GI Development •
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General GI tract tract be gins to form around around 4th 4th week ○ Endoderm forms intesti nal epithelium and glands ○ Mesoderm forms connective tissue, muscle, and wall of intestine ○ Neural crest cells form ENS Longitudinal folding brings heart down to proper position ○ Midgut herniates into the umbi licus during normal development Vitelline duct ○ Connection between the gut and the yolk sac ○ Improper vitel line duct formation can lead to an omphalocele Omphalocele is when the gut contents herniate into the umbi lical cord Allantosis ○ Becomes part of the umbili cal cord as well as forms an axis for umbili cal cord devel opment Gut tube regions Foregut ○ ○ Midgut ○ Hindgut
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Foregut Forms all structures from the es ophagus to the upper part of the duodenum ○ Esophagus Induced by transcription factor SOX2 ○ Stomach Rotates during deve lopment lopment "Turning a doorknob" □ Left stomach rotates anteriorly, □ right stomach rotates posteriorly Causes Vagus to rotate on the esophagus ○ Liver Induction is v ia transcription factors that BLOCK FGF2 & BMP Formed from hepatic cords that coalesce around ex traembryonic traembryonic veins Gall bladder is an outgrowth of the bil e duct ○ Pancreas Induced by PDX1, PAX4 & PAX6 PAX4 stimulates growth of β, δ □ and F cells □ PAX6 stimulates growth of α cells ○ Upper duodenum Also induced by PDX1 Sympathetic stimulation is via the Greater Splanchnic nerve ( T5-T9) T5-T9) Parasympathetic innervation is via the Vagus Blood supply is f rom the Celiac artery
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Midgut Herniates into the umbilicus during normal development Rotates 270⁰ counterclockwise around the axis of the Superior Mesenteric Artery Artery (SMA) (SM A) ○ SMA is the bl ood supply for midgut structures Forms all structures from the lower duodenum to the proximal 2/3 of the transverse colon ○ Lower duodenum Induced by PDX1 ○ Small intestine Induced by CDXC ○ Colon Colo n (cecum to to 2/3 transverse) Induced by CDXA Sympathetic inne rvation rvation is via the Lesser Splanchnic nerve (T9-T12) Parasympathetic innervation innervation is vi a the Vagus
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Hindgut Forms all structures from distal 1/3 of the transverse colon to the anal canal ○ Distal colon Induced by PDX1 ○ Anal canal Formed from the partitioning of the cloaca by the urorectal septum Forms the urogenital sinus and rectum □ Blood supply is via the Inferior Mesenteric Artery Sympathetic inne rvation rvation is via the Least Splanchnic nerve (T12-L2) Parasympathetic innervation innervation is vi a Pelvic splanchnic nerves
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Congenital Malformations of the GI G I Tract I •
Midgut Malformations Familial duodenal atresia ○ An autosomal recessive recessiv e mutation results in stenosis & atresia of the duodenum Lumen fails to recanulize recanulize ○ Associated wi th Down's, gastroschisis, gastroschisis, imperforate anus or intestinal intesti nal atresia ○ Diagnosis "Double- bubble" bubble" sign on x-ray due to dilation of the stomach and proximal proximal d uodenum ○ Treatment Duodenoduodenostomy/duodenojejunostomy Anastomosis of the proximal and distal small □ intestine intesti ne to bypass the obstruction obstruction Volvulus ○ Abnormal rotation of the midgut compromises blood flow Results in bilious emesis emesis in the newborn ○ Apple peel atresia ○ Distal portion of the proxi mal jejunum is coile d around a mesenteric mesente ric remnant Omphalocele Failure of gut to return to the abdominal cavity fol lowing lowi ng ○ herniation into the umbilicus Peritoneal Peritone al membrane covers intestine ○ Associated with: Beckwith-Wiedemann Beckwith-Wiedemann syndrome Gigantism, macroglossia & hypoglycemi a □ Pentalogy of Cantrell Diaphragmatic hernia, clef t sternum, sternum, absent □ pericardium and cardiac defects Often presents with el evated evated AFP ○ ○ Treatment is surgical reduction upon del ivery ivery Pyloric stenosis Result of el ongation and thickening thickening of the pylorus ○ ○ Associated wi th Turner's and Down's ○ More More common in 1st born males Increased risk wi th macrolide macrolide exposure exposure Presentation ○ Recurrent vomiting ( immediately immediately post-feeding) Leads to hypokalosi s/alkalosis □ "Olive "Oliv e mass" in the RUQ Jaundice "String/Apple core sign" on Barium swallow x -ray ○ Treatment is surgery Meckel'sd iverticulum iverticulum ○ Remnant of the vitel line duct connects the the umbil icus and and the ileum Digested f ood can exit through the umbilicus ○ Rule of 2's: 2% of the population 2 fe et from iliocecal junction 2 inches long
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General Gastroschisis ○ Failure of f usion of the e mbryonic mbryonic ventral fol ds which form the anterior abdominal abdominal wall ○ No sac covering the herniated bowel ○ Presents with el evated evated AFP ○ Treatment Surgical correction with temperature regulation, NG tube, antibioti cs and TPN
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Hindgut Malformations Problems wi th the urogenital septum Anal stenosis or atresia Imperforate anus ○ Rectum can merge with vagina or urethra ○ Anal agenesis Anal canal canal ends below pelvic diaphragm ○ Anorectal Anorectal agenesis Anal canal canal ends above above pelvic diaphragm Harder surgical surgical fi x
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Pancreatic Pancreatic Congenital Anomalie Anomaliess Ectopic pancreas ○ Extra pancreatic tissue Usually located in the stomach, duodenum, je junum, junum, il eum and Meckel's dive rticulum (if present) Pancreas divisum ○ Most common pancreatic anomaly ○ Failure of f usion of the major and minor pancreatic duct ○ Results in the bulk of the pancreas draining through the minor duodenal papilla Can cause pancreatitis ○ Annular pancreas ○ Dorsal and/or ventral folding fail ure ure results i n a pancreatic ring around around the duodenum Can cause obstruction
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Congenital Malformations of the GI G I Tract I •
Midgut Malformations Familial duodenal atresia ○ An autosomal recessive recessiv e mutation results in stenosis & atresia of the duodenum Lumen fails to recanulize recanulize ○ Associated wi th Down's, gastroschisis, gastroschisis, imperforate anus or intestinal intesti nal atresia ○ Diagnosis "Double- bubble" bubble" sign on x-ray due to dilation of the stomach and proximal proximal d uodenum ○ Treatment Duodenoduodenostomy/duodenojejunostomy Anastomosis of the proximal and distal small □ intestine intesti ne to bypass the obstruction obstruction Volvulus ○ Abnormal rotation of the midgut compromises blood flow Results in bilious emesis emesis in the newborn ○ Apple peel atresia ○ Distal portion of the proxi mal jejunum is coile d around a mesenteric mesente ric remnant Omphalocele Failure of gut to return to the abdominal cavity fol lowing lowi ng ○ herniation into the umbilicus Peritoneal Peritone al membrane covers intestine ○ Associated with: Beckwith-Wiedemann Beckwith-Wiedemann syndrome Gigantism, macroglossia & hypoglycemi a □ Pentalogy of Cantrell Diaphragmatic hernia, clef t sternum, sternum, absent □ pericardium and cardiac defects Often presents with el evated evated AFP ○ ○ Treatment is surgical reduction upon del ivery ivery Pyloric stenosis Result of el ongation and thickening thickening of the pylorus ○ ○ Associated wi th Turner's and Down's ○ More More common in 1st born males Increased risk wi th macrolide macrolide exposure exposure Presentation ○ Recurrent vomiting ( immediately immediately post-feeding) Leads to hypokalosi s/alkalosis □ "Olive "Oliv e mass" in the RUQ Jaundice "String/Apple core sign" on Barium swallow x -ray ○ Treatment is surgery Meckel'sd iverticulum iverticulum ○ Remnant of the vitel line duct connects the the umbil icus and and the ileum Digested f ood can exit through the umbilicus ○ Rule of 2's: 2% of the population 2 fe et from iliocecal junction 2 inches long
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General Gastroschisis ○ Failure of f usion of the e mbryonic mbryonic ventral fol ds which form the anterior abdominal abdominal wall ○ No sac covering the herniated bowel ○ Presents with el evated evated AFP ○ Treatment Surgical correction with temperature regulation, NG tube, antibioti cs and TPN
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Hindgut Malformations Problems wi th the urogenital septum Anal stenosis or atresia Imperforate anus ○ Rectum can merge with vagina or urethra ○ Anal agenesis Anal canal canal ends below pelvic diaphragm ○ Anorectal Anorectal agenesis Anal canal canal ends above above pelvic diaphragm Harder surgical surgical fi x
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Pancreatic Pancreatic Congenital Anomalie Anomaliess Ectopic pancreas ○ Extra pancreatic tissue Usually located in the stomach, duodenum, je junum, junum, il eum and Meckel's dive rticulum (if present) Pancreas divisum ○ Most common pancreatic anomaly ○ Failure of f usion of the major and minor pancreatic duct ○ Results in the bulk of the pancreas draining through the minor duodenal papilla Can cause pancreatitis ○ Annular pancreas ○ Dorsal and/or ventral folding fail ure ure results i n a pancreatic ring around around the duodenum Can cause obstruction
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Congenital Malformations of the GI Tract II •
Esophageal Malformations Esophageal atresia (EA) and a nd tracheoesophageal fistula fistula (TEF) Types ○ Isolated EA □ Esophagus ends in a blind pouch wi th no connections to the trachea EA with TEF of the proximal esophagus Esophagus ends in a pouch that connects to the trachea □ There is no connection connection betwee n the trachea and distal esophagus □ EA with TEF of the distal di stal esophagus Esophagus ends in blind pouch □ □ Distal esophagus connects to trachea EA with TEF of both proximal and distal e sophagus Proximal and distal esophagus esophagus connect to the trachea, but there is no direct □ connection betwee n the two segments TEF without EA Esophagus is continuous but has a small branch that conne cts to the trachea □ Presentation ○ Neonate s show coughing, cyanosis, and respiratory distress distress exacerbat ex acerbated ed by fe eding Late presentation prese ntation can involve recurrent pneumonia pneumonia due to fre quent aspirations aspirations Treatment is surgery ○
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Hirschsprung Dise Disease ase (HD) ( Congenital Megacolon) Absence of submucosa submucosa & myenteric neural plexuses plexuses lead l eadss to lack of pe ristalsis and complete complete large bowel obstruction Due to absence of neural crest cell mi gration gration ○ Associated wi th a mutation in the RET gene on Chr10q.11.2 Also associated wi th Down's syndrome ○ Presentation Always Alw ays involves the anus and then spreads proximally from there to varying degre es of severity ○ Can involve the entire colon Obstruction causes bowel bowe l dilation (congenital megacolon) megacolon) & failure of ne wborn to pass stool within ○ the first 48 hours hours of lif e Can also present with vomiting vomi ting and abdominal distension Diagnosis Diagnosis is via biopsy showing lack lack of ganglion cells in rectal tissue Treatment is surgical removal of the aganglioni c segment of intestine
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Abdominal Wall •
Landmarks Soft tissue ○ Linea semilunaris Lateral borders of the rectus abdominus muscle ○ Linea alba Midline Vertical fibrous band that extends from the pubic symphisis to the xyphoid process A weak linea alba can cause epigastric hernias Usually located superior to the □ umbilicus More common in men □ ○ Ingiunal ligament/inguinal groove Connects the ASIS to the pubic tubercle ○ McBurney's Point 2/3 from umbilicus to ASIS Located in the RLQ Appendi citis presents as pain here Also ide al for appendix removal □ Bony ○ Linea terminalis Runs along pectin pubis, arcuate line and sacral promontory Seperates the true & false pelvis
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Testes Migration Testes devel op retroperitoneally Attached to the gubernaculum ○ Attached inferi orly to the labial/sacral fold As the fetus/infant grows, the gubernaculum does NOT change length ○ The testes are pulled down through the i nguinal canal via their attachment to the gube rnaculum Migration fail ure (cryptorchidism)is associated with a high risk of testicular cancer As the testes/spermatic cord migrate into the scrotum they aquire layers of fascia (outside/in): 1. Skin 2. Dartos fascia & muscle i. Absent on the spermatic cord ii. Arises from Camper's fascia 3. External spermatic fascia i. From the external obli que muscle 4. Cremaster muscl & fascia i. From the internal obl ique muscle & fascia 5. Internal spermatic fascia i. From transversalis fascia 6. Tunica vaginalis (parietal & visceral layers) 7. Tunica albuginea i. Inside layer of the testes
Inguinal Canal Oblique passage through the inginal region Boundaries: ○ Deep inguinal ring Start of the canal Evagination of the transversalis fascia ○ Superfical inguinal ring End of the canal Trinagular opening in the aponeurosis of the external oblique muscle Lateral to the pubic tubercle ○ Anterior wall & roof Aponeurosis of the external and internal oblique muscles ○ Posterior wall & floor Aponeurosis of the inte rnal oblique and transversus abdominus muscles Form the inguinal & lacunar □ ligaments and conjoint tendon Transversalis fascia Contains: ○ Genital branch of the genitofemoral nerve ○ Ilioinguinal nerve ○ Spermatic cord (male) or round ligament (female) Pushes through the deep ingui nal ring, bringing the transversalis fascia with it Round ligament is a remnant of the gube rnaculum Spermatic cord ○ Contains: Artery of the ductus deferens Testicular artery Pampiniform plexus (veins) Ductus deferens □ Becomes the tail of the epi didymis
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Femoral Triangle Borders: ○ Inguinal ligament Superior ○ Sartorius muscle Lateral ○ Adductor longus muscle Medial Contains: ○ NAVEL (lateral to medial): N erve (femoral) Artery (femoral) V ein (femoral E mpty Lymphatics
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Abdominal Peritoneum and Viscera •
Peritoneum Parietal ○ Deepest layer of fascia Internal surface of the abdominopelvic wall ○ Sensitive to pain, touch etc. Intercostal and phrenic nerves (abdominal region) Obturator nerve (pelvic region) Visceral ○ Lines the organs ○ Insensi tive to pain, touch etc. Peritoneal cavity ○ Potential space between the two peritoneal layers ○ Lesser peritoneal sac Posterior to the stomach, liver and lesser omentum ○ Greater peritoneal sac Rest of the peritoneal cavity Surrounds intraperitoneal organs Communicates with the l esser sac via the Epiploic/Omental/Winslow's foramen □ Borders: Hepatoduodenal ligament Duodenum Posterior IVC Liver Mesentery ○ Double layer of peritoneum that contains vessels & nerves ○ Attaches organs to their specifi c blood supply and the abdominal wall ○ Attaches the small intesti ne to the posterior wall ○ Lesser omentum Attaches the liver, lesser curve of the stomach and duodenum Hepatoduodenal ligament attaches the liver to the duodenum Contains the Portal Triad □ Portal vei n Hepatic artery Bile duct Hepatogastric ligament ○ Greater omentum Hangs down over small intestine Attaches the greater curvature of the stomach, duodenum and transverse colon Gastrophrenic ligament Gastrocolicligament Gastrosplenic ligament
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Intra- and Extra-Peritoneal Organs Intraperitoneal viscera ○ Completely covered by peritoneum Transverse & sigmoid colon ○ ○ Stomach ○ 1st part of duode num ○ Small intestine Liver & gallbladder ○ ○ Tail of pancreas ○ Spleen Extraperitonealv iscera ○ Partially covered by peritoneum Rest of the duodenum ○ ○ Ascending & descending colon Head, neck & body of the pancreas ○ ○ Abdominal aorta ○ IVC ○ Kidneys, ureters and adrenals
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Peritone al Folds and Ligaments Ligaments are remnantsbeneath folds Supraumbilical ○ Falciform ligament Contains: Paraumbilical veins □ Round Ligament of the Liver □ Remnant of the umbilical vein Infraumbilical ○ Median umbilical ligament Obliterated urachus Medial umbilical ligaments ○ Obliterated umbilical arteries Lateral umbilical ligaments ○ Intact inferior epigastric arteries and veins
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Peritoneal Fossae Supravesical fossa ○ Caudal to median umbili cal ligament Medial inguinal fossa (Inguinal/Hesselbach's Triangle) ○ Between medial and lateral umbilical ligaments ○ A weak medial ingui nal fossa results in di rect inguinal hernias Lateral inguinal fossa Lateral to the lateral umbilical l igaments ○ ○ Weakness results i n indirect inguinal hernias
Autonomic Nervous System I •
General GI ANS Two major groups: Extrinsic ○ Parasympathetic Sympathetic ○ Intrinsic (Enteric Nervous System, ENS)
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Extrinsic Parasympathetic Supplied via the Vagus and Pelvic Splanchnic nerves Vagus ○ Provides sti mulation to the esophagus, stomach, gallbladder, pancreas, small intestine, and proximal half of the large intestine Pelvic splanchnic nerves ○ Arrise from S2-S4 ○ Innervate the di stal half of the large intestine Preganglionic fibers run all the way from the spinal cord to the target organ Postganglionic fi bers are withi n the target organ itself NT:Ach Parasympathetic stimulation increases the activity of the GI tract Contain stretch receptors
ExtrinsicSympathetic Arises at T5-L1 Preganglionic cell bodies are located in the lateral horn of the spinal cord (T5-L1) ○ Axons form the anterior root and combine to form the anterior ramus Anterior ramus axons synapse on Paravertebral ganglia/sympathetic trunk via white ramus Synaptic options: □ a) Synapse can occur at same level, or synapse above or below via ascending/descending symp athetic trunk b) Axons can exi t without synapsing and instead synapse on prevertebral ganglia around the abdominal aorta ◊ Celiac ganglion ◊ Superior mesenteric ganglion ◊ Aorticorenal ganglion ◊ Inferior mesenteric ganglion ○ NT: Ach Interacts with nicotinic receptors on the postganglionic neuron Postganglionic cell bodies are then either in the paravertebral or prevertebral ganglia ○ Axons that run from the paravertebral ganglia to the prevertebral gangl ia form the abdominopelvic splanchnic nerves Thoracic Splanchnic nerves: Greater Splanchnic nerve □ Origin is T5-T9 sympathetic/paravertebral ganglia Travels to the celiac ganglia □ Lesser Splanchnic nerve Origin is T10 & T11 sympathetic/paravertebral ganglia Travels to the superior mesenteric and aorticorenal ganglia Least Splanchnic nerve □ Origin is T12 sympathetic/paravertebral ganglia Travels to the renal ganglia Lumbar Splanchnic nerves: □ Origin is L1 & L2 Travels to the inferior mesenteric gang lia □ Postganglionic fibers then travel to indiv idual ○ organs/gut and synapse directly on them NT: NE Sympathetic stimulation of the GI tract is inhi bitory ○ Decreases motility and gland secretions Contain pain fibers
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Autonomic Nervous System II • •
Intrinsic Nerve pl exuses are contained entirely within the gut wall Two principle components: Myenteric (Auerbach's) plexus ○ Located betwe en the outer longitudinal and inner circular muscle layers Coordinates motility along the full le ngth of the gut wall Submucosal (Meissner's) plexus ○ Located in the submucosa □ Between the inne r circular muscle layer and muscularis mucosa Regulates se cretions, blood fl ow and absorption NT ○ Acetycholine Increases activity Vasoactive Intestinal Polypeptide (VIP) ○ Increases secretions and motili ty NE ○ Decreases ENS activity Motilin ○ Secreted by stomach, small intestine and colon ~every 100 minutes □ Unknown stimulus Increases motili ty NO ○ Relaxes smooth muscle Dysfunction can cause achalasia or Hirschsprung's dise ase
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Visceral Sensation Normal sensations include hunger and rectal distension Anything abnormal is percieved as pain "Cramping" pain ○ Different from parietal peritoneal pain, which tends to be sharp ○ Visceral pain is transmitted via sympathetic fibers Type C pain fibers ○ Colicky, cramping and poorly localized Results in referred pain ○ Due to embryonic origination and migration of blood suppl y and innervation from this area Heart: left arm/shoulder □ □ Esophagus: left chest □ Stomach, liver, gallbladder, small intestine, kidneys and colon all present with midline referred pain □ Ureters: right and left pel vic region
GI Tract I •
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General Contains 4 layers (inside -out): ○ Mucosa ○ Submucosa ○ Muscularis externa Serosa/adventitia ○
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Mucosa Epithelium ○ Stratifie d squamous or si mple columnar Lamina propria ○ Loose connective ti ssue that contains blood and lymph vessels Muscularis mucosa ○ Smooth muscle that functions in peristalsis Submucosa Made of fibrous connective tissue Contains lymph node s, large vessels andMeissner's plexus ○ Regulates secretions and blood flow
Oral Cavity Histology ○ Submucosa contains salivary glands Submandibular gland Contains both serous and mucous □ secretory cells Secretes hypotonic saliva: □ K+ Bicarbonate Innervated by CN VII □ Sublingual gland Composed of mucous cells □ Innervated by CN VII □ Parotid gland Composed of mostly serous cells □ α-amylase breaks down carbohydrates by hydrolysi ng α-1,4 bonds ◊ Innactivated by stomach pH Innervated by CN IX □ Tongue ○ Papillae: Filiform Contains no taste buds □ Conical and feathery shape □ Fungiform Contains a small amount of taste buds □ Mushroom-like shape □ Foliate Taste buds □ Von Ebner's glands □ Secrete lipase Leaf-like shape □ Circumvallate Taste buds and ducts of Von Ebner's □ glands Large, circular shape □ Sympathetic stimulation is via β-adrenergic receptors and increase viscous salivary secretions ○ Antichol inergic drugs (atropine) cause dry mouth
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Muscularis Externa Contains 2 layers of smooth muscle (insi de-out): ○ Inner circular layer ○ Longitudina l layer Auerbach's myenteric plexus is betwee n the two layers ○ Controls pe ristalsis Serosa/Adventitia Serosa ○ Made of loose connective tissue Covered wi th simple squamous ○ ○ Covers surfaces withi n the peritoneal cavity Adventitia ○ Made of loose connective tissue ○ Binds surfaces outside of the peritoneal cavity to the posterior abdominal wall
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GI Tract II •
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Esophagus Histology ○ Esophageal glands in the submucosa secrete mucus for lubrication and protection ○ Weakness in the muscularis externa at Killian's triangle can result in Zenker's Diverticulum Swallowing ○ Phase 1: voluntary Under cortical (medullary) control Tongue rolls food back to pharynx ○ Phase 2: pharyngeal Food bolus stimulates Nucleas Tract of Solitarius (NTS) Involuntary Inspiration is terminated, swallowing is initiated Glottis is blocked □ ○ Phase 3: esophageal Peristalsis moves bol us towards stomach Pressure is de creased in the UES to let the bolus through, then increased to prevent backflow Same for LES
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Stomach Anatomy ○ Cardia Attachment point for abdominal esophagus Contains cardiac glands that secrete mucus ○ Fundus Upper part of the stomach, cephalic to cardia ○ Body Continuation of the fundus Connects to pyloric antrum Parietal cells & chief cells secrete pepsinogen and IF ○ Pyloric Antrum is the most distal portion of the s tomach Connects to the pyloric sphincter □ G cells Histology ○ Mucosa throughout the stomach contains glands that secrete alkaline mucus Stimulated to PGE3 As a prostaglandin, PGE3 production is reduced □ by aspirin ○ Mucosa also contains chief cel ls, parietal cells, G cells, and EC cell s Chief cells Secrete pepsinogen, IF & gastric lipase □ Pepsinogen is converted to pepsin by HCl Pepsin digests proteins ◊ Errors produce celiac dise ase (undigestable gluten) or pancreatitis IF binds B12 Stimulated by gastrin and Ach (Vagus) □ Parietal cell s Secrete HCl □ Stimulated by histamine release induced by □ the combined action of Ach ( Vagus) and gastrin G cells Secrete gastrin □ Increases HCl secretion, pancreatic enzyme secretion and motili ty Stimulated by stomach distension □ EC cell s Secrete serotonin & substance P □ Increase gut motili ty Motility ○ Increased by gastrin, serotonin, su bstance P & distension Gastroenteric reflex also causes colon rel axation ○ Decreased by enterogastric reflex, CCK and secretin
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GI Tract III •
Small Intestine Duodenum ○ Superior is attached to mesentary and is the most common site of duodenal ulcers A posterior ulcer can result i n rupture of the gastroduodenal artery ○ Descending is fi xed retroperitoneally and receives the common bile duct and the main pancreatic duct via Hepatopancreatic (Vater's) ampulla ○ Horizontal is retroperitoneal ○ Ascending meets the jejunum and the duodenojejunal junction ○ Contains Brunner's glands that secrete bicarb to neutralize stomach HCl Jejunum ○ Has a larger diameter, simpl e vascular arcades and long vasa recta ○ Mucosa contains goblet cells, S cell s, Mo cells, I cells, L cells, K cells and Paneth's cells ○ S cells Secrete secretin in response to acid in the duodenum □ Increases pancreatic & bili ary bicarb and water secretion Decreases gastrin & acid release and □ stomach motili ty Mo cells ○ Secrete motilin Increases gut motili ty □ I cells ○ Secrete CCK □ Increases pancreatic enzyme secretion Gall bladder contraction □ Stimulated by fats & fiber in the duodenum L cells ○ Secrete GLP-1 Increases insulin secretion and □ decreases gastric acid release and stomach motili ty Secrete GLP-2 Stimulates growth of villi □ Stimulated by fats & fiber in the duodenum K cells ○ Secrete gastric inhibitory peptide Decreases gastric acid secretion □ ○ Paneth's cells Located i n crypts Secrete lysozyme Ileum ○ Contains compound arcades and short vasa recta ○ Ends at the ileocecal valve that connects the small intestine to the cecum (large intestine)
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Large Intestine (Colon) Histology ○ Contains lots of goblet cells ○ Epiploicappendages are tags of fat on the colon ○ Tenia coli are longitudinal bands of muscle ○ Haustra convolutions in the wall the slow feces movement Midgut derivations ○ All parasympathetic innervation is via the Vagus ○ Sympathetic innervations is from the aortic plexus or splanchnicnerves ○ Cecum Blood supply is via the il eocolic artery ○ Ascending colon Blood supply is via right colic artery ○ Transversecolon Blood supply is via middle colic artery Hindgut derivations ○ Sympathetic innervation is via aortic plexi or splanchnic nerves ○ Parasympathetic innervation is from S2- S4 ○ Descending colon ○ Sigmoid colon ○ Rectum Bordered inferiorly by the anorectal line □ Seperates the rectum from the anus Mucosa changes to stratifi ed squamous □ Anorectal angle is formed by □ puborectalis muscle ○ Anus Superior border is the anorectal line Just inferior to the anorectal line are anal columns The most inferior part of the anal columns contain anal sinuses Exude mucus when compressed to aid □ evacuation The pectinate line is just inferior to the anal sinuses and defines a divergence in blood supply, lymph & innervation Superior to pectinate line Inferior mesenteric artery □ □ Lymph drains superiorly to internal iliac nodes □ Nerves are visceral (non-painful) and vein is internal rectal Internal hemorroids are not painful Inferior to pectinate line □ Inferior rectal artery Lymphd drains to superficialinguinal □ nodes Nerves are somatic ( pain-sensitive) and □ vein is external rectal External hemorrhoids are painful
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GI Tract IV •
Liver Anatomy ○ Functional lobes Right & left Each has a primary branch from the hepatic artery, portal vein and hepatic duct ○ Anatomical lobes Right, left, caudate & quadrate ○ Lobule Radial arrangement of hepatocytes and si nusoids around a central vein to the portal triad ○ Visceral surface Ligamentum venosum is the remnant of the ductus venosum Continuous with the round ligament of the liver □ Remnant of the umbilical vein Bothare found wi thin the falciform ligament □ During fetal lif e, the ligamentum venosum connected the □ umbilical vein to the IVC Histology ○ Sinusoids Hepatic vessels that drain into the IVC Kupffer's cells □ Liver macrophages Endothelial cells that secrete bicarb ○ Space of Disse Between sinusoids and hepatocytes Ito cells □ Hepatic fibroblasts Hepatocytes ○ Function ○ Stores glycogen/gluconeogenesis ○ Detox by CYP450 enzymes ○ Secretes and synthesizes bile Blood supply ○ The live r has a dual blood supply that often protects it from ischemia ○ 20% from the hepatic artery ○ 80% comes from the portal vein/portal venous system Low in oxygen but high in nutrients as it comes directly from the spleen, intestine and colon Situated within the hepatoduodenal ligament Hepatic veins then drain into the IVC Portal vein anastomoses ○ Pathologies that cause portal HTN lead to varices and the use of collateral circulation ○ Esophageal varices Blood flow back through coronary veins to the esophageal venous plexus ○ Umbilical varices (Caput medusa) Blood backs up through the paraumbilical vein to the superior and infe rior epigastric veins ○ Rectum (hemorrhoids) Blood flows back through the superior rectal ve in to the middle and infe rior rectal veins
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Gallbladder Anatomy ○ Fundus ○ Body ○ Neck Connects to the cystic duct ○ Cystic duct joins the common hepatic duct to form the common bile duct ○ Common bile duct runs posterior to the head of the pancreas and joins the main pancreatic duct at the ampulla of Vater Function ○ Stores, concentrates and releases bile ○ Bile release is triggered by CCK Causes gallbladder contraction and relaxation of the sphincter of Oddi
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GI Tract V •
Pancreas Anatomy Extraperitoneal ○ Head □ Tip is the uncinate process Neck □ Overlies the SMV Body □ Overlies the aorta & L2 Intraperitoneal ○ Tail □ Passes through the splenorenal ligament Ducts ○ Main pancreatic □ Bile duct joins the main pancreatic duct forming the hepatopancreatic ampulla Enters the duodenum at the major duodenal papilla Accessory pancreatic Enters the duodenum and the minor duodenal papilla □ Superior to the major duodenal papilla Blood supply Celiac and SMA ○ Function Endocrine ○ Islets of Langerhans F cell □ Secrete pancreatic polypeptides that decrease exocrine pancreas secretions □ α cell Secrete glucagon G cell □ Secretes gastrin □ β cell Secretes insulin □ δ cells Secrete somatostatin which decreases GI & gallbladde r contractions Exocrine ○ Centroacinar cells Produce bicarb □ Stimulated by secretin □ Panreatic acinar cells Stimulaed by CCK and Ach □ Produce enzyme inhibitors that prevent self-digestion □ Produce digestive enzymes □ Amylase Lipase & co-lipase Proelastase, chymotrypsinogen, & procarboxypeptidase Trypsinogen ◊ Activated by enteropeptidase secreted in the duodenum ◊ Converted to trypsin ◊ Trypsin conve rts proelastase, chymotrypsinogen and procarboxypeptidase into elastase, chymotrypsin, & carboxypeptidase
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Liver I •
Hepatocytes Function ○ Synthesize bile ○ Produce serum proteins (albumin) ○ Uptake/synthesize chylomicrons Synthesize TGs ○ Produce plasma l ipoproteins ○ Drug, hormone and vitamin metabolism ○ Vitamin & mineral storage
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Bile Synthesis Bile i s made and secreted by hepatocytes Bile f unction ○ Emulsifi es lipids into micelles for easy absorption Bile synthesis requires the si mulataneous synthesis of phospholipids, cholesterol and bile salts Phospholipid synthesis ○ Indirect (Mechanism 1) Phosphatase converts phosphatidic acid to DAG Produces phosphatidylcholine and phosphatidylethanolamine ○ Direct (Mechanism 2) CTP reacts with phosphatidic acid to form CDP-DAG Produces phosphatidylinositol and cardiolipin Cholesterol synthesis ○ The rate limiting step is the conversion of AcetylCoA to mevalonate by HMG CoA Reductase Transcriptional regulation of this e nzyme is controlled by SREBP Proteolysis of HMGCoAR is increased by oligomerization Also target for statin drugs Bile synthesis Hepatocytes contain a bile canaliculus that ○ secretes bil e Stimulated by returning bile and secretin ○ Phospholipids increase the solubility of cholesterol, which is a necessary ingredi ent of bile Bile i s stored in the gallbladder ○ Bile salt synthesis begins when 7a-hydroxylase converts cholesterol to 7a-hydroxycholesterol ○ The addition of a conenzyme, taurine & glycine produces the final bile salts Taurocholic Glycocholic
Synthesis of TGs Done by h Glycerol ki nase converts glycerol of glycerol-3-phosphate (G3P) G3P is combined with two molecul es of AcylCoa to form TAG TGsare packed into chylomi crons for delivery to the rest of the body
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Carbon souces for gluconeogenesis: Lactate, Alanine, and Glycerol
Alcohol Metabolism First oxidation ○ Primary pathway Yields 13 ATP Occurs in the hepatocyte cytosol during the first couple drinks Alcohol dehydrogenase (ADH) converts EtOH to NADH & acetaldehyde Rate limiting step □ □ ADH2*3 is a variant among Native Americans that results in sickness/inefficient EtOH conversion ○ Secondary pathway Yields 8 ATP Occurs during excess EtOH in the ER MEOS induces CYP2E1, which converts EtOH to NADP+ & acetaldehyde Second oxidation ○ Acetaldehyde is converted to NADH & acetate by aldehyde de hydrogenasei n the liver mitochondria ALDH2 is a variant among East Asians that is less effi cient Produces "orie ntal f lush"/hangover □ Increased drinki ng history increases the amount CYP2E1 and decreases the amount of gastric ADH Acute effects ○ Increased NADH/NAD+ ratio: Induces ketogenesis and reduces gluconeogenesis □ Results in hypoglycemia, hyperuricemia, and lactic acidosis Inhibits FA oxidation Promotes FA & TAG synthesis □ □ "EtOH induced hyperli pidemia"/ "fatty liver" Chronic effects ○ Fatty live r Increased aldehyde ○ Toxic to liver mitochondria, heart, and skeletal muscle Accumulation leads to alcoholic hepatitis Results in fi brosis (irreversible) □
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Liver II • •
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Bilirubin/Heme Metabolism Heme is made in RBCs (covered in SBL) Reticuloendothelial system (RES) ○ Splenic destruction of old RBCs releases heme ○ Heme is oxidized to biliverdin by heme oxygenase ○ Biliverdin is reduced to bilirubin by bilive rdin reductase ○ Bilirubin is bound to plasma albumin and requires pyridoxal transported to the live r phosphate (B6) Liver ○ Hepatocytes conjugate bil irubin to glucoronic acid via UDP-glucuronyltransferase forming conjuga ted (soluable) bilirubin ○ Soluble bi lirubin i s excreted in bile ○ Some conjugated Intestine ○ Conjugated bilirubin is converted into urobilinogen by gut bacteria ○ Most urobili nogen is metabolized to stercobilinogenand then oxidized to stercobilin Stercobili n gives feces its' brown color ○ A small amount of urobilinogen is reabsorbed and excreted in the urine, along with the oxidized form urobilin Gives urine yel low color Kidney ○ Normally never filters any conjugated bilirubin Presence of urobi linogen is normal ○ Presence of conjugated bilirubin indicates liver damage Turns urine dark amber color
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Liver Protein Metabolism Nitrogen is transported to the l iver via glutamine and alanine Other proteins are simil arly degraded into AAs AA Catabolism keto acid and ammonia are produced ○ Types Oxidative deamination by dehydrogenase removes a NH2 group Transamination by transaminase transfers a to a keto acid recp NH2 group Dehydatase removes water, producing keto acids and ammonia Ammonia is removed via the urea cycle □ Urea cycle ○ 4 key enzymes: Ornithine transcarbamoylase Deficiency results in hyperammonemia □ Arginosuccinate synthetase □ Deficiency results in citrulinemia Arginosuccinase Deficiency results in arginosuccinic □ aciduria Arginase □ Deficiency results in hyperargininemia ○ Requires 3 ATP and 2 NH3 ( ammonia groups) and forms urea, which is excreted
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Alanine and Glutamine transport nitrogen to the liver
Inactivation and detoxification of Xenobiotics: -phase 1 rxns: polarity is increased (oxidation, red, hydroxylation, hydrolysis) -phase 2 rxns: functional groups are conjugated for safe excretion (sulfation, glucuronidation, methylation)
Acute Porphyrias: -Acute intermittent porphyria (AIP) -Variegate porphyria -Hereditary coproporphyria -gamma-aminolevulinic acid dehydrogenase deficiency porphyria Acute intermittent porphyria (AIP) -Caused by deficiency of porphobilinogen deaminase -Manifests w/ overproduction of porphyrin precursors -Increased in plasma and urine (red colored) -Symptoms include abdominal pain, constipation, muscle weakness -Autonomic dysfuction, peripheral neuropathy, encepalopathy, seizures -Treatment - intravenous hematin injections
These can cause back up of Heme
Small Intestine & Carbohydrate Metabolism •
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Small Intestine Main function is absorption ○ Brush border increases surface area and contains surface enzymes Non-fat, water soluble nutrients are absorbed through the intestine into the portal vein Fat-based nutrients into the mesenteric lymphatic system, bypassing the liver Duodenum ○ Absorbs: Water & ions Glucose & galactose Absorbed via Na+-dependent □ cotransporter SGLT1 Na+/K+ pump on the basol ateral □ side maintains a low Na+ gradient within the cell Exit the cell basolaterally via □ GLUT2 Lipids Emulsified by bile acids □ Absorbed and mixed with □ apoproteins to form chylomicrons Chylomi crons enter lymphatic □ system for systemi c distribution Vitamins A, D, E and K □ Proximal jejunum ○ Absorption continues Fructose Absorbed via facili tated diffusion □ through GLUT5 Exits basolaterall y via GLUT2 □ Protein □ Absorbed as tri-/ di- peptides and amino acids AA have specifi c Na+dependent cotransporters Terminal jejunum Water-soluble vitamins ○ Ileum ○ Protein absorption continues B12 absorption ○ Majority of water is reabsorbed in the j ejunum and ileum
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Carbohydrates Disaccharides ○ Types Lactose Glucose + galactose □ Digested by lactase □ Error causes lactoseintolerance Flatulance/diarrhea Sucrose Glucose + fructose □ □ Digested by sucrase- isomaltase ○ Disaccharidases (glycosidases) occur at the brush border of the small intestine Monosaccharides ○ Types Aldose □ Glucose Galactose □ Accumulation is due to errors in either galactokinase or galactose-1-P UDT ◊ Leads to failure-to- thrive, cataracts, jaundice and mental retardation Absorbed via Na+ dependent □ transporters Ketose Fructose □ Aldolase B deficiency leads to fructose intolerance ◊ Futile cycling, hypoglycemia and ATP depletion Absorbed via facili tated transporter □ GLUT transporters ○ GLUT1 Found on RBCs and brain ○ GLUT2 Located on liver, pancreas, and basolateral side of enterocytes Has a High Km Only pumps when concentration is high □ ○ GLUT3 Located in the brain ○ GLUT4 Located in adipose tissue and skele tel muscle Translocated to the membrane by insulin ○ GLUT5 Located on the lumenal si de of enterocytes
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CNS/GI Interations •
Hypothalamus Hormones ○ Anorexigenic hormones Decrease hunger CCK Serotonin □ Glucostats in the hypothalamus accumulate ATP during fed state Results i n K+ accumulation and release of serotonin (decreasing hunger) Leptin Made by adipocytes □ ○ Orexigenic hormones Increase hunger NPY Agoutirelated peptide (AGRP) Ghrelin Secretion increases with time □ Produced by the stomach □ Regions ○ Lateral Associated with hunger Stimulated by NPY & AGRP Inhibited by hepatic chemoreceptors & gut mechanoreceptors ○ Medial Activated by hepatic chemoreceptors Ventromedial □ Associated with satie ty □ Activated by leptin (via the arcuate nucleus) , serotonin, CCK & gut mechanoreceptors Dorsomedial Stimulation increases metabolism □ ○ Arcuate nucleus Serves as a relay from periphery to medial & lateral regions □ Mostly stimulates lateral region (hunger) Stimulated by ghrelin Produces NPY & AGRP
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Emetic Response PNS ○ Gastric irritants ○ Vagus stimulation CNS ○ Labyrinthe disorders ○ Trauma ○ Increased ICP ○ Duodenal chemoreceptors Activated by Ipe cac syrup ○ Chemorece ptor Trigger Zone (CTZ) Located on the dorsal surface of the medulla Activated by: □ NT Dopamine Gastrin Histamine Drugs □ Digoxin Opiates Nicotine Cancer chemotherapy □ Metabolism Uremia Diabetic ketoacidosis Hypoxia Hypercalcemia
Hernias •
InguinalHernias Direct ○ Medial to the inf erior epigastric vessels ○ Pushes directly through the abdominal floor Through the medial inguinal fossa ○ ABSENT hernia sac (peritoneum) Indirect ○ Lateral to the infe rior epigastric vessels ○ Due to a patent processus vaginalis Pushes through the lateral inguinal fossa and the deep & superficial inguinal ring PRESENT hernia sac ○
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Miscellaneous Hernias Richter's Hernia ○ Any bowel containing hernia that incorporates the intestinal wall Can cause perforation Epigastric Hernia ○ Occurs through the linea alba above the umbilicus ○ 2-3x more common in males Spigelian hernia ○ Occurs below the umbili cus but above the infe rior epigastric vessels along the semilunar line Incisional hernias ○ Surgical herniations ○ Due to: Excessive tension (obesity) Infection Increased pressure (COPD) Tobacco Poor technique
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Hiatal Hernias Due to weak esoph ageal hiatus (T10) Sliding ○ Abdominal e sophagus and stomach (cardia and fundus) herniate into the thorax Results in HERD and PUD ○ Paraesophageal ○ Defect in the diaphragm next to the esophageal hiatus allows the f undus of the stomach to herniate ○ Can threaten the blood supply to the fundus
Hernia Subtypes Reducible ○ Most common type Usually painless ○ ○ Treatment Reduction Patient i s sedated/analgesia □ Pressure is applied medially while □ simultaneously invaginating the distal hernia sac Incarcerated (irreducible) ○ Due to painful enl argement of a previous hernia ○ Hernia sac protrudes through a tight muscular ring Cannot be manipul ated/reduced Strangulated ○ Additional symptoms Hernia sac can appear toxi c/necrotic due to compromised blood supply Intensly painful and at high risk for perforation ○ Surgical emergency
Femoral Hernia Bulge through the femoral canal within the fe moral sheath ○ Medial to the femoral vein ○ Below the inguinal li gament, lateral to the pubic tubercle More common in female s
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Esophageal Disorders •
Obstructions Diverticula Saccular outpouchings ○ ○ Zenker's Located above the circopharyngeus muscle Muscle weakness at Killian's triangle ○ Presentation Emesis of undigested food Barium swallow is diagnostic Schatski's Ring ○ Presents as regurgitation of undigested food ○ Due to a submucosal/mucosal tissue ring near the LES ○ Associated with GERD and hiatal hernias Achalasia ○ Defined as "failure to relax" of the LES Etiology ○ Primary Absence of ganglionic cells i n the myenteric □ plexus Secondary Destruction of the myenteric plexus due to □ Chagas' disease (T. cruzei ) ○ Presentation Progressive dysphagia and nocturnal re gurgitation Barium swallow shows dil ated proximal esophagus is distal "bi rd-beak sign" narrowing
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Esophagitis Lacerations ○ Mallory-Weiss tears Due to prolonged vomiting "Coffee grounds" vomit □ Chemical induced ○ Such as lye, acids, detergents ○ Will shows a lack of neutrophils Infectious ○ Presentation Dysphagia and odynophagia Neutrophils on biopsy Risk factors ○ Diabetes, malnutrition, cancer, immunosuppressed and alcoholism Etiology ○ CMV □ Shallow ulcers Nuclear inclusion bodies □ Herpes Punched-out ulcers □ Nuclear inclusion bodies □ GERD
GERD Abnormal relaxation of the LES leads to gastric contents refluxing into the esophagus ○ Causes injury and chronic infl ammation Etiology ○ CNS depressants ○ Obesity ○ Alcohol & tobacco ○ Pregnancy ○ Hiatal hernia Presentation ○ Heartburn ○ "Sour taste" Morphology ○ Eosinophils Basal zone hyperplasia ○ ○ Deep red mucosa (hyperemia) Complications ○ Ulceration ○ Strictures ○ Barrett's esophagus Squamous cell metaplasia (to columnar & goblet cell s) Can lead to adenocarcinoma GERD is the probable cause of "colic" in pediatrics Child loves milk; healthy yet unhappy; does ○ well when upright, poor when down; Treatment ○ Lifestyle ○ PPIs ○ H2 blockers
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Esophageal Cancer Moe common in blacks, males and lower socioeconomic status ○ Diet related/vitamin deficiency : A, C, folate, E, B12 and riboflavi n Presentation ○ Dysphagia Weight loss ○ ○ Hematemesis/N/V ○ Hoarseness/cough SCC ○ Specific etiology Smoking, EtOH, nitrites, smoked opiates, fungal toxins, radiation, l ye and HPV ○ Located in the upper and middle esoph agus Adenocarcinoma ○ Specific etiology GERD ○ Located in the lower esophagus ○ Contains signet-ring morphology Treatment is esophagectomy
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Stomach Disorders I • •
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Gastritis Inflammation of the gastric mucosa Presentation ○ Abdominal pain and dyspepsia Acute ○ Etiology NSAIDs Stress Helicobacter pylori EtOH Chemo/radiation ○ Acute gastric ulceration Curling ulcers Located in the proxi mal duodenum □ Associated the burns/trauma □ Cushing ulcers □ Located in the stomach, duodenum and esophagus Associated with head □ trauma/intracranial disease Chronic ○ Etiology Type A Autoimmune gastritis □ Autoantibodies target parietal cells resulti ng in lack of IF (pernicious anemia) ◊ B12 deficiency Type B Due to Helicobacter pylori □ Urease of H. pylori degrades urea into ammonia, which is erosive to the stomach lini ng ○ Increased risk of gastric adenocarcinoma
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Hypertrophic Gastropathies Hyperplasia without inflammation Zollinger-Ellison disease ○ A tumor/gastrinoma of G cells (non- β-cells) of the pancreas produces a huge amount of gastrin Results in parietal cell hyperplasia and massive HCl production ○ Presentation Recurrent ulcers of upper GI tract (stomach, jejunum etc.) Steatorrhea/diarrhea Menetrier's disease ○ Hyperplasia of mucus-secreting cells results in rugal hypertrophy and atrophy of parietal cel ls ○ Presentation Weight loss Hypoproteinemia Diarrhea Edema ○ Increased risk of adenocarcinoma
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Peptic Ulcer Disease Ulcer formation in the stomach are 1st part of the duodenum secondary to mucosal di sruption Etiology is simil ar to gastritis ○ EtOH ○ Stress ○ Tobacco ○ NSAIDs ○ Helicobacter pylori Presentation ○ N/V ○ Acute abdominal pain ○ Hemorrhage Complications ○ Obstruction Perforation ○ Anterior will present as air in the peritoneal cavity Posterior will often rupture the gastroduodenal artery, resulting in hemorrhage Common in the elderly □ Presents with severe,sudden epigastric □ pain radiating to the right scapula Absent bowel sounds Rigidity with reboundpain Treatment is prompt surgery □ Treatment ○ Lifestyle ○ PPI, bismuth, sucralfate, PGE analogs and antibiotics against H. pylori
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Stomach Disorders II • •
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Stomach Cancer Second most common cause of cancer-rel ated deaths worldwide 85% are adenocarcinomas, 15% are l ymphomas or leiomyosarcomas ○ Stomach is the most common extranodal site for lymphoma formation Etiology ○ Helicobacter pylori ○ Tobacco ○ EtOH ○ Diet Carbohydrate rich High salt Pickled foods High nitrates (well water) Presentation ○ Upper abdominal pain ○ Weight loss ○ N/V ○ Dysphagia ○ Anemia Metastasis ○ Typically spreads locally to adjacent organs and peritoneum Left supraclavicular node (Virchow's node) ○ Ovaries (Krukenberg's tumor ) ○ ○ Umbilicus (Sister Mary Joseph's sign) Morphology Mucin lakes ○ Signet rings ○ Treatment ○ Surgery, radiation & chemo
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Small & Large Intestine I •
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Malabsorption Syndromes Presentation Diarrhea and steatorrhea ○ ○ Weight loss Vitamin & mineral def iciencies ○ Celiac sprue Tropical sprue ○ Occurs in tropical areas Unknown etiol ogy ○ Thought to be infectious Presents wi th similar symptoms of all ○ malabsorption syndrome Disaccharidase deficiencies Lactase ○ Whipple's disease ○ Secondary to infection by Tropheryma whippelii ○ Presentation Malabsorptive symptoms Fever Polyarthralgias ○ Morphology Distended lamina propria fil led with PAS+ macrophages with foamy cytoplas Abetalipoproteinemia Autosomal recessive mutation results in ○ a lack of ApoB Causes TG accumulation Pancreaticinsufficiency CF ○ Pancreatitis ○ Cirrhosis ○ Bile duct obstruction ○ Exogenous Laxatives ○ Antacids/Mg++ ○ Drugs ○ Diuretics ACEI H2 blockers Cochicine Toxins ○ Cola Coffee Mushrooms EtOH Infection/bacterial toxins ○
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Diverticular Disease Diverticulosis Formation of pouches (diverticula) in the sigmoid colon ○ Diverticulitis Inflammed diverticulosis ○ ○ Etiology Infection secondary to an impacted fecalith Diverticular rupture Presentation ○ LLQ pain Often with peritoneal signs (rebound □ tenderness) Fever Constipation LGI bleed Maroon stool □ Due to artery rupture into the dive rticula □ Barium enema and endoscopy are contraindicated due to possible perforation ○ Treatment IV hydration & antibioti cs
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Appendicitis Due to obstruction of the appendi ceal lumen by fe ces, a stone or lymphatic tissue Presentation ○ N/V Weight loss ○ ○ Acute abdominal pain Initially pe riumbilical but migrates to the RLQ over McBurney's point Rovsing's sign ○ Pain in RLQ upon palpation of left side Obturator sign ○ Pain on internal rotation of the right hip Iliopsoas sign ○ Pain on extension of the right hip Treatment is surgical removal
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Small & Large Intestine II •
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Bowel Obstruction Presentation ○ Diffuse abdominal pain Vomiting ○ ○ Constipation Can lead to perforation Mechanical (Dynamic) ○ Intraluminal Impacted feces Foreign body Gallstones ○ Intramural Tumor Inflammatory strictures Congenital atresia ○ Extraluminal Adhesions & hernias Past surgical procedures □ Frequently cause small bowel □ obstruction (SBO) Intussusception □ Telescoping of proximal bowel into distal segment Most common in children <2 □ Associated with rotavirus infection □ Other cases occur when peristal sis pulls on a segment of bowel instead of feces Cancer must be ruled out Presents with red-jelly stool, pain, and □ palpable sausage-shaped mass Treatment is an enema (barium or air), □ surgery if required Adynamic ○ Due to paralytic ileus (absence of peristalsis) ○ Will show gas in the rectum or sigmoid on x -ray SBO ○ Air present in the small bowel ○ No air in the large bowel on x-ray ○ No air in the rectum or sigmoid colon LBO No air in the small bowel ○ ○ Air in the large bowel ○ No air in the rectum or sigmoid colon
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Pseudomembranous Colitis ( Antibiotic-Associated Colitis) Acute infl ammation of the colon fol lowing a course of broad-spectrum antibiotics ○ Frequently flouroquinolones & cli ndamycin ○ Long-term antibiotics kills normal gut flora Increased undi gested carbohydrates causes an increased osmotic load □ Watery diarrhea Symptoms ○ Watery diarrhea ○ Pseudomembranes ○ Fever Severe ○ Bowel perforation Toxic megacolon Causative organism is C. difficile ○ Resistant to broad-spe ctrum antibiotics Treatment ○ Mild to moderate Metronidazole ○ Se Vere Vancomycin
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Small & Large Intestine III •
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Irritable Bowel Disease Presentation ○ Diarrhea & malabsorption ○ Ulcerations & blee ding ○ Acute abdominal pain & mucosal inflammation ○ Erythema nodosum More common in females Crohn's disease (CD) ○ Triggered by aerobicbacteria ○ Increased risk in smokers ○ Location Entire GI tract Mostly terminal ileum and colon □ Rectal sparing "Skip lesions" (discontinuous) □ ○ Morphology Transmural Non-caseating granulomas TH1 disease IL-12, TNF & IFN -γ □ ○ Systemic symptoms Arthralgia, arthritis and uveitis ○ Complications Obstruction Ulcerative colitis (UC) ○ Triggered by anaerobic bacteria Could also be autoimmune ○ Increased risk in ex- smokers ○ Location Rectum & colon Continuous □ ○ Morphology Confined to the mucosa & submucosa Ulcers & pseudopolyps TH2 disease IL-4 & IL-5 □ ○ Systemic symptoms Pyoderma, iritis and sclerosing cholangitis ○ Complications Increased risk of colo n cancer Toxic megacolon Treatment ○ Mild to moderate 5-ASA & corticosteroids ○ Severe IV hydration & steroids Antibiotics Monoclonal antibodies Colectomy for severe UC
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IBD (cont.) Result of i nappropriate immune reaction to normal gut flora ○ Controlled by: Genetics Enviornment Loss of microbial tolerance Genetics ○ Uncommon in Asians & Africans Enviornment ○ Smoking Increases small bowe l permeability and colonic mucus production Reduces mucosal cytokine p roduction Promotes leukocyte adhesion ○ Stress ○ Diet ○ Drugs Oral contraceptives & NSAIDs increase risk of IBD ○ Social High amony socioeconomic groups Characteristics ○ Intermittent remission & relapse ○ Antibodi es against bacteria ○ Increased gut permeability Bacteria components cross mucosal barrier Induces immune response □ ○ Mucosal inf lammation
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Irritable Bowel Syndrome (IBS) Simil ar to IBD Symptoms ○ Diarrhea or constipation ○ Recurrent discomfort with: Improvement with defecation Change in stool frequency Change in stool character Common in young females Pathogenesis ○ Abnormal gut motili ty ○ Visceral hypersensitivity ○ Stress ○ Genetics Treatment ○ Diet ○ Fiber
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Colorectal Cancer • •
Benign and Hereditary Polyps Protrusion of tissue above the mucosal surface Benign (hamartomatous) ○ Juvenille polyps Located in the rectum Smooth, peduculated with many glands Increased risk of aden ocarcinoma Herditary ○ Peutz-Jeghers Autosomal dominant Hyperpigmented mucocutaneous arborizing polyps Oral mucosa, hands & genitals □ Hamartamatous colon polyps Arborizing polpys of smooth muscle Increased risk of adenocarcinoma and intussusception ○ Famili al adenomatous polyposis (FAP) Autosomal dominant mutation in APC Have 100+ colorectal polyps 100% of colorectal cancer without colectomy ○ Gardner's syndrome Autosomal dominant Multiple ade nomatous colon polyps in cinjuction with othe r tumors Osteomas of the mandible and skull □ ○ Turcot's syndrome Autosomal recessive syndrome associated with coloni c polyps and tumors of the CNS Especially gli oblastoma multiforme and □ medulloblastoma
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Colorectal Cancer Usually adenocarcinoma Second most common cause of cancer deaths in the US Etiology ○ Colon polyps ○ High fat/meat diet ○ Low fiber diet ○ Tobacco/EtOH ○ Age ○ UC ○ HPV (rectal) HNPCC (Hereditary Nonpo lyposis Colorectal Cancer) ○ Autosomal domi nant disorder that causes cancer ○ Mutation in DNA mismatch repair gene hMLH1 or hMSH-2 Metastasis sites ○ Liver (colon) ○ Lung (rectum) ○ Peritone um & pelvis Left-sided colon cancer symptoms Bloody stools Pencil -thin stools "Napkin ring" or "apple core" constriction Right-sided colon cancersymptoms Anemia RLQ pain Occult blood in stool Rectal cancer symptoms Bright red bloody stools Tenesmus (painful/difficult defecation)
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Neoplastic Polyps Neoplastic (adenomatous) ○ By defintion, adenomatous polyps are dysplastic and precancerous ○ Classification Sessile On wall □ Pedunculated On a stalk □ ○ Tubular Most common Neopl astic glands of rounde d/tubular, dark red and can ulcerate 5% cancer risk ○ Villous Highest rate of cancer conversion( 40%) Neopl asms are cauliflower-like Neoplastic (squamous) ○ Rare ○ Arises in the anal canal
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Jaundice •
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General Serum bili rubin > 2.0 ○ Yellowed skin or sclera Etiology ○ Neonatal Bile obstruction ○ ○ Liver disease ○ Hyperbilirubinemia (genetic) Jaundice w/conjugated bilirubin: ○ Elevated direct serum bilirubin ○ Elevated urine bil irubin ○ Urine urobilinogen is normal ○ Hepatocellular diseases: Dubin-Johnson's syndrome Rotor's syndrome ○ Bile duct obstruction Gallstones Tumors Primary sclerosing cholangitis Parasites Jaundice w/unconjugated bilirubin: ○ Elevated indirect serum bilirubin Absent urine bilirubin ○ ○ Elevated urine urobilinogen ○ Hemolytic diseases ○ Inherited hepatocellular disease Crigler-Najjar (Type 1 & 2) Gilbert's syndrome ○ Aquired hepatocellular disease Cirrhosis Hepatitis Drugs Liver failure
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Neonatal Etiology (benign) ○ Relative deficiency in glucuronyl transferase in the immature liver ○ Hemolysis f rom mild trauma during birth Etiology (pathol ogic) ○ Erythroblastosis fe talis Rh- mom & Rh+ second-chil d ○ ABO blood type diff erence Hypothyroidism ○ Large tongue, poor muscle tone & shallow hair line ○ Obstructive Treatment ○ Phototherapy ○ Transfusion
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Hyperbilirubinemia Direct (conjugated) hyperbilirubinemia ○ Dubin-Johnson's syndrome Autosomal recessive de fect in the ABC transporter impairs hepatic bi lirubin secretion "Black liver" Treatment is usually not neces sary Phenobarbitol can be used in extreme cases □ Induces UDP-glucuronyl transferase ○ Rotor's syndrome Autosomal recessive disorder similar to DubinJohnson's syndrome Defects in he patocellular uptake and secretion of bilirubin Grossly liver is normal Patients respond well to phe nobarbitol Indirect (unconjugated) hyperbilirubinemia ○ Gilbert's syndrome Most common Reduced activity/amount of UDP-glucuronyl transferase Intermittent periods of j aundice are triggered by stress ○ Crigler-Najjar Syndrome (Type 1) Autosomal recessive disease characterized by absence of UDP-glucuronyl transferase Severe form Patient will develop kernicterus (bilirubin □ encephalopathy) without prompt treatment Bile is colorless Treatment Phototherapy □ Transfusions □ Liver transplant □ □ Unresponsive to phenobarbitol ○ Crigler-Najjar Syndrome (Type 2) Autosomal recessive disease characterized by partial lack of UDP-glucuronyl transferase Less severe Treatment Phototherapy □ □ Phenobarbitol
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Hepatitis & Cirrhosis •
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Hepatitis Presentation N/V ○ Fever ○ Jaundice ○ ○ Weight loss ○ Hepatomegaly ○ RUQ pain ○ Fatigue/malaise Labs ○ Elevated: LDH Indirect serum bilirubin Alkal ine phosphatase WBCs More so in viral hepatiti s □ Prothrombin time AST & ALT ○ Reduced: Albumin Platelets Viral hepatitis No fatty live r stage ○ Viral antibodies ○ IgM first, foll owed by IgG ○ Progresses to cirrhosis ○ AST << ALT Alcoholic hepatitis ○ More common in black w omen ○ Fatty liver Microvesicles give the liver a yellow, greasy appearance Progresses to alcoholic hepatitis and ultimatel y cirrhosis Morphology ○ "Ballooning" of hepatocytes Hepatocyte death Mallory hyali ne inclusion bodies Neutrophil infiltrate Fibrosis ○ AST >> ALT ○ Treatment EtOH rehabili tation Vitamin supplementation □ Thiamine, folate and vitamin K
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Cirrhosis Extreme fibrosis and architectural disruption of the liver Irreversible ○ Extensiv e collagen type I & III deposition i n the space of Disse Shunts blood from portal veins to hepatic veins, ○ bypassing the sinusoids Morphology ○ Bile stasis ○ "Hobnail" brown, shrunken liver Non-fatty Etiology ○ Progressive he patitis Viral, EtOH etc. Hemochromatosis ○ Wilson's disease ○ ○ Heart failure Additional symptoms ○ Impaired liver function Jaundice and pruritis Hypoalbuminemia Hyperestrogenism Spider hemangiomas □ Palmar erythema □ Gynecomasita □ Hypogonadism □ Anemia (from folate deficiency) Coagulopathies (f rom decreased clotting factors) ○ Portal hypertension Venous shunts Hemorrhoids □ Caput medusae □ Esophageal varices □ Splenomegaly resulting in thrombocytopenia ○ Ascites and peripheral edema Hypoalbuminemia decreases i ntravascular oncotic pressure Portal hypertension increase venous hydrostatic pressure ○ Hepatic encephalopathy Accumulation of toxi c metabolites (ammonia) due to shunting of blood around liver Asterixis Extemity tremors with wrist extension & □ dorsiflexion Treatment Banding of esophageal varices ○ ○ Paracentesis (draining ascitic flui d) ○ Supportive Low protein di et Vitamins Toxin avoidance Salt restriction and diuretics for edema
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Hemochromatosis & Wilson's Disease •
Hemochromatosis Autosomal recessive disorder characterize d by increased inte stinal iron absorption Mutations affect the HFE gene ○ HFE causes decreased affini ty for transferrin receptor to bind transferrin Excessive serum iron leads to deposition and damage to other organs Liver, pancreas, heart, joints and pituitary ○ gland Presentation Manife sts in 6th decade ○ Weakness & weight loss ○ Abdominal pain ○ Loss of li bido ○ Arthritis ○ Joint deposition Cirrhosis ○ Results in hepatomegaly DM-1 ○ Due to iron deposition i n pancreatic islet cells ○ HF Genetics ○ Type I:classic Mutation in HFE-1 C282Y (90%) □ H63D (10%) □ ○ Type II: juvenill e Mutation in HAMP (severe) or HJV Manife sts in 2nd decade Type III ○ Mutation in transferrin receptor Type IV ○ Mutation in ferroportin Autosomal dominant Treatment Phlebotomy ○ Chelation ○ Deferoxamine
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Wilson's Disease Autosomal recessive disorder characterize d by excess serum copper le ading to deposition in the liver, brain, kidneys & cornea Etiology ○ Mutation in ATP7B gene on Chr13q.14.3 Encodes a ATPase that transports copper into bil e and incorporates it intoceruloplasmin Presentation ○ Childhood or young adult onset Liver ○ Jaundice Amenorrhea & spontaneous abortions in women Hepatitis or cirrhosis ○ Cornea Keyse r-Fleischer rings Excess Cu++ deposition around the □ cornea Brain ○ Bradykinetic and hyperkinetic features Resting or postural tremors □ Chorea □ Rigidity □ Dysarthria & dysphagia □ Ataxia □ Personality/behavioral changes Dementia Psychosis/hallucinations Treatment ○ Chelation Penicillamine ○ Dietary Cu++ restricti on
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Liver Cancer • •
General Most common liver tumors are metastatic Benign ○ Hepatocellular adenoma (HA) Pale, ye llow/tan grossly with cords of hepatocytes Linked to oral contraceptives Usually located on the right lobe Palpable and painful Absent Kupffer cells ○ Focal nodular hyperplasia Well-demarcated yellow tumor with a white, central "stellate" scar Present Kupffer cells Malignant Hepatocellular carcinoma, HCC ○ Presentation RUQ pain □ Hepatomegaly □ Weight loss □ AFP & ALP elevation □ Diagnosis is based on i maging and biopsy Risk factors Cirrhosis and hepatitis □ Hep B or C virus □ Oral contraceptives □ Hemochromatosis □ Primary biliary cirrhosis □ Metastasizes to the breast, lung, pancreas and colon Cholangiocarcinoma ○ Increased risk due to liver f lukes Metastatic ○ Usually from the colon, stomach, pancreas, breast, and lung
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Gallbladder Disease • •
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Cholelithiasis Gall stones Risk factors (5 F's) Fat ○ Female ○ Forties ○ Fertile ○ Fair-skinned ○ Types of stones Cholesterol ○ Mostly radioluscent Mixed ○ Composed of cholesterol and pigment (bilirubin) Radioluscent Pigmented ○ Composed of bilirubin Radiopaque Presentation RUQ pain that is worse after meals ○ N/V ○ Fatty food intolerance ○ Diagnosis Ultrasound ○ Complications Cholecystitis ○ Choledocholithiasis ○ Cholangitis ○ Pancreatitis ○ Treatment Cholecystectomy ○
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Gallbladder Cancer Risk factors Cholelithiasis ○ Parasites ○ Primary sclerosing cholangitis ○ Presentation Jaundice ○ Hepatomegaly ○ RUQ pain ○ Dark urine ○ Light stools ○ Weight loss ○ Pruritis ○ N/V ○ Treatment Whipple ○
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Cholecystitis/Cholangitis Gallbladde r/bile duct inflammation Usually due to cholelithiasis Presentation Similar to cholelithiasis ○ Charcot's triad ○ RUQ pain □ May radiate to the right scapula ( Boas sign) Jaundice Fever Murphy's Sign ○ Abrupt arrest of inspiration upon palpation of RUQ Sclerosing cholang itis Caused by fibrosis, thickening and strictures of the bile ○ duct Primary ○ Associated with UC Secondary ○ Post surgery, trauma or chronic pancreatitis Often prese nts with hepatomegaly ○
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Pancreatitis & Pancreatic Cancer •
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Acute Pancreatitis Activation of pancreatic enzymes le ads to pancreatic autodigestion and hemorrhagic fat necrosis Etiol ogy (GET SMASHED) ○ Gallstones Duct obstruction ○ EtOH Increases ex ocrine pancreatic secretions Contracts sphincter of Oddi ○ Trauma/shock Stenosis/spasm of the Sphincter of Oddi ○ ○ Mumps ○ Autoimmune Scorpion sting ○ Hypercalcemia/hyperlipidemia ○ ○ ERCP ○ Drugs Presentation ○ Sudden onset, acute abdominal pain Radiates to the back and flanks A/N/V ○ Jaundice ○ Complications ○ DIC Hemolysis ○ ○ Shock Treatment Total oral restriction ○ Pain management ○ Meperidine Won't cause spasm of sphincter of □ Oddi (unlike other opiods)
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Chronic Pancreatitis Similar etiology as acute pancreatitis EtOH ○ ○ CF in children Additional symptoms ○ Weight loss ○ Steatorrhea Doubles the risk of pancreatic cancer Treatment ○ EtOH abstinence Analgesics ○ ○ Enzyme therapy ○ Surgery
Pancreatic Cancer Adenocarcinoma of the ex ocrine pancreas Risk factors Smoking ○ Chronic pancreatitis ○ ○ Obesity ○ Hereditary K-RAS mutation Presentation ○ Courvoisier's sign Painle ss obstructive jaundice Weight loss ○ ○ N/V ○ Trousseau's sign Migratory thrombophlebitis & hypercoaguability Diagnosis Tumor marker CA 19-9 ○ Treatment ○ Whipple (pancreaticoduodenoectomy)
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Hep B • •
DNA virus, double stranded Viral Ags ○ HBsAg Surface antigen, l ipoprotein coat ○ HBcAg Core antigen, capsid ○ HBeAg E antigen, 2nd epitope with the core Ag Epidemiology Blood, vaginal secretions, semen, breast ○ milk and saliva Treatment Recombinant human IFN ○ Control and prevention ○ Vaccine ○ Post-ex posure therapy Hepatitis B immune globul in (HBIG) ○ Screening of donated blood
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Pathogenesis Liver is only site of vi ral replication Damage to liver cells is immune mediated ○ Due to release of toxi c substances from infiltrating mononuclear cell s Viral replication doesn't cause significant liver cell damage An eff icient immune response involving T cytotoxic cells kills viral infected cells and rids the body of HBV Chronic infections occur when CTLs are inef ficient at killi ng viral infected cells ○ Indivi duals who have decreased IFN production ○ IFN upregulates MHC-I all owing CTLs to recognize infected cells ○ Without MHC-I upregulation virus persists
Signs and Symptoms 1/3 of cases are asymptomatic 1/3 are mild 1/3 are severe ○ Jaundice ○ Dark urine ○ Abdominal pain Fever Abdominal pain Nausea Malaise Vomiting Fatigue and anorexia
Outcome Acute ○ 90% of infections ○ Full recovery Chronic Two forms: ○ 1. Persistent Asymptomatic □ 2. Active Symptoms of chronic □ liver disease Jaundice □ Elevated serum liver □ enzymes and bil irubin Persistent virus shedding □
Antacids
CLASS
MOA
EFFECT
AE
Non-Systemic Aluminumsalts
Combine w/H+ & increase LES tone
Onset:slow, DOA:short, ANC:weak
Constipation, hypernatremia, hypophosphatemia
Non-Systemic Calcium-salts
"
Onset:rapid, DOA:long, ANC:very good
Constipation, hypercalcemia (Milk Alkal i syndrome: nephropathy & metabolic alkalosis), hypophosphatemia
Non-Systemic Magnesiumsalts
"
Onset:rapid, DOA:long, ANC:good
Diarrhea, hypermagnesemia
Non- Syste mic Magal drate
Combi ne w/H+ & increase LES tone; chemical complex of Mg & Al salts
Mix of Mg & Al
Mix of Mg & Al
Combine w/H+ & increase LES tone
Onset:rapid, DOA:short, ANC:fair
Gas/flatulence (bicarb burp). hypernatremia
Supplemental Al gi ni c Aci d Agents
Forms vi scous Nasolution that floats on top of GI contents
Coats esophagus during reflux
Supplemental Simethicone Agents
Surfactant
Decreases surface tension, aids in gas expulsion
Systemic
NAME
Sodium-salts
ANTACIDS. Drug-drug interactions; avoi d antacid- concomitant medication administration (take antacids 1-2 hrs before or 2-4 hrs af ter). Patie nt preference based on comorbidities and trail & error.
Antiulcer Agents CLASS
NAME
SUFFIX
MOA
EFFECT
AE/INTERACTIONS/ INDICATIONS
H2 Receptor Antagonists
Cimetidine, Famotidine, Nizatidine, Ranitidine
-tidine
Inhibit H2 (histamine) receptors on parietal cell
Inhibit 50% acid production
GI; Cimeti dine: decreases testosterone bi nding (M:gynecomastia, F:galactorrhea), inhibits CYP450 (many interactions)
Proton Pump Inhibitors (PPIs)
Esomeprazole, Dexlansoprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole
-prazole Inhibit K+/H+ Lasts 24 hrs, i nhibit 80-90% ATPase acid production (proton pump)
GI; Omeprazole: CYP450 inhibition (many interactions)
Surface Acting Agents
Sucralfate
Sulfated polysaccharide inhibi ts pepsinmediated hydrolysis
Inhibits mucosal erosion & ulcerations, viscous polymer binds to exposed epithelial cells i n ulcer crater, stimulate PGE production & epidermal growth factor
Constipation
PGE-1 Analogs
Misoprostol (Cytotec)
PGE-1 analog
Stimulates bicarb & mucous production, decreases pepsin, i ncreases blood flow
Indicated for preventi on of NSAID induced ulcers, pregnancy termination (w/Mifepristone), cervical ripening AE:GI
Bismuth Compounds
Bismuth Subsalicylate (Pepto/Kaopectate)
Increased production of bicarb & mucous, antibacterial
Constipation, black stools, many interactions
Antiulcer Agents. Always use for 4-8 we eks to heal ul cerations caused by H. pylori .
IBD CLASS
NAME
SUFFIX
MOA
5-ASA
Sulfasalazine, Mesalamine, Olsalazine, Balsalazide
- ine
Inhi bi ti on of PG & LT production via arachidonic acid pathway
Corticosteroids
Prednisone, Dexamethasone, Hydrocortisone, Methylprednisolone, Budesonide
-one
Inhi bi ts l eukocyte infiltration, suppresses humoral immunity, i nterfers with inflammatory mediators
Immune Modulators
Infliximab
Monoclonal antibody
EFFECT
AE/INTERACTIONS/INDIC ATIONS
Reduced Fever, malaise, HA, inflammation N/V/D, epigastric distress. ALA allergies! Indication:mild to moderate, maintenance "
Indication: severe. Increases glucose, BP, appetite and li pids. GI distress, fl uid retention, insomnia, nervousness & bone defects Indication:moderate to severe. "Steroid sparing effect." Increased infections & liver impairment.
IBD. Crohn's drugs only, Ulcerative colitis drugs only, drugs indicated for both.
IBS
CLASS
NAME
MOA
Antimuscarinics Hyoscyamine, Competitive inhibitor of autonomic Dicyclomine, postganglionic choli nergic receptors Clidinium w/Chlordiazepo xide, antidepressents
EFFECT
AE/INTERACTIONS/ INDICATIONS
Decreased GI Antichol inergic side motility/spasm eff ects; pulmonary, urinary, heart & eye. Indication: IBSD & pai n
Bulk-f orming & Psyllium, Laxative Agents Methylcellulose , Polyethylene glycol (PEG), Lactulose, Polycarbophil, Mg++
Indication:IBS-C
Anti-diarrheals
Loperamide, Diphenoxylate, Cholestyramine , Ca++, Bi smuth
Loperamide:related to opioids W/O opiod action. Diphenoxylate: related to opiods W/opioid actions at high doses (atropine added to discourage abuse)
Serotonin (5HT3) Antagonists
Alosetron
Selectively blocks GI-based 5HT3 receptors
Selective C2 Chloride Channel Activators
Lubiprostone
PGE1 agonist & C-2 chloride channel activator
Interferes w/peristalsis, Inhibits fluid & electrolyte secretion
Constipation, dizziness, drowsiness & urinary retention. Indication:IBS-D
Reduces Indication:women visceral pain, with severe IBS-D colonic transit & who haven't GI secretions benefited from traditional medications. BB Warning: Ischemic colitis & Death Increases flui d secretion
Indication:IBS-C (women), Chronic Idiopathic Constipation (CIC). Nausea, dyspepsia & dizziness
IBS-C -> IBS w/constipation. IBS-D -> IBS w/diarrhea.
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Rome Criteria for Diagnosis of IBS Recurrent abd. pain or discomfort at least 3 days per month in the l ast 3 months associated w/ 2+ of the following: Improvement w/defecation ○ ○ Onset associated w/change in form (appe arance) of stool ○ Onset associated w/change in fre quency of stool Criteria fulfi lled for the last 3 months w/symptom onset at least 6 months prior to diagnosi s