GI Lectures 6-10 PDF
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This document details various disorders of the upper gastrointestinal (GI) tract, including the gastric phase, somatostatin regulation, and the role of NSAIDs. It also discusses bilirubin metabolism, gallstones, and other related topics. The document seems to be part of a larger educational series on the GI system.
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Lecture 6: Disorders of upper GI V agal fibers release gastrin-releasing peptide (GRP) Grinding, mixing, gastric emptying of solids → antral motor function Gastric phase: ○ Food triggers vagovagal reflex...
Lecture 6: Disorders of upper GI V agal fibers release gastrin-releasing peptide (GRP) Grinding, mixing, gastric emptying of solids → antral motor function Gastric phase: ○ Food triggers vagovagal reflexes ○ Stimulates gastrin secretion Acidification of the gastric antrum stimulatessomatostatin Somatostatin ○ Inhibitsgastrin release and acid secretion ○ Vagal acetylcholine (Ach)inhibitssomatostatin NSAIDsreduceacid secretion Disruption of protective mechanisms → gastropathy/gastritis ○ inhibition of COX by NSAIDs ○ inhibition of gastric bicarb transporters by ammonium ions ○ reduced mucin and bicarb secretion ○ decreased oxygen delivery H. pyloriis implicated in almost all non-NSAID-induced GI mucosal inflammation ○ Causestype B gastritis(antrum and body of the stomach) ○ Peptic ulcer, Gastric adenocarcinoma, Gastric lymphoma Almost all patients withgastric cancerhave hadH.pyloriorgastric ulcer Neutrophils are present in acutegastritis Inflammatory cells are absent ingastropathy Carcinoid tumorssecreteserotonin ○ Serotonin secrets in thehepatic portal circulation Major components of bile → bilirubin, bile salts, cholesterol, phospholipids Bilirubin ○ Normal serum bilirubin = 0.3=1.2 mg/dL 2-2.5 mg/dLand above =jaundice ○ Rate of bilirubin production = hepatic uptake, conjugation, biliary excretion ○ Unconjugated→ largelyinsolubleand cannot be excreted in the urine ○ Conjugated→water-solubleand loosely bound to serum albumin, it can be excreted in the urine Hepatocellular disease, bile duct injury, biliary obstru3ction Black gallstones= calcium bilirubinate withmucin glycoproteins ○ Chronic liver disease, hemolytic disease Pigmented brown gallstones= calcium bilirubinate withfatty acid soapsthat bind with calcium ○ Biliary stasis, bacterial infections, biliary parasites Salivabecomeshypotonicdue to the duct reabsorbing NaCl (but not water) Most common site of fistulization = esophagus Most common form of congenital intestinal atresia = imperforate anus Most frequent cause of esophagitis = reflux of gastric contents Contraction occurs in the intersphincteric esophagus → peristalsis contractions Stones commonly formed within thegallbladder→ cholesterol and black stones Stones commonly formed within thebile duct→ brownstones C ommon cause ofepiglottitis→H. influenzae 4 main layers of the GI tract ○ Mucosa → Specialized epithelial cells that line the lumen Lamina propria→ contains small blood and lymphatic vessels, immune cells, and nerve fibers Muscular mucosa→ used to determine whether cancer of the GIT is still localized ○ Submucosa → contains larger blood and lymphatic vessels Nerve plexus of the intrinsic orenteric NS, termedthesubmucosal nerve (Meissner) plexus Controls absorption and secretion ○ Muscularis → responsible for the motility of the GIT Myenteric nerve (Auerbach) plexus, a division of theenteric NS that regulates motility ○ Serosa Enteric neuronsare organized bysubmucosalplexus&myentericplexus PNSefferents stimulateintestinal motility&exocrinesecretion Product Physiologic Actions Site of Release Stimulus for Release Disease Association True hormones Gastrin Stimulates acid secretion and growth of gastric oxyntic gland Gastric antrum (and Zollinger–Ellison syndrome, mucosa duodenum) Peptides, amino acids, distension, vagal peptic ulcer disease stimulation CCK Stimulates gallbladder contraction, pancreatic enzyme and Duodenum and jejunum bicarbonate secretion, and growth of exocrine pancreas Peptides, amino acids, long-chain fatty acids, (acid) Secretin Duodenum Acid (fat) timulates pancreatic bicarbonate secretion, biliary bicarbonate S secretion, growth of exocrine pancreas, and pepsin secretion; inhibits gastric acid secretion, trophic effects of gastrin GIP Stimulates insulin release (inhibits gastric acid secretion) Duodenum and jejunum Glucose, amino acids, fatty acids Other polypeptides with hormone function Stimulates gastric and duodenal motility Duodenum and Unknown Irritable bowel syndrome; Motilin jejunum diabetic gastroparesis Inhibits pancreatic bicarbonate and enzyme secretion Pancreatic islets of Protein (fat and glucose) Pancreatic peptide Langerhans Stimulates insulin secretion, thereby lowering blood glucose Ileum and colon Glucose and fat Inflammatory conditions lucagon-like G and diabetes mellitus peptide-1 (GLP-1) Paracrine factors Somatostatin I tract mucosa, pancreatic G Acid stimulates, vagus nerve inhibits release Gallstones Inhibits release of most other peptide hormones (eg, acid stimulates islets of Langerhans somatostatin to block gastrin) Prostaglandins Multiple Various NSAID-induced gastritis and ulcer Promote blood flow, increase mucus and bicarbonate secretion from disease gastric mucosa Histamine Oxyntic gland mucosa Gastrin and unknown others Stimulates gastric acid secretion Serotonin Increased intestinal motility and secretion enterochromaffin (EC) cells distension of the gut wall Carcinoid tumors arise from EC cells and most commonly secrete serotonin. Neurocrines VIP Relaxes sphincters and gut circular muscle; stimulates intestinal and Mucosa and smooth muscle of Enteric nervous system Secretory diarrhea pancreatic secretion GI tract Bombesin Stimulates gastrin release Gastric mucosa Enteric nervous system Enkephalins Stimulate smooth muscle contraction; inhibit intestinal secretion Mucosa and smooth muscle of Enteric nervous system GI tract Other products Intrinsic factor Binds vitamin B12 to facilitate its absorption Parietal cells of the stomach Constitutive secretion Autoimmune destruction of parietal cells causes pernicious anemia Mucin Lubrication and protection Goblet cells along the entire GI tract irritation Viscid mucus in cystic fibrosis, intestinal mucosa and surface attenuation in some cases of peptic cells in the stomach ulcer Acid Prevents infection; initiates digestion Parietal cells of the stomach Gastrin, histamine, acetylcholine, NSAIDs Acid-peptic disease (indirectly) Hirschsprung disease ○ RET gene ○ Lack of myenteric neurons in the distal colon Sjogren’s syndrome ○ an autoimmune disease that destroys exocrine glands and most commonly affects tear and saliva production ○ Dry eyes, mouth → halitosis & dental caries Gastroparesis ○ Complications ofdiabetes mellitus ○ Alterations in: Mucosal immune cell infiltration Cytokine expression Peptic Ulcer Disorder ○ Elevated gastric acid secretion or diminished mucosal defense Secretory diarrhea ○ secretagogues maintain elevated rates of fluid transport out of epithelial cells into the GI tract lumen Osmotic diarrhea ○ Malabsorbed nutrients ○ Poorly absorbed electrolytes that retain water in the lumen ○ Stops when the patient fast Gilbert Syndrome ○ The buildup of bilirubin → jaundice (icterus) Zollinger-Ellison syndrome ○ gastrin-producing tumors ○ gastrin-secreting tumor (gastrinoma) causeshypergastrinemia→ refractory PUD Most gastrinomas are found in the pancreas or duodenum ○ Tx: vagotomy GERD ○ Complication →Barrett’s esophagus ○ "heartburn" (substernal chest pain) ○ Occurs when the lower esophageal sphincter is incompetent → allowing the flow of gastric juices and contents back into the esophagus Barret’s esophagus ○ GI metaplasia of the lower esophagus that results from chronic GERD-induced esophagitis ○ Squamous epithelium → intestinal epithelium (metaplasia) → adenocarcinoma ○ Greatest clinical concern should be increased risk of esophageal adenocarcinoma Tracheoesophageal fistula ○ Abnormal connection between trachea and esophagus Esophageal atresia ○ A congenital condition in which the esophagus ends in a blind pouch Reflux of gastric contents ○ Due to functional abnormality of the LES ○ Recurrent reflux of gastric contents into the distal esophagus Achalasia ○ Caused by degeneration of the neurons in the esophageal wall → loss of inhibitory innervation in the LES ○ Esophageal manometry shows → incomplete LES relaxation, absent peristalsis in the distal esophagus ○ Barium swallow shows →bird-beak appearance ○ Typically present with → insidious onset and progressivedysphagiaforsolidsandliquids Choledocholithiasis→ stones in theextrahepatic bileduct Cholestasis→ obstruction of the bile flow withinthebiliary tract ○ Buildup of bile acid Hepatolithiasis→ stones in theintrahepaticbile ducts Cholecystolithiasis→ stones in thegallbladderorcystic duct Cholecystitis→ fever,leukocytosis,rebound tenderness,abdominal muscle guarding, biliary dilation,elevatedserum bilirubinand alkaline phosphatase Acute cholangitis→ abdominal pain, jaundice,fever(Charcot triad),Reynolds pentad(Charcot triad +hypotension and AMS) Lecture 7: Disorders of the small intestines and colon P olymers are broken down into → glucose and galactose ○ By bacteria and amylase SGLT-1with 2 Na+ ions absorbs glucose and galactose Extrusion of Na+ by Na+-K+ ATPase drives the absorption of glucose and galactose against their concentration gradients GLUT-5= fructose = facilitate diffusion Toxin from choleramodifies G proteins → activates adenylyl cyclase → increases levels ofcAMP ○ Patients with cholera may excrete up to20 L of diarrhea per day→ rapid dehydration and death Fluid and electrolyte secretionflushes bacterial products and toxins away ○ Plays a role in mucosal defense Secretagogues→ stimulate fluid and electrolyte secretion ○ Neurotransmitter= VIP and acetylcholine ○ Paracrine= bradykinin, serotonin, histamine, and prostaglandins ○ Luminal= bacterial toxins (cholera toxin) L actase deficiency ○ A rare autosomal recessive disorder caused by mutations in the gene encoding lactase. ○ Sx: explosive diarrhea with watery, frothy stools,osmotic diarrhea. Abdominal distention after milk ingestion ○ Congenital Mutations in the gene encoding lactase Explosive diarrhea with watery, frothy stool, and abdominal distention after milk ingestion ○ Acquired- most common Loss of lactase gene expression early in childhood Manifest after the age of weaning from breast milk ○ Transient Small bowel injury, infectious or inflammatory insults Reversible if the cause of the injury remits Diarrhea ○ Time-dependent water absorption → responsible for the normal soft/consistency of stool ○ Acute = < 2 weeks Usually due to infectious cause ○ Chronic = > 4 weeks ○ Medication side effects are the most common noninfectious causes ○ The majority are infectious, toxic, or related to dietary intake Osmotic diarrhea/malabsorption ○ Glucose-galactose or fructose malabsorption / Mannitol, sorbitol ingestion / Ingestion of nutrient-binding substances ○ Lactulose therapy / Bacterial overgrowth / Defective fat solubilization (disrupted enterohepatic circulation or defective bile formation) Some salts (eg, magnesium sulfate), antacids (eg, calcium carbonate) ○ ○ Generalized malabsorption / Lymphatic obstruction (eg, lymphoma, tuberculosis ○ Pancreatic enzyme inactivation (eg, by excess acid) / Loss of enterocytes (eg, radiation, infection, ischemia) Pseudomembranous colitis ○ Purulent inflammation in the inner lining of the bowel ○ Very suggestive ofC. diff Presents withwatery diarrhea(≥3 loose stools in 24 hrs), lower abd pain, fever Toxin released by C.diff→ribosylation of small GTPases→ disruption of the epithelial cytoskeleton,tight junction barrier loss, cytokine release, and apoptosis ○ Labs:leukocytosis, hypoalbuminemia and lactic acidosis (severe) ○ Dx bystool studies Abd imaging to r/otoxic megacolon,bowel perforation, and other surgical intervention requirements ○ Risk factors:hx of recent abx use(clinda most common),hospitalization, age > 65 Celiac disease ○ Celiac sprue or gluten-sensitive enteropathy, is an immune-mediated disorder triggered by ingestion of gluten-containing foods (wheat, rye, or barley) ○ Gluten is digested by luminal and brush-border enzymes into amino acids and peptides, including a 33-amino acid α-gliadin peptidethat is resistant to degradation by gastric, pancreatic, and small intestinal proteases. ○ Immune mechanisms involved in the tissue responses to gliadin: Innate ( CD8 + intraepithelial T-cells, activated by IL-15) Adaptive (CD4 +T cells and B-cells sensitization to gliadin) ○ Gliadin peptides interact withHLA-DQ2 or HLA-DQ8on antigen-presenting cells and in turn, stimulateCD4+ T cells to produce cytokines that exacerbate tissue damage ○ Almost all people with celiac disease carry the class IIHLA-DQ2 or HLA-DQ8 allele Intestinal Obstruction ○ Most common → small intestine (narrow lumen) ○ Collectively, hernias, intestinal adhesions, intussusception, and volvulus account for80% of mechanical obstructions Intussusception ○ Occurs when a segment of the intestine,constrictedby a wave of peristalsis,telescopesinto the immediatelydistal segment ○ Most common cause of intestinal obstruction in children younger than 2yo Uncommon in older children and adults ○ Etiology: idiopathic,viral infection, and rotavirus vaccines ○ 1% pts with CF develop intussusception A betalipoproteinemia ○ LDL-C < 60 mg/dL ○ Rare autosomal recessive disease → inability to assemble triglyceride-rich lipoproteins ○ Caused by mutation in microsomal triglyceride transfer protein(MTP, gene name MTTP) Requires for transfer of lipids to nascent apolipoprotein B polypeptide in the ER ○ Triglyceride accumulation = epithelial vacuolization ○ Presents in infancy with failure to thrive, diarrhea, and steatorrhea ○ Failure to absorb essential fatty acids → deficiencies of fat-soluble vitamins/lipid membrane defects Presence ofacanthocytes,red cells with spiky membrane protrusions, alteration in the lipid content of red cell membranes ○ Sx: progressive pigmented retinopathy → decreased night and color vision → reductions in daytime visual acuity → near-blindness ○ Lowcholesterol ○ Undetectable: chylomicrons, VLDLs, LDLs, and apoB ○ Acanthocytes→ severe liver disease, rare patients with McLeod blood group ○ Echinocytes→ severe uremia, in glycolytic red cell enzyme defects, and in microangiopathic hemolytic anemia Paralytic Ileus ○ spasms, which are very strong and often painful contractions that occur continuously in a dysregulated manner ○ ileus, in which contractile activity is markedly decreased or absent Ileus → irritation of the peritoneum that may occur with surgery, peritonitis, and pancreatitis. ○ Failure of normal intestinal motilityoften occurring after intestinal or abdominal surgery, acute pancreatitis,intestinal infection, cardiac dysfunction, or hypokalemia ○ Strangulated obstruction → blood flow compromised → intestinal ischemia/necrosis/perforation if left untreated ○ Chronic pseudo-obstruction associated with tumors or inflammatory disorders (large intestine) Diverticular disease ○ Usually at the site ofarterial insertion ○ Mucosa and submucosa herniate through the muscular layer ○ Predisposed by chronic constipation and connective tissue disease Diverticulitis ○ Irritation or obstruction of diverticular entrance → closure and infection ○ May cause perforation, abscess, fistula with surrounding structures Inflammatory bowel disease (IBD) ○ Chronic inflammatory condition triggered by the host immune response to intestinal microbes in genetically predisposed individuals ○ Encompasses two entities: Crohn disease Regional enteritis (bc of frequent ileal involvement) May involve any area of the GIT and often producestransmural inflammation Ulcerative colitis Limited to thecolonandrectumand involves only themucosaandsubmucosa May affect up to terminal ileum High risk for colon cancer Associated with PSC and Pyodermal Gangrenosum ○ Patho→ It is proposed that the initial trigger is thepresentation of microbial antigens to CD4+ helper T cells, which are induced to differentiate intoTh1 and Th17 cellsby cytokines such asIL-12 and IL-23 These then activate macrophages, recruit neutrophils, and releaseproinflammatory cytokines such as TNF depends on the specific mix of signaling proteins (cytokines) that the body produces in response to bacteria and other microbes Irritable bowel syndrome ○ Can cause diarrhea, constipation, or alternation of both ○ Idiopathic dysregulation of motility Likely multiple phenotypes and mechanisms Common threads of altered microbiota and enteric nervous system hypersensitivity to stress Lecture 8: Exocrine Pancreas E xocrine portion→ makes up the bulk of the organs and is amajor source of enzymesthat are essential for digestion Theretroperitoneal locationof the pancreas and the generally nonspecific signs and symptoms associated with disorders of the exocrine portionallow many pancreatic diseases to remain undiagnosed for extended periods. Normal pancreas ○ main pancreatic duct(the duct of Wirsung)joins the common bile duct just proximal to thepapilla of Vater, and the accessory pancreatic duct(the duct of Santorini)drains into the duodenum through a separate minor papilla Pancreatic divisum ○ Failure of fusion of the fetal duct systems of the dorsal and ventral pancreatic primordia → the bulk of the pancreas (formed by the dorsal pancreatic primordium) drains into the duodenum through the small-caliber minor papilla Full-blown acute pancreatitisis amedical emergencyof the first order ○ Elevated serum lipase and amylase(increase 4 to 12 hrs after onset of pain) Serum lipase remains elevated for 8-14 days Serum amylase returns to normal in 3-5 days Marker of acute pancreatitis → serum lipase Acute pancreatitis ○ Reversibleinflammatory disorder that varies in severity, from focal edema and fat necrosis to widespread hemorrhagic necrosis ○ Caused byautodigestionof the pancreas by intraacinar activation of pancreatic enzymes ○ Increasing due to obesity epidemic and related to increase in gallstone disease ○ Recurrent can lead to chronic pancreatitis ○ Common cause: Gallstone Chronic excessive alcohol use ○ Remainder: Non-gallstone-related obstruction of the pancreatic ducts, or parasites (Ascaris lumbricoides and Clonorchis sinensis) Metabolic disorders Hypertriglyceridemia (above 1000 mg/dL) Medications Anticonvulsants, cancer chemo therapeutic agents, thiazide diuretics, estrogens Infections Mumps virus or coxsackievirus Chronic pancreatitis ○ long-standing inflammation that leads toirreversibledestruction of the exocrine pancreas, followed eventually by loss of the islets of Langerhans ○ Common cause →chronic excessive alcohol consumption(esp. Middle-aged men) Lecture 10: Liver disease P ortal triads = portal vein, hepatic artery, bile duct Sinusoids= blood from portal vein + blood from hepatic artery mixed ○ Separated by chains of hepatocytes ○ Drain into thecentral vein Formhepatic veins→ drain intoinferior vena cava Space of Disse= space between hepatocytes and endothelial ○ Contains interstitial fluid ○ Stellate (Ito) cellslocated here Resting = antigen-presenting cells andstoring vitamin A Activate = myofibroblasts →liver fibrosis Zone I ○ Greatest delivery of oxygen and nutrients ○ Preferentially undertake oxidative metabolism, ureagenesis, and bile acid production Zone III ○ Conc of oxygen and nutrients is the lowest ○ Cells undertake glycolysis, ketogenesis, and detoxification reactions Endocrine functions ○ Main source of circulatingIGF-1 ○ Secretes the iron-regulating hormonehepcidin ○ Contributes to the activation ofvitamin D ○ Site for deiodination of thyroxine (T4) → tri-iodothyronine (T3) Markers forhepatocellular injury ○ AST ○ ALT Non-specific markets forbiliary duct injury ○ Alkaline phosphatase (AP) ○ Gamma-glutamyl transferase (γGT) Bilirubin→ function of hemoglobin breakdown and excretion pathway Albumin/total protein→ rough assessment of overall synthetic function Prothrombin time→ extrinsic clotting pathway Ammonia→ detoxification functions Hepatocytes secrete bileinto the canaliculi Sphincter of Oddi→ guards the opening of the ampulla into the duodenum In several diseases,glycogen degradation is depressed, with an abnormal intracellular accumulation Jaundice = accumulation of bilirubin and bilirubin glucuronide in the tissues Marker for elevated risk of CV disease→ apolipoproteins put on lipid particles and allow for endocytosis and use by cells Pro-atherogenic→ chylomicron remnants, VLDL, IDL, LDL, and Lp(a) Anti-atherogenic→ HDL Main lipids of chylomicron remnants → triglycerides and cholesterol Major structure protein of chylomicrons and chylomicron remnants →Apo B-48 Triglycerides carried in chylomicrons are metabolized in muscle and adipose tissue bylipoprotein lipase The endogenous lipoprotein pathway begins in the liver with the formation of VLDL Delivery of cholesterol to the cell decreases the activity ofHMG-CoA reductase&expression of LDL receptors Low LDL receptors = high plasma LDL levels High number of hepatic LDL receptors = low plasma LDL levels PCSK9regulates the rate the degradation of LDL receptors ApoB100is measured clinically to assess how many LDL particles are in the blood Mature HDL can acquire additional cholesterol from cells via → ABCG1, SR-B1, or passive diffusion Cholesterol efflux from macrophages to HDL →protecting from the development of atherosclerosis VLDL→ only lipoproteincontaining apolipoprotein Bthat is secreted from the liver Fibrosisactivates stellate cells ○ Drugs that can cause: methotrexate & excess vitamin A M irrizi syndrome ○ Common hepatic duct obstruction Extrinsic compression from an impacted stone in the cystic duct or infundibulum of the gallbladder ○ Sx: jaundice, fever, RUQ pain G allstone ileus ○ Caused by impaction of a gallstone in the ileum after being passed through a biliary-enteric fistula N eonatal jaundice ○ Elevated total serum bilirubin ○ Hyperbilirubinemia → bilirubin that is deposited into the skin ○ Sx: yellowish skin, sclerae, and mucous membranes ○ Physiologic jaundice→ mild, transient, and self-liming condition ○ Most common →unconjugated hyperbilirubinemia Higher RBC mass and decreased RBC lifespan Metabolic bilirubin clearance is also compromised due to impaired activity ofUGT Enzyme needed for bilirubin conjugation N onalcoholic fatty liver disease (NAFLD) ○ The most common liver diseasein Western countries ○ Associated risk with metabolic risk factors: obesity, dyslipidemia, insulin resistance, and type 2 diabetes mellitus ○ Insulin resistance→ key mechanism leading to hepatic steatosis and steatohepatitis ○ Lipid accumulation in hepatocytes→ increased influx of lipids to the liver or decreased lipid disposal C irrhosis ○ Irreversible distortion of normal liver architecture characterized by hepatic injury, fibrosis, and nodular regeneration ○ Clinical presentations are the consequence of both progressive hepatocellular dysfunction and portal hypertension ○ Advanced cirrhosis → spontaneous bacterial peritonitis H epatitis A - Picornavirus ○ Commoninfectiousetiologyofacute hepatitisworldwide ○ Abruptonset ○ Incubation period:15-50 days ○ Sx: n/v, fatigue, malaise, abdominal pain, poor appetite, fever ○ No chronic hepatitis or associated with malignancy ○ Transmitted through oral-fecal route via exposure to contaminated food, water, close physical contact ○ Earlyantibody response →IgM ○ Lateantibody response →IgG H epatitis B - Hepadnavirus ○ Insidious onset ○ Incubation period: 28-160 ○ Sx: arthralgia, rash, n/v ○ DNA virus ○ Sexual contact or contact with infected blood or other body fluids ○ Most common transmission in adults → sexual contact ○ Most common mode worldwide → perinatal and early childhood transmission ○ Can develop chronic hepatitis B ○ Marker ofactive viral gene expression→HBsAg ○ Marker ofinfectivity→HBeAg ○ Indication ofimmunity→anti-HBsoranti-HBe H epatitis C - Flavivirus ○ Insidious onset ○ Incubation period: 14-160 ○ Sx: n/v ○ No antigen ○ No vaccine H epatitis D - Delta Viridae ○ Insidious onset ○ Incubation period: 30-180 ○ Sx: fever, n/v, jaundice ○ No antigen ○ High mortality rate ○ No vaccine ○ Requires HBV helper function to cause infection ○ High risk for chronically infected with HBV, injection drugs users, hemophilia H epatitis E - Caliciviridae ○ Abruptonset ○ Incubation period:15-60 ○ Sx: arthralgia, rash, fever, n/v, jaundice ○ Severe in preggo ○ Fecal-oral route ○ Can progress to chronic hepatitis ○ Infected preggo during 3rd trimester →acute liver failure
