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Gi

by jshightower, Jun. 2012

Subjects: gi

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	GI Tract - Organization of Layers - Inner to Outer	Epithelium - surface lining Lamina Propria - loose vascular tissue, contains epithelial glands Muscularis Mucosae - smooth muscle layer, controls microperistalsis Submucosa - soft tissue surrounding mucosa Muscularis Propria - inner circular, outer longitudinal - smooth muscle controls peristalsis Serosa (Peritoneum) or Adventitia
	GI Tract - Epithelial Overview	Esophagus - squamous, no mucin or villi, neutral pH, endogenous bacteria Stomach - gastric, neutral mucin, no villi, acidic pH, no bacteria Small Intestine - columnar, acidic mucin, micro villi, neutral pH, endogenous bacteria Colon - columnar, acidic mucin, no villi, neutral pH, endogenous bacteria
	GI Tract - Ganglion Cells	Meissner's Submucosal Plexus - runs through submucosa, innervates glands Auerbach's Myenteric Plexus - runs between muscularis propria layers, innervates smooth muscle Both carry parasympathetic fibers
	GI Tract - Stem Cell Niche	Stem cells located at base of crypt Wnt signaling from supporting stroma promotes epithelial proliferation Mutations in Wnt signaling pathway lead to dysplasia and carcinoma
	GI Tract - Adult Structures Derived From Embryonic Foregut	Pharynx and Esophagus Stomach 1st and 2nd parts of Duodenum - up to entry point of common bile duct Innervated by Parasympathetic Vagus and Sympathetic T5-T9 Arterial blood supply to structures below diaphragm from Celiac Trunk
	GI Tract - Adult Structures Derived From Embryonic Midgut	2nd, 3rd, and 4th parts of Duodenum - from entry point of common bile duct Jejunum, Ileum, Cecum and Appendix Ascending and Proximal 2/3 of Transverse Colon Innervated by Parasympathetic Vagus and Sympathetic T10-T12 Arterial blood supply from Superior Mesenteric Artery
	GI Tract - Adult Structures Derived From Embryonic Hindgut	Distal 1/3 of Transverse Colon Descending, Sigmoid Colon, Rectum and Upper Anal Canal Innervated by Parasympathetic S2,3,4 and Sympathetic L1-L3 Arterial blood supply from Inferior Mesenteric Artery
	GI Tract - Boundaries Between Fore/Mid/Hindgut Structures	Foregut / Midgut = entry point of common bile duct in Duodenum Midgut / Hindgut = 2/3 of the distance of the transverse colon
	GI Tract - Autonomic Innervation	Foregut - Parasympathetic Vagus and Sympathetic Thoracic Splanchnics T5-T9 Midgut - Parasympathetic Vagus and Sympathetic Thoracic Splanchnics T10-T12 Hindgut - Parasympathetic Pelvic Splanchnics S2-S4 and Sympathetic Lumbar Splanchnics L1-L3 Sympathetics pain fibers - referred to dermatomes of body wall matching segmental innervation
	GI Tract - Peritoneum Layers	Parietal Peritoneum - closest to body wall Visceral Peritoneum - attached to surface of GI tract organs Mesentary - double layer of parietal and visceral peritoneum Peritoneal Cavity - potential space formed between parietal and visceral peritoneum
	GI Tract - Distribution of Dorsal and Ventral Mesentary	Entire GI tract below diaphragm has dorsal mesentary Only foregut also has ventral mesentary
	GI Tract - Embryonic Foregut Structure Movement	Foregut rotates 90 degrees to right about long axis Liver moves from ventral midline to left, suspended in ventral mesentary Stomach rotates to right, suspended in dorsal and ventral mesentary Spleen moves from dorsal midline to right, suspended in dorsal mesentary Pancreas (except tail) adheres to posterior body wall - becomes secondarily retroperitoneal
	GI Tract - Adult Structure Remnants of Embryonic Mesenteries	Falciform ligament - connects liver to anterior body wall - ventral mesentary Lesser Omentum - connects liver to lesser curvature of stomach - ventral mesentary Greater Omentum - connects greater curvature of stomach to spleen and GI tract - dorsal mesentary Epiploic foramen - opening to omental bursa - lesser sac of lesser omentum
	GI Tract - Embryonic Midgut Structure Movement	Midgut rotates 270 degrees counterclockwise about axis of superior mesenteric artery Forms three sided "picture frame" with colon - cecum in lower right
	GI Tract - Entry of IVC, Esophagus, and Aorta into Abdomen	I Ate Ten Eggs At 12 IVC - T8 Esophagus - T10 Aorta - T12
	GI Tract - Ligament of Treitz	Suspensory ligament of duodenum - connects duodenum to diaphragm Band of skeletal muscle arising from diaphragm and fibromuscular smooth muscle from duodenum Inserts at duodenojejunal flexure - contraction widens angle, allows passage of contents Hematemesis (blood in vomit) or melena (black tarry stool) indicate bleed proxmial to ligament Hematochezia (red blood or clots in stool) indicate bleed distal to ligament
	GI Tract - Esophagus Muscle Composition	Proximal 5% - voluntary skeletal muscle Middle 45% - mostly smooth muscle, some skeletal Distal 50% - involuntary smooth muscle Smooth Muscle - inner circular, outer longitudinal layers
	GI Tract - Anatomic Divisions of Stomach	Cardiac - entry point of esophagus, epithelial transition point Fundus - superior lobe extending above cardiac notch Body - large central area bounded by cardia, fundus, and pylorus Pylorus - antrum and canal, connects body to duodenum
	GI Tract - Stomach Muscle Composition	Outer longitudinal Middle circular Inner oblique
	GI Tract - Gastroesophageal Junction	Located 1.25 cm below diaphragm in abdomen Squamo-columnar cell juntion - forms Z line - cardia Esophageal squamous epithelium meets gastric oxyntic mucosal epithelium Site of physiologic inferior esophageal sphincter
	GI Tract - Parasympathetic Gastric Innvervation	Right Vagus Nerve --> Posterior Vagal Trunk --> Posterior Gastric Branches Left Vagus Nerve --> Anterior Vagal Trunk --> Anterior Gastric Branches
	GI Tract - Gastric Arterial Blood Supply	Left and Right Gastric Arteries supply Lesser Curvature Left Gastric A. from Celiac Trunk and Right Gastric A. from Common Hepatic Left and Right Gastroepiploic Arteries supply Greater Curvature Left GE A. from Gastroduodenal A. and Right GE from Splenic A.
	GI Tract - Anatomic Differences Between Jejunum and Ileum	J - plica circularis mucosal folds, simple arterial arcades, long vasa recta I - smooth mucosal wall, Peyer's patches, complex arterial arcades, short vasa recta
	GI Tract - Major Aortic Branches Supplying GI Structures	Celicac Trunk - Splenic A, Left Gastric A, Common Hepatic A Superior Mesenteric Artery - Middle Colic A, Right Colic A, Ileocolic A Inferior Mesenteric Artery - Left Colic A, Superior Rectal A, Sigmoid A
	GI Tract - Epithelial Cell Adhesion Structures	Tight Junctions - apical domain, cadherin based, attached to microtubules Desmosomes - attach cell surface ahdesion proteins to keratin cytoskeleton (intermediate filaments) Gap Junctions - directly connect cytoplasm through hydrophillic channels
	GI Tract - Esophagus Histology	Non Keratinizing stratified squamous epithelium Thick muscularis mucosae layer Salivary like glands under muscularis mucosae to lubricate esophageal lumen
	GI Tract - Gastric Chief Cell	Located in oxyntic mucosa of gastric corpus Basophilic H&E appearance - large amount of ER Secretes pepsinogen, gastric lipase, and rennin
	GI Tract - Brunner Glands	Located exclusively in duodenum Produce mucus rich alkaline secretion containing bicarbonate Provides protection from gastric acid and raises pH to activate digestive enzymes
	GI Tract - Sliding Hiatal and Paraesophageal Hernias	Sliding Hiatal - movement of GE junction into throacic cavity Paraesophageal - Portion of stomach herniates through esophageal hiatus into thoracic cavity
	GI Tract - Complications of a Posterior Duodenal Ulcer	Can erode into gastroduodenal artery - massive hemorrhage Direct suture ligation of ulcer +/- feeding vessels Gastroduodenal A, anterior superior pancreaticoduodenal A. right gastroepiploic A.
	GI Tract - Surgical Treatment of Peptic Ulcer Disease	Vagotomy and Pyloroplasty Bitruncal vagotomy at level of distal esophagus - removes vagal stimulation of acid secretion Pylorus rendered incompetent, stays open, to allow gastric drainage Can selectively lesion anterior vagal branch Preserve posterior vagal nerves of latarjet, antral innervation maintained, no pyloroplasty needed
	GI Tract - Surgical Treatment of Gastroesophageal Refulx Disease	Fundoplication - Nissen method Fundus of stomach mobilized by removing short gastric vessels Fundus wrapped around distal esophagus Crura of diaphragm repositioned to repair hiatal hernia
	GI Tract - Appendix Arterial Blood Supply	Appendicular Artery off Ileal branch of Ileocolic Artery
	GI Tract - Esophageal Rings	A Ring - muscular ring, transition from tubular esophagus to phrenic ampulla B Ring - mucosal ring, esophagogastric junction, band of mucosa and submucosa C Ring - diaphragmatic impression if there is a hiatal hernia
	GI Tract - Gallstone Radiology	Peripheral rim of calcification Layers of calcification around cholesterol nidus in gallbladder
	Radiology - XR v CT - spatial resolution and contrast resolution	XR has greater spatial resolution CT has greater contrast resolution
	GI Tract - Barium Sulfate	Inert element, coated with suspension agents Coats mucosal surface, fills grooves XR beam attenuated by barium, appears white
	GI Tract - Sling Fibers	Band of smooth muscle cross gastric cardia obliquely Help create angle of esophagus and stomach
	GI Tract - Phrenoesophageal Ligament	Tethers esophagus to esophageal hiatus of the diaphragm Loose enough to allow esophagus to elevate and shorten during swallowing Degenerates with age
	GI Tract - Agents That Decrease Lower Esophageal Sphincter Pressure	Anticholinergics, barbituates, calcium channel blockers, diazepam, dopamine, theophylline Caffeine, theobromine (chocolate), peppermint, ethanol, fat, smoking CCK, glucagon, estrogen, somatostatin, secretin Lower sphincter pressure results in more frequent reflux
	GI Tract - Rugal Folds	Large folds in gastric fundus and gastric body, no folds in antrum Composed of mucosa and submucosa Appear as smooth, tubular, radiolucent fillings in barium imaging
	GI Tract - Gastric Foveolar and Glandular Layers	Foveolae are conical depressions in mucosal surface, connect to gastric glands, lined by mucous cells Gastric Body - foveolae are upper 1/3, glands are lower 2/3 Gastric Antrum - foveolae are upper 1/2, glands are lower 1/2
	GI Tract - Distinguishing Feature of Gastric Body Mucosa	Presence of chief and parietal cells
	GI Tract - Areae Gastricae	Imaging pattern on barium study of stomach Fine reticular network, polygonal areas Most abundant in antrum, some present in fundus
	GI Tract - Valculae Conniventes	Small intestine mucosal folds perpendicular to longitudinal axis Contain mucosa and submucosa layers Increase surface area for absorption by 300% Taller, thicker, and more abundant in jejunum than ileum Radiologic abnormality suggests pathology in mucosa or submucosa Appear large like thumbprints with submucosal edema or hemorrhage on mesenteric border
	GI Tract - Pylorus Muscular Layer	Two thick bands fused superiorly at a bulge or torus Pylorus contracts, mucosa may bulge outward between bands Barium outpouching termed torus defect
	GI Tract - Colon Arterial Supply Anatomic Orientation	Arteries course through mesentery Attach to colon at mesenteric border Enter colonic wall on mesenteric domain of antimesenteric teniae Wall weakness at site of arterial perforation, site of diverticula formation
	GI Tract - Colon Longitudinal Muscle Layer	Coalesce into three distinct bands - teniae coli Haustral sacculations result from tension of teniae coli Stretches from cecum to beginning of rectum Fuse into single layer at rectum
	GI Tract - Aphthoid Ulcers	Occur at sites of lymph aggregates in the colon or small intestine Lymph tissue becomes inflamed, overlying mucosa ulcerates Earliest lesion in Crohns Disease
	GI Tract - Colon and Rectum Lymphatic Drainage	Right / Ascending and Proximal Transverse Colon drain up branches of the SMA Left / Descending Colon drain up branches of the IMA Anal Canal (including 2 cm above pecinate line) drain to inguinal lymph nodes
	GI Tract - Liver Venous Divisions	Middle Hepatic Vein divides liver into left and right lobes Left Hepatic Vein divides left lobe into medial and lateral segment Right Hepatic Vein divides right lobe into anterior and posterior segments All Hepatic Veins converge at dome of liver to join IVC
	GI Embryonic Development - Gut Tube Openings	Cranial end (foregut) terminates at buccopharyngeal membrane - future oral cavity Caudal end (hindgut) terminates at cloacal membrane - future rectum Opening to yolk sac narrows to form vitelline duct - becomes incorporated into umbilical cord
	GI Embryonic Development - Occlusion and Recanalization	Week 5 - hollow gut tube Week 6 - endodermal epithelial proliferation results in occluded gut tube Weeks 7-8 - tissue degenerates by vacuole formation to recanalize (open) gut tube Week 9 - endodermal lining differentiates into definitive mucosal epithelium Failure of complete or normal recanalization results in duplication, stenosis, or atresia
	GI Embryonic Development - Formation of Lung Rudiment	Respiratory diverticulum bud forms at day 22 Ventral out pouching of thoracic esophagus Sequential bifurcation of lung bud to bronchial buds resulting in terminal sacs
	GI Tract - Esophageal Atresia and Stenosis	Complete blockage or narrowing of esophagus Usually due to failure of recanalization 85% associated with tracheoesophageal fistula
	GI Tract - Tracheoesophageal Fistula	Caudal displacement of septum between trachea and esophagus Results in incomplete separation of respiratory and esophageal tubes Fetus cannot swallow and dispose of amniotic fluid - fluid accumulates resulting in polyhydramnios Newborn first swallow is normal, then fluid suddenly expelled and enters respiratory distress
	GI Tract - Congenital Hiatal Hernia	Failure of esophagus to elongate - short esophagus Displaces / pulls part of stomach into thoracic cavity
	GI Embryonic Development - Stomach Formation	Dorsal wall grows more rapidly than ventral wall Forms greater curvature (dorsal) and lesser curvature (ventral) Differential thinning of right side of dorsal mesentery 90 degree rotation of stomach around craniocaudal axis Greater curvature ends on left and lesser curvature ends on right Rotation results in displacement of duodenum - adheres to dorsal body wall
	GI Tract - Congenital Hypertrophic Pyloric Stenosis	Thickening of pylorus Severe stenosis and obstruction of food passage Newborns display distended stomach and projectile vomiting
	GI Tract - Duodenal Atresia and Stenosis	Complete blockage or narrowing of duodenal lumen Usually due to failure of recanalization Newborn vomiting within hours of birth - vomit contains bile Atresia occurs in 30% of infants with Down's Syndrome and 20% of premature births "Double Bubble" appearance on ultrasound - stomach and proximal duodenum dilated and filled with air
	GI Embryonic Development - Liver Formation	Hepatic Plate - endodermal thickening appears on ventral side of duodenum Hepatic plate proliferates to form hepatic diverticulum - grows into ventral mesentery Diverticulum gives rise to hepatic cords, bile canaliculi, and hepatic ducts Hepatic cords develop into hepatocytes Ventral mesentery connecting liver to stomach becomes lesser omentum Ventral mesentery connecting liver to ventral body wall becomes falciform ligament
	GI Embryonic Development - Gallbladder and Cystic Duct Formation	Cystic Diverticulum forms as second endodermal thickening on ventral side of duodenum Forms caudal to hepatic diverticulum Gallbladder and Cystic Duct form Cystic Diverticulum Cells at junction of hepatic and cystic ducts proliferate to form the bile duct
	GI Tract - Extrahepatic Biliary Atresia	Obstruction of bile duct Due to failure of canalization or fetal liver infection Jaundice develops soon after birth
	GI Embryonic Development - Pancreas Formation	Dorsal Pancreatic bud forms on duodenum opposite the hepatic diverticulum - grows into dorsal mesentery Ventral Pancreatic bud forms on ventral duodenum caudal to gallbladder - grows into ventral mesentery Ventral bud gives rise to hepatobiliary tree - main duct of ventral bud connects to bile duct Bile duct and ventral pancreatic duct migrate around duodenum to dorsal mesentery Pancreatic ducts fuse - dorsal pancreatic duct degenerates Head, neck, and body of pancreas fuse to dorsal body wall - tail remains peritoneal
	GI Tract - Anular Pancreas	Two ventral pancreatic buds form - rotate in opposite directions to fuse with dorsal bud Thin band of pancreatic tissue surrounds duodenum Can cause duodenal atrestia or stenosis - either at birth, or after inflammation or malignancy
	GI Embryonic Development - Midgut Formation	Primary intestinal loop - hairpin loop surrounding SMA - tip of turn attached to umbillicus by the vitelline duct Cranial loop gives rise to ileum, caudal loop gives rise to midgut colon Loop herniates into umbillicus and rotates 90 degrees to the right Loop retracts into abdominal cavity and rotates 180 degrees to the right Total 270 degree turn counterclockwise / right
	GI Tract - Congenital Omphalocele	Herniation of intestines into umbilical cord Failure of midgut to retract into abdominal cavity at week 10 Intestinal loops protrude from abdominal wall through umbilical cord, surrounded by amniotic membrane
	GI Tract - Umbilical Hernia	Midgut retracts normally into abdominal cavity at week 10 Failure of umbilicus to close completely Intestine herniates into umbilical cord
	GI Tract - Gastroschisis	Extrusion of midgut structures through ventral body wall Due to incomplete lateral folding during week 4 Involves all layers of abdominal wall from peritoneum to skin No involvement of umbilical cord
	GI Tract - Ileal (Merkel's) Diverticulum	Persistent remnant of stalk connecting yolk sac to GI lumen True diverticulum, contains all layers of GI wall May contain gastric or pancreatic tissue Can cause appendicitis-like complications and symptoms Present in 2% of population within 2 feet of ileocecal valve, if symptomatic present by age 2 (rule of 2s)
	GI Tract - Embryonic Rotation Defects	Nonrotation - left sided colon, second 180 degree rotation does not occur Mixed rotation - failure to complete final 90 degree rotation, cecum ends inferior to stomach Reversed rotation -second 180 degree rotation reversed, duodenum and transverse colon moved Cecum unattached in abnormal location - risk of internal rotation, hernia, ischemic twisting
	GI Tract - Midgut Volvulus	Twisting of the intestines Due to failure of midgut to retract normally into abdomen and failure of normal fixation to body wall Can result in blockage of gut lumen and blood supply to gut tissue
	GI Embryonic Development - Rectum and Urogenital Sinus Formation	Cloaca formation - distal hindgut formation sealed by cloacal membrane Urorectal septum divides cloaca into posterior rectum and anterior urogenital sinus Urorectal septum formed from fusion of superior Tourneux fold and two lateral Rathke folds Urogenital membrane and anal membrane fuse at perineum Anal membrane proliferates to form anal pit - invaginates to form anal canal
	GI Tract - Congenital Megacolon / Hirschprung's Disease	Failure of neural crest cell migration during weeks 5-7 Partial absence of enteric ganglion plexus Results in localized failure of peristalsis and dilation proximal to blockage Most common cause of neonatal colon obstruction
	GI Tract - Membranous Atresia	Anus is in normal position but sealed by anal membrane Failure of anal membrane perforation during week 8
	GI Histology - Presence of Villi	Exclusively small intestine
	GI Histology - Presence of submucosal glands	Esophagus and duodenum
	GI Histology - Areas Surrounded by Adventitia	Esophagus - above peritoneal cavity Rectum and Anus - below peritoneal cavity Mid and Lower duodenum - retroperitoneal Posterior Surface of Ascending and Descending Colon - retroperitoneal
	GI Histology - Stomach Regions and Cell Types	Cardia - mostly mucous secreting cells Fundus and Body - Parietal Cells, Chief Cells, and Enteroendocrine cells Antrum and Pylorus - G cells, enteroendocrine cells, and mucous cells
	GI Histology - Gastric Glands	Foveolae / pits - upper portion, contain mucous secreting cells Isthmic zone - connects pits and neck, contains epithelial stem cells Neck - Parietal cells and mucous cells Basal - deepest portion, contains chief cells, enteroendocrine cells, and enterochromaffin-like cells 2-7 deep glands empty into a single pit
	GI Histology - Parietal Cells	Pink eosinophilic cytoplasm - abundant mitochondria Secrete acid and Intrinsic factor - binds B12 for absorption H+/K+/ATPase contained in membrane of Tubulovesicles - rapidly inserted into surface membrane
	GI Histology - Chief Cells	Blue basophilic cytoplasm - abundant rER Secretory granules contain pepsinogen and weak lipases
	GI Tract - Entry of Bile and Pancreatic Ducts into Duodenum	Fusion of both ducts forms Ampulla of Vater Sphincter of Oddi regulates content release Penetrates medial wall of second part of duodenum
	GI Histology - Small Intestine Crypt Cells	Paneth cells - secrete defensins, lysozyme, and TNFa Enteroendocrine cells - secretory granules in basal domain, secrete contents into bloodstream - CCK and secretin CCK stimulates gallbladder bile release, secretion of pancreatic enzymes, and slows gastric emptying Secretin stimulates pancreatic bicarbonate secretion and enhances insulin secretion
	GI Histology - Large Intestine / Colon	Straight glands No villi Mucous secreting goblet cells, absorptive cells, and enteroendocrine cells Gut Associated Lymphoid Tissue (GALT/MALT) - not distinct Peyer's patches
	GI Histology - Location of Peyer's Patches	Ileum
	Esophagus - Diseases Differentially Affecting Upper v Lower Esophagus	Upper Striated - polymyositis, myasthenia gravis Lower Smooth - scleroderma, achalasia
	Esophagus - Upper Esophageal Sphincter	Separates pharynx from esophagus Inferior pharyngeal constrictor, circopharyngeus, and cervical esophagus muscles Pressure decreases to allow food into esophagus, belching and vomiting Pressure increases to prevent air entry into GI tract and reflux of gastric contents into pharynx Basal tonic muscle contraction tone - transiently inhibited to reduce pressure during swallowing
	Esophagus - Neural Control of Peristalsis	Nucleus Ambiguous stimulates progressive ACh driven contractions of proximal striated muscle Parallel Inhibitory and Excitatory innervation of smooth muscle - both vagal Cholinergic excitatory pathways most prominent proximally Noncholinergic inhibitory pathways most prominent distally Results in progressive delay in contractions along esophagus
	Esophagus - Lower Esophageal Sphincter Activity	Tonically closed at rest Pressure falls 2 seconds after swallowing, remains low for 5-6 seconds Allows content emptying into stomach during proximal food peristalsis Pressure increases when peristaltic wave reaches distal esophagus
	Gastroesophageal Reflux	Movement of gastric contents into the esophagus through the Lower Esophageal Sphincter Transient relaxation of LES stimulated by vagal afferents signaling stomach distension Occasional reflux is normal Gastroesophageal Reflux Disease when often enough to cause symptoms or complications
	Gastroesophageal Reflux Disease - Pathogenesis	Transient relaxation of lower esophageal sphincter - milder disease Hiatal hernia traps reflux contents near LES - more severe disease Hypotension of LES - more severe disease Increased duration of esophageal mucosa acidification - impaired emptying and decreased salivation
	GERD - Transient Lower Esophageal Sphincter Relaxations (TLSERs)	Stimulated by vagal afferents signaling stomach distension Responsible for most reflux episodes in patients without hiatal hernias - compared to strain or low LES pressure Less responsible for reflux episodes in patients with hiatal hernias BMI correlated with TLESR frequency - obesity predisposes to reflux
	GERD - Factors Affecting Severity and Complications	Duration of esophageal mucosa acidification (pH <4) and Bile exposure Increased duration correlated with increased incidence of esophagitis and Barrett's Bile exposure particularly important for Complicated Barrett's
	GERD - Other Conditions Mimicking GERD Symptoms	Coronary Artery Disease Gallstones Gastric or esophageal cancer Peptic Ulcer Disease Esophageal motility disorders Pill induced esophagitis Eosinophilic esophagitis
	GERD - Diagnosis	Empiric PPI antisecretory trial - evaluate response of symptoms to treatment Endoscopy > Manometry > Reflux Monitoring (pH measurements)
	GERD - Esophageal Erosion	Symptoms do not predict presence or severity of erosive esophagitis Non-erosive reflux disease (NERD) - reflux symptoms without mucosal erosion
	GERD - Therapy	Proton Pump Inhibitors - must take before food ingestion Histamine Receptor (H2R) Antagonists Laparoscopic Antireflux Surgery - for PPI refractory or intolerant, persistent regurgitation symptoms Lifestyle modifications - weigh loss, avoid precipitating foods
	GERD - Long Term Safety Concerns of PPI's	C. difficile infection Aspiration pneumonia Hip Fracture Fundic Gland Polyps
	GERD - Conditions that Decrease LES Tone or Increase Abdominal Pressure	Alocohol and tobacco Obesity CNS depressants Pregnancy Hiatal hernia Delayed Gastric Emptying / Increased Gastric Volume
	GERD - Complications	Esophageal Ulceration Hematemesis, Melena Stricture formation Barrett's Esophagus
	Gastric Cell Types- Location and Secretions	Parietal Cells - Body and Fundus - Acid and intrinsic factor G Cells - Antrum - Gastrin D Cells - entire stomach - Somatostatin ECL Cells - Histamine Chief Cells - Pepsinogen
	Peptic Ulcer Disease - Parietal Cell Signal Transduction	Vagus Nerve --> ACh --> M3 Receptor --> PLC --> Ca increase G Cell --> Gastrin --> Gastrin / CCK Receptor --> PLC --> Ca increase G Cell --> Gastrin --> ECL Cell --> Histamine --> H2 Receptor --> Adenylate Cyclase --> cAMP increase Final common output --> stimulate H/K/ATPase (proton pump) on luminal surface H Efflux, K influx, ATP hydrolysis
	Peptic Ulcer Disease - Negative Regulation of Gastric Acid Production	Low pH --> D Cells in Antrum --> Somatostatin --] G Cell and ECL Cell Inhibition Vagal ACh input not regulated by negative feedback Prostaglandins exert protective negative feedback role
	Peptic Ulcer Disease - Normal Gastric Protective Mechanisms	Prostaglandins (most important) - promote mucous and bicarbonate production and submucosal blood flow Mucous - secreted by neck cells, barrier to H+ back diffusion, traps alkaline secretions, buffers luminal acidity Bicarbonate - secreted into mucous layer, neutralizes acid entering mucous layer Basal membrane and apical tight junctions - barrier function Mucosal blood flow - provides oxygen and nutrients to prevent hypoxia and permit regeneration
	Peptic Ulcer Disease - Normal Gastric Damaging Agents	Acid - Secreted by Parietal Cells Pepsin - Secreted as Pepsinogen by chief cells, activated by low pH Pepsin is reversibly inactivated at pH > 4 - irreversibly inactivated at pH > 6, must be resynthesized Bile - backflow through duodenum into stomach
	Peptic Ulcer Disease - Duodenal v Antrum Ulcer Clinical Presentation	Dudodenal (usually bulb) - pinpoint epigastric burning pain relieved by food ingestion Stomach (usually antrum) - diffuse epigastric pain, nausea, vomiting worsened by food ingestion
	Peptic Ulcer Disease - Ulcer Causing Aggressive Agents	Acid - no acid no ulcer NSAID - local caustic effect and systemic inhibition of prostaglandins via COX-1 inhibition H pylori - increases gastric acid production (duodenal ulcers) and decreases mucosal protection (gastric ulcers) Steroids, smoking, alcohol, bile, caffeine
	Peptic Ulcer Disease - Approaches to Medical Treatment	Inhibit Acid Production - PPI and H2R Antagonists Neutralize Acid - Antacids Treat H pylori Avoid NSAID use Enhance protective mechanisms - sucralfate and misoprostal
	Peptic Ulcer Disease - H2 Receptor Antagonists	Competitive H2R antagonists - high specificity to GI tract Rapid absorption and onset - continuous dosing maintains gastric pH > 4 and inactivates pepsin Hepatic p450 metabolism and renal excretion Rare bradycardia, LFT elevation, anti androgenic effects in men Some potently bind p450 - increases levels of warfarin, phenytoin theophylline, and diazepam
	Peptic Ulcer Disease - Proton Pump Inhibitors	Irreversibly block H/K/ATPase - new pump must be re synthesized to resume acid secretion More effective and longer lasting than H2R Antagonists Delivered as prodrug - must be absorbed systemically to mediate effect Short half life, long duration, hepatic p450 metabolism, minimal drug interactions due to short half life Can increase gastrin production, long use may cause osteoporosis, disrupts normal stomach bacteria
	Peptic Ulcer Disease - PPI Delivery and Mechanism of Action	Delivered as prodrug in acid resistant coating to prevent degradation in stomach Outer layer dissolved by alkaline medium of small intestine - prodrug inactive at neutral pH Absorbed systemically - lipophilic prodrug diffuses across lipid membranes into acidified cellular compartments Enters Parietal cell, protonation traps it inside, becomes concentrated and sulphonated to active drug Drug binds H/K/ATPase and inactivates pump
	Peptic Ulcer Disease - Antacids	Weak bases neutralize HCL to form a salt and H20 Temporarily relieve symptoms of dyspepsia Bad taste, may affect absorption of other drugs such as tetracyclines High doses can result in symptoms from excess Mg, Al, and Ca
	Peptic Ulcer Disease - Antimicrobial Treatment of H. pylori	Triple regimens - 2 antibiotics + 1 PPI Ab - Clarithromycin, metronidazole, amoxacillin, tetracycline PPI - omeprazole, peptobismol May add bismuth subsalicyclate to coat ulcer acting as protective layer to prevent further damage
	Peptic Ulcer Disease - Medications Enhancing Protective Mechanisms	Misoprostol - PGE1 analogue - limited use due to bloating, diarrhea, and is an abortifacient Sucralfate - stimulates production of gastric mucous, HCO3, and PGE2 Sucralfate may bind other medications in GI lumen - Digoxin, Ciproflaxacin, Theophylline
	Zollinger Ellison Syndrome - Overview	Gastrin secreting tumor - gastrinoma - results in unregulated parietal cell acid secretion Gastrin induces parietal cell hyperplasia, neck cell hyperplasia, mucin hypersecretion Patients present with multiple duodenal ulcers or chronic diarrhea 60-90% are malignant - must be identified and removed 75% are sporadic solitary tumors - 25% due to Multiple Endocrine Neoplasia 1
	MEN 1 / Werner Syndrome	Multifocal hyperplasia and neoplasia Pituitary, Parathyroid, and Pancreatic Islets most common Adrenal cortex, lung, and thymus also affected Menin mutation Pancreatic tumors are gastrin secreting tumors - Zollinger Ellison Syndrome - malignancy determines prognosis
	Zollinger Ellison Syndrome - Pathophysiology	Unregulated gastrin production not subject to negative feedback via paracrine somatostatin Induces parietal cell acid secretion and hyperplasia Results in multiple recurrent non-healing peptic ulcers (usually duodenal) Inappropriate Hypergastrinemia - high gastrin secretion in the presence of gastric acid production
	Hypergastrinemia - Appropriate and Inappropriate Causes	Appropriate as normal response to hypo/achlorhydria Normal in setting of PPIs and H2RA, atrophic gastritis, H pylori, chronic renal failure, vagotomy Inapproriate in setting of normal gastric acid secretion Abnormal in ZES, retained antrum syndrome, antrum dominant H pylori, massive intestinal resection
	Gastric Analysis	Basal Acid Output - nasogastric collection tube for 1 hr overnight, measure volume H+ produced Maximal Acid Output - same measurement after Pentagastrin (synthetic gastrin) stimulation Must stop therapy prior to measurement
	Zollinger Ellison Syndrome - When to Suspect in Patients	Severe PUD - multiple, recurrent, non healing ulcers Diarrhea - due to acid secretion Non NSAID, non H Pylori ulcers MEN 1 patients
	Idiopathic Gastric Acid Hypersecretion	Increased Basal and Maximal Acid Output Increased parietal cell mass, meal stimulated acid output, and 24 hour acid secretory profile Results in Duodenal ulcers May be caused by increased parietal cell sensitivity, basal and meal stimulated hypergastrinemia, somatostatin deficiency, decreased bicarbonate secretion Most due to H pylori infection
	Heliobacter pylori - Pathophysiology	Fecal-oral or oral-oral transmission Urea --(urease)--> ammonia + H20 + CO2 --> ammonium + bicarbonate --> neutralizes acidic environment Flagellae and spiral morphology facilitate penetration of mucous layer Enzyme products - protease and phospholipase - disrupt mucosal barrier Adherence factors permit attachment to surface of mucous cells Chronic active inflammation of gastric mucosa and systemic humoral immune response Interferes with mucous production - does not invade mucosa
	Heliobacter pylori - Effects on Gastric Acid Secretion	Initial decrease in acid secretion - multiple progression pathways Antral predominant infections result in duodenal ulcers - acid hypersecretion Can develop into asymptomatic chronic gastritis - normal acid levels Can result in pangastritis and Gastric ulcers, risk of cancer and lymphoma - acid hyposecretion
	Heliobacter pylori - Mechanistic Link to Duodenal Ulcers	Antral infection inhibits somatostatin production --> unopposed gastrin release Basal and postprandial hypergastrinemia induce gastric acid hypersecretion Duodenal gastric metaplasia permits H pylori colonization of duodenal bulb Local bulb defenses are damaged in setting of acid hypersecretion --> duodenal ulceration Metaplasia occurs at junctional zone between stomach and duodenum
	Heliobacter pylori - Spectrum of Infections and Complications	Chronic Gastritis Duodenal Ulcers (75-90%) Gastric Ulcers (60-70%) - mainly via reduction of mucosal defenses Chronic Gastritis --> atrophy --> intestinal metaplasia --> dysplasia --> cancer MALToma Non Ulcer Dyspepsia
	Heliobacter pylori - Risk of Cancer	Chronic gastritis --> gastric atrophy --> intestinal metaplasia --> dysplasia --> Gastric Antral Cancer MALToma from monoclonal lymphocyte expansion during chronic lymphocytic gastritis
	Heliobacter pylori - Infection to Disease Pathways	Exposure --> Acute Infection --> Superficial Gastritis --> Hyper/Hyposecretory Hypersecretory --> Antral predominant --> Duodenal ulcer Hyposecretory --> Chronic pangastritis --> Chronic Atrophic Gastritis --> Gastric Ulcer or Gastric Cancer (0.05%) Hyposecretory --> Chronic pangastritis --> lymphocytic predominant --> MALToma
	Heliobacter pylori - Gastric Cancer	Infection associated with corpus and antral cancers - not with cardia and GE junction cancers CagA pathogenicity island associated with cancer - toxin directly injures epithelial cells CagA + infections associated with increased cytokine release and inflammation IL-1 host polymorphism increases risk for progressing to pangastritis and developing cancer
	Heliobacter pylori - Testing for Infection	Biopsy mucosa - thiazine stain, ISH, or IHC for pathogen CLO test - biopsy placed in chamber, pH becomes basic with urease activity Blood - test for antibodies, cannot determine active from past infection Breath test - ingest radioactive substrate, measure exhaled radioactive urea
	Acute Gastric Ulceration - Morphology	Sharply demarcated with normal adjacent mucosa Base is stained brown/black by acid digestion of extravasated blood No scarring and thickening of blood vessels that characterize chronic peptic ulcers
	Peptic Ulcer Disease - NSAID Induced Mucosal Injury	Local caustic damage - minor role Systemic COX1 inhibition results in decreased prostaglandin protective activity - major role COX1 inhibition --> reduced mucous and bicarbonate production, decreased blood flow H pylori infection induces COX2 - increases risk of ulceration
	Peptic Ulcer Disease - Prevention of Ulcers in NSAID Users	Misoprostol replaces prostaglandin protection - effective prevention of Gastric Ulcers Omeprazole (PPI) to reduce acid secretion - effective prevention of Gastric and Duodenal Ulcers
	Peptic Ulcer Disease - Curling's Ulcer and Cushing's Ulcer	Curling's - proximal duodenal ulcers seen in burn patients Cushing's - gastric, duodenal, and esophageal ulcers seen in patients with intracranial disease Cushing's Ulcers due to direct stimulation of vagal nuclei - high risk of perforation
	Non-Ulcer Dyspepsia - Other Non Ulcer Causes of Epigastric Pain	GERD, pancreatitis, gallstones Pneumonia, Pulmonary Embolus, Myocardial Infarction, Ruptured Aortic Aneurysm
	GI Tract - Active Inflammation	Indicated by presence of neutrophils above basement membrane contacting epithelial cells May be present in both acute and chronic disease states
	Stomach - Gastric Motor Functions	Fundus and Proximal Body - Storage Distal Body and Antrum - Processing and Emptying Pylorus - Processing and Emptying
	Stomach - Accommodation	Increase in gastric volume without a significant increase in intragastric pressure Stomach distension from food ingestion stimulates gastric mechanoreceptors Vago-Vagal reflex through brainstem --> stimulates prolonged gastric relaxation Stomach can accomodate 1-1.5 liters of food when relaxed
	Stomach - Gastric Slow Waves	Interstitial cells of cajal in greater curvature of proximal body serve as pacemaker cells Spontaneous waves 3x/ min - electrical current spreads distally and circumferetially Fasting - few slow waves result in contraction / post prandial - most slow waves trigger contraction
	Stomach - Fasting State Gastric Motility	Cyclical Migrating Motor Complex (MMC) - last 100 min each Phase I - long duration, quiescent, no contractions Phase II - few irregular motor contractions Phase III - 5 min long, regular high amplitude contractions, sweep particles out of stomach - housecleaning Different from postprandial contractions because pylorus remains open to allow emptying of contents Stimulated by Motilin or erythromycin activating Motilin receptors
	Stomach - Post Prandial Gastric Motility	Mixing waves - weak peristaltic contractions stimulated by gastric slow waves Propagates from mid stomach to antrum gathering strength as it travels Pylorus contracts when wave approaches, only small amount of content passes through Retropulsion - content pushed backwards and upstream from closed pylorus towards proximal stomach Allows mixing of food contents with gastric secretions and trituration - reducing particle size
	Stomach - Gastric Emptying of Liquids	Fluid empties at linear rate dependent on antroduodenal pressure gradient Determined by liquid volume and gastric tone Independent of contractile activity
	Stomach - Gastric Emptying of Solids	Ingested food mixed with gastric juices into semi-liquid called chyme Intense peristaltic waves force several millimeters of chyme through pylorus = pyloric pump Increased gastric food content stimulates stomach distension Myenteric nerves in stomach wall respond by stimulating pyloric pump contractions and reducing pyloric tone Food induced gastrin secretion stimulates same neural response
	Stomach - Effect of Food Content on Gastric Emptying	Larger volume empties faster than smaller volume Liquids empty faster than semiliquids that empty faster than solids Carbohydrates empty faster than proteins that empty faster than fat
	Stomach - Enterogastric Nervous Reflexes	Duodenal neural feedback to slow gastric emptying Vagal brainstem loop, enteric nervous connections from duodenum to stomach, and inhibitory sympathetics Enterogastric nervous feedback inhibits pyloric pump and increases pyloric tone Enterogastric nervous reflexes activated by high acid, protein, fat, or volume reaching duodenum
	Stomach - Enterogastric Hormonal Feedback	CCK released by jejunal epithelial cells in response to high fat slows gastric emptying Somatostatin, dopamine, and secretin all exert negative feedback
	Gastroparesis - Causes and Symptoms	Stomach paralysis - impaired transit of food from stomach to duodenum Diabetic, post surgical, medication induced and idiopathic most common causes Can be caused by paraneoplastic, rheumatologic, neurologic, and myopathic syndromes Nausea, vomiting, early satiety - morning nausea Bezoar formation
	Gastroparesis - Diagnosis	Gastric scintigraphy Radiolabelled low fat egg beaters - measure abdominal retention over 1-4 hours
	Gastroparesis - Management	Small, frequent, low fat, low fiber meals Glucose control in diabetic gastroparesis Medications - prokinetic and antiemetic agents Gastric electrical stimulation - high frequency, low energy, short pulse duration stimulation Surgery
	Gastroparesis - Metoclopramide	Prokinetic via DA Antagonism (myenteric plexus), 5 HT4 Agonism, and smooth muscle muscarinic stimulation Antiemetic via central DA and 5 HT3 antagonism Extrapyramidal Parkinsons-like side effects - DA mediated
	Gastroparesis - Domperidone	Prokinetic via DA Antagonism (myenteric plexus), 5 HT4 Agonism, and smooth muscle muscarinic stimulation Antiemetic via central DA and 5 HT3 antagonism Does not cross BBB - no extrapyramidal effects Used in patients that cant tolerate EPS of Metoclopramide or Parkinson's Patients with gastroparesis
	Gastroparesis - Erythromycin	Prokinetic - Binds and activates motilin receptors on GI smooth muscle Used for inpatients Interacts with CYP-3A inhibitors
	Gastroparesis - Scopolamine	Antiemetic - ACh M1 receptor antagonist Administered as path for severe nausea and motion sickness
	Gastroparesis - Ondansetron and Granisetron	Antiemetic - 5 HT3 antagonists
	GI - Dumping Syndrome	Rapid emptying of hypertonic liquids from stomach into intestine Often occurs in patients with gastrojejunostomy for gastroparesis Early nausea, flushing, diarrhea, and syncope - mediated by release of vasoactive factors Late hypoglycemia - mediated by release of insulin
	Non Ulcer Dyspepsia - Overview	Symptoms referable to upper GI tract not due to structural disease Post prandial distress syndrome - early satiety, bothersome fullness Epigastric pain syndrome - pain and burning
	Non Ulcer Dyspepsia - Pathophysiology	Delayed gastric emptying, poor compliance, ineffective gastric contraction patterns Visceral hypersensitivity to pain Psychological stress and personality traits influence symptoms May be alternative presentation of GERD
	Esophagitis - Etiologies	Reflux - most common Pill - localized caustic injury Allergy - eosinophillic esophagitis Viral - Herpes, CMV Crohns, trauma, radiation Fungal - Candida
	Eosinophilic Esophagitis	Allergic response to food antigen - hypersensitivity reaction Increased intraepithelial eosinophils, absence of acid reflux, damage affects entire length of esophagus Circular rings and longitudinal esophageal furrows - trachealization of esophagus Present with dysphagia (difficulty swallowing) and odynophagia (pain with swallowing) - refractory to PPI therapy Common comorbid atopic dermatitis, allergic rhinitis, asthma - uncommon peripheral eosinophilia or high IgE Treat with oral steroids and avoidance of food allergens
	Esophagus - Skin Disorders Affecting the Esophagus	Pemphigus - blistering autoimmune diseases - acantholysis, loss of intercellular adhesions Pemphigoid - blistering autoimmune disease w/o acantholysis Lichenoid Reaction
	Dysphagia - Webs and Rings	Webs - protrusions of mucosa, semicurcumferential eccentric lesions in upper esophagus Schatzki Rings - thick ring containing mucosa, submucosa, and hypertrophic muscularis propria - reflux induced A Rings - above GE junction, squamous mucosa B Rings - at or below GE junction, gastric cardia mucosa
	Dysphagia - Achalasia	Incomplete LES relaxation Increased LES tone Aperistalsis of esophagus Present with difficulty swallowing Food stasis and decay --> risk for squamous cell carcinoma
	Dysphagia - Scleraderma	Selective Atrophy (not fibrosis) of inner circular layer of muscularis propria Affects lower esophagus Seen in CREST presentation of Scleraderma
	Mallory Weiss Tear	Longitudinal tears of esophagus mucosa near GE junction Due to severe retching or vomiting caused by acute alcohol intoxication Failure of esophageal musculature to relax with prolonged vomitting Present as hematemesis, commonly heal completeley
	Barrett Esophagus - Pathophysiology	Intestinal metaplasia of esophageal squamous mucosa as complication of chronic GERD Presence of goblet cells required for diagnosis of intestinal metaplasia and Barrett Increased risk of esophageal adenocarcinoma
	Barrett Esophagus - Morphology	Red velvety mucosa extending upward from GE junction Long segment > 3 cm above GE junction / short segment < 3 cm involved Short v Long length of metaplasia determined at initiation of injury, do not interconvert Greater risk of cancer in long segments
	Barrett Esophagus - Histologic Changes	Intestinal metaplasia - presence of goblet cells Dysplasia - proliferation, atypical mitoses, hyperchromasia, increased N:C ratio, immature epithelial cells Gland architecture dysruption, budding, irregular shapes, cellular crowding High grade dysplasia exhibits more severe cytologic and architectural change Adenocarcinoma - invasion into lamina propria
	Esophageal Adenocarcinoma - Pathogenesis	Stepwise acquisition of genetic changes progressing from dysplasia to invasive cancers Transitions to invasive carcinoma after invading laminae propria Most often occurs in distal third of esophagus adjacent to Barrett esophagus Present with dysphagia, weight loss, hematemesis, chest pain, vomiting Often spreads to submucosal lymphatics at time of diagnosis - poor prognosis
	Esophageal Squamous Cell Carcinoma - Pathogenesis	Affects all portions of esophagus - 50% in middle In situ squamous dysplasia grows into tumor mass - commonly obstructs lumen No relation to reflux - commonly associated with EtOH and tobacco use Invade surrounding structures and spread via local lymph nodes Poor prognosis - advanced stage and large size at detection
	Esophageal Squamous Cell Carcinoma - Lymph Node Metastasis	Circumferential and Longitudinal spread along esophagus Lesions in upper 1/3 spread to cervical LN Lesions in mid 1/3 spread to mediastinal, paratracheal, and tracheobronchial LN Lesions in lower 1/3 spread to gastric and celiac LN Invade surrounding structures - lungs, aorta, mediastinum, pericardium Symptomatic tumors usually large at diagnosis - already invaded esophageal wall and metastasized
	GI Disturbances - Red Flags Concerning for Malignancy	Dysphagia Vomiting with meals, Early Satiety Weight Loss Blood in Stool Age > 45 years
	Dyspepsia - Definition and Differential Diagnosis	Upper abdominal (epigastric) discomfort, usually worse after meals, present for greater than 4 weeks DDx - Peptic Ulcer Disease, Non Ulcer Dyspepsia Atypical presentation for GERD, hepatobiliary disorders, pancreatitis, or non GI disease process
	Chronic Gastritis - Etiology	Helicobacter pylori and Autoimmune Gastritis most common Less often caused by radiation, chronic bile reflux, mechanical injury, systemic disease, amyloidosis
	Eosinophilic Gastritis	Tissue damage associated with eosinophilic infiltrate in mucosa and muscularis Most commonly affects antral or pyloric region Presents with vomiting, abdominal pain, diarrhea (protein losing enteropathy), GI bleeding, ascites Associated with peripheral eosinophilia and elevated serum IgE (opposite of whats seen in Eosinophilic Esophagitis) Allergic reaction most common cause - cow's milk, soy protein Can be cause by drugs or in association with systemic collagen vascular disease
	Atrophic Chronic Gastritis - Heliobacter pylori Infection	Loss of parietal and chief cells from oxyntic mucosa areas (body and fundus) H pylori induced intestinal metaplasia --> cells lack Lewis receptors needed for H pylori binding H pylori can spread up to body and fundus inducing gastritis and cellular damage
	Atrophic Chronic Gastritis - Autoimmune Gastritis	Autoantibodies directed against apical H+ pump or intrinsic factor in parietal cells Self reactive CD4 T cell mediated cell injury Achlorhydria --> Loss of acid --> hypergastrinemia and antral G cell and ECL cell hyperplasia Loss of intrinsic factor --> B12 deficiency --> pernicious anemia Loss of chief cells secondary to gland destruction --> reduced serum pepsinogen levels
	Atrophic Gastritis - Definition	Loss of parietal and chief cells from oxyntic mucosa areas (body and fundus)
	Autoimmune Atrophic Gastritis - Risk of Cancer	Prolonged hypergastrinemia stimulates ECL cell proliferation Risk of transformation into low grade neuroendocrine carcinoid tumor Intestinal metaplasia (goblet cells) of gastric mucosa --> risk of gastric adenocarcinoma No hypergastrinemia in H pylori mediated atrophic gastritis due to less severe parietal cell loss
	Autoimmune Atrophic Gastritis - Effects of Vitamin B12 Deficiency	Pernicious megaloblastic anemia Atrophic glossitis - tongue becomes smooth and beefy Subacute Combined Systems Degeneration - demyelination, axonal degeneration, neuronal death Paresthesias, numbness, loss of vibration sense and proprioceptions Sensory ataxia, positive Romberg sign, limb weakness, spasticity, Babinski sign Personality changes, memory loss, psychosis
	Inflammatory and Hyperplastic Gastric Polyps	Most common type (75%) of gastric polyps Chronic gastritis initiates injury and reactive hyperplasia leading to polyp growth Most commonly occur in antrum Variable size, single or multiple Small risk of neoplastic transformation, correlated with size
	Fundic Gland Polyps	Occur sporadically and in patients with Familial Adenomatous Polyposis Increased incidence with PPI therapy --> gastrin stimulated glandular hyperplasia Occur in gastric body and fundus Benign and usually asymptomatic
	Gastric Xanthelasma	Xanthelasma is a collection of lipid laden macrophages forming a yellowish plaque Not associated with underlying lipid metabolic disorder Can occur anywhere Must distinguish from gastric signet ring cancer
	Hypertrophic Gastropathies	Enlarged gastric rugal folds due to epithelial hyperplasia without inflammation Menetrier disease - foveolar mucous cell hyperplasia due to excessive TGF alpha secretion Zollinger Ellison Syndrome - parietal cell hyperplasia due to gastrin secreting tumor
	Menetrier Disease	Diffuse hyperplasia of foveolar mucousal epithelial cells Enlarged rugal folds due to epithelial hyperplasia without inflammation (hypertrophic grastropathy) Excessive mucin secretions lost in feces --> protein losing enteropathy --> hypoproteinemia Weight loss, diarrhea, peripheral edema, increased risk of gastric adenocarcinoma
	Mucosa Associated Lymphoid Tissue Lymphoma (MALToma)	Extra Nodal Marginal Zone B Cell Lymphoma Arise at sites of chronic inflammation - most commonly in GI Tract Most often arise in sites normally devoid of organized lymphoid tissue Indolent tumor can transform into aggressive diffuse large B cell lymphoma
	Gastric MALToma	Chronic inflammation (usually H pylori) drives formation of Gastric MALT MALT can progress to indolent extranodal marginal zone B cell lymphoma Lymphoepithelial lesions distinguish MALToma from chronic gastritis (lymphocytes don't invade epithelium) If associated with H pylori, infectin drives NFkB signaling through MLT and BCL-10 signaling Treat with antibiotics, remove inflammatory stimulus, reduce NFkB signaling --> tumor regression Translocations constituitively activating MLT and BCL-10 drive tumor progression
	Gastric Adenoma	Usually occur in background of chronic atrophic gastritis with intestinal metaplasia Composed of intestinal type columnar epithelial cells Represent dysplastic lesion - risk of adenocarcinoma correlated to size of lesion
	Diffuse Gastric Adenocarcinoma - Genetic Mutations	CDH1 / E Cadherin mutations in familial and 50% of sporadic forms Loss of function through mutation or promoter methylation is key step in cancer development CDH1 mutation also common in lobular breast carcinoma BRCA2 mutation carriers at increased risk of diffuse gastric cancer
	Intestinal Type Gastric Adenocarcinoma - Genetic Mutations	Increased risk in patients with FAP - APC mutation Mutations in beta catenin and mismatch repair genes seen Classic dysplasia --> carcinoma sequence of progression Genetic alterations resemble those seen in colon adenocarcinoma
	Diffuse Gastric Adenocarcinoma - Morphology and Histology	Infiltrative growth of small clusters of cells into mucosa and stomach wall Discohesive cells, do not form glands Large mucin vacuoles --> push nuclei to side --> signet ring cytology Evoke desmoplastic reaction, stiffen gastric wall --> linitis plastica
	Intestinal Type Gastric Adenocarcinoma - Morphology and Histology	Most commonly involve lesser curvature of antrum Bulky tumors composed of glandular structures Grow in broad cohesive fronts, form exophytic mass or an ulcerated tumor May present as non-healing ulcer Contain apical mucin vacuole
	Gastric Adenocarcinoma - Signs and Symptoms	Early - dyspepsia, dysphagia, nausea - resemble chronic gastritis Late - weight loss, anorexia, altered bowel habits, anemia, hemorrhage
	Intestinal Obstruction - Clinical Manifestations	Abdominal pain and distension, vomiting, constipation 80% of mechanical obstructions due to hernias, adhesions, intususceptions, and volvulus 10-15% of mechanical obstructions due to tumors and infarctions Most common in Esophagus, Duodenum, and Small Intestine - rare in colon, stomach, and anus
	Tracheo-esophageal fistula - Clinical Manifestations	90% have blind upper esophageal segment and fistula b/w lower esophagus and trachea Presents with aspiration, regurgitation, and respiratory distress Absence of GI gas pattern on X rays Often associated with other anatomic congenital anomalies
	Duodenal Stenosis - Clinical Manifestations	Vomiting beginning at birth - bilious if stenosis is distal to Ampulla of Vater Most occur in proximal portion near Ampulla Most due to a web - failure of lumen recanalization - or due to annular pancrease Double bubble sign on radiographs - gas pocket in stomach and dilated duodenum proximal to occlusion
	Small Intestineal Atresia - Clinical Manifestations	85% are single sites - 15% are multiple Usually due to intrauterine vascular accidents or known post natal vascular accidents Classified based on if blind ends are connected and if there is a defect in associated mesentery
	Anorectal Atresia - Clinical Manifestations	Manifest with abnormal perineum and imperforate anus Classified as above or below levator sling Associated with fistula to the bladder, urethra, or vagina Infant fails to pass meconium within first 48 hours - components ingested in utero
	Short Bowel Syndrome - Clinical Manifestations	Loss of bowel surface and absorptive area Decreased fluid and electrolyte reabsorption, nutrient and bile salt deficiency, chronic diarrhea Requires Total Parenteral Nutrition - can lead to chronic liver disease Common indication for bowel transplantation in children
	Gastrointestinal Cysts - Duplications	Intestinal duplication located on mesenteric border -shares common wall with GI lumen - does not communicate Most frequent in distal ileum - can occur anywhere in GI tract - location determines clinical manifestation Can be tubular or cystic - cystic duplications are larger and create mass compressive symptoms
	Gastrointestinal Cysts - Neurenteric Remnants	Originate from dorsal midline GI tract - attach or pass through vertebrae and spinal cord Most frequent in cervical and lumbar areas Dorsal cutaneous are of hypertrichosis or hyperpigmentation Present as GI obstruction, respiratory distress, CNS paralysis and infection
	Aganglionosis	Failure of neural crest cell migration or survival to form enteric nervous system Lack of neural relaxation signals results in tonic contraction Hirschprung - congenital, neonatal presentation with failure to pass meconium and abdominal distension Acquired - Chagas disease destroys enteric nervous system cells
	Necrotizing Enterocolitis	Most common GI Emergency in newborns - associated with prematurity Onset associated with enteral feeding - may introduce pathogen - initiate inflammatory cycle Cycle of mucosal barrier breakdown, transmural invasion of gut bacteria, inflammation --> mucosal damage Can cause ischemia, coagulative necrosis - progress to sepsis and shock Presents within first 2 weeks post natal with bloody stool, abdominal distension, apnea, and circulatory collapse Pneumatosis intestinalis - gas within bowel wall on radiographs Most frequently in terminal ileum, cecum, ascending colon - can affect any segment Post NEC stricture formation from fibrosis or short bowel syndrome from resection
	Intestinal Intussusception	Invagination of one intestinal segment into distal segment Intussusceptum invaginates into intussuscipiens Intestine relatively unteathered in childhood Repeatedly invaginates and recovers - multiple episodes of pain and resolution Can result in obstruction of lumen, compression of mesenteric vessels, and segment ischemia and infarction
	Cystic Fibrosis - GI Manifestations	CFTR functions to secrete Cl - mutations decrease water secretion --> thick mucous Meconium ileus - obstruction of lumen by viscid meconium plug - may rupture causing peritonitis Loss of exocrine pancreas function, recurrent pancreatitis Chronic hepatic disease, focal biliary or multilobar cirrhosis Nutritional failure to thrive, hypoporeteinemia, edema, deficiencies of fat soluble vitamins (ADEK)
	Bowel - Segmentation	Occurs in Fed State Gradient of peristaltic contraction rates to mix luminal contents and increase contact time with epithelium Increased frequency of segmenting contractions in duodenum > jejunum > ileum Driven by pacemaker cells Regulated by intrinsic reflex arcs, extrinsic neural input, and stimulated by postprandial gastrin release
	Bowel - Migrating Motor Complex	Occurs in fasting state Sequential, organized, short peristaltic waves starting in stomach and progressing caudally Initiated by motilin secretion from terminal ileum - stopped by gastrin release with next meal House keeping function - takes 100-150 min to reach terminal ileum
	Small Intestine - Secretions	1.5 Liters of water and mucous per day - total volume of 9-10 liters passes through per day Mucous lubricates lumen and protects cells - water needed for enzymatic nutrient hydrolysis Driven by Cl- secretion from apical CFTR in epithelial crypts - regulated by cAMP
	Small Intestine - Surface Epithelium Structure and Function	Villi - absorption Crypts - secretion
	Digestion - Carbohydrates	Salivary amylase initiates digestion of polysaccharides into disaccharides Pancreatic amylase secreted into duodenum continues digestion Polysaccharides --> Disaccharides --> Monosaccharides via brush border disaccharidases Cotransport of monosaccharides with Na into enterocytes Majority of glucose absorption occurs in Jejunum - lactose absorption variable due to genetic differences
	Digestion - Proteins	Initiated in stomach by HCl and Pepsin - continued in duodenum by pancreatic proenzyme activation Trypsinogen --(Enterokinase)--> Trypsin Other zymogen proteases and trypsinogen --(Trypsin) --> active proteases and trypsin Brush border aminopeptidases finalize digestion to single amino acids Cotransport of AA with Na through neutral, basic, and acidic AA transporters Cotransport of di and tripeptides with H+ Absorption occurs throughout jejunum and ileum
	Digestion - Fat Digestion and Emulsification	Digestion initiated in stomach by gastric lipase - TG --> FA and diglycerides (DG) Stable emulsion with inner TG, DG, cholesterol, vitamins and outer phospholipids, MG, FA, and bile salts Digestion in duodenum by pancreatic lipase - TG --> FA and monoglycerides (MG) Colipase secreted by pancreas facilitates TG interaction with lipase Phospholipase A2 secreted by pancreas digests phospholipids on emulsion and anchors lipase to emulsion No digestion by brush border enzymes on enterocytes
	Digestion - Absorption of Lipid Products	Products of lipid digestion solubulized into micelles - core MG, FFA, cholesterol with surrounding bile salts Micelles diffuse to apical brush border of enterocytes and release lipids Lipids diffuse into cells down concentration gradient - reesterified inside cell to form original products Lipids packaged with apoproteins into chylomicrons - exocytosed from basolateral domain Chylomicrons enter lacteals (lymphatic capillaries) - enter systemic circulation via throacic duct Bile salts remain in lumen - absorbed by distal ileum
	Digestion - Vitamins	Not digested - absorbed intact Water soluble - simple diffusion or carrier mediated - B complex, C Fat soluble - absorbed via micelles - ADEK B12 - bound by IF from gastric parietal cells, absorbed as complex in terminal ileum via specific transporter
	Vitamin B12 Absorption	Produced by microorganisms - large amounts in animal products, absent in plant products Ingested bound to binding proteins Gastric acid and pepsin releases B12 from binding proteins - binds salivary carrier R protein Pancreatic proteases release B12 from R protein in duodenum Parietal cells produce intrinsic factor - binds B12 and carries to terminal ileum IF-B12 absorbed in terminal ileum via IF receptors Transferred to transcobalamin II - delivers to liver, bone marrow, GI tract, and dividing cells in body
	GI Disease Affecting Vitamin B12 Absorption	Acid Hyposecretion - PPI therapy - can't liberate B12 from binding proteins in food Pancreatic insufficiency - chronic pancreatitis - can't liberate B12 from R binding protein Crohn's Disease or Terminal Ileum disease or resection - can't bind and absorb B12 bound to IF Autoimmune Gastritis - Destruction of Parietal Cells - no production of IF
	GI Disease Affecting Iron Absorption	Acid Hyposecretion - PPI therapy - acid required for conversion of ferric to absorbable ferros iron IBD / Celiacs - sloughing of enterocytes, loss of ferritin, impaired absorption
	GI Disease Affecting Calcium Status	Lactose intolerance - decreased absorption due to loss of brush border enzymes Celiac and Crohn Disease - decreased absorption due to enterocyte damage
	Small Intestine - Fluid Absorption	9-10 Liters per day pass through - all but 1.5 liters per day absorbed Absorption rate in Ileum > Jejunum > Duodenum Basolateral Na/K/ATPase pump Na into blood, bring K in Multiple Apical NaCl transporters bring NaCl into cell Water follows NaCl osmotically into cell through water permeable epithelium - NO CONCENTRATING
	Colon - Function	Salt and water absorption - iso osmotic - NO CONCENTRATING Waste storage No digestive function or nutrient absorption - no brush border
	Ileocecal Valve	One way valve regulates entry of material from ileum into colon Opens with ileal distension - closes on cecum contraction - prevents backflow of colonic bacteria and contents Ileal brake - fat sensors inhibit gastric motility - mediated by Peptide YY
	Colon - Motility and Absorption	Poor Motility --> Increased Absorption --> Hard Feces --> Constipation Excess Motility --> Decreased Absorption --> Loose Feces --> Diarrhea
	Colon - Absorption and Secretion	Surface cells absorb Na and Cl, secrete K and HCO3 Crypt cells secrete Cl in cAMP dependent pathway 1.5 L pass through per day - absorbs 1.4 L per day --> 100 ml per day in feces Iso osmotic absorption - NO CONCENTRATING Limited capacity compared to small intestine - easily overwhelmed resulting in diarrhea
	Colon - Motility Patterns	Segmentation - slow (2/hr), regulated by autonomic nervous system Propulsive - weak peristaltic waves stimulated by intrinsic nerves Gastrocolic reflex - gastrin released after meal stimulates strong contractions in proximal colon to move contents
	Colon - Bacteria	Faculative and obligate anaerobes Slow flow promotes bacterial growth Produce Short Chain Fatty Acids - direct nourishment for colonic epithelial cells Produce gas, vitamin K, stimulate immune development and IgA secretion Endogenous flora compete against pathogenic flora
	Defecation	Holding - contraction of puborectalis and external anal sphincter Skeletal response - relaxation of PR and EAS, contraction of levator ani, rectus and diaphragm muscles Smooth response - relaxation of internal anal sphincter, contraction of rectal muscles CNS control in hypothalamus - local reflex arc from fecal distension of rectum
	Collateral Circulation in Small Intestine v Colon	Colic arteries connected by marginal artery - rich collateral circulation Small intestine supplied by parallel arcade system - no collateral circulation Segmental infarct more common in small intestine Can tolerate slowly progressive loss of blood supply from single artery
	Ladd Bands	Fibrotic bands forming at sites of inappropriate adhesion of GI tract to abdominal wall May serve as rotation points resulting in obstruction and ischemia
	Ischemic Bowel Disease - Mucosal v Transmural Infarction	Mucosal - can involve any segment of GI tract, segmental, patchy, ulcerated hemorrhagic mucosa Bowel wall thickened by edema (thumb printing), no serosal hemorrhage or serositis Caused by acute or chronic hypoperfusion Transmural - watershed zones most susceptible, splenic flexure most common Sharply demarcated, congested, coagulative necrosis, perforation, serositis Caused by acute arterial obstruction
	Ischemic Bowel Disease - Pathogenesis	Initial hypoxic injury - minimal damage, epithelial cells resistant to transient hypoxia Reperfusion injury - majority of damage Damage due to free radical production, neutrophil infiltration, inflammatory mediators (complement and TNF) Mucosa most sensitive - inflammatory and necrotic changes begin at surface and progress through wall layers
	Ischemic Bowel Disease - Clinical Features	Acute transmural infarction presents with sudden severe abdominal pain, nausea, vomiting, bloody diarrhea Can progress to shock and vascular collapse from blood loss - sepsis from bacteria crossing damaged barrier Loss of peristaltic sounds, abdominal rigidity from muscle spasms Symptoms overlap with acute appendicitis, perforated ulcer, and acute cholecystitis
	Ischemic Bowel Disease - Possible Etiologies	Atherosclerosis, aortic aneurysm, hypercoagulable states, oral contraceptive use --> thromboembolism Cardiac failure, shock, dehydration, vasoconstrictive drugs --> hypoperfusion Systemic vasculitis, polyarteritis nodosum, wegner granulomatosis Mesenteric venous thrombosis, sigmoid volvulus
	Crohns Disease - Overview	Can affect any GI segment - relative sparing of rectum - discontinuous skip lesions Transmural inflammation - fistulae and stricture formation Extraintestinal manifestations Increased risk of carcinoma in inflammed areas Microscopic granulomas, fibrosis, cryptitis, and knife like ulcerations Significant genetic link - NOD2
	Crohns Disease - Genetic Predisposition	Significant genetic associations to disease phenotype NOD2 polymorphism identified NOD2 binds intracellular bacterial peptidoglycans (LPS) resulting in NFkB activation Defective NOD2 may prevent clearance of intracellular bacteria or result in impaired inflammatory regulation Mutations associated with Crohns are in Leucine Rich Repeats involved in LPS binding
	Crohns Disease - Morphology	Skip lesions - multiple sharply delineated lesions anywhere along GI tract Aphthous lesion - occur over lymphoid aggregates, may coalesce into linear ulcers on mesenteric side Cobblestone mucosa - ulceration alternating with normal mucosa, edema Creeping fat - mesenteric fat extends around serosal surface Transmural inflammation - knife like fissures, fibrosis, stricture and fistulae formation Hypertrophy of muscularis propria --> stricture formation
	Crohns Disease - Endoscopic Findings	Ileitis - stenosis, linear ulceration, mucopurulent exudate - loss of normal nodularity Deep fissures, cobblestoning, segmental lesions, rectal sparing
	Crohns Disease - Histology	Neutrophil infiltration through damaged epithelial barrier (cryptitis) cluster into crypt abscesses --> crypt destruction Distortion of mucosal architecture due to repeated crypt damage and regeneration Epithelial metaplasia --> gastric antral like glands or Paneth cell metaplasia in left colon Noncaseating granulomas, cutaneous granuloma nodules
	Crohns Disease - Clinical Presentation	Intermittent attacks of mild diarrhea, fever, and abdominal pain - interrupted by asymptomatic periods Weight loss, growth failure, perianal disease May mimic acute appendicitis or bowel perforation Physical or emotional stress or cigarette smoking may trigger reactivation Extraintestinal manifestations Increased risk of colonic adenocarcinoma
	Crohns Disease - Oral Manifestations	Oral lesions - may be initial presentation Persistent and painless enlargement of lips - fissures and cracking Anguluar chylitis, atrophic glossitis Linear ulcerations deep in tissue folds of oral mucosa Non caseating granulomas
	Inflammatory Bowel Disease - Clinical Presentation in Adults v Children	CD - Children most often present as colitis - growth failure is major feature - more inflammatory disease than adults UC - Children more frequently present with pancolitis or limited disease that progresses to extensive disease
	Inflammatory Bowel Disease - Extraintestinal Manifestations	Uveitis, migratory polyarthritis, sacroiliitis, ankylosing spondylitis - CD and UC Pericholangitis and primary sclerosing cholangitis - CD and UC Erythema nodosum, clubbing of fingertips - CD only
	Ulcerative Colitis - Overview	Limited to Colon - starts distal, progresses proximally Inflammation limited to mucosa Extraintestinal manifestations Increased risk of carcinoma in inflammed areas Cryptitis, crypt abscesses, crypt distortion - no granulomas or strictures Less significant genetic link than CD
	Ulcerative Colitis - Morphology	Continuous lesion from rectum extending proximally Pancolitis - entire colon / Left sided colitis - transverse colon / Ulcerative proctitis - limited distal disease Sparing of small intestine except for backwash ileitis in pancolitis Broad based ulcers alinged on long access, mucosal atrophy and loss of normal folds Pseudopolyps - islands of regenerating mucosa No mural thickening or stricture formation
	Ulcerative Colitis - Endoscopic Findings	Loss of vascular pattern Granularity Exudates Diffuse continuous disease
	Ulcerative Colitis - Histology	Neutrophil infiltration through damaged epithelial barrier (cryptitits) cluster into crypt abscesses crypt destruction and distortion Epithelial metaplasia Diffuse inflammatory process limited to mucosa No granulomas
	Ulcerative Colitis - Clinical Presentation	Attacks of bloody diarrhea with stringy mucoid material, lower abdominal pain, cramps Pain temporarily relieved by defecation Relapsing disorder - physical or emotional stress or smoking cessation may trigger reactivation Extraintestinal manifestations Increased risk of colonic adenocarcinoma
	Ulcerative Colitis - Risk of Cancer	Increased risk of colorectal adenocarcinoma with increased duration of disease and inflammation High grade flat dysplasia, dysplasia associated lesion or mass, primary sclerosing cholangitis increase risk
	Ulcerative Colitis - Oral Manifestations	Ulcerations of oral mucosa Angular cheilitis due to nutritional deficiencies
	IBD - Symptomatic Treatment	Limit diarrhea and maintain hydration Opioid mu receptor agonists - reduce intestinal motility, increase colonic transit time
	IBD - Aminosalicyclates Mechanism of Action	Aspirin + Amino group Reduces formation of prostaglandins and leukotrienes Inhibits NFkB activity, inhibits NK cells, mucosal lymphocytes and macrophages Scavenges reactive oxygen species Functions locally at GI epithelial cells - formulated to prevent systemic absorption in small intestine
	IBD - Indications for Aminosalicyclate Therapy	Mild to moderately active ulcerative proctoclitis or crohns disease Maintenance of disease remission
	IBD - Aminosalicyclate Administration and Delivery Options	AZO Compound - 5 ASA coupled to inert compound bound by AZO bond Activity of 5-ASA dependent on cleavage of AZO bond by colonic bacteria Limited use for small intestine inflammation of Crohns Mesalamine Compound - 5 ASA monomer inside carrier complex Formulated for targeted release (time, pH) in small intestine or other site
	IBD - Sulfasalazine	AZO compound - 5 ASA coupled to sulfapuridine by AZO bond Oral admin - activation of 5 ASA dependent on AZO bond cleavage by colonic bacteria Limited use for small intestine inflammation of Crohns Dyspepsia, nausea, headache, anoerxia side effects due to sulfapuridine
	IBD - Olsalazine	AZO compound - 5 ASA Dimer bound by AZO bond Oral admin - activation of 5 ASA dependent on AZO bond cleavage by colonic bacteria Limited use for small intestine inflammation of Crohns No sulfonamide --> reduced toxicity
	IBD - Balsalazide	AZO compound - 5 ASA bound with 4 ABA by AZO bond Oral admin - activation of 5 ASA dependent on AZO bond cleavage by colonic bacteria Limited use for small intestine inflammation of Crohns No sulfonamide --> reduced toxicity
	IBD - Pentasa	Mesalamine compound - 5 ASA inside ethylcellulose microgranule Oral admin - formulated for timed release in small intestine - no need for colonic bacteria activation Able to target small intestine affected by Crohns No sulfonamide --> reduced toxicity
	IBD - Asacol	Mesalamine compound - 5 ASA inside pH sensitive resin Oral admin - formulated to release at pH >7 - targets distal ileum and proximal colon No sulfonamide --> reduced toxicity
	IBD - Rowasa / Cenasa	Mesalamine compound - 5 ASA monomer Enema (Rowasa) or suppository (Cenasa) admin Effective for sigmoid colitis and proctitis No sulfonamide --> reduced toxicity
	IBD - Corticosteroid Mechanism of Action	Antinflammatory effects to reduce T cell inflammatory response in intestine Reduce formation of inflammatory cytokines - TNFa, IL 1, IL 6 Inhibit transcription of NFkB, PLA2, and COX2 If make wrong diagnosis miss infectious etiology - corticosteroids will inhibit the immune response and hurt patient
	IBD - Medical Management	ASA effective to treat mild to moderately active ulcerative disease ASA effective to maintenance of disease remission Corticosteroids effective to induce disease remission
	IBD - Corticosteroid Administration and Delivery Options	Oral - Prednisone Oral controlled release - budesonide IV - hydrocortisone, methylprednisone Enema - hydrocortisone - effective for left sided ulcerative colitis
	IBD - Corticosteroid Toxicity	Common toxic side effects seen with chronic use Myopathy, osteonecrosis, osteoporosis Fluid retention, hyperglycemia, weight gain, hypokalemia, hyperlipidemia, growth failure Dyspepsia, ulceration Depression, anxiety, psychosis Cataracts, glaucoma, skin manifestations
	IBD - Immunosuppressive Purine Antimetabolites	Azathioprine, 6 mercaptopurine, Methotrexate Inhibit DNA synthesis in rapidly dividing inflammatory lymphocytes
	IBD - Cyclosporine and Tacrolimus	Prevents translocation and nuclear import of NFAT subunit NFAT regulates transcription of IL 2, GM CSF, TNFa, and IFNg in T cells Inhibits lymphocyte function systemically and in intestinal mucosa Absorbed systemically --> systemic effect
	IBD - Infliximab	Monoclonal antibody against TNFa Blocks T cell inflammatory response IV admin - systemic effect Antibodies against the drug may develop and inhibit effect Must be hospitalized during therapy to prevent complication of infection
	IBD - Natalizumab	Monoclonal IgG4 antibody against integrin a4 subunit Prevents leukocyte binding to vascular adhesion molecules and migration into inflamed tissue Complication of reactivation of JC virus resulting in multifocal leukoencephalopathy Limited use for refractory patients only
	Celiac Disease - Overview	Malabsorptive diarrhea affecting proximal small bowel - may present as iron deficiency anemia Immune response generated against Gliadin after gluten ingestion --> tissue damage Villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis Auto antibodies generated against gliadin, tissue transglutaminase, and endomysium Responds to gluten free diet Diagnosis made on clinico-pathologic correlation
	Celiac Disease - Pathogenesis	Gliaden peptides induce expression of IL-15 by epithelial cells --> activate intraepithelial CD8 T lymphocytes Cytotoxic CD8 T lymphocytes induced to express NKG2D - kill epithelial cells expressing ligand MIC-A Epithelial damage allows gliadin peptides to cross barrier --> damidated by tissue transglutaminase (tTG) Deamidated gliaden peptides presented by CD4 Th1 cells by APC --> IFNg production and B cell clonal activation Gliaden specific CD4 T cells / anti gliadin, tTG, and endomysium B cell antibodies / non specific CD8 T cells
	Celiac Disease - Morphology and Histology	Most severe in 2nd portion of duodenum and proximal jejunum Intraepithelial CD8 T lymphocytosis, villous atrophy, crypt hyperplasia --> malabsorption Increased plasma cells, mast cells, and eosinophils in lamina propria CD8 T cells in epithelium, CD4 T cells in lamina propria No linear correlation b/w severity of mucosal damage and clinical symptoms
	Celiac Disease - Suggestive Endoscopic Findings	Scalloped appearance along duodenal folds Mucosal nodularity
	Celiac Disease - Clinical Presentation	Adults - anemia, diarrhea, bloating, fatigue Pediatric - irritability, abdominal distention, anorexia, diarrhea, failure to thrive, weight loss, muscle wasting Extraintestnal arthritis, seizure disorders, apthous stomatitis, iron deficiency anemia, pubertal delay, short stature Long term increased risk of anemia, female infertility, osteoporosis, and cancer
	Celiac Disease - Serology Tests	IgA anti Tissue Transglutaminase (TTG) - highly sensitive and specific IgA anti Endomysium (EMA) - highly sensitive and specific IgA and IgG anti Gliadin - less sensitive and specific Many patients with Celiacs are also IgA deficient - may need to test IgG TTG to confirm negative test result
	Celiac Disease - Diagnosis	Characteristic morphologic abnormalties in small bowel of patient ingesting gluten +/- presence of serum AGA, EMA, or TTG antibodies Clinical remission while on gluten free diet is gold standard
	Celiac Disease - Latent and Silent	Latent - positive serology, no mucosal abnormalities, signs or symptoms Silent - positive serology, mucosal damage and loss of villi, but no signs or symptoms
	Celiac Disease - Genetics	Strong HLA association 90% of patients have HLA DQ2 (only 30% of controls) Most of remainder have HLA DQ8 10% have affected 1st degree relative
	Celiac Disease - Oral Manifestations	Ulceartions of oral mucosa Enamel pitting - indicates enamel hypoplasia
	Microscopic Colitis - Collagenous and Lymphocytic Colitis	Present with chronic, non bloody, watery diarrhea without weight loss Grossly normal appearance - normal radiographic and endoscopic studies Collagenous - dense subepithelial collagen layer, intraepithelial lymphocytes, mixed inflammatory infiltrate Lymphocytic - normal subeithelial collagen, greater increase of intraepithelial lymphocytes, associated with Celiacs
	Allergic Proctocolitis	Eosinophilic infiltrate of superficial mucosa - patchy Neutrophilic cryptitis and no architectural distortion --> acute and active process Presents with blood streaked stool usually before age 1, diarrhea, abdominal pain - normal appearance and weight Fecal leukocytes, mild peripheral eosinophilia, rare hypoalbuminemia or anemia Often triggered by cows milk or soy milk - removing trigger allows clinical and symptomatic resolution Usually able to reintroduce trigger food later in life
	GI Radiology - Mucosal v Submucosal Lesions	Mucosal Lesions - nodular, granular, ulcerated surface Submucosal lesions - smooth surface, abrupt angles to luminal contour Extrinsic lesions - broad based, smooth tethered folds
	Candida Esophagitis	Fungal infection of esophageal mucosa Increased risk with esophageal obstruction, abnormal motility, or immunosuppression (AIDS) Presents with dysphagia and retrosternal pain Multiple, small confluent ovoid plaques separated by normal mucosa and pseudomembrane formation
	Small Esophageal Ulcers - Differential Diagnosis	Herpes Type I esophagitis Drug induced - tetracyclines, NSAIDs, KCl, Quinidine, Alendronate sodium Reflux
	Ulcer Edge Morphology	Thick lobulated edges seen in squamous cell carcinoma and adeonocarcinoma, drug induced, Barretts, or TB Central portion of lesion destroys blood supply, becomes necrotic and ulcerates --> inflammatory reaction Thin edge indicates no central lesion pathology or minimal reaction to pathology - HIV, CMV
	Distal Esophageal Stricture - Radiology Differential Diagnosis	Long Smooth - reflux esophagitis, nasogastric intubation, ZES, alkaline reflux Short Smooth - reflux esophagitis, Barrett Irregular Surface - squamous cell carcinoma, adenocarcinoma, carcinoma of cardia Schatzki Ring - reflux induced stricture Abnormal beak like appearance - Achalasia
	Boerhaave's Syndrome	Spontaneous esophageal perforation Sudden rapid increase in intraluminal pressure Most often caused by wretching and vomiting after EtOH ingestion Vertically oriented transmural tear of distal esophagus
	GI Radiology - Benign v Malignant Ulcers	Benign - hole protrudes outward from contour, thin overhanging edge, smooth straight radiating folds Malignant - mass effect, mucosal nodularity, clubbed nodular pointed folds radiate to irregular edge of ulcer
	Focal Gastric Mucosal Nodularity - Differential Diagnosis	Lyphoid hyperplasia secondary to H. pylori gastritis Gastric metaplasia Early gastric carcinoma MALT Lymphoma Normally shows polygonal shaped tufts separated by shallow grooves --> areae gastricae
	Gastric Polyps - Differential Diagnosis	Solitary Mucosal - hyperplastic polyp, fundic gland polyp, rare adenoma Multiple Mucosal - hyperplastic polyp, fundic gland polyp, FAP, PJ Hamartomas, Juvenile polyposis Solitary Submucosal - GI stromal tumor, Lipoma, Hemangioma, Neurofibroma, Granular Cell tumor, Lymphoma Multiple Submucosal - Lymphoma or Metastatic cancer
	Marasmus	Protein calorie malnutrition characterized by energy deficiency Wasting of muscle and fat - loss of adipose from buttocks and thighs Preservation of visceral and serum proteins Caused by inadequate intake of calories and protein
	Kwashiorkor	Acute protein calorie malnutrition characterized by edema and enlarged fatty liver Sufficient calorie intake and energy stores - insufficient protein consumption Edema - pedal edema, distended abdomen "the sickness the baby gets when the new baby comes" - weened off protein rich breast milk
	Gastroparesis - Nutritional Therapy	Maintain hydration, small frequent meals, low fat and low fiber to avoid delaying gastric emptying Risk of developing electrolyte, vitamin, and mineral deficiencies
	Inflammatory Bowel Disease - Nutritional Therapy	Elemental diet - partially digested components increase absorption Parenteral nutritional support to let bowel recover Risk of developing electrolyte, vitamin, and mineral deficiencies
	Celiac Disease - Nutritional Therapy	Gluten free diet - eliminate wheat, rye, and barley May suffer from secondary lactose intolerance form loss of brush border enzymes Risk of developing electrolyte, vitamin, and mineral deficiencies
	Malabosorption - Phases of Nutrient Absorption	Intraluminal digestion - macromolecules broken down into smaller components Terminal digestion - brush border enzyme digestion of nutrients into monosaccharides and amino acids Transepithelial transport - fluid, nutrients, and electrolytes transported form GI lumen into enterocyte Lymphatic transport - absorbed lipids transported to lymphatics
	Stool Osmolality	290 mOsm - gut cannot concentrate fluid, stool osmolality must always equal blood osmolality NaCl and KCl most abundant solutes in stool - 2(Na+K) + other solutes = 290 mOsm Normal gap of <50 mOsm between 2(Na+K) and 290 Increased Osm gap indicates presence of other soluble substances in stool - Mg laxative, undigested lactose If stool Osm measured to be less than 290 --> dilute solution has been added to stool
	Diarrhea - Secretory v Malabsorptive	Secretory - isotonic stool, occurs at all times, persists during fasting Malabsorptive - follows meals, relieved by fasting, associated with steatorrhea
	Diarrhea - Watery v Bloody	Injury to mucosa causing ulceration may cause bloody diarrhea Exudative diarrhea due to inflammatory damage characterized by bloody, purulent stool that persists with fasting E. Coli O157 and Shigella cause bloody diarrhea C. difficile releases toxins inducing mucin secretion, increasing stool osmolality resulting in watery diarrhea Damage to absorptive surface colon cells with normal secretive crypt cells --> secretory watery diarrhea
	Melanosis Coli - Brown Bowel	Caused by use of certain laxatives that stimulate motility and speed transit Surface epithelial damage impairs ability to absorb water Melanin like pigment accumulates in lamina propria macrophages Colon may appear brown on endoscopy
	Diarrhea - Vibrio cholerae	Severe watery "rice water" diarrhea Up to 1 liter lost per hour - dehydration, hypotension, muscular cramping, anuria, shock, death Flagellar proteins attach to enterocytes - hemaglutinin mediates detachment and shedding in stool Preformed toxin - B subunit binds GM1 ganglioside inducing endocytosis and retrograde transport to ER A subunit escapes degradation - ADP ribosylates and activates Gs --> adenylate cyclase --> cAMP cAMP opens CFTR channel --> Cl secretion --> Na, HCO3, and H20 secretion --> massive diarrhea
	Diarrhea - Shigella	Bloody diarrhea - fever and abdominal pain Low infective dose - resistant to acidic degradation in stomach Taken up by M cells over Payers patches - escape into laminae propria - engulfed by macrophages Induce apoptosis in macrophages --> inflammatory response damages epithelial barrier Shigella in lumen invade enterocytes via basolateral membrane or inject proteins via type III secretion system
	Diarrhea - Enterohemorrhagic E. Coli O157:H7	Bloody diarrhea and hemolytic uremic syndrome Produce shiga-like toxins
	Diarrhea - Enterotoxigenic E. Coli	Secretory, noninflammatory watery diarrhea - traveler's diarrhea LT - heat labile toxin - activates adenylate cyclase --> cAMP --> Cl secretion ST - heat stable toxin - activates guanylate cyclase --> gAMP --> electrolyte secretion
	Diarrhea - Clostridium difficile - Pseudomembranous Colitis	Watery diarrhea - fever, leukocytosis, abdominal pain, cramps, hypoalbuminemia Toxins released cause ribosylation of GTPases including Rho Induces disruption of cytoskeleton, tight junction barrier loss, cytokine release, and apoptosis
	Diarrhea - Neuroendocrine Tumors	Vasoactive Intestinal Polypeptide (VIP) secreting tumors stimulate water efflux into gut lumen Gastrinomas increase acid entering duodenum, may inactivate pancreatic enzymes and impair digestion
	Diarrhea - Volume	Large volume diarrhea indicates pathology in small intestine Small intestine responsible for majority of fluid absorption Small volume diarrhea indicates small intestine is functional - pathology must be in colon
	Irritable Bowel Syndrome	Chronic relapsing abdominal pain, bloating, and changes in bowel habits - most often constipation Pain relieved with defecation, onset associated with change in stool form and frequency Elevated baseline and postprandial sigmoid motility - can reduce with anticholinergic medications Normal gross and microscopic appearance - clinical diagnosis Impairment of brain-gut signaling - decreased modulation of incoming pain signals by frontal and limbic cortex Related to psychologic stressors, diet, abnormal GI motility, and heightened visceral sensitivity Comorbid chronic pain, fibromyalgia, lethargy, depression - must rule out colon cancer and IBD
	Irritable Bowel Syndrome - Therapy	Diet, stress reduction, psychologic therapy Diarrhea - bulking agents, antispasmodics, antidiarrheals Constipation - bulking agents, laxatives, asses pelvic floor function Tricyclic antidepressants and SSRIs may be effective
	Anismus	Paradoxic Puborectalis Syndrome - functional outlet obstruction constipation External anal sphincter and puborectalis muscle are abnormally recruited when attempting to defecate Patient contracts muscles when trying to relax Correct with EMG based biofeedback unit
	Anal Canal - Anatomy	Colonic glandular mucosa - endodermal origin - above pectinate line Anal squamous mucosa - ectodermal origin - below pectinate line Anal canal includes 2 centimeters of glandular mucosa above pectinate line Anal canal lymphatics drain to inguinal lymph nodes - rectal lymphatics drain to mesenteric and periaortic nodes
	Anal Canal - Epithelial Layer	External skin identified by adenexal structures (sweat glands) underneath epithelium External anal canal lined by keratinized squamous epithelium w/o underlying adnexal structures Epithelium loses keratinization proximally in anal canal
	Anal Canal - Differences Above and Below Pectinate Line	Below - ectoderm, stratified squamous, inferior rectal artery, inferior rectal vein into systemic circulation Lymphatics drain to inguinal nodes (includes 2cm above pectinate line) Inferior rectal somatic nerves, good sensation Squamous cell carcinoma, external hemorrhoids Above - endoderm, simple columnar, superior rectal artery, superior rectal vein into portal circulation Lymphatics drain to pelvic and lumbar nodes (starting 2 cm above pectinate line) Visceral autonomic innervation, poor sensation Adenocarcinoma, internal hemorrhoids
	Anal Canal - Anal Fissures	Tears occurring along dentate line - may become infected
	Anal Canal - Hypertrophied Anal Papillae	Surface squamous epithelium with underlying fibrovascular core No malignant potential or clinical consequences Occurs most frequently on dentate line
	Anal Canal - Hemorrhoids	Thin walled, dilated, submucosal vessels protruding beneath anal or rectal mucosa Internal - superior hemorrhoidal plexus - above pectinate line External - inferior hemorrhoidal plexus - below pectinate line Dilated collaterals connecting portal and caval venous systems form due to elevated venous pressure Increased plexus pressure from constipation, pregnancy, portal hypertension Subject to trauma, inflammation, thrombosis, and prolapse
	Anal Canal - Malignant Tumors	Squamous cell carcinoma from lower 1/3, glandular carcinoma from upper 1/3 Non keratinizing basaloid appearing tumors from transitional middle 1/3 Most frequent are SCC associated with HPV infection and condyloma accuminatum precursor lesion Progress through dysplasia sequence leading to in situ cancer and carcinoma - choiliocyte cells observed HPV E6 inhibits p53 , HPV E7 inhibits RB --> drive cell cycle progression, inhibit DNA repair Staging tumor invasion determines prognosis - different criteria for anal canal and rectal tumors
	Anal Canal - Extramammary Paget's Disease	Adenocarcinoma presenting as growth of single cells in squamous epithelium of anal canal No dysplasia sequence or precursor lesion May spread to peri anal skin resulting in itching and erythema
	Gastric Bypass Surgery - Most Common Complications	Iron and B12 deficiency Stricture at anastamoses
	Sleeve Gastrectomy - Mechanism of Action	Restrictive - reduce volume Remove majority of cells producing ghrelin - normally induces appetite and feeding
	Diverticulum - True v False	True - all layers of luminal wall present False - not all layers present, frequently just mucosa
	Diverticulum - Formation of False Diverticuli	Weak point created where blood vessels penetrate lumen wall at juncture of tenia coli and underlying muscle Increased intraluminal pressure results in compensatory hypertrophy of muscularis propria Hypertrophied muscle generates more intraluminal pressure --> cyclical Mucosa bulges into the weak point of the wall No diverticulum formation in areas lacking tenia coli and weak points - no diverticlum in rectum
	Diverticulum - Complications	Diverticulosis = Massive GI bleed - trauma to mucosa erodes into underlying artery - always bleeds INTO lumen Diverticulitis = inflammation Ischemia from increased pressure in enclosed space - bacterial stasis, entry into mucosa, fecolith trapping Inflammation, abscess formation, peritonitis if bacteria penetrate mucosa Fistulae and stricture formation from inflammation, wall thickening
	Diverticulum - Diverticuli in Small Bowel	Meckle's - True - congenital remnant of vitelline duct connecting yolk sac to embryo GI tract May have ectopic pancreatic and gastric tissue Acquired - True - scleraderma, myopathies - conditions weaken muscle creating hollow visceral myopathies Complications secondary to bacterial overgrowth
	Diverticulum - Diverticuli in Esophagus	Pseudo-diverticuli - inflammation causes dilation of submucosal salivary ducts - not actually diverticuli Zenkers - True - abnormal motility function results in herniation, seen in elderly patients Food can lodge in Zenkers, causing halitosis and increased risk of squamous cell carcinoma
	Appendix - Anatomy	Normal true diverticulum of the cecum - contains all layers of GI wall Lined by colonic type mucosa Has tenia coli - can get diverticuli disease
	Acute Appendicitis - Pathogenesis	Increased intraluminal pressure compromises venous outflow - obstruction by fecoltih, gallstone Impaired venous outflow --> edema and arterial compromise --> ischemic injury Stasis of luminal contents --> bacterial proliferation --> inflammatory response Neutrophilic infiltration of muscularis propria Hemorrhagic ulceration, gangrenous necrosis extending to serosa --> rupture and suppurative peritonitis
	Acute Appendicitis - Etiology	Obstruction Infection - parasites Ulcerative colitis and Crohns Disease Endometriosis Drugs - Kayexalate used in renal failure, may cause GI ulceration Radiation - damages proliferating cells at base of crypts
	Appendix - Malignancies	Carcinoid - most common, rarely metastasizes Epithelial - mucinous cystadenoma, mucinous cystadenocarcinoma, adenocarcinoma Pseudomyxomatous Peritonei - mucin accumulation in abdomen due to mucin producing tumor Lymphoma - large B cell, rare
	Adverse Food Reaction	Any abnormal reaction to a food or food additive Intolerance - non immune mediated Food allergy - immune mediated
	Food Allergy - Immediate Clinical Manifestations	Cutaneous - hives, swollen lips and tongue - occurs in 88% of cases GI - nausea, vomiting, diarrhea, abdominal pain Respiratory - runny nose, sneezing, congestion, cough, wheeze Multiorgan - neurologic and cardio manifestations
	Food Allergy - Treatment	Epinephrine - EpiPen Alpha Receptors - vasoconstriction, increased blood pressure, decreased capillary leak Beta Receptors - relax bronchial smooth muscle, increase heart rate and cardiac contractility
	Food Allergy - Factors that Promote Allergenicity	Small size - molecular weight <70kd Glycosylation Resistance to thermal or chemical degradation - antacid therapy may increase allergies Linear epitope Solubility in water
	Food Allergy - GI Immune System Activity	Mucous and secretory IgA inhibit absorption of 98% of luminal antigens Antigens taken up by epithelial dendritic cell processes or by M cells and delivered to underlying dendritic cells Dendritic cells can induce Tr1 cells or T reg cells - balance between tolerance and activation Normal response to GI antigen presentation is tolerance
	Food Allergy - Oral Tolerance Antigen Administration	Low dose repeated exposure activates regulatory T cells Single high dose induces anergy in reactive lymphocytes
	Food Allergy - Regulatory T Cells	Th3 - produce TGFb --> directs IgA switch, reduces delayed hypersensitivity reactions Tr1 - secrete IL-10, involved in developing oral tolerance CD4 CD25 T - Foxp3 T reg cells-
	Food Allergy - Anaphylaxis Mechanism	First exposure - antigen is presented to Th2 cells - does not need to occur through oral GI exposure Th2 --(IL4)--> IgE switch in B cells --> food antigen specific IgE secreted --> Fc portion binds to mast cells Th2 --(IL3,IL5)--> Eosinophil recruitment Next exposure - antigen binds and cross links IgE bound to Mast cells Mast cells release inflammatory mediators and activate eosinophils
	Colorectal Adenocarcinoma - Cell of Origin	2 independent genetic hits in the same cell required for dysplasia and carcinoma Likely to occur in dividing but long lived stem cell compartment
	Colorectal Adenocarcinoma - Wnt Signaling	Wnt signaling normally drives proliferation at base of crypt Wnt binding stimulates b-catenin signaling --> C myc and cell proliferation\ Mutations in APC lead to unregulated b-catenin signaling and cell proliferation APC mutations found in 85% of sporadic colon cancers APC mutations lead to dysplasia and adenoma - additional mutations required for invasive carcinoma
	Colorectal Adenocarcinoma - DNA Repair Pathway	DNA mismatch repair mechanism is defective in 10% of sporadic cases Recognition, excision, and patching of error mediated by MSH2 and MLH1 Mismatch errors occur during DNA synthesis and most often at di and tri nucleotide repeats Incorrect mismatch repair can alter coding region of genes
	Colorectal Adenocarcinoma - KRAS	GTP binding protein - normally activated as downstream target of growth factor receptor activation Active K ras activates RAF/MEK/MAP kinase pathway Activating mutations result in constitutive growth signal Found at higher frequency in large adenomas and invasive cancer Late mutation in chromosomal instability pathway - not mutated in mircosatellite instability pathway
	Colorectal Adenocarcinoma - COX2	Inducible form - generates PGE2 --> promotes epithelial proliferation Increased expression in colorectal adenocarcinomas NSAIDs suggested to have protective effect COX2 inhibition prevents tumor growth in animal models
	Colorectal Adenocarcinoma - Dysplastic Histology	Nuclear hyperchromasia, elongation, and stratification, high N:C Large nucleoli, eosinophilic cytoplasm, and reduction in goblet cells Failure of epithelial cell maturation during migration from crypt to surface Grade of dysplasia not relevant to prognosis - low grade can progress directly to invasive Defined as invasive when invades submucosa of colon to gain access to lymphatics
	Colorectal Adenocarcinoma - Dietary Risk Factors	High fat, low fiber diet - decreased stool bulk and altered composition of endogenous flora Increased production of oxidative bacterial products - deficiencies in vitamin antioxidants High fat intake promotes increased bile acid secretion - converted into carcinogens by intestinal bacteria
	Colorectal Adenocarcinoma - Location	Adenomas and adenocarcinomas most frequently occur in sigmoid and left colon
	Colorectal Adenocarcinoma - Prognosis	Prognosis based degree of wall invasion and lymph node metastases A - limited to wall - 80 to 90% 5 year survival B - through wall - 60 to 70% C - lymph node mets - 10 to 30%
	Colorectal Adenocarcinoma - Chromosomal Instability Pathway	Early mutation in APC leads to adenoma formation - sporadic or familial Late mutations of SMAD2/4 and KRAS promote cell growth p53 lost by chromosomal deletion late in progression Telomerase expression increases with tumor progression\
	Colorectal Adenocarcinoma - Microsatellite Instability Pathway	Early mutation in DNA Mismatch Repair enzymes - MLH1 and MSH2 Accumulation of mutations in di and tri nucleotide repeats (microsatellites) Mutations of tumor suppressors BAX TGFb Receptor promoters, activating mutations of BRAF Mutations of KRAS and p53 not seen Frequently affects right colon - more common in sessile serrated adenomas Carcinomas often have prominent mucinous differentiation and peritumoral lymphocytic infiltrates
	Colorectal Adenocarcinoma - Right v Left Sided Characteristics	Right - polypoid exophytic masses extending along one wall, rarely cause obstruction Present with fatigue and weakness due to iron deficiency anemia Left - annular constricting lesions, possible obstruction Present with occult bleeding, changes in bowel habits, or cramping LLQ discomfort
	Colorectal Adenocarcinoma - Metastasis	Liver is most common site May be seen in regional lymph nodes, lungs, and bones Rectal adenocarcinomas drain to inguinal lymph nodes, do not spread to Liver
	Colon Polyp - Hyperplastic Polyp	Most common small epithelial polyp - smooth nodular protrusion Mature goblet and absorptive cells - no dysplasia, no malignant potential Clonal expansion associated with KRAS mutations Result from decreased cell turnover and delayed shedding leading to piling up of cells Must be distinguished from sessile serated adenoma May occur as non specific reaction to adjacent or underlying mass or inflammatory lesion
	Colon Polyp - Benign Lymphoid Aggregate	Normal lymphoid aggregates underlying mucosa Hypertrophy under inflammatory stimulus Protrusion of overlying mucosa into lumen No malignant potential
	Colon Polyp - Juvenile Polyp	Hamartomatous polyp - focal malformations of mucosal epithelium and lamina propria Smooth, pedunculated, cystic central space, dilated glands filled with mucin and inflammatory debris Present with rectal bleeding +/- prolapse No dysplasia, no malignant potential of single polyp Juvenile polyposis - 100's of juvenile polyps, small proportion have dysplsia, increased risk of adenocarcinoma
	Juvenile Polyposis	Autosomal dominant syndrome resulting in development of many juvenile colon polyps Can have up to 100 hamartomatous polyps - can cause severe bleeding Associated with mutations in TGFb signaling - SMAD4, BMPR1A Dysplasia occurs in small proportion - increased risk of adenocarcinoma Extraintestinal manifestations - pulmonary arteriovenous malformations
	Hamartoma - Definition	Tumor like growths composed to mature tissues normally present at the site in which the develop
	Colon Polyp - Inflammatory Polyp	Result from chronic cycles of injury, inflammation, and healing Seen in ulcerative colitis, crohn's, and solitary rectal ulcer syndrome No dysplasia, no cysts
	Colon Polyp - Peutz Jegher Polyp	Hamartomatous polyp - large, pedunculated, arborizing network of smooth muscle with non dysplastic epithelium No epithelial dysplasia - no malignant potential of single polyp Poly can serve as traction point to initiate intussusception Peutz Jegher syndrome - multiple PJ polyps, increased risk of cancer
	Peutz Jegher Syndrome	Autosomal dominant - multiple GI hamartomatous polyps and mucocutaneous hyperpigmentation Multiple PJ polyps - arborizing network of smooth muscle with non dysplastic overlying epithelium Dark blue/brown macules around mouth, eyes, nostrils, buccal mucosa, hands, genetalia, and perianal region Freckles on fingers and toes is specific for PJS - increased melanin deposition, not melanocyte hyperplasia Increased risk of cancer of colon, pancreas, breats, lung, ovaries, uterus, and testicles - 95% lifetime risk GI adenocarcinomas develop independently of PJ poly - PJ polyps are not precursor lesions Germline mutation in LKB1/STK11 - regulates cell polarization and growth - post natal loss of heterozygosity
	Familial Adenomatous Polyposis - Overview	Autosomal dominant germ line mutation in APC - loss of heterozygosity results in colon adenomas Patients develop 100s of polyps - 100% chance of adenocarcinoma if untreated Prophylactic colectomy - still at risk of neoplasia at ampulla of Vater and stomach Gardner's variant - osteoma of mandible, skull, epidermoid cysts, desmoid and thyroid tumors, supernumary teeth Turcot variant - tumors of CNS, medulloblastomas
	Familial Adenomatous Polyposis - Extraintestinal Manifestations	Adenocarcinoma of duodenum near ampulla of vater and of stomach despite colectomy CHRPE - Congenital Hypertrophy of Retinal Pigment Epithelium Gardner's variant - osteoma of mandible, skull, epidermoid cysts, desmoid and thyroid tumors, supernumary teeth Turcot variant - tumors of CNS, medulloblastomas
	Familial Adenomatous Polyposis - Genetics	Inherited or sporadic g (30%) germline mutation of APC gene Post natal loss of heterozygosity leads to adenoma formation - unregulated Wnt signaling drives proliferation Classic FAP - truncating proteins in middle of gene Attenuated FAP - mutations limited to 3' or 5' of gene result in delayed development of polyps and adenocarcinomas CHRPE requires mutation distal to exon 9
	Hereditary Non Polyposis Colon Cancer - Overview	Autosomal dominant germ line mutation of DNA mismatch repair genes - MSH2 and MLH1 most common Loss of heterozygosity through mutation or methylation silencing Accumulation of mutations at di and tri nucleotide repeats - microsatellite instability Develop cancer earlier than sporadic, most commonly in right colon Fordyce granules - ectopic secaceous glands in oral mucosa Increased risk of cancer in breast, endometrium, stomach, ovary, ureters, brain, skin, and hepatobiliary tract
	Carcinoid Tumors of the Bowel	Epithelial tumors derived from mucosal endocrine cells Most common in appendix and terminal ileum - location correlates with malignant potential Appendiceal carcinoids rarely metastasize, rectal are usually benign, small intestine are more malignant Appendiceal tumors >2cm and goblet cell carcinoid tumors may be malignant Carcinoid Syndrome - hormonal secretion by metastatic tumor in liver - flushing, diarrhea
	Carcinoid Tumors - Overview	Well differentiated epithelial tumors derived from mucosal endocrine cells IHC positive for synaptophysin, chromogranin, and CD56 Majority found in GI - terminal ileum and intestine most common - also affect lungs Secrete hormones - ZES, Carcinoid Syndrome Variable metastatic and malignant potential
	Carcinoid Tumors - Carcinoid Sydrome	Caused by carcinoid tumor secreting serotonin into systemic circulation Cutaneous flushing, diarrhea, sweating, bronchospasm, colickly abdominal pain, right sided cardiac vulvar fibrosis Originate as ileal tumors - metastasize to gain access to systemic circulation - commonly liver Presence of Carcinoid Syndrome indicates metastasis to Liver
	Carcinoid Tumors - Metastatic Potential	Foregut - rarely metastasize Midgut - often multiple and more aggressive, deeper invasive, increased size, necrosis, and mitosis Hindgut - usually benign, rectal rarely metastasize, proximal colon are rare but more metastatic
	Malabsorption - Major Causes	Impaired mechanical digestion - poor dentition, gastrectomy, gastroparesis, vagotomy Impaired chemical digestion - enzyme insufficiency, cystic fibrosis or pancreatic insufficiency Impaired solubilization - insufficient bile salt secretion Impaired absorption - short bowel syndrome, celiacs, impaired fatty acid esterification or chylomicron synthesis
	Malabsorption - Carbohydrate	Carbohydrate malabsorption causes osmotic diarrhea Most common cases are lactose intolerance - lactase deficient Presents with bloating, abdominal cramps, and diarrhea
	Malabsorption - Fats	Steatorrhea - excessive fat loss in stool Weight loss, muscle wasting, failure to thrive, growth retardation Tetany, osteomalacia, bone pain, hypocalcemia, infertility, dysmennorhea, amenorrhea Impaired absorption of fat soluble vitamins ADEK
	Malabsorption - Impaired Absorption of Fat Soluble Vitamins	A - night blindness, hyperkeratosis, skin changes D - hypocalcemia, osteomalacia, rickets, hypophosphatemia E - neuropathy, hemolytic anemia K - prolongation of prothrombin time, easy brusing
	Malabsorption - Renal Manifestations	Oxalate stone formation due to malabsorption of bile salts and fats Normally, most dietary oxalate precipitates in GI lumen as Calcium Oxalate and excreted in feces Saponifaction of luminal Calcium with excess fatty acids - soluble Sodium Oxalate salts form and are absobed Kidney excretes oxalate, forms calcium oxalate stones in ureter Fluid depletion due to diarrhea exacerbates stone formation
	Malabsorption - Calcium	Most absorbed in duodenum - jejunum and ileum also contribute Clinical hypocalcemia presents as skeletal pain, tetany, paresthesia, osteoporosis, and stunted growth Absorption reduced if surface area is reduced or injured Fatty acid malabsorption saponifies luminal calcium and prevents absorption Vitamin D deficiency can impair absorption Must correct Ca measurement for hypoalbuminurea : add (4 - albumin g) x 0.8 to measured Ca
	GI Tract Leiomyomas	Benign smooth muscle derived tumor Most common in lower 1/3 of esophagus and in colon - may present with dysphagia Rare in stomach and small bowel Bland elongated spindle shaped cells, eosinophilic cytoplasm, expresses SM Actin and Desmin
	Gastrointestinal Stromal Tumor	Mesenchymal tumor of GI tract - common in stomach and small intestine, rare in colon and esophagus Symptoms related to mass effect or anemia due to ulcerative blood loss Most driven by activating mutations in c-Kit or PDGFRa - activate tyrosine kinase signaling Derived from interstitial cells of Cajal - GI pacemaker cells in muscularis propria Prognosis based on size, mitotic index, and location - small intestine more aggressive than stomach Metastasize to serosal peritoneal nodules or liver - rarely spread outside abdomen Spindle cell (thin elongated cells), epithelioid type, or mixed histology Treat with surgical resection or imatinib tyrosine kinase inhibitor - exon 11 mutation responds well, exon 9 poorly
	Gastrointestinal Stromal Tumor - Synromes	Neurofibromatosis Type 1 Carney's triad - non hereditary syndrome affecting young females GIST, paragangilomas, pulmonary chomdroma
	Lymph Node - Zones and Cell Types	Paracortex - T cells Mantle zone - naive B cells newly arrived from bone marrow --> Mantle Lymphoma Germinal Center - B cells interacting with dendritic cells --> Follicular Lymphoma Marginal zone - activated B cells --> MALToma
	Mucosa Associated Lymphoid Tissue Lymphoma (MALToma)	Extra Nodal Marginal Zone B Cell Lymphoma Arise at sites of chronic inflammation - most commonly in GI Tract - stomach Most often arise in sites normally devoid of organized lymphoid tissue Indolent tumor can transform into aggressive diffuse large B cell lymphoma
	Gastric MALToma	Chronic inflammation (usually H pylori) drives formation of Gastric MALT MALT can progress to indolent extranodal marginal zone B cell lymphoma Lymphoepithelial lesions distinguish MALToma from chronic gastritis (lymphocytes don't invade epithelium) If associated with H pylori, infection drives NFkB signaling through MLT and BCL-10 signaling Translocations constituitively activating MLT and BCL-10 drive tumor progression Treat with antibiotics, remove inflammatory stimulus, reduce NFkB signaling --> tumor regression Tumors with t(11:18) AP12-MALT1 translocation do not respond to H pylori eradication --> transform into DLBCL
	GI Lymphomas - Important Genetic Alterations	t(11:18) AP12-MALT1 - MALToma refractory to antibiotics --> transform into diffuse large B cell lymphoma t(11:14) IgH - Cyclin D1 - Mantle Cell Lymphoma - Naive Mantle Zone B Cell t(14:18) IgH-BCL2 - Follicular Lymphoma - Germinal Center B Cell t(8:14) IgH/k/l light chain - cMyc - Burkitt lymphoma - Mature B Cell
	GI Follicular Lymphoma	Clonal expansion of germinal center B cell - t(14:18) IgH - BLC2 prevents apoptosis Can be single mass like lesion or multiple lymphoid polyps (lymphomatous polyposis) Crowded follicles, monotonous clonal cell population, CD19+, CD20+, CD10+, Ig+, BCL6+, CD5- BCL2 + signature distinguishes follicular lymphoma from reactive follicular hyperplasia Indolent course with median survival 7 to 9 years - risk of transforming into aggressive DLBCL
	GI Lymphomatous Polyposis - Differential Diagnosis	Reactive Lymphoid Hyperplasia Mantle Zone Lymphoma - most often presents in colon Follicular lymphoma - most often presents in small intestine
	GI Mantle Cell Lymphoma	Clonal expansion of mantle zone (naive) B cells - t(11:14) IgH - Cyclin D1 drives G1 to S progression Most often presents in colon with lymphomatous polyposis Nodular lymphoid aggregates, monomorphic cells, condensed chromatin, scant cytoplasm, inconspicuous nucleoli Aggressive, median survival < 5 years
	GI Diffuse Large B Cell Lymphoma	High grade aggressive neoplastic mature B cell lesion Express B cell markers CD19 and CD20 Present as rapidly enlarging mass at nodal or extranodal site - rapidly fatal Activating mutations of BCL6 - represses germinal center B cell differentiation and arrest
	GI Burkitt Lymphoma	High grade aggressive neoplastic mature B cell - derived from germinal center B cell t(8:14) Igh - cMyc translocation or t(2:8) k light chain - cMyc or t(8:22) l light chain - cMyc Endemic - presents as mandible mass, 100% infected with EBV Sporadic - ileocecum and peritoneum involvement, 15% infected with EBV Immunodeficient associated - abdominal involvement, 25% infected with EBV Abdominal involvement may cause pain, nausea, vomiting, obstruction, GI bleeding High mitosis, high apoptosis, debris phagocytosed by macrophages creates clear cytoplasm --> starry sky
	Enteropathy Type T Cell Lymphoma	Aggressive lymphoma of intraepithelial T lymphocytes High association with Celiac disease - especially if not responding to gluten free diet Intraepithelial T cells acquire cellular atypia, aberrant T cell antigen expression and clonal gene rearrangement Most often involves jejunum or ileum Neoplastic lymphocytes within background of mixed inflammatory cells recruited by T cell cytokine release
	Enteric Nervous System - Actions of Neurotransmitters	Intestinal enterochromaffin cells release 5 HT in response to pressure and other stimuli Binding to 5 HT3 R on extrinsic afferent nerves induces nausea, vomiting, and abdominal pain Binding to 5 HT1P R on intrinsic primary afferent nerves (IPAN) stimulate motility and regulates peristalsis Binding to 5 HT4 R on presynaptic IPAN terminals enhances release of ACh and CGRP onto interneurons Extrinsic input mediated by ACh - binding to M3 receptors stimulates motility Extrinsic DA reduces cholinergic effects via D2 receptors
	Emesis - Circuitry	Vomiting center located in medullary reticular formation next to Chemoreceptor Trigger Zone (area postrema) CTZ located at base of 4th ventricle - no BBB allows monitoring of blood and CSF composition CTZ enriched for receptors - Histamine, 5 HT3, D2, NK1, Mu opioid Neural input to vomiting center from CTZ, vestibular apparatus, vagus and splanchnic afferents, and cerebral cortex
	Emesis - Histamine	H1 receptors in emesis circuitry stimulate nausea and vomiting Reversible H1 antagonists act as antiemetics H1 antagonists with antimuscarinic effects used for motion sickness and vertigo
	Emesis - Serotonin	5 HT3 receptors in GT tract and vomiting center precipitate vomiting reflex Especially important for vomiting triggered by chemicals Chemotherapy drugs induce increased 5 HT release from EC cells to stimulate afferent vagals to CTZ 5 HT3 Antagonists effective for n/v associated with chemotherapy or post operative pain Central and peripheral antagonism - no cross reactivity with D2 receptors --> no extrapyramidal side effects Side effect of constipation may be used to treat diarrhea
	Emesis - Dopamine	Inhibitory modulatory effect - inhibits ACh input to smooth muscle to decrease esophageal and gastric motility Antiemetic D2 antagonists also have activity at histamine, ACh and 5 HT3 receptors Used in chemotherapy sickness, motion sickness Metoclopramide is prokinetic used to treat diabetic gastroparesis Extrapyramidal side effects due to D2 activity
	Emesis - Acetylcholine	M1 receptor colocalizes with Histamine R in cerrebellum M1 antagonists (scopolamine) administered as transdermal patch for motion sickness
	Emesis - Neurokinin	NK1 receptor antagonists exert antiemetic effect through central blockade in CTZ Aprepitant - highly selective NK1 Receptor antagonist Used for chronic nausea in chemotherapy patients
	Emesis - Cannabinoids	CB1 receptors near CTZ inhibit emesis and stimulate appetite
	GI Motility - Metoclopramide	D2 receptor antagonist - increases ACh release from myenteric neurons - stimulates motility Indicated for diabetic gastroparesis, antiemetic agent, 3rd line therapy for GERD Extrapyramidal side effects limits use - restlessness, tremor, drowsiness
	GI Motility - Bethanechol	Cholinergic M3 receptor agonists Stimulates gastric emptying Indicated for autonomic neuropathy - gastroparesis Absorbed systemically - can also treat GERD and urinary retention due to autononomic neuroapthy
	GI Motility - Motilin	Binding to motilin receptors stimulates gastric motility Endogenous motilin released from pancreas and intestinal EC cells Erythromycin can act as motilin receptor agonist Indicated in for diabetic gastroparesis
	Achalasia Hypermotility Syndrome - Medical Therapy	Anticholinergics - decrease motility Calcium channel antagonists - inhibit smooth muscle contraction and spasms Botulinum toxin type A - inhibits ACh release from vesicles
	Constipation - Stimulant Laxatives	Increase intestinal motility Increase small intestine fluid secretion and decrease colonic reabsorption Not good for chronic use Caffeine, nicotine, fats, calories
	Constipation - Bulk Forming Laxatives	Complex polysaccharides or cellulose derivatives - fiber No systemic absorption Ingest with lots of water to prevent obstruction May also help lower LDL
	Constipation - Osmotic Laxatives	Hyperosmolar agents - induce movement of water into lumen Magnesium oxide, sorbitol, lactulose, magnesium citrate Polyethylene glycol used as bowel prep
	Constipation - Lubricant Laxatives	Mineral oils that coat bowel - reduce water absorption in colon Used for chronic constipation refractory to bulking agents Causes malabsorption of fat soluble vitamins and perianal irritiation
	Constipation - Stool Softners / Emollient Laxatives	Increase water secretion from small intestine and colon Act as surfactant to increase fecal mixing Used to treat post operative constipation in inpatients
	Constipation - Serotonin	5 HT4 receptor agonists Increases ACh release in myenteric neurons in stimulate GI motility Tegaserod Maleate - withdrawn due to risk of MI mediated by K channel effects Prucalopride has better SE profile
	Constipation - Chloride Channels	Lubiprostone stimulates type 2 Cl channels in small intestine Increase water secretion into lumen Nausea limits dosing and use
	Diarrhea - Octreotide	Synthetic somatostatin analogue Inhibits 5 HT release --> reduces GI motility Used for idiopathic secretory diarrhea and diarrhea caused by neuroendocrine tumors (VIP, gastrin, 5 HT) SE of hyperglycemia (inhibits insulin) and delayed gall bladder emptying and gall stone formation
	Diarrhea - Bismuth Subsalicylate	Inhibits small bowel secretions - bacteriocidal activity --> antiflatulence Decreases stool frequency and abdominal pain SE of encephalopathy, renal toxicity, black stools, and rare salicylate toxicity
	Diarrhea - Acetylcholine	Muscarinic receptor antagonists slow GI motility SE of tachycardia, dry mouth, fatigue, respiratory depression
	Diarrhea - Opioids	Opioid agonists Decrease peristalsis in small intestine, increase internal anal sphincter tone Decreases fluid and electrolyte secretion Reduces stool volume and abdominal cramps SE of CNS and respiratory depression, delayed gastric emptying, addictive potential
	Diarrhea - Serotonin	5 HT3 receptor antagonists - Alosetron Decrease gut afferent signaling - reduces symptoms of nausea, bloating, and abdominal pain Indicated for short term IBS treatment SE of severe constipation and ischemic colitis
	Liver - Anatomic and Functional Lobes	Anatomic border - falciform ligament - separates smaller left lobe from larger right, caudate, and quadrate lobe Functional border lies on vertical plane from IVC to gallbladder - separate bile drainage Left functional lobe includes caudate and quadrate lobe Liver can be divided into 8 resectable segments with independent blood supply and biliary drainage
	Pancreas - Collateral Circulation in Head of Pancreas	Celiac --> Gastroduodenal --> Anterior and Posterior SUPERIOR Pancreatoduodenal Arteries SMA --> Anterior and Posterior INFERIOR Pancreatoduodenal Arteries Anastamoses in head of pancreas provides route for collateral circulation
	GI Venous Drainage	Inferior Mesenteric Vein drains into Splenic Vein Superior Mesenteric Vein joins with Splenic Vein to form Portal Vein posterior to neck of pancreas Left gastric vein (lesser curvature of stomach and abdominal esophagus) drains directly into Portal Vein
	Sites of Porta-Caval Anastomoses	Umbilicus - Paraumbilical Veins --> Superficial Abdominal Wall Veins ==> Caput Medusa Rectum - Sup Rectal Veins --> Mid/Inf Rectal Veins ==> Internal Hemorrhoids Esophagus - Gastric Veins --> Azygous Esophageal Veins ==> Esophageal Varicies
	Salivary Glands	Located in mouth and esophagus Secrete digestive enzymes (amylase), lipids and proteins that strengthen tooth enamel Secrete lysozymes to prevent bacterial growth and IgA Serous glands - neutral pH Mucin glands - acidic pH, basophillic staining
	Pancreas - Acinar and Ductal Cells	Derived from same stem cell population Stem cells located at transition zone of acini and duct Duct - glandular cells secrete mucin and bicarbonate Acini - pyramidal cell, secrete bicarbonate and digestive enzymes
	Liver - Blood Supply to Hepatocytes	Portal vein provides 60-70% of nutrient rich deoxygenated blood from abdominal GI tract Hepatic artery provides 30-40% of oxygenated blood Enter liver through hilum / porta hepatis Branches travel in parallel portal tracts with bile duct branches carrying bile in reverse direction Blood from both sources mix in sinusoids
	Liver - Portal Triad	Branches of Portal Vein, Hepatic Artery, and Bile Duct Portal vein is largest Hepatic Artery and Bile Duct are the same size - HA has thick muscular wall Form peripheral points of hepatic lobules
	Liver - Space of Disse	Space between hepatocytes and endeothelium lining the sinusoids Hepatocyte microvilli protrude into space Hepatic stellate cells reside in space of Disse - store fat soluble vitamins (A) Sinusoidal lumen blood --> endothelial cell --> space of Disse --> Hepatocyte
	Liver- Ito / Stellate Cells	Mesenchymal cells that reside in space of Disse Storage of fat and fat soluble vitamins - hypertrophic in hypervitaminosis A TGFb stimulates them to secrete Type I collagen Contribute to liver scarring and cirrhosis - TGFb released by hepatocytes and kuppfer cells
	Liver - Collagen Types	Type I - surrounds portal vein and central vein - stains blue with Trichrome stain Type III - lines space of Disse in hepatic cords, visualized with reticulin stain
	Liver - Acinus Zone Model	Pyramid formed by two portal tracts at the base and central vein at the apex Zone 1 is closest to portal veins - oxygen and nutrient supply - glycogen and plasma protein synthesis Zone 2 is intermediate Zone 3 is furthest from afferent blood - enriched for p450 enzymes Zone 3 most sensitive to oxidative damage and ischemic damage
	Liver - Hepatocyte Zone Metabolic Functions	Zone 1 - glycogen synthesis and plasma protein synthesis Zone 3 - lipid, drug, and alcohol metabolism and detoxification, enriched for p450
	Gall Bladder - Structure of Wall	Lined by epithelium, lamina propria, and muscularis propria No submucosa or muscularis propria layers
	Pancreas Divisum	Embryologic malformation in which dorsal pancreatic duct does not fuse with ventral duct Secretions from dorsal duct directly enter duodenum via a minor duct (Santorini) Dorsal duct empties proximal to Ampulla of Vater Not clinically significant
	Pancreatic Insuloacinar Portal System	Venous blood from islets perfuses nearby acini before entering portal vein Islet hormones can exert local effect on exocrine function Insulin stimulates exocrine function - glucagon and somatostatin inhibit exocrine function
	Secretin	Released into systemic circulation by intestinal cells detecting acid in lumen - pH < 4.5 Secretin binding to pancreatic exocrine duct acinar cells activates adenylate cyclase and CFTR Opens apical Cl channel --> Cl efflux --> Bicarbonate exchanged for Cl --> Bicarbonate secretion Reduces gastric emptying and promotes mesenteric blood flow
	Pancreatic Enzyme Secretions	Amylase and Lipase - synthesized and secreted in active forms Other enzymes secreted as inactive proenzymes Brush border enterokinase converts trypsinogen to trypsin Trypsin activates other enzymes Trypsinogen, Chymotrypsinogen, Proelastase, Procarboxypeptidase Alpha amylase, Lipase, Procolipase, Prophospholipase A2, Carboxylesterase lipase DNAse, RNAse
	Pancreas - Mechanisms to Prevent Autodigestion	Proteolytic enzymes stored as inactive zymogens Peptide inhibitor of trypsin (PSTI or SPINK1) in cytosol inactivate any active trypsin Protease inhibitors (alpha 1 antitrypsin and alpha 2 microglobulin) in pancreatic interstitium and blood
	Pancreas - Amylase	Pancreatic and salivary isoforms - salivary initiates starch digestion Functions at neutral pH - requires bicarbonate secretion to neutralize gastric acid Splits 1,4 glycoside linkages - cannot split 1,6 glycoside linkages Generates maltose, maltotriose, and limit dextrans containing 1,6 linkages Brush border enzymes continue digestion to glucose
	Pancreas - Lipase	Pancreatic lipase functions at neutral pH - requires bicarbonate secretion to neutralize gastric acid Binds to oil/water interface of triglyceride droplets - hydrolyzes TG into 2 FA and MG Bile salts coat outside of lipid droplet - co lipase increases activity of lipase
	Pancreas - Proteolytic Enzymes	Secreted as inactive zymogen proenzymes Brush border enterokinase activates trypsinogen into trypsin Trypsin activates other proenzymes Includes trypsin, chymotrypsin, and elastase
	Pancreas - Regulation of Enzyme Secretion	Increases in cAMP and Calcium in cytoplasm increase vesicle fusion and enzyme secretion VIP and Secretin --> cAMP --> PKA --> Secretion CCK, ACh, GRP, Substance P --> PLC --> Ca --> Secretion Synergistic effects when both signals received
	Pancreas - Cholecystokinin (CCK)	Produced by proximal intestinal cells in response to peptides, amino acids, and fatty acids in lumen Stimulates exocrine pancreatic secretion and insulin secretion Contracts gallbladder, releases sphincter of Oddi, delays gastric emptying Elevated serum levels after meal ingestion
	Pancreas - Cephalic Phase of Secretion	Mediated by vagus nerve Chewing food without swallowing elicits 50% of maximal pancreatic enzyme secretion Blocked by Atropine - mACH
	Pancreas - Gastric Phase of Secetion	Vagovagal reflex arc Stimulated by gastric distension
	Pancreas - Intestinal Phase of Secretion	Stimulated by acid and chyme in intestinal lumen Hormonal - CCK, Secretin released from mucosa at pH < 4.5 Neural - enteropancreaic vagovagal reflex stimualtes secretion Products of digestion - peptides, amino acids, fatty acids - stimulate enzyme secretion
	Pancreas - Post Prandial Inhibition of Secretion	Intraluminal trypsin not complexed to protein inhibits CCK release Oleic acid in distal ileum inhibits gastric emptying and pancreatic secretion - mediated by peptide YY Intravenous amino acids and glucose inhibit CCK release via glucagon and somatostatin
	Pancreas - Test of Function	93% of ingested fat should be absorbed - < 7% should be present in stool Maldigestion results in excess fat and protein in stool - excess carbs digested by colonic bacteria Steatorrhea develops when enzyme function falls to <10% of normal --> pancreatic insufficiency Detect milder disease by measuring duodenal secretion post prandial or with structural tests
	Bile - Functions	Absorption of fat and fat soluble vitamins Excretion of polar metabolites from water insoluble waste products - bilirubin Excretion of cholesterol - directly and as bile derived from cholesterol
	Bile - Bile Salts Affecting Canalicular Flow	Ursodeoxycholate increases canicular flow Lithocholate reduces flow - cholestasis
	Bile - Secretion into Canaliculus	Bilirubin and bile salts are transported, metabolized, and secreted through seperate pathways Secreted from hepatocyte into canaliculus against concentration gradient - ATP dependent rate limiting step Farnesoid X factor nuclear receptor detects intracellular bile FXR increases canalicular secretion and suppresses bile salt synthesis Prevents accumulation of toxic intracellular bile
	Bile - Bile Salt Synthesis	Acetate --(HMG CoA Reductase)--> cholesterol 7a hydroxylation (rate limiting) and and Carboxylation of cholesterol 7a hydroxylase stimulated by depletion of bile salt pool 7b hydroxylation to ursodeoxycholic acid increases water solubility Primary bile salts synthesized by hepatocytes - cholic and chenodeoxycholic Secondary bile salts made by bacteria removing or isomerizing 7 OH - deoxycholic, urso, and lithocholic
	Bile - Bile Salt Conjugation	Before secretion, carboxyl side chains are conjugated with taurine or glycine Conjugation lowers pK, increases ionization of bile salts Ionization prevents back diffusion in bile duct and small intestine and limits intestinal absorption Conjugation allows binding and reabsoption by receptors in ileum
	Bile - Micelle Formation	Critical Micellar Concentration (CMC) - above which bile salts will form micelles Hyrdophillic portions external, hydrophobic portions internal Solubilization of lipids - cholesterol, phosphilipids - and fat soluble vitamins occurs in interior Addition of lecithin phospholipid creates mixed micelle - increased ability to solubilize cholesterol and lipids
	Bile - Enterohepatic Circulation	95% of conjugated bile salts absorbed bile ileum receptors and returned to liver via portal vein Liver synthesis equals fecal loss Increased fecal loss with ileal disease or resection
	Bile - Bacterial Alteration	Deconjugation of amino acids from bile salts - reduces ionization 7 OH removal or isomerization to produce secondary bile salts Deionized salts can precipitate in slightly acidic environment of small intestine Bacterial overgrowth --> increased deconjugation and deionization --> precipitation Can result in inadequate micelle formation and lipid and vitamin malabsorption
	Bile - Specific Bile Salts	Primary bile salts most abundant - cholic and chenodeoxycholic Deoxycholic is major secondary bile salt Lithocholic acid is toxic - can cause cholestasis Liver adds sulfate radical to lithocholic acid resulting in excretion in stool or urine
	Bile - Cholesterol Secretion	Cholesterol and Phospholipids secreted into canaliculi as bilayered water soluble vesicles Vesicles fuse with bile salt micelles to produce mixed micelles in bile ducts and gallbladder Cholesterol and phospholipids protect hepatocytes, bile duct and gallbladder mucosa from bile salt damage
	Parotid Gland	Serous salivary glands - paired at angle of mandible Drain inside the cheek through Stensen's duct 25% of saliva volume
	Submandibular Glands	Mixed serous / mucous glands paired inside the lower edge of mandible Predominance of serous cells Drain in the floor of the mouth near base of tongue through Wharton's duct 70% of saliva
	Sublingual Glands	Mixed serous / mucous glands paired at base of tongue Predominance of mucous cells Drain into mouth through multiple small ducts 5% of saliva
	GI Radiology - T1 Images	CSF - dark, low signal Fat - white, high signal Liver - intermediate / high signal Spleen - intermediate / low signal Metastatic liver disease has similar intensity as spleen Cysts and hemanagiomas look like CSF
	GI Radiology - T2 Images	CSF - bright, high signal Fat - dark, low signal Liver - intermediate / low signal Spleen - intermediate / high signal Metastatic liver disease has similar intensity as spleen Cysts and hemanagiomas look like CSF
	Hepatobiliary Bile Duct Drainage	Right and Left Hepatic ducts fuse to form common hepatic duct Cystic duct joins with common hepatic duct to form common bile duct Common bile duct joins with main pancreatic duct to form Ampulla of Vater
	Endoscopic Retrograde Cholangio Pancreatography (ERCP)	Endoscopic tube into duodenum to ampulla of vater Send out smaller camera to ascend up common bile duct or pancreatic duct
	GI Imaging - Double Duct Sign	Appearance of dilated common bile duct and pancreatic duct - lack of fusion Indicates obstruction - usually pancreatic cancer
	Acute Pancreatitis - Definition	Reversible pancreatic parenchymal injury associated with inflammation Clinically defined as having 2/3 : Typical pain - mid epigastric, acute onset, non undulating, referred to upper back and left shoulder Radiographic findings Elevations in blood chemistires (amylase or lipase) - long latency between onset and elevation
	Acute Pancreatitis - Pathogenesis	Inappropriate activation of trypsin --> activates other proenzymes --> autodigestion Local fat digestion by lipase - synthesized in active form Trypsin activates prekalikrein --> Factor XII --> activation of clotting and complement systems Inflammation and small vessel thromboses --> congestion and rupture of blood vessels Cytokine release by injured tissue, periacinar myofibroblasts, and leukocytes --> interstitial edema
	Acute Pancreatitis - Destructive and Protective Factors	Damaging - bile, low pH, trypsin, cathepsin B, high Ca, CCK, triglycerides Protective - SPINK1, mesotrypsin, alpha 1 antitrypsin, enzyme Y, alpha 2 microglobulin, somatostatin
	Acute Pancreatitis - Propagation of Inflammation and Damage	Trypsin activates prekalikrein --> Factor XII --> activation of clotting and complement systems TNF, IL 1, IL 6, and Platelet Activating Factor, complement activation, oxygen free radicals --> leaky vessels Edema, vascular insufficiency and ischemic injury Phospholipase A2 --> destruction of surfactant --> Acute Respiratory Distress Syndrome Thrombin activation --> Splenic Vein Thrombosis and / or DIC
	Acute Pancreatitis - Etiologies	Biliary tract disease and alcoholism - 80% Gallstones, triglycerides, tumor obstruction, ischemia, hypercalcemia, scorpions Infection - mumps Drugs - byetta Hereditary - deficiency in trypsin inactivation
	Acute Pancreatitis - Biliary Etiology	Most common cause - gallstones or biliary sludge - obstruction in ampulla of Vater Increased intrapancreatic ductal pressure - accumulation of enzyme secretions in interstitium Lipase secreted in active form - local fat necrosis --> release of inflammatory cytokines Inflammation, leaky vasculature, interstitial edema --> ischemic injury Can result in necrotizing pancreatitis ALT will be 3x upper limit of normal (>150)
	Acute Pancreatitis - Alcohol Etiology	Chronic alcohol ingestion increases protein rich pancreatic fluid - obstruction by protein plug If patient stops chronic drinking, increases fat and protein ingestion --> increased CCK Direct toxic effects on acinar cells - mitochondiral toxin, lysosomal instability Generates ROS, inflammation
	Acute Pancreatitis - Triglyceride Etiology	Occurs with TG > 500, endocrine emergency if > 1000 Alcohol ingestion or uncontrolled hyperglycemia can increase triglycerides Amylase and Lipase may appear normal - elevated TG interfere with assay
	Acute Pancreatitis - Trauma	Disruption of pancreatic duct where it crosses the spine After acute care, need ERCP to connect duct with stent to prevent tail apoptosis
	Acute Pancreatitis - Drug Induced Etiology	Early - hypersensitivity or direct damage - Azathiaprine, 6MP, sulfa, flagyl, ACE I, salicyclates Late - IgG or T cell related, build up of toxic metabolites - Didanosine, pentamidine, valproic acid Hypertriglyceridemia - tamoxifen, estrogen, finasteride, beta blockers, vit A, thiazides Angioedema - ACE inhibitors Directly Toxic - sulfa, diuretics
	Acute Pancreatitis - Clinical Presentation	Acute onset abdominal pain Constant, non undulating, intense - referred to upper back or left shoulder Nausea, vomiting, syncope, tachycardia, fevers, oliguria, tachypnea, hypotension Elevated plasma amylase (24 hrs) and lipase (72-96 hrs) Cullen's and Grey Turner signs - poor prognosis Subcutaneous Fat Necrosis
	Grey Turner's Sign	Brusing of flanks during acute pancreatitis Indicates intrabdominal bleeding - predicts severe disease course and high mortality
	Cullen's Sign	Superficial bruising and edema of sub cutaneous fat around umbilicus Predicts severe disease course and high mortality in acute pancreatitis
	Acute Pancreatitis - Mortality	Early - multisystem organ failure, DIC, hypocalcemia, shock, hypotension, compartment syndrome Aspiration, cholangitis, acidosis, hemorrhagic pancreatitis, intestinal ischemia from clotting Late - pancreatic abscess, infectious necrosis, secondary biliary obstruction, hypoalbuminemia, PE
	Acute Pancreatitis - Imaging	CT to rule our alternative diagnosis, to detect necrosis or abscess Dont use CT contrast - renal dysfunction occurs early US - check for obstructive gall stones
	Acute Pancreatitis - Therapy	Supportive IV fluids and analgesia Restrict oral intake or TPN to limit pancreatic activity Hydration Antibiotics is cholangitis is suspected or infectious necrosis Surgery if patient is unstable, infected necrosis, abdominal compartment syndrome, or gall stone obstruction
	Acute Pancreatitis - Morphology	Microvascular leakage causing edema Necrosis of Fat by lipases Acute inflammation Proteolytic destruction of parenchyma Interstitial hemorrhage Spots of hemorrhage interspersed with yellow chalky fat necrosis
	Acute Pancreatitis - Severity Predictors	HR > 60, Age > 44, BMI > 25/30 WBC > 16, Glucose > 200, LDH > 350, AST >250 pO2 < 60 mmHg, Systolic BP < 90, Creatinin > 2, GI bleeding DIC - platelets <100, fibrinogen < 1, D dimers > 80
	Chronic Pancreatitis - Definition	Irreversible destruction of exocrine parenchyma, fibrosis, and eventual destruction of endocrine parenchyma
	Chronic Pancreatitis - Pathogenesis	Repeated episodes of acute pancreatitis initiates perilobular fibrosis, duct distortion, and altered secretions Ductal obstruction by protein plugs from increased protein content of secretions - plugs may calcify Toxins - EtOH - direct toxic effects on acinar cells Oxidative Stress - EtOH induced, free radical damage, activation of AP1 and NFkB Profibrogenic chemokines
	Chronic Pancreatitis - Morphology and Histology	Parenchymal fibrosis, reduced number and size of acini, relative sparing of islets Variable dilation of pancreatic ducts Chronic inflammatory infiltrate
	Chronic Pancreatitis - Clinical Features	Variable presentation - repeated attacks of pain, jaundice, indigestion May be silent until full pancreatic insufficiency and diabetes mellitus develop May be precipitated by EtOH abuse, overeating, use of opiates Results in chronic pain, steatorrhea, diabetes, biliary obstruction, B12 deficiency, cancer
	Ampulla of Vater	Fusion of pancreatic duct with common bile duct True structural sphincter - controls flow of bile and pancreatic secretions into duodenum Lumen is lined by ductal epithelium - surface is lined by duodenal mucosa Surgical resection of head of pancreas requires excising part of the duodenum
	Pancreatobiliary Maljunction	Fusion of pancreatic duct and common bile duct proximal to ampulla of vater Smalle area creates increased pressure Pancreatic duct pressure is greater than common bile duct pressure Reflux of pancreatic secretions into biliary tree
	Pancreatic Pseudocysts	Localized collection of necrotic-hemorrhagic material rich in pancreatic enzymes Form by walling off of peripancreatic hemorrhagic fat necrosis with fibrous tissue Non epithelial lined fibrous walls of granulation tissue Commonly arise after acute pancreatitis, chronic alcoholic pancreatitis, or traumatic injury Usually resolve but can become infected or grow large enough to compress or perforate into adjacent structures
	Cystic Fibrosis of the Pancreas	CFTR Mutation --> abnormal chloride secretion --> viscous pancreatic secretions May develop exocrine pancreatic insufficiency due to atrophy of acini Atrophy due to prolonged plugging of small ducts with viscous mucous - not inflammation Typically do not develop fibrosis associated with chronic pancreatitis
	Autoimmune Pancreatitis / Lymphoplasmacytic Sclerosing Pancreatitis	Chronic pancreatitis mediated by autoimmune attack Characterized by duct centric mixed inflammatory infiltrate, venulitis, and hypergamma globulinemia Diffuse enlargement of pancreas, narrowing of main duct Stenosis of pancreatic portion of common bile duct --> cholestatic liver dysfunction Responds to steroids May clinically mimic pancreatic cancer - presents with pain, jaundice, +/- mass
	Pancreatic Ductal Adenocarcinoma - Overview	Most common pancreatic malignancy - highly aggressive Most occur in pancreatic head - obstruct bile duct and present as painless jaundice Mutations in KRAS (oncogene) and p16 (tumor suppressor) result in dysplasia progression to carcinoma Elicit desmoplastic stromal response of fibroblasts, lymphocytes, and ECM Commonly present at advanced stage - local invasion and distant metastasis
	Pancreatic Ductal Adenocarcinoma - Clinical Features	Remain silent until invade and compromise adjacent structures Obstructive jaundice, weight, loss, anorexia, malaise and weakness Migratory thrombophlebitis - Trousseau sign - releasing of coagluation factors by tumor Can directly invade spleen, adrenals, vertebrae, transverse colon, stomach - perineural invastion Spread to peripancreatic, gastric, mesenteric, omental, and portahepatic lymph nodes Distant metastasis to liver, lungs, and bones
	Pancreatic Ductal Adenocarcinoma - Inherited Syndromes	Familial atypical mole malignant melanoma - p16 mutation Peutz Jegher's HNPCC Hereditary pancreatitis BRCA2
	Pancreatic Endocrine Tumors	May be non functioning, insulinomas, gastrinomas, VIPomas, or glucagonoma Most insulinomas are benign - most other tumors are aggressive and malignant Slightly higher mortality with non functional tumors Presence of necrosis and high mitotic index are important prognostic factors Requires metastasis or invasion of adjacent organ to be diagnosed as pancreatic endocrine carcinoma
	Pancreatic Congenital Cysts	Anamolous development of pancreatic ducts Usually single, thin walled, lined by epithelium, enclosed by thing fibrous capsule, clear serous fluid May be part of autosomal dominant polycystic kidney disease of VHL disease Majority are benign - may become infected or perforate into adjacent structures 10% are neoplastic
	Pancreatic Serous Cystadenoma	Benign cystic neoplasm Lined by glycogen rich cuboidal cells, clear straw colored fluid May present with non specific abdominal pain or palpable abdominal mass Almost always benign
	Pancreatic Mucinous Cystic Neoplasm	Cystic mass associated with invasive carcinoma Painless, slow growing mass, usually in body or tail Filled with thick, tenacious mucin, lined by columnar mucin producing epithealial cells Associated with dense 'ovarian like' stroma 1/3 harbor associated invasive adenocarcinoma
	Pancreatic Solid Cystic Pseudopapillary Neoplasm	Large well circumscribed masses with solid and cystic components Cystic areas filled with hemorrhagic debris - neoplastic cells grow in papillary projections Most contain activating mutations of beta catenin May present with abdominal discomfort due to large size Some are locally aggressive - most are completely benign
	Pancreatic Intraductal Papillary Mucinous Neoplasm	Mucin producing intraductal neoplasm - connect to pancreatic duct systm Frequently involve head of pancreas, may be multifocal Lack dense 'ovarian like' stroma seen in mucinous cystic neoplasm May be benign or malignant - determined by tissue invasion on biopsy
	Pancreatic Acinar Cell Carcinoma	Neoplastic lesion with acinar cell differentiation - zymogen granules, exocrine enzymes Significant malignant potential - lack KRAS and p53 mutations like ductal adenocarcinoma Can develop metastatic fat necrosis due to release of lipase into circulation
	Cholesterolosis	Strawberry Gallbladder Cholesterol laden macrophages in lamina propria of gallbladder mucosa No clinical significance or relationship to systemic lipid disorder
	Acute Cholecystitis - Pathogenesis	Acute inflammation of gallbladder - 90% due to obstruction of biliary tree by gallstones Mucosal phospholipases hydrolyze luminal bile lecithins to toxin lysolecithins Protective glycoprotein mucous layer is disrupted - direct detergent effects of bile on mucosa Wall distension releases prostaglandins --> acute inflammatory infiltrate Gallbladder dysmotility, increased intraluminal pressure --> compromised blood flow
	Acute Acalculous Cholecystitis	Acute inflammation of gallbladder without obstruction by gallstone - 10% of acute cholecystitis cases Caused by ischemia of cystic artery - no collateral circulation Occurs in ill hospitalized patients with risk factors for vascular disease Can be initiated by primary bacterial infection Higher incidence of gangrenous cholecystitis and perforation than calculous causes
	Acute Cholecystitis - Clinical Presentation	Acute right upper quadrant or epigastric pain Mile fever, anorexia, tachycardia, sweating, nausea, vomiting Hyperbilirubinemia but infrequently jaundice - mild elevation of alkaline phosphatase serum levels
	Acute Cholecystitis - Morphology and Histology	Gallbladder is enlarged and tense Subserosal hemorrhages, fibrin coat, suppurative coagulated exudate Wall thickened by edema, congestion, hemorrhage, and inglammation Neutrophilic infiltration
	Chronic Cholecystitis - Pathogenesis	Can be caused by repeated attacks of acute cholecystitis May develop without preceding acute attacks No direct role for gallstones - obstruction of bile outflow not required Supersaturation of bile predisposes to chronic inflammation and gall stones independently Chronic inflamatory infiltrate, subserosal fibrosis
	Chronic Cholecystitis - Clinical Presentation	Recurrent attacks of steady or colicky right upper quadrant or epigastric pain Nausea, vomiting, intolerance for fatty foods
	Chronic Cholecystitis - Morphology and Histology	Thickened wall due to muscular hypertrophy and firbrosis Infiltrate of lymphocytes, plasma cells, macrophages Subepithelial and subserosal fibrosis Rokitansky Aschoff sinuses - outpouchings of mucosal epithelium through wall of gallbladder
	Rokitansky Aschoff Sinuses	Outpouchings of mucosal epithelium through wall of gallbladder Seen in chronic cholecystitis
	Cholecystitis - Complications	Bacterial superinfection with cholangitis or sepsis Gallbladder perforation and local abscess formation Gallbladder rupture with diffuse peritonitis Biliary enteric fistula - drainage of bile into adjacent organs, entry of air and bacteria into biliary tree Aggravation of preexisting conditions - pulmonary, renal, or liver decompensation
	Gangrenous Cholecystitis	Severe complication of acute cholecystitis Gallbladder necrosis and perforation Invasion of gas forming organisms - clostridia and coliforms - can cause acute emphysematous cholecystitis More common in acalculous cholecystitis in severely ill patients
	Porcelain Gallbladder	Extensive dystrophic calcification within the gall bladder wall Increased incidence of associated cancer Occurs in rare cases of chronic cholecystitis
	Laboratory Evaluation of Hepatocyte Integrity	Serum Aspartate Aminotransferase (AST) Serum Alanine Aminotransferase (ALT) Elevated values indicate liver disease Serum Lactate Dehydrogenase (LDH) less commonly used
	Laboratory Evaluation of Biliary Excretory Function	Serum bilirubin, urine bilirubin, and and serum bile acids - normally secreted in bile Serum Alkaline Phosphatase, Serum GGT - bile canaliculus plasma membrane enzymes Elevated values indicate liver disease
	Laboratory Evaluation of Hepatocyte Function	Serum albumin - secreted by hepatocytes - decreased levels indicate liver disease Prothrombin time - mediated by coagulation factors secreted by hepatocytes - elevated time indicates liver disease Serum Ammonia - hepatocyte metabolism - elevated levels indicate liver disease
	Glisson's Capsule	Liver encapsulation - contains nerve fibers activated by rapid stretching and signaling pain Posterior bare area under diaphragm only part not covered by peritoneum
	GI - Embryonic Bile Duct Development	Hepatic diverticulum from endodermal foregut lining Caudal portion differentiates into gallbladder and extrahepatic ducts Cranial portion differentiates into hepatic cords Hepatoblasts adjacent to portal vein induced to differentiate into bile duct cells by Jag1/Notch signaling Ring of bile duct precursors form ring around portal vein - asymmetric apoptosis results in eccentric ring Oldest bile ducts located in center - youngest bile ducts located in periphery
	Bile Duct Hamartoma	Benign lesion - multiple bile duct structures in portal triad Dilated bile ducts embedded in fibrous hyalinized stroma close to or within portal tract May reflect failure of apoptosis
	Congenital Hepatic Fibrosis	Developmental abnormality of bile duct plate Almost every portal tract involved by bile duct hamartoma Present with portal hypertension due to increased resistance in liver No compromise of synthetic or clearing functions
	Caroli's Disease	Developmental abnormality of bile duct development Multiple segmentally dilated large bile ducts Associated with portal tract fibrosis and congenital hepatic fibrosis Results in static bile and predisposes to stone formation Increased risk of cholangiocarcinoma
	Alagille Syndrome	Autosomal dominant mutation in Jagged1 - ligand for notch regulating cell fate Liver pathology - absence of bile ducts in portal tracts --> chronic cholestasis Peripheral stenosis of pulmonary artery, butterfly like vertebral arch defect Posterior embryotoxon eye defect, hypertelic facies Risk for hepatic failure and hepatocellular carcinoma
	Bile Duct - Blood Supply	Single blood supply from hepatic artery Hepatic artery forms plexus around bile duct
	Liver - Vasculature Supply and Drainage	Portal vein provides 60-70% of nutrient rich deoxygenated blood from abdominal GI tract Hepatic artery provides 30-40% of oxygenated blood Portal tracts --> sinusoids --> central veins --> hepatic veins Three hepatic veins from Right, Left, and Quadrate lobe fuse to form Hepatic Vein that feeds into IVC Caudate lobe has separate venous drainage into IVC
	Budd Chiari Syndrome	Obstruction of 2+ major hepatic veins --> acute venous outflow obstruction Liver enlargement, swollen and red with tense capsule, pain, portal hypertension and ascites Nutmeg appearance - alternating red congestion with lighter areas Hepatic damage from increased intrahepatic blood pressure Severe centrolobular (zone 3) congestion and necrosis Caudate lobe is spared - separate drainage - hypertrophies with chronic obstruction
	Budd Chiari Syndrome - Etiology	Hypercoagulable states Primary myeloproliferative disorders Antiphospholipid syndrome Paroxysmal nocturnal hemoglobinuria Intra-abdominal cancers - hepatocellular carcinoma Pregnancy or use of oral contraceptices
	Veno Occlusive Disease / Sinusoidal Obstruction Syndrome	Toxic injury to sinusoidal endothelium - embolization of damaged cells and occlusion of central vein Congestion and necrosis of perivenular hepatocytes, accumulation of debris in terminal hepatic vein Increased pressure causes fibrosis and collagen matrix deposition in sinusoids Obliteration of hepatic vein radicles Results from EtOH, Jamaican bush tea, chemotherapy drugs, bone marrow transplant drugs
	Liver Response to Outflow Obstruction	Chronic increased pressure induces collagen matrix deposition and venous sclerosis Pressure atrophy results in loss of hepatocytes Increased resistance --> portal hypertension --> ascites If due to hepatic vein obstruction --> caudate lobe sparing and hypertrophy If due to cardiac or pulmonary pressure --> no sparing of caudate lobe
	Vitamin A Overload	May lead to Stellate / Ito cell swelling in space of Disse Can block sinusoid blood flow leading to liver swelling and portal hypertension Chronic Vitamin A overload causes Ito cells to deposit collagen leading to cirrhosis
	Hepatic Infarction	Rare - dual blood supply - branch of hepatic artery can be occluded by embolism, neoplasm, PAD, or sepsis Ischemia results in coagulative necrosis of hepatocytes surrounded by transition zone of reversibly damages cells Necrotic area surrounded by hyperemic rim No fibrosis from ischemia
	Portal Vein Thrombosis	Occlusive disease may progress over time - usually no acute effect Abdominal pain, portal hypertension, esophageal varices Vein remodeling and collagen deposition around vein Impaired regeneration due to loss of growth factors delivered by portal vein No fibrosis of hepatic parenchyma
	Liver - Cardiac Sclerosis	Right sided cardiac failure --> passive congestion of liver Centrolobular congestion and atrophy Left sided cardiac failure --> shock, hypotension --> hepatic hyoperfusion and hypoxia Centrolubular ischemic coagulative necrosis Hemorrhage and necrosis --> nutmeg liver
	LFT - Alanine Aminotransferase (ALT)	Liver cytoplasm restricted enzyme - present in hepatocytes Acute hepatocyte damage releases ALT into serum - viral hepatitis or acetaminophen overdose Upper Limit of Normal = 40 IU/L
	LFT - Aspartate Transaminase (AST)	Enzyme present in hepatocytes - also in heart, skeletal muscle, kidney, brain, pancreas, spleen, and lung Located in cytoplasm and mitochondria - Mitochondria specific insult will be reflected by AST > ALT - EtOH, Wilson's Upper Limit or Normal = 35 IU/L
	LFT - Gamma Glutamyl Transpeptidase (GGT)	Liver enzyme located in bile canaliculus membrane Elevated serum levels indicate damage to biliary tree, bile duct obstruction, cholestasis, or inflitrative disease Upper Limit of Normal = 42 IU/L
	LFT - Alkaline Phosphatase (ALP)	Liver enzyme located in bile canaliculi - also in bone and placental tissue Elevated serum levels indicate damage to biliary tree, bile duct obstruction, cholestasis, or inflitrative disease Levels will be low in Wilson's, hypothyroidism, and congenital hypophosatasia Upper Limit of Normal = 120 IU/L
	LFT - Patterns of Damage	Hepatic Damage - Elevated ALT, normal AP and Bilirubin Cholestatic - Normal ALT, elevated AP, elevated Bilirubin Infiltrative - Normal ALT, elevated AP, normal Bilirubin
	LFT - DDx for Transaminases > 1000	Autoimmune hepatitis Viral hepatitis - B most common, C rare Fulminant Wilson's Toxins - acetaminophen Budd Chiari Shock
	Liver Injury - Hepatic Pattern	ALT and AST elevation with no elevation of AP, GGT, or Bilirubin Portal tracts infiltrated with lymphocytes and plasma cells Hepatocytes can die by apoptosis, necrosis, ballooning degeneration, or cholestasis Causes - Hep C, autoimmune hepatitis
	Liver Injury - Hepatocyte Apoptosis	Mediated by Fas pathway Response from cytotoxic cell injury Results in elevated ALT/AST, normal GGT, AP, and Bilirubin
	Liver Injury - Steatosis	Hepatocytes engulfed with neutral lipids - appears as white vacuole Occurs in diabetes, obesity, and EtOH ingestion Mild elevation of ALT/AST and/or GGT/AP, normal bilirubin
	Liver Injury - Cholestatic	Bile plugs composed of bilirubin becomes trapped between hepatocytes Delta-bilirubin in serum, first seen in zone 3 Extremely elevated AP/GGT, elevated bilirubin, slightly elevated ALT/AST Causes - gallstone, tumor, drugs, gram negative bacterial sepsis
	Bilirubin - Formation	End product of heme degradation - 80% from RBC / 20% from hepatic heme or hemoproteins Heme --(Heme Oxygenase)--> Fe + CO + Biliverdin --(Biliverdin Reductase)--> Bilirubin Bilirubin transported to liver hydrogen bonded to albumin - carrier mediate uptake at sinusoidal membrane Conjugation with glucaronic acid in ER and excretion into bile
	Jaundice and Icterus	Yellow discoloration of skin (jaundice) and sclera (icterus) Occurs when serum bilirubin is 2x the Upper Limit of Normal
	Bilirubin - Conjugation	Unconjugated bilirubin is toxic to CNS - especially newborn Polar proprionic acid groups hidden internally in bilirubin structure --> water insolbule Addition of glucuronide by UDP glucuronosyltransferase in ER Opens molecule, exposes proprionic acid groups --> water soluble and excretable Light exposure can break internal hydrogen bonds and make unconjugated bilirubin water soluble Deconjugated in GI lumen by bacterial glucuronidases and degraded to colorless urobilinogens
	Bile - Formation	Bilirubin secreted into canaliculus against concentration gradient - rate limiting Separate ATP dependent transporters for phospholipids and bile salts 66% bile salts, 22% phospholipid, 5% cholesterol, 5% protein, 1% bilirubin
	Bilirubin - Delta Bilirubin	Conjugated bilirubin covalently bound to albumin Found in serum of patients with conjugated hyperbilirubinemia Indicates obstruction of bile secretion, build up in hepatocyte and backflow into serum Covalent bond prevents dissociation at hepatocyte membrane Albumin binding prevents excretion in urine and prolongs half life
	Bilirubin - Urobilinogen	GI bacteria deconjugate bilirubin to colorless water soluble urobilogen Bacteria then convert urobilogen to pyrroles --> stool coloration
	Jaundice - Urine Testing	Unconjugated hyperbilirubinemia - hydrogen bonding to albumin prevents passage into urine Conjugated hyperbilirubinemia - water soluble conjugated bilirubin passes into urine Urine dipstick test for bilirubin distinguishes unconjugated from conjugated Delta bilirubin convalently bound to albumin cannot pass into urine
	Unconjugated Hyperbilirubinemia - Causes	Overproduction - hemolytic anemia, ineffective erythropoiesis, internal hemorrhage Reduced uptake - drugs (rifamycin), portasystemic shunting Impaired conjugation - Crigler Najjar Syndromes, Gilbert's Syndrome,
	Physiologic Jaundice of the Newborn	Hepatic machinery for conjugating and excreting bilirubin not fully mature until 2 weeks post natal Most newborns develop mild transient unconjugated hyperbilirubinemia Deconjugating enzymes in breast milk can exacerbate jaundice with breast feeding Sustained jaundice longer than two weeks suggests neonatal cholestasis
	Kernicterus	Accumulation of unconjugated bilirubin in the brain --> neurologic damage
	Crigler Najjar Syndrome	Type 1 - complete absence of hepatic UGT1A1 --> inability to conjugate bilirubin Severe unconjugated hyperbilirubinemia, jaundice, and icterus Fatal < 18 months due to kernicterus without liver transplant Type 2 - reduced activity of UGT1A1 --> can only monoglucuronidate bilirubin Very yellow skin is only major consequence Phenobarbital treatment can cause hypertrophy of hepatocellular ER and improve function
	Gilbert's Syndrome	Common benign inherited condition Mutations in promoter of UGT1 reduce transcription --> 30% activity of conjugation system Mild fluctuating unconjugated hyperbilirubinemia, normal LFT, no bilirubin in urine Clinically benign - may be more susceptible to adverse effects of drugs, fasting may cause jaundice
	Conjugated Hyperbilirubinemia - Causes	Inherited - Dubin Johnson and Rotor Syndromes Acquired - cholestatic and necrotizing hepatocellular injury Injury to cell or biliary obstruction causes reflux into serum
	Dubin Johnson and Rotor Syndromes	DJ - chronic conjugated hyperbilirubinemia - defect of MDRP2 - excretes bilirubin across canicular membrane Rotor - chronic conjugated hyperbilirubinemia - defects of uptake and excretion of bilirubin pigments Asymptomatic except for jaundice
	Cholestasis - Overview	Pathologic impaired bile formation and bile flow --> bile pigment accumulation in hepatic parenchyma Can be caused by extrahepatic or intrahepatic obstruction or defects in secretion Jaundice, pruritus, skin xanthomas, and deficiencies of fat soluble vitamins Characteristic elevation of Alk Phos and GGT
	Cholestasis - Morphology and Histology	Accumulation of bile pigment within hepatic parenchyma Elongated green/brown bile plugs in dilated bile canaliculi - distension of upstreatm ducts Bile extravasation and phagocytosis by kupffer cells Accumulation in hepatocytes --> fine foamy appearance --> feathery degeneration Portal tract edema, neutrophilic infiltrate Dissolution of hepatocytes by bile detergent --> bile lakes
	Cholestasis - Biochemical Findings	Elevated Alk Phos and GGT Increased synthesis of canicular Alk Phos in response to increased pressure Elevated bilirubin
	Cholestasis - Extrahepatic Causes	Obstruction Benign - gallstones, strictures, pancreatitis Malignant - cancer of pancreas, bile duct, or gallbladder
	Cholestasis - Intrahepatic Causes	At Hepatocyte - EtOH, drugs, Hep A, sepsis, TPN At Canaliculus - Pregnancy, estrogen, drugs At Bile Duct - TB Granulomatous, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis
	Bilirubin - Maximum Serum Levels	30-35 mg/dl is maximum amount possible from isolated obstruction Urine clearance matches amount generated from hemoglobin degradation Can exceed 30-35 if simultaneous hemolysis or renal failure occurs with obstruction
	Gallstones - Types	Cholesterol stones - form in gallbladder Black pigment stones - mainly unconjugated bilirubin - form in gallbladder Brown pigment stones - mainly unconjugated bilirubin - form in bile duct
	Gallstones - Formation	Supersaturation of bile with cholesterol or bilirubin Stasis of bile Mucous hypersecretion promotes crystal nucleation Cholesterol and Black stones form in gallbladder, brown stones form in bile duct
	Cholesterol Gallstones	50-90% cholesterol, 5-10% mucin, small amounts of calcium salts Risk factors - female, fat, fertile, forty (4F) Cholesterol supersaturation compared to relatively low bile salts and phospholipids Gallbladder stasis promotes nucleation and is accelerated by mucous hypersecretion Treated with ursodeoxy and chenodeoxycholic acid - not effective in pigment stones Appear radiolucent - increasing amounts of calcium carbonate makes them radiopaque
	Black Pigment Gallstones	Form in sterile gallbladder bile Abnormal insoluble calcium salts and unconjugated bilirubin Calcium phosphates and carbonates --> radiopaque Associated with elderly, hemolytic anemia, and cirrhosis
	Brown Pigment Gallstones	Form in bile duct associated with bacterial infection Bacteria deconjugate bilirubin in duct Radiolucent due to calcium soaps and minimal calcium salts
	Gallstones - Clinical Features	Most asymptomatic Biliary pain, constant or colicky, radiate to right shoulder Complications include empyema, perforation, fistulas, cholangitis, obstructive cholestasis Smaller stones can travel through ducts and become trapped in common ducts Increased risk for gallbladder carcinoma
	Biliary Atresia - Overview	Complete or partial obstruction of lumen of extrahepatic biliary tree w/ 3 months neonatal Progressive inflammation and fibrosis of bile ducts Fetal form - abnormal development, associated with polysplenia and other developmental anomalies Perinatal form - normal development, inflammatory destruction, viral trigger?
	Biliary Atresia - Clinical Features	Neonatal cholestasis - normal birth weight and post natal weight gain Initially normal stools become acholic Serum conjugated bilirubin > 6-12, moderately elevated ALT, elevated AP and GGT Diagnose with operatice cholangiogram, ultrasound or Disida scintiscan - radio tracer taken up and excreted by liver Biopsy shows bile duct proliferation, ductal bile plugs, and portal fibrosis
	Biliary Atresia - Treatment	Kasai hepatoportoenterostomy - surgical resection and bypass of biliary tree Limited by intrahepatic progression of disease, bacterial contamination and experience of surgeon More effective when performed at younger age Only possible for 10% of cases that don't involve bile ducts above porta hepatis Transplantation is only cure
	Metabolic Liver Disease - Hepatic Presentations	Hepatomegaly - Glycogen storage disease, defective breakdown, present with hypoglycemia Hepatosplenomegaly - Niemann Pick disease, abnormal lipid accumulation in reticuloendothelial cells Liver Failure - Tyrosinemia, toxic metabolites cause liver damage Cholestasis - cystic fibrosis
	Inherited Causes of Cirrhosis - Pediatrics v Adults	Peds - A1AT 50% of cases, Hemochromatosis rare Adults - Hemochromatosis 75% of cases
	Alpha 1 Antitrypsin Deficiency - Overview	Autosomal recessive deficiency in A1AT - low serum levels and impaired subcellular trafficking Synthesized by Liver - functions to inhibit neutrophil elastase in lung --> protects from inflammatory damage Early onset emphysema +/- Liver disease Z allele misfolds and accumulates in hepatocyte ER inducing damage Affected patients may have underlying impairment in protein trafficking --> susceptible to accumulation Presents with neonatal hepatitis and cholestatic jaundice or later with hepatitis or cirrhosis
	Alpha 1 Antitrypsin Deficiency - Treatment	Avoid cigarette smoking, treat complications, screen for hepatocellular carcinoma May require liver or lung transplantation Carbamazepine may be used to enhance autophagy and increase clearance of accumulated protein
	Alpha 1 Antitrypsin Deficiency - Histology	Round cytoplasmic globular inclusions in hepatocytes Acidophilic, stain strongly with PAS
	Wilson Disease - Normal Copper Metabolism	Ingested Cu is absorbed in duodenum and proximal intestine - transported to Liver Taken up by hepatocytes, incorporated into apoceruloplasmin to form ceruloplasmin, and excreted into bile Ceruloplasmin circulates in blood before being taken up by liver, degraded, and Cu eliminated in bile ATP7B - Cu transporting ATPase, required to excrete into bile and incorporate into ceruloplasmin
	Wilson Disease - Pathophysiology	Autosomal recessive deficiency in ATP7B - Cu transporting ATPase Decreased Cu excretion into bile, incorporation into ceruloplasmin, and secretion of ceruloplasmin into blood Cu accumulation in liver --> ROS production --> toxic liver injury Hemolysis, deposition in Descemet's membrane in eye and basal ganglia Treat with Cu chelating agents or Zinc therapy
	Kayser Fleishcer Rings	Green to brown deposits of Cu in Descemet's membrane in the limbus of the cornea Visible under slit lamp exam Occurs in almost all patients with Wilson's Disease
	Wilson Disease - Clinical Presentation	Acute or chronic liver disease - hepatic symptoms present earlier than neurologic symptoms Neurologic changes - parkinson like syndrome, rigidity, tremors, gait, choreiform Kayser Fleischer rings - visible under slit lamp exam Decreased serum ceruloplasmin, increased hepatic Cu (sensitive), increased urinary Cu (specific May be silent until sudden onset of critical systemic illness Elevated ALT/AST but LOW ALK PHOS
	Hemochromatosis - Iron Metabolism	Iron levels regulated by intestinal absorption via Hepcidin - no regulated excretion Hepcidin binds to ferroportin on intestinal cells, internalizes it to prevent release of iron from intestinal cells Hepcidin transcription is increased by inflammation and iron Hepcidin transcription is decreased by iron deficiency, hypoxia, and ineffective erythropoiesis Hepcidin deficiency results in iron overabsorption Hepcidin regulated by HJV, TfR2, and HFE
	Hereditary Hemochromatosis - Pathophysiology	Deficiency in Hepcidin via hepcidin mutation or mutation in HJV, TfR2, or HFE that regulate Hepcidin Excessive accumulation of iron - deposition in liver, pancreas, heart, joints, and endocrine organs Increased enteral absorption --> early hemosiderin deposition in Zone 1 hepatocytes Iron causes lipid peroxidation via free radical reactions, stimulates stellate cell collagen deposition Iron generates ROS and directly interacts with DNA causing lethal cell injury - increased risk of HCC
	Hereditary Hemochromatosis - Clinical Features	Classic triad of hepatomegaly, diabetes mellitus, and skin pigmentation Death from cardiac disease and cirrhosis progressing to hepatocellular carcinoma Arthralgias, cardiac disease, infections Abdominal pain, weakness, lethargy, impotence, gynecomastia, testicular atrophy, splenomegaly Diagnose with high levels of serum iron and ferritin and with liver biopsy Hemosiderin deposition in Zone 1 hepatocytes - if from transfusion, will deposit in Kupffer cells Treat with phlebotomy
	Hereditary Hemochromatosis - HFE	Most common mutation in adult hemochromatosis Intestinal epithelial cell senses iron levels in body based on intracellular iron pool Uptake of iron bound to transferrin carrier regulated by HFE determines intracellular pool Body levels of iron indicated by levels of transferrin - synthesis in liver stimulated by low iron / ferritin Mutated HFE results in false detection of high transferrin levels Interpreted as low serum iron --> increased intestinal absorption of iron
	Alcoholic Liver Disease - Alcohol Metabolism	Low levels - EtOH --(ADH)--> Acetaldehyde --(ALDH)--> Acetate (+ 2 NAD+ --> 2 NADH) High levels - EtOH --(MEOS)--> Acetaldehyde --(Oxidases)--> Acetate (+ 2 reactive oxygen species)
	Alcoholic Liver Disease - Steatosis Pathogenesis	Short term EtOH ingestion results in mild reversible hepatic steatosis Generation of NADH via alcohol dehydrogenase and acetaldehyde dehydrogenase Results in increased Fatty acid synthesis, decreased fatty acid oxidation, and impaired secretion of lipoproteins Fatty acids accumulate, are esterified, and stored as triglycerides in hepatocytes Microvesicular lipid droplets - compress and displace nuclei
	Alcoholic Liver Disease - Hepatitis Pathogenesis	Acetaldehyde and free radicals induce lipid peroxidation Decreased glutathione (requires NAD+ to regenerate) sensitizes liver to oxidative injury Induction of CYP2E1 enhances oxidation metabolism of other drugs Alcohol induces release of bacterial endotoxins into portal circulation --> inflammatory response Alcohol induces release of endothelins from sinusoid --> vasoconstricion and stellate cell activation
	Alcoholic Liver Disease - Steatosis Clinical Features	Tender hepatomegaly, non specific symptoms of fatigue, malaise, anorexia, abdominal discomfort Mild elevation of bilirubin, Alk Phos, and ALT/AST Macrovesicular steatosis seen on histology More commonly seen with chronic abuse
	Alcoholic Liver Disease - Hepatitis Clinical Features	Jaundice, splenomegaly, palmar erythema, asterixis, ascites AST > ALT (2:1), increased prothrombin time Macrovesicular steatosis, neutrophil infiltrate, centrilobular swelling, ballooning degeneration, mallory bodies Severe --> portal hypertension --> esophageal varices, ascites, hepatic encephalopathy Malnutrition from calorie displacement Appear in chronic drinker after acute ingestion of large amounts of EtOH
	Mallory Bodies	Accumulations of ubiquinated intermediate filaments in hepatocytes Appear as eosinphilic cytoplasmic clumps Seen in alcoholic liver disease - also in NAFLD, PBC, Wilsons, cholestatic syndromes, and hepatocellular tumors
	Alcoholic Liver Disease - Mortality	Hepatic coma, massive GI bleed, infection, hepatorenal syndrome, hepatocellular carcinoma Good prognosis if abstain from EtOH Signs of decompensation reflect poorer prognosis
	Non Alcoholic Fatty Liver Disease - Overview	Hepatic steatosis with no history of alcohol abuse Includes seatosis, NASH (steatohepatitis), and Cirrhosis Risk factors - obesity, hyperglycemia, T2D, hypertriglyceridemia Metabolic Syndrome - obesity, high TG, low HDL, elevated BP and fasting plasma glucose
	Non Alcoholic Fatty Liver Disease - Pathogenesis	Combination of insulin resistance and hepatocyte oxidative stress IR --> increased peripheral lipolysis + hyperinsulinemia --> hepatic fat accumulation Hyperinsulinemia --> increases glycolysis and de novo fatty acid synthesis, decreased apo B100 and VLDL export FFA upregulate hepatocyte p450 enzymes --> oxidative stress Hepatic fat accumulation --> oxidative stress --> lipid peroxidation --> ROS --> Hepatocyte damage
	Non Alcoholic Fatty Liver Disease - Clinical Features	AST:ALT is less than 3:1 - commonly > 3:1 in alcoholic steatohepatitis Fatigue, right sided abdominal discomfort, cardiovascular comorbidity
	Non Alcoholic Fatty Liver Disease - Treatment	Weight reduction and correction of central obesity Insulin sensitizing agents - rosiglitazone/pioglitazone - may worsen obesity Antioxidants - vitamin E,C, Betaine
	Vitamin C Deficiency - Clinical Features	Required for hydoxylation of proline and lysine on collage, antioxidant activity, increases iron absorption Impaired collagen formation - poor blood vessel strength, inadequate osteoid synthesis, impaired wound healing Pain and extremity weakness in children Erythema on gingica, buccal ulcers, hard palate lesions Petechia and bruises, eczema flare, microcytic anemia Cork screw hemorrhagic hair follicles
	Rickets - Clinical Features	Vitamin D deficiency Hypotonia and muscle weakness Tetany and seizures Bone pain, decreased linear growth Bone and cartilage deformities Respiratory infections
	Rickets - Pathophysiology	Vit D Deficiency --> Secondary Hyperparathyroidism --> Phosporus Deficiency PTH stimulates Ca reabsorption, renal Vit D activation, and bone remodelling Elevated serum Ca and Urinary Phosphate Excretion Transient increase in Pi absorption --> FGF23 release --> increased Pi excretion Return low Ca levels to normal at expense of phosphorus
	Rickets - Biochemical Status	Low serum Ca, Low serum Pi, high Alk Phosphatase, high PTH, low 25-OH-D Elevated Alk Phosphatase and PTH are earliest markers Measure 25-OH-D when suspect nutritional rickets - reflects dietary intake Don't measure 1,25-OH2-D - will be misleadingly normal or high
	Vitamin D - Source	Photochemical conversion in skin of 7-dehydrocholesterol --> Vitamin D3 via UVB radiation (90%) Dietary - fish, plants, grains - fat soluble vitamin requires adequate fat absorption Transport of D3 to liver via α1-globulin Liver convrsion to 25-OH-D via 25-hydroxylases Kidney conversion to 1.25-OH2-D via α1-hydroxylase
	Vitamin D - Regulation of Renal Conversion to 1.25-OH2-D	Parathyroid Hormone activates 1α-hydroxylase PTH released in response to hypocalcemia Hypophosphatemia directly activates 1α-hydroxylase Increased levels of 1,25-OH2-D feedback to inhibit 1α-hydroxylase
	Vitamin D - Effects of Calcium and Phosphorus Homeostasis	Stimulates intestinal Ca absorption - transcription of TRPV6 Ca transport channel Stimulates renal Ca reabsorption - transcription of TRPV5 Enhance expression of RANKL (w/ PTH) --> osteoclast differentiation Osteoclasts dissolve bone --> release Ca and Phosphorus into circulation Mineralization of bone
	Zinc Deficiency	Associated with chronic diarrhea - decreased time for absorption or absorptive surface area Commonly seen in Celiac Disease Hair loss, red papular skin rash, diarrhea Impaired growth, developmental delay, impaired wound healing Treat with Zinc supplementation and gluten free diet
	Choledochal Cyst	Congenital dilation of common bile duct Results in true diverticuli and dilation of ducts Predispose to stone formation, stenosis, stricture, pancreatitis, and obstructive biliary complications May present with jaundice and biliary colic pain --> mechanical obstruction Increased risk to develop adenocarcinoma
	Gallbladder Carcinoma	Develop from adenoma precursor dysplastic lesion 95% are adenocarcinoma - 5% are squamous cell carcinoma Gallstones are most important risk factor Non specific symptoms - abdominal pain, jaundice, anorexia, nausea and vomiting Most have spread to liver by time of detection
	Cholangiocarcinoma	Malignancy of biliary tree - can be intrahepatic or extrahepatic Klatskin tumor - perihilar tumor at junction of right and left hepatic duct Hilar and distal tumors present with biliary obstruction, cholangitis, and RUQ pain Intrahepatic tumors not detected until late in course Associated with primary sclerosing cholangitis, ulcerative colitis, caroli disease, choleodochal cysts
	Acute Cholangitis	Bacterial infection of bile duct - enter through sphincter of oddi, ascending infection Results from obstructed bile flow - choledocholithiasis and biliary strictures Enteric gram negative aerobes - E coli, Klebsiella, interococcus, enterobacter, clostridium, and bacterioides Presents with fever, chills, abdominal pain, jaundice, neutrophil infiltration - sepsis
	Choledocholithiasis	Presence of stones within the bile duct of biliary tree (cholethiasis is stones in gall bladder) Asymptomatic or symptoms from obstruction, pancreatitis, cholangitis, hepatic abscess, biliary cirrhosis
	Primary Biliary Cirrhosis - Overview	Inflammatory autoimmune disease affecting intrahepatic bile ducts Nonsuppurative inflammatory destruction of medium sized intrahepatic bile ducts Dense infiltrate by dense accumulation of lymphocytes, macrophages, plasma cells Progressive destruction leads to fibrosis and cirrhosis - portal hypertension and variceal bleeding Presence of antimitochondrial antibody Associated with other autoimmune diseases
	Primary Biliary Cirrhosis - Biochemical Findings	Elevated Alk Phos and GGT early in progression- cholestasis Elevated cholesterol --> eyelid xanthelasmas due to cholesterol laden macrophages Hyperbilirubinemia is late development - indicates ensuing hepatic decomposition
	Primary Biliary Cirrhosis - Pathology	Aberrant expression of MHC II on bile duct epithelial cells Accumulation of autoreactive T cells around bile ducts Mitochondrial antibodies target E2 component of pyruvate dehydrogenase Cellular immunologic attack - biliary epithelial cell death
	Primary Biliary Cirrhosis - Treatment	Ursodeoxycholic Acid Promotes endogenous bile acid secretion, stabilizes biliary epithelial cell membranes Alters bile epithelial cell HLA expression, decreases cytokine production Improves LFT, histologic progression, risk of decompensation, and overall survival No impact on symptoms
	Primary Sclerosing Cholangitis - Overview	Inflammation and obliterative fibrosis of intra and extrahepatic bile ducts Irregular strictures and dilation of ducts - Beading seen on ERCP Strong association with ulcerative colitis Elevated GGT, Alk Phos, Bilirubin - Autoantibodies - P-ANCA common, No AMA (contrast with PBC) Increased risk of cholangiocarcinoma, chronic pancreatitis, and hepatocellular carcinoma
	Decompensated Cirrhosis - Major Complications	Ascites Spontaneous bacterial peritonitis Hepatorenal syndrome Portosystemic shunts --> Variceal bleeding Hepatic encephalopathy
	Portal Hypertension - Fluid Dynamics	Pressure = Flow x Resistance Splanchnic capillary beds are major site of flow control Hepatic sinusoids are main site of resistance control
	Portal Hypertension - Pre/Intra/Post Sinusoidal Causes	Presinusoidal - obstructive thrombosis, narrowing of portal vein, splenomegaly increasing splenic vein flow Sinusoidal - cirrhosis, schistosomiasis, diffuse fibrosing granulomatous disease (sarcoidosis), NRH Postsinusoidal - right sided heart failure, constrictive pericarditis, Budd Chiari Syndrome
	Portal Hypertension - Pathogenesis of Increased Resistance and Flow	Resistance - Sinusoidal constriction of vascular smooth muscle cells and myofibroblasts Disruption of blood flow by scarring Decreased NO and increased endothelin, angiotensinogen, and eicosanoids --> vasoconstriction Flow - Splanchnic arterial vasodilation stimulated by Nitric Oxide NO production stimulated by reduced clearance of bacterial DNA absorbed from gut due to sinusoidal pathology
	Portal Hypertension - Ascites Pathogenesis	Sinusoidal hypertension drives fluid into space of Disse --> activates baroreceptors Reduced clearance of bacterial DNA absorbed from gut --> NO production NO stimulates splanchnic capillary vasodilation --> pooling of arterial blood --> reduced arterial pressure Activation of vasoconstrictors and activation of renin angiotensin system --> retention of sodium and water Extravasation of fluid into abdominal cavity
	Ascites - SAAG	Serum Ascites Albumin Gradient Serum Albumin - Ascietes Albumin > 1.1 indicates portal hypertension - sinusoids intact or sclerotic Cirrhosis, CHF, Constrictive pericarditis, alcoholic hepatitis, Budd Chiari < 1.1 indicates leaky or damaged sinusoids Peritoneal carcinomatosis, peritoneal tuberculosis, pancreatitis, serositis, nephrotic syndrome
	Transjugular Intrahepatic Portosystemic Shunting	Stent inserted to bypass blood around the liver Shunt from portal vein directly to hepatic vein Decreases resistance --> Decreases portal pressure
	Hepatic Failure - Clinical Signs	Jaundice Hypoalbuminemia --> peripheral edema Hyerammonemia --> encephalopathy Fetor Hepaticus - distinctive body odor Impaired estrogen metabolism --> hyperestrogenemia --> palmar erythema, spider angiomas, gynecomastia
	Hepatorenal Syndrome	Clinical triad of chronic liver disease, hypoxemia, and intrapulmonary vascular dilations Associated with refractory ascites
	Spontaneous Bacterial Peritonitis	Infection of ascietes fluid in setting of portal hypertension - SAAG >1.1 Hypoalbuminemia predisposes to infection - decreased complement production Fever, abdominal pain, confusion, renal failure >250 Neutrophils / cc collected via paracentesis is diagnostic Multiple organisms indicates perforated bowel or secondary infection Most common E Coli, Klebsiella, streptococcus Treat with antibiotics and IV albumin to protect kidneys
	Portal Hypertension - Varicies	Portocaval anastamoses - Esophageal varicies at junction of esophagus and stomach Gastric varicies - can also result from focal occlusion of splenic vein in pancreatic cancer Size predicts risk of bleeding - appear as cherry red spots on esophageal mucosa Treat large varicies with non selective beta blockers - reduce portal inflow, reduce pressure IV Octreotide for active bleeds - splanchnic vasoconstrictor Band ligation to prevent or stop bleeding
	Portal Hypertension - Hepatic Encephalopathy	GI bacteria catabolize proteins into ammonia - normally cleared by functional liver Cirrhosis results in elevated blood ammonia levels --> converted to glutamine by astrocytes Results in mental status changes - can progress to deep coma and death Precipitated by hemorrhage (protein meal), tranqulizers, sedatives, azotemia for renal failure Treat with lactulose - non absorbable disaccharide, acidifies GI lumen, traps ammonia
	End Stage Liver Disease - Prognosis	MELD - Model for End Stage Liver Disease Based on creatinine, bilirubin, and INR - score between 6-40 Excellent 3 month mortality predictive ability
	Cirrhosis - Morphology and Histology	Bridging fibrous septa link portal tracts together or link portal tract to central veins Parenchymal nodules from cycles of hepatocyte regeneration and scarring Diffuse disruption of architecture of entire liver Collagen type I and III deposited in space of Disse - normally only type IV
	Cirrhosis - Pathologic Changes	Death of hepatocytes, extracellular matrix deposition, and vascular reorganization Surviving hepatocytes proliferate as spherical nodules within fibrous septa Deposition of collagen type I and III in space of Disse - normally only type IV - create fibrotic septal tracts Formation of new vascular channels in fibrotic septa connecting portal vessels to hepatic veins Capillarization of sinusoids - loss of endothelial fenestrations Both processes shunt blood away from liver parenchyma
	Cirrhosis - Pathogenisis	Stellate cell proliferation and activation into myofibroblasts --> deposit type I and III collagen in space of Disse Stellate cells activated by inflammatory processes - TNF, IL 1B, lymphotoxin Myofibroblasts stimulated to contract by endothelin 1 --> constrict sinusoids and increase resistance Surviving hepatocytes proliferate as spherical nodules in confines of fibrous septa
	Cirrhosis - Clinical Features	Asymptomatic until advanced disease progression Anorexia, weight loss, weakness - can progress to signs of hepatic failure Hepatopulmonary syndrome - severely impaired oxygenation Death from progressive liver failure, portal hypertension complication, or hepatocellular carcinoma
	Cavernous Hemangiomas	Blood vessel tumor - occur in many places Most common benign liver tumor Vascular channels in bed of fibrous connective tissue Must diagnose to rule out metastatic tumors
	Hepatic Adenoma	Benign hepatocyte neoplasm - normal cell appearance, minimal dysplasia Occur in young women using oral contraceptives - usually regress if OCPs are removed May rupture and cause intraperitoneal hemorrhage, may be mistaken for HCC, rarely transform into HCC Lack portal tracts - solitary arterial and venous vessels distributed throughout tumor
	Angiosarcoma	Rare malignant tumor of endothelial cells - CD31 + Liver angiosarcoma associated with exposure to vinyl chloride, arsenic, or thorotrast - long latency Highly aggressive, metastasize widely, poor prognosis
	Hepatoblastoma	Most common liver tumor of childhood Derived from fetal / embryonal hepatic cells Activating mutations of Wnt pathway - associated with FAP Epithelial type - cells form acini, tubules, or papillary structures Mixed type - epithelial structures + foci of mesenchymal differentiation - osteoid, cartilage, striated muscle Treat with resection and chemotherapy
	Metastatic Liver Tumors - Most Frequent Orign	GI - 45% - colon most common Lung - 24% Urogenital - 8% Breast - 8% Leukemia, Lymphoma, and Melanoma Primary Liver - 12%
	Nodular Regenerative Hyperplasia	Liver entirely covered with spherical nodules in absence of fibrosis Occurs with reduced oxygenation of liver Diffuse obliteration of portal vein radicles and compensatory increase in arterial blood supply Zone 1 cells receive adequate oxygen supply Zone 3 cells receive sub adequate oxygen supply - become smaller Repetitive alterations of hepatocellular size creates nodular appearance
	Focal Nodular Hyperplasia	Well demarcated but poorly encapsulated nodule Focal obliteration of portal vein radicles and compensatory increase in arterial blood supply Central gray stellate scar with fibrous septa radiating out to periphery Central scar contains large arterial vessels Intense lymphocytic infiltrate and bile duct proliferation along septa
	Eichonicocus	Infectious agent forms eichonicocal cysts in liver Visualize scolex inside cyst - identify with acid fast stain
	Hepatocellular Carcinoma - Major Etiologies	Chronic viral infection - HBV, HCV Chronic alcoholism Non Alcoholic Steatohepatitis Food Contaminants - aflatoxins Tyrosinemia, glycogen storage disease, hemochromatosis, NAFLD, A1AT Deficiency
	Hepatocellular Carcinoma - Morphology and Histology	Malignant hepatocyte tumor - can be unifocal, multifocal, or diffusely invasice Well differentiated to anaplastic hepatocyte appearance - no bile ducts in lesion - accumulation of green bile Increased N:C, hyperchromatic nuclei, mitotic figures - serum alpha fetoprotein usually elevated Macrotrabelular architecture - sinusoids at least 4 cells thick instead of normal 1-2 Prognosis based on grade of nuclear atypia and presence of vascular invasion
	Hepatocellular Carcinoma - Fibrolamellar Carcinoma	Distinct variant of HCC - not associated with underlying chronic liver disease Malignant hepatocytes, AFP not elevated Central large scar, green appearance from accumulated bile Nests or cords of hepatocytes separated by parallel lamellae of dense collagen bundles Potentially metastatic
	Liver - Piecemeal Necrosis	Death of hepatocytes at limiting plate and erosion of limitng plate Limiting plate = hepatocytes at junction of portal tract and parenchyma Classically was defining feature of active hepatitis - now defined as lymphocyte spilling into parenchyma
	Liver - Active Hepatitis	Classically defined by piecemeal necrosis - death of hepatocytes at limiting plate Now defined by whether lyphocytes are confined to vessels or spill into parenchyma
	Liver - Feathery Degeneration	Hepatocyte swelling due to accumulation of bile salts - droplets of bile pigment Commonly seen in cholestatic conditions
	Liver - Ballooning Degeneration	Diffuse swelling of hepatocytes - hydropic swelling Cytoplasm appears empty with only scattered eosinophilic remnants of organelles Commonly seen in acute hepatitis
	Hepatitis - Activity and Stage	Activity = degree of inflammation and hepatocyte apoptosis Increased activity is prognostic for faster progression to cirrhosis in HCV infection Stage = degree of fibrosis - no septa, septa, bridging fibrosis, cirrhosis Prognostic indicator for Wilson's and primary biliary cirrhosis
	Patterns of Hepatic Fibrosis	Portal to portal bridging - seen in most chronic conditions - viral, autoimmune Central vein to central vein - seen with etiologies that affect zone 3 - EtOH, Budd Chiari Uniform collagenization of the space of Disse - vitamin A toxicity
	Hepatitis C - Molecular Features	Flaviviridae family - ssRNA - single polypeptide with one reading frame processed into functional units 5' end encodes conserved nucleocapsids E1 and E2 3' end encodes cis acting agents required for viral replication RNA polymerase high error rate --> mutations --> multiple genotypes --> no vaccination ability Most antibodies directed against E2 - E2 is most variable region of genome 6 genotypes - 1 most common in US, poor response to therapy - 2,3 respond better
	Hepatitis C - Transmission	Transmitted through blood contact IV drug use, unprotected sex, needle sticks, surgery, children may be infected perinatal
	Hepatitis C - Clinical Features	Majority of patients progress to chronic infection - progress to cirrhosis and HCC May be initially cleared with strong cell mediated immune response - occurs infrequently Evades immune response by inhibiting IFN mediated cellular response Repeated cycles of hepatic damage - episode elevations in serum ALT/AST Risk of HCC increases with repeated injury, regeneration, and cirrhosis
	Hepatitis C - Clinical Outcomes	Acute infection --> 30% recover, 70% chronic infection Chronic --> 30% maintain normal ALT, 70% have mild/moderate/severe active infection and damage Chronic active infection --> Cirrhosis --> Decompensation or HCC
	Hepatitis C - Treatment Goals and Options	Goal - sustained responder (cure) - long term undetectable HCV RNA Combination of injectable Pegylated IFN and oral Ribavirn nucleoside analogue Treatment + no decrease in HCV RNA --> non responder, no benefit from further treatment Treatment + decreased HCV RNA --> stop and observe if relapse Viral genotype 1 is less responsive to therapy than 2/3 Host IL 28B polymorphism predicts responsiveness to therapy
	Hepatitis C - Treatment Side Effects	IFN - flue like symptoms, depression, insomnia, alopecia, leukopenia, thyroiditis, autoimmunity Ribavirn - Hemolytic anemia, cough, dyspnea, rash, pruritis, insomnia, anorexia - teratogenic
	Hepatitis C - Ribavirin Mechanism of Action	Guanosine analogue Inhibits viral RNA dependent RNA polymerase Induces mutations in HCV RNA, depletes GTP, and modulates T cell response to favor Th1 Not effective without IFN treatment Important in preventing relapse after discontinuing treatment
	Hepatitis C - IFN Alpha Mechanism of Action	Delivered as Pegylated form to prolong duration of action and reduce frequency of administration Enhances MHC I expression, amplifies cytotoxic CD 8T and NK cells, enhances macrophage activity Inhibits HCV attachment, uncoating, and activation of cellular RNAses required to process polypeptide viral proteins
	Hepatitis C - Directly Acting Antiviral (DAA) Therapy	Small molecules targeting specific components of viral replication cycle NS 3/4a protease inhibitors NS5B viral polymerase inhibitors NS5A viral assembly inhibitors Improved efficacy, risk of resistance
	Hepatitis B - Molecular Features	Hepadnaviridae family - DNA - partially ds circular genome - four open reading frames HBcAg - nucleocapside core - remains in hepatocyte for viron assembly HBeAg - polypeptide indicates active viral replication HBsAg - surface envelope glycoprotein Pol - polymerase with DNA and RT activity - replication with RNA intermediate - DNA --> RNA --> DNA HBx - transcriptional activator, important in development of HCC
	Hepatitis B - Transmission	Transmitted through blood contact High prevalence - vertical perinatal transmission during childbirth - high carrier rate Intermediate prevalence - horizontal transmission through minor cuts in childhood Low prevalence - unprotected sex, IV drug use
	Hepatitis B - Serology	HBsAg acute or chronic active infection appears before onset of symptoms HBeAg, HBV DNA, and DNA Pol indicate active viral replication IgM (acute) anti HBc appears before onset of symptoms - replaced by long lasting IgG (chronic) Active Infection - HBsAg, HBeAg, IgM anti HBc Past Infection - IgG anti HBs, anti HBc, and anti HBe Vaccine - IgG anti HBs
	Hepatitis B - Clinical Outcomes	Infection --> acute hepatitis - 70% subclinical, 30% icteric 90% recovery from acute, 5% progress to chronic hepatitis, 0.5% experience fulminant hepatitis Chronic hepatitis --> Recovery, Healthy Carrier State, or Cirrhosis (20%) Cirrhosis --> Hepatocellular Carcinoma or Decompensation
	Hepatitis B - Phases of Infection	Immune tolerant - high HBV DNA, low ALT, minimal immune response - seen in neonatal infections Immune clearance - immune response to clear virus, decreasing DNA, increasing ALT Inactive carrier state - no symptoms but can transmit infection, low DNA and ALT Reactivation - Elevated DNA and ALTs
	Hepatitis B - Treatment Goals and Indications	Goal - slow disease progression, reduce liver damage, prevent cirrhosis, decomensation or HCC Goal - HBsAg clearance and seroconversion - difficult to acheive Reduce HBV DNA, loss of HBeAg, develop HBeAg antibodies, Normalize ALT, histologic improvement Indications - chronic patients in immune clearance or reactivation phase HBeAg and HBV DNA elevated for > 6 months, persistent ALT elevation, biopsy evidence of chronic infection Don't treat acute infection or patients in quiescent carrier state
	Hepatitis B - Treatment	Combination injectable Pegylated IFN and oral antiviral nucleoside analogues IFN - Widespread damage, significant side effects, no development of resistance Don't use IFN in patients with cirrhosis --> can cause fulminant liver failure and death Antivirals - lamivudine, adefovir, entecavir - cannot target virus in nuclear phase of cycle Minimal side effects, used in cirrhosis, decompensation, immunocompromised Require longer duration, risk of drug resistant mutants
	Hepatitis B - IFN Treatment	Finite length of therapy, no viral resistance, High relapse rate, significant side effects, cant use in patients with cirrhosis or decompensation Limited use in HBV DNA high / ALT low - immune tolerant phase
	Hepatitis B - Nucleoside Analogue Treatment	Well tolerated, useful in HBeAg negative patients as long term therapy, can use in decompensated cirrhosis High risk of resistant mutations, long term therapy required
	Hepatitis A - Molecular Features	Picornavirus family - ssRNA
	Hepatitis A - Transmission	Spread by ingestion of contaminated water and food Shed in stool for 2-3 weeks before and 1 week after symptoms Fecal - oral transmission in areas with substandard hygiene and sanitations Can be transmitted through shellfish that concentrate HAV from water contaminated with human waste Only transient viremia - blood borne transmission is possible but rare
	Hepatitis A - Clinical Features	Causes acute hepatitis - self limiting, no chronic or carrier states - rarely fulminant Hepatocellular injury mediated by CD8 T cellular immune response Diagnose with serum IgM anti HAV antibodies --> acute active infection IgG antibodies develop for long term immunity
	Hepatitis D	Dependent on HBsAG to complete viron assembly Requires preexisting or co infection with HBV
	Viral Hepatitis - Chronic Infection	Symptomatic, biochemical, or serologic evidence of infection > 6 months Young infection --> weaker immune response --> less likely to clear --> more likely to remain chronic Fatigue, malaise, jaundice, spider angiomas, palmar erythema, hepatosplenomegaly Prolonged PT time, hyperglobulinemia, hyperbilirubinemia, elevated Alk Phose Immune complex disease, vasculitis, glomerulonephritis, cryoglobulinemia
	Viral Hepatitis - Carrier State	No manifest symptoms but can transmit organism - reservoir for infecction No HBeAg, low HBV DNA, positive anti HBe antibodies, normal ALT/AST Neonatal / childhood infection --> 90% progress to carrier state
	Autoimmune Hepatitis - Pathogenesis	Chronic and progressive - unknown etiology Cell damage mediated by CD4 ad CD8 T cells producing IFNg and CD8 Cytotoxic T cells Absence of viral serology, elevated serum IgG and gamma globulin, serum autoantibodies Type 1 - anti nuclear, smooth muscle, actin, liver and pancreas antigens Type 2 - anti liver kidney micrsome 1 and anti liver cytosol antibodies
	Autoimmune Hepatitis - Clinical Feautres	May be acute appearance of clinical illness and fulminant onset hepatic encephalopathy May take chronic and progressive course and lead to cirrhosis May show destruction of bile ducts Clusters of plasma cells and lymphocytes in limiting plate observed Treat with immunosuppression
	Liver Toxins - Mechanisms of Damage	Direct toxicity to hepatocytes or biliary epithelial cells --> necrosis and apoptosis Hepatic conversion of xenobiotic to active toxin Toxin acts as a hapten to convert a cellular protein to an immunogenic antigen
	Liver Toxins - Acetaminophen	Dose predictable damage due to p450 conversion into toxic metabolite --> zone 3 hemorrhagic necrosis High doses saturate normal sulfation and glucuronidation clearance mechanisms - consumes NAD Excess is converted by p450 into NAPQ1 --> cytotoxic Chronic EtOH abuse upregulates p450 enzymes and depletes glutothione --> increases susceptibility Treat with mucomyst - competes for p450 binding
	Steatosis - Location of Lipid Deposition	Microvesicular - Reyes, valproic acid, pregnancy Macrovesicular - EtOH, obesity, hyperlipidemia Zone 3 - EtOH, obesity, diabetes Zone 1 - Hep C, AIDS, Kwashiorkor
	Steatohepatitis	Fatty liver with cellular death due to fat accumulation - inflammation not necessary Ballooning degeneration due to fat accumulation Mallory's Hyaline - ubiquinated intermediate filament cellular inclusions - attracts neutrophils Collagenization of space of Disse (chicken wire), venosclerosis, cirrhosis
	Oral Aphthous Stomatitis	T cell mediated localized destruction of oral mucosa Initiates on non keratinized mucosa - may extend to keratinized surfaces Increased incidence in patients with ulcerative colitis and other GI disorders
	Pyostomatitis Vegetans	Oral expression of IBD or GI malignancy - no cutaneous counterpart Yellowish, slightly elevated pustules and ulcerations or oral mucosa Intracellular edema, acantholysis, eosinophilic infiltration May precede onset of intestinal disease Seen in Crohns, Ulcerative Colitis, and as a paraneoplastic phenomenon
	Malignant Acanthosis Nigricans	Paraneoplastic phenomenon Manifestation of GI adenocarcinoma or other internal malignancy May be due to cytokine secretion by tumor cells Finely papillary, hyperkeratotic brownish patches, velvety texture, affects flexural areas of skin

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