Gastroenterology Slides 2022 PDF

Gastrointestinal Embryology Jason Ryan, MD, MPH GI Embryology Wikipedia/Public Domain GI Embryology Zephyris/Wikipedia GI Embryology Endoderm → GI tract GI tract epithelium, glands Many organs bud off: liver, pancreas, trachea Mesoderm → Surrounding structures...

Gastrointestinal Embryology Jason Ryan, MD, MPH GI Embryology Wikipedia/Public Domain GI Embryology Zephyris/Wikipedia GI Embryology Endoderm → GI tract GI tract epithelium, glands Many organs bud off: liver, pancreas, trachea Mesoderm → Surrounding structures Stroma (GI tract connective tissue) Muscles Peritoneum Spleen  Pharyngeal Pouches Esophagus Foregut Celiac Trunk Yolk Sac (Vitelline Duct) SMA Midgut IMA Hindgut Portions of GI Tract Foregut Celiac trunk Mouth to Ampulla of Vater Midgut SMA Ampulla of Vater to transverse colon Hindgut IMA Transverse colon to rectum Wikipedia/Public Domain Mesentery Double layer of peritoneum Suspends abdominal organs from cavity walls Intraperitoneal organs Enclosed by mesentery Retroperitoneal organs Covered by peritoneum only on anterior wall Lie against posterior abdominal wall Mesentery Wikipedia/Public Domain Mesentery Dorsal mesentery Gut moves away posterior wall in development Dorsal mesentery grows between gut and posterior wall Covers most abdominal structures Ventral mesentery Only exists bottom esophagus, stomach, upper duodenum Derived from septum transversum (mesenchyme tissue) Liver grows into this mesentery In adult: lesser omentum and falciform ligament Mesentery Wikipedia/Public Domain Mesentery Olek Remesz/Wikipedia Mesentery Mesogastrium Mesoduodenum Mesocolon Omentum Latin: “apron” Greater omentum Hangs from greater curvature of stomach Covers intestines Formed from mesogastrium Lesser omentum Between stomach and liver Formed from ventral mesentery Foregut Development Lung “buds” off from foregut “Respiratory diverticulum”; “lung bud” Tracheoesophageal septum divides diverticulum Matures into separate trachea and esophagus Abnormal septum development → pathology Esophageal atresia (closed esophagus) Occurs when septum deviates posteriorly Esophageal Atresia EA with TEF H-Type Pure EA Most Common Lewis Spitz. Oesophageal atresia. Orphanet Journal of Rare Diseases Esophageal Atresia Clinical Features Esophageal atresia Esophagus does not connect to stomach Polyhydramnios (baby cannot swallow fluid) Drooling, choking, vomiting (accumulation secretions) Cannot pass NG tube into stomach Fistula esophagus → trachea Gastric distension (air in stomach on CXR) Reflux → aspiration pneumonia → respiratory distress Esophageal Atresia Clinical Features Treatment: surgical repair Prognosis: Sometimes residual dysmotility GERD Midgut Development Herniation About 6th week of development Abdomen temporarily becomes too small Intestines “herniate” through umbilical cord “Physiologic herniation” Visible on fetal ultrasound! Reduction of hernia occurs by 12th week Omphalocele Persistence of normal herniation = omphalocele Intestines covered by membrane outside body “Simple omphalocele” Liver does not herniate If lateral embryonic folds fail → liver in omphalocele Liver-containing omphalocele Key features: Covered by peritoneum Through umbilical cord CDC/Public Domain Omphalocele Normal GI function Many genetic defects Trisomy 21 (Down syndrome) Trisomy 18 (Edwards syndrome) Trisomy 13 Many associated conditions Congenital heart defects (up to 50% babies) Orofacial clefts Neural tube defects Gastroschisis Extrusion of bowel through abdominal wall Exact mechanism unclear Probably involves incomplete closure of abdominal wall Paraumbilical abdominal wall defect Usually on right side of umbilical cord Not covered by peritoneum Gastroschisis Poor GI function Often associated with atresia, stenosis Few associated defects If GI function restored, good prognosis Rarely associated with Down, other congenital disease Abdominal Wall Defects Treatment for both: Surgical reduction/closure Midgut Development Rotation During physiologic herniation, bowel rotates Midgut rotates around SMA Continues after return to abdomen Results in normal positioning of small bowel, colon Cecum in right lower quadrant Malrotation Obstruction Cecum in mid-upper abdomen Peritoneal tissue (Ladd bands) Duodenal obstruction Volvulus Wellcome Images/Wikipedia Small bowel twists around SMA Vascular compromise → ischemia → obstruction Vomiting, sepsis (bowel necrosis) Abdominal distention, blood in stool Treatment: surgery Left sided colon Anatomic variant Vitelline Duct Pathology In early development, midgut open to yolk sac Does not become enclosed like other portions of gut By week 5, connection with yolk sac narrows “Yolk stalk,” “vitelline duct,” “omphalomesenteric duct” Normally, vitelline duct disappears by week 9 Persistence → congenital anomalies Meckel’s diverticulum (most common) Cysts, polyps Meckel’s Diverticulum Most common congenital GI abnormality Persistent remnant of vitelline duct Diverticulum of small bowel (ileum) “Outpouching,” “Bulging” Meckel’s Diverticulum “True diverticulum” Contains all layers of bowel: mucosa, submucosa, muscular Most diverticulum only mucosa/submucosa Usually defect (hole) in muscular layer Often contains stomach tissue “Ectopic gastric tissue” Origin unclear Sometimes pancreatic tissue also Raziel/Wikipedia Meckel’s Diverticulum Usually no symptoms Can present any age but 50% 90%) Mucin, glycoproteins Martin Brändli /Wikipedia Lubricate food Bind bacteria IgA antibody Lysozymes → disrupt bacterial cell walls Lactoferrin → prevent bacterial growth Proteins that protect teeth Saliva Important for innate immunity Protects against infectious agents Loss of saliva (Sjogren’s) → infections Dental carries (cavities) Saliva Two important enzymes for digestion α amylase (digests carbohydrates) Lingual lipase (digests lipids) α-amylase Salivary amylase Optimal pH >6 Inactivated in stomach Pancreatic amylase Functional in small intestine Lipase Enzymes Salivary (lingual) lipase Minor contributor to lipid metabolism in adults More important in newborns (lower pancreatic enzyme levels) Pancreatic lipase Main lipase for lipid digestion Salivary Electrolytes Salivary fluid produced by acinar cells Modified by ductal cells Public Domain/Wikipedia  Salivary Electrolytes Initial fluid similar to plasma (isotonic) Same Na, Cl, K, HCO3- concentration Ductal cells (impermeable to water): Remove Na, Cl Secrete K, HCO3- (bicarb raises pH → protects against acid) Na K Na Cl K Cl HCO3- HCO3-  Salivary Electrolytes Saliva becomes hypotonic from removal Na, Cl Lower concentrations than plasma Saliva: higher concentration of K, HCO3- than plasma Na K Na Cl K Cl HCO3- HCO3- Salivary Electrolytes Composition varies with flow rate Higher flow: Less time for ductal modification Fluid becomes more like plasma Closer to isotonic with plasma [Bicarb] goes up at high flow rates More CO2 in glandular cells → more bicarbonate  Aldosterone Effects salivary glands similar to kidneys ↑ Na absorption ↑ K secretion Na K Na Cl K Cl HCO3- HCO3- Regulation of Saliva Increased by sympathetic AND parasympathetic Not regulated by gastrointestinal hormones Sympathetic: smaller effect Parasympathetic: greater effect (major system) Activated by food smell, sight, etc. Muscarinic receptors (M1 and M3) important Regulation of Saliva Muscarinic antagonists Cause dry mouth Atropine, Scopolamine Muscarinic agonists Increase saliva production Pilocarpine (used in Sjogren’s syndrome) Cholinesterase poisoning → salivation Salivary Duct Stones Sialolithiasis Obstruction of salivary flow Pain/swelling of gland PGA/Wikipedia Usually aggravated by eating Most common in submandibular glands Risk factors: Dehydration, diuretics Anticholinergic medications Treatment: NSAIDs, hydration; rarely surgery Sialadenitis Inflammation of salivary gland Often secondary to obstructing stone Most often due to Staph Aureus Also often contains anaerobes Common treatment: Nafcillin (Staph coverage) Metronidazole or Clindamycin (anaerobes) Mumps Caused by RNA mumps virus Largely prevented by vaccination (MMR) Key feature: Parotitis Often bilateral Inflammation of parotid glands (facial swelling) Wikipedia/Public Domain Salivary Tumors Usually present in the parotid gland Often present as facial swelling Most are benign Mobile (not growing into other tissues) Painless (not invading nerves) When pain present usually indicates invasive lesion May involve facial nerve (paralysis) Pleomorphic Adenoma Benign Mixed Tumor Most common salivary gland tumor Usually benign Rarely can undergo malignant transformation Often results in pain, facial nerve dysfunction Most common in superficial lobe of parotid gland Painless, mobile mass at angle of jaw Pleomorphic Adenoma Benign Mixed Tumor Epithelial and stromal tissue cells Epithelial: Glandular cells Stromal: Cartilage, sometimes may see bone KGH/Wikipedia Pleomorphic Adenoma Benign Mixed Tumor Risk factors: Prior radiation Treatment: Surgery +/- radiation Can have local recurrence Often has irregular margins Tumor cells left behind after surgery → recurrence Warthin’s Tumor Papillary Cystadenoma Lymphomatosum Second most common salivary tumor Usually occurs in parotid gland Key risk factor: Smoking (8x more common!) Warthin’s Tumor Papillary Cystadenoma Lymphomatosum Key histological finding: Cysts filled with fluid Cysts surrounded by dense lymphoid infiltrate Lymph tissue can aggregate into germinal centers KGH/Wikipedia Mucoepidermoid Carcinoma Most common malignant salivary tumor Key risk factor: prior radiation Occur in parotids Sometimes invade facial nerve (paralysis) Can also cause pain Also commonly found in minor salivary glands Mucoepidermoid Carcinoma Mixture of cells: Squamous (epidermoid) cells Mucus-secreting cells Intermediate hybrid cells KGH/Wikipedia Hernias Jason Ryan, MD, MPH Hernia Protrusion of organ through cavity wall Can lead to organ dysfunction, necrosis/infection Common in areas of discontinuity of abdominal wall Inguinal canal Esophagus Umbilicus Femoral Vessels Wikipedia/Public Domain Wikipedia/Public Domain Femoral Vessels Lateral to medial Nerve-artery-vein-lymphatics “NAVeL” “Venous to the penis” Femoral triangle Superior: Inguinal ligament Medial: Adductor longus Lateral: Sartorius Wikipedia/Public Domain Femoral Sheath Tunnel of fascia Below inguinal ligament Contains femoral vein, artery, and ring Does not contain nerve Wikipedia/Public Domain Femoral Ring and Canal Opening to femoral canal is femoral ring Site of femoral hernias Component of femoral sheath Lymph vessels and deep inguinal nodes Wikipedia/Public Domain Inguinal Canal Runs across femoral vessels Testes descend through inguinal canal to scrotum Spermatic Cord Travels in inguinal canal Ductus deferens, arteries, veins, nerves Three fascial layers External spermatic fascia Cremasteric fascia Internal spermatic fascia Inguinal Canal Passage in abdominal wall Carries spermatic cord in males Round ligament in females Entrance: Deep inguinal ring Exit: Superficial inguinal ring Floor: Inguinal ligament Inguinal Canal Deep/Internal Inferior Inguinal Ring Epigastric Vessels Inguinal Rectus Abdominis Ligament Muscle Superficial/ External Femoral Artery Inguinal Ring Femoral Vein Lateral Medial Inguinal Hernias Three types of hernias occur in inguinal region Indirect inguinal hernias Direct inguinal hernias Femoral hernias Indirect Inguinal Hernia “Indirectly” through abdominal wall Travel through inguinal canal Not “directly” through a hole Origin lateral to epigastric vessels Follows path of descent of testes Covered by all layers of spermatic fascia Contrast with direct hernias (outer layer only) Congenital defect Bowel protrudes through patent processus vaginalis Should close after descent of testes Indirect Inguinal Hernia Wikipedia/Public Domain Processus Vaginalis Testes descend behind processus vaginalis Outpouching of peritoneum Remains open in newborn period Should close (“obliterate “) in infancy Replaced by fibrous tissue Part remains as tunica vaginalis testis Serous covering of testes Indirect Inguinal Hernia Demographics Most common type of inguinal hernia Males = 50% hernias are indirect Females = 70% are indirect More common in men Men 10x more likely than women Typically occurs right side Persistent processus vaginalis more common on right Commonly extend into scrotum Indirect Inguinal Hernia Demographics Usually occurs in adulthood with risk factors Heavy lifting Straining (constipation) Can occur in newborns on mechanical ventilation Daisydeee/Wikipedia Indirect Inguinal Hernia Key Points Through internal and external inguinal rings Follows path of descent of testes (in men) In women follows round ligament toward labia majora In men, covered by spermatic fascia (three layers) Origin lateral to inferior epigastric vessels Most common type of inguinal hernia Direct Inguinal Hernia Bowel bulges “directly” through abdominal wall Protrudes through Hesselbach’s triangle Origin is medial to epigastric vessels Through external ring (not deep/internal) Covered by external spermatic fascia only Should never bulge into scrotum Hesselbach’s Triangle Inguinal ligament Inferior epigastrics Rectus abdominis Floor: Transversalis fascia Direct Inguinal Hernia Caused by transversalis fascia breakdown Weakness in floor of inguinal canal Usually occurs in older men Years of stress on connective tissue (“acquired”) Public Domain Femoral Hernias Hernia through femoral ring Medial to femoral vessels Bowel protrudes below inguinal ligament Differentiates from both types of inguinal hernias More common in women than men But indirect most common type for both genders High risk of incarceration Femoral ring is small opening Femoral Hernia Inguinal Hernias Physical Exam Most hernias obvious on inspection Bulge in the groin Coughing often increases size of bulge Increased abdominal pressure with cough Inguinal Hernias Complications Incarceration Bowel trapped in hernia sac Cannot be “reduced” back into abdomen/pelvis Inguinal Hernias Complications Strangulation Blood flow cutoff Bowel in hernia sac becomes ischemic/necrotic Painful, red, swollen Fever Urgent surgery indicated Femoral hernias in women Inguinal Hernias Diagnosis Usually diagnosed clinically Ultrasound/CT sometimes used James Heilman/Wikipedia Inguinal Hernias Treatment All treated surgically Primary closure Mesh placement Garrondo/Wikipedia Ventral Hernias Anterior abdominal wall Many subtypes Umbilical – near umbilicus Incisional hernias – site of abdominal incision Hiatal Hernias Stomach herniation into thorax Leads to GERD (heartburn) Major risk factor: obesity Wikipedia/Public Domain Hiatal Hernias Type I: Sliding hiatal hernia (95%) Displacement of GE junction above diaphragm Stomach in usual alignment Fundus remains below GE junction “Hourglass” appearance Herniation through hiatus Wikipedia/Public Domain Hiatal Hernias Types II, III, IV: Paraesophageal GE junction in normal location Protrusion of stomach fundus Defect in the “phrenoesophageal membrane” Bowel sounds in lung fields is classic finding Wikipedia/Public Domain CDH Congenital diaphragmatic hernia Developmental defect of diaphragm Defective formation pleuroperitoneal membrane Hole in diaphragm Abdominal organs herniate into chest In utero herniation → pulmonary hypoplasia Often fatal PinkStock Photos, D. Sharon Pruitt/Wikipedia Bile Jason Ryan, MD, MPH Bile Produced in liver Stored in gall bladder Secreted into duodenum after meal Wikipedia/Public Domain Mostly water Phospholipids, electrolytes Bile salts – necessary for lipid absorption Bilirubin – mode of excretion from body Lipids Glycerol Fatty Acid Triglyceride Absorption of Fats Fatty Acids Triglyceride Pancreatic Lipase Mono-glyceride H H Bile Salts Emulsification Lipids Bile Salts Water Bile Salts Surfactant Hydrophobic Lipids Hydrophilic Bile Acids Cholic acid Cholesterol Chenodeoxycholic acid Bile Acids Taurine (organic acid) and glycine (AA): hydrophilic Conjugation to bile acids → better surfactant One end = hydrophobic One end = hydrophilic Taurine Cholic acid Glycine  Hydrophobic Hydrophilic Bile Salts Taurocholic acid Taurine Glycocholic acid Glycine Cholic acid Bile Acids Synthesis Synthesized only in liver Two pathways: classic (>90%) and acidic (> ↑ AST/ALT Primary site of dysfunction is bile ducts Some secondary effects on hepatocytes Wikipedia/Public Domain Hepatocellular Damage Primary site of dysfunction is hepatocytes ↑ AST/ALT >> ↑ Alk Phos Some secondary effect on bile ducts Seen in many forms of liver disease Patterns of Bile/Liver Damage When ↑ Alk Phos >> ↑ AST/ALT Primary abnormality relates to bile ducts “Cholestatic pattern” When ↑ AST/ALT >> ↑ Alk Phos Primary abnormality relates to hepatocytes “Hepatocellular pattern” Example #1 Example #2 AST 100 IU/L AST 500 IU/L ALT 120 IU/L ALT 550 IU/L Alk Phos 500 IU/L Alk Phos 200 IU/L Magnitude of LFT change Normal AST: less than 40 U/l Normal ALT: less than 50 U/l Magnitude of ↑ AST/ALT suggests underlying cause 500 or less 500 to 1000s Approaching 10,000 Cirrhosis Chronic viral hepatitis Acute viral hepatitis Shock (ischemia) liver Fatty liver disease Autoimmune hepatitis Acetaminophen toxicity Alcoholic Hepatitis Cholestasis Best first test: Right upper quadrant ultrasound Differentiates extrahepatic from intrahepatic Cholestasis Extrahepatic causes (workup: additional imaging) Gallstones Pancreatic mass Biliary strictures Intrahepatic causes (workup: lab tests, biopsy) Primary biliary cirrhosis Cholestasis of pregnancy Contraceptives Erythromycin Bilirubin Jason Ryan, MD, MPH Bile Produced in liver Stored in gall bladder Secreted into duodenum after meal Wikipedia/Public Domain Mostly water Phospholipids, electrolytes Bile salts – necessary for lipid absorption Bilirubin – mode of excretion from body Bilirubin Bilirubin Heme (brown/yellow color) Heme Metabolism Heme released from old RBCs Some from myoglobin, cytochromes Macrophages engulf residual heme Converted to biliverdin then bilirubin NADPH NADPH Bilirubin Heme Biliverdin ( brown/yellow) Heme Biliverdin Oxygenase (green) Reductase Bilirubin Poor solubility in water Carried by albumin to liver Bilirubin Bilirubin Conjugation in Liver Unconjugated Bilirubin UDP glucuronyltransferase Glucuronic Acid Conjugated Bilirubin (Bilirubin diglucuronide) Bilirubin Conjugation Bilirubin-UDP-glucuronyltransferase (UGT) Adds glucuronic acid molecules to bilirubin Produce more water soluble compounds Bilirubin monoglucuronide Bilirubin diglucuronide ↑ water solubility facilitates excretion with bile Bilirubin Metabolism Intestines Two conversions by bacteria #1: Converted back to unconjugated in intestines Distal small intestine and colon Bacteria beta-glucuronidase enzymes #2: Unconjugated bilirubin → urobilinogen Via bacterial enzymes Open Stax College Urobilinogen Bilirubin Urobilinogen Urobilinogen Fate #1: Excretion in feces (80-90%) Converted to stercobilin (makes stool dark) Fate #2: Reabsorbed by intestines (10-20%) Most taken up by liver Small amount excreted in urine Converted to urobilin (makes urine yellow) Stercobilin Urobilin  Bilirubin Unconjugated Bilirubin Urobilinogen Urobilin Open Stax College β-glucuronidase Conjugated Unconjugated Urobilinogen Stercobilin Bilirubin Bilirubin Bacteria Bacteria Bilirubin Clinical Measurements Van den Bergh reaction Coupling of bilirubin with a diazonium salt Forms a colored complex Serum Conjugated bilirubin Soluble in water Can directly undergo the reaction in solution Serum Unconjugated bilirubin Not soluble in water Must be mixed with alcohol first Then can add to Van den Bergh medium “Indirect” bilirubin Bilirubin Clinical Measurements Urine Bilirubin (conjugated only): Normal absent Urobilinogen: Normally a small amount Jaundice Yellowing of skin, conjunctiva, mucous membranes Scleral icterus (eyes) often earliest sign Also visualized early under the tongue Normal: total bilirubin 3.0mg/dl Jaundice James Heilman, MD Dark Urine Seen with elevated conjugated bilirubin Only conjugated bilirubin is water soluble Also seen in: Rhabdomyolysis (myoglobin) Hematuria any cause Dehydration (common in actual practice) James Heilman, MD Bilirubin Metabolism Clinical Assessment #1: Serum bilirubin Total Direct Indirect #2: Urine urobilinogen (normally small amount) #3: Urine bilirubin (conjugated - normally absent) Hyperbilirubinemia Four general causes of ↑ bilirubin Hemolysis Biliary obstruction (cholestasis) Liver disease Special causes Hyperbilirubinemia Hemolysis Hemolysis or large hematomas → ↑ heme metabolism Elevated serum unconjugated bilirubin Too much bilirubin to liver (overwhelms capacity) No urine bilirubin detected Unconjugated bilirubin cannot cross glomerulus Increased urobilinogen More bilirubin → more urobilinogen Ed Uthman/Flikr Hyperbilirubinemia Biliary Obstruction Cholestasis = lack of bile flow Extrahepatic: Gallstone, pancreatic mass Intrahepatic: Alcoholic liver disease, viral hepatitis Conjugation occurs normally Excretion impaired → Elevated direct bilirubin Hyperbilirubinemia Biliary Obstruction Findings: Cholestatic LFT pattern: ↑ AlkP >> ↑ ALT/AST Clay colored stools (lack of stercobilin) Hyperbilirubinemia Biliary Obstruction Urine bilirubin detected Conjugated bilirubin water soluble Crosses glomerulus → urine Results in dark urine Absent urobilinogen No bilirubin to intestine Loss of formation of urobilinogen Hyperbilirubinemia Primary Liver Diseases Bilirubin fractionation unreliable for liver disease Often mixed increase of direct/indirect Usual finding: elevated total bilirubin Diagnosis made by: LFTs, antibody tests, imaging, biopsy Hyperbilirubinemia Primary Liver Diseases Unconjugated hyperbilirubinemia Occurs in liver disease with significant hepatocyte damage Chronic hepatitis, advanced cirrhosis Conjugated hyperbilirubinemia Occurs in “intrahepatic cholestasis” Liver disease with prominent damage to bile ducts Viral hepatitis, alcoholic hepatitis, NASH Many liver diseases have elements of hepatocyte and intrahepatic bile duct involvement Urobilinogen Primary Liver Diseases ↑↑ early in liver disease Urobilinogen from intestines reabsorbed as usual Cannot be excreted in bile Spills into urine ↓↓ late in liver disease Lack of conjugated bilirubin to intestines Less formation of urobilinogen Less urobilinogen in urine Source: Sircar, S. (2008) Principles of Medical Physiology, Thieme Medical Publishers Hyperbilirubinemia Lab Findings Disorder Bilirubin Type Urine Bilirubin Urobilinogen Hemolysis Indirect Normal (none) Increased Obstruction Direct Increased (dark) Absent Liver Disease Mixed Usually ↑ Variable Hyperbilirubinemia Special Causes Rifampin/Probenecid Gilbert’s Syndrome Crigler-Najjar Syndrome Dubin-Johnson Syndrome Rotor’s Syndrome Neonatal Jaundice Rifampin/Probenecid Rifampin (antibiotic) Probenecid (gout) Compete with bilirubin for uptake by liver Blunt hepatic uptake of unconjugated bilirubin Result: mild ↑ unconjugated bilirubin (and total) All other LFTs normal Gilbert’s Syndrome ↓ UDP-glucuronyltransferase function Commonly defective promoter UGT gene Result: Mild decrease in enzyme levels Findings: Mild ↑ total and unconjugated bilirubin (usually 20 mg/dl) Jaundice Kernicterus (cause of death) Often fatal Kernicterus Unconjugated bilirubin soluble in fats Easily crosses blood-brain barrier or enters placenta Acts as a neurotoxin Basal ganglia; brain stem nuclei Usually need bilirubin level >25mg/dl Newborns (esp. preterm) particularly vulnerable Andwhatsnext/Wikipedia Crigler-Najjar Syndrome Type II: Less severe (bilirubin AlkP Isolated No Evaluate AST/ALT Hyperbilirubinemia? Alk Phos Yes AlkP>AST/ALT Direct Indirect Dubin-Johnson Hemolysis Cholestatic Pattern Rotor’s Drugs Gallstones Gilbert’s Pancreatic Mass Crigler-Najjar Neonatal Gastrointestinal Secretions Jason Ryan, MD, MPH Gastric Acid Parietal cells of stomach Found in gastric glands Secrete hydrochloric acid (HCL) Maintains very low pH in stomach (plasma Cl- 6 Inactivated in stomach Pancreatic amylase Functional in small intestine Elevated in acute pancreatitis α-amylase Maltose Maltotriose Amylopectin Amylose Limit Dextrins α-amylase Further digestion of carbs at intestinal brush border “Oligosaccharide hydrolases” Maltase Sucrase Lactase, etc. Rate limiting step of carbohydrate digestion All carbs broken down to glucose, fructose, galactose Only monosaccharides are absorbed All isomers of glucose (same formula: C6H12O6) Pancreatic Fat Digestion Pancreatic Lipase Hydrolyzes 1- and 3- bonds of triglycerides Result: fatty acids plus monoglycerides Also elevated in acute pancreatitis Fatty Acids Triglyceride Pancreatic Lipase Mono-glyceride H H Pancreatic Fat Digestion Colipase Assists pancreatic lipase Phospholipase A2 Hydrolyzes phospholipids Secreted as inactive pro-phospholipase A2 Activated by trypsin Protein Digestion Several different pancreatic enzymes Trypsin Chymotrypsin Elastase Carboxypeptidases All secreted as proenzymes (zymogens)  Protein Digestion Trypsin secreted as inactive trypsinogen Activated by brush border enzyme: enterokinase Trypsin activates all other protein enzymes Proelastase Chymotrypsinogen Procarboxypeptidase Trypsinogen Trypsin Enterokinase Chymotrypsin Carboxypeptidase Elastase Acute Pancreatitis Acute inflammation of pancreas Epigastric pain, nausea, vomiting Blocked secretion of enzymes while synthesis ongoing Large amounts of trypsin activated Trypsin activates more trypsin Also activates phospholipase, chymotrypsin, and elastase “Auto-digestion” by enzymes occurs Acute Pancreatitis Diagnosis: Elevated serum pancreatic enzyme levels ↑ Amylase and lipase Both elevated in conditions other than pancreatitis Lipase more specific for pancreatic damage Pancreatic Enzyme Replacement Multiple commercial replacements available Different ratios of lipase, protease, and amylase Uses: Cystic fibrosis Chronic pancreatitis Post pancreatectomy Ragesoss/Wikipedia Esophageal Disorders Jason Ryan, MD, MPH GERD Gastroesophageal Reflux Disease Gastric juice from stomach to esophagus “Reflux” back into esophagus Represents a failure of lower esophageal sphincter Decrease in LES tone Precise mechanism not well established Reflux Esophagitis Inflammation of epithelial layer Mucosa: erythema and edema Erosions (loss of epithelial layer) Samir@enwiki/Wikipedia Reflux Esophagitis Histology: Basal zone (epithelium) hyperplasia Lamina propria papilla elongate Eosinophils and neutrophils Samir@enwiki/Wikipedia Bobjgalindo/Wikipedia Pediatric GERD Immature lower esophageal sphincter Vomiting Crying Voiceboks/Wikipedia GERD Risk Factors Alcohol Smoking Obesity Fatty foods Caffeine Hiatal Hernia GERD Symptoms Heartburn Retrosternal “burning” sensation After meals, or when lying flat Dysphagia Painful esophagitis Respiratory symptoms Reflux into respiratory tract Asthma (adult-onset) Cough Dyspnea Damage to enamel of teeth GERD Treatment Weight loss Dietary modification (avoid triggers) Fatty foods Caffeine Chocolate Spicy foods Carbonated beverages Peppermint Wikipedia/Public Domain Refractory GERD: Nissen fundoplication GERD Treatment Histamine (H2) blockers Famotidine, Ranitidine, Nizatidine, Cimetidine Block histamine receptors in parietal cells Proton Pump Inhibitors Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole Inhibit H+/K+ pump in parietal cells Ulcers, Fibrosis, Strictures Potential consequences of GERD Acid destroys mucosa (causes ulcers) Replaced by fibrous tissue Can lead to strictures → dysphagia Ingestion of Lye Alkali substances Contain sodium or potassium hydroxide Usually ingested accidentally by children Found in household cleaners, drain openers Causes liquefactive necrosis Rapid injury through mucosa into wall of esophagus Neutralized in stomach by acid Child usually recovers Can result in strictures Wikipedia/Public Domain Barrett’s Esophagus Result of long-standing GERD Metaplasia of esophagus Squamous epithelium → intestinal epithelium Olek Remesz/Wikipedia Barrett’s Esophagus Normal Esophagus Barrett’s Esophagus Non-keratinized Intestinal Mucosa Squamous epithelium Non-ciliated Columnar Epithelium Samir@enwiki/Wikipedia Goblet Cells Nephron/Wikipedia Barrett’s Esophagus Endoscopy often performed in GERD patients If Barrett’s seen → regular surveillance endoscopy Biopsies taken to look for carcinoma Normal (squamous): White Intestinal: Pink/Red Samir/Wikipedia Esophageal Cancer Squamous cell or adenocarcinoma Both types: ↑ risk in smokers Often presents late with advanced disease/mets Presents with “progressive” dysphagia Starts with solids Progresses to liquids as tumor grows Other symptoms Weight loss Hematemesis Esophageal Cancer Adenocarcinoma most common in US Normally no glandular tissue lining the esophageal lumen Need GERD → Barrett’s → Glandular epithelium Develops in lower 1/3 of esophagus (near stomach acid) Obesity is risk factor (also GERD) Olek Remesz/Wikipedia Esophageal Cancer Squamous cell most common worldwide Usually in middle or upper esophagus Results from processes that damage upper esophagus Food (alcohol, hot tea) Achalasia (backup of food) Esophageal webs (backup of food) Zenker’s Lye ingestion Can cause special symptoms due to upper location Hoarse voice (recurrent laryngeal nerve) Cough (tracheal involvement) Lymph Nodes Upper esophagus (neck): Cervical nodes Middle (chest): Mediastinal nodes Tracheobronchial nodes Lower (abdomen): Celiac nodes Gastric nodes Wikipedia/Public Domain Esophagitis Infectious causes Candida White membranes Pseudohyphae on biopsy HSV-1 Samir/Wikipedia Usually causes oral herpes Can involve esophagus “Punched out” ulcers CMV AIDS (CD4 ↑ALT in alcoholic hepatitis Alanine Aminotransferase (ALT) Located in cytoplasm ↑ ALT > ↑AST in most types of hepatitis with cellular damage Liver Tests Alkaline phosphatase (Alk Phos) Enzyme from liver, bones, GI tract Precise function not known ↑ synthesis with obstructed bile flow (cholestasis) Serum levels rise with cholestasis Levels rise in many non-liver conditions Pregnancy (placenta) Thyroid disease Bone disease Liver Tests Gamma-glutamyl transpeptidase (GGT) Similar to alk phos but not elevated in bone disease Used to determine origin of alk phos elevation ↑ Alk Phos plus ↑ GGT = hepatobiliary cause of ↑ Alk Phos Also elevated after heavy alcohol consumption 5'-Nucleotidase Bilirubin (total, direct, indirect) Liver Tests Tests of Synthetic Function Albumin PT/PTT (coagulation factors) Glucose Need liver for glycogen breakdown and gluconeogenesis Abnormalities = severe liver disease Alcoholic Liver Disease Three ways alcohol (ethanol) can damage liver #1: Alcoholic fatty liver disease #2: Acute hepatitis #3: Cirrhosis Wikipedia/Public Domain Alcoholic Fatty Liver Disease Accumulation of fatty acids (fatty infiltration of liver) Usually asymptomatic among heavy drinkers May cause hepatomegaly on exam Abnormal LFTs (AST>ALT) Often reversible with cessation of alcohol ↑ risk of cirrhosis ToNToNi/Wikipedia Liver Lobules 1 2 3 Reytan /Wikipedia Portal Triad Reytan /Wikipedia  Fatty infiltration in Liver Zones Alcoholic Liver Disease begins here Hepatic Artery (also fibrosis in cirrhosis) Hepatic Vein Portal Vein Bile Duct Zone I Zone II Zone III Periportal Mid Zone Centrilobular NAFLD Non-alcoholic Fatty Liver Disease Fatty infiltration of liver not due to alcohol NAFL: Fatty liver NASH: Steatohepatitis (fat and inflammation) Often asymptomatic Abnormal LFTs (ALT>AST) May progress to cirrhosis Associated with obesity May improve with weight loss Alcoholic Hepatitis Classically occurs after heavy, binge drinking on top of long history of alcohol consumption Toxic effects from acetaldehyde Symptoms Fever Jaundice RUQ pain/tenderness Alexandre Normand/Flikr Mallory bodies Classic histopathology finding alcoholic liver disease Cytoplasmic inclusions Damaged intermediate filaments in hepatocytes Wikipedia Budd Chiari Syndrome Thrombosis of hepatic vein Abdominal pain, ascites, hepatomegaly Zone 3 congestion, necrosis, hemorrhage Common causes: Myeloproliferative disorder (P. vera, ET, CML) Hepatocellular carcinoma OCP/Pregnancy Hypercoagulable states Right Heart Failure “Cardiac cirrhosis” Rare cause of liver failure Chronic liver edema → cirrhosis Results in nutmeg liver Mottled liver like a nutmeg Also seen Budd Chiari David Monniaux/Wikipedia Reye’s Syndrome Rare cause of liver failure and encephalopathy Children with viral infections who take aspirin Classically chicken pox (varicella zoster) and influenza B Rapid, severe liver failure Evidence that aspirin inhibits beta oxidation Mitochondrial damage seen Fatty changes in liver (hepatomegaly) Vomiting, coma, death Avoid aspirin in children (except Kawasaki’s) α1 Anti-trypsin Deficiency Inherited (autosomal co-dominant) Decreased or dysfunctional AAT AAT balances naturally occurring proteases Proteases Anti-Proteases α1 Anti-trypsin Deficiency Lung Emphysema Imbalance between neutrophil elastase (destroys elastin) and elastase inhibitor AAT (protects elastin) Liver Cirrhosis Abnormal α1 builds up in liver (endoplasmic reticulum) Pathologic polymerization of AAT Occurs in endoplasmic reticulum of hepatocytes α1 Anti-trypsin Deficiency AAT polymers stain with PAS resist digestion by diastase (unlike glycogen) Jerad M Gardner, MD Liver Abscess Walled-off infection of the liver In the US usually bacteria Bacteremia Cholangitis (GN Rods; Klebsiella often identified) Entamoeba histolytica (protozoa) Cysts in contaminated water → bloody diarrhea (dysentery) Ascends in the biliary tree Echinococcus (helminth) Fecal-oral ingestion of eggs Massive liver cysts Hellerhoff/Wikipedia Viral Hepatitis Hepatitis A, B, C, D, or E Very high AST/ALT Often >1000 (>25x normal) Hyperbilirubinemia and jaundice If severe, may see abnormal synthetic function Hypoglycemia, elevated PT/PTT, low albumin Diagnosed via viral antibody tests Autoimmune Hepatitis Autoimmune inflammation of the liver Most common among women in 40s/50s Range of symptoms Asymptomatic → acute liver disease → cirrhosis Anti-nuclear antibodies (ANAs) Most common antibody abnormality Sensitive, not specific Anti-smooth muscle antibodies (ASMA) More specific for AHA Treatment: steroids and immunosuppressants Tylenol Overdose Acetaminophen, Paracetamol, APAP (N-acetyl-para-aminophenol) Maximum recommended dose = 4 grams per 24 hours Overdose causes acute liver failure (hepatic necrosis) Extremely high AST/ALT (in 1000s) Katy Warner/Wikipedia Tylenol Overdose Treatment Activated charcoal may prevent absorption N-acetylcysteine is treatment of choice Used to replenish glutathione Usually given orally to patients with overdose N-acetylcysteine Cysteine Glutathione Tylenol Overdose Treatment Three metabolites of acetaminophen NAPQI is toxic to liver N-acetyl-p-benzoquinone imine Metabolized by glutathione Wikipedia/Public Domain Shock Liver Ischemic Hepatitis Diffuse liver injury from hypoperfusion Often seen in ICU patients with shock from any cause Markedly elevated AST/ALT (1000s) Usually self-limited Pathology: zone 3 necrosis (near central vein) Cirrhosis Jason Ryan, MD, MPH Cirrhosis End stage liver disease (irreversible) Result from many causes of chronic liver disease: Viral Hepatitis (especially B and C) Alcoholic liver disease Non-alcoholic fatty liver disease Cirrhosis Shrunken liver Liver tissue replaced by fibrosis and nodules Smoother liver surface replaced by nodules Wellcome Images Cirrhosis Clinical Features Hyperammonemia Asterixis, confusion, coma Hyperammonemia Treatment Low protein diet Lactulose Synthetic disaccharide (laxative) Colon breakdown by bacteria to fatty acids Lowers colonic pH; favors formation of NH4+ over NH3 NH4+ not absorbed → trapped in colon Result: ↓plasma ammonia concentrations Cirrhosis Clinical Features Jaundice Loss of bilirubin metabolism Hypoglycemia Loss of gluconeogenesis Coagulopathy Loss of clotting factors Elevated PT/PTT Hypoalbuminemia James Heilman, MD May cause low oncotic pressure Contributes to ascites, edema Cirrhosis Capillary Fluid Shifts Capillary hydrostatic pressure (Pc) Drives fluid out of capillaries into tissues Capillary oncotic pressure (∏c ) Proteins (albumin) pull water into capillaries Resists movement of fluid out of capillaries Pc ∏c Cirrhosis Clinical Features Elevated estrogen Normally removed by liver Gynecomastia in men Spider angiomata Palmar erythema Image courtesy Dr. Mordcai Blau/Wikipedia ANNAfoxlover Herbert L. Fred, MD and Hendrik A. van Dijk Portal Hypertension Blood flows portal vein → liver → hepatic vein Cirrhosis → obstructed flow through liver High pressure in portal vein (“hypertension”) Portal Hepatic Vein LIVER Vein Cirrhosis ↑Nitric Oxide Hemodynamics ↓ Albumin ↑ Splanchnic vasodilation ↓ Oncotic Pressure ↓ SVR ↓ BP ↓ Effective Circulating Sympathetic Volume Activation ↑ RAAS ↑ CO ↑ ADH ↑ Na/H2O ↑ Total Body Water Ascites and Edema ↑ Total Body Portal Water HTN Edema Ascites ↓ albumin Patients with cirrhosis but without portal HTN do not develop ascites Venous Collaterals Venous Anastamoses High portal pressure opens “venous collaterals” Connection between portal-systemic veins Normally small, collapsed vessels Engorge in portal hypertension Key collaterals: Umbilicus – physical exam finding: “caput medusa” Esophagus – upper gastrointestinal bleeding Stomach – upper gastrointestinal bleeding Rectum – hemorrhoids which may also bleed Esophageal Varices Esophageal Veins Most esophageal venous drainage via esophageal veins to Left Gastric Vein SVC (coronary vein) Small amount of superficial blood via left gastric vein to portal vein Esophageal Varices Wikipedia/Public Domain Gastric Varices Short gastric veins Left Gastric Vein drain blood from (coronary vein) stomach fundus to left gastric vein and splenic vein (both part of portal Splenic system) Vein Superior Mesenteric Vein Inferior Mesenteric Vein Caput Medusa Caput Medusa is a physical exam finding of engorged veins around the umbilicus Paraumbilical Vein Epigastric Veins  Internal Hemorrhoids Internal hemorrhoids (above dentate line) occur in portal HTN Superior Rectal Vein Middle/Inferior Rectal Veins  Hypersplenism Engorgement of the spleen in portal HTN leads to low platelets Splenic Vein Portal Vein Thrombosis Rare cause of portal hypertension Acute onset abdominal pain Splenomegaly (palpable spleen one exam) May result in gastric varices with bleeding Liver biopsy will be normal Ascites Accumulation of fluid in peritoneal cavity In liver disease, from portal hypertension +/- low albumin James Heilman, MD/Wikipedia SAAG Serum Ascites Albumin Gradient Test of ascitic fluid Two reasons for new/worsening ascites Portal hypertension Malignancy (leaky vasculature) Sample of ascitic fluid via paracentesis Serum albumin – ascites albumin = SAAG SAAG Serum Ascites Albumin Gradient SAAG >1.1 g/dL Large difference between serum and ascites albumin High pressure driving fluid (not albumin) into peritoneum Seen in portal hypertension SAAG 40 = 71% mortality 10 years before most cancers form) Extent of disease (more disease = more risk) Involvement into right colon = more disease “Right sided colitis” or “pancolitis” are risk factors Screening colonoscopy recommended Multiple biopsies taken Colectomy sometimes required Antibody Tests p-ANCA Antibody seen in vasculitis syndromes Churg-Strauss and Microscopic Polyangiitis Also seen in ulcerative colitis Anti-saccharomyces cerevisiae antibodies (ASCA) Saccharomyces cerevisiae: type of yeast Elevated antibody levels seen in Crohn’s Both tests suggested to distinguish forms of IBD Not reliable for routine clinical use Crohn’s Disease Pathologic Features Granulomatous inflammation Entire wall affected (“transmural”) Any portion of the GI tract can be affected “Mouth to anus” Oral ulcers can be seen Crohn’s Disease Pathologic Features Terminal ileum is common location Malabsorption Vitamin deficiencies (B12) Malabsorption of bile salts May have non-bloody diarrhea due to malabsorption May have right lower quadrant pain Often spares the rectum Often “skips” sections Crohn’s Disease Pathologic Features Terminal ileum is common location Malabsorption Vitamin deficiencies (B12) Malabsorption of bile salts May have non-bloody diarrhea due to malabsorption May have right lower quadrant pain Often spares the rectum Often “skips” sections Crohn’s Disease Pathologic Features RicHard-59/Wikipedia Crohn’s Disease Microscopy Non-caseating granulomas Nephron /Wikipedia Crohn’s Disease Gross Morphology Cobblestone mucosa Public Domain/Wikipedia Crohn’s Disease Gross Morphology Fistulas Peri-anal Abdominal Bladder (“enterovesical fistula”) Crohn’s Disease Gross Morphology Creeping fat Transmural inflammation heals Condensed fibrous tissue pulls fat around bowel wall Can wrap around bowel Strictures Healing leads to fibrous tissue Dense fibrous tissue narrows lumen “String sign” Adenocarcinoma Risk only when colon involved When colon involved, surveillance colonoscopy Crohn’s Disease Extra-intestinal Features Migratory polyarthritis Most common extra-intestinal manifestation Arthritis of large joints (knees, hips) Erythema nodosum Inflammation of fat tissue under skin James Heilman, MD Crohn’s Disease Extra-intestinal Features Kidney stones Calcium oxalate stones High oxalate levels seen in Crohn’s Fat malabsorption → Fat binds to calcium Oxalate free to be absorbed in the gut Ankylosing spondylitis Uveitis Immunology T-cells: major contributor both disorders Ulcerative colitis Th2 mediated disorder No granulomas Crohn’s disease Th1 mediated disorder Granulomatous disease Smoking Improves outcomes in UC Worsens outcomes in Crohn’s Pixabay/Public Domain IBD Treatments Corticosteroids Azathioprine Methotrexate 6-MP Infliximab/adalimumab Sulfasalazine 5-ASA Sulfasalazine Not active until reaches colon Perfect for UC! Acetylsalicylic acid (aspirin) Sulfasalazine Colonic Bacteria Sulfapyridine 5-aminosalicylic acid (5-ASA) Sulfasalazine Side Effects GI upset (nausea, vomiting) Sulfonamide hypersensitivity Oligospermia in men Mechanism unclear Reversible with drug cessation Problem for men trying to conceive on therapy Gilberto Santa Rosa/Wikipedia 5-ASA Mesalamine Many side effects of sulfasalazine due to sulfa sulfasalazine - sulfa moiety = 5-ASA Less side effects BUT absorbed in jejunum Less delivery to colon Modified 5-ASA compounds resist absorption Coating or delayed release capsules Asacol, Pentasa 5-aminosalicylic acid (5-ASA) Colon Cancer Jason Ryan, MD, MPH Colon Polyps Raised outgrowth of tissue into lumen May be pre-cancerous Removal can prevent colon cancer Rsabbatini /Wikipedia Hyperplastic Polyp Benign Most common type of polyp Common in rectosigmoid colon Normal cellular structure, no dysplasia Classically have a “saw tooth” or serrated pattern Usually no special screening required after biopsy Hyperplastic Polyp Jeremy T. Hetzel/Flikr Adenomatous Polyp Dysplastic with malignant potential Several sub-classifications By Shape By Histology Adenomatous Adenomatous Polyp Polyp Sessile Pedunculated Tubular Villous Sessile vs. Pedunculated Sessile: broad base attached to colon Pedunculated: attached via stalk Tubular vs. Villous Tubular Most common subtype (80%+) Adenomatous epithelium forming tubules Villous Less common type Often sessile Long projections extending from surface High risk of development into colon cancer Tubular Polyp Nephron/Wikipedia Villous Polyp Nephron/Wikipedia Polyp Symptoms Almost always asymptomatic Screening colonoscopy done for detection Large polyps may cause bleeding Usually not visible in stool (“occult”) Basis for screening with fecal occult blood testing Stephen Holland, MD/Wikipedia  Villous Adenomas Often sessile Can have a broad base (3-4cm) Can lead to excessive mucous secretion Rarely cause a secretory diarrhea Usually when located in rectosigmoid Watery diarrhea → Hypokalemia Bruno et al. The Mckittrick-Wheelock Syndrome: A Rare Cause of Severe Hydroelectrolyte Disorders and Acute Renal Failure. Case Reports in Nephrology Volume 2011 (2011), Article ID 765689, 3 pages High Risk Polyps Likely to develop into cancer Villous histology (villous = villain) Dysplasia grade Determined by pathologist “High grade dysplasia” = ↑ risk Patient likely to develop more polyps Metachronous adenoma: new lesion ~ six months after prior >1 cm in diameter = ↑ risk Number of polyps = ↑ risk Juvenile Polyps Benign tumors (hamartomas) that occur in children Usually in rectum Usually pedunculated Cause painless rectal bleeding Often “auto-amputate” Juvenile polyposis syndrome Multiple (usually >10) polyps Increased risk of cancer Surveillance colonoscopy Peutz-Jeghers Syndrome Autosomal dominant disorder Multiple hamartomas throughout GI tract “Peutz-Jeghers polyps” Pigmented spots on lips and buccal mucosa Often presents in childhood with spots around lips Risk of gastric, small intestinal, and colon CA Wikipedia/Public Domain Genetics of Colon Cancer 1. Two well-defined genetic pathways to colon cancer Chromosomal Instability Pathway Microsatellite Instability 2. Cyclooxygenase-2 expression ↑ in colon cancer 3. DCC gene mutated in advanced colorectal cancers Chromosomal Instability Pathway “Adenoma-Carcinoma sequence” Sequence of genetic events seen in colon cancer Leads to colon cancer over many years Progression probably takes 10-40 years “Somatic” mutations occurs with aging More common in left sided tumors Descending colon, sigmoid, rectum William Crochot  Chromosomal Instability Pathway Step 1: APC mutation Adenomatous polyposis coli protein/gene Tumor suppressor gene Prevents accumulation of β-catenin (activates oncogenes) Loss of APC → ↑ β-catenin → oncogene activation Leads to ↑ risk for polyps Normal At Risk Colon Colon APC Mutation  Chromosomal Instability Pathway Step 2: K-RAS mutation Proto-oncogene Aberrant cell signaling Leads to adenoma polyp formation Normal At Risk Polyp Colon Colon APC KRAS Mutation Mutation  Chromosomal Instability Pathway Step 3: p53 Loss of p53 tumor suppressor gene Tumor cell growth Normal At Risk Colon Polyp Colon Colon Cancer APC KRAS P53 Mutation Mutation FAP Familial Adenomatous Polyposis Autosomal dominant disorder Germline mutation of APC gene (chromosome 5q) Always (100%) progresses to colon cancer Treatment: Colon removal (colectomy) Samir/Wikipedia FAP Variants All have APC gene mutation Polyposis plus extra-intestinal signs/symptoms Gardner’s Syndrome Turcot Syndrome Gardner’s Syndrome Polyposis plus multiple extra-colonic manifestations Benign bone growths (osteomas) especially mandible Skin cysts: Epidermal cysts, fibromas, lipomas, Connective tissue growths: “desmoid tumors”, “fibromatosis” Hypertrophy of retinal pigment CHRPE Congenital Hypertrophy of the Retinal Pigment Epithelium Flat dark spot in retina Seen on slit lamp exam Usually a benign finding with no symptoms When seen with polyposis = Gardner’s syndrome E. Half, D. Bercovich, P. Rozen. Familial adenomatous polyposis „ Orphanet J Rare Dis”. 4, s. 22 (Oct 2009) Turcot Syndrome Polyposis plus brain tumors Mostly medulloblastomas and gliomas Homer-Wright Rosette of Medulloblastoma Image courtesy of Jensflorian Microsatellite Instability Less common mechanism of colon CA development More common in right sided (proximal) tumors These can arise “de novo” without polyp William Crochot Microsatellite Instability What is a microsatellite? Short segments of DNA (usually non-coding) Repeated sequence (i.e. CACACACA) Different density from other DNA Separate from other genetic material in testing (“satellites”) What is a stable microsatellite? Successive cellular divisions: same length microsatellites Each person has unique, “stable” length of microsatellites Different person-to-person; same for each individual Microsatellite Instability What is a mismatch? Bases should be paired (A-T; G-C) If wrong base/nucleotide inserted into DNA = mismatch Mismatch repair enzymes resolve base errors Gene mutations can lead to accumulation of errors This can occur in microsatellites in cancer cells Result is microsatellite instability PCR testing Different length of microsatellites in tumor cells vs other cells Indicates mismatch repair enzyme dysfunction HNPCC Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome Inherited mutation of DNA mismatch repair enzymes Leads to colon cancer via microsatellite instability About 80% lifetime risk Arise with out pre-existing adenoma Usually right-sided tumors Also increased risk of: Endometrial cancer (most common non-colon malignancy) Other cancers (ovary, stomach, others) Classic case Patient with right sided colon CA Multiple 1st family members also with cancer Cyclooxygenase-2 Lipids (cell membranes) Phospholipase A2 Arachidonic acid Lipoxygenase Cyclooxygenase Leukotrienes Thromboxanes Prostaglandins Cyclooxygenase-2 Increased expression in colon cancer cells More common in left sided cancers Rationale for aspirin therapy Reduces risk of colorectal cancer 20-40% BUT increases risk of bleeding/ulcers No clinical trial evidence supporting routine aspirin use for prevention DCC Gene Deleted in Colorectal Cancer (DCC) gene Tumor suppressor gene (chromosome 18q) Frequently mutated in advanced colorectal cancers Colon Cancer 3rd most common cancer 3rd most deadly cancer More common after 50 years of age Colon Cancer May occur anywhere in colon Different sites may have different symptoms Treated with surgery +/- chemotherapy Colon Cancer Right Sided Left Sided (Proximal/Ascending) (Distal/Descending) Iron-deficiency anemia LLQ Pain Weight loss Blood streaked stool “Exophytic” tumors Circumferential lesions Microsatellite instability Change in stool “caliber” Adenoma-Carcinoma Sequence William Crochot Metastasis Most common site is liver James Heilman, MD  Colon Cancer Screening Colonoscopy Recommended at age 45 then every ten years Fecal occult blood testing Regular digital rectal exam Colonoscopy if blood detected James Heilman, MD https://uspreventiveservicestaskforce.org/uspstf/draft-recommendation/colorectal-cancer-screening3 Strep Bovis Normal colonic bacteria Gram positive cocci (gamma hemolytic) Lancefield group D Rare cause bacteremia/endocarditis Strongly associated with colon cancer Classic question: S. Bovis endocarditis identified What test next? Answer: Colonoscopy Image courtesy Y tambe/Wikipedia CEA Carcinoembryonic Antigen Tumor marker Elevated in colon CA and other tumors (pancreas) Poor sensitivity/specificity for screening Patients with established disease CEA level correlates with disease burden Elevated levels should return to baseline after surgery Can be monitored to detect relapse Carcinoid Tumors Jason Ryan, MD, MPH Carcinoid Tumors Neuroendocrine tumors Neuroendocrine cells = nerve and endocrine features Found in many organs: GI tract, lungs, pancreas Small intestine (GI) most common Carcinoid = “cancer like” Named for slow growth Carcinoid Tumors Secrete serotonin Responsible for majority of clinical effects Diarrhea (serotonin stimulates GI motility) ↑ fibroblast growth and fibrogenesis → valvular lesions Flushing (other mediators also) Serotonin 5-hydroxytryptamine (5-HT) Carcinoid Syndrome Symptoms secondary high serotonin levels Liver and lung metabolize (inactivate) serotonin No carcinoid syndrome unless metastatic to liver No left sided heart symptoms: inactivated in lungs Carcinoid Syndrome Altered tryptophan metabolism Normally ~1% tryptophan → serotonin Up to 70% in patients with carcinoid syndrome Tryptophan deficiency reported Tryptophan → Niacin (B3) Symptoms = Pellagra Tryptophan 5-HIAA 5-Hydroxyindoleacetic acid Metabolite of serotonin Appears in urine in carcinoid syndrome 24-hour urine sample for diagnosis Monoamine Oxidase (MAO) Serotonin 5-hydroxyindole 5-hydroxytryptamine acetaldehyde 5-Hydroxyindoleacetic (5-HT) acid (5-HIAA) Carcinoid Heart Disease Fibrous deposits tricuspid/pulmonic valves Stenosis/regurgitation Serotonin inactivated by lungs Left sided lesions rare Carcinoid Syndrome Clinical scenario: Abdominal pain Flushing Diarrhea Pulmonic/tricuspid valve disease Treatments Surgical excision Hepatic resection Octreotide Octreotide Analog of somatostatin Used in GI bleeding and other niche roles Somatostatin receptors on many carcinoid tumors Inhibit release of bioactive amines Serotonin, catecholamines, histamine Octreotide therapy used Flushing and diarrhea significantly improve Gastrointestinal Pharmacology Jason Ryan, MD, MPH Antacids Over the counter therapy Often used for GERD symptoms Sodium Bicarbonate Calcium carbonate Aluminum hydroxide Magnesium hydroxide Midnightcomm Sodium Bicarbonate Alka Seltzer Bloating, belching (CO2) Alkalosis (bicarb absorption) Fluid retention (NaCl resorption) NaHCO3 + HCl  NaCl + H2O + CO2 Calcium Carbonate Tums Bloating, belching (CO2) Alkalosis (bicarb absorption) Can cause constipation (calcium: ↓ GI motor activity) Hypercalcemia (calcium chloride) Special use: Treatment of hypocalcemia CaCO3 + 2HCl  CaCl2 + H2O + CO2 Calcium Carbonate Tums Milk alkali syndrome High intake calcium carbonate (ulcers) Triad: Hypercalcemia, metabolic alkalosis, renal failure Acid rebound Mild acid surge once antacid leaves stomach Probable mechanism: stimulation of acid secretion by calcium Can happen with other antacids Detected by stomach pH monitoring studies Clinic effects questionable Aluminum Hydroxide No bloating or alkalosis Constipation (aluminum: ↓ GI motor activity) Binds phosphate in gut (aluminum-phosphate) Can be used in renal failure to lower phosphate levels “Phosphate binder” Can cause hypophosphatemia Muscle weakness Al(OH)3 + 3HCl  AlCl3 + 3H2O Aluminum Toxicity Usually only occurs in renal failure patients Bones/muscles Bone pain Muscle weakness Osteomalacia Microcytic Anemia Accumulates in bone marrow “Resistant to iron” (normal iron studies; no benefit to iron) Dementia Magnesium Hydroxide No bloating or alkalosis Diarrhea Poorly absorbed → colon → osmotic diarrhea Also used as an osmotic laxative (milk of magnesia) Draws fluid into colon → promotes peristalsis Hypermagnesemia symptoms Hypotension Bradycardia Cardiac arrest Mg(OH)2 + 2HCl  MgCl2 + 2H2O Maalox Magnesium and aluminum hydroxide Diarrhea-constipation effects offset Wikipedia/Public Domain Drug Absorption Altered by all antacids Drug may bind antacid Increased gastric pH may affect absorption Key drugs Tetracycline Fluoroquinolones Isoniazid Iron supplements Tetracycline Al – Ca - Mg Histamine (H2) blockers Famotidine, Ranitidine, Nizatidine, Cimetidine Block histamine receptors in parietal cells Most have few side effects Can cause confusion, especially among the elderly Rarely elevated AST/ALT or cardiac arrhythmias Histamine (H2) blockers Famotidine, Ranitidine, Nizatidine, Cimetidine Cimetidine 1st H2 blocker; rarely used in modern era Potent P450 inhibitor Anti-androgen: Gynecomastia, impotence, prolactin release Crosses BBB: Dizziness, confusion, headaches Reduces creatinine excretion (↑SCR) Proton Pump Inhibitors Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole Inhibit H+/K+ pump in parietal cells Few side effects (usually well tolerated) Potential adverse effects with long term use Proton Pump Inhibitors Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole C. Difficile infection (loss of protection from H+) Pneumonia (more pathogens in upper GI tract) Proton Pump Inhibitors Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole Malabsorption Hypomagnesemia (↓ absorption) Hip fractures (↓ Ca absorption) B12 deficiency H+ required to cleave B12 from dietary proteins Iron Vitamin C Bismuth Salicylate Pepto-Bismol/Kaopectate Coats ulcers/erosion Protects from acid Most effective in H. Pylori ulcers Salicylate Inhibits prostaglandins Reduced stool frequency in diarrheal illnesses In colon, bismuth reacts with hydrogen sulfide Forms bismuth sulfide Blackens the stools Bismuth Salicylate Pepto-Bismol/Kaopectate Antimicrobial against H. Pylori Part of “quadruple” therapy: Proton pump inhibitor Clarithromycin Amoxicillin/Metronidazole Bismuth Salicylate Sucralfate Sulfated polysaccharide + aluminum hydroxide Binds to ulcers Negatively charged drug molecule to positively charge proteins Protects from acid Result: Ulcer healing Adverse effects Not absorbed so very rare Potential aluminum toxicity Osmotic Laxatives All draw water into intestines → bowel movement Used in constipation, bowel prep for colonoscopy Potential side effects of most: Dehydration Electrolyte abnormalities Osmotic Laxatives Magnesium hydroxide (milk of magnesia) Magnesium citrate: Magnesium plus citric acid Polyethylene glycol (Miralax, GoLYTELY) Synthetic polymer Powder (mix with water) Osmotic Laxatives Sodium polystyrene sulfonate (Kayexalate) “Cation Exchange Resin” (i.e. polymer) Bind potassium – used in hyperkalemia Sorbitol: Sugar alcohol Sodium phosphate Lactulose Synthetic disaccharide (laxative) Also used in hyperammonemia Colon breakdown by bacteria to fatty acids Lowers colonic pH; favors formation of NH4+ over NH3 NH4+ not absorbed → trapped in colon Result: ↓plasma ammonia concentrations Other Laxatives Bisacodyl (Dulcolax), Senna (Senokot) “Stimulant laxatives” Poorly understood mechanism Increase GI motility Docusate Stool softener Makes stool soft, slippery Laxative Abuse Factitious diarrhea Bulimia Clues: Diarrhea Dehydration (signs of hypovolemia, hypotension) Hypokalemia Metabolic acidosis from loss of bicarb 5-HT3 Receptor Antagonists Ondansetron Used to treat vomiting (anti-emetic) Block serotonin (5-hydroxytryptamine) receptors 5-HT3 receptors Found in vomiting center in medulla Also in vagal/spinal nerves to GI tract 5-HT3 Receptor Antagonists Ondansetron Commonly used in patients receiving chemotherapy Few side effects Headache Constipation Metoclopramide Reglan Dopamine (D2) receptor antagonists In gastrointestinal tract Dopamine (via D2) blocks ACH effects Blockade → Increased esophagus and gastric motility No effect on small intestine or colon Used in gastroparesis Metoclopramide In central nervous system Dopamine (via D2) activates chemoreceptor trigger zone Area postrema in medulla Blockade → Decreased nausea/vomiting Used as anti-emetic Also effective in migraines Metoclopramide Common Adverse Effects Drowsiness Movement symptoms “Extrapyramidal symptoms” Parkinsonian movements Restlessness Akathisia (constant motion) Dystonia (spasms) Tardive dyskinesia (long term use) Metoclopramide Rare Adverse Effects Nausea, diarrhea (GI effects) Lowers seizure threshold Should not be used in patients with epilepsy Elevated prolactin levels Galactorrhea, gynecomastia, impotence, menstrual disorders Metoclopramide Contraindications Known seizure disorders Parkinson’s disease Bowel obstruction