Alimentary System: Understanding Nutrition, Immunology & Disease Management

1. Alimentary 2 SachiniRanasinghe

2. Slides available: • https://muslimmedics.co.uk/year-1/

3. Topics to be covered: • Appetite Regulation • Immunology • Cancer of the gut • Nutrition/Clinical Nutrition • Obesity • Control of Function • Hydration

4. Learning Objectives • 1-LSS-ALI-MECH-05: Appetite control: recall the hormones (hypothalamic, leptin, ghrelin, peptide YY) and neuronal populations involved in the regulation of appetite; explain how mutations disrupting these systems can influence energy balance and theories which aim to explain the obesity epidemic • 1-LSS-ALI-IMM-01: MALT and GALT: Define mucosa-associated lymphoid tissue (MALT) and gut-associated lymphoid tissue (GALT) • 1-LSS-ALI-IMM-02: Peyer's patches: recall the structure and function of Peyer's patches • 1-LSS-ALI-IMM-03: IgA: define the role of IgA in the gastrointestinal tract • 1-LSS-ALI-IMM-04: Lymphocyte circulation: explain the circulation of lymphocytes within the alimentary system • 1-LSS-ALI-PATH-18: Irritable bowel syndrome: explain the role of dietary management to treat irritable bowel syndrome • 1-LSS-ALI-PATH-19: Coeliac disease: recall the pathophysiology and dietary management of coeliac disease • 1-LSS-ALI-PATH-17:  Inflammatory bowel disease: explain the dietary management and nutritional significance of inflammatory bowel disease  • 1-LSS-ALI-PAN-05: Pancreatitis: define acute and chronic pancreatitis; recall causes, symptoms and signs, investigations and complications

5. 1-LSS-ALI-PATH-07: Gastrointestinal cancer: list the common sites of cancer in the gastrointestinal system, recall associated cell types, explain clinical features and investigation of gastrointestinal cancer, including oesophageal, bowel and pancreatic • 1-LSS-ALI-PATH-11: Nutritional screening: Recall how nutritional screening is performed and its significance • 1-LSS-ALI-PATH-12: Malnutrition assessment: Recall how to assess for malnutrition clinically • 1-LSS-ALI-PATH-14: Malnutrition management: recall how to manage malnutrition with nutritional support interventions • 1-LSS-ALI-PATH-13: Refeeding syndrome: explain the pathophysiology of refeeding syndrome • 1-LSS-ALI-PATH-14: Malnutrition management: recall how to manage malnutrition with nutritional support interventions • 1-LSS-ALI-PATH-15: Critical care: compare enteral and parenteral feeding and associated problems, and identify reasons for the use of tracheotomy within ICU • 1-LSS-ALI-PATH-16: Short bowel syndrome: identify the nutritional consequences and management options of short bowel syndrome • 1-LSS-ALI-PATH-10: Health eating guidelines: Recall the healthy eating guidelines • 1-LSS-ALI-PATH-08: Energy requirements: identify the energy requirements in exercise and how exercise in extreme conditions impacts on requirements • 1-LSS-ALI-PATH-09: Fuel sources: distinguish between fuel sources for different exercise types and evaluate uses and limitations of supplements • 1-LSS-ALI-PATH-21: Cancer: identify changes that contribute to the development malnutrition in cancer patients • 1-LSS-ALI-PATH-06: Alcohol: recall the biochemistry and metabolism of ethanol, recall the physiological effects of alcohol and the pathophysiological mechanisms of alcohol induced disease, demonstrate awareness of the impact of alcohol on individuals and society and recommended limits of consumption

6. Appetite Regulation

7. HYPOTHALAMUS Appetite control: recall the hormones (hypothalamic, leptin, ghrelin, peptide YY) and neuronal populations involved in the regulation of appetite; explain how mutations disrupting these systems can influence energy balance and theories which aim to explain the obesity epidemic Arcuate Nucleus Paraventricular Nucleus • Appetite regulation largely involves the following: • Hormones • Hypothalamus • Incomplete BBB  access to brain • NPY/Agrp(Medial) • *POMC (Lateral) • *MC4R  when activated decreases food intake. • Axons from arcuate nucleus release neuropeptides that bind to receptors in the Paraventricular nucleus. • Paraventricular Nucleus: • Alpha-MSH acts as an agonist to MC4R • Agrp binds to MC4R and acts as an antagonist, blocking the satiety signal from α-MSH *Known mutations  obesity

8. Long term regulation of Food Intake Adipostat Mechanism Leptin (as a specific example) Made by adipocytes (fat) Circulates in the blood Reaches hypothalamus  appetite and thermogenesis control MORE FAT, MORE LEPTIN • Hormone produced by fat • Hypothalamus detects conc • Hypothalamus increases/decrease food intake CAN LEAD TO OBESITY!!

9. Leptin and Obesity If leptin decreases appetite how is it an issue relating to obesity? • If you have no leptin you will not decrease appetite or increase energy expenditure = FAT • Normal leptin levels but the system just isn’t working – FAT • Fat people can have leptin but cannot respond to it (receptor defect) = FAT *Leptin is only effective as a therapy in congenital leptin deficiency – NOT as a weight loss drug.

10. Short term regulation of food intake • Peptide YY: • Post-prandial hormone • Released in proportion to how much you eat • DECREASES APPETITE • Ghrelin: • Peptide hormone with a fatty acid at position 3 • Basically the opposite of PYY – it is released before a meal • INCREASES APPETITE

11. SBA Which of the following hormones decreases appetite? • Ghrelin • PYY • Insulin • Sodium • Orexin

12. SAQ • Explain 3 mechanisms in which leptin regulation can cause obesity? (6 marks) • Explain how ghrelin works (3 marks)

13. Immunology

14. Quick Recap! • Lots of microbiota in the gut • The epithelium of the gut is an EXTERNAL environment • The gut has a massive SA – why is this good? Bacteria recap: • Millions in mouth • Not many in stomach – why?? • Not many in the SI • Massive beyond ileocaecal valve (into LI)

15. 1-LSS-ALI-IMM-01: MALT and GALT: Define mucosa-associated lymphoid tissue (MALT) and gut-associated lymphoid tissue (GALT) Mucosa associated lymphoid tissue • Found mainly in the mouth e.g. tonsils (M cells) which can initiate an immune response • MALT is a umbrella term for many immunological tissues Gut associated lymphoid tissue Organised – Peyer’s patches • Found in the small intestines and lymphocytes in the lymph nodes Disorganised • Lamina propria lymphocytes  IgA secreting B cells • Intraepithelial cells  lymphocytes below basolateral membrane of the epithelium of the gut

16. 1-LSS-ALI-IMM-02: Peyer's patches: recall the structure and function of Peyer's patches What are Peyer’s patches? • Found in the ileum of the small intestine (highest conc is distally) • Aggregated lymphoid tissue • Mucus  B cells and T cells How is mucosal epithelium specialised? • No goblet cells • No secretory IgA • Lack microvilli

17. 1-LSS-ALI-IMM-03: IgA: define the role of IgA in the gastrointestinal tract Steps in formation of secretory IgA: • 2 IgA molecules are bound by a J chain in the plasma cell • This is secreted into the interstitial space • The dimer binds to a pIgR receptor on the basolateral surface of enterocytes • This receptors Is the secreteory component which binds to IgA SIgA. • SIgA is endocytosed into the epithelial cell and eventually exocytosed into the gut. • TAKE HOME MESSAGE: The secretory component is very important because it protects the antibody dimer from acidic/enzymatic degradation. This means SIgA can bind to pathogens.

18. 1-LSS-ALI-IMM-04: Lymphocyte circulation: explain the circulation of lymphocytes within the alimentary system • Mucosal lymphocytes in Peyer's patches, once stimulated by an antigen, migrate into the local mesenteric lymph nodes and drain into the lymphatic system. • They re-the systemic circulation via the thoracic duct and travel in the blood. • Lymphocyte homing occurs  lymphocytes remain in the blood until activated by tissue-specific endothelial adhesion molecules, which enable migration of the lymphocytes into the gut mucosa.

19. 1-LSS-ALI-PATH-18: Irritable bowel syndrome: explain the role of dietary management to treat irritable bowel syndrome What is it? Describes a pattern of recurrent bouts of abdominal pain in abnormal bowel motility – diarrhoea/constipation. • Abdo pain relieved after pooping NB: NOT the same as IBD because IBD has the same symptoms + ulcers. • Treatments • Diet modifications  avoiding foods e.g. cauliflower, apples • Constipation meds  laxatives • Spasms and pain  anti-diarrheal meds • Control stress and anxiety! Features? • Lactose or fructose, often trigger the symptoms • Diarrhoea or Constipation! • Flatulence due to fermentation of sugars (Farting basically)

20. 1-LSS-ALI-PATH-19: Coeliac disease: recall the pathophysiology and dietary management of coeliac disease • An immune system mediated disorder where gluten triggers the body’s immune cells to attack self-cells in the small intestine. • The main problem is gluten specifically a 33 aa peptide called gliadin. Gliadin is very hard to breakdown! • MOST DAMAGE OCCURS IN THE DUODENUM – crypt hyperplasia and villus atrophy Symptoms • Bloating • Diarrhoea • In children abdo distension and failure to thrive Treatment • Dietary management  gluten-free diet (duh) and medication Note: cross contamination at home and holidays, lifestyle and eating out can affect compliance

21. Why is gliadin a problem? • Gliadin gets into SI via SIgA in the mucosal membrane • Normally anything bound to SIgA is destroyed by immune cells however gliadin binds up to transferrin receptors (these are overexpressed in CD patients) • The complex is transcytosed into the lamina propriae (lining of the gut wall) – basically through the enterocyte • Tissue transglutaminase (TTG) cleaves an amide group from gliadin • Deamidated gliadin is consumed by macrophages and presented on MHC II • Presented to immune cells • CD4+ T helper cells recognise this and release inflammatory cytokines (IFN-gamma and TNF)  destruction of villi in SI.

22. 1-LSS-ALI-PATH-17:  Inflammatory bowel disease: explain the dietary management and nutritional significance of inflammatory bowel disease  Learn the characteristics of both conditions by using this easy table!

23. Crohns Disease • This is an inflammatory bowel disease that causes inflammation in the bowel – classified as an immune related disorder Pathogenesis: • Triggered by a foreign pathogen in the GI tract e.g. listeria • This activates the immune system by antigen presentation. • T helper cells release cytokines (TNF /IFN )  inflammatory response. • Cytokines recruit macrophages which release even more inflammatory mediators which contribute to inflammation

24. Continued.. Facts: • genetic influence • Unregulated inflammation  massive tissue destruction (usually transmural from mucosa to serosa) • Cobbled appearance – inflammation isn’t continuous **ILEUM AND COLON MOST AFFECTED** Treatments: • Immunosupressants • Antibiotics • Diet  liquid diet, low fibre, restriction of diet basically

25. Ulcerative Colitis • A type of inflammatory bowel disease that specifically refers to inflammation in the colon or the large intestine • Characterised by ulcers in the large intestine and rectum • Most common IBD • Symptoms: • Patients experience pain in the Left Lower Quadrant (rectum location) • Severe and frequent diarrhoea +/- blood! • Treatments: • Dietary manipulation to minimise diarrhoea • Pre/probiotics: to treat and prevent pouchitis and helps remission of ulcerative colitis. Prebiotics may cause ab- dominal pain, bloating diarrhoea and flatulence • Diarrhoea: drink fluid, nutritious drinks, replace salt.

26. SAQ • What is the characteristic histological feature of Coeliac Disease? (2 marks) • Name 2 specific inflammatory bowel conditions (2 marks) • State 4 differences between Crohns Disease and Ulcerative Colitis (4 marks)

27. Cancer

28. 1-LSS-ALI-PAN-05: Pancreatitis: define acute and chronic pancreatitis; recall causes, symptoms and signs, investigations and complications • Pancreatitis is inflammatory disease of pancreas  acute or chronic Acute Pancreatitis: • Is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems. • Causes = alcoholism and cholelithiasis • Diagnosis = upper abdo pain, vomiting and abdo tenderness. Ecchymosis on the body wall. Increased amylase/lipase/pancreatic enzymes. Increased bilirubin/liver enzymes/RBCs • MRCP = non invasive investigation of bile duct • ERCP = In patients thought to have severe biliary pancreatitis secondary to gallstones

29. Chronic Pancreatitis • Same definition – just long term • Causes = alcoholism, microlithisasis (sludge) and idiopathic causes. Rare causes - hereditary pancreatitis, hyperparathyroidism, and obstruction of the main pancreatic duct • Diagnosis = amylase, lipase are both normal. Inflammatory markers increase. Pancreatic calcifications on X-Ray • Treatment = similar to acute pancreatitis + fluids and diet restriction (less fat and protein).

30. 1-LSS-ALI-PATH-07: Gastrointestinal cancer: list the common sites of cancer in the gastrointestinal system, recall associated cell types, explain clinical features and investigation of gastrointestinal cancer, including oesophageal, bowel and pancreatic OESOPHAGEAL CANCER Adenocarcinoma Squamous cell carcinoma • Metaplastic columnar epithelium • Lower 1/3 • Acid reflux • Common in Developed countries • Oesophageal squamous epithelium • Upper 2/3 • Acetaldehyde pathway • Developing countries

31. Colon Cancer • ! RISK FACTORS ! • Family history • Uncontrolled uclerative colitis • Age • Previous Polyps • Specific inherited conditions e.g FAP or HNPCC Investigations (tests for diagnosis) • Abdominal X-Ray • Computer Tomography (CT) • Barium enema • Colonoscopy • CT virtual colonscopy Epidemiology • 14% in men, 12% in women • 30000 new cases per year

32. Pancreatic Cancer SILENT KILLER  symptoms not easily detected and therefore late diagnosis. • Probably the worst cancer you can get • 5 year survival is 2% (very very low!) Symptoms: • Depression • Abdo pain • Glucose intolerance • Weight loss • Jaundice • Ascites (accumulation of fluid) • ! RISK FACTORS ! • Smoking • Drinking • Obesity • Family History e.g. MEN

33. SBA • Which of the following cancers is known as a ‘silent killer’? • Stomach cancer • Kidney cancer • Liver cancer • Pancreatic cancer • Lung cancer

34. SAQ • State two differences between Adenocarcinoma of oesophagus and squamous cell carcinoma of the oesophagus? (2 marks) • List 3 causes of chronic pancreatitis? (3 marks) • What does ERCP stand for and what can it be used for? (2 marks)

35. Nutrition/Malnutrition

36. 1-LSS-ALI-PATH-12: Malnutrition assessment: Recall how to assess for malnutrition clinically • Largely through asking the right questions and in conjunction with nutritional screening • Need to be aware that malnutrition costs the NHS billions of £££ - so it’s a massive clinical issue Associated with: • Reduced mobility • Increased risk of falls • Infections • Confusion • Increased hospital admissions NB treatment = nutritional support e.g. high energy food drinks

37. 1-LSS-ALI-PATH-11: Nutritional screening: Recall how nutritional screening is performed and its significance • Nutritional screening is used to assess a patient’s nutritional status and identify those with malnutrition using scores/flowcharts. For example; • Calculating BMI • Assessing special diets/reduced appetite/supplements • GI symptoms (pain/diarrhoea/ constipation) • history of diabetes • functional impairment (exercise tolerance/lethargy/daily activities).

38. 1-LSS-ALI-PATH-13: Refeeding syndrome: explain the pathophysiology of refeeding syndrome • Refeeding syndrome A syndrome consisting of metabolic disturbances that occurs when nutritional support is reinstated in severely malnourished/starved patients Characteristics: • Hypokalaemia • hypomagnesaemia • Hypophosphataemia • thiamine deficiency • salt and water retention

39. Fasting • Depleted electrolyte stores • Refeeding • Increased insulin driving synthesis • Uptake of PO4-, K+ and Mg2+ further depletion  low levels of PO4-, K+ and Mg2+ Cardiac arrythmias and cardiac failure, confusion, convulsions, coma and fatality

40. Treatment for Refeeding syndrome Monitoring: • Urea / electrolytes • Bone profile (calcium and phosphate) • Magnesium levels daily • Additional measures: Parenteral feeding, nasogastric feeds, nil by mouth Dehydration and electrolyte imbalance Many elderly patients admitted are malnourished

41. 1-LSS-ALI-PATH-15: Critical care: compare enteral and parenteral feeding and associated problems, and identify reasons for the use of tracheotomy within ICU In intensive care we need to provide nutrition for patients who cannot eat on their own - either enterally or parenterally. • Enteral = via GI tract • Parenteral = bypasses GI tract e.g. through the blood

43. Tracheotomy • an incision made in the trachea to enable breathing e.g. for patients with obstruction or patients in intensive care

44. 1-LSS-ALI-PATH-16: Short bowel syndrome: identify the nutritional consequences and management options of short bowel syndrome • Short bowel syndrome is when a patient undergoes significant removal of the bowel which leaves less than 100 cm of functional intestinal tract. • Usually for conditions: Crohn’s disease, cancer, ischaemia, ulcerative colitis, irradiation Consequences: • dehydration • malnutrition • malabsorption Management: • To provide adequate nutrition for patients • To ensure adequate water and electrolytes to maintain homeostasis • Correction and prevention of acid base imbalance

45. 1-LSS-ALI-PATH-10: Health eating guidelines: Recall the healthy eating guidelines • Health eating is about reaching nutritional potential. The definition of depends on the context: • - In developing countries: Nutritional security  • - In developed countries: Limiting the development of chronic disease in the developed countries  • Healthy eating is largely to encourage the public to change their feeding habits in order to target the following: • Obesity • CHD • Diabetes • Veg consumption

46. 1-LSS-ALI-PATH-08: Energy requirements: identify the energy requirements in exercise and how exercise in extreme conditions impacts on requirements1-LSS-ALI-PATH-09: Fuel sources: distinguish between fuel sources for different exercise types and evaluate uses and limitations of supplements • Energy requirements of exercise depend on the intensity, duration and type of the exercise being conducted. • Different fuel sources are utilised at varying levels to produce energy in the form of ATP.  Types: Anaerobic exercise: • glycogen  ATP by glycolysis • Phosphocreatine lasts for 20secs of max activity • Lactic acid is produced (by product) Aerobic exercise: • Oxidation of CO and fats produce ATP – the amount produced depends on how intense the exercise is • Low intensity  fat is the preferred substrate • High intensity  CHO is the preferred substrate

47. Muscles • Muscle Anabolism: balancing the breakdown and synthesis of muscle proteins can affect the muscle mass. Muscle protein synthesis > Muscle protein breakdown for hypertrophy/muscle gain Creatine supplementation: • often taken by athletes to increase the contraction time of muscles. • The risks include fluid retention and therefore increased body mass. Can also affect blood flow.

48. 1-LSS-ALI-PATH-21: Cancer: identify changes that contribute to the development malnutrition in cancer patients • Weight change is a common presenting complaint in patients who are ultimately diagnosed with cancer. It is a predictor for outcome in cancer. Reasons for malnourishment in cancer patients: • Iatrogenic  decreased food intake/increased energy expenditure • Chemotherapy  fatigue/nausea/vomiting • Poor symptom control loss of appetite, D/N/V • Increased metabolic rate in cancer patients Cancer cachexia = metabolic response due to the presence of a tumour resulting in catabolic action (this is why cancer patients are anorexic and weak). Nutritional support cannot completely reverse this.

49. 1-LSS-ALI-PATH-06: Alcohol: recall the biochemistry and metabolism of ethanol, recall the physiological effects of alcohol and the pathophysiological mechanisms of alcohol induced disease, demonstrate awareness of the impact of alcohol on individuals and society and recommended limits of consumption • 3 routes of metabolism: • Ethanol  acetaldehyde  acetate • Ethanol  Acetaldehyde via CYP2E1 • Ethanol  Acetaldehyde via NAD+ Metabolism can be influenced by genetics (polymorphisms) and race e.g Asian flush

50. Effects of Alcohol