GI Development

General GI tract begins to form around 4th week Endoderm forms intestinal 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 umbilicus during normal development Vitelline duct Connection between the gut and the yolk sac Improper vitelline duct formation can lead to an omphalocele Omphalocele is when the gut contents herniate into the umbilical cord Allantosis Becomes part of the umbilical cord as well as forms an axis for umbilical cord development Gut tube regions Midgut Foregut Herniates into the umbilicus during normal development Midgut Rotates 270 counterclockwise around the axis of the Hindgut Superior Mesenteric Artery (SMA) SMA is the blood supply for midgut structures Foregut Forms all structures from the lower duodenum to the Forms all structures from the esophagus to the proximal 2/3 of the transverse colon upper part of the duodenum Lower duodenum Esophagus Induced by PDX1 Induced by transcription factor SOX2 Small intestine Stomach Induced by CDXC Rotates during development Colon (cecum to 2/3 transverse) "Turning a doorknob" Induced by CDXA Left stomach rotates anteriorly, Sympathetic innervation is via the Lesser Splanchnic nerve right stomach rotates posteriorly (T9-T12) Causes Vagus to rotate on Parasympathetic innervation is via the Vagus the esophagus Liver Induction is via transcription factors that BLOCK FGF2 & BMP Hindgut Formed from hepatic cords that Forms all structures from distal 1/3 of the transverse coalesce around extraembryonic veins colon to the anal canal Gall bladder is an outgrowth of the bile Distal colon duct Induced by PDX1 Pancreas Anal canal Induced by PDX1, PAX4 & PAX6 Formed from the partitioning of the cloaca PAX4 stimulates growth of , by the urorectal septum and F cells Forms the urogenital sinus and rectum PAX6 stimulates growth of cells Blood supply is via the Inferior Mesenteric Artery Upper duodenum Sympathetic innervation is via the Least Splanchnic nerve Also induced by PDX1 (T12-L2) Sympathetic stimulation is via the Greater Parasympathetic innervation is via Pelvic splanchnic Splanchnic nerve (T5-T9) nerves Parasympathetic innervation is via the Vagus Blood supply is from the Celiac artery

Embryology Page 1

Congenital Malformations of the GI Tract I

Midgut Malformations Familial duodenal atresia An autosomal recessive mutation results in stenosis & atresia of the duodenum Lumen fails to recanulize Associated with Down's, gastroschisis, imperforate anus or intestinal atresia Diagnosis "Double-bubble" sign on x-ray due to dilation of the stomach and proximal duodenum Treatment Duodenoduodenostomy/duodenojejunostomy Anastomosis of the proximal and distal small intestine to bypass the obstruction Volvulus Abnormal rotation of the midgut compromises blood flow Results in bilious emesis in the newborn Apple peel atresia Distal portion of the proximal jejunum is coiled around a mesenteric remnant Omphalocele Failure of gut to return to the abdominal cavity following herniation into the umbilicus Peritoneal membrane covers intestine Associated with: Beckwith-Wiedemann syndrome Gigantism, macroglossia & hypoglycemia Pentalogy of Cantrell Diaphragmatic hernia, cleft sternum, absent pericardium and cardiac defects Often presents with elevated AFP Treatment is surgical reduction upon delivery Pyloric stenosis Result of elongation and thickening of the pylorus Associated with Turner's and Down's More common in 1st born males Increased risk with macrolide exposure Presentation Recurrent vomiting (immediately post-feeding) Leads to hypokalosis/alkalosis "Olive mass" in the RUQ Jaundice "String/Apple core sign" on Barium swallow x-ray Treatment is surgery Meckel's diverticulum Remnant of the vitelline duct connects the umbilicus and the ileum Digested food can exit through the umbilicus Rule of 2's: 2% of the population 2 feet from iliocecal junction 2 inches long General Gastroschisis Failure of fusion of the embryonic ventral folds which form the anterior abdominal wall No sac covering the herniated bowel Presents with elevated AFP Treatment Surgical correction with temperature regulation, NG tube, antibiotics and TPN

Hindgut Malformations Problems with the urogenital septum Anal stenosis or atresia Imperforate anus Rectum can merge with vagina or urethra Anal agenesis Anal canal ends below pelvic diaphragm Anorectal agenesis Anal canal ends above pelvic diaphragm Harder surgical fix

Pancreatic Congenital Anomalies Ectopic pancreas Extra pancreatic tissue Usually located in the stomach, duodenum, jejunum, ileum and Meckel's diverticulum (if present) Pancreas divisum Most common pancreatic anomaly Failure of fusion 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 failure results in a pancreatic ring around the duodenum Can cause obstruction

Embryology Page 2

Congenital Malformations of the GI Tract II

Esophageal Malformations Esophageal atresia (EA) and tracheoesophageal fistula (TEF) Types Isolated EA Esophagus ends in a blind pouch with 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 between the trachea and distal esophagus EA with TEF of the distal esophagus Esophagus ends in blind pouch Distal esophagus connects to trachea EA with TEF of both proximal and distal esophagus Proximal and distal esophagus connect to the trachea, but there is no direct connection between the two segments TEF without EA Esophagus is continuous but has a small branch that connects to the trachea Presentation Neonates show coughing, cyanosis, and respiratory distress exacerbated by feeding Late presentation can involve recurrent pneumonia due to frequent aspirations Treatment is surgery

Hirschsprung Disease (HD) ( Congenital Megacolon) Absence of submucosa & myenteric neural plexuses leads to lack of peristalsis and complete large bowel obstruction Due to absence of neural crest cell migration Associated with a mutation in the RET gene on Chr10q.11.2 Also associated with Down's syndrome Presentation Always involves the anus and then spreads proximally from there to varying degrees of severity Can involve the entire colon Obstruction causes bowel dilation (congenital megacolon) & failure of newborn to pass stool within the first 48 hours of life Can also present with vomiting and abdominal distension Diagnosis is via biopsy showing lack of ganglion cells in rectal tissue Treatment is surgical removal of the aganglionic segment of intestine

Embryology Page 3

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 Appendicitis presents as pain here Also ideal for appendix removal Bony Linea terminalis Runs along pectin pubis, arcuate line and sacral promontory Seperates the true & false pelvis 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 internal 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 inguinal ring, bringing the transversalis fascia with it Round ligament is a remnant of the gubernaculum Spermatic cord Contains: Artery of the ductus deferens Testicular artery Pampiniform plexus (veins) Ductus deferens Becomes the tail of the epididymis

Testes Migration Testes develop retroperitoneally Attached to the gubernaculum Attached inferiorly to the labial/sacral fold As the fetus/infant grows, the gubernaculum does NOT change length The testes are pulled down through the inguinal canal via their attachment to the gubernaculum Migration failure (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 oblique muscle 4. Cremaster muscl & fascia i. From the internal oblique 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

Femoral Triangle Borders: Inguinal ligament Superior Sartorius muscle Lateral Adductor longus muscle Medial Contains: NAVEL (lateral to medial): Nerve (femoral) Artery (femoral) Vein (femoral Empty Lymphatics

Anatomy Page 4

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 Insensitive 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 lesser 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 specific blood supply and the abdominal wall Attaches the small intestine 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 vein 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 Gastrocolic ligament Gastrosplenic ligament Intra- and Extra-Peritoneal Organs Intraperitoneal viscera Completely covered by peritoneum Transverse & sigmoid colon Stomach 1st part of duodenum Small intestine Liver & gallbladder Tail of pancreas Spleen Extraperitoneal viscera Partially covered by peritoneum Rest of the duodenum Ascending & descending colon Head, neck & body of the pancreas Abdominal aorta IVC Kidneys, ureters and adrenals

Peritoneal Folds and Ligaments Ligaments are remnants beneath 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 Peritoneal Fossae Supravesical fossa Caudal to median umbilical ligament Medial inguinal fossa (Inguinal/Hesselbach's Triangle) Between medial and lateral umbilical ligaments A weak medial inguinal fossa results in direct inguinal hernias Lateral inguinal fossa Lateral to the lateral umbilical ligaments Weakness results in indirect inguinal hernias

Anatomy Page 5

Autonomic Nervous System I

General GI ANS Two major groups: Extrinsic Parasympathetic Sympathetic Intrinsic (Enteric Nervous System, ENS) Extrinsic Sympathetic 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 sympathetic trunk b) Axons can exit 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 ganglia 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 ganglia Postganglionic fibers then travel to individual organs/gut and synapse directly on them NT: NE Sympathetic stimulation of the GI tract is inhibitory Decreases motility and gland secretions Contain pain fibers

Extrinsic Parasympathetic Supplied via the Vagus and Pelvic Splanchnic nerves Vagus Provides stimulation to the esophagus, stomach, gallbladder, pancreas, small intestine, and proximal half of the large intestine Pelvic splanchnic nerves Arrise from S2-S4 Innervate the distal half of the large intestine Preganglionic fibers run all the way from the spinal cord to the target organ Postganglionic fibers are within the target organ itself NT:Ach Parasympathetic stimulation increases the activity of the GI tract Contain stretch receptors

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Autonomic Nervous System II

Intrinsic Nerve plexuses are contained entirely within the gut wall Two principle components: Myenteric (Auerbach's) plexus Located between the outer longitudinal and inner circular muscle layers Coordinates motility along the full length of the gut wall Submucosal (Meissner's) plexus Located in the submucosa Between the inner circular muscle layer and muscularis mucosa Regulates secretions, blood flow and absorption NT Acetycholine Increases activity Vasoactive Intestinal Polypeptide (VIP) Increases secretions and motility NE Decreases ENS activity Motilin Secreted by stomach, small intestine and colon ~every 100 minutes Unknown stimulus Increases motility NO Relaxes smooth muscle Dysfunction can cause achalasia or Hirschsprung's disease

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 supply 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 pelvic region

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GI Tract I
General Contains 4 layers (inside-out): Mucosa Submucosa Muscularis externa Serosa/adventitia Oral Cavity Histology Submucosa contains salivary glands Submandibular gland Contains both serous and mucous secretory cells Secretes hypotonic saliva: K+ Bicarbonate Mucosa Innervated by CN VII Epithelium Sublingual gland Stratified squamous or simple columnar Composed of mucous cells Lamina propria Innervated by CN VII Loose connective tissue that contains blood Parotid gland and lymph vessels Composed of mostly serous cells Muscularis mucosa -amylase breaks down Smooth muscle that functions in peristalsis carbohydrates by hydrolysing -1,4 bonds Submucosa Innactivated by stomach Made of fibrous connective tissue pH Contains lymph nodes, large vessels and Meissner's Innervated by CN IX plexus Tongue Regulates secretions and blood flow Papillae: Filiform Contains no taste buds Muscularis Externa Conical and feathery shape Contains 2 layers of smooth muscle (inside-out): Fungiform Inner circular layer Contains a small amount of taste buds Longitudinal layer Mushroom-like shape Auerbach's myenteric plexus is between the two layers Foliate Controls peristalsis Taste buds Serosa/Adventitia Von Ebner's glands Serosa Secrete lipase Made of loose connective tissue Leaf-like shape Covered with simple squamous Circumvallate Covers surfaces within the peritoneal cavity Taste buds and ducts of Von Ebner's Adventitia glands Made of loose connective tissue Large, circular shape Binds surfaces outside of the peritoneal cavity Sympathetic stimulation is via -adrenergic receptors to the posterior abdominal wall and increase viscous salivary secretions Anticholinergic drugs (atropine) cause dry mouth

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GI Tract II
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 bolus towards stomach Pressure is decreased in the UES to let the bolus through, then increased to prevent backflow Same for LES 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 stomach 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 cells, parietal cells, G cells, and EC cells Chief cells Secrete pepsinogen, IF & gastric lipase Pepsinogen is converted to pepsin by HCl Pepsin digests proteins Errors produce celiac disease (undigestable gluten) or pancreatitis IF binds B12 Stimulated by gastrin and Ach ( Vagus) Parietal cells 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 motility Stimulated by stomach distension EC cells Secrete serotonin & substance P Increase gut motility Motility Increased by gastrin, serotonin, substance P & distension Gastroenteric reflex also causes colon relaxation Decreased by enterogastric reflex, CCK and secretin

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Large Intestine (Colon) Histology Small Intestine Contains lots of goblet cells Duodenum Epiploic appendages are tags of fat on the colon Superior is attached to mesentary and is the most Tenia coli are longitudinal bands of muscle common site of duodenal ulcers Haustra convolutions in the wall the slow feces A posterior ulcer can result in rupture of the movement gastroduodenal artery Midgut derivations Descending is fixed retroperitoneally and receives All parasympathetic innervation is via the Vagus the common bile duct and the main pancreatic Sympathetic innervations is from the aortic plexus or duct via Hepatopancreatic (Vater's) ampulla splanchnic nerves Horizontal is retroperitoneal Cecum Ascending meets the jejunum and the Blood supply is via the ileocolic artery duodenojejunal junction Ascending colon Contains Brunner's glands that secrete bicarb to Blood supply is via right colic artery neutralize stomach HCl Transverse colon Jejunum Blood supply is via middle colic artery Has a larger diameter, simple vascular arcades Hindgut derivations and long vasa recta Sympathetic innervation is via aortic plexi or Mucosa contains goblet cells, S cells, Mo cells, I splanchnic nerves cells, L cells, K cells and Paneth's cells Parasympathetic innervation is from S2-S4 S cells Descending colon Secrete secretin in response to acid in the Sigmoid colon duodenum Rectum Increases pancreatic & biliary bicarb Bordered inferiorly by the anorectal line and water secretion Seperates the rectum from the anus Decreases gastrin & acid release and Mucosa changes to stratified squamous stomach motility Anorectal angle is formed by Mo cells puborectalis muscle Secrete motilin Anus Increases gut motility Superior border is the anorectal line I cells Just inferior to the anorectal line are anal Secrete CCK columns Increases pancreatic enzyme The most inferior part of the anal columns secretion contain anal sinuses Gall bladder contraction Exude mucus when compressed to aid Stimulated by fats & fiber in the duodenum evacuation L cells The pectinate line is just inferior to the anal Secrete GLP-1 sinuses and defines a divergence in blood Increases insulin secretion and supply, lymph & innervation decreases gastric acid release and Superior to pectinate line stomach motility Inferior mesenteric artery Secrete GLP-2 Lymph drains superiorly to internal iliac Stimulates growth of villi nodes Stimulated by fats & fiber in the duodenum Nerves are visceral (non-painful) and K cells vein is internal rectal Secrete gastric inhibitory peptide Internal hemorroids are not painful Decreases gastric acid secretion Inferior to pectinate line Paneth's cells Inferior rectal artery Located in crypts Lymphd drains to superficial inguinal Secrete lysozyme nodes Ileum Nerves are somatic (pain-sensitive) and Contains compound arcades and short vasa recta vein is external rectal Ends at the ileocecal valve that connects the small External hemorrhoids are painful intestine to the cecum (large intestine)

GI Tract III

Anatomy Page 10

GI Tract IV
Liver Gallbladder Anatomy Anatomy Functional lobes Fundus Right & left Body Each has a primary branch from the hepatic artery, portal vein Neck Connects to the cystic duct and hepatic duct Anatomical lobes Cystic duct joins the common Right, left, caudate & quadrate hepatic duct to form the Lobule common bile duct Radial arrangement of hepatocytes and sinusoids around a Common bile duct runs posterior central vein to the portal triad to the head of the pancreas and Visceral surface joins the main pancreatic duct at Ligamentum venosum is the remnant of the ductus venosum the ampulla of Vater Continuous with the round ligament of the liver Function Remnant of the umbilical vein Stores, concentrates and Bothare found within the falciform ligament releases bile During fetal life, the ligamentum venosum connected the Bile release is triggered by CCK Causes gallbladder umbilical vein to the IVC Histology contraction and relaxation Sinusoids of the sphincter of Oddi 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 liver 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 inferior epigastric veins Rectum (hemorrhoids) Blood flows back through the superior rectal vein to the middle and inferior rectal veins

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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 cell Secrete glucagon G cell Secretes gastrin cell Secretes insulin cells Secrete somatostatin which decreases GI & gallbladder 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 converts 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 lipoproteins Drug, hormone and vitamin metabolism Vitamin & mineral storage Synthesis of TGs Done by h Glycerol kinase converts glycerol of glycerol-3-phosphate (G3P) G3P is combined with two molecules of AcylCoa to form TAG TGs are packed into chylomicrons for delivery to the rest of the body

Bile Synthesis Bile is made and secreted by hepatocytes Bile function Emulsifies lipids into micelles for easy absorption Bile synthesis requires the simulataneous 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 enzyme 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 bile Stimulated by returning bile and secretin Phospholipids increase the solubility of cholesterol, which is a necessary ingredient of bile Bile is 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

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 dehydrogenase in the liver mitochondria ALDH2 is a variant among East Asians that is less efficient Produces "oriental flush"/hangover Increased drinking 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 hyperlipidemia"/ "fatty liver" Chronic effects Fatty liver Increased aldehyde Toxic to liver mitochondria, heart, and skeletal muscle Accumulation leads to alcoholic hepatitis Results in fibrosis (irreversible)

Carbon souces for gluconeogenesis: Lactate, Alanine, and Glycerol

Physiology Page 13

Liver II
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 biliverdin reductase Bilirubin is bound to plasma albumin and requires pyridoxal transported to the liver phosphate (B6) Liver Hepatocytes conjugate bilirubin to glucoronic acid via UDP-glucuronyltransferase forming conjugated (soluable) bilirubin Soluble bilirubin is excreted in bile Some conjugated Intestine Conjugated bilirubin is converted into urobilinogen by gut bacteria Most urobilinogen is metabolized to stercobilinogen and then oxidized to stercobilin Stercobilin 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 yellow color Kidney Normally never filters any conjugated bilirubin Presence of urobilinogen is normal Presence of conjugated bilirubin indicates liver damage Turns urine dark amber color Liver Protein Metabolism Nitrogen is transported to the liver via glutamine and alanine Other proteins are similarly 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
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

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Small Intestine & Carbohydrate Metabolism

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 basolateral 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 Chylomicrons enter lymphatic system for systemic distribution Vitamins A, D, E and K Proximal jejunum Absorption continues Fructose Absorbed via facilitated diffusion through GLUT5 Exits basolaterally via GLUT2 Protein Absorbed as tri-/ di-peptides and amino acids AA have specific Na+dependent cotransporters Terminal jejunum Water-soluble vitamins Ileum Protein absorption continues B12 absorption Majority of water is reabsorbed in the jejunum and ileum Carbohydrates Disaccharides Types Lactose Glucose + galactose Digested by lactase Error causes lactose intolerance 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 facilitated 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 skeletel muscle Translocated to the membrane by insulin GLUT5 Located on the lumenal side 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 in 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 satiety 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 Emetic Response PNS Gastric irritants Vagus stimulation CNS Labyrinthe disorders Trauma Increased ICP Duodenal chemoreceptors Activated by Ipecac syrup Chemoreceptor 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

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Hernias
Inguinal Hernias Direct Medial to the inferior epigastric vessels Pushes directly through the abdominal floor Through the medial inguinal fossa ABSENT hernia sac (peritoneum) Indirect Lateral to the inferior epigastric vessels Due to a patent processus vaginalis Pushes through the lateral inguinal fossa and the deep & superficial inguinal ring PRESENT hernia sac Femoral Hernia Bulge through the femoral canal within the femoral sheath Medial to the femoral vein Below the inguinal ligament, lateral to the pubic tubercle More common in females

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 umbilicus but above the inferior epigastric vessels along the semilunar line Incisional hernias Surgical herniations Due to: Excessive tension (obesity) Infection Increased pressure (COPD) Tobacco Poor technique

Hiatal Hernias Due to weak esophageal hiatus (T10) Sliding Abdominal esophagus 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 fundus of the stomach to herniate Can threaten the blood supply to the fundus

Hernia Subtypes Reducible Most common type Usually painless Treatment Reduction Patient is sedated/analgesia Pressure is applied medially while simultaneously invaginating the distal hernia sac Incarcerated (irreducible) Due to painful enlargement of a previous hernia Hernia sac protrudes through a tight muscular ring Cannot be manipulated/reduced Strangulated Additional symptoms Hernia sac can appear toxic/necrotic due to compromised blood supply Intensly painful and at high risk for perforation Surgical emergency

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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 in the myenteric plexus Secondary Destruction of the myenteric plexus due to Chagas' disease ( T. cruzei) Presentation Progressive dysphagia and nocturnal regurgitation Barium swallow shows dilated proximal esophagus is distal "bird-beak sign" narrowing GERD Abnormal relaxation of the LES leads to gastric contents refluxing into the esophagus Causes injury and chronic inflammation 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 cells) 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

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

Esophageal Cancer Moe common in blacks, males and lower socioeconomic status Diet related/vitamin deficiency : A, C, folate, E, B12 and riboflavin Presentation Dysphagia Weight loss Hematemesis/N/V Hoarseness/cough SCC Specific etiology Smoking, EtOH, nitrites, smoked opiates, fungal toxins, radiation, lye and HPV Located in the upper and middle esophagus Adenocarcinoma Specific etiology GERD Located in the lower esophagus Contains signet-ring morphology Treatment is esophagectomy

Pathology Page 18

Stomach Disorders I
Gastritis Hypertrophic Gastropathies Inflammation of the gastric mucosa Hyperplasia without inflammation Presentation Zollinger-Ellison disease Abdominal pain and dyspepsia A tumor/gastrinoma of G cells (non--cells) of Acute the pancreas produces a huge amount of gastrin Etiology Results in parietal cell hyperplasia and NSAIDs massive HCl production Stress Presentation Helicobacter pylori Recurrent ulcers of upper GI tract EtOH (stomach, jejunum etc.) Chemo/radiation Steatorrhea/diarrhea Acute gastric ulceration Menetrier's disease Curling ulcers Hyperplasia of mucus-secreting cells results in Located in the proximal duodenum rugal hypertrophy and atrophy of parietal cells Associated the burns/trauma Presentation Cushing ulcers Weight loss Located in the stomach, duodenum Hypoproteinemia Diarrhea and esophagus Associated with head Edema Increased risk of adenocarcinoma trauma/intracranial disease Chronic Etiology Peptic Ulcer Disease Type A Ulcer formation in the stomach are 1st part of the Autoimmune gastritis duodenum secondary to mucosal disruption Autoantibodies target parietal Etiology is similar to gastritis cells resulting in lack of IF EtOH (pernicious anemia) Stress B12 deficiency Tobacco Type B NSAIDs Due to Helicobacter pylori Helicobacter pylori Urease of H. pylori degrades Presentation urea into ammonia, which is N/V erosive to the stomach lining Acute abdominal pain Increased risk of gastric adenocarcinoma 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 rebound pain Treatment is prompt surgery Treatment Lifestyle PPI, bismuth, sucralfate, PGE analogs and antibiotics against H. pylori

Pathology Page 19

Stomach Disorders II
Stomach Cancer Second most common cause of cancer-related deaths worldwide 85% are adenocarcinomas, 15% are lymphomas 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

Pathology Page 20

Small & Large Intestine I

Malabsorption Syndromes Diverticular Disease Presentation Diverticulosis Diarrhea and steatorrhea Formation of pouches (diverticula) in the sigmoid colon Weight loss Diverticulitis Vitamin & mineral deficiencies Inflammed diverticulosis Celiac sprue Etiology Tropical sprue Infection secondary to an impacted fecalith Occurs in tropical areas Diverticular rupture Unknown etiology Presentation Thought to be infectious LLQ pain Presents with similar symptoms of all Often with peritoneal signs (rebound malabsorption syndrome tenderness) Disaccharidase deficiencies Fever Lactase Constipation Whipple's disease LGI bleed Secondary to infection by Tropheryma Maroon stool Due to artery rupture into the diverticula whippelii Presentation Barium enema and endoscopy are contraindicated Malabsorptive symptoms due to possible perforation Fever Treatment Polyarthralgias IV hydration & antibiotics Morphology Distended lamina propria filled with PAS+ macrophages with foamy cytoplas Appendicitis Abetalipoproteinemia Due to obstruction of the appendiceal lumen by feces, a Autosomal recessive mutation results in stone or lymphatic tissue a lack of ApoB Presentation Causes TG accumulation N/V Pancreatic insufficiency Weight loss CF Acute abdominal pain Pancreatitis Initially periumbilical but migrates to the RLQ Cirrhosis over McBurney's point Bile duct obstruction Rovsing's sign Exogenous Pain in RLQ upon palpation of left side Laxatives Obturator sign Antacids/Mg++ Pain on internal rotation of the right hip Drugs Iliopsoas sign Diuretics Pain on extension of the right hip ACEI Treatment is surgical removal H2 blockers Cochicine Toxins Cola Coffee Mushrooms EtOH Infection/bacterial toxins

Pathology Page 21

Small & Large Intestine II

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 peristalsis 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 Pseudomembranous Colitis (Antibiotic-Associated Colitis) Acute inflammation of the colon following a course of broad-spectrum antibiotics Frequently flouroquinolones & clindamycin Long-term antibiotics kills normal gut flora Increased undigested 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-spectrum antibiotics Treatment Mild to moderate Metronidazole Se Vere Vancomycin

Pathology Page 22

Small & Large Intestine III

Irritable Bowel Disease Presentation Diarrhea & malabsorption Ulcerations & bleeding Acute abdominal pain & mucosal inflammation Erythema nodosum More common in females Crohn's disease (CD) Triggered by aerobic bacteria 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- 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 colon cancer Toxic megacolon Treatment Mild to moderate 5-ASA & corticosteroids Severe IV hydration & steroids Antibiotics Monoclonal antibodies Colectomy for severe UC IBD (cont.) Result of inappropriate immune reaction to normal gut flora Controlled by: Genetics Enviornment Loss of microbial tolerance Genetics Uncommon in Asians & Africans Enviornment Smoking Increases small bowel permeability and colonic mucus production Reduces mucosal cytokine production Promotes leukocyte adhesion Stress Diet Drugs Oral contraceptives & NSAIDs increase risk of IBD Social High amony socioeconomic groups Characteristics Intermittent remission & relapse Antibodies against bacteria Increased gut permeability Bacteria components cross mucosal barrier Induces immune response Mucosal inflammation

Irritable Bowel Syndrome (IBS) Similar 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 motility Visceral hypersensitivity Stress Genetics Treatment Diet Fiber

Pathology Page 23

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 adenocarcinoma 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 Familial adenomatous polyposis (FAP) Autosomal dominant mutation in APC Have 100+ colorectal polyps 100% of colorectal cancer without colectomy Gardner's syndrome Autosomal dominant Multiple adenomatous colon polyps in cinjuction with other tumors Osteomas of the mandible and skull Turcot's syndrome Autosomal recessive syndrome associated with colonic polyps and tumors of the CNS Especially glioblastoma multiforme and medulloblastoma Neoplastic Polyps Neoplastic (adenomatous) By defintion, adenomatous polyps are dysplastic and precancerous Classification Sessile On wall Pedunculated On a stalk Tubular Most common Neoplastic glands of rounded/tubular, dark red and can ulcerate 5% cancer risk Villous Highest rate of cancer conversion(40%) Neoplasms are cauliflower-like Neoplastic (squamous) Rare Arises in the anal canal 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 Nonpolyposis Colorectal Cancer) Autosomal dominant disorder that causes cancer Mutation in DNA mismatch repair gene hMLH1 or hMSH-2 Metastasis sites Liver (colon) Lung (rectum) Peritoneum & 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)

Pathology Page 24

Jaundice
General Serum bilirubin > 2.0 Yellowed skin or sclera Etiology Neonatal Bile obstruction Liver disease Hyperbilirubinemia (genetic) Jaundice w/conjugated bilirubin: Elevated direct serum bilirubin Elevated urine bilirubin 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 Neonatal Etiology (benign) Relative deficiency in glucuronyl transferase in the immature liver Hemolysis from mild trauma during birth Etiology (pathologic) Erythroblastosis fetalis Rh- mom & Rh+ second-child ABO blood type difference Hypothyroidism Large tongue, poor muscle tone & shallow hair line Obstructive Treatment Phototherapy Transfusion Hyperbilirubinemia Direct (conjugated) hyperbilirubinemia Dubin-Johnson's syndrome Autosomal recessive defect in the ABC transporter impairs hepatic bilirubin secretion "Black liver" Treatment is usually not necessary Phenobarbitol can be used in extreme cases Induces UDP-glucuronyl transferase Rotor's syndrome Autosomal recessive disorder similar to DubinJohnson's syndrome Defects in hepatocellular uptake and secretion of bilirubin Grossly liver is normal Patients respond well to phenobarbitol Indirect (unconjugated) hyperbilirubinemia Gilbert's syndrome Most common Reduced activity/amount of UDP-glucuronyl transferase Intermittent periods of jaundice 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

Pathology Page 25

Hepatitis & Cirrhosis

Hepatitis Presentation N/V Fever Jaundice Weight loss Hepatomegaly RUQ pain Fatigue/malaise Labs Elevated: LDH Indirect serum bilirubin Alkaline phosphatase WBCs More so in viral hepatitis Prothrombin time AST & ALT Reduced: Albumin Platelets Viral hepatitis No fatty liver stage Viral antibodies IgM first, followed by IgG Progresses to cirrhosis AST << ALT Alcoholic hepatitis More common in black women Fatty liver Microvesicles give the liver a yellow, greasy appearance Progresses to alcoholic hepatitis and ultimately cirrhosis Morphology "Ballooning" of hepatocytes Hepatocyte death Mallory hyaline inclusion bodies Neutrophil infiltrate Fibrosis AST >> ALT Treatment EtOH rehabilitation Vitamin supplementation Thiamine, folate and vitamin K Cirrhosis Extreme fibrosis and architectural disruption of the liver Irreversible Extensive collagen type I & III deposition in 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 hepatitis 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 (from decreased clotting factors) Portal hypertension Venous shunts Hemorrhoids Caput medusae Esophageal varices Splenomegaly resulting in thrombocytopenia Ascites and peripheral edema Hypoalbuminemia decreases intravascular oncotic pressure Portal hypertension increase venous hydrostatic pressure Hepatic encephalopathy Accumulation of toxic metabolites (ammonia) due to shunting of blood around liver Asterixis Extemity tremors with wrist extension & dorsiflexion Treatment Banding of esophageal varices Paracentesis (draining ascitic fluid) Supportive Low protein diet Vitamins Toxin avoidance Salt restriction and diuretics for edema

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Hemochromatosis & Wilson's Disease

Hemochromatosis Autosomal recessive disorder characterized by increased intestinal iron absorption Mutations affect the HFE gene HFE causes decreased affinity 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 Manifests in 6th decade Weakness & weight loss Abdominal pain Loss of libido Arthritis Joint deposition Cirrhosis Results in hepatomegaly DM-1 Due to iron deposition in pancreatic islet cells HF Genetics Type I:classic Mutation in HFE-1 C282Y (90%) H63D (10%) Type II: juvenille Mutation in HAMP (severe) or HJV Manifests in 2nd decade Type III Mutation in transferrin receptor Type IV Mutation in ferroportin Autosomal dominant Treatment Phlebotomy Chelation Deferoxamine
Wilson's Disease Autosomal recessive disorder characterized by excess serum copper leading to deposition in the liver, brain, kidneys & cornea Etiology Mutation in ATP7B gene on Chr13q.14.3 Encodes a ATPase that transports copper into bile and incorporates it intoceruloplasmin Presentation Childhood or young adult onset Liver Jaundice Amenorrhea & spontaneous abortions in women Hepatitis or cirrhosis Cornea Keyser-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++ restriction

Pathology Page 27

Liver Cancer
General Most common liver tumors are metastatic Benign Hepatocellular adenoma (HA) Pale, yellow/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 imaging 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 flukes Metastatic Usually from the colon, stomach, pancreas, breast, and lung

Pathology Page 28

Gallbladder Disease
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 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

Cholecystitis/Cholangitis Gallbladder/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 cholangitis Caused by fibrosis, thickening and strictures of the bile duct Primary Associated with UC Secondary Post surgery, trauma or chronic pancreatitis Often presents with hepatomegaly

Pathology Page 29

Pancreatitis & Pancreatic Cancer

Acute Pancreatitis Activation of pancreatic enzymes leads to pancreatic autodigestion and hemorrhagic fat necrosis Etiology (GET SMASHED) Gallstones Duct obstruction EtOH Increases exocrine 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) 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 exocrine pancreas Risk factors Smoking Chronic pancreatitis Obesity Hereditary K-RAS mutation Presentation Courvoisier's sign Painless 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, lipoprotein 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-exposure therapy Hepatitis B immune globulin (HBIG) Screening of donated blood 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 bilirubin Persistent virus shedding

Pathogenesis Liver is only site of viral replication Damage to liver cells is immune mediated Due to release of toxic substances from infiltrating mononuclear cells Viral replication doesn't cause significant liver cell damage An efficient immune response involving T cytotoxic cells kills viral infected cells and rids the body of HBV Chronic infections occur when CTLs are inefficient at killing viral infected cells Individuals who have decreased IFN production IFN upregulates MHC-I allowing CTLs to recognize infected cells Without MHC-I upregulation virus persists

Pathology Page 31

Antacids
CLASS NAME MOA EFFECT AE

Non-Systemic Aluminumsalts
Non-Systemic Calcium-salts

Combine w/H+ & increase LES tone

"

Onset:slow, DOA:short, ANC:weak

Onset:rapid, DOA:long, ANC:very good

Constipation, hypernatremia, hypophosphatemia

Constipation, hypercalcemia (MilkAlkali syndrome: nephropathy & metabolic alkalosis), hypophosphatemia

Non-Systemic Magnesiumsalts
Non-Systemic Magaldrate

"

Onset:rapid, DOA:long, ANC:good

Mix of Mg & Al

Diarrhea, hypermagnesemia

Combine w/H+ & increase LES tone; chemical complex of Mg & Al salts

Mix of Mg & Al

Systemic

Sodium-salts

Combine w/H+ & increase LES tone Forms viscous Nasolution that floats on top of GI contents
Surfactant

Onset:rapid, DOA:short, ANC:fair Coats esophagus during reflux

Decreases surface tension, aids in gas expulsion

Gas/flatulence (bicarb burp). hypernatremia

Supplemental Alginic Acid Agents

Supplemental Simethicone Agents

ANTACIDS. Drug-drug interactions; avoid antacid-concomitant medication administration (take antacids 1-2 hrs before or 2-4 hrs after). Patient preference based on comorbidities and trail & error.

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Antiulcer Agents
CLASS
H2 Receptor Antagonists

NAME
Cimetidine, Famotidine, Nizatidine, Ranitidine

SUFFIX
-tidine

MOA
Inhibit H2 (histamine) receptors on parietal cell

EFFECT
Inhibit 50% acid production

AE/INTERACTIONS/ INDICATIONS
GI; Cimetidine: decreases testosterone binding (M:gynecomastia, F:galactorrhea), inhibits CYP450 (many interactions)

Proton Pump Inhibitors (PPIs)

Esomeprazole, Dexlansoprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole Sucralfate

-prazole Inhibit K+/H+ Lasts 24 hrs, inhibit 80-90% ATPase acid production (proton pump)

GI; Omeprazole: CYP450 inhibition (many interactions)

Surface Acting Agents

Sulfated polysaccharide inhibits pepsinmediated hydrolysis PGE-1 analog

Inhibits mucosal erosion & ulcerations, viscous polymer binds to exposed epithelial cells in ulcer crater, stimulate PGE production & epidermal growth factor Stimulates bicarb & mucous production, decreases pepsin, increases blood flow

Constipation

PGE-1 Analogs

Misoprostol (Cytotec)

Indicated for prevention of NSAID induced ulcers, pregnancy termination (w/Mifepristone), cervical ripening AE:GI Constipation, black stools, many interactions

Bismuth Compounds

Bismuth Subsalicylate (Pepto/Kaopectate)

Increased production of bicarb & mucous, antibacterial

Antiulcer Agents. Always use for 4-8 weeks to heal ulcerations caused by H. pylori.

Pharmacology Page 33

IBD
CLASS NAME SUFFIX MOA EFFECT AE/INTERACTIONS/INDIC ATIONS

5-ASA

Sulfasalazine, Mesalamine, Olsalazine, Balsalazide

Prednisone, Dexamethasone, Hydrocortisone, Methylprednisolone, Budesonide Infliximab

-ine

Inhibition of PG & LT Reduced Fever, malaise, HA, production via inflammation N/V/D, epigastric distress. arachidonic acid ALA allergies! pathway Indication:mild to moderate, maintenance
Inhibits leukocyte infiltration, suppresses humoral immunity, interfers with inflammatory mediators Monoclonal antibody " Indication: severe. Increases glucose, BP, appetite and lipids. GI distress, fluid retention, insomnia, nervousness & bone defects Indication:moderate to severe. "Steroid sparing effect." Increased infections & liver impairment.

Corticosteroids

-one

Immune Modulators

IBD. Crohn's drugs only, Ulcerative colitis drugs only, drugs indicated for both.

Pharmacology Page 34

IBS
CLASS NAME MOA EFFECT AE/INTERACTIONS/ INDICATIONS

Antimuscarinics Hyoscyamine, Competitive inhibitor of autonomic Dicyclomine, postganglionic cholinergic receptors Clidinium w/Chlordiazepo xide, antidepressents Bulk-forming & Psyllium, Laxative Agents Methylcellulose , Polyethylene glycol (PEG), Lactulose, Polycarbophil, Mg++ Anti-diarrheals Loperamide, Loperamide:related to opioids W/O Diphenoxylate, opiod action. Diphenoxylate: related Cholestyramine to opiods W/opioid actions at high , Ca++, Bismuth doses (atropine added to discourage abuse) Alosetron Selectively blocks GI-based 5HT3 receptors

Decreased GI Anticholinergic side motility/spasm effects; pulmonary, urinary, heart & eye. Indication: IBSD & pain Indication: IBS-C

Interferes w/peristalsis, Inhibits fluid & electrolyte secretion

Constipation, dizziness, drowsiness & urinary retention. Indication: IBS-D

Serotonin (5HT3) Antagonists

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 fluid secretion Indication: IBS-C (women), Chronic Idiopathic Constipation (CIC). Nausea, dyspepsia & dizziness

Selective C2 Chloride Channel Activators

Lubiprostone

PGE1 agonist & C-2 chloride channel activator

IBS-C -> IBS w/constipation. IBS-D -> IBS w/diarrhea.

Rome Criteria for Diagnosis of IBS Recurrent abd. pain or discomfort at least 3 days per month in the last 3 months associated w/ 2+ of the following: Improvement w/defecation Onset associated w/change in form (appearance) of stool Onset associated w/change in frequency of stool Criteria fulfilled for the last 3 months w/symptom onset at least 6 months prior to diagnosis

Pharmacology Page 35

Laxative & Cathartics

CLASS Stimulants (Irritants) NAME MOA EFFECT Water & electrolyte accumulation in lumen "
"

EFFICACY AE/INTERACTIONS/INDICATIONS (HRS) 2-8 AE: Urine discoloration (brown/red), mucosal discoloration, cramping Contraindication: obstruction, ileus, impaction "
"

Anthraquinolones Na+/K+ ATPase (Senna, Cascara inhibition; Increase sagrada) PGE synthesis via cAMP/GMP; Irritation Diphenymethanes (Bisacodyl)
Castor oil

"
"

" (suppository)
Hydrolyzed to riconeleic acid, functions as anthriquinolones

0.5-2
2-8

Osmotics (salines)

PEG

Poorly absorbed, Hyperosmolar; prevents ion passage water across membrane retention in tract Hyperosmolar; (Mg may also increase CCK to stimulate secretions) Dissaccharide; also used for liver diseae (hyperammonemia) "

AE: Bloating, N/V Interaction: diuretics Caution: renal disease, CHF/HTN " AE: Hypermagnesemia/ natremai/phosphatemia, hypocalcemia, abd. Pain, flatulence "

"

Magnesium salts, Sodium phosphates

6-8

"

Lactulose

" (pH traps ammonia) " Increase motility

"

" Bulk-Forming agents

Sorbitol/mannitol Non-absorbed sugars Fiber/Bran, Increase bulk volume Psyllium, & water Methylcellulose/ Carboxymethyllce llulose, Calcium Polycarbophil, Malt Soup extract
Docusate salts, Mineral oil Increase fluid secretion

" 24-72

" AE: bloating/obstruction Interactions: LOTS!

Surfactant agents

Softens stools

24-72

AE: cramping, leakage (mineral oil)

SerotoninType 4 Partial Agonists

Tegaserod

Stimulates peristaltic reflex, increases secretions

Softens & increases frequency

Requires FDA approval. AE: hypotension, dizziness/syncope Contraindication: cardiac disease (MI) renal/hepatic disease Indication: IBS-C & chronic idiopathic constipation (women only) AE: N/V/D, cramping, pain AE: cramping

PGE1 analog

Lubiprostone

Activates Clchannels

Increases secretion & motiliy Softens

24

Miscellaneous

Glycerin

(Suppository) Trihydroxyl alcohol

0.5-2

Pharmacology Page 36