Gastrointestinal Disorders Module 5 Lecture Notes PDF

6/25/24 Gastrointestinal Disorders Module 5 1 Outline Background Gastroesophageal Reflux Disease Gastritis/Peptic Ulcer Disease Inflammatory Bowel Disease Hepatitis Disorders of the Gallbladder Pan...

6/25/24 Gastrointestinal Disorders Module 5 1 Outline Background Gastroesophageal Reflux Disease Gastritis/Peptic Ulcer Disease Inflammatory Bowel Disease Hepatitis Disorders of the Gallbladder Pancreatitis 2 1  6/25/24 Structures of the Digestive System McCance & Huether (2019); Figure 41.1 3 Wall of the Gastrointestinal Tract McCance & Huether (2019); Figure 41.2 4 2  6/25/24 Intestinal Wall Structure Nature Reviews Immunology 11, 215 (March 2010) 5 Function https://inspiritvr.com/digestive-system-study-guide/ 6 3  6/25/24 Accessory Digestive Organs Liver Detoxification Storage of nutrients Production of bile salts Production of plasma proteins Gallbladder Stores bile salts and secretes them into duodenum McCance & Huether (2019); Figure 41.17 7 Accessory Digestive Organs Pancreas Location within the abdominal cavity, behind the stomach Exocrine secretions enter the duodenum via the ampulla, which is shared between the liver/gallbladder and pancreas McCance & Huether (2019); Figure 41.23 8 4  6/25/24 Accessory Digestive Organs Pancreas Functionally divided into exocrine and endocrine structures Exocrine Function –Enzymes include amylase, lipase, trypsin, chymotrypsin, and carboxypeptidase –Enzymes typically produced as zymogens (inactive) Pearson Education, Inc. (2010) 9 Accessory Digestive Organs Pancreas Endocrine Function –Islets of Langerhans –Secrete glucagon (α cells) and insulin (β cells) into the bloodstream McCance & Huether (2019); Figure 21.15 10 5  6/25/24 Gastroesophageal Reflux Disease (GERD) 11 Gastroesophageal Reflux Disease Defined as the reflux of chyme from the stomach to the esophagus or more proximal regions of the digestive system – Causes noticeable symptoms or complications Prevalence is estimated at 18-27% in North America Risk factors – Sliding hiatal hernia – Obesity – Smoking – Alcohol – Drug of chemicals that relax the LES – Certain foods (coffee, mints, citrus fruits, fats) – Conditions or activities that increase abdominal pressure https://ssl.adam.com/content.aspx?productid=617&pid=1&gid=000265&site=makatimed.adam.com&login=MAKA1603 12 6  6/25/24 Gastroesophageal Reflux Disease Chyme is normally retained within the stomach by the lower esophageal sphincter Patients with GERD exhibit reduced resting pressures of the lower esophageal sphincter The lower esophageal sphincter undergoes periods of relaxation in healthy individuals – Relaxation often occurs after a meal and is stimulated by fats in the duodenum These periods of relaxation are more frequent in patients with GERD https://ssl.adam.com/content.aspx?productid=617&pid=1&gid=000265&site=makatimed.adam.com&login=MAKA1603 13 Gastroesophageal Reflux Disease Chyme is acidic and can damage the esophageal epithelium – Unlike the stomach, the esophagus does not have a protective layer of mucous Damage to the epithelium causes esophageal inflammation (reflux esophagitis) and heartburn – May lead to esophageal erosions Acid in the esophagus can cause chronic coughing and throat clearing, as well as dysphagia Aspiration of acid into airways can cause airway inflammation In severe cases, ulcers and/or strictures may occur https://ssl.adam.com/content.aspx?productid=617&pid=1&gid=000265&site=makatimed.adam.com&login=MAKA1603 14 7  6/25/24 Gastroesophageal Reflux Disease https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/barretts-esophagus-treatment 15 Gastroesophageal Reflux Disease McCance & Huether (2019); Figure 42.2 and 42.3; https://my.clevelandclinic.org/health/diseases/21456-esophageal-strictures 16 8  6/25/24 Gastroesophageal Reflux Disease Barrett’s 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 https://bme240.eng.uci.edu/students/07s/jpuckett/page_215.htm 17 Gastroesophageal Reflux Disease Symptoms Patients typically experience burning pain in the middle of their chest or upper abdomen (heartburn) within 1 hour of eating May be accompanied by a sour taste in their mouth Other symptoms include, hoarseness, dry cough, worsened asthma symptoms, bad breath, earaches, and increased saliva production During more severe illness, patients may experience dysphagia, anemia, nausea, vomiting and involuntary weight loss 18 9  6/25/24 Gastritis 19 Gastritis Gastritis refers to an acute or chronic inflammation of the gastric mucosa (lining of the stomach) Acute Gastritis – Typically caused by medications (NSAIDs), excessive alcohol use, chemotherapy or Helicobacter pylori infections – Results in diffuse superficial lesions in stomach Normal Acute Gastritis https://padmavathigastro.com/stomach/acute-gastritis.html 20 10  6/25/24 Gastritis Acute Gastritis – Spontaneously resolves within a few days – Patients may be asymptomatic – Common symptoms of acute gastritis include: Epigastric discomfort (bloating) Nausea Vomiting Belching Loss of appetite Acute abdominal pain https://padmavathigastro.com/stomach/acute-gastritis.html 21 Gastritis Normal Chronic gastritis – Tends to occur in older adults – Commonly caused by H. pylori infections, autoimmune reactions or chronic use of alcohol, tobacco or NSAIDs – Ongoing inflammation causes mucosal atrophy and epithelial metaplasia Increases the risk of developing gastric cancer Chronic Gastritis – Can also progress to peptic ulcer disease https://padmavathigastro.com/stomach/acute-gastritis.html 22 11  6/25/24 Gastritis Autoimmune Metaplastic Atrophic Gastritis – Autoimmune reaction against gastric parietal cells – Parietal cells produce intrinsic factor and HCl Intrinsic factor is required for vitamin B12 absorption – Autoantibodies target intrinsic factor and proton pumps – Parietal cells are destroyed Reduction in intrinsic factor production can lead to pernicious anemia https://www.mdpi.com/2077-0383/11/12/3523 23 Gastritis Autoimmune Metaplastic Atrophic Gastritis https://www.aafp.org/pubs/afp/issues/2003/0301/p979.html 24 12  6/25/24 Peptic Ulcer Disease 25 Peptic Ulcer Disease Defined as the ulceration of the lower esophagus, stomach or duodenum – Can be acute or chronic Affects approximately 10%-17% of population Can lead to bleeding or perforations in severe cases Exact mechanism of causation is not known, but major risk factors include NSAIDs and H. pylori http://www.physio-pedia.com/Peptic_Ulcers; McCance & Huether (2019); Figure 42.8 26 13  6/25/24 Peptic Ulcer Disease Non-steroidal anti-inflammatory drugs (NSAIDs) – Reduce inflammation by inhibiting cyclo-oxygenase enzymes, which synthesize prostaglandins from arachidonic acid – Prostaglandins are constitutively produced in the stomach Promote bicarbonate secretion and mucin production Inhibit HCl secretion Promote platelet aggregation following injury – NSAIDs expose the epithelial cells to a more acidic/proteolytic environment, which causes cell damage and ulceration – Anti-thrombotic effects impair repair mechanisms https://www.researchgate.net/publication/276528002_Endoplasmic_reticulum_stress_response_in_the_roadway_for_the_effects_of_non-steroidal_anti-inflammatory_drugs/figures?lo=1 27 Helicobacter Pylori Gram-negative bacterium that infects approximately 50% of the world’s population Helical (spiral or curved) morphology with flagella – Burrows into the mucosa Well-suited to colonize the acidic environment within the stomach Secretes urease, which converts urea to ammonia and bicarbonate – Neutralizes acid Secretes mucinase Adheres to epithelium https://pubmed.ncbi.nlm.nih.gov/22500191/ 28 14  6/25/24 Helicobacter Pylori H. pylori is found in almost all cases of peptic ulcer disease when the use of NSAIDs is ruled out When H. pylori is treated and eradicated, the rate of ulcer recurrence is dramatically reduced H. pylori infections typically originate early in life and persist throughout an individual’s lifetime if not treated In approximately 15% of patients with H. pylori infection, peptic ulcer disease will eventually occur Most gastric adenocarcinomas and lymphomas are concurrent with or preceded by an infection with H. pylori https://www.sepalabs.com/educational-resources/sepa-patient-focus/h-pylori-helicobacter-pylori-infection/ 29 Helicobacter Pylori VacA Pore-forming toxin that makes the epithelial cell membrane permeable to ions Also promotes apoptosis Mucinase Degrades the protective layer of mucous lining the stomach Exposes epithelial cells to acidic/proteolytic environment Inflammation Infiltrating immune cells release cytotoxic substances, such as reactive oxygen species, that damage the epithelial barrier https://www.nature.com/articles/35073084 30 15  6/25/24 Peptic Ulcer Disease Duodenal Ulcers Most common location of peptic ulcers Typically caused by exposure of the proximal duodenum to higher than normal concentrations of HCl or pepsin – Can be due to NSAIDs, H. pylori, increased acid/pepsin production, rapid gastric emptying, decreased duodenal bicarbonate secretion HCl and pepsin damage the mucosal barrier and promote ulceration McCance & Huether (2019); Figure 42.8 31 Peptic Ulcer Disease Duodenal Ulcers Symptoms Some patients remain asymptomatic Most common symptom is chronic, intermittent pain in epigastric area (middle upper abdominal region) often beginning 2-3 hours after eating Pain often occurs at night Pain is relieved by ingestion of food or antacids Has a relapsing and remitting course Treatment Antacids to neutralize gastric acid and pepsin H2 receptor inhibitors and proton pump inhibitors to decrease acid production Eradication of H. pylori 32 16  6/25/24 Peptic Ulcer Disease Gastric Ulcers H. pylori initiates inflammation and also degrades gastric mucous, exposing gastric wall to HCl NSAIDs reduce mucous production and impair repair mechanisms Duodenal reflux of bile salts can also lead to gastric ulcers Symptoms are similar to duodenal ulcers Main differences: – Eating does not relieve pain – Onset of pain following meal is more rapid than that of duodenal ulcers https://www.hopkinsmedicine.org/health/conditions-and-diseases/peptic-ulcer-disease 33 Inflammatory Bowel Disease 34 17  6/25/24 Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is a chronic, debilitating disorder characterized by relapsing and remitting inflammation of the GI tract Affects approximately 320,000 Canadians – Canada has one of the highest incidences of IBD around the world – More prevalent among white populations and Ashkenazi Jews Unknown etiology – Thought to result from an aberrant immune response to the intestinal microbiota in a genetically susceptible host Two most common types of IBD: – Crohn’s disease (CD) – Ulcerative colitis (UC) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10478802/pdf/gwad004.pdf; https://www.nature.com/articles/ncpgasthep0528 35 Inflammatory Bowel Disease Crohn’s Disease Inflammation can affect any portion of the GI tract from mouth to perianal area – Typically occurs in the terminal ileum and proximal colon Inflammation is discontinuous (skip lesions) Inflammation is transmural and affects the entire thickness of the GI wall – Leads to ulceration – Severe inflammation can cause perforations or fistulae to develop Fibrous scar tissue develops, which narrows the lumen and can cause strictures Increased risk of developing colon cancer McCance & Huether (2019); Figure 42.11 36 18  6/25/24 Inflammatory Bowel Disease Crohn’s Disease Granuloma https://www.cag-acg.org/images/cddw/small-bowel-crohns-disease_church-halder.pdf; https://academic.oup.com/ibdjournal/article/8/3/168/4718386 37 Inflammatory Bowel Disease Crohn’s Disease Genetic Component Concordance in twins: – 42%–58% for monozygotic (identical) twins – 0%–5% for dizygotic (fraternal) twins; same percentage for non-twin siblings NOD2/CARD15 gene (chromosome 16): – involved in bacterial recognition and defense against foreign intruders – loss of function mutation associated with increased risk of developing CD However, 60%–70% of CD patients have no NOD2/CARD15 mutations: – other gene mutations may be involved (polygenic) – several other chromosome loci are linked to CD 38 19  6/25/24 Inflammatory Bowel Disease Crohn’s Disease Symptoms Abdominal pain Diarrhea – Often accompanied by blood and mucous Pernicious anemia (impaired vitamin B12 absorption) Weight loss Anal fissures, perianal abscesses and fistulas are common Intestinal obstructions 39 Inflammatory Bowel Disease Ulcerative Colitis Inflammation typically begins in the rectum and extends proximally through a variable portion of the large intestine Inflammation is continuous and is generally limited to the mucosa – Leads to crypt distortion and abscesses – Loss of goblet cells – In mild disease, the mucosa is edematous and hyperemic (red) – Epithelial cells begin to proliferate in response to damage and inflammatory polyps (pseudopolyps) may form Increased risk of developing colon cancer McCance & Huether (2019); Figure 42.11 40 20  6/25/24 Inflammatory Bowel Disease Ulcerative Colitis McCance & Huether (2019); Figure 42.11; https://digitalcommons.otterbein.edu/cgi/viewcontent.cgi?article=1272&context=stu_msn 41 Inflammatory Bowel Disease Ulcerative Colitis Symptoms Frequent diarrhea – Often accompanied by blood and purulent mucous Cramping pain Urge to defecate Bowel obstructions If severe, fever, tachycardia, very frequent diarrhea (> 10 movements per day), urgency, bloody stools and continuous pain may occur – Can cause dehydration, weight loss, anemia 42 21  6/25/24 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) 43 Inflammatory Bowel Disease 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 numbers of Th17 T helper cells 44 22  6/25/24 Inflammatory Bowel Disease 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 Xavier & Podolsky (2007) 45 Hepatitis 46 23  6/25/24 Hepatitis Hepatitis is a general term used to describe acute or chronic inflammation of the liver There are many causes of hepatitis, including viruses, alcohol abuse, drugs, toxins, trauma, fat buildup and autoimmune disorders The most common form of hepatitis is viral hepatitis, which is caused by one of the hepatitis viruses (A, B, C, D, E or G), the Epstein-Barr virus or the varicella virus – Hepatitis A, B and C are the most common causes of viral hepatitis Vaccines are available for hepatitis A and B McCance & Huether (2019); Figure 41.17 47 Hepatitis Hepatitis A Previously known as infectious hepatitis because virus is transmitted by fecal- oral route in contaminated food or water – Can also be transmitted by blood transfusions Once ingested, the virus crosses the intestinal barrier and infects hepatocytes in the liver Virus replicates in hepatocytes and is subsequently shed into bile – allowing it to be transmitted to others Virally infected hepatocytes are attacked by the immune system causing hepatitis In most patients, hepatitis A causes self-limiting inflammation, and the patients develop life-long immunity to the virus – does not cause chronic hepatitis In severe cases, hepatitis A can cause liver failure and even death, but typically hepatitis A infections are less severe than hepatitis B or C infections 48 24  6/25/24 Hepatitis Hepatitis B Transmitted through contact with infected blood – Sharing needles and other drug equipment – Multiple sexual partners – Can be passed from mother to infant if mother becomes infected during 3rd trimester – Co-infection with hepatitis C and D and HIV are common Eight genotypes (A though H) with many sub-genotypes In 70% of patients the infection is asymptomatic and self- limiting Progresses to chronic hepatitis in 15-30% of cases – Immune system cannot clear the virus Major cause of cirrhosis and hepatocellular carcinoma Can lead to acute fulminating hepatitis characterized by massive hepatocyte necrosis and liver failure 49 Hepatitis Hepatitis C Transmitted through contact with infected blood and contaminated needles In 50-80% of cases, acute inflammatory response is unable to clear the virus Chronic inflammation ensues and is accompanied by fibrosis 20-30% of patients go on to develop cirrhosis Most common cause of chronic liver disease in the Western world 50 25  6/25/24 Hepatitis Symptoms Acute inflammatory phase begins with fatigue, anorexia, malaise, nausea, vomiting, headache, cough and low-grade fever Hepatocellular damage and bile stasis results in jaundice In chronic hepatitis, clinical manifestations and inflammation persist http://iahealth.net/jaundice/ 51 Cholelithiasis 52 26  6/25/24 Cholelithiasis Cholelithiasis refers to the development of gallstones in the gallbladder that can obstruct the flow of bile Gallstones form in bile that is supersaturated with cholesterol Cholesterol crystalizes and these crystals then aggregate and begin to grow Potential causes Enzyme defect; increases cholesterol synthesis Decreased secretion of bile acids to emulsify fats Decreased reabsorption of bile acids from the ileum Gallbladder smooth muscle hypomotility, stasis Genetic predisposition Combination of any or all of the above McCance & Huether (2019); Figure 41.23 53 Cholelithiasis Gallstones can either remain in the gallbladder or enter the cystic or common duct where they then become lodged and obstruct bile flow Obstructions caused by gallstones result in epigastric pain and inflammation of the gallbladder (cholecystitis) If the gallstone obstructs the common bile duct, jaundice will occur If the gallstone obstructs the ampulla, pancreatitis can occur McCance & Huether (2019); Figure 41.23 54 27  6/25/24 Cholecystitis 55 Cholecystitis Cholecystitis refers to acute or chronic inflammation of the gallbladder Commonly caused by obstructions in the cystic or common bile duct by gallstones Obstruction of bile flow causes distention and inflammation of the gallbladder Distention decreases blood flow, which can result in ischemia and necrosis Patients experience acute abdominal pain, fever and rebound tenderness 56 28  6/25/24 Pancreatitis 57 Pancreatitis Pancreatitis is a general term used to describe acute or chronic inflammation of the pancreas – Caused by alcoholism, cholelithiasis, peptic ulcers, trauma, hyperlipidemia and certain medications Pancreas contains exocrine glands that secrete digestive enzymes into the duodenum These enzymes are secreted in an inactive form and are not activated until they contact enterokinase present within the duodenum Premature activation of pancreatic enzymes can cause tissue destruction and inflammation McCance & Huether (2019); Figure 41.23 58 29  6/25/24 Pancreatitis Acute Pancreatitis Initiated by the intrapancreatic activation of proteases and lipases Primarily caused by obstruction to outflow tract for pancreatic enzymes – Gallstones, chronic alcoholism Proteases and lipases become activated and destroy nearby cells and blood vessels This initiates an inflammatory response, which further perpetuates pancreatic damage Common symptoms include pain, fever, nausea and vomiting 59 Pancreatitis Chronic Pancreatitis Commonly caused by chronic alcohol abuse Alcohol is metabolized by pancreatic acinar cells and converted into toxic metabolites that damage these cells The release of proteases promotes further damage and initiates inflammatory response Over time, inflammation promotes fibrosis, strictures, pancreatic cysts and ductal obstructions Common symptoms include abdominal pain and weight loss As pancreatic damage accumulates, diabetes mellitus may occur Risk factor for pancreatic cancer 60 30  6/25/24 Pancreatitis https://www.nature.com/articles/labinvest200919 61 62 31