Digestion

Lymphatic system of the breast

75% of drainage from the breast goes to axillary lymph nodes. 25% drains to the parasternal nodes. Cancer metastasis from breast is most likely to the axilla. Can also spread from breast to breast via parasternal nodes.

Antioxidant vitamins

A, C and E are antioxidants, may counter damage of free radicals such as superoxids, O2rad-, hydroxyl radical OHrad-, reactive nitrogen species NOrad

NME 2.15 Vitamin absorption Fat soluble vitamins

A, D E and K.

Physiological stimulation of chloride secretion by calcium

Ach, Bradykinin, 5-HT, bile acids do this

Physiological regulation

Aldosterone: increases colonic Na absorption - upregulation of ENaC and Na/K ATPase. Increases potassium secretion. Vasoactive intestinal polypeptide (VIP) release from ENS stimulates Cl secretion from crypt cell Cl channels. Increases opening of CFTR etc on apical membrane. Also inhibits absorption in villous cells. Prostaglandins: stimulate Cl- secretion, inhibit absorption in villous cells. Result is imbalance, more likely to get secretory diarrhoea. Gyuanylin: secreted by cells in intestinal mucosa, stimulates Cl- secretion as a response to flush away pathogens.

Cholera

Along with VIP and E.Coli labile form activate cAMP. Toxin produced by Vibrio cholerae Binds to enterocytes brush border, monosialoganglioside (Gm1) receptor. Causes endocytosis, activates adenylate cyclase, increase cAMP, activation of PKA, open CFTR, NaCl secretion and water waters.

Starch digestion

Amylose (plants) -> (via salivary and pancreatic alpha amylase) Maltotriose -> Maltose -> Glucose Amylopectin (plants) and glycogen (animals) -> (via salivary and pancreatic alpha amylase) -> alpha-limit dextrins which have a 1-6 bond in them which the amylase could not cut. This is incomplete digestion at this point by amylase.

Endocrine factors

Angiotensin II increases NaCl absorption (increases Na/H exchange activity). Aldosterone acts in colon to increase Na absorption. These two effects in the gut mirror the effects in the kidney. Somatostatin decreases Ca, increases NaCl absorption, decreases HCO3- secretion

PepT1 substrates include

Angiotensin-converting enzyme (ACE) inhibitors (captopril), B-lactam antiobiotics (cephalexin), Antitumour agent (bestatin), renin and thrombin antagonists, prodrugs (valacyclovir and alpha methyldopa-Phe)

Inflammatory response

Antigen binds to receptor on mast cells in lamina propria below gut epithelia. These mast cells contain vesicles with histamine - when receptor is bound vesicles exocytose to release histamin into interstitium. This can act directly on H1 inflammatory receptors, G protein - cAMp, PKA, Cl channels promote secretion. Histamine can act indirectly by acting on ENS, Ach activates M3 receptors, G proteins, Calcium and Cl channels. Intestinal smooth muscle also stimulated - motility and blood vessel tone. Overall antigen results in secretion of more fluid and increases motility to flush antigen out.

Not a B vitamin, Vitamin C

Ascorbic acid Source: Fruit and vegetables Role: Synthesis of hydroxyproline (collagen synthesis) Deficiency: Scurvy - Bruising, bleeding, impaired healing due to failure of collagen synthesis

Pathological regulation

Bacterial toxins: Cause secretory diarrhoea. 1. Activation of adenylate cyclase, incr cAMP, PKA, phosphorylate proteins, enhanced secretion/decreased absorption: eg. cholera toxin, E. coli heat-labile toxin. 2. Some activate guanylate cyclase, eg. E-coli heat-stable toxin. Binds to guanylin receptor. 3. Opening of tight junctions ZOT - Vibrio cholerae zonula occuludens toxin. Acts on zonula occludens (tight junctions) so allow fluid to pass to lumen more easily.

Contrasts: barium and iodine

Barium meals used for oesophageal visualsation for dysphagia, dyspepsia, hiatus hernia, GORD, bleeding. Single contrast: barium only, sees compression, displacement, dysfunction. Double contrast uses CO2 too to visualise mucosal details. Barium safe within GI tract as isn't soluble to be absorbed, toxic outside so not used in suspected perforation. Iodine used in similar fashion, safe everywhere but airways.

Why does stoma faeces have reduced K+?

Because K+ is secreted by the colon.

Voluntary defecation before 18mmHg

Before pressure that relaxes external sphincter is reached, voluntary defecation can be initiated by voluntarily relaxing external sphincter and contracting abdominal muscles. Flexure of hips etc.

Treatment for diarrhoea

Oral rehydration fluids Adsorbents: Kaolin (chalk) Reduce motility - morphine, loperamide. Inhibit secretion - opiates, NSAIDS Antibiotic and pro-biotic therapy.

Types of diarrhoea

Osmotic diarrhoea: caused by malabsorption Secretory diarrhoea: ion transport defect, imbalance between secretion and absorption. Motility disturbance: insufficient time for absorption.

Micelles

Small, 5nm at most to 20 lipid molecules at least, which allows them to get very close to the enterocyte microvilli. Contain: Monoglycerides, fatty acids, bile salts, cholesterol, fat soluble vitamins ADEK.

B1

Thiamine Source: Grains, pulses, pork, offal Role: Decarboxylation of pyruvate + alpha keto acids Deficiency: Beri-beri

Treatment

Treat diarrhoea, pain, inflammation, steroids like prednisolone, nutritional supplements. As inflammation wanes, fibrotic scar tissue without elasticity of muscle causes ridid tubes, lost motility and blockages. Must get rid of really damaged tissue.

Chaga's disease

Trypanosome infection (a particular genus of pathogen). Destroys ganglia in distal parts of intestine, results in same thing as Hirchsprung's disease.

Trypsin deficiency

Trypsin cleaves pro-peptidases (pancreas) to active form e.g. chymotrypsin. Trypsin deficiency causes marked protein malabsorption - severe diarrhoea, failure to thrive, hypoproteinaemia and resulting oedema.

More lymphatic pathologies: Thoracic duct injury: chylothorax

Type of pleural effusion, accumulation of lymphatic fluid (chyle) in pleural cavity. Can be due to cancer or trauma, caused by thoracic duct leakage, treated by drainage of lymphatic fluid.

Vitamin A

Type: Group of hydrocarbons including retinol, retinal and retinoic acid and provitamin A carotenoids including beta-carotene. Source: animal fat, fish fat, liver. Role: retinal pigment Deficiency: Night blindness

Vitamin D

Type: Hormone. Calciferols. Source: animal fat, fish fat, skin in sun Role: Calcium absorption. Deficiency: Rickets, osteomalacia

Vitamin K

Type: Quinones Source: Plants, gut flora Role: Prothrombin and factor VII, IX, X synthesis Deficiency: Haemorrhagic disease

Vitamin E

Type: Tocopherols Source: Most foods Role: Antioxidant Deficiency: Peripheral neuropathy

UC and Crohn's

UC and crohn's cause moderate to severe inflammation, leads to immune response -leukocytes release reactive O2 species, damage to enterocytes, less nutrient absorption, resulting in osmotic diarrhoea.

Ulcerative Colitis

Ulcerative colitis, always colon and usually rectum. More continuous inflammation.

Ultrasound

Ultrasound utilizes high frequency sound waves to visualize tissues. It is very safe because no ionizing radiation is used and is cheap. Ultrasound is good for visualizing gallstones, the liver and kidneys. However, it is bad for visualizing gases such as those present in the bowel.

Secretory diarrhoea: Two major clinical acute diarrhoea syndromes

Watery, noninflammatory - watery stools, no blood, pus, tenesmus (need to go but nothing happens), little abdominal pain, large volume with dehydration, no damage to intestine so no leukocytes. eg. cholera, enterotoxinogenic e. coli, staphylococcal, norovirus. Inflammatory - damage so mucoid and bloody stools, tenesmus, fever, abdominal pain, small volume, many leukocytes, occult blood. eg. invasive and cytotoxin producing microorganisms, salmonella, shigella (dysentery) invasive E. Coli, C. difficile.

Handling and water electrolytes and with ileostomy

With an ileostomy more fluid is lost, ileum does take on SOME of colon's dessicant role. Colon normally secretes potassium, less potassium is lost without it. Colon can take up 3L water per day, if presented with more you will get diarrhoea. Small intestine, 17L (twice normal amount presented to it).

Describe imaging of GI and hepatobiliary system

X-ray, contrasts with barium (single and double contrast), iodine and endoscopic retrograde cholechopancreatography (ERCP). Ultrasound, computerised tomography and magnetic resonance imagery.

X ray

X-ray: limited use in GI as soft tissue shows up poorly, however chest and abdominal x rays can show blockages or dilation.

Bristol stool chart

Higher numbers up to 7, more fluid. Best is 3-4.

Oral rehydration therapy

Improving fluid balance in diarrhoea. Principle: glucose absorption with NaCl is accompanied by absorption of water. Glucose and galactose taken up into cell coupled with Na in SGLT1. Cl follows Na and water follows NaCl into cells from lumen.

Postassium secretion and absorption

In jejunum and ileum: Potassium absorbed by solvent drag - the NaCl, nutrients and water pull potassium along. Another mechanism in colon: potassium linked to acid exchange (Similar to kidney). H out, K in. Potassium secretion: particularly in colon (net secretion) - can occur by 1. passive route because of the Na absorption system through ENaC: it makes lumen more negative, meaning Cl in drawn along with it OR potassium is draw into negative lumen. 2. also occurs by K channels in crypt cells. Chloride secretion occurs and K is recycled, however K can also leave into lumen via apical channels too. Upregulating/downregulating the amount of these apical channels, as through the action of aldosterone (upreg) can regulate K homeostasis, depends on diet. Similar system in kidney.

More lymphatic pathologies: Lymphadenopathy

Inflammation of lymph vessels + nodes, superficial lymph nodes may be enlarged on examination, swollen lymph nodes can be due to tumour, infection or autoimmunity, commonly seen as non-specific symptom of infection.

Prolidase deficiency

Insufficient prolidase (cytosolic exopeptidase) results in impaired collagen turnover and resulting skin lesions.

NME 2.18: Bowel motility ICC and potential

Interstitial cells of cajal, waves of membrane potential due to sporadic calcium release. This passes through the syncitium (the muscle) sub threshold - little contraction. With stimuli threshold reduction more contraction occurs.

Lactase deficiency

Lactase enzyme in membrane of brush border is not functioning properly - Lactose does not get broken down into constituents, is not absorbed. Lactose in lumen is an osmolyte causes osmotic diarrhoea. Increased stretch on wall increases motility = cramps. Flatulence occurs because bacteria break down the lactose. Breath H2 also increases for the same reason.

Osmotic diarrhoea

Laxatives - Mg salts Non-absorbed food like sorbitol Congenital/aquired disorders of digestion - eg. lactase deficiency, glucose-galactose malabsorption.

Abdominal lymphatics

Mesenteric and inguinal lymph drain into abdominal viscera Nodes located on posterior abdominal wall, often named by adjacent structures. Axillary lymph nodes drain lymph from above umbilicus. Superficial inguinal nodes drain lymph from below umbilicus.

Lipoprotein particle family

(in order of increasing density and reducing size) Chylomicrons are lipoproteins which transport dietary fats (but contain triglycerides, phospholipids cholesterol and proteins) from intestine (exogenous lipid transport in lymphatics, transported to fat and muscle). After deposition of triglyceride cargo in tissues, chylomicrons are known as chylomicron remnants. Cholesterol carrying lipoproteins transport endogenous synthesised lipids which are synthesised and processed in liver and transported to other tissues. VLDL transports fat from liver IDL is intermediate LDL transports cholesterol to tissues HDL removes excess tissue cholesterol

Dietary lipids

-Triesters of glycerol + long chain fatty acids from 16-18 carbons in length. -Short chain fatty acids also, from dairy products. -Phospholipids. These substitute 1 fatty acid chain with a phosphoester of an organic base - choline, inositol, serine, ethalamine. Same as components of plasma membrane.

Osmotic vs secretory diarrhoea

1. Effect of fasting - osmotic diarrhoea stops with fasting, secretory continues. 2. Osmolality - osmotic diarrhoea osmolality higher, most important is osmotic gap. Measure faeces osmolality and amount of ions and take off (Na + K) (times 2 for associated anions). In osmotic diarrhoea the osmotic gap is large because some other osmolyte is causing loss of water. In secretory the secretion of Na/K is responsible so most osmolytes are Na/K so osmotic gap is low.

Aquired causes of CbI malabsorption

1. Gastric surgery and atropic gastrisis - Inadequate release of CbI bound to food. 2. Total gastrectomy - lack of IF 3. Pernicious anaemia (caused by lack of IF related to parietal cell damage) 4. Pancreatic insufficiency - Incompleted CbI transfer from haptocorrin to IF due to lack of pancreatic proteases 5. Zollinger-Ellison syndrome - impaired CbI transfer from Hc to IF because of maintenance of low intraluminal pH 6. Bacterial overgrowth - competition for CbI uptake by bacteria 7. Surgical resection or ileal disease - decreased number of ileal receptors

Membrane bound enzyme action

1. Maltotriose & Maltose -Maltase> Glucose 2. Lactose -Lactase> Glucose & Galactose 3. Sucrose, Maltotriose & Maltose -Sucrase> Fructose & Glucose 4. alpha limit dextrins, Sucrose, Maltose and Maltotriose -Sucrase-isomaltase> Glucose & Fructose

Small intestine pattern of activity 2: Digestive periods

1. Segmentation: (splitting GI into segments, within which materials are shuffled around) Non-propulsive, no net movement of contents down. Uncoordination circular muscle contraction. Dominant pattern, causes mixing and churning for more chance of absorption. 2. Caudal propulsion caused by peristalsis for absorption or elimination in stool.

Exogenous lipid metabolism pathway

1.Bile salts digest lipids into smaller lipid particles 2. Enterocytes absorb, lipids made into chylomicrons. 3. Chylomicrons with more triacylglycerol than esterified cholesterol transported into lacteals (lymphatic capillaries in small intestines) 4. Apolipoproteins attach to chylomicron. CII activates lipoprotein lipase which hydrolyses tracylglycerol to fatty acids and glycerol. 5. Chylomicrons deposity fatty acids and glycerol to tissues, chylomicron remnants remain and return to liver or to lacteal where other apolipoproteins are added to form HDLs, forming a cycle.

Stool fluid excretion in health

100-200ml

NME 2.12: Lipid digestion and absorption. Bile salts.

Bile salts emulsify lipids to increase their surface area for pancreatic lipase enzyme action in water - it can only act at the oil/water interface so splitting into small drops in suspension (emulsifying) and stabilising the lipid throughout the water solution increases this surface area contact. Monoglycerides and free fatty acids form. All stabilised into micelles. Enterocyte absorbs monoglycerides + fatty acids, reesterification to triglycerides - from these we get absorption.

Biotin

Biotin Source: Liver, yeast Role: Carboxylation Deficiency: neurologic changes

How is cellulose broken down

By colonic bacteria (not taken into body) into organic acids and gas

NME 2.20: Carbohydrate absorption Key points in carbohydrate absorption

Carbohydrate only absorbed as monosaccharides. Absorption in small intestine, primarily proximal, more or less complete by end of jejunum. Colonic bacteria utilise undigested carbohydrates, produce short chain fatty acids for our use.

Defecation reflex: Constipation

Causes: Low dietary fibre. (Water stays with fibre, partly digested by colonic bacteria, bulk also present to promote peristalsis). Behavioural - poor habits. Pregnancy (progesterone). Old age, due to reduced muscle function in gut. Psychological effects: depression, anxiety.

Chloride absorption and secretion

Cl can move passively in small and large intestine through channels and paracellularly, both following Na, Na removed by Na out K in ATPase. Cl also moved in due to action of Cl in, HCO3- out transporter, using H2O and CO2 and carbonic anhydrase. Cl then removed to basolateral side. Some secretion of Cl occurs in crypt cells. Unlike other secretory cells, basolateral Na/2Cl/K in cotransporter. K and Na removed by channels. Cl builds up in cell and free movement of Cl into lumen by CFTR and similar channels occurs. Na follows paracellularly, water follows these osmolytes out. The secretion (1L) is masked by dominant fluid absorption (7L)... However this system is the target for diarrhoea causing bacteria and drugs.

B12

Cobalamin Source: animal products only Role: Coenzyme in amino acid (homocysteine:methionine methyltransferase metabolism. Deficiency: Pernicious anaemia (megaloblastic) Liver storage lasts 1-3 yrs.

B vitamins

Coenzymes - cofactors in key enzymic processes B1 - thiamine B2 - riboflavin B3 - niacin B6 pyridoxine B12 cobalamin Biotin Folic acid Pantothenic acid

Colectomy and ileostomy

Colectomy - Complete removal of the colon. Ileostomy - ileum pulled through to surface and folded back on itself to expose the luminal side then sewed down. Ileum itself can take on some colonic functions. Can also do ileorectal anatamosis if rectum is okay. Stoma bag collects waste.

CT

Computerised Tomography (CT) scans use very high doses of X-rays to visualize cross-sections of the body. They are highly detailed and are able to resolve structures that conventional radiographs cannot. CT is useful in staging malignant diseases and monitoring response to therapy and provides good pre-operative information.

Hirchsprung's disease

Congenital absence of submucosal and myenteric ganglia in distal intestine: rectum and colon. Internal anal sphincter does not relax after rectal distension (mass movement into rectum normally initiates reflex to open sphincter). Leads to constipation and megacolon (build up increases colonic diameter).

Lymph node histology

Cortex consists of tightly-packed lymphocytes arranged in follicles. Afferent vessels supply nodes with lymph and antigen. Efferent vessels drain lymph to venous blood.

Case 13 - A Young Woman With Violent Diarrhoea Crohn's disease

Crohn's disease can affect any part of the gut from mouth to anus, most commonly terminal ileum, usually colon but not always, with effects on rectum unlikely. See inflammation, narrowing of lumen, blood. Vitamin B12 and bile salts absorbed, reduction in bile salts = fat malabsorption and steatorrhoea. Discontinuous inflammation. Can affect anywhere so can affect any digestion.

Defects in transporters

Defect in system B = Hartnup disease. Autosomal recessive, defective neutral amino acid transport at apical membrane. Neutral aminoaciduria, loss of neutral amino acids in urine because we have same in kidney. Example tryptophan, pellegra-like symptoms as Trp is used to make niacin. Bo+ and bo+ (Na coupled and not) = cystinuria Autosomal recessive. Defective apical, increased urinary secretion of cystine (causing stones) and cationic amino acids. No nutritional imbalance as absorption in di/tripeptide form compensates. y+ = Lysinuric protein intolerance Autosomal recessive, rare, more serious. Defective cationic amino transport, system y+L, cationic amino acids can't leave cells. Causes cationic aminoaciduria - vomiting, diarrhoea, coma when fed protein. Arginine and ornithine deficiency, restricted urea cycle (hyperammonaemia) Lysine deficiency as it can't be synthesised - skeletal and imunological abnormalities. Restrict protein in diet, supplement with citrulline (neutral)

Glucose-galactose malabsorption

Defective SGLT 1. This prevents intake of glucose and galactose coupled with Na. Fructose absorption is unaffected as it passes through GLUT5. Glucose and galactose stay in lumen and cause osmostic diarrhoea and cramps and flatulence. Increased breath H2 due to bacterial breakdown.

Water soluble vitamin absorption: two examples. First is folate

Dietary form is pteroylheptaglutamate. Hydrolysed by jejunal brush border conjugase enzymes in membrane to pteroylglutamate (individual units). A folate transporter (anion exchanger folate/OH) moves across luminal membrane by facilitated diffusion. Intracellular reduction and methylation to 5-methyl-tetrahydro-folate maintains concentration gradient. Tetrahydrofolate is active form.

Paracrine factors

Distension of the gut, 5-HT release increases secretion. Immune cells: lamina propria, histamine direct and indirect via ENS

Sodium absorption

Duodenum and jej: pH Microclimate. Na absorbed, exchanged for H+ out in proximal small intestine. Na kept out of cell by Na out, K in ATPase. In jejunum and ileum, (nutrient coupled Na absorption) most Na absorption is coupled to nutrients like glucose and AAs. Again Na/K ATPase keeps Na balance. In ileum and prox. colon (electroneutral Na absorption) - again H out, Na in exchanger. In addition Cl in HCO3- pump results in net HCO3- secretion. (The H and HCO3- come from CO2 and H2O being converted by carbonic anhydrase.) The Na gradient is maintained by Na/K pump. Colon: (electrogenenic Na absorption) ENaC sodium channel moves Na in, Na out K in ATPase on basal side absorbs Na.

Which part of intestine absorbs most fluid? order

Duodenum and jejunum, then ileum, then colon. (it is in order)

Linear or branched, which is easiest to digest? Why?

Easily digest linear, partially digest branched. Linear = alpha 1-4 glycosidic bonds. Branched = alpha 1-6 bond. Amylase can't cut 1-6 bonds or any 1-4 bonds also with a 1-6 attached.

Absorption and rate limiting step for lipid absorption and maintenance of gradient

Emulsion droplets become unilaminar droplets which become mixed micelles. These micelles, which can become almost pure bile salt containing by the end, diffuse across from the bulk phase in the intestinal lumen into the aqueous unstirred layer at the enterocyte surface. From this layer the lipids are absorbed. The rate limiting step is the unstirred layer as the lipids are not freely soluble in water so are unlikely to enter. The surface of the small intestine is about 6, slightly acidic, a pH produced by Na/H exchanger and required for small peptide absorption. This acidic environment also allows fatty acids to leave micelles. Monoglycerides and fatty acids can transfer by free diffusion, fatty acid transporters also help. The concentration gradient utilised means that as enterocyte conc increases with absorption, re-esterification occurs to keep conc gradient going.

Lipoprotein properties

Enable lipids to be transported through aqueous environment of body fluids. Synthesised mainly in liver hepatocytes and also in intestines. Change composition and proteins present throughout route as components are taken up by tissues. Lipoprotein remnants then return to liver. They have apolipoproteins.

50% of protein absorption is from where?

Endogenous sources - enzymes, mucins, desquamated cells of GI tract = recycling

Contrasts: ERCP

Endoscopic retrograde cholechopancreatography (ERCP) evaluates the biliary tree and pancreatic ducts - a contrast medium is inserted through a catheter.

E. Coli (heat stable)

Enterocytes have Cl transports, CFTR and others. E coli acts on guanylin receptor, increases cGMP to activate Cl- channels.

Enterokinase deficiency

Enterokinase (duodenal mucosa) cleaves trypsinogen (Secreted by pancreas) to trypsin. Enterokinase deficiency presents as trypsin deficiency.

Secretory diarrhoea

Enterotoxins - escherichia coli, cholera. Laxatives - Dioctyl sodium sulfosuccinate, rinoleic acid (castor oil), aloe. Hormone secreting tumours - VIP or serotonin. Medications side effects (cholinergics, beta blockers, ace inhibitors) Allergy - IBD, inflammatory bowel disease.

Control of motility: extrinsic factors

Extrinsic factors: Parasympathetic NS - Ach (muscarinic receptors) is excitatory. Sympathetic NS - NE (Beta receptors), inhibitory. Beta blockers cause diarrhoea as they prevent this inhibition. Sphincters: Beta = relaxation, alpha = contraction. Presynpatic interneuron: alpha = inhibits Ach release.

Differences in vitamin storage

Fat soluble: stored, deficiency has a time delay Malnutrition is a common cause of deficiency, ie. general lack of food not specific foods. Problems with fat absorption (including liver disease) affects these vitamins. Overdosage can be toxic, concern Vitamin A in pregnancy ie. from eating liver. Water soluble: not stored but enough to last 6-12 months, ie. vitamin B12 injections needed in ileal resection. Readily excreted in urine. Generally due to overall malnutrition again not single food missing, things like scurvy rare today.

Folic acid

Folic acid Source: Liver, greens, yeast Role: Synthesis of purines and thymine Deficiency: Megaloblastic anaemia

Vitamin B12 (cyanocobalamin)

Gastric phase - Pepsin liberates B12 from food, which binds to salivary or gastric haptocorrin (R proteins) to prevent bacterial absorption. Intestinal phase - Haptocorrin is then digested by pancreatic proteases. B12 binds to gastric intrinsic factor, produced by parietal cells, when it moves into the duodenum at a neutral pH. The IF-b12 complex is resistant to breakdown digestion. The IF-b12 complex binds to an IF receptor in the ileum. The complex is internalised and B12 liberated. B12 is then transferred to transcobalamin II in the cell and secreted across the basal membrane into mesenteric veins. Travels as TCII-B12 in the blood.

Protein absorption

Gastric phase: Dietary protein + pepsin -> polypeptides and amino acids. Intestinal luminal phase: Polypeptides + Trypsin, chymotrypsin, elastase, carboxypeptidase A and B = Oligopeptides + AAs Intestinal brush border phase: Oligopeptides + Brush border peptidases -> Di/tri peptides + AAs Intestinal intracellular phase: Di/tripeptides + Cytosolic peptidases -> AAs

Ceoliac disease and case round up

Gluten causes damage to villi. Anaemia: Iron insufficiency, low ferratin (which stores iron in the liver and heart) and low folate levels caused the microcytic-hypochromic anaemia. ADEK fat soluble vitamin absorption inhibited due to damaged villi. Lack of vitamin D absorption due to damaged villi, resulting in prolonged PT. Vit K insufficiency means that there is a lack of active clotting factors II, VII, IX and X. This leads to abnormal bruising and abnormally long PT. The triolein breath test uses C13 or C14 to test for fat malabsorption in diseases such as pancreatic dysfunction, celiac disease and CF. Ankle oedema is caused by low oncotic pressure from reduced albumin due to protein malabsorption.

NME 2.22 Water and electrolyte absorption Cells in colon crypts

Like in small intestine cells begin at crypt base and migrate up, changing role. More goblet in cells in colon, dried faeces requires more lubrication. Microvaculated columnar cells are lymphocyte like for immunity. Stem cells are responsible for replacement due to sloughing of cells. Endocrine cells are also present.

Problem with bile salts and lipases

Lipase works from the aqueous phase to digest triglycerides. Bile salts required to increase lipid surface area and produce micelles but they also inhibit the activity of lipase. This catch-22 is broken by the action of colipase at it prevents the inhibition of lipase by bile salts while allowing it to solubilise the lipid.

NME 2.13: Lympatics and lipid transport

Lipid transport into lymphatics, into blood via chylomicrons and lipoprotein lipase breaks these down into fatty acids and glycerol, constituents of triglycerides. Fatty acids end up in tissues, used as energy source, can't be used be brain.

Diarrhoea definition

Loss of fluid and electrolytes of greater than 500ml per day from GI.

Lymphatic flow

Lymphatic flow aided by peristalsis of surrounding intestinal wall (no muscle associated with lymph itself) hydrostatic pressure causes opening (expansion phase) and closure (compression phase) of lymphatic valves.

Lymphatic system composition

Lymphatic vessels, nodes along the way filter foreign particles from lymph. Thymus - T cells production. Spleen - immune response, filtering foreign particles from blood. Lymphoid tissues in tonsils, bone marrow, GALT in GI tract, lymphocytes in blood etc. involved in blood. Organs have plexuses which drain into lymphatic vessels. Major lymphatic sac in abdomen is cisterna chyli, part of lymphatic duct. Most lymph drains through the thoracic duct into the venous system.

MRI

Magnetic resonance imaging uses magnetic influence on the spin of hydrogen nuclei to create an image. It provides images in high detail.

Triglyceride resynthesis

Maintains diffusion gradient. Re-esterification of long-chain fatty acids, triglycerides tansferred to chylomicrons and VLDL. Occurs in smooth endoplasmic reticilum - together with protein from rough ER, joined in golgi to form chylomicrons which enter lymphatics. Lymphatics appear milky white due to fat entry. Bypass liver, thoracic duct to circulation. Glycerol and short/medium (less than C12) transferred as FFAs to portal circulation, transported bound to albumin. Go straight to liver.

Lymph node structure

Major site of lymphocyte exposure to antigens. Bean-shaped. Surrounded by a capsule with an outer cortex and an inner medulla. A few mm in length when inactive but enlarged during immune response. Blood supply and drainage form capillary networks.

Lymphatic pathologies 1

Metastases of malignant tumours: Metastasis can occur by seeding of membranes eg. pleura, peritoneum, seeding of blood or lymphatic system. Lymphatic metastasis is most common, spread can be predicted by lymphatic flow direction. Lymphoedema: Retention of fluid caused by dysfunction in lymphatic fluid drainage. Most common in lower lymphs, progresses with age, treated by complete decongestive therapy (CDT) - manual lymphatic drainage, compression bandaging, massage + exercise.

Control of motility: intrinsic factors

Motor neurones of ENS Excitatory: Ach, Substance P. Inhibitory: NO, VIP, ATP. Sensory and enteric interneurones: bolus stretch mechanoreceptors, bacteria etc. activate inhibitory neurones ahead (Ach, Substance P: relax) and excitatory neurones increase membrane potential behind (contraction).

B3

Niacin Source: Meat, liver, grains, pulses Role: Nicotinamides like NAD and NADP Deficiency: Pellegra (skin), nerve bowel, mental disorders

Large intestine pattern of activity:

No difference in motility in fed or fasted state - constant patterns. (1) Haustration - Churning with a small caudal movement - like segmentation, non propulsive. First three roles of colon: 1. Fermentation by bacteria produces short chain fatty acids (symbiotic relationship.) 2. Dessication of stool. 3. Storage of faecal material until it's convenient to remove it. Dominant pattern of activity. (2) Mass peristalsis. 4th role of colon: Elimination. Sequential haustration. Mass movements of about 20cm. Only occurs 1-3 times per day.

Colonic fermentation

Non-starch polysaccharides are not digested in small intestine. eg. cellulose & pectin. Cellulose (glucose beta 1-4 bonds) amylase can't act on. Pectin composed of oxidised galactose (glucoronic acid). Since we can't digest these colonic digestion by bacterial enzymes produces short chain fatty acids (useful), hydrogen and methane. More breath H2, more colonic fermentation = measure of this.

Treatment for diarrhoea

Oral rehydration fluids -Absorbants - kaolin (Chalk) Reduce motility: -(morphine and opiate analogues like loperamide) -Atropine Inhibit secretion -Opiates

Di/tripeptide and amino acid absorption

Overall process is secondary active transport. Heart drugs may interfere with it. About 50% of protein absorption is as small peptides, kinetic advantage over single AAs as the transporter brings one molecule at a time, so the peptide transporter is more efficient. 1. Na in, H out transporter called NHE3 secretes acid. 2. Na out, K in ATPase removes Na from cell to basal side to maintain this. Heart drugs can interfere. 3. Low pH under mucosa layer, lower pH than cell. H+ gradient is the basis for AA and di/tripeptide transport. PepT1 is a (di/tri) in, H+ in cotransporter. PAT1 is an amino acid in, H+ in cotransporter. Finally amino acids may also be brought in coupled to Na. 4. Cytoplasmic peptidases further break down di/tripeptides. At the basolateral side of the enterocyte AAs are removed by a number of diffusion transporters. Di/tripeptide transporter is unknown.

CF

Pancreas fails to provide pancreatic amylas to digest starch. Salivary amylase only, without enzyme supplementation you can get carbohydrate malabsorption.

Pantothenic acid

Pantothenic acid Source: Most foods Role: It is coenzyme A, crucial in carbohydrate and fat metabolism Role: "General illness"/malaise

Small intestine pattern of activity 1: The interdigestive state (fasting)

Pattern is migrating myoelectric complex (MMC) set by ENS. Essentially slow peristaltic waves. 1. Prolonged period of quiesence. 2. Rising activity to a peak (associated with a rise in motilin), 3. A decline to another quiescent period. over about 90 minutes. This slow wave moves contents slowly down to colon, pushing bacteria and desquamated cells downwards. Also larger particles are able to pass pylorus in this state. MMCs are suppressed by feeding through vago-vagal reflexes, GI hormones gastrin, secretin, CCK (caused by food contents leaving stomach to small intestine).

Crohn's questions case round up

Pepsin in gastric acid releases B12 from food, salivary/gastric haptocorrin (r-protein) binds. Intestinal phase: haptocorrin digested in neutral pH by pancreatic proteases, intrinsic factor from parietal cells of stomach binds to B12 to form IF-B12 complex resistant to breakdown. IF binds to receptor on terminal ileum enterocyte. Broken into IF and B12, B12 travels as B12-transcobalamin II in blood. Describe the features of the enterohepatic circulation. Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs, or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver via hepatic portal vein. Steatorrhoea may be caused by the lack of bile salts/acids in the small intestine. If there is interruption of the enteroheptaic circulation, bile salts may not be secreted or reabsorbed by the small intestine and, as a result, fat is not digested and passes in the stool.

Lead up to defecation

Presence of food in stomach causes gastro-colic reflex. Presence of chyme in duodenum activates duodeno-colic reflex. These trigger colonic mass movement. This fills rectum. Enteric, autonomic and conscious control. 1. Distension of rectum. 2. Rectum accommodates. Urge to defecate 3. Senses contents. 4. Triggers, via the rectosphincter reflex, relaxation of internal anal sphincter. 18mmHg for urge to defecate, if ignored builds to 55mmHg - voluntary defecation is overriden. Reflex response via ENS is relaxation of internal anal sphincter. External anal sphincter is under voluntary control, pudendal nerve. If waiting long enough, faecal material moves back into colon.

Drugs affecting motility

Prokinetics: Presynaptic adrenergic block (blocks sympathetic action). Laxatives: Mg2+ salts (osmotic), lactulose (osmotic), senna and castor oil (stimulate secretory pathways, inhibit absorption) - all of these increase fluid and bulk. Opposite: opioids, loperamide, act like endogenous enkephalin, reduce peristalsis.

B6

Pyridoxine Source: Most foods Role: Transamination in synthesis of amino acids Deficiency: Skin lesions, convulsions

High risk groups for infectious diarrhoea

Recent travel, unusual food/food hygeine, day care (contact with children), institutionalised people like in nursing homes.

Lipid malabsorption

Results in steatorrhoea. Luminal side: Pancreatic deficiency - reduced lipase. Bile acid deficiency - reduced micelles. This can include liver disease, biliary obstruction (gallstones, tumour), bacterial overgrowth in small intestine (increased bile acid metabolism reducing its effectiveness, remember secondary bile acids produced by bacteria. One example is intestinal diverticular disease, outpouche provides stagnant contents for bacterial growth, another example is being achlorhydric,reduced parietal acid production prevents bacterial destruction), ileal disease or resection preventing bile salt reuptake. Non-luminal side: Chylomicron formation deficiency - abetalipoproteinaemia. Lympathic deficiency - congenital lymphangiecstasis & Whipple's disease.

B2

Riboflavin Source: Most foods Role: Flavin nucleotides like FAD and FMN used in many reactions Deficiency: Sore mouth, normocytic

Thoracic lymphatics

Right and left bronchomediastinal lymphatics drain lymph from each pleural cavity. Right lymphatic duct drains into the -> right venous angle (of the right jugular and subclavian.) On the left the lymph drains into the thoracic duct.

ENS

Secretagogues (eg Ach, 5-H5, VIP) or cAMP in crypt epithelia to increase Cl secretion. Enkaphalins and norepinephrine decrease Ca2+, increase Na (and therefore Cl) absorption and reduce HCO3- secretion. Morphine can act like these and decrease both motility and increase absorption = excessive drying with low motility = constipation. Anti-diarrhoeals.

Chylomicrons

Small (75-100nm) lipoprotein particles. Mostly triglyceride to keep gradient then bundle with phospholipid and cholesterol and protein coat. Apoproteins target chylomicrons towards end tissues.

Lipid digestion

Some occurs in stomach due to bile reflux, most in duodenum. Emulsification: fat droplets - 1micrometre -Lipid plus bile salts. Core lipids are at the centre of the droplet with adsorbed layers of biliary lipids and lipases which digest them. Digestion: pancreatic lipase, co-lipase, cleaves 1 or 3 linkage to give 2 free fatty acid chains and a single 2-monoglyceride (glycerol with central fatty acid) Isomerisation of the 2-monoglyceride occurs in 30% of cases to produce a glycerol and further fatty acid. Digested lipids are budded off into vesicles called mixed micelles with a variety of lipid contents and vitamins (pure micelle would be just bile salts, this is mixed). Phospholipases also break down phospholipids.

Apolipoproteins

Stabilise lipoprotein structure: eg ApoB in chylo, VLDL and LDL. Act as ligands for lipoprotein receptors: ApoB for LDL. ApoE for IDL. Regulate enzymes that metabolise lipoproteins: ApoC-II in chylomicrons.

Breakdown by membrane bound enzymes and transport across membrane for starch and glycogen

Starch and glycogen are broken down by amylase to maltose. Maltase breaks this into two glucose. These are taken up by SGLT1, a secondary active transporter using Na influx gradient. Gradient maintained by Na/K pump using ATP. Lactose -> lactase -> glucose and galactose -> SGLT1 Sucrose -> sucrase -> fructose and glucose. Glucose -> SGLT1 but fructose -> GLUT5 (facilitative transporter, no energy just gradient of fructose. Conc builds up in lumen, transporter opens and facilitates flow) Basolateral membrane - all three monosaccharides (glucose, galactose, fructose) via GLUT2 down concentration gradient due to build up in the cell.

Sucrase-isomaltase deficiency

Sucrose isomaltase enzyme is the only one to break to the 1-6 branched bonds of alpha-limit dextrins. Defect = no digestion, reduced glucose production, alpha limit dextrins remain in lumen. Cramps, flatulence, diarrhoea, H2.

Pathological alterations to fluid in lumen

ie. in inflammatory bowel disease Nutrient malabsorption - osmotic Intestinal hypermotility ie. via distension or susbtances which increase peristalsis Congenital chloride diarrhoea - Cl malabsorption (Cl/HCO3 exchanger fault) - imbalance between absorption and secretion, diarrhoea. More common in Kuwait, 1 in 3000. Pancreatic cholera - Verner-Morrison syndrome (VIP secreting tumour). VIP inhibits absorptive processes, promotes secretory, cholera-like diarrhoea, achlorhydria (decreased HCl secretion by stomach as VIP acts to stop it) and hypokalaemia (acts on absorptive processes). Excess gastric acid secretion: Zollinger-Ellison syndrome (gastrin tumour) Excessive acid decreases lipase activity (due to low pH) leading to fatty stool and diarrhoea.