GI intro

• 8L/day, 99% absorbed (82% sm. intestine, 17% lrg intestine)
• 1200 ml from drinking water
• 1500 ml from saliva
• 2000 ml from gastric secretion
• 500 ml from bile
• 1500 ml from intestinal secretions

• -- Neural regulation
• a. extrinsic nervous system: autonomic nerves.
• b. The intrinsic/enteric nervous system: local neural network - neurotransmitters and neuromodulators
• -- Hormones and Paracrine Factors

• Anticipation!
• parasympathetic efferent pathway activates enteric nerves -> parietal cells secrete HCl and stimulate the G cells to secrete the hormone gastrin => increased motility

• Food enters stomach
• Amino acids and peptides -> G cells secrete gastrin -> parietal cells secrete HCl, activate stomach motility.
• Distention -> vagus nerve -> enteric nervous system -> parietal cell secretion of HCl and G cell secretion of gastrin
• Mechanoreceptors -> enteric nerves -> G cells and parietal cells.
• Caffeine -> parietal cells -> HCl.

• Distention
• acidity
• hyperosmolarity
• fat/amino acids
• -> neural reflexes and hormone secretion

• No hormonal reg
• Parasympathetic - facial and glossopharyngeal nerves release ACh, bind to muscarinic receptors
• Sympathetic - thoracic spinal nerves T1-3, B adrenegeric receptors

• Pressure -> afferent to brainstem -> efferent to pharynx
• Stuck food, contractions w/o swallowing

• Fundic/cardiac, Body, Antrum
• Orad - top half, relaxes w/LES, expands
• Caudad - perstaltic contractions

• Parasympathetic activation, and secretion of gastrin and motilin depolarize Vm
• Sympathetic activation hyperpolarizes Vm

• parietal cell - H+/K+ ATPase, Cl- channel on luminal, HCO3-/Cl exhanger on serosal
• ACh, gastrin, histamine - # H+/K+ ATPases
• pepsinogen -> pepsin by HCl

• B12: water-soluble, must form complex w/IF to be absorbed - other H2O-soluble vits are taken up by Na+ exchangers
• Fat-soluble - chylomicrons ->lymph -> systemic circulation

• Autonomic - increased salivation, sweating, increased heart rate, skin pallor, and nausea
• Retching: Deep breath, close glottis, and elevation of soft palate. Abs contract. Relaxation of LES, body of stomach -- stomach contents into esophagus
• Vomiting: large pressure increase, UES opens, reverse peristalsis

• acidity: enteric neural reflex, contraction
• fat content: CCK, contraction
• hyperosmotic chyme: contraction

• Chyme after a meal - higher frequency contractions at proximal end than distal (9-12/min)
• MMC - during fasting, 1/90min, sweep undigested contents

• a. Fasting -> secretion of motilin -> MMC
• b. Eating -> CCK, gastrin, insulin – segmentation and peristaltic contractions.
• c. Eating -> serotonin secretion from enterochromaffin cells of the GI and enteric NS -> stimulate motility.
• d. Stress -> adrenal medulla -> Epi -> inhibits motility

• Na+/H+ ATP-dependent transport basolateral, HCO3-/Cl- luminal, Cl- channel luminal
• Acid in sm. intestine -> Secretin increases HCO3- secretion and insertion of Cl- channels

• zymogens secreted from acinar cells
• trypsinogen activated by membrane-bound enterokinase
• Trypsin then converts other zymogens to amylase, lipase, cholesterol ester hydrolase, phospholipase A2,(fats) chymotrypsin, elastase, carboxypeptidase(proteins), ribonucletidases
• FA,AA -> CCK -> inc. zymogens

• released in duodenum
• bile salts, phospholipids, cholesterol, bile pigments, and inorganic ions (e.g., Na+, K+, Ca2+, Cl- and HCO-3)
• 95% reabsorbed in ileum to liver via enterohepatic circulation
• CCK causes contraction of gallbladder + relaxation of sphincter of Oddi

• before meal, illeocecal sphincter is closed, reflex relaxation, then distention causes contraction
• Segmentation - 1/30min, slow
• Mass movement - gastrin, CCK after meal
• Defecation - mechanoreceptor reflex

• a. GLUT-5: facilitated diffusion of fructose across luminal membrane
• b. SGLT-1: secondary active transport of glucose and galactose across luminal membrane
• c. GLUT-2: facilitated diffusion of monosaccharides across basolateral membrane
• d. Role of Na-K-ATPase on basolateral membrane in setting up diffusion gradient for SGLT-1 function

• visceral peritoneum: same blood & lymphatic vasculature and visceral nerve supply as the organ it is attached to, autonomic, insensitive to pain
• parietal: same as abdominal wall, somatic

• potential space between layers of peritoneum. Thin layer of fluid lubricates, allows organs to move
• Connects organ to peritoneum or organs to each other

• almost completely covered with visceral peritoneum
• outside the peritoneal cavity (external or posterior to the parietal peritoneum) and are only partially covered by peritoneum.

• splenic -> left gastroepiploic
• common hepatic
• -> gastroduodenal -> posterior superior pancreaticoduodenal, anterior superior pancreaticoduodenal, R gastroepipoic
• -> hepatic proper -> right gastric, R and L hepatic (R hepatic gives off cystic)
• L gastric

• -> ileal and jejunal branches (15-18)
• -> ileocolic, right colic, middle colic, common inferior pancreaticoduodenal ileocolic - ileal, colic, anterior cecal, posterior cecal and appendicular

superior rectal, sigmoids and left colic. marginal artery forms an anastomosis w/ superior mesenteric artery

• Formed at L2 by superior mesenteric + splenic veins (+ inf mesenteric)
• -> liver -> hepatic vein -> IVC

• (1) between L gastric (portal) and esophageal (caval) veins
• (2) between paraumbilical (portal) and epigastric (caval) veins
• (3) between colic (portal) and retroperitoneal (systematic) veins
• (4) between the superior rectal (portal) and middle & inferior rectal (caval) veins.

• 5HT1A partial agonist
• treatment for dyspepsia/anxiolytic

• Only sympathetics synapse here, parasymps (vagal and pelvic splanchnics) run thru to synapse @ organ
• celiac, aorticorenal, sup mesenteric, inf mesenteric

• Ganglion cells communicate thru interneurons
• Submucosal (Meissner’s) plexus and the myenteric (Auerbach’s) plexus
• Symps modulate (not part of ENS) - sphincter tone (smooth muscle) and vascular tone

hepatocytes, bile canaliculi, (interlobular) bile ductules, left and right hepatic ducts, common hepatic duct, common bile duct, hepatopancreatic ampulla/sphincter, major duodenal papilla and finally into the duodenum.

• distal esophagus, stomach, 1st & 2nd parts of the duodenum, liver, gallbladder and pancreas
• NOT spleen
• greater splanchnics (T5-9), anterior vagal trunk

• from 3rd part of duodenum to prox 2/3 of transverse colon
• lesser and least splanchnics (T10-12), posterior vagal trunk

• Vasa recta are long in the jejunum and short in the ileum.
• Arterial arcade loops are large & few in the jejunum and short & many in the ileum.
• Encroaching fat is not found on the jejunum but on the ileum.
• Circular folds (plicae circulares) are large, tall & closely packed in the jejunum but low & sparse in the ileum.
• The ileum has aggregated lymphoid nodules (Peyer’s patches).

• Teniae coli: 3 thickened bands of muscle
• Haustra: sacculations
• Epiploic appendices: fat

• Distal 1/3 of transverse colon to anus
• Lumbar splanchnic (symp T12-L2) Pelvic splanchnics (parasymp)

• external anal sphincter: deep, superficial & subcutaneous part
• anal canal: columnar zone (endoderm derived), anal pectin (transitional zone) & cutaneous zone (ectoderm derived).
• Puborectalis muscle keeps an 80 deg anorectal flexure

• bile duct, hepatic artery, portal vein, lymph
• hexagon: blood flows from traid -> central vein, bile flow opposite
• zone 1 - at triad, high O2 & gluconeogenesis
• zone 3 - at CV, low O2, liponeogenesis

• Portal vein - 70%
• Hepatic artery - 30%
• Fenestrated endothelium
• 1/3-1/2 can be regenerated
• splanchnic capillaries & liver sinusoids = portal system

• Portal vein thrombosis
• Schistosomiasis

• Venoocclusive disease
• Budd Chiari
• IVC Web
• Heart failure

• apical - between cells, where bile is secreted into canniculi
• basolateral - adj to sinusoids

67 % Bile Salts

• 26 % Phospholipids
• (lecithin) and cholesterol

4.5 % Proteins

0.3 % Bilirubin

• 1.Form mixed micelles (hydrophobic core) with fatty acids and monoglycerides for cholesterol transport
• 2.Solubilize “fatty” vitamins A,D,E, and K to promote their absorption
• 3.Promote the absorption of heavy metals (Fe++)
• 4.Keep intestinal surface clean
• 5.May promote intestinal motility
• 6.Mild bacteriostatic effects
• 7.In colon they induce water secretion and stimulate colonic motility

Bile with > 10% cholesterol tends to form cholesterol crystals and then gallstones

• 1.Increasing age
• 2.Female > male
• 3.Obesity
• 4.Hemolytic anemia (pigment stones)
• 5.Pregnancy
• 6.Estrogens
• 7.Total parenteral nutrition (TPN)
• 8.Fasting
• 9.Ethnicity (Pima)
• 10. Diabetes
• 11. Cirrhosis
• 12. Terminal ileal disease (IBD)
• …think about disruption of the enterohepatic circulation!

• 1. Cholelithiasis (Gallstones)
• 2. Jaundice
• 3. Pruritus
• 4. Darkening of urine (bilirubin spilling into urine)
• 5. Malabsorption (A,D,E,K)
• 6. Steatorrhea
• 7. Pain (epigastric, RUQ, right shoulder)
• 8. Hepatotoxicity (untamed bile acids are highly toxic)
• 9. Kernicterus (neonates)

• • Remove the obstruction
• • Remove the offending agent
• • Treat the underlying condition (sepsis, PBC)
• • Lower cholesterol (DM, hyperlipidemia)
• • Ursodiol: Partially inhibits cholesterol synthesis (HMG-CoA reductase) inhibition; Stabilizes canalicular membrane; Solubilizes cholesterol and improves biliary flow; “dissolves stones”

• macrophages: heme->bilirubin&biliverdin
• plasma: unsoluble bili binds to albumin
• liver: bili separates from albumin, is taken up, conjugated w/glucoronic acid
• bile: conj. bili -> urobilogen in intestine
• @ high levels, urobilogen is reabsorbed and excreted in urine

• heme taken up into enterocytes
• transporter converts Fe3+ to Fe2+
• Stored in ferritin (apo) - some leaks into plasma, can judge Fe levels by this
• Apoferritin synth inhibited when Fe levels are low
• Converted back into Fe2+ at basolateral membrane

• excessive absorption of Fe
• mutation of HFE or hepcidin genes
• in the fetus, hepcidin regulates transport of Fe by ferroportin
• bronze skin, damaged liver, heart, pancreas

• hecipidin induced by cytokines
• normally produced by liver
• binds to ferroportin
• causes macrophages to accumulate Fe
• MCV is not as low as in anemia of Fe deficiency because high hepcidin will prevent nascent RBCs from exporting Fe to restore plasma Fe levels

• Fe accumulation in erythroblasts
• Excess ferritin can precipitate to form“hemosiderin”
• Hereditary defect in heme synth or acquired (lead poisoning)

• defects in heme synthesis
• acute: earlier steps (ALA)
• cutaneous: later steps, sun lesions, red teeth, urine

• H2 receptor antagonist
• antacid
• inhibits many CYP450s
• SE: diarrhea, dizziness, headache, rash, confusion

• antibiotic/motilin agonist
• binds to 50s bacterial
• SE: GI upset

• SSRI antidepressant
• GI discomfort, diarrhea, nervousness, anxiety, nausea

• 5HT3 antagonist, 5HT4 agonist
• D2 antagonist
• prokinetic drug (antiemitic)
• treats reflux esophagitis
• SE: diarrhea, drowsiness, depression

• PG E1 analog
• prevents gastric ulcers
• mucus and bicarb secretion
• SE: diarrhea, dyspepsia, abd pain

• carbamate-type AChEI
• increases bladder tone, gastric motility, treats myasthenia gravis
• SE: bowel cramps, diarrhea

• somatostatin analog
• treats diarrhea, orthostatic hypotension, variceal bleeding
• inhibits gastrin/pepsinogen secretion
• reduces motility, gallbladder contractions
• SE: cramps and nausea

• inhibits Fe release from macrophages by binding ferroportin
• high levels of ferritin intracellular -> high [ferritin] plasma also
• apoferritin synth inhibited by low intracellular Fe3+
• defect secondary to chronic disease

• glutaminase in kidney
• aminotransferases
• bacterial digestion
• catabolism of catecholamines and nucleotides

• urea exreted by kidney 75%, intestine 25%
• arginine increases excretion (allows regeneration of ornithine and synthesis of arginosuccinate, which is efficiently excreted by the kidney)
• Sodium benzoate, sodium phenylacetate

• shunts secondary to portal hypertension cause NH3 absorbed from GI to bypass the liver
• decreased urea synthesis due to damaged hepatocytes
• toxicity due to: increased synth of glutamate, lack of alpha-KG, lack of ATP, hepatic encephalopathy

• disulfiram
• consumes NADPH, which is needed to power glutathione reductase to regenerate GSH
• GSH keeps Hb Fe in ferrous state
• Anti-oxidant

• aspirin - inhibits synth of thromboxane A2
• clopidegrel - blocks binding of ADP to receptor on platelet

• activated in vitro by interaction of factor XII, kininogen and kallikrein with the damaged surface of container
• activation process is not important in vivo because factor XII, kininogen and kallikrein are not required in vivo

• Cleaves fibrinogen to fibrin
• Cleave a thrombin receptor on platelets to activate platelets (second pathway of platelet activation)
• Cleave V and VIII to from active Va and VIIIa
• Limit clot formation by eventually cleaving Va and VIIIa

• Protein C activated by thrombin complex + Protein S -> cleaves Va, VIIIa
• antithrombin + active protease -> inactive complex (heparin increases the activity of antithrombin)

• TPA = tissue plasminogen activator
• plasminogen-TPA->plasmin
• plasmin breaks down fibrin clot