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How many liters of fluid go into the GI tract/day? Where do they come from?
- 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
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2 basic types of GI regulation?
- -- Neural regulation
- a. extrinsic nervous system: autonomic nerves.
- b. The intrinsic/enteric nervous system: local neural network - neurotransmitters and neuromodulators
- -- Hormones and Paracrine Factors
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Cephalic Phase
- Anticipation!
- parasympathetic efferent pathway activates enteric nerves -> parietal cells secrete HCl and stimulate the G cells to secrete the hormone gastrin => increased motility
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Gastric Phase
- 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.
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Intestinal Phase
- Distention
- acidity
- hyperosmolarity
- fat/amino acids
- -> neural reflexes and hormone secretion
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Secretion of salivary
- No hormonal reg
- Parasympathetic - facial and glossopharyngeal nerves release ACh, bind to muscarinic receptors
- Sympathetic - thoracic spinal nerves T1-3, B adrenegeric receptors
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Swallowing
Secondary peristalsis
- Pressure -> afferent to brainstem -> efferent to pharynx
- Stuck food, contractions w/o swallowing
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Anatomical and physiological divisions of stomach
- Fundic/cardiac, Body, Antrum
- Orad - top half, relaxes w/LES, expands
- Caudad - perstaltic contractions
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BER/slow waves
- Parasympathetic activation, and secretion of gastrin and motilin depolarize Vm
- Sympathetic activation hyperpolarizes Vm
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HCl secretion in stomach
- parietal cell - H+/K+ ATPase, Cl- channel on luminal, HCO3-/Cl exhanger on serosal
- ACh, gastrin, histamine - # H+/K+ ATPases
- pepsinogen -> pepsin by HCl
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vitamin absorption
- 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
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Vomiting (3 steps)
- 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
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Pyloric sphincter reg
- acidity: enteric neural reflex, contraction
- fat content: CCK, contraction
- hyperosmotic chyme: contraction
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Motility of small intestine
- Chyme after a meal - higher frequency contractions at proximal end than distal (9-12/min)
- MMC - during fasting, 1/90min, sweep undigested contents
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hormonal and paracine reg of sm intestine motility
- 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
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Exocrine pancreas: HCO3-
- 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
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Exocrine pancreas
- 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
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Bile
- 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
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large intestine contractions
- 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
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Saccharide absorption
- 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
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visceral v. parietal peritoneum
- 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
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peritoneal cavity
peritoneal ligament
- potential space between layers of peritoneum. Thin layer of fluid lubricates, allows organs to move
- Connects organ to peritoneum or organs to each other
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Intraperitoneal organs
Retroperitoneal organs
- almost completely covered with visceral peritoneum
- outside the peritoneal cavity (external or posterior to the parietal peritoneum) and are only partially covered by peritoneum.
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Celiac trunk branches
- 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
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Superior mesenteric artery branches
- -> ileal and jejunal branches (15-18)
- -> ileocolic, right colic, middle colic, common inferior pancreaticoduodenal ileocolic - ileal, colic, anterior cecal, posterior cecal and appendicular
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Inferior mesenteric artery branches
superior rectal, sigmoids and left colic. marginal artery forms an anastomosis w/ superior mesenteric artery
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Portal vein
- Formed at L2 by superior mesenteric + splenic veins (+ inf mesenteric)
- -> liver -> hepatic vein -> IVC
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anastomosis occurs in 4 areas
- (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.
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Busiprone
- 5HT1A partial agonist
- treatment for dyspepsia/anxiolytic
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Aortic (pre-aortic) plexus ganglia
- Only sympathetics synapse here, parasymps (vagal and pelvic splanchnics) run thru to synapse @ organ
- celiac, aorticorenal, sup mesenteric, inf mesenteric
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Enteric Nervous System
- 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
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Path of bile
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.
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Foregut
- distal esophagus, stomach, 1st & 2nd parts of the duodenum, liver, gallbladder and pancreas
- NOT spleen
- greater splanchnics (T5-9), anterior vagal trunk
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Midgut
- from 3rd part of duodenum to prox 2/3 of transverse colon
- lesser and least splanchnics (T10-12), posterior vagal trunk
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5 differences between ileum and jejunum
- 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).
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Features of large intestine
- Teniae coli: 3 thickened bands of muscle
- Haustra: sacculations
- Epiploic appendices: fat
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Hindgut
- Distal 1/3 of transverse colon to anus
- Lumbar splanchnic (symp T12-L2) Pelvic splanchnics (parasymp)
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Anal canal
- 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
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Portal triad and direction of flow in liver
- 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
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Blood supply to liver
- Portal vein - 70%
- Hepatic artery - 30%
- Fenestrated endothelium
- 1/3-1/2 can be regenerated
- splanchnic capillaries & liver sinusoids = portal system
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pre-sinusoidal portal hypertension
- Portal vein thrombosis
- Schistosomiasis
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post-sinusoidal portal hypertension
- Venoocclusive disease
- Budd Chiari
- IVC Web
- Heart failure
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where is the apical membrane in the liver?
- apical - between cells, where bile is secreted into canniculi
- basolateral - adj to sinusoids
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vitamins lost in diarrhea
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Fat soluble vitamins A,D,E,K and water soluble vitamin B12 lost
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Composition of bile
67 % Bile Salts
- 26 % Phospholipids
- (lecithin) and cholesterol
4.5 % Proteins
0.3 % Bilirubin
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functions of bile
- 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
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What puts you at risk for gallstones?
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!
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Consquences of cholestasis
- 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)
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Cholestasis treatment
- • 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”
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Pathway of bilirubin metabolism
- 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
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Uptake of Fe3+ from diet
- 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
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hemochromatosis
- 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
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anemia of chronic disease
- 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
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sideroblastic anemia
- Fe accumulation in erythroblasts
- Excess ferritin can precipitate to form“hemosiderin”
- Hereditary defect in heme synth or acquired (lead poisoning)
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porphyrias: acute
- defects in heme synthesis
- acute: earlier steps (ALA)
- cutaneous: later steps, sun lesions, red teeth, urine
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Cimetidine
- H2 receptor antagonist
- antacid
- inhibits many CYP450s
- SE: diarrhea, dizziness, headache, rash, confusion
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erthyromycin
- antibiotic/motilin agonist
- binds to 50s bacterial
- SE: GI upset
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Fluoxetine
- SSRI antidepressant
- GI discomfort, diarrhea, nervousness, anxiety, nausea
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Metoclopramide
- 5HT3 antagonist, 5HT4 agonist
- D2 antagonist
- prokinetic drug (antiemitic)
- treats reflux esophagitis
- SE: diarrhea, drowsiness, depression
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Misoprostol
- PG E1 analog
- prevents gastric ulcers
- mucus and bicarb secretion
- SE: diarrhea, dyspepsia, abd pain
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neostigmine
- carbamate-type AChEI
- increases bladder tone, gastric motility, treats myasthenia gravis
- SE: bowel cramps, diarrhea
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Octreotide
- somatostatin analog
- treats diarrhea, orthostatic hypotension, variceal bleeding
- inhibits gastrin/pepsinogen secretion
- reduces motility, gallbladder contractions
- SE: cramps and nausea
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hepcidin
- 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
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Sources of NH4+
- glutaminase in kidney
- aminotransferases
- bacterial digestion
- catabolism of catecholamines and nucleotides
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urea cycle
- 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
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acquired hyperammonemia
- 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
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EtOH abuse
- disulfiram
- consumes NADPH, which is needed to power glutathione reductase to regenerate GSH
- GSH keeps Hb Fe in ferrous state
- Anti-oxidant
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action of aspirin v. clopidegrel
- aspirin - inhibits synth of thromboxane A2
- clopidegrel - blocks binding of ADP to receptor on platelet
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Intrinsic pathway
- 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
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thrombin
- 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
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limiting clot formation
- Protein C activated by thrombin complex + Protein S -> cleaves Va, VIIIa
- antithrombin + active protease -> inactive complex (heparin increases the activity of antithrombin)
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dissolution of clot
- TPA = tissue plasminogen activator
- plasminogen-TPA->plasmin
- plasmin breaks down fibrin clot
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