, decreases proportion of amylases Pancreatic enzymes (and bile) are essential for normal digestion of a meal Lack of these can lead to malnutrition even if the dietary input is OK (unlike salivary, gastric enzymes)

Answer 212

Anti-obesity drug Inhibits pancreatic lipases to limit intestinal fat absorption -> Steatorrhoea (increased faecal fat) because pancreatic lipase secretion significantly reduced

Answer 213

INITIAL CEPHALIC PHASE Pancreatic secretion begins before food enter the duodenum via a vagal reflex in response to the sight/smell/taste of food Involving cholinergic synapses which result in enzyme-rich component only Low volume- mobilises enzymes GASTRIC PHASE When food arrives in the stomach-> stimulates pancreatic secretion Same mechanisms as the cephalic phase ``` INTESTINAL PHASE (70-80% of pancreatic secretion) Hormonally mediated when acid chyme enters the duodenum from the stomach Hormones= secretin and CCK: cholecystokinin, into the blood Both components of pancreatic juice stimulated ```

Answer 214

Bicarbonate secretin is controlled by secretin release (involves cAMP) Enzyme secretion is controlled by vagal reflex and CCK (cholecystokinin) - In response to fats/proteins and stimulates enzyme secretion - Also stimulates bile secretion - Involves Ca2+ and PLC via vagus reflex

Answer 215

Cephalic phase ends when meal is eaten Intestinal phase ends with absorption of fats and peptides (removes the local luminal stimulus for CCK release)

Answer 216

Synergistic interaction between CCK and secretin i CCK alone= no effect on bicarbonate secretion CCK combined with secretin= shows marked increase in bicarbonate secretion compared to secretin alone Vagus nerve has similar effect to CCK

Answer 217

Food mixed, digested in stomach, pH 2 -> Chyme squirted into duodenum H+ ions in duodenum - > Stimulate release of secretin - > Stimulate release of pancreatic juice (plus bile and Brunner’s gland secretions) to raise pH to neutral/alkaline Peptides and fat in duodenum - > Cause sharp rise in CCK and vagal nerve - > Stimulates pancreatic enzyme release (peaks by 30 mins, continues until stomach empty) CCK potentiates effects of secretin on aqueous component (necessary because most of duodenum not at low pH)

Answer 218

``` Colon Cecum Appendix Rectum Anal canal ```

Answer 219

Blind pouch just distal to the ileocecal valve | Larger in herbivores

Answer 220

Thin, finger-like extension of the cecum | Not physiologically relevant in humans

Answer 221

Function= reabsorption of electrolytes and water, elimination of undigested food/waste

Answer 222

1.5m long | 6cm diameter

Answer 223

ASCENDING On the R side of abdomen Runs from cecum to hepatic flexure TRANSVERSE Hangs off the stomach (attached by mesocolon) Running from hepatic flexure to splenic flexure DESCENDING On the L side of abdomen Runs from splenic flexure to sigmoid colon SIGMOID S shaped colon running from descending colon to rectum

Answer 224

Appendices epiploicae Taeni coli Haustra Solitary nodules

Answer 225

Fatty tags of the peritoneum surrounding colon | Structural/functional purpose unknown- possible protective against intra-abdominal infections

Answer 226

3 longitudinal bands running along length of colon | Important for large intestine motility

Answer 227

Pouchings of the colon wall | Taenia coli are shorter than the length of the colon -> forms pouched avoid segments

Answer 228

Nodules of lymphoid tissue in the wall of the colon

Answer 229

Middle colic artery | Branch of the superior mesenteric artery

Answer 230

Inferior mesenteric artery

Answer 231

Embryological division between the midgut and hindgut NB. Region between the two is sensitive to ischaemia

Answer 232

Nodules of lymphoid tissue Common in the walls of the distal small intestines (In large intestine= solitary nodules)

Answer 233

Colon absorbs electrolytes and water More in proximal colon Na+ and Cl- absorbed by exchange mechanisms and ion channels Water follows by osmosis K+ moves passively into lumen Large intestine can reabsorb approx 4.5 litres water (usually 1.5 litres) Above this threshold = diarrhoea Ions, vitamins and minerals

Answer 234

Approx 4.5 litres water (usually 1.5 litres)

Answer 235

Dilated distal portion of the alimentary canal Terminal portion= anal canal

Answer 236

Similar to the colon | But distinguished by transverse rectal folds in its submucosa and the absence of taenia coli in its muscularis externa

Answer 237

Anal sphincters: Internal (circular) muscle External (striated) muscle

Answer 238

Enterocytes and goblet cells are abundant Abundant crypts Stem cells found in the crypts IMPORTANT DIFFERENCE IS THAT VILLI ARE ABSENT

Answer 239

Mucosa appears smooth at the gross level because it has no villi (smaller SA than small intestine) Enterocytes have short, irregular microvilli and primarily concerned with resorption of salts (Water is absorbed as it passively follows the electrolytes, resulting in more solid gut contents) Crypts are dominated by goblet cells

Answer 240

Higher number of goblet cells than small intestine More prevalent in the crypts than along the surface Number increases distally toward the rectum

Answer 241

Acetylcholine (parasympathetic and enteric nervous system)

Answer 242

The mucus facilitates the passage of the increasingly solid colonic contents, and covers bacteria and particulate matter

Answer 243

Goblet cells (dominate crypts) Microvilli (glycocalyx doesn't contain digestive enzymes like it does in small intestine) NB. No paneth cells Enteroendocrine cells (rarer than in small intestine)

Answer 244

Glycocalyx in large intestine don't contain digestive enzymes (does in SI)

Answer 245

Like the small intestine, muscularis externa consists of an inner circular and outer longitudinal layer CIRCULAR LAYER Circular muscles segmentally thickened LONGITUDINAL LAYER Longitudinal layer concentrated in three bands- taenia coli Between the taenia, longinitudinal layer is thin Bundles of muscle from the teniae coli penetrate the circular layer at irregular intervals Shorter than circular muscle layer (have haustra= ovoid segments) Can contract individually Movements of large intestine are more complicated than small intestine

Answer 246

Colonic contractions- kneading process (minimally propulsive- 5-10cm/hr at most) Promotes absorption of electrolytes and water PROXIMAL COLON= ‘antipropulsive’ patterns dominate to retain chyme TRANSVERSE AND DESCENDING COLON= localised segmental contractions of circular muscle (Haustral contractions) cause back and forth mixing Short propulsive movements every 30 mins Increase in frequency following a meal

Answer 247

1-3 times daily- mass movement- resembles peristaltic wave Can propel contents 1/3-3/4 of length of large intestine in few seconds Food that contains fibre (indigestible material) promotes rapid transport through colon)

Answer 248

PARASYMPATHETIC Vagus nerve= controls ascending colon and most of the transverse colon Pelvic nerves= innervates more distal colon part SYMPATHETIC Lower thoracic and upper lumbar spinal cord External anal sphincter controlled by somatic motor fibres in the pudendal nerves ENTERIC

Answer 249

Enteric nervous system also important- Hirschsprung’s disease (no enteric intramural ganglia) Myenteric plexus ganglia concentrated below taenia coli Presence of food in stomach can stimulate mass movement- hormonal? Neural? Hormonal/paracrine control e.g. aldosterone promotes sodium and water absorption (synthesis of Na+ ion channel, Na+/K+ pump)

Answer 250

Rectum filled with faeces by mass movement in the sigmoid colon Stores stool until convenient to void Defecation reflex controlled primarily by the sacral spinal cord- both reflex and voluntary actions Reflex to sudden distension of walls of rectum Pressure receptors send signals via myenteric plexus to initiate peristaltic waves in descending, sigmoid colon and rectum Internal anal sphincter inhibited (Weak intrinsic signal augmented by autonomic reflex) External anal sphincter under voluntary control Urge resisted, sensation subsides

Answer 251

Internal anal sphincter inhibited (weak intrinsic signal augmented by autonomic reflex) External anal sphincter under voluntary control

Answer 252

Last few centimeters of the rectum known as the "social part" Can distinguish between solid, liquid and gas Perceptual ability is important in knowing what can be passed appropriately in what circumstance

Answer 253

150g/day adult Two thirds water Solids: cellulose, bacteria, cell debris, bile pigments, salts (K+) Bile pigments give colour Bacterial fermentation gives odour

Answer 254

All mammals have symbiotic relationships with their gut microbial community (microbiome) Stomach and small intestine have few bacteria- protected Large intestine contains many, essential to normal function - Diverse, highly metabolically active community - Approximately 1.5kg of live bacteria in average adult human (active biomass=major human organ)

Answer 255

Synthesize and excrete vitamins e.g. Vitamin K- germ-free animals can have clotting problems Prevent colonization by pathogens by competing for attachment sites or for essential nutrients Antagonize other bacteria through the production of substances which inhibit or kill non-indigenous species Stimulate the production of cross-reactive antibodies Antibodies produced against components of the normal flora can to cross react with certain related pathogens, and thereby prevent infection or invasion Stimulate the development of certain tissues, including cecum and lymphatic tissues Fibre (indigestible carbohydrate) can be broken down by colonic bacteria Produces short chain fatty acids which can regulate gut hormone release, or be absorbed to be used as an energy source or to influence functions such as food intake or insulin sensitivity directly

Answer 256

BACTEROIDES (most prevalent) Gram-negative, anaerobic, non-sporeforming bacteria Implicated in the initiation colitis and colon cancer BIFIDOBACTERIA Gram-positive, non-sporeforming, lactic acid bacteria Have been described as "friendly" bacteria Thought to prevent colonization by potential pathogens

Answer 257

``` Drug metabolism Insulin resistance Bile acid metabolism Lipid metabolism Obesity ```

Answer 258

Process whereby atoms or molecules intermingle because of their random thermal motion Rapid over microscopic distances, slowover macroscopic distances

Answer 259

The cell membrane acts as a diffusion barrier Enables cells to maintain cytoplasmic concentrations of substances different from their extracellular concentrations Lipid soluble (non-polar) molecules can cross more easily than water soluble (polar) molecules

Answer 260

Different protein populations in different places on cell Apical plasma membrane Lateral plasma membrane Basal plasma membrane Tight junction

Answer 261

Through tight junctions and lateral intercellular spaces

Answer 262

Through the epithelial cells | Into basal lamina

Answer 263

Simple diffusion Facilitates transport Active transport

Answer 264

Channel proteins form aqueous pores allowing specific solutes to pass across the membrane Carrier proteins bind to the solute and undergo a conformational change to transport it across the membrane Channel proteins allow much faster transport than carrier proteins

Answer 265

Ion-selective filter in aqueous pore Hydrophilic surface lines pore Hydrophobic surface in lipid bilayer Can be ligand-gated (IC or EC) or mechanically gated

Answer 266

Uniport= transported molecule in Symport (coupled)= transported molecule in and co-transported ion in Antiport (coupled)= transported molecule in and co-transported ion out

Answer 267

Water and ions Calcium Iron Vitamins (B12)

Answer 268

99% of the H2O presented to the GI tract is absorbed The absorption of water is powered by the absorption of ions Many ions slowly absorbed by passive diffusion (Calcium and iron are incompletely absorbed, and this absorption is regulated)

Answer 269

In the small intestine (approx 8L a day) | Especially the jejunum

Answer 270

``` 2L= ingest 1.2L= saliva 2L= gastric secretions 0.7L= bile 1.2L= pancreas 2.4L= intestinal ``` (8L absorbed in SI, 1.4L in LI)

Answer 271

Driven by Na+ Transport of Na+ from lumen into enterocyte- complex and varies between species (NB. Ions= Na, Cl, HCO3, K) Osmotic flow of water from the gut lumen via adjacent cells, tight junctions into the intercellular space Water distends the intercellular channels and causes increased hydrostatic pressure Ions and water move across the basement membrane of the epithelium and are carried away by the capillaries

Answer 272

Active transport of Na+ into the lateral intercellular spaces by Na+K+ATPase transport in the lateral plasma membrane

Answer 273

SECONDARY ACTIVE TRANSPORT Cl- co-transported with Na+ (ileum) Cl- exchanged with HCO3- (colon) into enterocytes [Electrical potential created by Na transport) PASSIVE TRANSPORT K+ diffuses in via paracellular pathways in small intestine, leaks out between cells in colon

Answer 274

Fluid there would be hypertonic

Answer 275

Becomes more efficient as travel down intestine: - Counter-transport in exchange for H+ (proximal bowel) - Co-transport with amino acids, monosaccharides (jejunum) - Co-transport with Cl- (ileum) - Restricted movement through ion channels (colon)

Answer 276

Duodenum and Ileum absorb Ca2+ Ca2+ deficient diet increases gut’s ability to absorb Vit D and parathyroid hormone stimulate absorption

Answer 277

Diet 1-6g/day Secretions 0.6g Absorb 0.7g

Answer 278

Low intracellular [Ca2+]= 100 nM (0.1µM) But can increase 10– to 100-fold during various cellular functions). High extracellular fluid [Ca2+] = 1-3mM. (Plasma [Ca2+] approx 2.2-2.6 mM) (Luminal [Ca2+] varies in mM range)

Answer 279

Intestinal calcium-binding protein (IMcal)- facilitated diffusion Ion channel

Answer 280

Ca acts as an intracellular signalling molecule Binds to calbindin in cytosol, preventing its action as an intracellular signal (facilitates transport of Ca through cytosol of the intestinal epithelial cell) PLASMA MEMBRANE CA ATPASE Ca2+ pumped across basolateral membrane by plasma membrane Ca2+ ATPase (PMCA) against concentration gradient PMCA has a high affinity for Ca2+ (but low capacity) Maintains the very low concentrations of calcium normally observed within a cell PLASMA MEMBRANE NA/CA EXCHANGER Ca2+ pumped across basolateral membrane by plasma membrane Na+/Ca2+ exchanger against concentration gradient. The Na+/Ca2+ exchanger has a low affinity for Ca2+ but a high capacity Requires larger concs of Ca2+ to be effective

Answer 281

Essential for normal Ca2+ absorption (by enhancing synthesis of calbindin and Ca-ATPase) Deficiency causes rickets, osteoporosis 1, 25-dihydroxy D3 taken up by enterocytes: - Enhances the transport of Ca2+ through the cytosol - Increases the levels of calbindin - Increases rate of extrusion across basolateral membrane by increasing the level of Ca2+ ATPase in the membrane

Answer 282

Can act as electron donor and electron acceptor - Oxygen transport (red blood cells) - Oxidative phosphorylation (mitochondrial transport chain) Critical BUT poisonous if too much (body has no mechanism for actively excreting iron) Need to absorb quickly as required but also limit that absorption

Answer 283

Adult Ingests approx 15-20mg/day Absorbs only 0.5-1.5mg/day (5% inorganic iron ingested, absorbed by small intestine)

Answer 284

Inorganic iron (Fe3+ ferric, Fe2+ ferrous) As part of haem group (haemoglobin, myoglobin and cytochromes)

Answer 285

Cannot absorb Fe3+, only Fe2+ Fe3+ insoluble salts with: hydroxide, phosphate and HCO3- Vit C reduces Fe3+ to Fe2+ Haem smaller part of diet, but more readily absorbed (20% of presented, rather than 5%)

Answer 286

Dietary haem is highly bioavailable Haem is absorbed intact into the enterocyte Evidence that this occurs via heme carrier protein 1 (HCP-1), and via receptor-mediated endocystosis Fe2+ liberated by Heme oxygenase

Answer 287

Duodenal cytochrome B (Dcytb) catalyzes the reduction of Fe3+ to Fe2+ in the process of iron absorption in the duodenum of mammals Fe2+ transported via divalent metal transporter 1 (DMT-1), a H+-coupled co-transporter Fe2+ binds to unknown factors, carried to basolateral membrane, moves via ferroportin ion channel into blood

Answer 288

Fe2+ moves across baslolateral membrane via ferroportin Fe3+ binds to apotransferrin, travels in blood as transferrin (Hepcidin, the major iron regulating protein, suppresses ferroportin function to decreases iron absorption) OR FERRITIN

Answer 289

Hephaestin is a transmembrane copper-dependent ferroxidase Converts Fe2+ to Fe3+

Answer 290

Binds to apoferritin in cytosol to form ferritin micelle Ferritin is globular protein complex Fe2+ is oxidised to Fe3+ which crystallises within protein shell A single ferritin molecule can store up to 4,000 iron ions In excess dietary iron absorption or increased iron concentration in the cytosol-> produce more ferritin Prevents absorption of too much iron - Irreversible binding of iron to ferritin in the epithelial cells - Iron/Ferritin is not available for transport into plasma. - Iron/Ferritin is lost in the intestinal lumen and excreted in the faeces. - Increase in iron concentration in the cytosol increases ferritin synthesis

Answer 291

Organic compounds that cannot be manufactured by the body but vital to metabolism

Answer 292

Passive diffusion predominant mechanism Fat soluble vitamins (A, D, E, K) transported to brush border in micelles K taken up by active transport Specific transport mechanisms for vitamin C (ascorbic acid), folic acid, vitamin B1 (thiamine), vitamin B12

Answer 293

Liver contains a large store (2-5mg) Impaired absorption of vit B12 retards the maturation of red blood cells- pernicious anaemia Most Vit B12 in food is bound to proteins

Answer 294

To avoid denaturation of B12 HOW DOES IT WORK? In the stomach, low pH and the digestion of proteins by pepsin releases free vit B12 But B12 is easily denatured by HCl Binds to R (haptocorrin) released in saliva nad from parietal cells R proteins digested in duodenum

Answer 295

Vit B12 binding glycoprotein secreted by parietal cells Vit B12/IF is resistant to digestion No IF then no absorption of vit B12 Vit B12/IF complex binds to cubilin receptor, taken up in distal ileum (mechanism unknown, but thought to involve receptor-mediated endocytosis) Can then enter cell

Answer 296

Once in cell, Vit B12/IF complex broken- possibly in mitchondria B12 binds to protein transcobalamin II (TCII), crosses basolateral membrane by unknown mechanism Travels to liver bound to TCII TCII receptors on cells allow them to uptake complex Proteolysis then breaks down TCII inside the cell

Answer 297

SOCRATES ``` Site Onset Character Radiation Associated symptoms Timing Exacerbating/relieving factors Severity ```

Answer 298

Initially poorly located Onset usually over hours (can be very quick) Usually more of a dull ache May have associated GI symptoms

Answer 299

``` FOREGUT Oesophagus Stomach Pancreas Liver Gallbladder Duodenum ``` MIDGUT Duodenum-> mid transverse colon HINDGUT Transverse colon-> anal canal RETROPERITONEAL ORGANS Kidney Pancreas DIAPHRAGM Liver Gallbladder Duodenum

Answer 300

The site of abdominal pain depends on whether the visceral or parietal peritoneum is stimulated (the innervation of which depends on its embryological origin)

Answer 301

``` Foregut= epigastrium Midgut= umbilical region Hindgut= suprapubic Retroperitoneal organs= back pain (or epigastric that radiates to back) Diaphragm= shoulder tip pain ```

Answer 302

(Imagine 9 quadrants labelled in rows- top 123, middle 456, bottom 789) ``` Oesophagus= 2 Stomach= 2 (towards 3) Small Bowel= 5 (non-specific in centre of abdomen) Large Bowel= 5 or 8 Appendix= 7 (starts in 5) Hepatic pain= 1 Biliary Pain= 1 Pancreatitis= 2 (epigastric radiates to back) ```

Answer 303

Sharp Very severe Well-located initially but becomes more generalised Worse on movement Guarding= involuntary, abdominal muscles tense up when someone touches abdomen Rebound tenderness= push hand onto stomach is ok, but take away-> rebound (very painful)

Answer 304

Starts and stops abruptly e.g. renal stones Muscular contractions of a hollow tube in an attempt to relieve an obstruction by forcing content out It may be accompanied by vomiting and sweating

Answer 305

``` Renal Ureter Urethra Colon Bile ducts Pancreatic ducts ```

Answer 306

Gradual onset with left flank pain Comes and goes Radiates from flank to groin Worst ever pain (no relief from pain killers, can't stand still)

Answer 307

``` Renal pain= flank to groin Bladder= suprapubic Pneumonia= upper quadrant Heart attack= epigastric Pelvic Inflammatory Disease= lower abdomen Musculo skeletal= anywhere ```

Answer 308

1. RUQ/right hypochondriac region 2. Epigastrium region 3. LUQ/left hypochondriac region 4. Right lumbar region 5. Umbilical region 6. Left lumbar region 7. Right ileac region 8. Suprapubic region 9. Left ileac region

Answer 309

Severe epigastric and RUQ pain going through to the back Onset after drinking alcohol Intermittent similar pain in past Usually fit and well (Significant smoking and alcohol history)

Answer 310

Jaundiced/cholangitis Unwell and in shock Tachycardic (body trying to maintain perfusion to organs by making heart beat faster in response to dropped blood pressure) Hypotensive Severe epigastric and RUQ pain on palpation (radiating to back) Nausea and vomiting common May have organ failure (chest/kidney)

Answer 311

HISTORY EXAMINATION TESTS: SIMPLE Blood pressure Pulse Urine dipstick TESTS: BLOOD TESTS Full Blood Count Urea and Electrolytes (show kidney function) Inflammation markers (CRP, ESR)(raised indicates ongoing inflammation, relevant to liver) Liver Function Tests Clotting (clotting worse with severe inflamation) Calcium Glucose (increases in pancreas not working well, enough insulin not being produced) TESTS: COMPLEX BLOOD TEST Amylase (Lipase) Triglycerides TESTS: SIMPLE IMAGING Chest Xray Abdominal Xray TESTS: CROSS SECTIONAL IMAGING Ultrasound CT scan MRCP (Magnetic Resonance Cholangiopancreatography) TESTS: INVASIVE TEST ERCP ERCP (Endoscopic Retrograde Cholangio-Pancreatography)

Answer 312

SIMPLE Hb 132 WCC 17.8 (high, normal

Answer 313

GET SMASHED ``` Gallstones Ethanol Trauma Steroids Mumps Autoimmune Scorpion venom (only in Trinidad and Tobago) Hyperlipidaemia/Hypercalcaemia ERCP Drugs (azathioprine, NSAID, furosemide, sulphonamides) ```

Answer 314

``` SYSTEMIC Hypovolaemia Hypoxia Hypocalcaemia Hyperglycaemia DIC Multiple organ failure ``` ``` LOCALISED Pancreatic necrosis Fluid collections- mature into pseudocysts Splenic vein thrombosis/pseudoaneurysm Chronic pancreatitis ```

Answer 315

``` GI Renal Reproductive Musculoskeletal Neurological ```

Answer 316

Disease caused by an uncontrolled division of abnormal cells in a part of the body

Answer 317

Cancer arising directly from cells in an organ

Answer 318

Cancer spreads from another organ | Directly or by blood/lymph

Answer 319

EPITHELIAL CELLS Squamous= squamous cell carcinoma Glandular= adenocarcinoma (most common) NEUROENDOCRINE CELLS Enterochromaffin= carcinoid tumours Interstitial cells of Cajal= GI stromal tumours ``` CONNECTIVE TISSUE (mostly fairly benign) Smooth muscle= leiomyoma/leiomyosarcomas Adipose tissue= lipomas ```

Answer 320

Difficulty swallowing

Answer 321

``` How long? What can’t you swallow? Vomiting? Other symptoms e.g. weight loss Risk factors (previous reflux, overweight, smoking, alcohol) ```

Answer 322

1. Cervical oesophagus- narrow 2. Middle oesophagus (includes aorta, left main bronchus) 3. Lower oesophagus (includes left atrium) As you go down: Increased smooth muscle Reduced skeletal muscle

Answer 323

Adenocarcinoma Squamous cell carcinoma Should have squamous cells lining oesophagus But common acid reflux-> cells to change to be more like stomach lining to get metaplastic columnar epithelium

Answer 324

From metaplastic columnar epithelium Lower 1/3 of oesophagus Related to acid reflux More common in developed world NB. As you go down: Increased smooth muscle Reduced skeletal muscle

Answer 325

From normal oesophageal squamous epithelium Upper 2/3 Acetaldehyde pathway More common in less developed world NB. As you go down: Increased smooth muscle Reduced skeletal muscle

Answer 326

Endoscopy OGD Gastroscopy

Answer 327

Chronic exposure to acid Injury (ongoing inflammation, cytokine drive) Oesophagitis (inflammation)-> Barrett's (metaplasia)-> Dysplasia-> Carcinoma (neoplasia) 15% of population -> GORD 5-13% with GORD-> Barrett's 5% with Barrett's-> Dysplasia 0.5-30% with Dysplasia-> Carcinoma

Answer 328

Replacement of the Squamous cell mucosa with columnar mucosa Form of metaplasia Body tries to prevent damage to oesophagus but becoming like stomach

Answer 329

0.12% per year Real concern is... Low grade dysplasia= 0.5% annual risk of cancer High grade dysplasia= 5-30% annual risk of cancer -> oesphageal adenocarcinoma

Answer 330

Expansion in immature cell types replacing more mature cells

Answer 331

Replacement of one differentiated cell type with another

Answer 332

Reassure her Start her on anti-acid medication (proton pump inhibitor-> doesn't affect reflux but not acid so less inflammation) Start surveillane (ACG) Think about aspirin

Answer 333

ACG (Seattle protocol) 4 biopsies every 1 cm along segment Barrett’s Oesophagus (no dysplasia) Every 3-5 years (NICE 2013) Low grade dysplasia Every 6 months until no dysplasia High grade dysplasia Flat – RFA (e.g. HALO) Nodular – endoscopic mucosal resection then HALO

Answer 334

10-20% risk of cancer

Answer 335

Family history Specific inherited conditions- FAP, HNPCC, Lynch Syndrome Uncontrolled ulcerative colitis (8-10y without treatment-> huge risk increase) Age (biggest risk factor, >60) Previous polyps

Answer 336

Sequence of genetic errors (APC, K-ras, p53, 18q) so not simple Mendelian inheritance 1. Normal epithelium (APC mutation) 2. Hyperpoliferative epithelium and aberrant cryptic foci (COX-2 overexpression) 3. Small adenoma (K-ras mutation) 4. Large adenoma (p53 mutation, then loss of 18q) 5. Colon carcinoma

Answer 337

JUST STUDY ATM 1. Normal epithelium (Aspirin and other NSAIDs, folate, calcium) 2. Hyperpoliferative epithelium and aberrant cryptic foci (Aspirin and other NSAIDs) 3. Small adenoma (Oestrogen, aspirin and other NSAIDs,) 4. Large adenoma 5. Colon carcinoma

Answer 338

Asymptomatic (incidental anaemia) Change in bowel habit (normally diarrhoea or occasionally/late constipation) Blood in stool Acute intestinal obstruction

Answer 339

Rectal bleeding with anal symptoms - Itch - Soreness / discomfort - External lump - Prolapse Change in bowel habit to harder or less frequent stool Abdominal pain in the absence of obstruction Positive findings at colonoscopy are as frequent as for completely asymptomatic age matched control

Answer 340

Colonoscopy CT Virtual colonoscopy ``` Abdominal X-Ray (not much use) CT Scan (can't see small lesions) Barium enema (not comfortable and time-consuming) ```

Answer 341

ADVANTAGES Cheap Easy Quick DISADVANTAGES 4x radiation than chest Xray Sensitivity for obstruction 77% Specificity for obstruction 50%

Answer 342

ADVANTAGES Easy Quick See large lesions DISADVANTAGES May miss smaller lesions No tissue No therapy

Answer 343

Barium liquid is instilled into the large intestine through the anus then pump up air behind it ADVANTAGES Reasonable sensitivity and specificity DISADVANTAGES Time Intensive Technically demanding Unacceptable to patients

Answer 344

``` ADVANTAGES Safe Relatively quick High Sensitivity Able to obtain tissue ``` DISADVANTAGES Bowel prep: 2 days of iatrogenic diarrhoea Small risk of perforation (

Answer 345

CT scan but with 'labelled poo' Modified (reduced) bowel prep “Tag” stool using Bismuth Computer aided subtraction to create images Reconstruct bowel from images

Answer 346

``` ADVANTAGES Quick Easy Reduced Bowel prep more tolerable As good as colonoscopy for lesions >6mm ``` DISADVANTAGES Unable to obtain tissue Unable to remove lesions

Answer 347

Pain – 70% Anorexia – 10% Weight loss – 10% Often non-specific unwell for a while May present with diabetes = adenocarcinoma of the pancreas

Answer 348

EARLY Abdominal pain Depression Glucose intolerance ``` LATE Weight loss Jaundice Ascites= fluid building up into peritoneum Obstructed gall bladder ```

Answer 349

Outcome is poor: - Only 20% are suitable for a resection - Surgery is curative in 20-25% of cases 1 year survival 18% 5 year survival 2%

Answer 350

Smoking Drinking Obesity Family (especially rare conditions such as MEN)

Answer 351

Evidence that the gut flora drives the inflammation in IBD

Answer 352

Pathogens Dietary antigens Everything that lives in it

Answer 353

Surface area of GI tract 400m2 Massive antigen load - Resident microbiota 10^14 bacteria - Dietary antigens - Exposure to pathogens State of restrained activation Tolerance vs. active immune response Immune homeostasis of gut requires presence of bacterial microbiota

Answer 354

Qualitative and quantitative information about different microbes present in a system The ecological community of commensal, symbiotic and pathogenic microorganisms that share our body space 10^14 gut bacteria and 10^13 cells in body (genes in gut flora 100 times our own genome) 4 major phyla Provide traits we have not had to evolve on our own “Virtual” organ Mostly anaerobic Host-specific (more similar to family, change e.g. with antibiotic/surgery or becoming vegan)

Answer 355

Bacteroidetes Firmicutes Actinobacteria Proteobacteria)

Answer 356

A single commensal bacteria switches on genes involving: ``` Mucosal barrier function Nutrient absorption/ dietary energy extraction Enteric nervous system Intestinal maturation Immune system development ```

Answer 357

A catalogue of the metabolites in the same (e.g. in tissue or isolate) Metabolic profiles Biomarkes Metabotypes

Answer 358

The functions that microbiata have e.g. bile metabolism

Answer 359

Either 'gain of function' or DNA-based approach to create gene catalogues (to define microbiome)

Answer 360

Creation of 16S rRNA gene inventories Used to define microbiota ``` Population/community dynamics Diversity indices Microbial biomarkers DNA=diversity RNA=metabolic activity Robust, strong bioinformatic support – software and databases £20-£50 per sample ```

Answer 361

BOTTOM-UP (info from DNA-> RNA-> metabolites) Metagenomics (what are they doing) and metataxonomics (who's there and is it changing) TOP DOWN Metabolomics/metabonomics

Answer 362

50-55% (including mucus etc.) | 50-250g

Answer 363

The large intestine contains 1-2 kg of microbial biomass Have microbes all way through GI (even very acidic stomach because about pH5 between meals) Thus it is one of the most densely populated microbial ecosystems on Earth

Answer 364

Used to think so Mucus plug in anus= contains bacteria Some may be exposed to bacteria in utero In first 18 months, established community First, baby is colonised from exposure to mother (reflects C-section= skin bacteria and vaginal birth= vagina bacteria) Metabolites tell if preterm birth In the first year of life the process can be influenced by antibiotics

Answer 365

Viruses: 1200 viral genotypes Limited information Eukaryotes: Very few studies of the human gut, but murine (mouse) systems show large fungal diversity Bacteria: MAJORITY 16S rDNA sequence inventory >1000 bacterial species in total, but 160 species per person present and possibly >7000 strains Immune system developed to not respond to certain bacteria in gut (so can see when bad bacteria are in) So humans= superorganisms, with it’s own genome contributing to the various phenotypes with which we are familiar and an extended genome (predominantly bacterial)

Answer 366

Predictable to a phylum level but large degree of randomness (so much variability between people) Don't know consequences of where you are in the continuum of possible bacterial ratios Community does show remarkable stability in large intestine

Answer 367

``` MICROBIOTA AS AN ASSET Defence - bacterial antagonism Priming of mucosal immunity Peristalsis (works musculature in gut) Metabolism of dietary carcinogens (from cooking food e.g. carbon sauces) Synthesis of B & K vitamins Epithelial nutrients (e.g. short chain fatty acids like acetate, proprionate, butyrate)= made by bacteria breaking down plant material- colonocytes use as an energy source and controls gut hormones Conversion of prodrugs Utilisation of indigestible (CH2O)n ``` MICROBIOTA AS A LIABILITY Procarcinogens carcinogens Overgrowth syndromes (e.g. of c.diff diarrhoea) Opportunism - Translocation (after surgery/trauma, organisms leak out of gut-> sepsis) Essential ingredient for IBD MAYBE (LIABILITY) Utilisation of indigestible (CH2O)n – obesity Role in insulin resistance and non-alcoholic fatty liver disease

Answer 368

``` Asthma/eczema IBD Colon cancer Heart disease Depression Non-alcoholic fatty liver disease Obesity Diabetes ``` Also affect drug activation/inactivation (Also non-GI affect breast cancer and metabolic syndrome)

Answer 369

``` Intestinal Exocrine Endocrine Vascular Infection Immunity Epithelial Morphology Metabolism Nutritional Hepatic ``` I=3, E=3, M= 2, N/B/H= 1 each NB. Without germs, animals do survive (so microbiota not essential for survival) but altered function and causes intolerance - Immune function (without germs-> oral tolerance) - Metabolic function (without germs-> altered enzymes) - Physiological function (without germs-> altered motility) - Trophic function (without germs-> altered cell turnover)

Answer 370

+= win, -= loss, 0= neutral Parasitism/predation E.g. H. pylori or C. difficile GOOD FOR HOST? - GOOD FOR MICROBIATA? + ``` Amensalism Microbes which cause inadvertent damage to the host GOOD FOR HOST? - - 0 GOOD FOR MICROBIATA? 0 - - (I.e. 3 options= 0-, --, -0) ``` ``` Commensalism Probiotic microbes which don't reproduce in host E.g. L. lactis GOOD FOR HOST? + GOOD FOR MICROBIATA? 0 ``` Mutualism E.g. FMT for CDAD GOOD FOR HOST? + GOOD FOR MICROBIATA?+

Answer 371

Microbes which cause inadvertent damage to the host I.e. organism grows and in doing so inadvertently damages another BUT unlike a pathogen not evolved to do so (collateral damage) E.g. make phenol which can-> colorectal cancer

Answer 372

No 1 causative agent (multifactorial) Doesn't develop in sterile rodents Microbiota may be causing disease

Answer 373

Don't have an organism | No way to verify pathogenic traits

Answer 374

Co-evolved Same number of bacterial cells as there are human cells, but 150x more genes than in the human karyome Probably due to metabolites (communication between proteomes and metabonomes)

Answer 375

Link between host genome and gut microbiome probably because of communication between proteomes and metabonomes Bacterial proteases are a potential virulence factor in colorectal cancer and IBD Also compromise tight junction integrity

Answer 376

Places colonized by microbes All niches are colonized from mouth-rectum But there are different species in each niche

Answer 377

Cholesterol homeostasis Dietary lipid / vitamin (fat soluble ADEK) absorption ``` Removal of xenobiotics/ drugs/ endogenous waste products E.g. - Cholesterol metabolites - Adrenocortical hormones - Other steroid hormones ``` Alkaline phosphatase (ALP also excreted into bile)

Answer 378

``` PERCENTAGES OF COMPOSITION Water= 97 Bile salts= 0.7 Inorganic salts= 0.7 Bile pigments (BR= bilirubin, bilivirden)= 0.2 Fatty acids= 0.15 Lecithin= 0.1 Fat= 0.1 Cholesterol= 0.06 ``` Alkaline phosphatase Drug metabolites (higher mw>urine) Trace metals e.g. Fe, Zn, Mn, Pb, Cu IN AN ALKALINE ELECTROLYTE SOLUTION

Answer 379

500ml per day

Answer 380

60% hepatocytes (liver cells) Up to 40% by cholangiocytes (biliary epithelium) Bile drains from liver, through bile ducts into duodenum and duodenal papilla

Answer 381

Glucoronides of bile pigment

Answer 382

HEPATOCYTES (60% bile) Lipids, bile acids and organic ions added CHOLANGIOCYTES (40% bile) Alters pH, fluidity and modifies bile as it flows through H20 drawn INTO bile (osmosis through paracellular junctions) Luminal glucose and some organic acids also reabsorbed HCO3- and Cl- actively secreted INTO bile by CFTR mechanism (Cystic Fibrosis Transmembrane Regulator) Cholangiocytes contribute IgA by exocytosis (SUMMARY= H2O in , Cl- in for Cl- out/HCO3- out)

Answer 383

Bile flow closely related to concentration of bile acids and salts in blood TRANSPORTERS Biliary excretion of bile salts and toxins performed by transporters on apical surface of hepatocytes and cholangiocytes These biliary transporters also govern rate of bile flow Dysfunction of the transporters -> cholestasis (slow bile flow) Main transporters include the: - Bile Salt Excretory Pump (BSEP) - MDR related proteins (MRP1 & MRP3) - Products of the familial intrahepatic cholestasis gene (FIC1) and multidrug resistance genes (MDR1 & MDR3)

Answer 384

ABCB11 gene Active transport of bile acids across hepatocyte canalicular membranes into bile Secretion of bile acids is a major determinant of bile flow

Answer 385

Mediates canalicular excretion of xenobiotics, cytotoxins

Answer 386

Encodes a phospholipid transporter protein that translocates phosphatidylcholine from inner to outer leaflet of canalicular membrane

Answer 387

PRIMARY (formed in liver) Cholic acid Chenodeoxycholic acid SECONDARY Deoxycholic acid Lithocholic acid Converted by colonic bacteria

Answer 388

Reduce surface tension of fats | Emulsify fat preparatory to its digestion/absorption

Answer 389

Detergent-like actions | Irritates gut lining

Answer 390

Central veins-> coalesce-> hepatic veins-> inferior vena cava

Answer 391

8.4 seconds from: | Blood in portal vein-> liver lobule-> central hepatic vein

Answer 392

Ampulla of bile duct Controlled by Sphincter of Oddi Closed between meals Gall bladder stores bile in this time CCK (cholecystikinin) released when food enters stomach-> sphincter opens and gall bladder contracts and pumps bile into duodenum Why gallstones-> worse after eat (gall bladder squeezes against stones)

Answer 393

BETWEEN LIVER AND GUT Liver makes bile and liver cells transfer various substances, including drugs, from plasma to bile (into duodenum and intestine) Some bile acids and some drug toxic metabolites are reabsorbed from blood and go back into the liver (Reabsorbed particularly in terminal ileum-> transported out of enterocytes-> uptake by hepatocytes-> bile-> repeat) Can also return to liver by portal blood

Answer 394

Many hydrophilic drug conjugates (esp. glucoronide) are concentrated in bile GUT-> glucoronide hydrolysed-> active drug re-released-> reabsorbed-> cycle repeated 'Reservoir' of re-circulating drug Can prolong the action e.g. morphine Affects dose especially in patients with liver acids

Answer 395

95% bile salts absorbed from small (terminal) ileum - By Na+/bile salt co-transport Na+-K+ ATPase system 5% converted to 2o bile acids in colon: - Deoxycholate absorbed - Lithocholate 99% excreted in stool Absorbed bile salts -> back to liver via portal vein then re-excreted in bile 3g bile salt pool re-cycles repeatedly in enterohepatic circulation (2x/meal; 6 – 8x/day)

Answer 396

2x per meal

Answer 397

Decreased bile salt reabsorption Increased stool [fat] Because enterohepatic circulation interrupted and liver can’t increase rate of bile salt production enough to make it up

Answer 398

50% ingested fat in faeces | Malabsorption of fat soluble vitamins (ADEK)

Answer 399

Hepatic duct bile= 2-4% | Gallbladder bile= 10-12%

Answer 400

Hepatic duct bile= 10-20 | Gallbladder bile= 50-200

Answer 401

Hepatic duct bile= 7.8-8.6 | Gallbladder bile= 7.0-7.4

Answer 402

Cholecystectomy= removal of gallbladder Periodic discharge of bile from GB aids digestion BUT is NOT ESSENTIAL (so get regular drip of bile not released when possible) Normal health and nutrition exist with continuously slow bile discharge into duodenum Avoid foods with high fat content (bile isn't concentrated enough to efficiently digest bile)

Answer 403

BR = H2O-INSOLUBLE, yellow pigment BR bound to albumin from spleen (haemoglobin broken down)-> unconjugated bilirubin mostly dissociated in liver Free BR enters hepatocyte and binds cytoplasmic proteins-> conjugated to glucoronic acid (UDPGT from smooth ER)-> diglucoronide-BR Diglucoronide-BR is more soluble than free BR -> Transported across concentration gradient into bile canaliculi- (bile is mostly water)> GI tracts

Answer 404

Free unconjugated BR (from spleen before liver) Conjugated BR (conjugated in hepatocytes and is in bile ducts and gut)

Answer 405

75% BR from Hb breakdown 22% from catabolism of other haem proteins 3% from ineffective bone marrow erythropoiesis

Answer 406

H2O-SOLUBLE, colourless derivatives of BR formed by action of GIT bacteria Formed mainly in intestines

Answer 407

SPLEEN RBCs broken down in spleen (release haem) Unconjugated bilirubin bound to albumin Travels in blood to liver LIVER Unconjugated bilirubin splits from albumin Becomes conjugated by UDPGT (enzyme) ``` Bilirubin can be made soluble and travel in bile Enters duodenum (and kidneys) ``` KIDNEYS Small amount goes to kidneys and is excreted as urobilinogen COLON Remaining bilirubin (conjugated) enters colon Reduced by gut bacteria to stercobilinogen (comes out in faeces)

Answer 408

Permeable to unconjugated BR and urobilinogens

Answer 409

Oxidation of stercobilinogen to stercobilin

Answer 410

Pale faeces Cessation of bile flow -> Usually results in jaundice (but jaundice doesn't mean there is cholestasis)

Answer 411

Excess bilirubin in blood (>34-50 microM/L) -> Yellow tinge to skin, sclerae, mucous membranes)

Answer 412

Haemoglobin-> globin and haem Haem-> bilirubin and iron

Answer 413

Pre-hepatic Hepatic/hepatocellular Post-hepatic/obstructive

Answer 414

Increased quantity of BR: - Haemolysis - Massive Transfusion - Haematoma resorption - Ineffective erythropoiesis Look for: Hb drop without overt bleeding; better than liver function test

Answer 415

1. Defective uptake - Drugs (contrast, rapamycin) - CCF 2. Defective conjugation (with glucoronate) (2A) LOW CONJUGATION - Hypothyroidism - Gilbert's - Crigler-Najjar (2B) HIGH CONJUGATION - Congen: HH, Wilson’s, α1ATD - Infection: Hep A/B/C, CMV, EBV - Toxin: EtOH, drugs - AI: Auto-immune hepatitis - Neoplasia: HCC, mets - Vasc: Budd-Chiari 3. Defective BR excretion Too low - Dubin-Johnson - Rotor's Liver Failure: - Acute/Fulminant - Acute on Chronic - Viral hep, EtOH, AID, PBC, PSC etc. Intrahepatic cholestasis: - Sepsis, TPN, Drugs

Answer 416

Defective Transport of BR by biliary duct system E.g. common bile duct stones, HepPancBil malignancy, local LNpathy Look out for sepsis (cholangitis)

Answer 417

Commonest hereditary cause of increased bilirubin - Up to 5% of the population - Autosomal recessive inheritance - Elevated unconjugated bilirubin in bloodstream CAUSE 70%-80% reduction in glucuronidation activity of the enzyme UDPGT-1A1 SYMPTOMS No serious consequences Mild jaundice may appear under: exertion, stress, fasting, infections Usually asymptomatic

Answer 418

Imbalanced hepatocyte destruction and hepatocyte regeneration ``` CAUSES Toxins= paracetamol, amanita phalloides, bacillus cereus Pregnancy diseases Idiosyncratic drug reactions Vascular diseases Metabolic causes ``` AETIOLOGY Apoptosis (e.g. Acetaminophen= Paracetamol): - Follows activation of caspases (cystein proteases) after oxidative mitochondrial damage - Nuclear shrinkage but no cell membrane rupture - Therefore no release of intracellular content, no secondary inflammation Necrosis (Ischaemia): - Caused by same insults as apoptosis - Associated with ATP exhaustion (depleted stores) resulting in swollen cell - Eventually lyses-> release of intracellular content-> seconddary inflammation Other factors (that regulate pathways of hepatocyte death) - Cellular nitric oxide (NO) - Antioxidants - Various pro- and anti-inflammatory cytokines e.g. IFN, IL-10, IL-12, natural killer cell-derived IL-5 SYMPTOMS Initially non-specific (malaise, nausea, lethargy) Jaundice Catastrophic illness Can rapidly lead to coma/death due to multi-organ failure

Answer 419

``` FULMINANT HEPATIC FAILURE Rapid development ( ```

Answer 420

Relatively uncommon (

Answer 421

TOXINS Over past 30y, paracetamol (Acetaminophen, ACM) is commonest cause= up to 70% ALF cases DISEASES OF PREGNANCY AFLOP, HELLP, hepatic infarction, HEV, Budd-Chiari IDIOSYNCRATIC DRUG REACTIONS Single Agent: Isoniazid, NSAID’s, valproate Drug combinations: Amoxicillin/clavulanic acid, trimethoprim/sulphamethoxazole, rifampicin/isoniazid VASCULAR DISEASES Ischaemic hepatitis, post-OLT hepatic artery thrombosis, post-arrest, VOD METABOLIC CAUSES Wilson’s disease, Reye’s syndrome

Answer 422

Toxicity possible > 10g Severe toxicity certain > 25g Lower doses potentially hepatotoxic in: Chronic alcoholics Malnutrition or fasting Tegretol, Phenobarbital, Rifampacin Of all cases of paracetamol self-poisoning:

Answer 423

(1. Normal, 2. Consequence of hepatic failure) Detoxification Encephalopthay and cerebral oedema Glycogen storage Hypoglycaemia Production of clotting factors Coagulopathy and bleeding Immunological function and globulin production Increased susceptibility to infection Maintenance of homeostasis Circulatory collapse, renal failure

Answer 424

Decreased albumin -> ascites and oedema Decreased clotting factors-> bruising and bleeding Decreased complement -> infection and sepsis

Answer 425

Carbohydrate -> hypoglycaemia Protein catabolism -> low urea Ammonia Clearance -> encephalopathy and coma

Answer 426

Accumulated neurotoxic substances in brain.? Affecting astrocyte function? ``` E.g. Short-chain fatty acids False neurotransmitters e.g. tyramine, octopamine, and beta-phenylethanolamines Manganese Ammonia Gamma-aminobutyric acid (GABA) ```

Answer 427

ALF accounts for 15% of liver transplants/yr in UK, BUT 70% of transplants in Far East Differences in aetiology - Usually drug-induced in West - Viral hepatitis in developing world and Far East (endemic) Exacerbations of chronic hep B (Hong Kong), Hepatitis E (India)

Answer 428

``` Bacterial and fungal infections Circulatory instability Cerebral Oedema Renal failure Respiratory failure Acid-base and electrolyte disturbance Coagulopathy ```

Answer 429

Emergency liver transplant Timing/selection of patients is crucial Unnecessary transplant: - Carries

Answer 430

5 year survival rate with OLT ranges between 60-80% No recurrence of disease BUT patient will require life-long immunosuppression NB. 5% of all transplants in the UK

Answer 431

5 year project launched by NIH published in Nature 242 healthy men/women - samples from different body sites 10,000 different types of organism found Is there a core set of microbes that all humans share?

Answer 432

Oral candidiasis Helicobacter pylori Infective diarrhoea (bacterial, viral, amoebic) Clostridium difficile

Answer 433

Caused by candida albicans Carried in 50% individuals WHAT DOES IT CAUSE Yeast/ fungal infection In immunocompromised states e.g. HIV; chemotherapy; or treatment with corticosteroids TREATMENT Treat with oral anti-fungals e.g. nystatin; or IV antifungals if immunocompromised

Answer 434

Gram negative microaerophilic rod WHAT DOES IT CAUSE Leads to Gastritis/ gastric or duodenal ulcers/ gastric carcinoma BUT 80% infected individuals are asymptomatic INVESTIGATION Blood antibody, stool antigen, urea breath test, biopsy ureases test TREATMENT 1 week eradication therapy with proton pump inhibitor and clarithromycin / amoxicillin

Answer 435

``` Escherichia coli (E coli) Shigella Salmonella Cholera Rotavirus Norovirus Giardia ```

Answer 436

Acute gastroenteritis

Answer 437

E. coli is the type species of the genus (Escherichia) Escherichia is the type genus of the family Enterobacteriaceae ENTEROTOXIGENIC Cholera like toxin Watery diarrhoea ENTEROHAEMORRHAGIC EO157/H7 Verotoxin/shigatoxin Haemolytic uraemic syndrome ENTEROPATHOGENIC: EPEC Common in kids nurseries ENTEROINVASIVE Shigella like illness Bloody diarrhoea Megacolon

Answer 438

Clostridium difficile Causes large intestine infection Antibiotics kill many commensal gut bacteria so c. diff gains a foothold and produces toxins-> mucosal injury Neutrophils and RBCs leak into gut between injured epithelial cells ``` LEADS TO Overgrowth of c. diff-> pseudomembranous colitis (antibiotic associated colitis) Bloody diarrhoea Mucous Abdominal pain ``` TREATMENT Isolation Stop current antibiotics Metronidazole and vancomycin

Answer 439

Gram negative extracellular bacillus Targets Cl- channels -> huge water and salt loss in ricewater like diarrhoea LEADS TO Causes extreme dehydration and possible hypovolaemic shock TREATMENT Supportive (fluid replacement, salt, water, sugar and IV fluids)

Answer 440

Diarrhoea | Other common GI disease symptoms

Answer 441

Multi-centre long-term follow-up colonoscopic FMT for recurrent c. diff infection - > Cure rate of 98% - > Symptoms for ~ 1 year before FMT and 74% better in 3 days Stool resembles donor stool in 2 weeks Persistence for over 30 days post FMT (Compared to other treatments: FMT 1/16 recurrence Vanc only 8/13 recurrence Vanc and lavage 7/13 recurrence)

Answer 442

``` Gastric acid Commensal oral flora Peristalsis Mucus secretion from goblet cells Proteases- intraluminal enzymes Protective shield of the enterocyte membrane and brush border ```

Answer 443

MALT (mucosa associated lymphoid tissue) GALT (gut associated lymphoid tissue)

Answer 444

Anatomical (epithelial barrier, peristalsis) | Chemical (enzymes, pH gastric acid)

Answer 445

MUCUS LAYER Goblet cells EPITHELIAL MONOLAYER Tight junctions Antimicrobial peptides Transports IgA PANETH CELLS Bases of crypts Defensins Lysozyme

Answer 446

The oral cavity | E.g. tongue, palatine, lingual and pharyngeal tonsils

Answer 447

Thymus and bone marrow – primary lymphoid organs Spleen and lymph nodes – secondary lymphoid tissues

Answer 448

NOT-ORGANISED Intra-epithelial lymphocytes (mainly CD8) Lamina propria lymphocytes (antigen presenting cells) ORGANISED Cryptopatches (tiny lymphoid aggregates in colon) Peyer’s patches (in small intestine, distal ileum) Isolated lymphoid follicles Mesenteric lymph nodes

Answer 449

Generates lymphoid cells and antibodies IgA secretory and interstitial IgG IgM Cell mediated immunity (adaptive and innate)

Answer 450

In small intestine (mainly distal ileum) Development requires exposure to bacterial microbiota - 50 in last trimester foetus - 250 by teens Organised collection of naïve T and B-cells Covered by follicle associated epithelium (FAE) Antigen uptake (antigen sampling) via M (microfold) cells within FAE Similar isolated lymphoid follicles elsewhere in GI tract (30,000 in total)

Answer 451

Under follicle associated epithelium (FAE) there is a sub-epithelial dome (dendritic cells) with M cells This is connected to a follicle (with B cells) that is: - Surrounded by T cell areas (naive T cells) - Connected to lymph nodes FAE - No goblet cells - No secretory IgA - Lack microvilli - Infiltrated by T-cells, B-cells, macrophages, dendritic cells

Answer 452

Form portal of entry for antigens (instead of mucosal epithelium) Antigen sampling/uptake controlled by M-cells Transport to antigen-presenting cells in sub-epithelial dome DCs take up antigen and process Present to naïve B or T-cells in Peyer’s patch or transport antigen to lymph nodes Results in development of gut homing markers Transfer to mesenteric lymph node to proliferate

Answer 453

B-cells - Mature naïve B-cells expressing IgM in PPs - Upon antigen presentation class switch to IgA - Influenced by presence of T-cells and epithelium via cytokines Further maturation to become IgA secreting plasma cells Populate lamina propria

Answer 454

IgA= specialised immunoglobulin of the gut IgA secreting cell numbers reflects bacterial load Up to 90% of gut B-cells secrete IgA STRUCTURE Dimeric structure secreted by plasma cells in submucosa TRANSPORT - Dimeric Ig binds to poly-Ig receptor on epithelial cell membrane - Receptor and IgA endocytosed to form vesicle (then undergo enzymatic cleavage-> form secretory IgA-> secreted into lumen from epithelial cells by transcytosis) ``` EFFECTS Binds luminal antigen Prevents invasion Prevents adherence Does not activate complement or cytotoxic lymphocytes ```

Answer 455

Make up one fifth of the intestinal epithelium Conventional T cells (also lamina propria) - Migrated from other tissues Unconventional T cells (Innate) - Resident - Express unusual combinations of CD4, CD8 or γδ T cell receptor Other innate immune cells -Resident NK cells (e.g. NKp44+ NK cells)

Answer 456

Determined by 3 signals: 1. Presentation of antigen (by DC) within MHC 2. Co-stimulatory signals on DC 3. Secretion of cytokines by DC

Answer 457

The pool of cytokines Affects development of the unconventional resident T cells of the gut The plastic response of T-cells to this milieu can lead to a proinflammatory environment Leading to an increase in Th1, ThIL17 with a decreased Treg cell count

Answer 458

Mechanism by which activated T cells and antibody-secreting cells (ASCs) are targeted to both inflamed and non-inflamed regions of the gut in order to provide an effective immune response Lymphocytes proliferate in MLNs - > Enter lymphatics to thoracic duct - > Enter circulation - > Selectively home to sites similar to initial priming Antigen presentation in GALT favours ‘gut homing’ characteristics (Integrins and chemokine receptors) Partly regulated by the adhesive interactions between lymphocytes and specialised post-capillary microvascular endothelial cells, such as high endothelial venules (HEVs) of lymphoid tissue

Answer 459

Lymphocytes track into areas of gut inflammation Mediated by expression of tissue-specific adhesion molecules on vasculature walls

Answer 460

α4β7 integrin/MAdCAM-1 adhesion facilitates local gut inflammation Likely that these interactions mediate selective lymphocyte trafficking to GI mucosa and gut-associated tissues α4β7 integrin is a critical component of lymphocyte tracking to sites of local inflammation in IBD

Answer 461

Tolerance= food antigens, commensal bacteria Immunoreactivity= pathogens

Answer 462

Suppression of immune responses towards antigens

Answer 463

MECHANISMS OF IMMUNE TOLERANCE Deletion of responding lymphocytes Anergy TReg cells LOSS OF TOLERANCE (maybe->) Inflammatory bowel disease Coeliac disease Food allergy

Answer 464

``` Food allergy= IgE and histamine response Nuts Hen egg white Cows milk Wheat Sesame seeds Soya Shell fish ``` Food intolerance= not mediated by immune system

Answer 465

Coeliac disease is an autoimmune condition NOT an allergy or an intolerance to gluten In cases of coeliac disease, the immune system mistakes substances found inside gluten as a threat to the body and attacks them This damages the surface of the small bowel (intestines), disrupting the body's ability to absorb nutrients from food Inflammatory reaction (dendritic cells of submucosa mature in a proinflammatory environment)-> subtotal villous atrophy Can’t absorb B12, folate…. So often present as anaemic

Answer 466

Majority DQ8 HLA, some DQ2 (also need another HIIT)

Answer 467

Around 300,000 people in the UK have IBD Overall incidence of UC is higher than Crohn’s, but Crohn’s is increasing more Increasing incidence, especially in young and non-western societies Highest incidence rates in North America and northern/western Europe

Answer 468

Combo of: Genetic background (>160 susceptibility genes, 2/3 genes shared between UC/CD) Immune system Environmental factor Inappropriate chronic immune response against resident gut microbes - May be on account of distinct changes in the gut microbiota termed as dysbiosis Smoking-> in crohns is very bad (more likely to need operations and stronger drugs) In ulcerative colitis (removal of smoking= trigger factor)

Answer 469

Creates protein relating to how body reacts to bacteria

Answer 470

Faecal stream diversion alleviates Crohn’s Reanastomosis triggers recurrence

Answer 471

Overall CD is not caused by diminished diversity alone – but requires a susceptible genotype – as confirmed by research in mice with human relevant susceptibility mutations Shift-> increases in virulence and secretion pathways Fusobacteriaceae= biomarker, progression of colon cancer Pastueurellacaea, veillonellaceae, pathogenic E. coli= link with ulcer formation

Answer 472

Decrease in Faecalibacterium prausnitzii and Roseburia hominus in UC (decrease in butyrate production)

Answer 473

``` Clinical Phenotype Confounders Age, gender, smoking Ethnicity, diet, surgery Medications “Healthy” controls ``` SAMPLING Faeces v mucosa - Axial and longitudinal variation Replication - Multiple samples from same region - Longitudinal sampling ``` COMMUNICATION Clinicians Microbial ecologists Bioinformatics Statisticians ``` ``` TECHNICAL 16S sequence Metagenomics Metatranscriptomics Metabonomics Economics ```

Answer 474

Inflammatory condition of the biliary tree associated with IBD May cause cholangiocarcinoma Cause is T-cell misdirection to the liver whether they contribute to inflammation and biliary destruction

Answer 475

Hormones released by cells in the vicinity of the target cell and reach target cell by diffusion

Answer 476

Nervous system (intrisic/enteric and extrinsic/autonomic) Paracrine Endocrine

Answer 477

Integrates motor and secretory activities (Independently of CNS) ``` Regulates: Motility Blood flow Water and electrolyte transport Secretion Absorption ``` GI tract wall= concentration of neurons 2nd only to CNS Rich plexus (network) of ganglia (nerve cells and glial cells) interconnected by tracts of fine, unmyelinated nerve fibres

Answer 478

Inflammation (UC or CD) Post-operative injury Irritable bowel syndrome Ageing (constipation)

Answer 479

Myenteric plexus (Auerbach’s plexus) Minor plexuses (including deep muscular plexus (inside circular muscle) Submucosal plexus (Meissner's)

Answer 480

Located between the circular and longitudinal smooth muscle layers Controls activity of muscularis externa Controls gut motor function

Answer 481

Deep muscular plexus (inside circular muscle) | Ganglia supplying biliary system and pancreas

Answer 482

Sensing environment within lumen Blood flow, epithelial and endocrine cell funpaction

Answer 483

Regulates smooth muscle, cardiac muscle and glands Not accessible to voluntary control Two branches: - Sympathetic - Parasympathetic

Answer 484

Activation of the sympathetic nerves usually inhibit the activities of the GI system (by inhibiting blood flow) Neurotransmitter= norepinerphrine (NA)

Answer 485

Thoracic splanchnic nerves carry innervation to fore and midgut Lumbar splanchnic nerves carry sympathetic innervation to the remainder of the gut

Answer 486

Cell bodies of preganglionic neurons in the thoracic and lumbar spinal cord Cell bodies of postganglionic neurons in the pre- and para- vertebral ganglia

Answer 487

Excitation usually stimulates the activities of the GI tract Neurotransmitter= Acetylcholine (ACh)

Answer 488

Most of the GI tract via branches of the vagus nerve (down to the level of the transverse colon) Remainder of the colon, the rectum and the anus receive parasympathetic fibers from the pelvic nerves

Answer 489

Cell bodies of preganglionic neurons in the brainstem and sacral spinal cord (cranio-sacral)

Answer 490

SEE DIAGRAM ANS -> Parasympathetic- vagal nuclei (vagus nerve) and sacral spinal cord (pelvi) nerves)-> enteric nervous system or ANS -> Sympathetic- thoracic and lumbar SC-> sympathetic ganglia-> blood vessels and enteric nervous system -- Enteric nervous system (myenteric plexus submucosal plexus) - > Smooth muscle - > Secretory cells - > Endocrine cells - > Blood vessels

Answer 491

Terminate on neurones in the intramural plexuses Majority sympathetic fibres do not directly innervate structures in the GI tract BUT: Vasoconstrictor sympathetic fibres do directly innervate the blood vessels of the GI tract- coeliac, superior and inferior mesenteric

Answer 492

SEE DIAGRAM CNS -> Sympathetic and parasympathetic efferents -> Enteric nervous system or -> Directly-> ABCD ------ Chemoreceptors and mechanoreceptors in wall of GI tract -> Splanchnic and vagal afferents -> CNS or -> Local afferents-> enteric nervous system ``` --- Enteric nervous system (myenteric plexus submucosal plexus) -> Smooth muscle (A) -> Secretory cells (B) -> Endocrine cells (C) -> Blood vessels (D) ```

Answer 493

INTRINSIC INNERVATION Neurons of the enteric nervous system EXTRINSIC INNERVATION Afferents (pain, nausea, fullness) Afferents (coordination - sympathetic and parasympathetic nervous systems) Complexity allows fine control of the GI tract

Answer 494

PARASYMPATHETIC Innervates the gut via long preganglionic neurones (mostly via the vagus nerve) and short postganglionic neurones -> Promotes gut motility, secretion and digestion SYMPATHETIC Innervates the gut via short preganglionic and long post ganglionic fibres -> Inhibits gut motility and secretion -> Causes constriction of blood vessels and contraction of sphincters

Answer 495

Produced by endocrine cells in the mucosa or submucosa of the stomach, intestine and pancreas Can act as paracrine or neurocrine factors REGULATES MECH PROCESS OF DIGESTION E.g. smooth muscle of GI tract and sphincters, gall bladder REGULATES CHEM PROCESS OF DIGESTION E.g. secretory cells located in the wall of the GI tract, pancreas and liver CONTROLS POST ABSORPTIVE PROCESSES (Post absorptive processes involved in the assimilation of digested food and CNS feedback regulating intake) E.g. GIP stimulates insulin release from pancreatic beta cells, PYY3-36 acts on the CNS to suppress appetite EFFECTS ON GROWTH/DEVELOPMENT OF GIT E.g. GLP-2 promotes small intestinal growth

Answer 496

``` STOMACH Gastrin Ghrelin Somatostatin Histamine ``` ``` PANCREAS Insulin Glucagon Somatostatin Pancreatic Polypeptide ``` UPPER DUODENUM/JEJUNUM Secretin CCK Somatostatin ``` ILEUM PYY GIP GLP-1 GLP-2 Oxyntomodulin Neurotensin Somatostatin ``` ``` COLON PYY GLP-1 Oxyntomodulin Neurotensin Somatostatin ```

Answer 497

Histamine release from the stomach wall cells is key to HCl secretion from the gastric parietal cells Somatostatin from the stomach can inhibit this secretion

Answer 498

SYNTHESIS In gastric antrum and upper small intestine RELEASE STIMULATED BY: - AAs and peptides in the lumen of the stomach - Gastric distension - Vagus nerve directly ACTION Gastrin stimulates gastric acid secretion Release inhibited when pH of stomach falls below pH 3

Answer 499

SYNTHESIS In endocrine D cells of the gastric and duodenal mucosa, pancreas (also hypothalamus) RELEASE In response to a mixed meal ACTION Somatostatin is a universal inhibitor (Endocrine Cyanide) Inhibits: Gastric secretion, motility, intestinal and pancreatic secretions, release of gut hormones, intestinal nutrient and electrolyte transport, growth and proliferation Analogues used to treat neuroendocrine tumours

Answer 500

SYNTHESIS S cells in upper duodenum and jejunum RELEASE STIMULATED BY: Presence of acid in duodenum (pH below 4.5) ACTION Stimulates pancreatic bicarbonate secretion (effect potentiated by CCK)

Answer 501

SYNTHESIS Secreted by cells most densely located in the small intestine RELEASE Stimulated by fat and peptides in the upper small intestine Independent of the vagus ACTION - Stimulates pancreatic enzyme release - Delays gastric emptying - Stimulates gallbladder contraction. - Decreases food intake and meal size

Answer 502

SYNTHESIS Secreted by mucosal K cells (predominant in the duodenum and jejunum) RELEASE Following ingestion of a mixed meal ACTION Stimulates insulin secretion. GIP receptor antagonists reduce postprandial insulin release

Answer 503

SYNTHESIS Cells found throughout the mucosa of the terminal ileum, colon and rectum RELEASE From L cells post prandially (particularly protein) from intestines ACTION - PYY reduces intestinal motility, gallbladder contraction and pancreatic exocrine secretion - Inhibitor of intestinal fluid and electrolyte secretion - PYY3-36 inhibits food intake

Answer 504

Developed because longer half life than somatostatin | Wouldn’t need to constantly infuse them-> so octreotide can chronically manipulate it but taken practically

Answer 505

Body fluid osmolality is increased Blood volume is reduced Blood pressure is reduced Plasma osmolality increased is the more potent stimulus – change of 2-3% induces strong desire to drink Decrease of 10-15% in blood volume or arterial pressure required to produce the same response

Answer 506

Antidiuretic hormone (ADH) or vasopressin Acts on kidneys to regulate the volume and osmolality of urine Low plasma ADH -> large volume of urine is excreted (water diuresis) High plasma ADH -> small volume of urine is excreted (anti diuresis)

Answer 507

Hypothalamus, organum vasculosum (OVLT)and subfornical organ (SFO) Circumventricular organs (characterized by their extensive vasculature and lack of a normal BBB)

Answer 508

Found in the hypothalamus, OVLT, and SFO Sense changes in body fluid osmolality Cells shrink or swell in response (expand when plasma more dilute, and vice versa) Send signals to the ADH producing cells in the hypothalamus to alter ADH release Same regions seem to regulate thirst

Answer 509

INCREASED PLASMA OSMOLALITY Invokes drinking and ADH release Increased ADH stimulates kidney to conserve water DECREASED PLASMA OSMOLALITY Thirst is suppressed and ADH release decreased Absence of ADH the kidney excretes more water

Answer 510

Don't know as much as about food intake Receptors in mouth, pharynx, oesophagus seem to be involved Relief of thirst sensation via these receptors is short lived Thirst is only completely satisfied once plasma osmolality is decreased or blood volume or arterial pressure corrected Circuits may be involved

Answer 511

Angiotensinogen from liver (with renin from juxtaglomerular cells) -> angiotensin I Angiotensin I (with ACE)-> angiotensin II-> thirst and other effects of vasonconstriction ANGIOTENSIN II-> SENSATION OF THIRST

Answer 512

AII (angiotensin II) is increased when blood volume and pressure are reduced Activates SFO neurones AII contributes to the homeostatic response to restore and maintain the body fluids at their normal level Other factors? Neurotransmitters?

Answer 513

INTO HYPOTHALAMUS Ghrelin, PPY and other hormones Neural input from periphery and other brain regions Leptin HYPOTHALAMUS Responding to many inputs Integrated system OUT OF HYPOTHALAMUS Food intake Energy expenditure

Answer 514

``` Lateral hypothalamus Paraventricular nucleus Ventromedial hypothalamus Arcuate nucleus around 3rd ventricle ```

Answer 515

Key brain area involved in the regulation of food intake Incomplete blood brain barrier, allows access to peripheral hormones Integrates peripheral and central feeding signals Two neuronal populations: - Stimulatory (NPY/Agrp neuron) - Inhibitory (POMC neuron)

Answer 516

``` Sensing what goes on outside brain Incomplete BBB (peripheral factors gain access) ```

Answer 517

Circulating factors in blood - > Arcuate nucleus - > Through 3rd ventricle SIGNALS TO PVN Increases feeding or decreases feeding PVN= controls appetite and energy expenditure

Answer 518

POMC (in arcuate nucleus)-> alpha-MSH -> stimulates MC4R (in paraventricular nucleus) Agrp (in arcuate nucleus)-> Agrp -> inhibits MC4R (in paraventricular nucleus)

Answer 519

No NPY or Agrp mutations associated with appetite discovered in humans (very dramatic and not common) POMC deficiency and MC4-R mutations cause morbid obesity Mutations not responsible for the prevalence of obesity- but useful to explain signalling

Answer 520

Higher centres Amygdala- emotion, memory Other parts of the hypothalamus, e.g. lateral hypothalamus Vagus to brain stem to hypothalamus

Answer 521

Long term- Leptin | Short term- Ghrelin, PYY

Answer 522

Circulating hormone produced by fat Hypothalamus senses the concentration of hormone Hypothalamus then alters neuropeptides to increase or decrease food intake Perhaps a problem with the regulation of the adipostat mechanism leads to obesity?

Answer 523

Big mouse= missing gene for leptin (hormone)

Answer 524

167 AA protein hormone (leptin) coded for but missing in ob/ob mouse Made by adipocytes in white adipose tissue Circulates in plasma Acts upon the hypothalamus regulating appetite (intake) and thermogenesis (expenditure) When you get fatter-> release more leptin-> regulation But doesn't happen in ob/ob mouse Ob/ob mouse can be normalised when given leptin

Answer 525

Low when low body fat | High when high body fat

Answer 526

ABSENT LEPTIN Thought obese people had adipose tissue lacking leptin REGULATORY DEFECT Obese people had normal leptin levels but that more fat over a point meant no more leptin ``` LEPTIN RESISTANCE (this was the case) High leptin levels but hypothalamus doesn't lead to food intake, energy expenditure or fat/glucose metabolism ```

Answer 527

Leptin circulates in plasma in concentrations proportional to fat mass Fat humans have high leptin Obesity due to leptin resistance- hormone is present but doesn’t signal effectively Leptin is ineffective as a weight control drug

Answer 528

Small number of cases identified Mutation in ob gene- homologous to ob/ob mouse Severely hyperphagic and obese

Answer 529

Leptin replacement Reduces body weight

Answer 530

Not bulk in stomach or nutrients in circulation Hormonal signal from the gut (Grehlin in stomach and PYY in descending colon/rectum)

Answer 531

Post-prandial secretion of PYY Released in proportion to calories you're eating Directly modulates neurones in the arcuate nucleus - Inhibits NPY release - Stimulates POMC neurones - Decreases appetite

Answer 532

"Hunger hormone"= opposite of PYY release Peptide hormone produced by ghrelinergic cells in the gastrointestinal tract Fatty acid chain at Ser3 (to access brain and bind to R) Released before a meal, drops after Directly modulates neurones in the arcuate nucleus - Stimulates NPY/Agrp neurons - Inhibits POMC neurons - Increases appetite

Answer 533

PYY (from intestines) - 36 AA chain, truncated version in food intake - Increases after meal Directly modulates neurones in the arcuate nucleus - Inhibits NPY release - Stimulates POMC neurones - Decreases appetite -- GHRELIN(from stomach) - Opposite of PYY release - Increases before meal Directly modulates neurones in the arcuate nucleus - Stimulates NPY/Agrp neurons - Inhibits POMC neurons - Increases appetite

Answer 534

PYY Rat= wants to eat (hungry) Increasing doses of PYY-> suppresses food intake GHRELIN In rats that aren't hungry Increasing doses of ghrelin-> think they are hungry-> eat more (Ghrelin suppresses hunger in humans)

Answer 535

Gut hormones may represent a novel treatment for obesity Target only relevant circuits. Released daily without ‘side effects’ Exert effects throughout life without escape

Answer 536

Obesity is associated with comorbidities E.g. depression, sleep apnoea, stroke, MI, hypertension, diabetes, peripheral vascular disease, gout, osteoarthritis. bowel cancer, liver disease, lung disease, abnormal periods/infertility in women

Answer 537

James Neel 1962 Specific genes selected for to increase metabolic efficiency and fat storage In the context of plentiful food and little exercise these genes predispose their carriers to obesity and diabetes Evolutionarily sensible to put on weight (thin humans didn’t survive famines, so didn’t pass their genes on to modern humans) Populations historically prone to starvation become most obese when exposed to Western diet and sedentary life-style (e.g. Pima Indians, Pacific Islanders)

Answer 538

Normal distribution of body weight: the fat are eaten, the thin starve 10-20K yrs ago, humans learned to defend against predators Thus obesity not selected against Putting on body fat then a neutral change (genetic drift). (though unlikely to put on much weight) In current context, the inheritors of these genes become obese

Answer 539

``` Ethyl group (methyl group and methylene group) Hydroxy group ``` Structural formula= CH3CH2OH (C2H6O) Ethanol is practically insoluble in fats and oils The concentration of ethanol depends on the relative water content of the tissue (reaches equilibrium quickly with the concentration of ethanol in the plasma) Ethanol is not bound to plasma proteins

Answer 540

Ethanol-> ADH (NAD+->NADH) -> Acetaldehyde -> ALDH (NAD+->NADH) -> Acetate Ethanol-> Catalase (H202->H20) -> Acetaldehyde Ethanol-> CYP2E1 (NADPH-> NADP+ and H2O) -> Acetaldehyde ADH – alcohol dehydrogenase ALDH - Aldehyde dehydrogenase

Answer 541

ADH-> Hypoxia (displaced ratio-> cell death) CYP2E1 and acetaldehyde-> ROS (-> free radical formation) Acetaldehyde (toxic) binds to certain AAs-> protein adduct formation (recognised as foreign-> inflammatory response)

Answer 542

Alcohol-use disorders identification test (IDs 92% hazardous and harmful drinkers, excludes 93% who aren't) ``` Staging risk 1–7: low-risk drinking 8–15: hazardous drinking 16–19: harmful drinking 20+: possible dependence ```

Answer 543

Liver disease is the third biggest cause of premature mortality (in working life) Alcohol kills at a young age Productivity, taxes, working-> useful to state 75% of deaths from liver disease are result of excess alcohol consumption

Answer 544

Cellular and molecular mechanisms involved remain poorly understood Liver damage might be the result of direct toxic actions of ethanol or its metabolites within hepatocytes-> CELL DEATH

Answer 545

NADH Introduction of xenobiotic metabolism Free radical generation Protein adduct formation ``` -> Myocardial and pancreatic injury Fatty liver Hypoxic liver damage Allergic reactions Cell damage Carcinogenesis Enhanced toxicity ```

Answer 546

Decreased FA oxidation - > FA ethyl esters-> myocardial and pancreatic injury - > increased triglyceride production-> fatty liver Increased glyceraldehyde reduction -> increased triglyceride production-> fatty liver Decreased galactose tolerance Increased oxygen consumption -> increased oxygen consumption-> hypoxic liver damage

Answer 547

ALDH-> adenosine-> vasodilation-> hypoxic liver damage

Answer 548

Decreased microtubule function-> abnormal diagnostic tests Antibody formation-> allergic reaction and cell damage Directly to cell damage

Answer 549

Lipid peroxidation-> fatty liver Directly to carcinogenesis

Answer 550

- > carcinogenesis | - > enhanced toxicity (e.g. halogenated hydrocarbons)

Answer 551

NB. Not everyone who drinks same amount will develop cirrhosis 90-95% -> steatosis (fatty liver) or steatohepatitis (inflammation) 10-20% from steatosis-> fibrosis 40-50% from steatohepatitis-> fibrosis 8-20%-> cirrhosis In some people steatohepatitis-> cirrhosis directly 3-10% cirrhosis-> HCC (hepatocellular carcinoma)

Answer 552

GENETIC Female SNPs Hemochromatosis ``` ENVIRONMENTAL Binge drinking Viral hepatitis HIV Obesity and insulin resistance Cigarette smoking ```

Answer 553

``` Fatty liver Fat droplets deposited in the liver Occurs in up to 50-90% of heavy drinkers Leads to steatohepatitis and abnormal LFT’s Reversible if alcohol reduced ```

Answer 554

Irreversible scarring of liver with fibrous bands and regenerative nodules (as hepatic cells begin to die) Eventually develops in 20% after 15 years Impaired function Development of portal hypertension (back up of blood diverted to other veins and causes problems) Morbidity common, associated with jaundice, ascites, bleeding, cachexia, infections, and encephalopathy 3-5% per annum risk of developing liver cancer Death in most within 10 years

Answer 555

``` Fatty= smooth, fat Cirrhotic= pinker, rougher, nodules ```

Answer 556

Compensated vs decompensated OR Asymptomatic vs symptomatic

Answer 557

Jaundice (from bilirubin retention) Ascites (retention of water in abdominal cavity, pressure gradient issue as high portal hypertension and low pressure within abdominal cavity) Bleeding varices Encephalopathy

Answer 558

Child-Pugh is a way of classifying liver disease | A= least severe, C= worst

Answer 559

Stop drinking-> liver can regenerate in early stages In cirrhosis-> can't reverse, can have transplant, abstinence still useful to improve 5yr survival rate (if Child-Pugh A)

Answer 560

``` Cirrhosis Chronic pancreatitis Alcoholic cardiomyopathy Stroke Neurological Fetal alcohol syndrome ```

Answer 561

Up to 45% due to alcohol Exocrine insufficiency -> Steatorrhoea, vitamin deficiencies, hypocalcaemia Endocrine insufficiency -> Diabetes Chronic Pain Weight Loss

Answer 562

Chronic long-term abuse of alcohol (i.e. ethanol) leads to heart failure Toxicity-> heart unable to pump blood efficiently, leading to heart failure Heart much bigger (3x), become dilated and baggy (radius of ventricles has increased so have to contract under higher pressure to -> SV) Higher BP in people who consume more alcohol Hypertension appears to reverse within 2 to 3 weeks of cessation of alcohol intake

Answer 563

High alcohol intake is associated with the risk of stroke The effect is dose dependent – findings suggest a J-shaped curve (consuming small amounts of alcohol may be beneficial or just maybe better health/lifestyle) Increased risk of haemorrhagic stroke

Answer 564

Ability to perform tasks, recall info and coordinate/balance are reduced HEAVY ALCOHOL CONSUMPTION (often together, malnutrition, deficiency in thiamine) Wernicke’s encephalopathy Korsakoff’s psychosis Optic toxicity Autonomic dysfunction Peripheral neuropathy

Answer 565

Specific pattern of facial features Pre- and/or postnatal growth deficiency Evidence of central nervous system dysfunction Microencephaly (small brain) and migration anomalies (neural and glia cells don't migrate properly, just go to top of cortex) Agenesis of corpus callosum and ventricles are dilated Cerebellar anomalies Some babies are born with obvious FAS, many other babies will appear normal, but never reach their full potential as a result of the effects of alcohol in utero

Answer 566

In 2014, there were 8,697 alcohol-related deaths registered in the UK In 2013/14, there were an estimated 1,059,210 admissions in England related to alcohol consumption The overall number of people in treatment for alcohol dependency during 2013-14 in England was 114,920 The total annual cost to society of alcohol-related harm is estimated to be £21bn The NHS incurs £3.5bn a year in costs related to alcohol Alcohol-related crime in the UK is estimated to cost between £8bn and £13bn per year

Answer 567

Deprived populations that apparently consume the same or less alcohol than less deprived populations suffer greater levels of harm ``` May be due to: Under reporting Drinking patterns Compounding / social and health resilience Health services Poverty gradient ```

Answer 568

14 units a week for women and men max recommended | Should be spread evenly over 3+ days

Answer 569

Percentage (ABV%) x volume (ml) Divided by 1000

Answer 570

Beer 4. 5%, 568ml 2. 6 units Red wine 13. 0%, 250ml 3. 3 units White cider 7. 5%, 3L 22. 5 units

Answer 571

CARBS Glycogen-> (glycogenolysis)-> glucose -> (glycolysis)-> pyruvate-> acetyl CoA FATS Triglycerides-> (lipolysis)-> free fatty acids -> (B oxidation)-> acetyl CoA PROTEIN Protein-> (proteinolysis)-> amino acids -> (deamination and oxidation)-> acetyl CoA

Answer 572

Inadequate consumption Poor absorption Excessive loss of nutrients (NB. Malnutrition includes overnutrition)

Answer 573

``` A third of the global population live below recommended nutritional needs Most T2D -> 30-40% CVD -> Many cancers (risk factors) -> Many chronic diseases ```

Answer 574

If human potential is to be fulfilled there are a number of basic needs that have to be met ``` (From bottom to top) Biological/physiological Security/safety Social needs Ego Self fulfilment ``` Building blocks to perform at best level (need bottom the most) Basic needs are oxygen, food, water and shelter

Answer 575

Lot of ways assessing body composition BMI clinically relevant method of estimating adiposity Weight kg/height Much more useful to use with waist measurement

Answer 576

>20 underweight 20-25 desirable weight 26 - 30 overweight 31-40 obese

Answer 577

BMI not as good for undernutrition as obesity/overweight Monitoring body weight -> Can be complicated by fluid balance Arm circumference (or measure triceps skinfold) NB. Hard in children because growing (but use growth charts0

Answer 578

Total cell mass In some case of malnutrition body weight is not reflective of nutritional status because of complications of oedema (oedema confounds body weight)

Answer 579

Reflect the nutritional needs of a population A way of assessing nutritional adequacy Needed because people need many different nutrients to maintain health and reduce the risk of diet-related diseases These are different in requirements of nutrients at different stages of life e.g. women of childbearing age need more iron than men.

Answer 580

Fall in normal distribution Estimated Average Requirement (EAR)= Mean requirement Reference Nutrient intake (RNI)= 2.5 SD above EAR (97.5%) Lower nutrient reference intake (LRNI)= 2.5 SD below EAR (population at risk below here e.g. of iron deficiencies, used for calories in UK) Not set at EAR because below what 50% of population needs so normally set it at RNI (cover majority of population)

Answer 581

Ascorbic acid Anti oxidant Convert Fe3+ to Fe2+ Important in formation of collagen Varied amount for different ages/sexes/pregnancy/lactation Deficiency: Scurvy NB. James Lind 1700s, 12 men from ship (discovered citrus fruit can cause scurvy)

Answer 582

WHEN WEIGHT IS STABLE Energy in = energy out and energy stored ``` WEIGHT GAIN Energy in > energy out - Increase intake - Decrease expenditure - Decrease in metabolic rate ```

Answer 583

Total energy expenditure= heat produced and work on environment (when organism is at rest, all energy expenditure is equal to heat produced) Adaptive thermogenesis Physical activity (variable) Obligatory energy expenditure (BMR)

Answer 584

Extra energy when digest food or expended to keep warm Variable, regulated by brain Responds to temperature and diet Occurs in brown adipocyte mitochondria, skeletal muscle and other sites

Answer 585

Majority of energy expenditure BMR Required for performance of cellular and organ functions

Answer 586

Fat 9 Cho 4 Protein 4 Alcohol 7

Answer 587

RNI | 2.5 SD above the EAR

Answer 588

Energy demand gets greater as you grow | Energy demand decreases as muscle mass is lost

Answer 589

``` Pyruvate AA FAs Ketone bodies TCA ```

Answer 590

Glycogen= stored in the liver and muscle Adipose tissue= major store Muscle= prolonged starvation Alcohol can't be stored-> changes other balances

Answer 591

Intake (alcohol, CHO, protein, fat) MINUS Expenditure (alcohol, CHO, protein, fat) EQUALS Stores (alcohol, CHO, protein, fat) Autoregulation perfect of alcohol, excellent of protein and carbs but poor of fat Burn alcohol first-> shift rest into storage Changes oxidation hierarchy - Alcohol, CHO, protein automatic adjustment of oxidation to intake, fat is not - Oxidation hierarchy leads to fat sparing

Answer 592

Human body will increase in weight twenty fold from a baby to an adult All material in weight gain enters the human body as food and drink Grossly abnormal diets will cause changes in body weight, configuration and composition NB. Height 100 years ago limit related to energy intake, now possibly reach our genetic maximum

Answer 593

``` BODY WEIGHT- increases Fetus (20-25w)= 0.3 Full term baby= 3.5 Infant (1y)= 20 Adult man= 70 Obese man= 100 ``` ``` WATER (%)- decreases Fetus (20-25w)= 88 Full term baby= 69 Infant (1y)= 62 Adult man= 60 Obese man= 47 ``` ``` PROTEIN (%)- increases slightly (until obese) Fetus (20-25w)= 9.5 Full term baby= 12 Infant (1y)= 14 Adult man= 17 Obese man= 13 ``` ``` FAT (%)- increases Fetus (20-25w)= 0.5 Full term baby= 16 Infant (1y)= 20 Adult man= 17 Obese man= 35 ``` ``` REMAINDER (%)- increases Fetus (20-25w)= 2 Full term baby= 3 Infant (1y)= 4 Adult man= 6 Obese man= 7 ``` Fetus doesn't need fat because energy from mother

Answer 594

Ghrelin PYY Leptin

Answer 595

10%= impaired immunity, increased infection (10% mortality) 20%= decreased healing, weakness, infection (30% mortality) 30%= too weak to sit, pressure sores, pneumonia, no healing (50% mortality) 40%= death, usually from pneumonia (100% mortality)

Answer 596

Delays in chemical maturation | Can effect IQ

Answer 597

``` Politics Climate Poor water Poor agricultural policy Demand of the developed world Food security will become the biggest public health issue in the coming years ```

Answer 598

Age Change in social circumstances - Isolation - Death of a partner - Poor housing Illness 10% of free living elderly people are under nourished to a degree where their function is effected

Answer 599

David Blaine-> 30% body weight lost Ketones begin to supply energy to brain, muscle supplies amino acids for glucose Body begins energy conservation measures Some brain cells are still dependent on glucose, so a little gluconeogenesis occurs from protein catabolism

Answer 600

``` Weight loss Loss of subcutaneous fat (loose skin on extremities) Muscle wasting Peripheral oedema (no cardiac disease) Glossitis, cracking edges of mouth Hair loss Chronic infections Poor wound healing, chronic wounds, pressure sores Listless, apathetic Recurrent pulmonary infections ```

Answer 601

Reduction in RMR ``` 1. Response to negative energy balance - Hormonal events - Decreased insulin - Decreased T4-> T3= decreased T3 - Glucagon - GH ``` - > - Substrate mobilisation - FFA and AAs -> PASSIVE (weight loss and change in body composition) --- 2. Response to reduced energy flux - Decreased SNS activity and catecholamines - > - Decreased metabolic flux - Decreased energy expenditure -> ACTIVE (decrease in metabolic activity of FFM)

Answer 602

No change in brain Gut and liver have 33% loss of weight Some (5% ) loss in muscle and fat

Answer 603

No change in brain Gut and liver still have 33% loss of weight Large (50% ) loss in muscle and fat (to protect brain)

Answer 604

Kwashiokor | Marasmus

Answer 605

Disease of under nutrition ``` General energy deficit Growth failure No oedema Uncommon to be mental changes Good appetite ```

Answer 606

Disease of under nutrition ``` Relative protein deficit Growth failure Oedema (looks pregnant) Mental changes Poor appetite ```

Answer 607

Thiamine= vitamine B1 Thiamine occurs in the human body as free thiamine and as various phosphorylated forms ``` Thiamine monophosphate (TMP) Thiamine triphosphate (TTP) Thiamine pyrophosphate (TPP) ``` Critical for release and utilisation of energy from food and nerve function Occurs naturally in unrefined cereals and fresh foods, particularly whole grain bread, fresh meat, legumes, green vegetables, fruit, and milk

Answer 608

Beriberi Nervous system ailment caused by a deficiency of thiamine (vitamin B1) in the diet Thiamine is involved in the breakdown of energy molecules such as glucose, and is also found on the membranes of neurones SYMPTOMS Include severe lethargy and fatigue Complications affecting the cardiovascular, nervous, muscular, and gastrointestinal systems

Answer 609

Chronic alcoholics with an inadequate diet (Wernicke-Korsakoff syndrome) Gastric bypass surgery People with diets mainly consisting of polished white rice (low thiamine because thiamine-bearing husk removed)

Answer 610

Vitamin B3 (synthesised from troptophan) Nicotinamide is the derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) 200 enzymes require the niacin coenzymes

Answer 611

Pellagra Thought initially to be an infectious disease as it swept though Europe and the Far East Noted it appeared as staple crop was replaced by maize Not in Mexico because maize was softened with lime-> made niacin bio- available

Answer 612

INTAKE Protein Fat Carbohydrates EXPENDITURE Physical activity Thermogenesis REE= resting energy expenditure (>2/3 of expenditure)

Answer 613

Too much fat, lower carbs | Protein roughly ok but slightly too low

Answer 614

FFM is proportional to REE

Answer 615

Weight Morbidity and mortality BMI (varies by ethnicity) Waist to hip ratio (central obesity)

Answer 616

About 6th in world (1/4 of population are obese) ``` USA= most Japan= least ``` Rising

Answer 617

``` Central obesity (ratio taken of waist circumference and hip circumference) High= at risk of metabolic syndrome of obesity ```

Answer 618

Combination of various conditions which-> more risk of CVD and increasing mortality 1 part is obesity (waist circumference M>102cm, F>88cm) Also: Hypertension (135/80) HDL (M6mmol/l)

Answer 619

``` ENERGY INTAKE Energy per person of food sold fairly constant Increase in fast food outlets Too much fat, not enough carbs Diet composition and weight gain Little ability to store protein and CHO Autoregulation following fat ingestion difficult Satiety complex endocrine regulation ``` ENERGY USAGE Big reduction in energy expenditure over recent years. Difficult to quantify Amish community studies GENES Most obesity not monogenic The amount and site of weight gain is in part genetic Chronic overfeeding in identical twins is associated with better intra-twin than inter-twin correlation of amount and site of gain NB. Obesity genes BRAIN & ENDOCRINOLOGY Important physiological role in postprandial satiety and represent therapeutic targets BEHAVIOUR & CULTURE Individual behaviour and societal changes have contributed to obesity

Answer 620

PPY, Ghrelin and Leptin into hypothalamus (White adipose tissue-> leptin) Hypothalamus - > Energy expenditure AND satienty and intake (insulin) - > White adipose tissue

Answer 621

Lifestyle diet and exercise Pharmacological Bariatric surgery

Answer 622

``` Psychological benefit PCOS and fertility better Oesophagitis (imporved reflux) CHD risk improved Osteoarthritis (better mobility) Liver function improved ``` ``` DIABETES (10% weight loss) Mortality 20% decrease Glycaemic control better Blood pressure Cholesterol levels improve ```

Answer 623

Lifestyle= diet and exercise (needs supervision to work long term) Pharmacological Bariatric surgery Government should do more

Answer 624

Orlistat= prevents absorption of fat (works on lipase enzyme)-> diarrhoea and fatty stool FUTURE Contrave (naltrexone/ buproprione) Oral GLP-1

Answer 625

Adjustable band Sleeve gastrectomy Gastric bypass (shouldn't need diabetes meds anymore)

Answer 626

Improved glycaemic control Occurs immediately after the gastric bypass Change in insulin resistance Change in insulin secretion Changes in gut microbiota Changes in bile salt secretion

Answer 627

MORTALITY Lower cumulative mortality 16 years of follow up than without surgery CV EVENTS Reduces number of total and fatal cardiovascular events

Answer 628

Resolution/improvement of T2DM Resolution/improvement of hypertension Improved lipid profile Resulting in overall reduction in cardiac risk Resolution of obstructive sleep apnoea Resolution of PCOS and improved fertility Reduced cancer related deaths Regression of non-alcoholic fatty liver disease Reduced mortality

Answer 629

BMI >40 kg/m2 with no comorbidities BMI > 35 kg/m2 with comorbidities BMI 30-34.9kg/m2 with a short duration of type 2 diabetes

Answer 630

Sept 2010 report from the Office of Health Economics Direct cost of obesity and related illnesses to the NHS is £4.3 billion a year 1.1 million patients are eligible according to NICE guidelines If 25% had surgery the gain within 3 years would be £1.3 billion

Answer 631

Endoscopically-delivered liner that creates a physical barrier between ingested food and the duodenum/ proximal jejunum EndoBarrier liner prevents the interaction of food with enzymes and hormones in the proximal intestine. In effect, food bypasses the duodenum (without surgery) Can be removed (bariatric surgery can't be undone) Weight loss and improved glycaemic control