Module 5 GI Professor Student Version Final 2024 PDF

Gastrointestinal Disorders Module 5 November 6,7, 2024 Overview- Wed. November 6th Time Topic Duration 6:00-6:05 Time-check in, Module 4 quiz review 5 minutes 6:05-6:30 Normal GI System ov...

Gastrointestinal Disorders Module 5 November 6,7, 2024 Overview- Wed. November 6th Time Topic Duration 6:00-6:05 Time-check in, Module 4 quiz review 5 minutes 6:05-6:30 Normal GI System overview 25 min Diarrhea (mini quiz), Constipation, Irritable Bowel Syndrome Diverticulitis, Appendicitis, Inflammatory Bowel Disease- mini quiz 6:35-6:55 Clinical Consult- GERD, H Pylori 15 min + 5 min Gui Li (Lacey) 7:00-7:20 Clinical Consult-NSAID on the gut 15 min +5 min Jaskirat Duhra (Jas) 7:25-7:30 Wrap up- GERD. Hiatus Hernia 5 min Gastritis and Peptic Ulcer Disease, H Pylori 7:30-7:45 Break 15 min 7:45-8:05 Clinical Consult- Hepatitis B 15 min + 5 min Sandeep Kaur 8:10-8:30 Hepatitis, 20 min Gallbladder and Pancreatic Disease, Gastrointestinal Cancers 8:30-8:45 Practice Quiz 15 min 8:50-9:00 Wrap up 10 minutes 2  Overview- Thurs. November 7th Time Topic Duration 10:00-10:10 Time-check in 10 minutes 10:10-10:25 Normal GI System overview 15 min Diarrhea, Constipation, Irritable Bowel Syndrome Diverticulitis, Appendicitis 10:30-10:50 Clinical Consult- GERD, H Pylori 15 min + 5 min Brandon Miller 10:55-11:15 Clinical Consult-NSAID on the gut 15 min +5min Dana Bell 11:20-11:30 Wrap up- GERD. Hiatus Hernia 10 min Gastritis and Peptic Ulcer Disease, H Pylori 11;30-11:45 Break 15 min 11:45-12:05 Inflammatory Bowel Disease (mini quiz) 20 min Hepatitis 12:10-12:20 Gallbladder and Pancreatic Disease, Colorectal Cancers 15 min 12:25-12:45 Practice Quiz 20 min 12:45-13:00 Wrap up 15 minutes 3  Pulmonary Hypertension Progression The normal pulmonary artery systolic pressure is 20 mm Hg or less, and the normal mean (average) pulmonary artery pressure is 12 mm Hg. A number of disease processes affect the pulmonary circulation and increase the pressure levels in the pulmonary arteries and right ventricle. If these pressure elevations are sufficiently severe or sustained, right-sided heart failure may develop. The Digestive System 5 Functions of GI system The GI system carries out at least four major functions: Digestion of food, Absorption of nutrients, Secretion of hormones, and Defense against pathogens. 6 Supporting resource Human Digestive System- Animation Video https://www.youtube.com/watch?v=X3TAROotFfM 14 minutes 7 Wall of the Gastrointestinal (GI) Tract- 4 layers 8 Intestinal wall- Small intestine Small intestine- lots of villi to increase surface for absorption https://www.youtube.com/watch?v=X3TAROotFfM 9 Wall of the Large Intestine (Colon) 10 https://www.youtube.com/watch?v=X3TAROotFfM Lecture slide 11 The Stomach 12 13  Enteric Nervous System Enteric Nervous System (ENS) (intramural or intrinsic to the GI system) Myenteric (Auerbach’s) Plexus Submucosal (Meissner’s) Plexus Normal digestive function requires links between the intrinsic ENS system AND externally to the Central Nervous System (CNS) Myenteric Plexus: Motility- longitudinal and circular muscle layer (peristalsis) Submucosal Plexus: Involved with local conditions and controls local secretion & absorption, and local muscle movements. The mucosa and epithelial tissue associated with the submucosal plexus have sensory nerve endings that feed signals to both layers of the enteric plexus and to the CNS 14 Current Programs of Research Mechanisms of microbiota-gut-brain communication The effect of antibiotics in early-life on brain function and behaviour Supplemental information 15 Learning Compare and contrast osmotic and secretory diarrhea Outcomes Describe the pathophysiology of constipation Diarrhea, Explain the hypothesized Constipation pathophysiological mechanisms and Irritable and known clinical manifestations Bowel of irritable bowel syndrome Syndrome  Mini quiz – Choose the correct type of diarrhea Characteristic of Diarrhea Osmotic Secretory Diarrhea Diarrhea 1 Loss of electrolytes and water into intestinal lumen 2 If you fast, diarrhea does will improve 3 Usually < 1 L/day fluid loss Can result from: 4 Rotavirus (especially in children < 5 years of age) 5 Ingestion of poorly absorbed ions or sugars (e.g. lactose, fructose, sorbitol) 6 Luminal secretagogues (such as bile acids or laxatives), 7 Celiac disease 8 Antibiotics by destroying the normal intestinal bacteria. 9 Reduced absorptive surface area following bowel surgery 10 Bacterial toxins (infection with an enterotoxin (e.g., Escherichia coli, Cholera) Type in “O” or “S” into the chat box as we go through the questions  Diarrhea Osmotic diarrhea Secretory diarrhea Due to the ingestion of poorly Due to disruption of epithelial absorbed ions or sugars electrolyte transport. Cause osmotic gradient and then If you fast, diarrhea does not water follows improve Only draws water and not Loss of electrolytes and water electrolytes Stool high in sodium and potassium If you fast, diarrhea improves Usually >1 L/day fluid loss Usually < 1 L/day fluid loss “Severe” “Ordinary”  Diarrhea- examples of causes Osmotic Secretory Certain foods, and sugar Bacterial toxins (infection with substitutes in dietetic foods, an enterotoxin (e.g., candy, and chewing gum (for Staphylococcus, Escherichia coli, example, hexitols, sorbitol, and Cholera) mannitol) Reduced absorptive surface area Lactase deficiency caused by disease or resection, Celiac Luminal secretagogues (such as An overgrowth of normal bile acids or laxatives), intestinal bacteria or the growth Various hormones (produced by of bacteria normally not found in cancer ) the intestines. Antibiotics can Drugs, and poisons, and medical cause osmotic diarrhea by problems that compromise destroying the normal intestinal regulation of intestinal function. bacteria. Vibrio Cholerae (Cholera) V. cholerae releases a toxin that binds to ganglioside receptors on the surface of intestinal epithelium cells This toxin is internalized by endocytosis and triggers the production of cyclic AMP (a second messenger) within the cell Cyclic AMP (cAMP) activates specific ion channels within the cell membrane, causing an efflux of ions from the cell The build up of ions in the intestinal lumen draws water from cells and tissues via osmosis – causing acute diarrhea  Supplemental Resource https://www.youtube.com/watch?v=Gip_wVJAd94&t=9s 8 minutes Bristol Stool Chart https://uomustansiriyah.edu.iq/media/lectures/2/2 _2018_02_02!08_48_55_AM.pdf  Constipation is difficult or infrequent defecation. Constipation means: A decrease in the number of bowel movements per week, Hard stools, Constipation- Straining, Definition Abdominal pain, and Difficult evacuation. The definition of constipation must be individually determined because normal bowel habits range from one to three evacuations per day to one per week.  Primary Constipation-Causes Constipation can occur as a primary or secondary condition. Chronic idiopathic or primary constipation is generally classified into three categories. Overlap may exist between these three classifications, and the classifications are not mutually exclusive. A. Functional constipation- defecation normal rate of stool passage but difficulty with stool evacuation. B. Slow transit constipation (STC)- impaired colonic motor activity with symptoms of infrequent bowel movements, straining to defecate, mild abdominal distention, and palpable stool in the sigmoid colon. C. Constipation-predominant irritable bowel syndrome (IBS-C)- associated with chronic constipation and abdominal pain. Lack of access to toilet facilities, consistent suppression of the urge to empty the bowel, pelvic floor dyssynergia, and dehydration may be other causes of primary constipation.  Constipation- Secondary Diet Medications Neurogenic disorders in which neural pathways or neurotransmitters are diseased or degenerated, resulting in altered or delayed colon transit time. Structural- Rectal fissures, strictures, or hemorrhoids also may cause constipation. Neurological: multiple sclerosis, Parkinson's disease, spinal injuries, and the neuromuscular disease muscular dystrophy. People with these conditions can have problems relaxing muscles in the pelvic floor which makes it hard to push stool out. Why do people have GI side effects from Opioids? Opioid receptors are widely distributed in the enteric nervous system (ENS) of the GI tract The primary opioid receptors include the: mu opioid receptor (MOR), delta opioid receptor (DOR) kappa opioid receptor (KOR). Activation of opioid receptors leads to: https://ccforum.biomedcentral.com/articles/10.1186/s13054-021-03793-1  Supplemental resource slide Rome IV Diagnostic Criteria for Functional Constipation https://www.mdcalc.com/calc/10003/rome-iv-diagnostic-criteria-functional-constipation  Supplemental resource slide Rome IV Diagnostic Criteria for Child Functional Constipation Patients with any of the following features must be evaluated clinically for other diagnoses, even though functional constipation may be present https://www.mdcalc.com/calc/10331/r ome-iv-diagnostic-criteria-child- functional-constipation IRRITABLE BOWEL SYNDROME  Question: Irritable Bowel syndrome can be associated with the following except: a) Diarrhea and/or constipation b) Adhesions on the mucosal lining of the colon c) Abdominal pain and bloating d) Altered bowel motility e) Altered microbiome  Irritable Bowel Syndrome IBS currently is considered a disorder of brain-gut interaction (previously termed a functional GI disorder) characterized by: Abdominal Recurrent abdominal pain with altered bowel habits. pain, cramping and bloating The exact cause of IBS is poorly understood, but various factors that may contribute to the pathology of the disease Abdominal pain, include: cramping and bloating Alteration in gut microbiota Excess gas Alterations in the Diarrhea “brain-gut” axis and/or constipation Diet Medication use Mucous in the stool Low grade gut inflammation http://nshealthadvocate.ca/understanding-irritable-bowel-syndrome-causes-symptoms-and-treatment-options/  Three Major Pathophysiological Concepts for Irritable Bowel Syndrome Visceral Hypersensitivity Altered Altered Motility (Stretch Receptors) Microbiome https://www.youtube.com/watch?v=qWq-Jvz_ddE  Clinical diagnosis Diagnostic Criteria for Irritable Bowel Syndrome  Supplemental resource IBS https://www.youtube.com/watch?v=E86eXpVBTcI Supplemental resource  Compare and contrast the pathophysiological mechanisms, the nature of inflammatory Learning damage and the clinical manifestations of Crohn's disease Outcomes and ulcerative colitis* Discuss the main characteristics of Diverticulitis diverticulitis and diverticulosis Describe the pathophysiology and and clinical manifestations of Inflammatory appendicitis Bowel Disease *covered in pre-lecture video  Diverticular Disease Diverticula are herniations or sac-like outpouchings of the mucosa and submucosa through the muscle layers, usually located in the wall of the sigmoid colon and they are more common in older adults They rarely occur in the small intestine. Diverticulosis is asymptomatic diverticular disease. Diverticulitis represents inflammation of the diverticula and occurs in approximately 10% to 15% of cases of diverticular disease of the colon https://www.youtube.com/watch?v=UYUiplMgcUM  Diverticular Disease of the Colon- Predisposing Factors The cause of diverticular disease is unknown, but it is associated with increased intracolonic pressure, abnormal neuromuscular function, and alterations in intestinal motility. Predisposing factors include: Older age, Genetic predisposition, Obesity, Smoking, Diet, Lack of physical activity, and Medication use (e.g., aspirin and NSAIDs). Lack of dietary fiber may or may not contribute to diverticular disease. Altered intestinal microbiota, visceral hypersensitivity, and abnormal colonic motility also may be contributing factors. https://www.youtube.com/watch?v=tvJIp_9t7oM 9 minutes  Appendicitis Appendicitis is an inflammation of the vermiform appendix, which is a projection from the apex of the cecum. Appendicitis is a medical emergency. It is the most common surgical emergency of the abdomen, usually occurring between 10 and 19 years of age (although it may develop at any age). The incidence in the United States is 10 cases per 10,000 persons. The exact mechanism of the cause of appendicitis is not well understood. Obstruction of the lumen with stool, tumors, or foreign bodies, with consequent bacterial infection, is the most common https://www.mountsinai.org/health-library/diseases-conditions/appendicitis theory.  Appendicitis https://www.youtube.com/watch?v=r9amif1DQMc Overview of Appendicitis Appendicitis (https://www.youtube.com/watch?v=r9amif1DQMc) by Osmosis (https://open.osmosis.org/) is licensed under CC-BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0/). https://www.youtube.com/watch?v=r9amif1DQMc https://www.youtube.com/watch?v=r9amif1DQMc McBurney’s Point https://www.youtube.com/watch?v=r9amif1DQMc McBurney’s point is located two thirds the distance from the navel to the right anterior superior iliac spine, or the bony projection of the right hip bone. It is found at about 3.8–5.1 cm (1.5–2 inches) from the top of the hip bone towards the navel. This point corresponds to the base of the appendix, where it is attached to the cecum, or the beginning of the colon. INFLAMMATORY BOWEL DISEASE  Healthy Gastrointestinal Immune System Intestinal bacteria and ingested substances are detected by dendritic cells Dendritic cells activate T cells that promote tolerance instead of inflammation (regulatory T cells) Plasma cells secrete IgA antibodies to keep normal flora in check Tight balance between tolerance of normal flora/ingested substances and protection against pathogens Hooper & Macpherson (2010)  Animation of the local immune response Supporting resource 7 minutes Peyer patches are a group of well- organized lymphoid follicles located in the lamina propria and submucosa of the distal portion of the small intestine—the ileum and jejunum and sometimes in the duodenum. Almost 50% of these patches are in the distal ileum. Peyer patches are the private immune system of the gut that helps in identifying the antigens and in producing antibodies https://www.youtube.com/watch?v=gnZEge78_78&t=28s  Mini Quiz Characteristic Crohn’s Ulcerative Both Disease Colitis 1 Restricted to the colon 2 Continuous lesions 3 Genetic predisposition 4 Transmural lesions 5 Loss of goblet cells 6 Primarily involves T2 Helper (Th2) cells 7 Can lead to perforations or fistulas 8 Can lead to bowel obstruction 9 Pseudo-polyps can develop 10 Reduction in T regulatory (Treg) cells 11 Can be associated with a granuloma 12 Increased risk of colon cancer 13 May lead to pernicious anemia Please text in your response to the chat box: Indicate CD for Crohn’s disease; UC for Ulcerative Colitis; B for both  Lecture slide material IBD Pathophysiology Increased exposure of immune cells to intestinal contents – Protective mucous barrier is thinner than that of healthy individuals – Epithelial cells exhibit increased permeability Excessive inflammation – Increased reactivity of adaptive immune system toward intestinal normal flora – Resident tolerant macrophages are replaced by inflammatory macrophages that are recruited to the GI tract Secrete excessive amounts of TNF-α, which stimulates inflammatory response and further perpetuates mucosal damage – Impaired T cell apoptosis – Reduction in T regulatory cells – Increased number of Th17 T helper cells Crohn’s disease is characterized by a predominantly Th1 T helper cell mediated immune response Ulcerative colitis is characterized by a predominantly Th2 T helper cell mediated immune response Crohn’s Disease Lecture slide material Lecture slide material  Lecture slide material IBD-Immune Pathophysiology Crohn’s disease is characterized by a predominantly Th1 T helper cell mediated immune response – Th 1 helper cells facilitate cell mediated immunity leading to the activation of macrophages and cytotoxic T cells and release cytotoxins within the GI tract further promoting damage Ulcerative colitis is characterized by a predominantly Th2 T helper cell mediated immune response – This is facilitated by the humoral immunity with contributions from B cells and plasma cells as well as different types of cytokines that will be secreted. Note- The lines become a bit blurred because Th 1 T helper cells can be involved with UC and Th 2 helper cell involved with CD. But ultimately, CD is a Th1 type disorder and UC is a Th 2 type disorder and Th17 cells contribute to both  Supplementary resource https://www.youtube.com/watch?v=ZA4xFrtCeZg Supporting resource 9 minutes Topic 2: IBD Conventional therapy for IBD is often ineffective in a subgroup of patients and may have significant side effects. What are some of the novel treatments for IBD? Neurath MF. Nature Review 2016;14:269–278 LOI possibility- tip  Clinical Consult GERD and H. Pylori Gui Li (Lacey) Wed Nov 6th, 2024 56  Clinical Consult GERD and H. Pylori Brandon Miller Thursday Nov 7th, 2024 57 Learning Describe the pathophysiology and clinical manifestations of Outcomes gastroesophageal reflux disease (GERD) Gastroesoph ageal Reflux Note- covered in detail in the pre-lecture video. Disease The following slides can be used as a reference as we will not be going through them in detail (GERD) during the seminar.  Gastroesophageal Reflux Disease Defined as the reflux of chyme from the stomach to the esophagus (or beyond) that causes troubling symptoms that affect well-being or cause complications Affects approximately 10-20% of the population in Western countries Risk factors – Smoking – Alcohol – Stress – Certain foods (coffee, mints, citrus fruits, fats) – Conditions that increase abdominal pressure (e.g., obesity, pregnancy)  GERD Concept Map Risk factors Causes Obesity Smoking Decreased esophageal sphincter resting pressure and relaxation Disturbance of normal anti- Alcohol Certain foods (coffee, Hiatus hernia reflux barrier mints, citrus fruits, fats) Infection by bacteria Weakness of esophageal Conditions that increase Imbalance between mucus damaging sphincter abdominal pressure (HCl, pepsin) and mucus protective Stress agents (mucus, bicarbonate) Smoking Chyme reflux into esophagus NSAIDs ANXIETY! Leads to inflammation, damage, esophageal erosions Severe cases: ulcers and/or strictures Treatments Neutralize acid secretion Antacids (Mg and Al salts Clinical manifestations neutralizes acid and raise pH; Burning pain in the middle of the chest short-acting) (heartburn) TUMS = Calcium Sour taste in mouth Non-pharm Hoarseness, dry cough, worsened asthma Prevent acid secretion symptoms, bad breath, earaches, and 1. H2 blockers (i.e. Famotidine) increased saliva production Inhibit histamine RED FLAGS: dysphagia, anemia, nausea, Barrett’s esophagus receptors increases risk of vomiting and involuntary weight loss 2. Proton pump inhibitors esophageal 3. ACh blockers (i.e. atropine) adenocarcinoma GERD and Barrett Esophagus Barrett Esophagus A small percentage of patients with GERD exhibit abnormal repair processes following exposure to acidic chyme In these patients, the squamous epithelium lining the esophagus is replaced by metaplastic columnar epithelium Barrett’s esophagus increases the patient’s risk of developing esophageal adenocarcinoma http://pathology2.jhu.edu/beweb/cancer.cfm Learning Outcomes Compare and contrast sliding hiatal hernias and paraesophageal hiatal hernias Hiatal Hernias Hiatal Hernia The esophageal hiatus is an opening in the diaphragm for the esophagus and vagus nerves. Hiatal hernia is a common disorder characterized by a protrusion or bulging of an abdominal structure into the thoracic cavity. Causation is from a weakening of the diaphragm muscle  Types of Hiatal Hernias The most Paraoesophageal hiatal common hernia (type 2) is a herniation of the type is a greater curvature of the sliding stomach through a hiatal secondary opening in hernia the diaphragm (type 1) alongside the esophagus that moves into the thorax above the diaphragm Mixed hiatal hernia (type 3), less common, is a combination of sliding and paraoesophageal hiatal hernias Clinical Consult NSAID and the Gut Jaskirat Duhra Wed Nov 6th, 2024 66  Clinical Consult NSAID and the Gut Dana Bell Thurs. Nov 7th, 2024 67  Compare and contrast the causes, Learning pathophysiological mechanisms and clinical manifestations of Outcomes gastritis and peptic ulcer disease (PUD). Gastritis Note- this material was covered in the pre- and Peptic lecture video, including H Pylori and will not be discussed in detail in the seminar. The Ulcer following slides are for reference. Disease Gastritis and Peptic Ulcer Disease Lecture slide video content  Lecture slide material Autoimmune Metaplastic Atrophic Gastritis Lecture slide material Lecture slide material  Lecture slide material Peptic Ulcer Disease- NSAIDS Lecture slide material Lecture slide material Lecture slide material Supporting Information- H Pylori 7 minutes https://www.youtube.com/watch?v=5n1F_UE5rag Break Time See you at 78 Clinical Consult Hepatitis B Sandeep Kaur Wed Nov 6th, 2024 79  Describe the clinical course of viral hepatitis. Learning Compare and contrast the Outcomes mechanisms of disease transmission used by the Hepatitis Hepatitis A, B, C, and D viruses This material is covered in the lecture video and the slides are for reference only- we will not discuss these slides in detail during the seminar on Wed. evening.  Viral Hepatitis 12 min https://www.youtube.com/watch?v=eocRM7MhF68 MHC- Major histocompatibility complex Hepatitis- causes Cause Description Pathogens (viruses) See additional slides on Hepatitis Autoimmune Very rare and characterized by lymphocyte infiltration. hepatitis Cause is unknown. Antinuclear and anti-smooth muscle antibodies often formed. Alcohol use Toxic intermediates (acetaldehyde) damage liver resulting in (steatohepatitis) inflammation MASLD Metabolic dysfunction–associated steatotic liver disease (MASLD) – accumulation of fat (TGs, cholesterol, etc) in hepatocytes leads to inflammation. Not associated with alcohol use. Leads to NASH – non-alcoholic steatohepatitis Hepatotoxic Too many to list. Here are some: acetaminophen, aspirin, NSAIDs, medications anabolic steroids, antibiotics (e.g., sulfas), some herbal supplements. Hepatitis A and E Differences between Hep A and Hep E viruses: No vaccine for Hep E Hep E can be very dangerous in pregnant women- it can lead to fulminant hepatitis and liver failure https://www.youtube.com/watch?v=eocRM7MhF68 Hepatitis C Virus (HCV) Enzyme immunoassay- Hep C virus IgG (Hep C antibodies) (but don’t protect you from infection) Gold standard- Hep C RNA test- measure the viral load in the blood; can detect virus within 1-2 weeks of exposure. Can be used to monitor recovery (levels decreasing) or chronic condition (levels remain elevated) Less than half of people who get hepatitis C are able to clear the virus in the first 6 months after infection without treatment. No vaccine https://www.cdc.gov/hepatitis-c/index.html Hepatitis B (HBV) A B 2 antigens associated with HBV A. Surface Antigen- “supervillain”- IgG antibodies needed to ‘kill the virus’ B. Core Antigen- easier to manage- IgM antibodies can control but not kill the virus Hepatitis D Virus (HDV) Can only infect if the host has Hep B Viral Hepatitis Transmission, Prevention, Detection, Treatment AA Fecal-Oral IgM or IgG Home or hospital supportive care anti-HBs B Blood anti-HBc IFN + D Semen HBsAg Testing not often done Vaginal Fluid Co-infection can progress disease C Blood anti-HCV RNA IFN + E Fecal-Oral IgM or IgG Home or hospital supportive care Hepatitis Fibrosis Staging (F-Scores) Score Description F4 Cirrhosis Serum markers F3 F2 Severe fibrosis Moderate fibrosis Fibroscan F1 F0 Mild fibrosis No fibrosis Biopsy  Hepatitis notes Liver fibrosis: Indicator of the severity of liver disease Scored F0 (no fibrosis) to F4 (cirrhosis) Cirrhosis = presence of scars that alter liver architecture and interfere with proper hepatic blood flow. Serum markers vs fibroscan vs biopsy Serum markers – presence of liver enzymes (ALT, AST, GGT), increased bilirubin, decreased albumin, increased prothrombin time. Fibroscan – ultrasound of liver anatomy. Can detect changes consistent with increased liver fibrosis. Can also detect steatosis (fatty liver). Biopsy – sample of liver tissue harvested for histological examination Hepatitis What do you call these tests? ALT (Alanine aminotransferase) AST (Aspartate aminotransferase) ALP (Alkaline phosphatase) GGT (Gamma-glutamyl transferase) Liver enzymes → NOT Liver Function Tests What ARE liver functions tests? Liver Function Tests Alanine aminotransferase (ALT) - an enzyme found in the liver that helps convert proteins into energy for the liver cells Aspartate transaminase (AST) - an enzyme that helps metabolize amino acids. may indicate liver damage, disease or muscle damage. Alkaline phosphatase (ALP) - an enzyme found in the liver and bone and is important for breaking down proteins. Indicate liver damage or disease, such as a blocked bile duct, or certain bone diseases. Can be fractionated. Gamma-glutamyltransferase (GGT)- an enzyme in the blood. Higher-than-normal levels may indicate liver or bile duct damage. Liver Function Tests: Albumin, Bilirubin, INR (related to prothrombin time – PT) Note: Liver function can be normal until advanced cirrhosis  Elevated Bilirubin Conjugated bilirubin leaks through the Liver unable to damaged liver cells in the bile duct conjugate bilirubin Unconjugated bilirubin is the form of bilirubin that is bound to albumin in the blood and travels to the liver. Direct bilirubin (sometimes referred to as conjugated) is the form of bilirubin which has been conjugated with glucoronic acid (to make it water soluble) and is excreted in the bile.  Describe the risk factors, Learning pathophysiological mechanisms and Outcomes clinical manifestations of acute and chronic pancreatitis. Gallbladder Explain the causes and consequences and of cholelithiasis and cholecystitis. Pancreatic Disease Lecture video  Duct of Wirsung The pancreas contains exocrine glands that produce enzymes important to digestion. These enzymes include: Trypsin and chymotrypsin to digest proteins; Amylase for the digestion of carbohydrates; and Lipase to break down fats. Normal Pancreatic Structure  Pathophysiology of Acute and Chronic Pancreatitis Acute pancreatitis is acinar injury and Similar to acute pancreatitis, except for: pancreatic inflammation caused by Prolonged inflammation mechanical obstruction of ducts, or Macrophages make up the majority of the immune systemic factors that trigger landscape premature activation of digestive Cellular stress causes pancreatic stellate cells activation, enzymes. causing increased oxidative stress, inflammation and Acinar cell injury drives expression of fibrosis that cumulative increase acinar cell death and, pro-inflammatory cytokines that in some cases, promote adipocyte infiltration. promotes immune infiltration  Acute and Chronic Pancreatitis https://www.youtube.com/watch?v=met9SntRZe8 Pathogenesis of acute pancreatitis- beyond the pancreas Regardless of the etiology, an early event in pathogenesis of acute pancreatitis is intra-acinar activation of pancreatic enzymes (including trypsin, phospholipase A2, and elastase), leading to the autodigestive injury of the gland. The enzymes can damage tissue and activate the complement system and the inflammatory cascade, producing cytokines and causing inflammation and edema; which may cause necrosis. Activated enzymes and cytokines that enter the peritoneal cavity cause a chemical burn and third spacing of fluid; those that enter the systemic circulation cause a systemic inflammatory response that can result in acute respiratory distress system and acute kidney injury. The systemic effects are mainly the result of increased capillary permeability and decreased vascular tone, which result from the released cytokines and chemokines. Conditions that can lead to pancreatitis Abdominal surgery Alcoholism (single most common cause of chronic pancreatitis) Certain medications Cystic fibrosis (main cause of chronic pancreatitis in children) Gallstones (Single most common cause of acute pancreatitis, 80% of cases o acute pancreatitis are caused by alcohol or gallstones) High calcium levels in the blood hypercalcemia), which may be caused by an overactive parathyroid gland (hyperparathyroidism) High triglyceride levels in the blood (hypertriglyceridemia) Infection Injury to the abdomen Obesity Pancreatic cancer Alcohol induced Acute Pancreatitis https://www.youtube.com/watch?v=met9SntRZe8 Chronic Pancreatitis Pancreatitis due to a blocked bile duct from gallstones Hepatobiliary system Question- What are gallstones made of? Components of gallstones can include: A Calcium, cholesterol, carbohydrates B Bilirubin, bile, bicarbonate C Carbohydrates, bile, bacteria D Cholesterol, bilirubin, calcium  Gallstone Formation – Contributing Factors Note: >85% of stones are cholesterol stones in the Western world Brown (and black) stones are associated with bacterial infection. They are comprised of excess bilirubin. Lammert et al. 2016  Mechanisms of gallstone formation Stones composed of cholesterol, bilirubin, calcium Supersaturation of cholesterol (too much cholesterol or not enough bile salts) Sludge (thickened mucoprotein) Pigment stones (excess bilirubin) Lammert et al. 2016 Terms- mini quiz-Question Condition- Gallstones are present in the gallbladder Term A Cholecystitis B Cholelithiasis C Cholestasis D Biliary Colic E Choledocholithiasis Terms- mini quiz-Question Condition- Inflammation of the gallbladder Term A Cholecystitis B Cholelithiasis C Cholestasis D Biliary Colic E Choledocholithiasis Terms- mini quiz- Question Condition- Stones present in the common bile duct Term A Cholecystitis B Cholelithiasis C Cholestasis D Biliary Colic E Choledocholithiasis Terms- mini quiz-Question Condition- Intermittent RUQ pain cause by gallstones irritating the bile ducts Term A Cholecystitis B Cholelithiasis C Cholestasis D Biliary Colic E Choledocholithiasis Why is biliary colic triggered by fatty food ?  Resource slide Stone locations and terms Learning Describe the risk factors, Outcomes pathophysiological mechanisms 8. and clinical manifestations of GI Gastrointesti cancers, focusing on cancers of nal Cancers the colon and rectum Colon cancer Uncontrolled growth of colon cells that can invade other tissues. Progression to colon cancer: – Polyp development (benign) aka benign adenoma Usually arise as a result of DNA mutations Slow growing, non-invasive, capsulated – Carcinoma (technically an adenocarcinoma as cancer of epithelial origin) Malignant, cancerous, grow rapidly, uncapsulated, invasive and usually have a large blood supply Arise from many DNA mutations https://fightcolorectalcancer.org/prevent/about-colorectal-cancer/  CRC begins with the formation of an adenoma, termed “tumor initiation.” The progression to carcinoma is termed “tumor progression” and is a multistep process of genetic mutations that may take 8 to 10 years. Risk Factors Textbook https://www.youtube.com/watch?v=FbXTPe23zHc Adenomatous Polyposis Coli (APC) Gene Mutation Autosomal dominant genetic defect Other tumor suppression genes  Types of Polyps Adenomatous Polyposis Coli Hereditary nonpolyposis, (APC) gene mutation Lynch syndrome (Tumor suppressor gene) e.g., K-RAS , p53 genes Leads to uncontrolled growth cell division (e.g., 100s -1000’s of polyps) Usually develop colon cancer by age 40  Stages of Colon Cancer Stage 0: Adenoma cells in mucosa layer (benign polyp) Stage I: Tumour spread to muscle layer Stage II: Tumour spread from colon wall to serosa Stage III: Tumour has spread to nearby lymph nodes Stage IV: Metastasis (terminal stage)  Colon Cancer- mini quiz Right or Left? Proximal colon Descending Colon (Right side) (Left side) Obstruction is common Bright red blood on stool surface More common in women Iron deficiency anemia Typically asymptomatic and evolves to pain over time Pencil-shaped stools Liver metastases due to penetration into the inferior mesenteric veins that drain into the portal circulation  Cancers on the right side On the right side (proximal colon), the lesions extend along one wall of the cecum and ascending colon. These tumors may be: silent, evolving to pain, a palpable mass in the lower right quadrant, iron deficiency anemia, fatigue, dark red or mahogany-colored blood mixed with the stool. These tumors can become large and bulky with necrosis and ulceration, contributing to persistent blood loss and anemia. Obstruction is unusual because the growth does not readily encircle the colon. These tumors are more common in women and have a poorer prognosis with the occurrence of metastasis.  Cancers on the left side- Descending Colon Tumors of the left, or descending, colon (distal colon) start as small, elevated, button- like masses and are more common in men. This type grows circumferentially, encircling the entire bowel wall and eventually ulcerating in the middle of the tumor as the tumor penetrates the blood supply. Obstruction is common but occurs slowly, and stools become narrow and pencil shaped. Manifestations include progressive abdominal distention, pain, vomiting, constipation, a need for laxatives, cramps, and bright red blood on the surface of the stool. Systematic lymphatic distribution occurs along the aorta to the mesenteric and pancreatic lymph nodes. Liver metastasis is common and follows invasion of the mesenteric veins (left colon) or superior veins (right colon), which drain into the portal circulation.  Supplementary resource Blood supply and the Intestines Blood supply to the abdominal organs is provided by three major unpaired vessels arising from the abdominal aorta, namely the celiac trunk and the superior and inferior mesenteric arteries. The branches of these vessels form anastomotic systems that provide a rich blood supply to the adjoining organs. The gastrointestinal (GI) tract receives blood from three main arteries that branch off the abdominal aorta: Celiac artery: Supplies the stomach and the first part of the small intestine Superior mesenteric artery: Supplies the rest of the small intestine and the beginning of the colon Inferior mesenteric artery: Supplies the remaining part of the colon Blood supply to the abdominal organs is provided by three major unpaired vessels arising from the abdominal aorta, namely the coeliac trunk and the superior and inferior mesenteric arteries. The branches of these vessels form anastomotic systems that provide a rich blood supply to the adjoining organs.  Supplementary resource The Celiac Axis/Trunk The Celiac ‘trunk’, ‘axis’, ‘artery’ 3 branches arise from the celiac trunk: Left gastric Common Hepatic Splenic These 3 branches continue to divide and supply the: Abdominal Aorta Stomach Liver Gallbladder Pancreas Spleen Part of the duodenum (distal esophagus) https://www.youtube.com/watch?v=xKBqenJNtRY 132  Supplementary resource Visual description of the blood supply to the lower GI tract and the accessory GI organs https://www.youtube.com/watch?v=xKBqenJNtRY 133 Topic 2: Colon Cancer A) Describe the progression and stages of colon cancer. B) What are the current Ontario guidelines? https://www.cancercar eontario.ca/en Ontario Colon Cancer Guidelines The ColonCancerCheck program has two arms for colorectal cancer screening Average risk – Ages 50–74, asymptomatic, no first-degree relative who has been diagnosed with colorectal cancer – No personal history of pre-cancerous colorectal polyps requiring surveillance or inflammatory bowel disease (i.e., Crohn’s or UC) Screening recommendations- see next slide Increased risk – People with a family history of colorectal cancer (1 or more first-degree relative who has been diagnosed with colorectal cancer, but do not meet the criteria for colorectal cancer hereditary syndromes) Screening recommendations: – Asymptomatic people get screened with colonoscopy – Screening should begin at 50 years of age, or 10 years earlier than the age their relative was diagnosed, whichever occurs first  Ontario Colon Cancer Screening Average risk Fecal Immunochemical Test (FIT) every two years If patient chooses to be screened with flexible sigmoidoscopy, should be screened every 10 years ColonCancerCheck program recommends against screening for colorectal cancer using metabolomic (blood or urine) tests, DNA (blood or stool) tests, computed tomography colonography, capsule colonoscopy, double contrast barium enema https://www.cancercareontario.ca/sites/ccocancercare/files/assets/H-FIT_PCC_2742_ClinicalToolForProviders.pdf Benefits and limitations of screening Benefits of regular stool tests Limitations of regular stool tests Doing a stool test reassures you if the A stool test may suggest a polyp or result is normal colorectal cancer even though it is not A stool test can prevent cancer by present (called a false positive) detecting blood from polyps (can be A stool test may not detect a polyp or removed before they become cancerous) colorectal cancer even though it is present A stool test helps find cancer early before (called a false negative) you have symptoms Some colorectal cancers would not A stool test helps find cancer before it necessarily lead to death or decreased spreads when it is easier to treat quality of life (overdiagnosis) Most colorectal cancers are harmful and A colonoscopy may be needed after a should be found and treated as early as positive stool test. There can be risks with possible this procedure such as bleeding and bowel Early detection may mean less treatment perforation and less time spent recovering The earlier colorectal cancer is detected, the better your chance of survival Taken from: http://www.cancer.ca/en/prevention-and-screening/reduce-cancer-risk/find-cancer-early/get-screened-for-colorectal- cancer/benefits-and-limitations-of-screening-for-colorectal-cancer/?region=on#ixzz5Vqd5u6Vm PRACTICE QUESTIONS  GI pain presentation may be quite difficult, especially if patients are unable to communicate a clear history, and symptoms are overlapping, do not quite fit diagnostic criteria. Cartwright et al. (2008) NEXT STEPS  Wrap up- Wed pm Lectur e These slides are intended to be an additional resource Video to support your learning- supplemental information Slide that extends beyond your learning objectives and not part of test material. Module 4 test – opens Thursday, Nov 7th afternoon and closes by 5 pm Nov 20th Clinical consults Nov 20th Please submit your clinical consult presentation to Karen by email by November 4th  Wrap up- Thurs am Lectur e These slides are intended to be an additional resource Video to support your learning- supplemental information Slide that extends beyond your learning objectives and not part of test material. Module 4 test – opens Thursday, October 24th afternoon and closes by 5 pm Nov 6th Clinical consults Nov 7th Please submit your clinical consult presentation to Karen by email by November 5th Letter of Intent-tip for refining your search Future directions for research in review article help signal topics of interest  Letter of information Sections Description Describe your disease A brief overview on the general characteristics of the disease of your choosing. * Brief You may include information on common symptoms of the condition, the general mechanism of disease development and the epidemiology of the condition. You may also discuss the significance of this disease to an individual and to Canadian society. Identify a new research You are encouraged to focus on one specific factor that has recently development (last 12 months) been shown to be involved in the pathophysiology of your disease. in patho. of your disease Please identify an Original Research Study for this assignment; review articles will not be accepted * Bulk of assignment Potential influence on clinical A brief discussion on how these recent research developments may practice influence clinical practice either now or in the future. * Brief Please see the course syllabus for further details. SPARE SLIDES Digestive Glands Examples of digestive glands include: Salivary glands – secrete saliva which contains amylase (breaks down starch) Gastric glands – secretes gastric juices which includes hydrochloric acid and proteases (breaks down protein) Pancreatic glands – secretes pancreatic juices which include lipase, protease and amylase Intestinal glands – secretes intestinal juices via crypts of Lieberkuhn in the intestinal wall 146 147