Module 2 Study Guide: GI Disorders, Esophageal & Gastric Disorders - PDF

Module 2 Study Guide Highlight Questions Lecture 2.1: Intro to GI Disorders 1.​ What are anatomical specializations that enable function along the length of the GI tract? Mouth ​ Mechanical digestion (chewing) ​ Salivary Glands o​ Amylase – Breakdown of carbs o​ Lipase –...

Module 2 Study Guide Highlight Questions Lecture 2.1: Intro to GI Disorders 1.​ What are anatomical specializations that enable function along the length of the GI tract? Mouth ​ Mechanical digestion (chewing) ​ Salivary Glands o​ Amylase – Breakdown of carbs o​ Lipase – Breakdown of fats/lipids Esophagus – Peristalsis to move food down to stomach Stomach ​ Mechanical digestion (mixing via peristalsis) ​ HCl (Parietal cells) ​ Pepsin (Chief cells) ​ Lipase (Chief cells) Liver & Gallbladder ​ Produce & store bile, respectively Pyloric sphincter (between stomach & duodenum of small intestine) Duodenum – Further digestion Pancreas ​ Amylase ​ Trypsin ​ Chymotrypsin ​ Lipase ​ Bicarbonate (neutralizes stomach acid) Jejunum – Nutrient absorption Ileum – Nutrient absorption Ileocecal Sphincter (between small & large intestine) Colon (large intestine) – Absorption of Water & Fiber GI Anatomy: Mucosa – Most Variable – Composed of 3 parts: 1)​ Epithelium: cells that line the lumen 2)​ Lamina Propria: connective tissue hosts immune cells 3)​ Muscularis Mucosa: thin muscle layer – provides structure & is important in secretion Submucosa – Dense connective tissue containing glands, as well as blood & lymphatic vessels – Important for taking up nutrients into the body Muscularis – Circular & longitudinal smooth muscle layers that contains myenteric plexus (enteric neurons) – Necessary for gut motility Serosa – Mesothelium that lines the organ – cells produce moist environment to prevent damage when cells rub together 2.​ What are the main functions of the GI tract? 1)​ Digestion: Breakdown of food into macronutrients 2)​ Secretion: Exocrine & Endocrine (e.g. CCK - Cholecystokinin) 3)​ Absorption: Uptake of nutrients, water, and ions from the lumen into the body 4)​ Motility: Mixing & movement of food to facilitate digestion & absorption 5)​ Defense: Immune barrier against harmful components 6)​ Host’s Gut Microbiome: Many important functions in various diseases 3.​ What are the main symptoms of GI disorders? 1)​ Pain: ​ Pain Pathways/Signaling: o​ Ascending pathway senses damage o​ Sends neural information along the spinal cord to the thalamus o​ Relays the perception of pain to the somatosensory cortex o​ Descending pathway inhibits the ascending signals at the level of the spinal cord ​ Visceral Pain: o​ Poorly localized o​ Often referred to somatic structures 2)​ Altered Ingestion: ​ Nausea/Vomiting o​ Nausea: a feeling of sickness in the stomach w/ an inclination to vomit o​ Vomiting: Forcible ejection of undigested GI content from the mouth – Defense mechanism 1.​ Relaxation of LES 2.​ ↑ Intraabdominal pressure – contraction of diaphragm & abdominal muscles 3.​ Closing of epiglottis o​ Vomiting Reflex Mechanism & Medication (Question 4 below) ​ Dysphagia (difficulty swallowing) & Odynophagia (painful swallowing) ​ Anorexia (lack of appetite) o​ Primary anorexia – Anorexia Nervosa o​ Secondary Anorexia – Consequence of disease ▪​ GERD ▪​ Peptic ulcer  ▪​ Crohn’s disease ▪​ Ulcerative Colitis ▪​ Cholecystitis o​ Not treated – CGRP receptor antagonist may be useful in treating anorexia in the future 3)​ Altered Bowel Movements: ​ Diarrhea or constipation 4)​ GI Tract Bleeding – Location & color of the blood can help in diagnosis ​ Stool o​ Bright red blood coating the stool (hematochezia) – Rectum o​ Dark blood mixed w/ the stool (hematochezia) – Colon o​ Black or Tarry stool (Melena) – Esophagus/Stomach/Duodenum ​ Vomit (Hematemesis) o​ Bright red in vomit – Esophagus/Stomach o​ “Coffee-grounds” appearance – Stomach/Duodenum ​ Signs of fatigue and/or anemia may indicate occult blood (“hidden” blood that we can’t see upon visual inspection, but we can test for it) 4.​ What are the mechanisms of action of drugs aimed at treating the main symptoms of GI disorders? 1.​ Pain ​ Pain Pathways/Signaling: a.​ Ascending pathway senses damage b.​ Sends neural information along the spinal cord to the thalamus c.​ Relays the perception of pain to the somatosensory cortex d.​ Descending pathway inhibits the ascending signals at the level of the spinal cord ​ Opioids o​ Inhibit the signal sent from the damaged tissue to the brain via the ascending pathway o​ Stimulate the descending pathway, which inhibits the ascending pathway signals at the level of the spinal cord ​ NSAIDs – inhibition at the level of the tissue damage 2.​ Vomiting Reflex Mechanism & Medication ​ 5-HT3 Receptor Antagonists (e.g. Ondansetron): o​ Blocks 5-HT3-R on Chemoreceptor Trigger Zone Prevents transmitter release to Vomiting Center Prevents Vomiting Reflex o​ Blocks 5-HT3-R in the gut Blocks stimulation of Vagus nerve Blocks ACh release onto Muscarinic receptors on Vomiting Center Prevents Vomiting Reflex ​ D2 Receptor Antagonists (e.g. Prochlorperazine): o​ Blocks Dopamine D2-R on Chemoreceptor Trigger Zone Prevents transmitter release to Vomiting Center Prevents Vomiting Reflex ​ Muscarinic Receptor Antagonist (e.g. Scopolamine – patch for motion sickness): o​ Block Muscarinic Receptor on Vomiting Center Prevents ACh from binding Prevents Vomiting Reflex  3.​ Anorexia (Secondary Anorexia – NOT anorexia nervosa) ​ CGRP Receptor Antagonist would block CGRP release from parabrachial nucleus Prevent CGRP action in Central Amygdala Facilitates food intake as hunger signal would ​ So does that mean ghrelin would block CGRP release??? Lecture 2.2: Esophageal Disorders 1.​ What is the function of the esophagus, and how is the function of the esophagus affected in Achalasia? ​ Function of the esophagus – Transport swallowed food to the stomach w/ 2 main functions: 1)​ Propulsive Functions – Peristalsis: a.​ Food transferred to esophagus via pharynx b.​ UES allows entry of food into esophagus c.​ Esophagus transports bolus from pharynx to stomach d.​ LES allows entry of food into stomach 2)​ Protective Effects: a.​ UES protects airway from swallowed material & gastric reflux b.​ Esophagus clears material refluxed from stomach c.​ LES protects esophagus from gastric reflux ​ Peristalsis – Wavelike propulsion of food – mostly under control of enteric neurons between muscle layers of tunica muscularis o​ Involuntary contraction of muscles behind food – Stimulatory neurons o​ Relaxation of muscles ahead of food – Inhibitory neurons ​ Achalasia: Over-contraction of the LES – Incomplete LES relaxation o​ Difficult for food & liquid to traverse the esophagus ​ Achalasia Pathophysiology o​ Inflammation of the myenteric plexus of the esophagus ▪​ Cause of inflammation unknown: Viral? Toxin?  ▪​ Combined w/ genetic predisposition o​ ↓ in NO synthase containing inhibitory enteric neurons ▪​ Cytotoxic Autoimmune T cells o​ Failure of the LES to relax 2.​ What type of epithelium is normal in the esophagus and how does it change in different disease conditions (e.g. Barrett’s Esophagus)? ​ Normal Epithelium in Esophagus: Stratified Squamous epithelium o​ Beneficial due to constant abrasion of food allowing the top cells to be sequentially sloughed off & replaced without exposing the basement membrane ​ Esophageal Epithelium in Barrett’s Esophagus: Single Columnar epithelium (same as stomach) o​ GERD from defective LES that fails to prevent acid reflux into esophagus, ↑ intragastric pressure, or ↑ acid & pepsin o​ Prolonged GERD can lead to metaplasia of esophageal epithelium cells transform to Columnar epithelium (same as stomach) – Barrett’s Esophagus ▪​ Can progress to Barrett’s Esophagus w/ Dysplasia → Can lead to Adenocarcinoma ​ Prolonged GERD can also lead to erosive esophagitis (inflammation of the epithelium) & peptic strictures (narrowing of the esophagus from scarring of tissue) 3.​ How does the treatment of GERD target the pathophysiological mechanisms? ​ Pathophysiological Mechanisms of GERD: o​ ↓ LES tone → Defective LES fails to prevent acid reflux o​ ↑ Intragastric Pressure → makes it easier for acid to reflux into the esophagus o​ ↑ Acid & Pepsin → ↑ likelihood for acid to reflux into esophagus ​ Pharmacological Treatments Targeting Pathophysiological Mechanisms of GERD: o​ Proton Pump Inhibitor (PPI): Inhibits the H+-K+ Antiporter (ATP-driven) on Parietal cells that is responsible for secreting H+ into the stomach → ↓ Acid secretion o​ H2 Receptor Antagonists: Block histamine H2-Rs on Parietal cells → Prevents histamine (secreted by ECL cells) from binding H2-Rs on Parietal cells → ↓ Proton Pump activity → ↓ Acid secretion o​ Antacids: Neutralize HCl in stomach produced by Parietal cells ​ Lifestyle Modifications Targeting Pathophysiological Mechanisms of GERD: o​ Weight loss: Obesity leads to ↑ intragastric pressure o​ Small regular meals:  ▪​ Large/fatty meals → Delayed gastric emptying → ↑ intragastric pressure, as well as ↑ acid & pepsin o​ Not eating prior to sleep: Eating prior to sleep → delayed gastric emptying → ↑ intragastric pressure o​ Stop smoking: ▪​ Nicotine → ↓ LES tone → Defective LES fails to prevent acid reflux o​ Avoid: ▪​ Certain medications: ​ Anticholinergics → ↓ LES tone → Defective LES fails to prevent acid reflux ​ NSAIDs → ↑ acid & pepsin ▪​ Carbonated drinks → ↑ intragastric pressure ▪​ Caffeine → ↓ LES tone → Defective LES fails to prevent acid reflux ▪​ Alcohol, citrus or spicy foods → ↑ acid & pepsin Lecture 2.3: Gastric Disorders 1.​ What are the anatomical differences in epithelium between the body & antrum and how does it regulate acid secretion? Body – Gastric pits w/ Oxyntic Acid-producing cells ​ Parietal cells (acid-producing cells) – secrete H+ & Cl− ions into lumen (luminal side) o​ Stimulated by gastrin, PSNS, histamine (from ECL cells) o​ Inhibited by somatostatin ​ ECL cells (release histamine to stimulate Parietal cells) – secrete Histamine on basolateral side o​ Stimulated by gastrin, PSNS o​ Inhibited by somatostatin ​ Chief cells (secrete digestive enzymes) – secrete pepsinogen, gastric lipase into lumen (luminal side) o​ Stimulated by gastrin, PSNS ​ Surface mucus (Foveolar) cells – Secrete mucus, bicarbonate, & surfactant into lumen (luminal side) Antrum – Contains Endocrine cells ​ Gland & Surface mucus (Foveolar) cells – Secrete mucus, bicarbonate, & surfactant into lumen (luminal side) ​ G cells – Secrete Gastrin (Basolateral side) o​ Stimulated by amino acids (from protein-rich meal) o​ Inhibited by somatostatin ​ D cells – Secrete Somatostatin in response to low pH (Basolateral side) Regulation of Acid Secretion: 2.​ What are the protective barriers of the stomach and how are these disrupted in peptic ulcer disease? 1)​ Regulation of Acid & Enzyme Production ​ Only released in response to food (amino acids) 2)​ Mucosal Barrier ​ Apical membrane resistance (to ↓ pH) ​ Gastric surfactant ​ Mucus ​ Bicarbonate 3)​ Epithelial Regeneration ​ ↑ Vascularization ​ Thick mucoid cap ​ Prostaglandins ↑ cell turnover Peptic Ulcer Disease (PUD) ​ Helicobacter pylori: o​ CagA injected into epithelial cells → disrupts epithelial integrity o​ VacA promotes apoptosis → Acid infiltration through damaged epithelium → ↑ inflammation → ↑ Vagus (PSNS) stimulation & ↑ Gastrin (G cells) → stimulation of ECL cells & Parietal cells → damage to mucosa & submucosal layers ​ NSAIDs: 1)​ Disrupt protective mechanisms ​ Cytotoxic to epithelial cells ​ ↓ Mucus production via Foveolar cells 2)​ ↓ Epithelial repair ​ ↓ Epithelial blood flow → ↑ Bleeding  3)​ ↑ Acid production – Not enough on its own to cause PUD 3.​ How does the treatment of Zollinger-Ellison Syndrome target the pathophysiological mechanism? Zollinger-Ellison Syndrome Mechanism: ​ Gastrin-producing tumor (gastrinmoa) causes ↑ gastrin secretion → stimulates ECL cells (release histamine to stimulate parietal cells) & Parietal cells (secretes acid) o​ Gastrinoma does NOT respond to somatostatin (inhibitory signal) produced by D cells → Continuous gastrin secretion How the treatment targets the pathophysiological mechanism: ​ Proton Pump Inhibitors (PPIs) block the ATP-driven H+-K+ antiporter (Proton pump) on parietal cells → Inhibition of acid (HCl) secretion despite the ↑ parietal cell stimulation by gastrin & gastrin-mediated histamine release from ECL cells ​ Antacids neutralize the ↑ HCl secretion stimulated by ↑ gastrin ​ Surgical removal of sporadic gastrinoma: Physically removes gastrin-producing tumor 4.​ What is the Pathophysiology of gastric cancer? Lecture 2.4: Liver Disorders 1.​ What are the main functions of the liver? 1)​ Processing of Nutrients Carbs Protein Lipids ​ Bile acids help in the digestion of fats ​ Fatty acids in the blood are absorbed by hepatocytes & metabolized to ATP and can be converted to glucose by gluconeogenesis, and then stores it as fat 2)​ Protection & clearance of harmful & toxic chemicals from the body ​ Immune System o​ Kupffer cells: Phagocyte system o​ Capture & digest bacteria, fungi, parasites, worn-out blood cells, and cellular debris ​ Detoxification o​ Phase 1: Oxidizes toxins to make them soluble o​ Phase 2: Conjugation to glutathione o​ Excretes toxins & waste through bile/urine ▪​ Breaks down alcohol, drugs, environmental chemicals into inactive metabolites ▪​ Metabolic end products (e.g. ammonia into urea) and bacterial endotoxins 3)​ Synthesis of plasma proteins & bile salts ​ Albumin (~50% of plasma proteins) o​ Oncotic pressure that allows blood to travel through capillaries ​ Coagulation factors necessary for blood clots o​ Fibrinogen o​ Prothrombin ​ Transport & Binding of iron o​ Apoferritin (iron storage) o​ Transferrin (transport of iron) ​ Bile salts 2.​ What is the pathogenesis of cirrhosis? How does the pathogenesis result in further complications? What are the current & possible treatment options for treating the pathogenesis? Pathogenesis of Cirrhosis – Ultimately caused by inflammation in the Space of Disse ​ Mechanism of Inflammation in the Space of Disse (using alcoholic liver disease as model) 1)​ Alcohol acts as solvent for lipids → Dissolves phospholipid membranes → Disrupts hepatocyte function → Inflammation in the Space of Disse 2)​ Alcohol metabolized by ADH to acetaldehyde → NFκB activation → Cytokine expression → Inflammation in the Space of Disse  a.​ ↑ ADH activity → ↑ NADH → Kupffer cell activation → Cytokine expression → Inflammation in the Space of Disse b.​ ↑ ADH activity → ↓ NAD+ & ↑ NADH → Inhibition of gluconeogenesis (lack of fat oxidation) → ↑ Fat deposits in space of Disse → Inflammation in the Space of Disse c.​ 2° Oxidation when ADH is exhausted → ↑ Free radicals → DNA damage → Inflammation in the Space of Disse ​ Mechanism Leading to Cirrhosis: 1)​ Cytokines activate steallate cells (key player) 2)​ Fibrin & collagen deposits in Space of Disse 3)​ Scarring in the Space of Disse → acts like dams a.​ ↓ Blood & bile flow 4)​ Hepatocytes starved of nutrients → Hepatocytes Die 5)​ ↑ Inflammation → Repeat Step 1 (Vicious Cycle) Cirrhosis Pathogenesis Results in Further Complications: ​ Portal Hypertension (most serious): Destruction of sinusoidal architecture → ↑ resistance to portal flow → portal hypertension o​ Ascites: ▪​ Portal hypertension → ↑ Hydrostatic pressure + ↓ Albumin (↓ Oncotic pressure) → Ascites ▪​ Portal hypertension → Splanchnic vasodilation → Systemic arterial underfilling → Activation of AVP & RAAS → Renal Na+ & water retention – Ascites o​ Variceal hemorrhage: Portal hypertension → ↑ Pressure beyond maximal point → Rupture & bleed ​ Bacterial Peritonitis: usually from infection of the ascites fluid → Inflammation of peritoneum where ascites fluid leaks into ​ Hepatic Encephalopathy: Buildup of toxic compounds (e.g. NH3) damages the brain o​ Liver unable to efficiently convert NH3 to urea following amino acid metabolism → ↑ [NH3] → NH3 gets into brain and damages neurons → Hepatic Encephalopathy  ​ Hepatocellular Carcinoma: 2° Oxidation pathway → ROS (free radicals) → DNA damage → potential genetic mutations that can lead to hepatocellular carcinoma Current & Possible Treatment Options for Treating the Pathogenesis of Cirrhosis: ​ Cirrhosis: o​ Liver transplant – Cirrhosis is irreversible o​ Antifibrotic drugs are being investigated as future therapy ​ Cirrhosis due to Viral Hepatitis – Pre-Emptive Treatment: o​ Vaccination against HepA, HepB, and HepE o​ Don’t drink so much ​ Underlying Conditions of Cirrhosis: o​ HepC: interferon & ribavirin o​ Autoimmune: Corticosteroid prednisone, immunosuppressants (e.g. Azathioprine) o​ NASH (Non-Alcoholic Steatohepatitis): weight reduction through diet & exercise o​ Alcoholic Liver Disease: Abstain from drinking ​ Complications of Cirrhosis: o​ Ascites: Restrict dietary salt, diuretics (Aldactone), abstention from alcohol o​ Peritonitis: Antibiotic therapy (e.g. Cefotaxime) o​ Encephalopathy: Protein restricted diet to ↓ NH4+ o​ Portal Hypertension: β-Blockers to ↓ portal blood flow Also Important: 3.​ What are the different types of cholestasis? What is the pathogenesis and what are the treatment options? 2 Main Types of Cholestasis: Hepatocellular Cholestasis Obstructive Cholestasis G Damaged, malfunctioning hepatocytes are not able Intrahepatic (i.e. Compression of biliary canaliculi) e to pump bile salts & conjugated bilirubin into the ​Gallstones bile ducts ​Hepatocellular swelling – e.g. Fatty liver, NASH n ​ Bile synthesis is driven by bile acid secretion into ​Solid tumors – e.g. Cholangiocarcinoma e canaliculi, so if bile acids build up within hepatocytes, ​Fibrosis around the biliary system – e.g. Chronic Hepatitis r this results in downregulation of overall bile production Extrahepatic (i.e. Outside liver) – Physical Blockage a ​Conjugated (direct) bilirubin also builds up in the hepatocytes → Excess bilirubin will leak out into the ​Tumors – e.g. Pancreas, biliary tract, duodenum l ​Inflammation – e.g. Pancreatitis blood → Jaundice ​Fibrosis – e.g. Chronic pancreatitis I o​ Conjugated bilirubin transported by MRP2 transporter n f o Intrahepatic – Gallstone Formation P a t h o Gallstone Diseases g 1)​ Cholelithiasis (gallbladder) 2)​ Cholecystitis (gallbladder) e Gallstones in gallbladder – usually Inflammation of the gallbladder n cholesterol stones (also estrogen) ​ Usually caused by gallstone e blocking cystic duct s i s & T r Treatment(s): ​ Tends to be asymptomatic, but can e Prevent bile acids from getting into the blood ​ Ursodeoxycholic acid (UDCA, 2° bile acid present as biliary colic ​ Diagnosis: Ultrasound ​ Symptoms: Abdominal pain, fever, nausea a synthesized by black bear): ↓ Bile acids in blood by ​ Complications: Cholecystitis, ​ Diagnosis: Ultrasound choledocholithiasis, pancreatitis t preventing re-uptake from intestine & ↓ bile acid ​ Complications: Gangrenous cholecystitis, production Treatment: perforated gallbladder, death m Elective cholecystectomy Treatment: ​ Cholestyramine: Chaperones bile acids out in the e feces (NOT as effective as UDCA) Cholecystectomy n ​ Dexamethasone: Steroid to help ↓ itch t ( Newer Drugs (Phase 3 Trials): ​Inhibition of Bile Acid Synthesis s o​ FGF19 Analogs & FXR Agonists: ↓ de novo ) bile acid synthesis by blocking rate-limiting enzyme of bile acid generation CYP7A1 ​Block Bile Acid Re-Uptake at Terminal Ileum o​ ASBT Inhibitors & FXR Agonists: Block ASBT transporters so that bile is lost via the feces 3)​ Choledocholithiasis (bile duct) 4)​ Cholangitis (bile duct) – Gallstones in the bile duct – usually Choledocholithiasis w/ bacterial pigment stones (but can also be infection cholesterol stones) → Proximal inflammation & obstructive jaundice ​ Harciot’s Triad: Jaundice, Fever, Upper-right quadrant pain ​ Diagnosis: Dilated hepatic bile ducts ​ Diagnosis: Ultrasound ​ Complications: Gallstone pancreatitis, ​ Very severe – high likelihood of Cholangitis death if not immediately treated Treatment: Treatment: ERCP (Endoscopic Retrograde Emergent ERCP Cholangio-Pancreatography) – to remove small blockage Lecture 2.5: Pancreas Disorders 1.​ What are the main products of exocrine pancreas? How are these regulated? Main Products of Exocrine Pancreas (>90% of pancreas) 1)​ Digestive enzymes necessary for digestion – 3 predominant types released by Acinar cells 1.​ Proteolytic enzymes (Protein digestion) – 3 types that target different peptide linkages ​ Trypsinogen – peptide bonds (not terminal), activated by enterokinase into active Trypsin ​ Chymotrypsinogen – peptide bonds (not terminal), activated by Trypsin into active Chymotrypsin ​ Procarboxypeptidase – terminal AA on carboxyl terminus o​ Secreted in inactive form o​ End result is formation of small peptide chains & amino acids 2.​ Pancreatic Amylase (Carb digestion) o​ Catalyzes conversion of polysaccharides → maltose (disaccharide) o​ Secreted in active form because no risk for auto-digestion of the pancreas 3.​ Pancreatic Lipase (Fat digestion) – Requires bile salts to be present o​ Catalyze hydrolysis of triglycerides into monoglyceride + free fatty acids o​ Only enzyme that can digest fat – Secreted in active form ​ Stored in zymogen granules – Released by exocytosis o​ Sufficient for digestion of all food 2)​ Secretion of bicarbonate (HCO3−) to neutralize stomach acid Regulation of Main Products of Exocrine Pancreas 1)​ Digestive Enzymes: 1.​ Fat & Protein products in duodenal lumen → 2.​ ↑ CCK (cholecystokinin) release from duodenal mucosa → CCK carried by blood 3.​ CCK stimulates pancreatic Acinar cells → 4.​ ↑ Release of digestive enzymes by Acinar cells: ​ CCK is the Primary Regulator ​ Also exhibits a (–) feedback role as available fats & proteins ↓ ​ Lipases produced by pancreas are inactivated by ↓pH 2)​ Bicarbonate (HCO3−) secretion: 1.​ Acid present in duodenal lumen → 2.​ ↑ Secretin release from duodenal mucosa → secretin carried by blood 3.​ Secretin stimulates duct cells → 4.​ ↑ NaHCO3 (aq) secretion into duodenal lumen → Neutralizes acid a.​ Also serves negative feedback role on Secretin release 2.​ What are the causes of pancreatitis? What are the mechanisms that result in loss of pancreatic function? How do acute & chronic pancreatitis differ? Causes of Acute Pancreatitis Anything that results in early activation of trypsinogen, resulting in autodigestion of the pancreas → Major Causes: Heavy alcohol use & Gallstones ​ Injury to acinar cells ​ Impaired secretion of proenzyme ​ Alcohol-Induced Blockage: o​ Alcohol-induced synthesis of enzymes o​ Over-sensitization of acini to CCK ​ Gallstone Pancreatitis: o​ Obstruction at the Ampulla of Vater and/or o​ Reflux of bile into the pancreatic duct due to transient obstruction of the Ampulla of Vater Mechanism Resulting in Loss of Function in Acute Pancreatitis ​ Autodigestion Mechanism (Hypotheses) 1)​ Hyperactive acinar cells results in inappropriate zymogen granules fusion w/ lysosomes ​ Promotes activation of trypsinogen ​ → Autodigestion of pancreas 2)​ Blockage causes swelling & compression of blood vessels leading to ischemia of acinar cells ​ Necrosis of the pancreas & inflammation ​ Inflammatory cytokine released from acinar cells → recruits neutrophils that release superoxide & proteases ​ → Digestion of pancreas Causes of Chronic Pancreatitis: Also caused by autodigestion of the pancreas – Major Causes: 1)​ Persistent alcohol abuse ​ Associated w/ calcium deposits that harden the protein plug & therefore less likely to reverse 2)​ Repeated bouts of acute pancreatitis ​ ↑ Potential for cyst & damage to pancreatic tissue ​ Fibrotic tissue accumulates, causing narrowing of ducts & acinar cell atrophy 3)​ Hereditary (e.g. trypsinogen defects) 4)​ Cystic Fibrosis ​ CFTR gene mutations disrupts ion transport, resulting in pancreatic juices being thick & sticky ​ ↑ Cysts & fibrosis generation ​ Main cause of chronic pancreatitis in children  Mechanism Resulting in Loss of Function in Chronic Pancreatitis 1)​ Irreversible changes to pancreatic structure ​ Acinar atrophy ​ Fibrotic strictures ​ Calcification ​ Protein plugs 2)​ ↓ Function of the pancreas ​ Pancreatic insufficiency → makes it difficult to digest food 3)​ Destruction of α & β cells ​ Prevents release of insulin & glucagon, and normal energy storage → can lead to diabetes Acute vs. Chronic Pancreatitis Acute Pancreatitis Chronic Pancreatitis G e n Sudden inflammation of the pancreas that resolves Persistent, chronic inflammation of the pancreas (Reversible) – Caused by autodigestion of pancreas ​Also caused by autodigestion of pancreas, but results in e ​May be mild structural damage r ​ If severe → Life-threatening ​ Irreversible a l Pain Pain S ​Typical: Gradual chronic severe debilitating pain in upper ​Typical: Sudden onset dull abdominal pain, radiates to back y – Lasts several days, exacerbated w/ eating abdomen – Can radiate to back ​Atypical: Lower abdominal pain (50%) m Altered Ingestion Altered Ingestion ​Typical: Nausea p ​ALARM: Loss of appetite ​Typical: Nausea, Loss of appetite ​Typical: Malabsorption & Malnutrition (enzymes necessary t Excretion for digestion are absent) o ​Typical: Vomiting Excretion ​Typical: Diarrhea & fatty, pale stools, Vomiting m s Blood Serum D ​Amylase & Lipase can be ↑ or absent i ​Destruction of acinar cells can result in no synthesis of amylase & lipase a Transabdominal CT Scan g ​Look for calcification in dilated pancreatic duct n Serum o ​ ↑ Amylase: 3× normal levels rapidly s ​ ↑ Lipase: Elevated about a week Abdominal X-ray: Exclude gastroduodenal perforations i CT Scan: Gallstones, inflammation, necrosis, pseudocysts s 1.​ INTENSIVE CARE REQUIRED Medication that perform pancreas function T ​PPI & Pancreatic enzyme supplements ​Electrolyte replacement: IV fluids r ​Pancreatic rest (no food) – Since pancreatitis usually from Manage Pain ​NSAIDs/Opioids/Tricyclic antidepressants e overstimulation of pancreas Lifestyle Modifications 2.​ Treating Symptoms a ​Pain: IV (NOT morphine – it ↑ contraction of Sphincter of ​Dietary changes (low-fat foods) → ↓ CCK release → ↓ Load on pancreas t Oddi) ​Stop smoking, Avoid alcohol m ​Antiemetics ​Treatment for gallstones 3.​ Identify & treat underlying cause (e.g. alcohol abuse) Surgery e ​Stent of pancreatic duct to maintain duct patency → n Probably the MOST effective treatment t  Pancreatic Pseudocyst Malabsorption C ​ Fibrous tissue that fills w/ pancreatic juices ​Steatorrhea (excretion of abnormal quantities of fat w/ o ​ Ruptured release of pancreatic enzymes into abdominal cavity can feces due to ↓ fat absorption by intestine) result in systemic inflammatory response syndromes (SIRS) – m Inflammatory state that affects the whole body & can lead to acute Malnutrition ​↓ Enzymes prevents appropriate digestion & absorption p organ failure (specifically lungs & kidneys) of food Disseminated Intravascular Coagulation (DIC) l ​ Blood clots form in the body using up all clotting factors Diabetes i ​ ↑ Risk of hemorrhage ​ Extensive pancreatic damage → loss of α cells Acute Respiratory Distress Syndrome (ARDS) (glucagon) & β cells (insulin) c ​ Massive inflammation from pancreas leads to alveolar collapse in a the lungs → Makes it hard to breath ​ Leading cause of death t i o n s Sudden Inflammation Persistent Inflammation Autodigestion Structural Damage Reversible Irreversible 3.​ What is the role of the endocrine pancreas? What function does insulin perform? What is the cause of Type 1 Diabetes? Role of the Endocrine Pancreas (2% of the pancreas) Endocrine cells clustered in Islets of Langerhans ​ α cells release glucagon → Promotes energy utilization o​ Glycogenolysis: Break down stored glycogen into glucose (used for energy) o​ Gluconeogenesis: Convert amino acids and/or fatty acids to glucose (used for energy) ​ β cells release insulin → Promotes energy storage o​ Glycogenesis: Glucose uptake from blood to be stored as glycogen (liver & muscle) o​ Glycolysis: Glucose uptake from blood for normal aerobic respiration ​ δ cells release somatostatin → Inhibits release of glucagon & insulin Functions Performed by Insulin Ultimately, insulin signals a state of energy abundance ​ Insulin activates glucose uptake, metabolism, and storage as glycogen ​ Insulin facilitates amino acid uptake into tissues → Important for protein synthesis ​ Insulin restrains processes that release stored energy Cause of Type 1 Diabetes Autoimmune: T cells infiltrate Islets of Langerhans & destroy β cells → Pancreas cannot produce insulin → Glucose remains in blood & cannot be taken up be cells Lecture 2.6: Small Intestine Disorders 1.​ What anatomical specializations of the small intestine are involved in digestion & absorption of macronutrients? Digestion: ​ Epithelial cells express enzymes to break down macronutrients into smaller components ​ Carbohydrates: o​ Pancreatic Amylase secreted into small intestine lumen o​ Disaccharidases secreted by small intestine epithelium ​ Protein: o​ Dipeptidases, Carboxypeptidase, and Aminopeptidase secreted by small intestine epithelium ​ Fat: o​ Bile salts secreted into small intestine lumen → mixing → micelle formation → pancreatic lipase digests fats to fatty acids + monoglycerides Absorption: ​ Various Cell Types: o​ Enterocytes: Absorptive cells o​ Goblet Cells: Mucus secreting; promote diffusion of gut content o​ Enteroendocrine cells: secrete hormones that regulate digestion & absorption ​ Modified epithelium to ↑ surface area for ↑ absorption (Total SA is ~100× larger than SA of the body) o​ Plicae: folds in small intestinal mucosa o​ Villi w/ Crypts: each villus contains as many as 1000 microvilli that collectively make up the brush border o​ Microvilli: luminal membrane of each epithelial cell consists of ~1000 microvilli (brush border membrane) 2.​ How does gluten cause Celiac disease? How does it cause inflammation & damage to the epithelium? Gluten composed of 2 proteins – Glutenin & Gliadin (Gliadin important in pathogenesis of Celiac disease):  1)​ Gliadin activates CxCr3 → CxCr3 activates zonulin 2)​ Zonulin causes disengagement of zona occludin (tight junctions) 3)​ ↑ Intestinal permeability allows gliadin to enter lamina propria 4)​ Gliadin can also promote enterocyte release of IL-15 a.​ IL-15 activates intra-epithelial lymphocytes to express NKG2D (NK cell) receptors 5)​ Gliadin (or stress) also promotes MycA synthesis in enterocytes a.​ MycA activates NKG2D & lymphocytes (NK cells) release granzymes & perforins 6)​ Enterocytes die 7)​ More gliadin enters the lamina propria 8)​ Tissue transglutaminase (TTG) removes the amide group from gliadin → deamidated gliadin (↑ immunogenicity) 9)​ Gliadin is processed by APC & presented by MHC-II receptors (HLA-DQ2 or 8) to Helper T cells (CD4) 10)​T cell stimulation → cytokine release → further tissue damage a.​ Helper T cells also activate B cells b.​ B cells make Abs against TTG & Gliadin 3.​ What are the different mechanisms by which Celiac disease & lactose intolerance cause malabsorption? Celiac Disease: 1)​ Villous Blunting: Flattening of the villi → ↓ SA → ↓ Absorption 2)​ Lymphocyte Proliferation: NK cell activation & Helper T cell activation → B cell activation 3)​ Crypt Elongation: ↓ Exposed/available SA (combined w/ villous blunting) → ↓ Absorption Also, enterocyte (absorptive cell) death (step 6 above) → ↓ Absorption Collectively, this results in: ​ ↓ Absorption of Vitamin A, zinc, & nutrients necessary for healthy immune system ​ ↓ Absorption of Ca2+ & Vitamin D → ↑ risk of bone fractures Lactose Intolerance: 1)​ Lactase enzyme deficiency (normally in brush border) → Cannot hydrolyze lactose to glucose & galactose 2)​ Lactose travels to large intestine → Fermented by bacteria 3)​ Production of gas & acids → Flatulence & abdominal pain  ​ Leads to inflammation → Epithelial cell damage → ↓ Absorption ​ Lactose (osmotically active) retained in small intestinal lumen creates osmotic gradient → osmotic diarrhea → nutrients spend less time in intestinal tract & are removed more quickly → ↓ Absorption 4.​ What are the management options for treating Celiac disease & lactose intolerance? Celiac Disease ​ Only effective treatment option is a gluten-free diet – No wheat, barley, rye, etc. Lactose Intolerance ​ No “cure” (no way to promote lactase expression on brush border of small intestine) ​ Avoid dairy to reduce irritation & inflammation symptoms ​ Take supplements to fix digestive problems (e.g. lactase enzyme prior to dairy-containing meals) ​ Consume probiotics & prebiotics to improve gut health – Some evidence supports this Lecture 2.7: Large Intestine Disorders 1.​ What is the role of the large intestine in fluid absorption? What cells are involved? What is the mechanism of fluid absorption? Main function of the large intestine is absorption of water, bile salts, and electrolytes ​ Fluid is critical for intestinal function – GI tract secretes a HUGE volume of fluid each day: o​ Permits contact of food w/ digestive enzymes o​ Diffusion of digested nutrients to site of absorption o​ Fluidity of contents allows transit without damage to the epithelium ​ Large intestine is very efficient in conserving fluid Cells Involved: ​ Enterocytes (w/o villi/microvilli) – Absorption of water, bile salts, and electrolytes ​ Crypt cells – secretion of Cl− → for creating electrical potential that attracts Na+ into the lumen to create osmotic gradient for pulling water into the lumen (opposite of absorption) Mechanism of Fluid Absorption from the Lumen: Overall, water diffuses in response to the osmotic gradient established by Na+ 1)​ Na+-Glucose & Na+-Amino Acid symporters are primary mechanisms for Na+ transport: ​ Na+ binds transporter → ↑ affinity for glucose/AA ​ Change in conformation releases Na+ into the cell & reduces the affinity for glucose/AA → glucose/AA released into cell 2)​ Once in the cell, Na+ is rapidly pumped out (toward interstitial space) through an active Na+-K+-ATPase 3)​ Na+ reaches very high conc. in the narrow space between enterocytes ​ A potent osmotic gradient is thus formed across apical cell membranes 4)​ Water is absorbed into the intercellular space & through tight junctions by diffusion down the osmotic gradient Note about Water Secretion into Lumen during Digestion: ​ As digestion proceeds, luminal osmolarity ↑ dramatically → water pulled into lumen → ↑ luminal osmotic pressure ​ As osmotic molecules are absorbed, water is reabsorbed – Water absorption driven by Na+ 2.​ What are the different mechanisms that are disrupted in diarrhea? What are the treatment options? Mechanisms Disrupted in Diarrhea Osmotic Secretory Motility Inflammatory G e n e r ↑ Luminal Osmolarity Excessive secretion of water & electrolytes into intestinal lumen Change in intestinal motility Inflammation a l C ​Malabsorption syndromes ​ Infection from enterotoxigenic ​ Surgery ​ IBD (Crohn’s disease, (e.g. Celiac disease) bacteria/pathogens or virus ​ Medications Ulcerative Colitis) a ​Lactose intolerance ​ Pancreatic tumor, u Zollinger-Ellison syndrome ​Mg2+-containing antacids ​ Laxatives & other drugs that ↑ s cAMP – cAMP drives CFTR (a e cAMP-dependent Cl− channel) s  ​Ingestion of poorly ​ Hyperactivity of CFTR or CaCC ​ ↑ Motility → ↓ Contact time ​ Destruction of epithelium due to P absorbed substrates – e.g. (apical membrane) → ↑ Cl− w/ epithelium → ↓ immune response → ↓ a carbs or divalent ions, release into lumen → draws Na+ Absorption → ↑ Defecation epithelium integrity → ↓ t lactose intolerance into lumen → water drawn into volume absorption h lumen by Na+ ​ Compounded by secretory & ​Malabsorption osmotic mechanisms: o o​ Normal mechanism for water absorption is disrupted due to o​ Secretory diarrhea: Due to p ↑ CFTR or CaCC activity inflammatory h mediators/cytokines y o​ Osmotic diarrhea: Damaged s epithelial cells replaced by i immature cells w/o fully o functional brush border l enzymes or transporters o necessary for digestion & nutrient absorption, g respectively → Osmotic y diarrhea C Ceases w/ fasting ​ Large stool volumes (>1 L/day) ​ Rapid, small, coupling ​ Bowel movements h ​ Fasting does NOT alter stool bursts of waves of diarrhea consisting of only mucus, a volume exudate, and blood r a c t e r i s t i c s Treatment Options for Diarrhea: ​ Opiates & opioid derivatives (e.g. Loperamide) o​ Delayed intestinal motility o​ Prolong contact time w/ epithelium & absorption ​ Bismuth Subsalicylates (e.g. Pepto-Bismol) o​ Anti-secretory o​ Reduction in motility o​ Bactericidal action 3.​ What are the mechanisms that lead to IBD? What is the difference between Crohn’s disease & Ulcerative colitis? What are the treatment options? IBD (Inflammatory Bowel Disease) – Hypothesized Mechanisms 1)​ Dysregulated Immune Response ​ Genetic risk factors – ↑ Genetic Risks are a critical component of the IBD pathogenesis o​ Leads to immune system that overreacts to environmental & microbial stresses o​ This specifically occurs w/ APCs that will take up bacteria/toxic compound & signal inappropriately → cascade of events → inflammation → T cell recruitment → Apoptosis & necrosis of mucosal lining ​ Incorrect overactivity of immune cells: o​ IBD triggered when immune system mistakenly recognizes something normally considered harmless to be a threat → mount an attack against it 2)​ Persistent Infection & Dysbiosis ​ IBD PTs tend to have different bacterial composition compared to normal healthy PTs 3)​ Defective Mucosal Integrity ​ Hypothesis: Bacteria can pass through & trigger immune response  Ulcerative Colitis vs. Crohn’s Disease ​ Ulcerative Colitis: o​ Rectal bleeding more common than in Crohn’s disease o​ Only affects Mucosa (outermost layer) ​ Crohn’s Disease: o​ Nutrient malabsorption more common due to patchy inflammation o​ Fistulas can make their way all the way down through the muscularis to the serosa Symptoms of Ulcerative Colitis & Crohn’s Disease Ulcerative Colitis Crohn’s Disease Abdominal pain Abdominal pain Rectal bleeding Diarrhea Nausea Bloody diarrhea Vomiting Weight loss Starts at the rectum & progresses continuously Has a discontinuous pattern throughout the GI tract through the colon Affects only the colon Can affect the entire GI tract ​ Complications of Ulcerative Colitis & Crohn’s Disease Ulcerative Colitis Crohn’s Disease Toxic megacolon Fistulas Severe bleeding Sepsis Perforated colon Intestinal obstruction ↑ Risk of colon cancer Vitamin B-12 malabsorption Treatment Options for Ulcerative Colitis & Crohn’s Disease  Ulcerative Colitis Crohn’s Disease Control Acute Flares Aminosalicylates Aminosalicylates Corticosteroids Corticosteroids Thiopurines Antibiotics Maintain Remission Aminosalicylates Immunomodulators Thiopurines TNFα Inhibitors Ciclosporin (severe UC) Methotrexate IBS – Hypothesized Mechanisms: ​ Altered GI Motility – Associated w/ the Altered Bowel Movements – Primarily for IBS-D only 1)​ Osmotic: Unabsorbed osmotic carbohydrates act as solutes drawing water across the epithelium into the lumen 2)​ CRF-mediated: Low-grade immune response activates dendritic cells to release corticotropin-releasing factor (CRF) to ↑ motility → ↓ water reabsorption → diarrhea ​ Visceral Hypersensitivity – Associated w/ the Recurrent Abdominal Pain 1)​ Inflammatory: Tachykinins released from enteric neurons of the gut cause inflammation near sensory fibers 2)​ Bacterial Gas: Bacterial consumption of unabsorbed carbohydrates produce gas that triggers stretch receptors on sensory fibers Module 2 (Lecture 2.8) GI & Liver Assessment Diseases & Associated Symptoms Disease Symptoms GERD ​ Burning sensation (heartburn) ​ Occurs after eating ​ May worsen at night (Gravity issue: Go to sleep after eating → laying down makes it easier for acid to travel into the esophagus) ​ Acid regurgitation ​ Chest pain ​ Difficulty swallowing (dysphagia) ​ Chronic cough ​ New or worsening asthma ​ Disrupted sleep PUD Common Symptoms: More Severe Symptoms (not specific to PUD – need ​ Burning pain of the stomach to evaluate w/ other factors too) ​ Feeling of fullness, bloating or belching ​ Vomiting of blood ​ Heartburn ​ Black or tarry stool ​ Nausea ​ Trouble breathing ​ Fatty food intolerance ​ Fainting ​ Unexpected weight loss Could indicate more serious problems, including cancer Liver Possible Causes Typical Symptoms Diseases ​ Viral Hepatitis ​ Right-upper-quadrant pain ​ Cholestatic syndromes ​ Jaundice ​ Drug-induced (e.g. Acetaminophen) ​ Fatigue ​ Alcoholic ​ Itching ​ Non-Alcoholic fatty liver ​ Nausea ​ Autoimmune ​ Poor appetite ​ Genetic ​ Abdominal distension ​ Systemic diseases affecting the liver ​ Intestinal bleeding ​ Vascular injury ​ Asymptomatic ​ Mass lesions ​ Found on routine screening or visits Lab Tests & Markers of Injury Liver Marker Normal Range Origin Specificity Clinical Significance Mainly Less specific than ↑ AST (>35 IU/L): hepatocytes, but ALT Hepatocellular Damage AST (Aminotransferase) < 35 IU/L also skeletal & (although not necessarily cardiac muscle true – need to do other tests to confirm) Predominantly More specific for Ratio AST/ALT >2:1 ALT (Alanine Aminotransferase) < 35 IU/L from hepatocytes hepatocyte damage suggests alcoholic liver disease Biliary tract & >4× ULN → Biliary Obstruction ALP 30–120 IU/L bone > ALP elevation Hepatocellular disease ALP elevation >> AST/ALT elevations Cholestatic disease (↓ bile flow) AST/ALT > 1:1 Cirrhosis (hepatitis C) AST:ALT ≈ 1:1 w/ ↑ GGT Viral/Drug-induced Other Markers of Function Marker Normal Range Characteristics Clinical Significance Important for: ↓ Serum albumin (< 3.3 g/L) synthesis in Serum Albumin 3.3–5.0 g/L ​ Maintaining Chronic Liver Disease Most abundant serum protein osmotic pressure ​ Binding drugs Indirect Subtherapeutic INR → ↑ risk of thromboembolism measuring of Supratherapeutic INR → ↑ risk of bleeding coagulation PT/INR factors ↓ PT synthesis (↑ INR) in Chronic Hepatocellular (Prothrombin Time/International 0.9–1.2 disease Normalized Ratio) Vitamin K deficiency also ↑ INR (↓ clotting factors ⇒ ↑ INR) Conjugated/Direct ↑ Unconjugated Bilirubin → ↓ Bilirubin metabolism → Bilirubin from Liver Gilbert’s syndrome (Genetic disease w/ mutation in [Tbili] = 0.1–1.2 mg/dL UGT1A1 gene – usually not harmful) Unconjugated/ Serum Bilirubin Indirect Bilirubin Mixed ↑ Tbili & Dbili: [Dbili] = ≤ 0.2 mg/dL from RBC ​ Need to consider liver enzymes, liver source Total [Tbili] Conjugated/Direct [Dbili] metabolism (NOT confirmation w/ elevated liver enzymes [Unconjugated/Indirect] from liver) ​ Exceptions: Liver enzymes may be normal in severe = ≤ 0.1–1.0 mg/dL liver disease; e.g. Cirrhosis ​Determine if it’s hepatocellular or cholestatic disease NOTE: “AST/ALT > 1:1 – Cirrhosis (hepatitis C)” and “AST:ALT ≈ 1:1 w/ ↑ GGT – Viral/Drug-induced” on liver test interpretation (red boxes) were from undergrad pathophysiology – these were not mentioned in our lectures.