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1297 Cards in this Set
- Front
- Back
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Stomach function
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Hold recently ingested food
Digestions (mixing, grinding, pepsinogen) Release in a controlled fashion into duodenum (50 micron particles) Allows for intermittent feeding |
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Cardia
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Ill defined region of stomach adjacent to esophagus
Begins at Z-line Transition from squamous to columnar (for protection from acid) Shallow gastric pits w/ surface mucosal cells |
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Fundus
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Projects above cardia/fundus
Dome-shaped area In contact with left hemidiaphragm and spleen Accommodates food |
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Body of stomach
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Bulk of stomach
Between fundus and antrum Accommodates food |
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Antrum of stomach
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From incisura angularis to pyloris
Gastrin secretion Mixing, grinding, sieving particles Regulation of fnc by gastrin/somatostatin |
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Incisura angularis
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Fixed sharp indentation two thirds down lesser curvature
End of fundus/beginning of antrum |
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Pylorus
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Tubular structure connecting stomach to duodenum
Contains palpable circular muscle (sphincter) Typically 2 cm right of midline at L1 |
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Oxyntic gland mucosa
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Mucosa of proximal 80% of stomach
Secretes acid Body and fundus |
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Pyloric gland mucosa
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Mucosa of distal 20% of stomach
Secretes gastrin Antrum |
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Stomach embryologic development
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Dilation of distal forgut @ 4 weeks
Dorsal grows faster than ventral 90 degree rotation brings dorsal (greater) to left and ventral (lesser) to right |
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Vagal innervation of stomach
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Left vagus -- anterior wall
Right vagus -- posterior wall This is due to embryologic rotation |
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Stomach layers
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Mucosa - deep mucosa/lamina propria - submucosa - muscularis propria -- serosa
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Stomach mucosa
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Lines gastric lumen
In rugae if not distended Appears smooth, velvety Contains most of the functional secretory machinery of the stomach |
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Stomach submucosa contents
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Collagen/Elastin
Immune cells Submucosal plexus |
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Muscularis propria of stomach
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Three layers
Inner oblique -- present throughout Middle circular -- thickens distally to for pyloric sphincter Outer longitudinal -- mostly along curvatures |
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Where are gastric pits in stomach?
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Throughout
Deepest in fundus, most shallow in cardia Entrance to deep gastric glands Amplify surface area |
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Glands of the cardia
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Tortuous branching
Mucus, endocrine, undifferentiated cells |
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Oxyntic/Parietal glands
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Isthmus-- surface mucus cells
Neck -- parietal cells, neck mucus cells Base -- chief cells, some parietla mucus Scattered throughout: somatostatin D-cells, endocrine cells, enterochromaffin-like cells Makes acid, intrinsic factor, most gastric enzymes |
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Enterochromaffin-like cells secrete?
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Histamine
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Gastric gland growth
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Precursors cells are in mid-neck region
Division send cells up to become mucus cells and down to become parietal/chief/endocrine cells Replenishing surface cells <1 week, several weeks for lower (more specialized cells) |
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Surface and neck cells
Secretion products and function |
Mucus - lubrication/protection
HCO3 -- protection |
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Parietal cells
Secretion products and function |
H + -- protein digestion, protection from bacteria
Intrinsic factor -- B12 binding |
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Chief cells
Secretion products and function |
Pepsinogen -- protein digestion
Gastric lipase -- triglyceride digestion |
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Endocrine cells
Secretion products and function |
D-cells -- somatostatin -- regulation
ECL-cells - histamine G-cells - gastrin -- regulation of acid |
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Surface cell renewal time
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3 days
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Parietal cell structure
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Lots of mitochondria
need energy for concentration of H+ Tubovesicular system if not secreting Tubocvesicles are incoorporated into extensive cannicular system if secreting Apical carbonic anhydrase and N/K-ATPase 1 billion/stomach |
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Parietal cell function
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Exchange H for K via ATPase
Form HCL HCL excreted Intrinsic factor is secreted by exocytosis |
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Parietal cell stimulation
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Morphs into acid-secreting cell in 10 minutes
H/K exchanger to membrane AcH, gastrin, histamine stimulate |
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PPI site
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Inhibits the H/K-ATPase at the apical surface of parietal cells
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H2 blocker site
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Inhibits histamine receptor
Prevents one pathway of stimulation of parietal cell |
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Parietal cell inhibitors
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Somatostatin -- inhibits parietal cell and gastrin secretion
Based on acidity, having food buffer increases total H secretion PGE2 -- links to an inhibitory G-protein in parietal cells, opposes H2 activation pathway |
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Bicarb and Parietal cells
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Released interstitially
Transported by capillaries to luminal cells for protection from luminal acid |
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Gastric juice concentrations
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Isotonic with plasma
Increase H and Cl with high secretion Decreased Na |
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Metabolic effects of prolonged vomiting
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Loss of H+, K+, Cl-, H20
Alkalosis, Hypokalemia, Hypochloremia, Dehydration Cramps, nausea, muscular weakness, lethargy |
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Rehydration with long term vomiting?
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Don't just use NaCl
They are in hypokalemia metabolic acidosis |
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Mucus secretion regulation
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Surface cells - increased secretion of mucus in response to physical contact with food or chemicals (ethanol)
Neck cells -- vagus, ACh mediated |
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What is mucus
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Glycoproteins
Linked by disulfied bonds -- mucus gel |
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Mucus barrier
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Secreted mucin plus shed surface cells
Protects mucosa by trapping alkaline secretions/acid secretions Also allows for the huge concentration gradient |
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What disrupts the gastric mucosal barrier?
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Weak acids -- aspirin
Alcohols -- ethanol NSAIDs Detergents -- bile salts |
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What is the gastric response to a meal?
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Increased acid secretion
Mediated by endocrine, neural, paracrine systems |
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Gastrin secreted in response to
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AA and small peptides in stomach
Distention of stomach Vagally stimulation via gastrin release peptide |
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Gastrin secretion inhibited by
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H + in lumen
Somatostatin |
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Gastrin actions
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Stimulation of parietal cell
Stimulation of ECL-cell to make histamine (which stimulates to parietal cell) Gastric mucosal growth Pepsinogen secretion |
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Cholecystokinin
from? when? fnc? |
I-cell in duodenum
In response to AA, small peptides, fatty acids Stimulates H+ secretion by parietal cell Inhibits gastric emptying |
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Secretin
from? when? fnc? |
S-cell in duodenum
In response to H+ in duodenum, fatty acids in duodenum Inhibits H+ secretion by parietal cells |
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Glucose-dependent insulinotropic peptide (GIP)
from? when? fnc? |
Secreted from duodenum, jejunum
In response to glucose, fatty acids, amino acids Inhibits H+ secretion by parietal cells |
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Somatostatin
from? when? fnc? |
D-cells in antrum
In response to H+ in lumen Inhibited by vagus PARACRINE Inhibits secretion of acid and release of all GI hormones |
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Histamine from ECL cell, stimulate and inhibit
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Stimulated by Vagal/ACh, gastrin
Inhibited by somatostatin, histamine |
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Histamine from ECL action
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Paracrine
Stimulation of parietal cells Potentiates action of gastrin/vagus to increase H+ secretion |
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Gastrin releasing peptide
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Vagal neurotransmitter
Released by axons innervating G-cells Results in release of gastrin |
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Phases of response to meal
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Cephalic -- response to sight, smell, taste, thought of food
Gastric -- response to food in lumen Intestinal - response to movement of food out of the stomach and low pH in GI tract |
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What phase is responsible for greatest meal related increase in acid secretion?
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Gastric -- mechanical, peptides -- 50% of response
Basal - 15% Cephalic -- 30% (vagal pathways) Intestinal -- 5% -- digestive products |
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Vagus actions in acid secretion
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Sight/smell/taste of food stimulated vagus
Directly stimulates parietal, chief cells, ECL, G cells Neurocrine secretion of G cells via GRP-- strong effect |
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Gastric phase response to food
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Food lowers pH of stomach -- increased gastrin
AA and protein breakdown products -- increased gastrin Stomach distention -- parietal cell stimulation via vagal reflex arc and gastrin release |
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Cessation of response to food
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Once food moves out of gastric lumen, distention stimulus and acid neutralization is lost
Rising H+ concentration stimulates somatostatin, which inhibits G cells |
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Enterogasterones
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Hormones secreted from the duodenum in response to FAs or hyperosmolar solutions
Inhibit gastric emptying and ?acid |
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Peptic ulcer disease presentation
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Asymptomatic (40%)
Gnawing epigastric pain Relieved by eating, antacids Worse on empty stomach May awaken from sleep |
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Is history enough for PUD diagnosis?
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No
Ulcer-like symptoms occur w/o ulcer -- 80% of time Need upper endoscopy (used to be UGI barium) |
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What is concern if ulcer is seen on endoscopy?
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Gastric cancer
Need to FOL with w/ Bx Duodenal ulcers this is not a problem |
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Complications of PUD
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May run benign course
or Hemorrhage, perforation, gastric outlet obstruction |
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Perforated ulcer
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Life threatening
Free air on xray Associated with age, NSAID use (even baby aspirin), cocaine Sudden intense abdominal pain, some resolution, peritonitis...death |
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Treating perforated ulcer
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IV resuscitation
Antibiotics Surgical repair of ulcer |
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Ulcer surgery
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Get rid of the acid
Vagotomy -- truncal w/ pylorplasty or highly selective Antrectomy -- Billroth I or II (more distal reanastomosis) --remove gastrin and cholinergic stimulus |
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Complications of ulcer surgery
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Truncal vagotomy - gastroparesis
Antrectomy -- Small gastric pouch, ulcer in displaced tissue, afferent loop syndrome, diarrhea (10%), dumping syndrome, alkaline reflux |
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Peptic ulcer disease occurs when
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the pre-epithelial, epithelial and mucosa defense mechanisms against acid are overwhelmed
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Epithelial defense mechanisms against acid
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Tight junctions
Basolateral Ion pumps Rapid restitution of cell gaps with wandering epithelial cells |
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Mechanism of cell damage in peptic ulcer
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Direct acid damage
Stimulation of mast cell degranulation |
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What keeps treated ulcers from recurring?
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Acid control
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Why do ulcers bleed?
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Erosion into vessel
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Helicobacter pylori generally
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Spiral shaped
Gram negative Tropic to gastric mucosa Highly motile Associated with gastric, duodenal ulcers, chronic gastritis |
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H pylori virulence factors
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A lot
Urease --Urea to ammonia: neutralizes acid Acid inhibitory protein Shape, flagella, mucolytic enzymes to burrow into mucosa Adhesins attach specifically to gastric epi Vacuolating toxin, secretory enzymes injur mucosa Cytoxin associated antigen causes increased inflammatory response |
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H pylori epidemiology
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Developing (80%) > industrialized (10% 18-30, 50% >60)
Childhood acquisition most common Inversely proportional to SE status Probably fecal/oral |
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Why does H pylori cause ulcers?
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Disruption on mucus barrier
Adherence to gastric cells Increased host immune response All increase susceptibility to gastric acid damage |
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Complications of H pylori infection
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Gastroduodenal ulcers
Gastric adenocarcinoma Gastric MALT ? protective against esophageal adeno |
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Outcomes of H pylori infection
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80% - mild mixed gastritis -- not significant
10-15% -- antral prominence -- increased gastrin and acid -- duodenal ulcer 5-10% -- corpus predominance -- low acid -- gastric cancer, atrophy |
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Acute H pylori infection
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High concentrations -- acute epigastric pain, gastritis
Typical innoculum probably mildly symptomatic |
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H pylori and evolution
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Probably used to be a helpful comensal
?protective against diarrheal disease Gastric cancer not an issue during lifespan of evolutionary humans, diet changes have increased acid secretion |
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Helicobacter and pets
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Can move from pets to humans and cause gastroenteritis
Pylori has been isolated from domestic cats |
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Testing for H pylori
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Urease breath test, serology for IgG, H pylori stool antigen
Endoscopy with biopsy: histology (93% sens, 99% spec), urease activity (90-5% sens 95-100%s spec), culture |
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Histology in H pylori
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PMNs in inflamed mucosa
Helicobacter can be seen better with Giemsa, Genta, Warthin-Starry stains Need to get the right sample, interobserver variability |
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H pylori stool antigen test
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Sense -- 94%
Spec -- 86-92% Testing for erradication at 4 weeks (94/95%) False negs with therapy: lansoprazole, bismuth |
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What does H pylori eradication do?
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Dramatically reduces PUD recurrence
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Treating H pylori
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0-35% eradication rate with single agent, rapid resistance
Amoxicillin, metronidazole, tetracylcine, bismuth, furazidolone, rifabutin, fluroquinaolones |
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Amoxicillin in treating H. pylori
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Very sensitive in vitro, but works best at neutral pH, rarely resistant
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Tetracycline in treating H. pylori
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Active at low pH
Resistance rare in west (6% in Korea, Japan) |
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Metronidazole/tinidazole
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Actively secreted into gastric juice
Activity independent of pH Resistance is common but dose can increased |
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Clarithromycin
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High cure rate
High resistance rate (cannot be overcome by dose) Acid stable, well tolerate (compared to erythro) |
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Bismuth
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Topical antimicrobial that disrupts bacterial cell walls
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Rifabutin
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Low MIC for H pylori
Inhibits bacterial RNA polymerase |
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Quinolones
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Can be used in combo therapy
Rapid resistance |
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Antisecretory agents
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H2 and PPI (slightly better)
Not necessary to heal an H pylori ulcer Can help ABx work better and/or increase immune response by increasing pH |
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Recommended therapy for H pylori
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10-14 days of
PPI + clarithromycin, amoxicillin (77-80%) or clarithromycin, metronidazole (70-85%) or bismuth, metronidazole, tetracylcine 75-90% |
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New ideas in H pylori antibiotic therapy
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Sequential therapy
Amoxicillin then clarithromycin overcomes clarithromycin resistance because no cell walls left for efflux pumps |
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Treatment for resistant H pylori
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Assume clarithromycin resistance
Keep using a PPI and try different antibiotics Consider culture Use quadruple therapy |
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Did treatment of H pylori work?
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Check 4 weeks later via stool or breath (not serology)
Should stop PPI for two weeks to check |
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NSAID mediated ulcers
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Topical irritation of gastric mucosa
and COX-1 inhibition results in reduced prostaglandins Prostaglandins stimulate production of mucus, mucosal blood flow, mucosal proliferation |
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Where are NSAID mediated ulcers found?
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Anywhere in stomach or duodenum
But most commonly in antrum |
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Risk factors for NSAID ulcer
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Prior PUD
Prior NSAID- GI complication Age High dose Combo of aspirin and NSAIDs Concomitent use of glucocorticoids or anticoagulants Comorbid disease ?H pylori, smoking, EtOH |
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Esophageal development
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Gut formation through incorporation of yolk sac into embryo
Tracheoesophageal septum divides into ventral trachea and dorsal esophagus (4th week) Rapid elongation - by week 7 is at final relative length |
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Developmental abnormalities of the esophagus
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Uncommon
Atresia -- usually tracheoesophageal fistula Short esophagus Esophgeal stenosis |
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Esophagus structure
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Muscular tube with sphincter at either end
UES - C6 LES and diaphragmatic hiatus - T10 20-25 cms |
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Esophageal muscle
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Proximal 5% - striated
Middle 35% -- mixed Distal 60% -- smooth Outer longitudinal - off cricoid cartilage, cricopharyngeus -- UES Inner circular -- full length of esophagus, forms LES |
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UES and LES tone
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Tonically contracted to prevent air swallowing and reflux
UES - pharyngeal branch of vagus (inferior constrictor, cricopharygeus, prox esophagus) 30-120 mmHg LES -- diaphragm, pharyngeosophageal ligament, muscle -- 14-35 mmHg |
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Layers of esophagus
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Mucosa -- stratified squamous
Submucosa Muscularis propria (outer longitudinal, inner circular) Adventitia NO serosa |
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Dysphagia
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Difficulty swallowing
Sensation of sticking |
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Odynophagia
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Painful swallowing
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Globus
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Sensation of fullness in upper throat
Relieved with swallowing |
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Pyrosis
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Substernal heartburn
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Regurgitation
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Return of sour gastric contents
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Water brash
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Spontaneous salivation from GER
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Rumination
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Chewing cud
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Gastric motility
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Muscle and nerve function in GI tract
Silent, subconscious Disorders can by myopathic, neuropathic or both |
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Where does aorta contact esophagus
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T3
Impingment -- dysphagia aortica |
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Arterial supply to esophagus
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Upper -- Inferior thyroid
Middle -- right and left bronchial arteries Distal -- small branches of aorta, esophageal branch of left gastric |
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Venous drainage of the esophagus
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Upper -- inferior thyroid veins
Mid -- azygous and hemiazygous veins Distal -- left gastric vein |
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Innervation of esophagus
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Enteric -- myenteric plexus
Sympathetic and parasympathetic Sensory -- vagus to nucleus tractus solitarius |
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Act of swallowing
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Bolus of masticated food is pushed backwards
Soft palate elevates-- closes nasopharynx Larynx elevates, vocal cords close, epiglottis tips forward UES opens, LES opens, pharynx contracts Peristalsis |
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Oropharyngeal dysphagia
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Problem with mechanisms of mouth, pharynx or UES
Issue of food transfer Difficulty initiating a swallow Sticking in throat, nasal regurg, coughing with swallow |
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Esophageal dysphagia
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Intralumenal obstruction
Either anatomic (ring, stricture, compression) or functional (spasm, muscle failure) Food feel stuck in chest, although typically below where patient points Problem of food transport |
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Steps necessary for successful swallow
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Initiation
Sealing of nasopharynx (avoid regurg) Protect airway (avoid aspiration) Clearing (avoid residual in vallecula) |
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Causes of oropharyngeal dysphagia: neuro
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Neurologic : CVA, TIA, CN palsy, AML, MS, Parkinson's, Huntington's, Wilson's, Spinocerebellar degeneration, polio, tabes dorsalis, neurosyph, botulism, tetanus, diptheria
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Causes of oropharyngeal dysphagia: muscular
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Skeletal muscle disorders
polio, dermatomyositis, MG, myotonic dystrophy, metabolic myopathy, amyloidosis |
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Causes of oropharyngeal dysphagia: structural
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Oropharyngeal malignancies
Inflammation Extrinsic compression Post surg/xrt Zencker's diverticulum Web/bar Xerostomia |
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Zencker's diverticulum
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Diverticulum off posterior pharynx
Above cricopharyngeal muscle Can produce extrinsic narrowing Treated with diverticulectomy or endoscopic resection of wall between diverticulum and lumen |
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Primary peristalsis
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Initiated by swallow
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Secondary peristalsis
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Initiated by luminal distension
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Tertiary peristalsis
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Ineffective, non-peristaltic contractions
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What are some studies to assess esophageal function?
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Barium swallow
Upper endoscopy (EGD) Esophageal manometry pH studies Cine-esophagogram (video of barium coated stuff swallowed) Impedance |
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Esophageal manometry
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Thin pressure sensitive tube passed down esophagus
Used to assess LES fnc or esophageal body peristalsis |
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Normal LES relaxation
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Occurs in anticipation got bolus arrival. Neurally mediated
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Achalsia
Define and etiology |
LES unable to relax
Loss of NO containing neurons in myenteric plexus Loss of ganglion cells, exact etiology unclear: inflammatory, genetic, viral/bacterial, autoimmune, degenerative |
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Achalsia
Incidence and prevalence |
Incidence: 1/100,000 per year
Prevalence 9/100,000 |
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Achalasia
Epidemiology |
Women = men
Rare in <20 years Mean age for diagnosis 30-60 |
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Achalasia
Natural history |
Generally progressive
4.5 years of symptoms before diagnosis, often with several physicians visits |
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Achalasia
Symptoms |
Majority: Dysphagia of solids, liquids
Difficulty belching Many: Chest pain, noctural regurgitation Some: Aspiration, loss of heart burn |
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Diagnosis of achalasia by chest xray
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Dilated esophagus
Air/fluid line in esophagus Lack of gastric air bubble |
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Diagnosis of achalasia by barium swallow
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Characteristic "bird beak"
Symmetrically tapered distal esophagus Dilated esophagus Delayed esophageal emptying Aperistalsis Lack of gastric air bubble |
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Esophageal manometry in achalasia
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Gold standard
Incomplete relaxation of LES LES resting pressure elevated Aperistalsis Simultaneous contractions Mirror image or low amplitude contractions |
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Vigorous achalasia
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Achalasia with high amplitude, vigorous esophageal contractions
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Endoscopy and achalasia
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Not great for diagnosis, but rule out obstruction of esophagus
Finding is food in a dilated esophagus Pinpoint of opening of the LES, resistant to endoscope |
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Achalasia treatment
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Endoscopic balloon dilation (70% success)
Drugs: nitrates, ca channel blockers, botulinum toxin, myotomy Myotomy -- allows food to fall down via gravity, reflux is a problem (30% success) |
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Diffuse esophageal spasm
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Typical symptoms: chest pain and dysphagia
10-20% of chest pain of unknown origin Diagnosed by manometry Treated with relaxants |
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Diffuse esophageal spasm on barium swallow
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Corkscrew appearance
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Nutcracker esophagus
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Chest pain and dysphagia (or asymptomatic)
High amplitude, long duration esophageal contractions diagnosed on manometry Etiology unknown Treated with relaxants |
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Hypertensive LES
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High resting tone of LES (>45 mmHg) with complete relaxation
Normal or high amplitude peristaltic contractions of esophagus Chest pain and dysphagia Treated with: meds, endoscopic dilation, botulinum, surgery (severe cases) Etiology unknown |
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Scleroderma and the esophagus
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Vascular obliteration and fibrosis in smooth muscle
Weak LES --reflux Poor esophageal contractility Delayed gastric emptying |
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Transient Lower Esophageal Sphincter Relaxations (TLESRs)
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Prolonged relaxation of LES (>6 s) without preceding swallow
Major underlying mechanism in acid reflux disease |
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GERD incidence
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Effects 40% of US adults monthly and
7% daily |
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GERD secondary causes
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Hypotensive LES
Ineffective esophageal motility Gastroparesis Symptoms: pyrosis, waterbrash, regurg |
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GERD treatment options generally
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Lifestyle
Antacids H2RAs PPIs surgery |
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Hypotensive LES
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Myopathic problem of some type or idiopathic
resting LES <10 mmHg Risk for reflux Treatment underlying disorder, acid reduction |
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Ineffective esphageal motility
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30% or more of
lower esophageal contractions are low amplitude (<30mmHg) and total contractions not transmitted Reflux, regurg, dysphagia Frequent finding in persistent GERD patients, but does not always cause GERD Etiology mixed: reflux, myopathy, infiltrative, endocrine |
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Causes of esphageal strictures
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Rings and webs
Reflux esophagitis Tumors Caustic ingestions Infections Derm disorders Iatrogenic: pill, xrt, NG tube, sclerotherapy |
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Esophageal compression causes
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Vascular -- aortica, lusoria (pulm vasculature)
Mediastinal mass |
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Esophageal web
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Thin membrane in upper or middle esophagus
Mucosa and submucosa |
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Esophageal ring
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Muscular ring around narrowing esophagus
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Schatzki ring
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Mucosal ring at squamocolumar junction narrowing esophagus
Can be congenital GERD also a factor |
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What to worry about with strictures in esophagus
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Top and bottom - motility disorders
Middle -- cancer |
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Squamous cancer of the esophagus
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Most common worldwide
Related to smoking, alcohol Proximal or mid esophagus Predisposing conditions: achalasia, celiac sprue, lye stricture, plummer-vinson, head and neck cancer, tylosis |
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Adenocaricnoma of the esophagus
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50% of esophageal cancer in US
Distal esophagus Related to reflux, Barrett's |
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Cancer on a barium swallow?
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Shelf -- area where stricture is released is where cancer ends
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Staging in esphageal cancer
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Tumor based on invasion (into submucosa, into muscle, into adventitia, into adjacent structures)
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Treating esophageal cancer
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Surgery/Radiation for potential cure
Chemo for treatment of mets Surgery can be morbid/mortal, but provides immediate relief XRT -- takes longer, complicated by inflammation of surrounding tissue, but less acute morbidity Chemo -- not super effective |
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Palliating esophageal cancer
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Dilation
Stenting Tumor ablation with laser, phototherapy, tumor probe, chemical injection |
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Candida esophagitis on barium
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Spiculations
Very painful |
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Most common cause of esophageal symptoms in AIDS?
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Candida
Also HSV, CMV |
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Questions to ask in dysphagia
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How long?
Intermittent/constant/progressive? What kind of food? If liquids and solids now, which first? Age Heartburn Red flags-- weight loss, blood loss |
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Pyrosis
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Substernal burning or discomfort that may radiate into mouth or throat
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Regurgitation
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Involuntary movement of liquids or solids up into the mouth or throat
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GERD, what is it?
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Symptoms with or without presence of tissue damage 2/2 reflux of gastric contents
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Typical manifestations of GERD
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Heartburn and regurgitation
With erosive esophagitis 30-50% of the time |
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Atypical manifestations of GERD
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Asthma
Cough Laryngitis Chest pain Dental erosions |
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Complications of GERD
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Stricture
Ulcer Cancer -- adeno Intestinal metaplasia - Barrett's esophagus |
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Pathophysiology of GERD
|
Increase in transient LES relaxations
Decrease in basal LES tone Hiatal hernia Delayed gastric emptying (too much acid dwell time) Impaired esophageal clearance Impaired mucosal defense |
|
|
Factors that aggravate GERD
|
Alcohol, tobacco
Pregnancy (hormone and anatomic) Drugs Hiatal hernia Fat, caffeine, chocolate, juices Posture, obesity |
|
|
GERD and obesity
|
Obese patients twice as likely as normal weight patients to have a mechanically defective LES
|
|
|
Diagnosis of GERD
|
Symptoms
Empiric acid suppression Endoscopy with concerning symptoms Can use UGI, barium, pH studies |
|
|
When to endoscopy in GERD?
|
Guidelines: odynophagia, dysphagia, GI bleeding, anemia
Conventional practice: staging esophagitis, one type look for metaplasia |
|
|
Grading esophagitis
|
By size of mucosal breaks (<5mm is A)
Whether breaks go across the mucosal ridges Total circumference (75% is D) |
|
|
Radiotelemetry pH system
|
pH capsule can be swallowed and transmit nearby recorder
Better that 24 hour transnasal option |
|
|
pH in esophagus
|
Normal is 5
Below 4 is cut off for considering disease |
|
|
Testing for pH and impedence in GERD
|
Before meds -- for diagnosis
On meds -- to see if breakthrough symptoms are caused by reflux (acid or non-acid) |
|
|
Goal of GERD therapy
|
Relieve symptoms
Improve QOL Heal esophagitis Maintain remission/ prevent complications Be cost effective Be safe |
|
|
Life style modifications in GERD?
|
Smoking cessation
Weight loss Elevate head of bed Small meals, not before bed, low fat Avoid reflux promoting agents: alcohol, coffee, theophylline |
|
|
H2RAs name some
|
cimetidine, famotidine, nizatadine, ranitadine
|
|
|
PPIs name some
|
omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, dexlansoprazole
|
|
|
Prokinetics in GERD
|
Not a big role
Do not seem to effect LES or esophageal motility much Metaclopramide - SE limited Domperidone -- safer, availability limited |
|
|
Baclofen
|
Reduce TLESRs
GABA receptor agonist Limited by CNS SEs Need to be able to target peripherally rather than centrally |
|
|
Key to healing GERD and keeping it away?
|
Acid control
Control, relapsing disease if acid is not controlled |
|
|
GERD surgery indications
|
Med failure/intolerance
Best candidates have typical symptoms, some response to med, young age, documented reflex |
|
|
Nissen fundoplication
|
Stomach wrapping supports hiatus, LES
90-95% symptom control rate, 3-5% SEs 5-10 years later, wear out in 50% |
|
|
Medical vs surgical outcomes in GERD
|
About the same
5-10 years later need revisions/increased doses in about half of patients |
|
|
Eosinophilic esophagitis
|
Chest distress, dysphagia
Easy to confuse with GERD Likely to be esosinphilic w/ feline esophagus rings, food allergies, dysphagia |
|
|
Eosinophilic esophagitis --an allergy?
|
Associated with other allergies
Elimination of food products in kids with this disease can help Responds to allergy medication |
|
|
Risk of GERD
|
Chronic, severe GERD raises risk of esophageal adenocarcinoma by 7.7
Barrett's esophagus is seen in 3-5% of chronic GERD (1% of asymptomatic) |
|
|
Barrett's metaplasia to adenocarcinoma
|
Barrett's
Indefinite dysplasia Low grade dysplasia High grade dysplasia Cancer Can go in either direction at any point |
|
|
Options to manage Barrett's esophagus
|
Surveillance for early cancer
Prophylactic esophagectomy Endoscopic ablation of metaplastic tissue |
|
|
Issues with esophagectomy as treatment for Barrett's
|
Mortality of surgery (up to 7% in not center of excellence)
Morbidity-- long term >50% |
|
|
Controlling Barrett's with endoscopy
|
Ablate down to muscularis mucosa only
|
|
|
Endoscopic mucosal resection
|
Resect out to beginning of muscularis
(removes mucosa and submucosa) Used to resect minimally invasive tumors |
|
|
Techniques for endoscopic mucosal ablation
|
EMR
Argon beam Multi-polar coagulation RFA Lasers Cryo Photodynamic |
|
|
Overproduction of gastric acid as a GERD cuase?
|
Very rare
|
|
|
Concern with OTC meds in GERD
|
hypercalcemia
|
|
|
PPIs vs H2RAs for GERD
|
PPIs are better, H2RA are better than nothing
PPIs do not work as symptomatic control |
|
|
ERCP
Uses |
Endoscopic retrograde cholangiopancreatography
Gold standard for choledocolithiasis Used only for therapy because of 5% risk of pancreatitis |
|
|
New thing in visualizing esophagus
|
Endoscopy with magnification and narrow band imaging
|
|
|
Endoscopic US
|
Use endoscopically manipulated transducer to do transesophageal US
Can see pancreas |
|
|
Endoscopic biopsy
|
Biospy the esophagus
Also possible to through wall and biopsy ex mass in pancreas |
|
|
Catheter scope
|
Allow for direct visualization
SpyGlass is used in in direclty visualizing the biliary system |
|
|
Therapeutic endoscopy techniques
|
Polypectomy
Sphincterotomy Endoscopic mucosal resection Tissue ablation Pancreatic cyst gastrosomy Tissue aposition (fistula, perfs) |
|
|
Natural orifice translumenal endoscopic surgery (NOTES)
|
Assessing peritoneal cavity endoscopically through the GI tract
|
|
|
Potential advantages of natural orifice surgery
|
No scar
Reduction in post-op pain Quicker recovery Less chance of hernia |
|
|
Robots in surgery
|
Computer assisted -- surgeon holds tools, computer assists in positioning
Robotic surgery - robot performs surgery under control of surgeon |
|
|
Advantages of robotic surgery
|
Reduced tremor
Better visualization Force-feedback Data fusion Remote surgery |
|
|
What is holding back natural orifice surgery?
|
Need for better devices
|
|
|
Infections of the mouth and esophagus
|
Candida
Herpes and CMV in immunocompromised Fungal - mucor, aspergillus, histoplasma |
|
|
What does non-candidal fungal esophagitis represent?
|
Widespread, usually fatal, systemic fungal infection
Mucor, aspergillus, histoplasma |
|
|
Pathologic signs of herpes infection
|
Multinucleated cells
Intranuclear smudy/steel gray inclusions Ulcers Vesicles HSV infects epithelial cells |
|
|
CMV infects?
|
Mesenchymal or endothelial cells
|
|
|
CMV infected cells pathologically
|
Owl eye nuclear inclusions
Also cytoplasmic inclusions |
|
|
Oral thrush
|
Candida infection
Budding yeast and pseudohyphae Most common is albicans Also: tropicallis, krusei, parapsilosis, guillermondi |
|
|
Aspergillus pathologically
|
Septate hyphae with parallel walls
45 degree branching Angioinvasive Common species: niger, fumigatus, flavus |
|
|
Mucormycosis pathologically
|
Hyphae only
Broad, bulbus, non-septate hyphae Right angle branching Angioinvasive Types: mucor, rhizopus, absidia |
|
|
Tzanck test
|
Scraping ulcer base to look for herpes infected cells
|
|
|
Pyogenic granuloma
|
Misnomer
Actually: Lobular capillary hemangioma with surface ulceration Inflammation is secondary Typically on gingival surface Looks like hamburger meat, can ooze |
|
|
Aphthous ulcer
|
Painful, shallow ulcer in oral mucosa
Idiopathic Resolve |
|
|
Oral leukoplakia
|
Descriptive term indicating white plaque
Between 5-25% are premalignant |
|
|
Hairy leukoplakia
|
EBV associated
Hyperparakeratosis Acanthosis Balloon cells Immuno compromise patients |
|
|
Oral Erythroplakia
|
Red velvety lesion in mouth
May be flat or depressed Atypical epithelium High risk of malignant chance than leukoplakia |
|
|
Oral squamous cell cancer
|
95% of oral cancers
50% mortality Tobacco, alcohol, HPV |
|
|
Salivary gland tumor, liklihood of malignancy?
|
Smaller the gland, the more likely to be malignant
Parotid - 30% malignancy Submandibular - 40% are malignant Sublingual - 80% |
|
|
Pleomoprhic adenoma of salivary gland
|
50% of salivary neoplasms
Benign Biphasic with ductal (epithelial) and myoepithelial components Low, but definite risk of malignant transformation 2% @ 5 years, 10% @ 10 years 60% of parotid tumors |
|
|
How pleomorphic is a pleomorphic adenoma of the salivary gland
|
Two cell types: epithelial and myoepithelial
Epithelial: ducts or sheets Stromal: mucin or collagen |
|
|
Warthin tumor
|
Benign salivary neoplasm
Mixed tumor Epithelial component has dense, eosinophilic, granular cytoplasm Lymphoid component 5-10% of salivary neoplasms Primarily in parotid 10% are bilateral |
|
|
Mucoepidermoid carcinoma of salivary gland
|
15% of salivary neoplasms
Squamous and mucus-secreting cells Better prognosis with predominance of mucus cells (=low grade) |
|
|
Outcomes with mucoepidermoid carcinoma of salivary glands
|
Low grade (mucus cell predominance):
15% recurrence, 90% 5 year survival High grade (squamous cell predominance) 25% recurrence, 50% 5 year |
|
|
Adenoid cystic carcinoma of the salivary gland
|
Hyaline, basement membrane material, perineural invasion common
Slow growing but high recurrence rate 30% 10 year survival 5% of salivary tumors |
|
|
Worst salivary cancer to get?
|
Carcinoma arising in pleiomorphic adenoma
Poorly differentiated Adenoid cystic if you are looking long term |
|
|
Hiatal hernias can be
|
Sliding -- whole stomach up through diaphragm
Rolling (paraesophageal) hernia -- part of stomach herniates next to esophagus |
|
|
Where do you find esophageal webs?
|
Upper esophagus of women over 40
|
|
|
Plummer-Vinson syndrome
|
Esophageal web
Iron deficiency Glossitis Cheilosis Risk for carcinoma of the upper esophagus |
|
|
Clinical presentation of esophageal ring
|
Episodic dysphagia
|
|
|
Mallory-Weis tear
|
Laceration of the gastroesophageal junction
Result of forceful vomiting and tight LES |
|
|
Boerhaave syndrome
|
Esophageal rupture
Catastrophic event |
|
|
Esophageal varices
|
Dilated submucosal veins
Consequence of portal hypertension Major cause of GI bleed Present in 90% of cirrhotic patients |
|
|
What does reflux esophagitis look like pathologically?
|
Eosinophils present with squamous cells
|
|
|
Risk factors for squamous cancer of the esophagus
|
Smoking
EtOH Fungal carcinogens Nitrosamines |
|
|
Diagnostic criteria for Barrett's esophagus
|
Endoscopic evidence of columnar epithelium in distal esophagus
AND Intestinal metaplasia (ie goblet cells) mucosal biopsy from this site Long segment if > 3 cm Short if < 3 cm |
|
|
Appearance of Barrett's esophagus
|
Microscopically defined by goblet cells
Grossly -- red appearance from vessel density |
|
|
Oral herpes pathologic progression
|
Vesicles caused by acantholysis of squamous cells
Progress to ulcers Associated with viral changes in keratinocytes Multiple nuclei with molding Smudgy gray chromatin Occasional viral inclusion bodies |
|
|
Oral CMV infection clinically
|
Ulcer
Chronic inflammation |
|
|
Common sites for oral cavity cancer
|
Floor of mouth
Tongue Hard palate Base of tongue |
|
|
Layers of the stomach
|
Mucosa
Foveolar compartment Glandular compartment Submucosa Muscularis propria Serosa |
|
|
Pancreatic heterotopia
|
Pancreatic cells in stomach wall
|
|
|
Acute gastritis
|
Acute mucosal injury
Severe cases characterized by erosion/hemorrhage Can progress to ulcer |
|
|
Acute gastritis causes
|
NSAIDs
Alcohol Acid/Alkali ingestion Bile reflux Heavy smoking Severe hypotension/shock Severe stress (trauma, burns) |
|
|
Stress ulcers
|
Seen in trauma, burns, sepsis, shock
No chronic morphologic changes seen Treat underlying condition |
|
|
Chronic Helicobacter Gastritis
|
90% of chronic gastritis is H pylori
Antral or diffuse Bacteria colonize foveal layer |
|
|
Autoimmune gastritis
|
Antibody mediated destruction of parietal cells
Pernicious anemia Gastric atrophy and intestinal metaplasia 2-4% long term risk of adenocarcinoma Increased risk of neuroendocrine (carcinoid) tumors Hyperplasia of ECL cells |
|
|
Ulcer definition
|
Loss of tissue down into the submucosa
|
|
|
Defining gastric carcinoma
|
> 0.5 cm
Submucosal invasion |
|
|
Menetrier disease
|
Hypertrophic gastropathy
Marked hypertrophy of foveolar tissue |
|
|
Types of gastric polyps
|
Hypertrophic
Gastric fundal gland Peutz-Jeghers (hamartomatous) Adenomatous -- premalignant potential |
|
|
Gastric fundal gland polyp
|
Associated with long term PPI use
Also familal adenomatous polyposis Can also be sporadic Almost always benign |
|
|
Peutz-Jeghers polyp
|
Hamartomatous
Aborizing smooth muscle polyp |
|
|
Gastric malignancies
|
Adenocarcinoma -- 90%
Lymphoma - 4% Carcinoid - 3% GIST - 2% |
|
|
Intestinal type gastric adenocarcinoma
|
Exophytic, ulcerative, or infilitrating
Dysplasia is precursors Gland formation Male 2: 1 Female Decreasing in incidence |
|
|
Diffuse type gastric adenocarcinoma
|
Linitus plastica (leather bottle appearance)
Arising de novo (without dysplasia) Individual malignant cells Male 1: 1 Female Incidence steady |
|
|
Signet ring cell carcinoma
|
Large mucin vacuole with flattened peripheral nucleus
These cells are >50% of tumor |
|
|
Muscinous adenocarcinoma
|
Large, extracellular pools of mucin >50% of tumor
|
|
|
Staging gastric cancer
|
T -- depth of invasion
M N |
|
|
Virchow node
|
Supraclavicular node metastasis
Abdominal cancer |
|
|
Kruckenberg tumors
|
Ovarian metastasis from gastric cancer
Usually bilateral |
|
|
Gastric lymphoma
|
Majority arise (>80%) in chronic H pylori gastritis
B-cell lymphomas of mucosal associate lymphoid tissue (MALT lymphomas) Lympho-epithelial lesions |
|
|
MALT lymphoma pathogenesis progression
|
H pylori stimulates T cells
T cells activate B cells Clonal expansion of B cells Mutations in B cells lead to independent B cell proliferation (t 11;18) |
|
|
Gastric carcinoid
|
Arising mostly from ECL cells
Indolent endocrine tumor Arise in MEN/ZES or rarely sporadically |
|
|
GIST tumor
|
Histologenetically linked to interstitial cells of Cajal
c- Kit and PDGFR Solitary or multiple (NF1) Difficult to distinguish benign and malignant (use size, mitoses) Disseminated disease treated with TKI |
|
|
Pathologic diagnostic criteria for chronic gastritis
|
Increased chronic inflammatory cells in the lamina propria
|
|
|
What's different between a GIST and true smooth muscle tumors
|
GIST are negative for desmin
|
|
|
Where are gastric carcinomas usually found?
|
Disproportionally in Antrum/Pylorus
More in cardia (10%) than size warrants Only 15% in body/fundus |
|
|
Early vs advanced gastric carcinoma
|
Early -- does not penetrate the muscularis propria
Advanced -- cancer invades into muscularis propria |
|
|
Common metastatic cancers to the stomach
|
Breast and lung can look like the diffuse type of gastric carcinoma
Primary nodal lymphomas may secondarily involve the GI tract Fatal melanoma involves GI tract in 60% of cases, 1/4 of which are in stomach |
|
|
Location of pancreas
|
Left side (tail) bordered by spleen
Right side (head) bordered by duodenum Anteriorly bordered by stomach Posteriorly bordered by large vessels |
|
|
Common bile duct goes through the?
|
Head of the pancreas
|
|
|
Pancreatic blood supply
|
SMA and celiac
Rare to get vascular occlusion ischemia |
|
|
Pancreatic drainage and consequences
|
Splenic vein to superior mesenteric vein
Pancreatic disease can lead to splenic vein occlusion Vascular engorgement of spleen Shunt drainage leading to upper gastric varices, which can bleed |
|
|
Exocrine pancreas
% and secretion |
85% of pancreas
Acini and ducts Secretes: digestive enzymes, water, NaHCO3 Into the duodenum |
|
|
Pancreas embryology
|
Ventral and dorsal buds of duodenum
Ventral pancreas and common bile duct are rotated to join dorsal Ductal systems fuse Ventral ductal system predominates Wirsung - major Santorini -- minor |
|
|
Divisum
|
Lack of fusion of pancreatic ductal systems embryologically
Results in dorsal and ventral pancreas reaching duodenum separately 10% of people Increased risk for pancreatitis |
|
|
Without your pancreatic enzymes you get...
|
Malabsorption
|
|
|
Secretory product of pancreatic
Acini Ducts Islet |
Acini -- proenzymes and enzymes
Ducts -- Water and electrolytes Islets -- insulin, glucagon, somatostatin, amylin, pancreatic polypeptide |
|
|
Pancreatic polypeptide fnc
|
Regulation of GI fnc
|
|
|
Regulation of exocrine pancreas
|
Neural and endocrine
Acini -- Neural: ACh, GRP, VIP, Substance P, CCK via Vagus, Hormonal: Secretin Ducts: Neural- ACh Hormonal - secretin Duct- Neural: ACh, Hormone: Secretin |
|
|
Response to low pH in duodenum
|
pH below 4.5 results in secretion of secretin from basolateral side of S cells
This acts hormonally on the pancreatic duct cells, resulting in bicarb/water secretion Duodenum also absorbs some H |
|
|
Why is neutralization in duodenum important?
|
Inactivates pepsinogen
Increases FA and bile acid solubility Optimize pH for pancreatic and brush border enzymes Prevents mucosal damage |
|
|
Pancreatic polypeptide
|
Negative feedback mechanism for vagl stimulated pancreatic enzymes secretion
Secreted based on vagal stimulation Hormonal action in brain (dorsal vagal complex) to decrease vagal activity |
|
|
What is in pancreatic secretion
|
Water
Bicarbonate Enzymes: Proteases (90%) - as proenzymes Amylase (7%) Lipases (2%) Nucleases (1%) |
|
|
Activation of pancreatic proenzymes
|
Enterokinase in brush border activates some trypsinogen to trypsin
Trypsin activates rest of trypsinogen and other proezymes |
|
|
Pancreatic zymogens and their active forms
|
Chymotrypsinogens -- Chymotrypsins
Kallikreinogen -- Kallikrein Procarboxypeptidases -- Carboxypeptidases Proelastase -- Elastase Proprotease E -- Protease E Trypsinogn -- trypsin |
|
|
What mechanisms protect pancreas from autodigestion
|
Proteases/phospholipases are stored as zymogens
Trypsin inactivator packaged with proenzymes Membrane bound compartments segregate proenzymes Enterokinase is restricted to small intestine |
|
|
Trypsin inactivator mutation results in
|
Chronic pancreatitis
|
|
|
High BUN with normal creatinine?
|
Dehydration
|
|
|
Labs in acute pancreatitis
|
High LFTs
High Bili Wildly elevated lipase, amylase |
|
|
Acute pancreatitis
|
Self limiting
Acute abdominal pain Elevated pancreatic enzymes Acute inflammation |
|
|
Chronic pancreatitis
|
Chronic abdominal pain
Progressive loss of pancreatic exocrine and endocrine funciton |
|
|
Acute pancreatitis, does it matter?
|
50/100K incidence in US/year
1.7 billion in health care costs 250 million in work days lost |
|
|
Pathogenesis of acute pancreatitis
|
Insult to pancreas
Activation of zymogens Damage to pancreatic parenchyma Elaboration of cytokines/chemokines Further pancreatic damage Systemic inflammatory response |
|
|
Acute pancreatitis presentation
|
Abdominal pain
Radiates from upper abdomen to back, improved by leaning forward, lying on left side N/V Tachycardia -- volume depletion Gaurding/loss of bowel sounds -- prognostics |
|
|
Gray Turner sign
|
Ecchymosis on flank
Extravasation of pancreatic hemmorhage Poor prognositic in acute pancreatitis |
|
|
Cullen sign
|
Ecchymosis in periumbilical area
Extravasation of pancreatic hemorrhage Poor prognostic in acute pancreatitis |
|
|
Serum amylase
|
Sensitive test of acute pancreatitis, some limits to specificity (especially at low concentrations
Amylase leaks from inflamed pancreas into venous/lymphatic spaces |
|
|
What tissues is amylase made in?
|
Pancreas
Salivary glands Fallopian tube Ovary Prostate Lung |
|
|
Serum lipase
|
Sensitive and specific test for acute pancreatitis
Elevates first day of illness, remains elevated Can be elevated in other intrabdominal processes, but usually <1000 U/L |
|
|
What conditions raise serum amylase
|
Parotiditis
Bililary disease Pancreatitis Renal failure Intestinal obstruction/damage Ectopic preg Macroamylasemia Perforated viscus |
|
|
What conditions raise both serum amylase and serum lipase
|
Pancreatitis
Intestinal damage reabsorption of luminal enzymes Perforated viscus Biliary problems will slightly raise lipase, as will renal failure |
|
|
Diagnosing acute pancreatitis
|
H/P
Labs R/O other conditions CT: not required but can help to confirm, r/o, define severity |
|
|
DDx pancreatitis
|
Biliary colic
Acute cholyecystitis Ascending cholangitis Perforated viscus Mesenteric ischemia Infarcted bowel Intestinal obstruction Inferior Wall MI Aortic dissection Ectopic pregnancy |
|
|
Charcot's triad
|
Fever, jaundice, RUQ pain
Ascending cholangitis (Biliary tree infection) |
|
|
Causes of acute pancreatitis
|
Alcohol
Biliary obstruction Idiopathic Other |
|
|
Mechanism of biliary obstruction leading to pancreatitis
|
Either gall stone obstructs ampullary opening of the common bile duct and pancreatic duct or
Dilation of the common bile duct based on the stone obstructs the pancreatic ducts |
|
|
Factors predictive of gall stone cause of pancreatitis
|
Age > 50
Female Amylase >4000 AST >100 Alkaline phosphatase > 300 (fat, female, fertile, forty) |
|
|
Acute effect of alcohol on pancreas
|
Abnormal blood flow
Sensitization to the effects of CCK Toxic metabolics -- free rad damage Sphincter of Oddi spasm Stimulation of CCK and secretin release |
|
|
Alcohol and acute pancreatitis
|
5% of chronic alcohol abusers develop pancreatitis
How much you drink over a 10 year period matters Women takes less than men |
|
|
US in biliary stone disease
|
Stone with shadow
Microlithiasis -- sludge-like in dependent region of gallbladder Microlithiasis can be treated like gall stones |
|
|
Drugs that commonly cause pancreatitis
|
Asparaginase
Azathioprine 6-mercaptopurine didanosine pentamidine valproate |
|
|
Drugs that uncommonly cause pancreatitis
|
ACE-I
acetaminophen 5 amino ASA furosemide sulfasalazine thiazides |
|
|
Drugs that rarely cause pancreatitis
|
carbamazepine
corticosteroids estrogens minocylcine nitrofurantoin tetracycline |
|
|
Infectious etiologies of pancreatitis
|
Viral - coxsackie
Parasitic - ascaris via obstruction Fungal - candida Bacterial - salmonella via toxin |
|
|
Ampulla--- what's in there?
|
Papilla of vater -- sticks out into duodenum
Biliary duct sphincter Pancreatic duct sphincter Sphincter of OddiL most distal |
|
|
Autoimmune pancreatitis
|
New onset, subacute pancreatic symptoms
Mass lesion is common Steroid responsive Irregular narrow duct Periductal lymphocyctic, plasmacytic infiltrate, inflammation, fibrosis IgG4, IgE are markers |
|
|
Inherited causes of pancreatitis
|
Trypsinogen mutations
CFTR (via abnormal ion movements) weak mutations can result in isolated pancreatic disease Familial hypertriglyceremia |
|
|
Hypertriglyceremia and pancreatitis
|
Rare cause
TGs usually > 1000 mg/dL Cause cause acute and chronic Mechanism likely related to increased FFas and their damage to pancreas Drug induced: estrogens, alcohol, isotretinoin, HIV protease inhibitors |
|
|
Traumatic pancreatitis
|
Usually midline -- where pancreas can be compressed against vertebral column
Complete severing of pancreatic duct Damage to pancreatic duct with leak -- can develop stenosis over time |
|
|
Etiologies of pancreatitis in childhood
|
Traumatic
Infectious (viral) Structural Drug-induced (isoretinoin, valproate) Metabolic |
|
|
Tytius serrulatus
|
Scorpion
Bite can cause pancreatitis |
|
|
Acute pancreatitis outcomes
|
Mild -- self limited
Severe (necrotizing)-- can die |
|
|
Danger signals in acute pancreatitis
|
Encephalopathy
Hypoxemia Tachycardia >130 Hypotension <90 Hct >50 Oliguria Azotemia (high nitrogen compounds) |
|
|
Causes of mortality in acute pancreatitis
|
First week -- multiorgan failure, systemic inflammatory response syndrome (SIRS)
Later -- infectious complications Necrotizing pancreatitis has 15-30% mortality, about 5% all comer mortality |
|
|
How to assess prognosis with acute pancreatitis
|
Bedside assessment (often underestimates)
Scoring systems Serum markers (trypsinogen activation peptide (TAP) , c-reactive peptide, cytokines) CT criteria-fluid collections, necrosis |
|
|
Signs of severe acute pancreatitis
|
Age >55
WBC >16000 Glucose >200 LDH >350 AST >120 48 hours later Hct drop by >10% BUN increase >5 Ca < 8 PaO2 <60 Base deficit > 4 Negative fluid balance > 6 L |
|
|
Serum markers in severity of acute pancreatitis
|
Use TAP early and CRP later
|
|
|
Negative prognostic factor in acute pancreatitis
|
Obesity
|
|
|
Complications of acute pancreatitis
|
Local : fluid collections, necrosis, infection, ascites, erosion into adjacent structures, GI obstruction, hemorrhage
Systemic: pulmonary, renal, CNS, multiorgan failure Metabolic: hypercalcemia, hyperglycemia |
|
|
Systemic Inflammatory Response Syndrome
|
Two or more of
Temp >38 or <36 RR >24 HR > 90 min WBC >12K or <4K or >10% bands |
|
|
Multiple-organ dysfunction syndrome
|
Dysfunction of more than one organ requiring intervention to maintain homeostasis
|
|
|
Systemic complications of pancreatitis
|
Shock from third spacing -- vol replete
Coagulopathies from proteases - treat with FFP Resp failure from ARDS - ventilate RF from acute tubular necrosis, pre-renal -- dialysis Hyperglycemia -- insulin Hypocalcemia from decreased albumin - calcium |
|
|
Fluid collections seen in acute pancreatitis
|
Acute collections
Necrosis Pseudocysts Abscesses |
|
|
Pancreatic necrosis treatment
|
Prophylactic antibiotics
Debridement Don't always do either |
|
|
Is this necrotic pancreas infected?
|
Need to do an aspiration of fluid collection
Might have fever, high WBC w/ infected or not |
|
|
Acute fluid collections in acute pancreatitis
|
Ill defined collections of fluid
Usually self-resolve Treat/drain if infected |
|
|
Pancreatic pseudocysts
|
Localized collections
Lack epithelial wall >4 weeks from disease From either ductal disruption or pancreatic necrosis |
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Treatment of severe acute pancreatitis
|
Aggressive fluid and elecrolyte replacement
Monitoring Analgesia, antiemetics Acid suppression, antibiotics, NG tube, nutritional support, urgent ercp |
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Morphine in acute pancreatitis
|
Some evidence that it increases sphincter of Oddi tone
Use others |
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Nutritional support in acute pancreatitis
|
Necessary if protracted course
Need to feed gut to avoid breakdown of barrier to bacteria leading to infection Can use post-pancreas NG tube Use TPN to supplement nutritional status if necessary |
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Prophylactic antibiotics in severe acute pancreatitis
|
Usually used w/ >30% of pancreas necrosis
Decrease overall infections Have seen increase in Candida and resistant Staph |
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Acute pancreatitis caused by cholangitis
|
Need to get stone out
Need to get gallbladder out if stones are cause, especially in older pts |
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Complications of pancreatic pseudocysts
|
Infection
Rupture Mass effect -- obstruction Pain Bleeding |
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Treatment of pseudocyst
|
Endoscopic cyst gastrotomy
Surgery |
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Etiology of chronic pancreatitis
|
Mostly alcoholic
Also Idiopathic CF Hereditary Hypertriglycermia Autoimmune Fibrocalcific |
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Chronic effects of alcohol on pancreas
|
Decreased blood flow
Fibrosis Cytoxic lymphocytes Changes to acinar secretion (more trypsinogen, less trypsinogen inactivator) Enhanced secretion of proteins that promote stone formation |
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Symptoms in chronic pancreatitis
|
Early (after 10 years of drinking) usually just pain
Later: less pain, significant malabsorption, diabetes, calcification |
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Why is chronic pancreatitis painful
|
Ischemia
Stones Pseudocyst Neural inflammation (may not resolve after pancreatectomy) |
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|
How much of the exocrine pancreas do you need?
|
Really only about 10%
Dramatic increase in stool fat after that threshold |
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CT signs of chronic pancreatitis
|
Calcification
Dilated ducts |
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Complications of chronic pancreatitis
|
Common bile duct stenosis
Duodenal obstruction Splenic vein thrombosis Pancreatic ascites Pseudocyst Pleural effusion |
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Nutritional modification with exocrine pancreas insufficiency
|
Modify fat intake
Medium chain fatty acids Enzyme replacement Supplement fat soluble vitamins, B12, calcium |
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Best way to replace pancreatic enzymes?
|
Coated enzymes
or Enzymes plus acid suppression But anything is better than nothing based on stool fat findings |
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Treating pain in chronic pancreatitis
|
Narcotics can be complicated in this patient population (alcoholics)
Neuromodulators Anti-inflammatory Anti-secretory Enzymes Not much works weel |
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|
Best way to replace pancreatic enzymes?
|
Coated enzymes
or Enzymes plus acid suppression But anything is better than nothing based on stool fat findings |
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|
Treating pain in chronic pancreatitis
|
Narcotics can be complicated in this patient population (alcoholics)
Neuromodulators Anti-inflammatory Anti-secretory Enzymes Not much works weel |
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Why is chronic pancreatitis painful
|
Ischemia
Stones Pseudocyst Neural inflammation (may not resolve after pancreatectomy) |
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|
How much of the exocrine pancreas do you need?
|
Really only about 10%
Dramatic increase in stool fat after that threshold |
|
|
CT signs of chronic pancreatitis
|
Calcification
Dilated ducts |
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|
Complications of chronic pancreatitis
|
Common bile duct stenosis
Duodenal obstruction Splenic vein thrombosis Pancreatic ascites Pseudocyst Pleural effusion |
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Nutritional modification with exocrine pancreas insufficiency
|
Modify fat intake
Medium chain fatty acids Enzyme replacement Supplement fat soluble vitamins, B12, calcium |
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Acinar cells histologically
|
Apical - zymogen granules
Basolateral -- Golgi and RER |
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Notable histologic feature of pancreatic ducts
|
Thick wall of collagen
To prevent leakage |
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Acute pancreatitis pathologically
|
Acute inflammation
Often with necrosis |
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Chronic pancreatitis pathologically
|
Atrophy and fibrosis
Acinar cells atrophy first Fibrosis is intralobular and perilobular Often with chronic chronic inflammation |
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How to classify chronic pancreatitis
|
With or without malabsorption
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Viruses that can cause pancreatitis
|
CMV
Mumps |
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Mild acute pancreatitis pathologically
|
Interstitial edema with inflammatory infiltrate
Separation of lobules by edema Minimal or no necrosis |
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Course of mild acute pancreatitis
|
Rapid resolution with no tissue damage
or Chronic pancreatitis if persistent |
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Severe acute pancreatitis AKA
|
Necrotizing pancreatitis
necrosis of parenchyma and nearby fat Hemorrhagic pancreatitis due to leakage from vessels |
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Pathology of severe acute pancreatitis
|
Necrosis and inflammation
Acini lost, then ducts, then islets Fat necrosis as well |
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Severe acute pancreatitis course
|
Focal -- scar
Multifocal -- patchy scar and chronic pancreatitis Extensive -- systemic inflammatory response, death, complications (psuedocyst, abscess) |
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Pseudocyst pathologically
|
Walled off collection of fluid or liquified tissue within or adjacent to pancreas in acute pancreatitis
Wall may include nearby organs and becomes progressively fibrotic |
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Infections in severe acute pancreatitis
|
Necrotic tissues or pseudocyst can become infected
If liquid -- abscess Organism is from blood or bowel |
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Chronic pancreatitis course
|
Exocrine insufficiency
Diabetes (later) Increased (14x) risk for pancreatic cancer |
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Risk of pancreatic cancer in patients with hereditary chronic pancreatitis?
|
50 fold increase
|
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Pathogenesis of pancreatitis
|
Injury of acinar cells (intracellular/interstitial activation of pancreatic enzymes)
-alcohol, drugs Ductal obstruction with increased intraductal pressure (Interstital leakage and activation of pancreatic enzymes) |
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Causes of pancreatitis
|
Alcohol, gallstones, drugs, hereditary, autoimmune, trauma, viruses
|
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|
Cathepsin B
|
Leukocyte enzyme that activate trypsinogen to trypsin
Problem in pancreatitis with leakage of proenzymes |
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|
What can cause pancreatic duct obstruction
|
Gallstones
Abnormal secretions (CF) Intraductal neoplasms Extrinsic compression (neoplasms) Parasites |
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Pathogenesis of chronic pancreatitis
|
Persistant or recurrent inflammation of the pancreas
Caused by: Alcoholism (60-70%) Hereditary pancreatitis Duct obstruction NOT gallstones |
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Necrosis-fibrosis theory
|
Repeated episodes of acute pancreatitis leads to patchy scarring and ductal distortion
Eventually to chronic pancreatitis |
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|
Mutant cationic trypsinogen gene
|
Hereditary pancreatitis
Eliminates a self-destruction site on trypsinogen AD with high penetrance 40% have pancreatic Ca by 70 years |
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CF and the pancreas
|
Problem in electrolyte secretion
Cannot adequately hydrate mucus Ductal obstruction Chronic pancreatitis -- exocrine insufficiency, glucose intolerance/diabetes |
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Pathologic finding in autoimmune pancreatitis
|
Intense inflammation around the ducts
Chronic pancreatitis with lymphocytes, plasma cells, sometimes: eos, PMNs |
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Symptoms of lesion in head of the pancreas
|
Weight loss -- 90%
Jaundice -- 80% Pain -- 70% Anorexia -- 65% |
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Why do pancreatic lesions cause pain?
|
Involvement of the celiac plexus
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Symptoms of lesion in tail/body of pancreas at time of diagnosis
|
Weight loss - 100%
Pain -- 90% Weakness - 40% Jaundice - 7% These lesions ususally present later than head because of lack of jaundice |
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Diagnostic studies in pancreatic cancer
|
CT - staging information
US -- gallstones/biliary dilation ECRP -- can endoscopically biopsy and also stent for relief CA19-9 |
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CA 19-9
|
Pancreatic cancer tumor marker
Has pre/post op prognostic significance Can use to monitor response to systemic therapy |
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|
Extent of disease at presentation in pancreatic cancer
|
25% resectable
35% have involvement of mesenteric vessels 40% have distant metastasis |
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Resecting tumors involving the mesenteric vessels
|
Resectable if there is a fat plane between tumor and SMA, celiac, portal, SMV
Borderline if tumor abuts SMA, celiac or >180 degrees of portal Unresectable if tumor surrounds SMA, celiac or occults portal Portal resections can work, SMA resections have not yet |
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|
Treatment of patients with metastatic pancreatic cancer
|
Gemcitabine (+ erlotinib)
FOLFIRINOX (5FU, leukovorin, oxiplatin, irinotecan) longer PFS, median survival, also more toxic Palliation |
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|
Palliative treatment in pancreatic cancer
|
Stenting of biliary obstruction
Pain management with celiac plexus block or radiation therapy |
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What surgery for a resectable pancreatic tumor
|
Tail -- distal pacreatectomy
Head - whipple |
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|
Whipple procedure
|
Pancreaticoduodenectomy
Resention of distal stomach, duodenum, mid pancreas and bile duct Anatamose: Gall bladder to jejunum (choledochojejunostomy) Pancreas to jejunum Pancreatiocjejunostomy Stomach to jejunum Gastrojejunostomy |
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|
Staging laproscopy in pancreatic cancer?
|
10% of patients with no evidence of metastatic disease on CT will have some disease on laproscopy
These patients are unresectable |
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|
Whipple procedure M and M
|
Mortality--
worse in low volume hospitals Morbidity Leaks from pancreaticojejunostomy (5%) Infections (10-20%) Poor gastric emptying (10-20%) |
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|
Treatment effect of whipple
|
With negative resection margins
25% alive 5 years, 15% alive 10 years With no other treatment |
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|
Adjuvant treatment in pancreatic cancer
|
Treating post-resection with xrt/chemo or gemcitabine alone improves median overall survival
This seems (at least with XRT) mediated by a decrease in local recurrence |
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|
Workup/treatment/outcomes of pancreatic cancer
|
Staging with CT/laproscopy
20% deemed resectable 90% have successful resection 25% alive at 5 years Overall, 5% of patients alive at 5 years |
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|
Neoadjuvant treatment in pancreatic cancer
|
Use XRT/chemo first
Then surgery Idea: more patients get all 3 modalities, avoid missing occult metastatic disease, more successful resections |
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|
Does neoadjuvant therapy decrease local recurrences in pancreatic cancer?
|
Dartmouth studies say so
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|
Where do patients with resectable pancreatic cancers recur?
|
Locally most of the time
These are symptomatic recurrences with weight loss, pain |
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|
Non functional neuroendocrine tumors of the pancreas
|
1/3 are isolated to pancreas - resect
Liver mets -- carcinoid syndrome - resect Unresectable --poor prognosis-- try sunitinib |
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|
Insulinoma
Age Malignant? |
Avg age - 45
95% benign and solitary lesion |
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|
Presenting symptoms of an insulinoma
|
Visual disturbances
Confusion Altered consciousness Weakness Sweating Tremors Fasting glucose low and insulin high |
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|
Insulinoma treatment
|
Localize -- Ca stimulation, CT, US
Remove |
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|
Gastrinoma
|
Hypergastrinemia leads to gastric acid hypersecretion and ulcers
Duodenum, pancreas, LNs 50% malignant -- can only tell by presence of metastasis Zollinger Ellison syndrome |
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|
Gastrinoma treatment
|
Control acid medically
Surgical resection after somatostatin scan Usually whipple is not necessary |
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|
Gastrinoma outcomes
|
Five years later
95% are free of disease on imaging 40% are biochemically cured (no detectable gastrin) |
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|
Cancers of the pancreas
|
Exocrine (ducts or acini)
Neuroendocrine (islets) Primitive/mixed (stem cells) Sarcomas (stroma) --rare |
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|
Ductal adenocarcinoma of the pancreas
|
90% of pancreatic cancers
Including subtypes: Adenosquamous carcinoma Anaplastic Mixed ductal-endocrine Colloid (non cystic muscinous) |
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|
Risk factors for developing pancreatic cancer
|
Chronic pancreatitis
Smoking Diabetes Male African america Hereditary pancreatitis |
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|
Age of ductal adenocarcinoma of the pancreas diagnosis
|
Median - 66
Rare <50 In younger patients think of other tumors, hereditary predispositions |
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|
Nerves and pancreatic cancer
|
Perineural invasion is common
Tissue behind head of pancreas is rich in nerves Pain |
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|
Genetic mutations in ductal adenocarcinoma of the pancreas
|
Kras common
Multiple mutations rule Kras - p16 - p53/DPC4/BRCA |
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|
Pancreatic intraepithelial neoplasm
PaIN |
Premalignant change in pancreas
Cytologic changes/architectural atypia Seen in small (<5mm) ducts Grades 1-3 3 is CIS |
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|
Non malignant masses of the pancreas
|
Cysts -- serous cystadenoma, intraductal papillary-muscinous neoplasm, muscinous cystic neoplasms
Pseudocysts Mass of inflammation: autoimmune pancreatitis, groove pancreatitis (cystic dystrophy) |
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|
Borderline tumors of the pancreas
|
Muscinous cystic neoplasm with moderate dysplasia
Intraductal papillary-mucinous tumors with moderate dysplasia Solid pseudo-papillary tumor |
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|
Most common pancreatic neoplasm in young children?
|
Pancreatoblastoma
5 year survival -- 60% Malignant but 65% are isolated at diagnosis |
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|
Pancreatic tumor often seen in young women?
|
Solid pseudopapillary neoplasm
Usually cured by excision Can invade liver |
|
|
Mucinous cystic neoplasm patient population?
|
45-50 year old women
Rare in men 10-20% malignant |
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|
What goes into pathology report about pancreatic cancer specimen
|
Histologic type
Grade Resection margin involvement Size Extension into other organs Lymph node involvement |
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|
Histologic appearance of ductal adenocarcinoma of the pancreas
|
Infiltrative growth pattern
Poorly formed glands Perineural/lymphatic invasion Cytologic atypia |
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|
Acute cholecystitis histologically
|
PMNs
Edema Hemorrhage Mucosal ulceration |
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|
Chronic cholescystitis
|
Fibrosis of wall
Mild chronic inflammatory cells Rokintansky-Aschoff sinuses |
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|
Cholesterolosis histologically
|
Foamy histiocytes in lamina propria
|
|
|
Function of the appendix
|
Help in digesting nuts
Safe haven for GI commensals necessary for repopulation after diarrheal illness Immune function which helps prevent IBS? |
|
|
Risk of developing appendicitis?
|
4% by age 20
7-8% lifetime Pretty rare after 50 |
|
|
Appendix location
|
Usually around McBurney's point
But can be in a variety of locations including retroperitoneally |
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|
Causes of appendicitis
|
Stool (fecalith)
Lymphoid hyperplasia Foreign body Carcinoid tumor Low fiber diet is a risk factor |
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|
Pathogenesis of appendictis
|
Obstruction of lumen
Continue mucus production Intraluminal hypertension Lymphatic/venous congestion Edema and local inflammation Arterial obstruction, ischemia, gangrene, perforation |
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|
Appendictis time course
|
Onset to perf (36-48 hours)
First pain is epigastric, based on T10 innervation of stretch receptors on appendix RLQ pain 4-8 hrs later, based on peritoneal irritation, vibration is painful |
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|
Appendicitis symptoms
|
Pain
Anorexia (usually w/o vomitting) Point tenderness (McBurney's point) |
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|
Appendicitis PE
|
Lying still
Low grade fever Guarding (if involuntary worry about diffuse peritonitis) Rebound tenderness Positive psoas, obturator, Rovsings |
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|
Rebound tenderness abdominal exam
|
Movement of peritoneum is painful
Refuse to hop Percussion is painful Shaking exam table is painful |
|
|
Rovsing's sign
|
Rebound right sided tenderness to left sided pressure
|
|
|
Psoas/obturator signs
|
Psoas -- voluntary leg flexion against resistance
Obturator-- involuntary external rotation Flexing muscles will produce pain if inflammed appendix is in contact |
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|
Other exams to do in appendicitis
|
CVA
Rectal Pelvic |
|
|
DDx appendicitis
|
Gastroenteritis
Meckle's Crohn's Cecal diverticulitis Cholescystitis Pyelonephritis Torsed ovary Ectopic Ruptured ovarian cyst PID |
|
|
Give patients with abdominal pain narcotics in the ER?
|
Not if they need to be assessed for appendicitis
|
|
|
Appendicitis lab tests
|
WBC - elevated in 2/3
Urinalysis to rule out pyelonephritis Amylase/lipase to r/o pancreatitis Beta HCG |
|
|
Radiology in appendicitis
|
CT can be helpful in patients with equivocal findings
95% PPV, 95% NPV US/MRI can be used in pregnancy Decrease unnecessary appendectomies, risk of radiation |
|
|
Appearance of appendicitis on CT
|
Dilated appendix (diameter >6mm)
Appendiceal wall thickening/enhancement Periappendicial fat stranding --inflammation |
|
|
Who is most likely to suffer a perforated appendix?
|
Extremes of age
|
|
|
Laproscopic vs open appendectomy
|
No proof that laproscopic is better
Lower wound rates but higher intrabdominal abscess rates with lap Lap takes longer and is more expensive Post op day 1 pain is reduced with lap |
|
|
Perforated appendix treatment
|
Appendectomy
Irrigate Delay skin closure on primary wound by 3 days IV antibiotics until afebrile with a normal WBC count Home on oral antibiotics |
|
|
How many Americans have diverticular by age 60?
|
50%
10% will have symptoms of this |
|
|
Diverticulum
|
Outpouching from colon wall of serosa and mucosa
Lacks muscular layer |
|
|
Diverticulum pathogenesis
|
Most are acquired
Thought to be result of high intraluminal pressure generated in response to dense stools from low fiber diet Areas of weakness (usually well vessels penetrate) cannot withstand pressure |
|
|
Diverticulitis
|
Inflammation of diverticulum
Present with slow onset abdominal pain (most often LLQ), sometimes low fever, tenderness, guarding |
|
|
CT in diverticulitis
|
If high fever, high WBC count
|
|
|
Treatment of diverticulitis
|
Without signficant fever, WBCs, treat with oral Abx
With those, IV ceftriaxone, CT scan Follow up colonoscopy to r/o cancer |
|
|
Complications of diverticulitis and their treatment
|
Perforation - rxn and colostomy
Obstruction - rxn and colostomy Large abscess - rxn and colostomy or CT-guided percutaneous drainage and resection w/ primary reanastomosis |
|
|
Why a colostomy and then a take down when treating complicated diverticular disease?
|
High rates of leak with primary anastomosis
|
|
|
Cholesthiasis
|
Cholesterol stones
Pigmented stones Mixed stones In US - 80% are cholesterol or mixed |
|
|
Cholesterol stones
|
>50% cholesterol
Yellow Radiolucent |
|
|
Pigmented gall stones
|
<20% cholsterol
Brown-black Radiopaque |
|
|
Complications of gall stones
|
Cholescystitis (empyema, perforation and peritonitis, cholescytentero fistula)
Choledocholithiasis (obstructive jaundice, ascending) Acute pancreatitis Increased risk of gallbladder carcinoma Biliary enteric fistula |
|
|
Acute cholecystitis
|
Acute inflammation of the gall bladder
Most often caused by obstruction of the neck or cystic duct of the gallstone Smaller stones are more likely to cause problems because they can move into duct |
|
|
Gangrenous (nectrotizing) cholecystitis
|
Rare
Coagulative necrosis of gallbladder wall Perf common 10% mortality |
|
|
Acalculous cholescystitis
|
Cholecystitis in absence of gall stones
Up to 10% of cases Usually in a severely ill patient Caused by ischemia, stasis, biliary sludge formation, secondary bacterial contamination, dehydration and pigmentation from transfusions |
|
|
Chronic cholescystitis causes and appearance
|
Gall stones almost always present
Previous episodes of acute cholescystitis Variable morphology Infiltration of lymphocytes and plasma cells |
|
|
Porcelain gallbladder
|
Extensive dystrophic intramural calcifications
20% of patients will develop carcinoma of the gallbladder |
|
|
Cholesterolosis
|
Strawberry gallbladder
20% of resected gallbladders May be asymptomatic, chornic cholescystiti, cholesterol stones Choesterol accumulates in lamina propria |
|
|
Neoplasia of the gallbladder
|
Most are malignant
Often with late presentation, asymptomatic early Poor outcome in advanced stage tumors |
|
|
Adenocarcinoma of the gallbladder risk factors
|
Gall stones
Chronic cholescystitis Porcelain gallbladder Congenital abnormalities (choledocal cysts, polycystic) Chronic infections Primary sclerosing cholangitis |
|
|
Intrahepatic cholangiocarcinoma
|
Tumor of intrahepatic bile ducts
|
|
|
Klatskin tumor
|
Cholangiocarcinoma at liver hilium/bifurcation of the bile duct
|
|
|
Polarity of a hepatocyte
|
Apical faces sinusoid
Lateral - gap junct w/ other hepatocytes Basal faces canniculus |
|
|
What comes together to form the portal vein
|
Splenic vein and superior mesenteric vein
|
|
|
What separates the bile and blood in the liver
|
Hepatocytes and gap junctions between them
Allows for the passage of ions and water |
|
|
Bile acid secretion physiology
|
Active process by hepatocytes
Involves microvilli, contractile elements, permeability of cannicular membrane |
|
|
Composition of bile
|
Bile salts (which drive process)
cholesterol and phospholipids Ions, water (solvent drag) Bilirubin |
|
|
How does body break down cholesterol?
|
It can't
Only option is excretion as bile acid/salt |
|
|
Formation of bile salts
|
Cholesterol is turned into
Cholic and Chenodeoxycholic acids Conjugation with glycine/taurin Yield primary bile salts Liver fats turn these into micelles |
|
|
How do bile duct cells modify bile?
|
Add secretion rich in H2O and HCO3
|
|
|
Gallbladder function
|
Storage, concentration, and controlled release of bile
Actively pumps Na Increase bile salt concentration-- more micelles Increase H+ concentration means CaCO3 does not precipitate |
|
|
Sphincter of Oddi function
|
Unidirectional delivery of bile and pancreatic secretions to GI tract
|
|
|
Results of decrease in gallbladder contractility
|
Prolonged residence of bile
Precipitation of cholesterol and bile salts Gall stone formation |
|
|
Control of gallbladder secretions
|
Bile flow is lowest during fasting
CCK increases gall bladder contraction, sphincter relaxation, release of pancreatic enzymes Secretin also increase bile secretion |
|
|
Total bile flow
|
600 ml/day
Hepatocytes make most in a bile salt dependent and independent fashion Cholangiocytes make some too |
|
|
Function of bile
|
Fat digestion and absorption
Also fat soluble vitamins Elimination of excess cholesterol |
|
|
How do bile salts aid in fat digestion
|
Make micelles, which solubilizes
LC fatty acids, 2-monoglycerides, cholesterol, phospholipids, ADEK Amphipathic molecules Cholesterol portion is hydrophobic Amino acid portion is hydrophilic |
|
|
Enterohepatic circulation of bile acids
|
Large amounts of bile acids are secreted into colon every day, only small quantities are lost
Duodenum contains large amounts of bile acids Jejunum/ileum -- micelles, fat digestion/absorption Terminal ileum - active transport of 99% of bile acids Colon -- passive uptake of unconjugated bile acids |
|
|
Secondary bile acids
|
1% of bile acids lost in colon
Deconjugated and dehydroxylated by colonic bacteria into secondary |
|
|
How much cholesterol is eliminated daily?
|
500 mgs
|
|
|
What happens when ileal function is lost?
|
Interruption of the enterohepatic circulation
Steatorrhea Diarrhea Renal stones Cholelithiasis |
|
|
Jaundice
|
Yellow discoloration of skin, mucosa, sclera from overproduction or underclearance of bilirubin
|
|
|
Causes of jaundice generally
|
Increase in unconjugated bilirubin (indirect): overproduction of bilirubin (hemolysis, ineffective poesis), defective uptake, defective conjugation
Increase in conjugate bilirubin (direct): Defective excretion-- intra/extrahepatic |
|
|
Gilbert's syndrome
|
Hereditary hyperbilirubinemia
Decreased activity of glucoronosyl transferase (UGT) a bile conjugating enzyme 5% of adults, benign |
|
|
Crigler-Najar syndrome
|
Hereditary hyperbilirubinemia
Loss (type 1) or extreme deficiency (type 2) in glucoronsyl transferase (UGT) a bile conjugating enzyme |
|
|
Dubin-Johnson and Rotor syndromes
|
Hereditary hyperbilirubinemia
Increase in conjugated (direct) bilirubin AR Decreased ability to secrete bile into canaliculus Liver hyperpigmented in DJ, not in Rotor |
|
|
Cholestasis
|
blockage in bile flow
|
|
|
Causes of cholestasis
|
Intrahepatic-- intrinsic liver disease, defect in secretion of bile across canalicular membrane
Extrahepatic -- obstruction of bile ducts |
|
|
Diagnosing cholestasis
|
Jaundice w/ gray stool, dark urine
Pruritis Increased bili, alp, ggt Increased cholesterol, xanthomas Malabsorption of fats and ADEK |
|
|
Extraheptic cholestasis
Labs Causes |
Increased direct bilirubin
Gallstones, strictures, neoplasia, parasites |
|
|
Cholesterol gall stone risk factors
|
Female
Estrogen Pregnancy Crohn's disease Weight loss Obesity Abstinence from EtOH Low fiber, high cal, high carb diet DM High TGs High LDL in women |
|
|
Pigmented gallstone clinical setting
|
Hemolysis
Cirrhosis Biliary infection |
|
|
Why do gall stones form?
|
Increase in gall bladder cholesterol with decrease in bile acids and phospholipids
|
|
|
Course of gall stones
|
Asymptomatic, which is 70-80%, have relatively benign course
Symptomatic have 1-2% rate of biliary complication/year |
|
|
Biliary pain
|
RUQ pain
Crescendo, plateau, decrescendo pattern Usually lasting about half an hour Often at night Accompanied by n/v Biliary complications usually only come after the pain attacks |
|
|
Who gets biliary complications without preceding pain attacks?
|
Old age
Immunodeficient Poorly controlled diabetics Renal failure |
|
|
Acute cholescystitis presentation
|
Ongoing RUQ pain
Preceeding episodes (that did resolve) Positive Murphy's sign Elevated bili, AST, ALT |
|
|
Choledocolithiasis presentation
|
Asymptomatic
Recurrent RUQ pain Nonspecific exam Elevations in bili, alp, ggt, (alt, ast) which may be transient |
|
|
Complications of choledocolithiasis
|
Cholangitis
Pancreatitis Cirrhosis |
|
|
Choledocolithiasis define
|
Gall stone in common bile duct
|
|
|
Ascending cholangitis
|
Obstruction in bile duct leads to stasis bacterial overgrowth and infection
Acute, life threatening Preceded by previous pain episodes RUQ pain, jaundice, fever MS changes, shock |
|
|
US in ascending cholangitis
|
Dilated common bile duct
|
|
|
Charot's triad
|
Symptoms of ascending cholangitis
RUQ pain jaundice fever |
|
|
Reynold's pentad
|
Symptosm of ascending cholangitis
RUQ pain jaundice fever MS changes shock |
|
|
Risk factors for gallstones in men
|
Increasing age
men >65 also have increasing risk for complications Increasing triglycerides |
|
|
Peak incidence of gall stones
|
Women 30-39
Women have 2-3 times higher risk than men |
|
|
Cholescystitis and pregnancy
|
0.5/1000 pregnancies
Increased GB residual and decreased contractility Often absent Murphy's, alk phos not useful because elevated in preg Often require cholecystectomy (hopefully in 2nd trimester) Second most common surgery during pregnancy |
|
|
Imaging you could do in gallstone disease
|
Abdominal US
CT Endoscopic US ERCP MRCP HIDA scan |
|
|
Best imaging to see gall stones?
|
US
Abdominal is good, endoscopic is a little more sensitive Also for dilated bile ducts |
|
|
Cholescystitis on US
|
Pericholecystic fluid
Thickened wall Sonographic Murphy's sign |
|
|
Endoscopic US and gall stones
|
Sensitivity for detecting bile duct and gall bladder stones is >95%
|
|
|
MRCP
|
Non invasive method to detect common bile duct stones
>95 sens/spec |
|
|
Management of gall stone disease
|
Expectant if asymptomatic
Surgical, endoscopic, medical |
|
|
Medical management of gall stones
|
Oral dissolution therapy
Ursodiol -- ursodeoxycholic acid Successful with small non-calcified stones 60-80% success with 30-50% recurrence |
|
|
Surgical management of gall stone disease
|
Cholecystectomy - main treatment of symptomatic gall stones
Bile duct can be explored for ductal stones |
|
|
Gallbladder polyps
|
Adenoma, hyperplastic, inflammator
Adenoma size is correlated with risk of cancer GB resection for polyps > 1cm |
|
|
Primary sclerosing cholangitis (PSC)
|
Chronic inflammatory, sclerosis, stricturing process of the medium and large bile ducts
Obliteration of the biliary tree Biliary cirrohsis 90% of patients with PSC have UC, so its probably autoimmune M>F |
|
|
Secondary sclerosing cholangitis
|
Chronic biliary obstruction with secondary fibrosing process
Biliary cirrhosis |
|
|
Choledocal cysts
|
Type I - 75-85% - segmental dilations of common bile duct
Type II - diverticula off extrahepatic ducts III/IV - cysts IV - intrahepatic cysts of Caroli's disease |
|
|
Caroli's disease
|
Hereditary disoder
Dilated intrahepatic bile ducts |
|
|
Cholangiocarcinoma
|
Hepatic tumor of the cholangiocytes
Rare, but increasing incidence Risks: primary sclerosing cholangitis, clonorchis sensis infection Poor outcomes |
|
|
Mirizzi syndrome
|
Stone lodged in cystic duct or neck causes common bile duct compression
|
|
|
Gall stone ileus
|
Stone in GI tract cause obstruction
|
|
|
Bouvert's syndrome
|
Gastric outlet obstruction by a gall stone lodged in the duodenum
|
|
|
Murphy's sign
|
Palpation of RUQ causes pain and inspiratory arrest on a deep breath
|
|
|
Most common cause of 'idiopathic' pancreatitis?
|
Microlithiasis of gall bladder
|
|
|
Recurrence rate of biliary pain?
|
50% of patients w/in the year
30% patients not w/in 10 years |
|
|
Shock wave treatment of gall stones
|
Extracorporeal shockwave lithotripsy
Best with solitary <2cm radiolucent stones Recurrent 30-50% |
|
|
Methyl ter-butyl ether treatment of gall stones
|
Perfusion of gall bladder with powerful organic solvent
Resolves non-calcified cholesterol stones |
|
|
Postcholescystectomy pain
|
Persistent non-gall bladder pain
Duodenal-specific viseral hyperalgesia |
|
|
Estrogen/progesterone and gall stones
|
Decrease bile acid secretion
and Progesterone decreases the CCK mediated contraction of the gallbladder Higher progesterone receptors in GB correlated with increased risk for disease, as is taking exogenous steroids |
|
|
Primary bile duct stones
|
Malnutrition and parasite related
Mostly seen Asia |
|
|
Primary sclerosing cholangitis is associated with what bowel disease?
|
Ulcerative colitis
|
|
|
Arterial supply of the GI tract
|
Stomach, liver, proximal duodenum -- celiac
Distal duodenum -- splenic flexure --SMA Splenic flexure - rectum -- IMA |
|
|
Sympathetic innervation of the GI tract
|
Stomach, liver, proximal duodenum -- celiac ganglion
Distal duodenum -- splenic flexure -- superior mesenteric ganglion Splenic flexure - rectum -- inferior mesenteric ganglion |
|
|
Parasympathetic innervation of the GI tract
|
Vagus down the splenic flexure, then sacral preganglionics
|
|
|
Enteric NS function
|
Gut motility, water and electrolyte secretion, blood flow, acid secretion
Endocrine and immune fnc |
|
|
Enteric immune system influences
|
Can function independently
Receives input from CNS and ANS |
|
|
"Law of the intestine"
|
Local stimulation produces excitation above and inhibition below
Based on the enteric NS action |
|
|
Enteric NS embryology
|
Neural crest cells
Vagal (somites 1-7) neural crest cells are most important, sacral may also have a role Population occurs foregut to hindgut Differentiation and proliferation occur on site (MASH1, GDNF, endothelin 3) |
|
|
Structure of the Enteric NS
|
Two connected ganglionc plexi:
Submucosal and myenteric Submucosal is deep to mucosa Myenteric is between the two muscle layers Submucosa does not really show up until small intestine |
|
|
Myenteric plexus
|
AKA Auerbachs
Between the outter longitudinal and inner circular muscle layers Innervates these muscles Secretomotor innervation to the mucosa |
|
|
Submucosal plexus
|
AKA Meissner's
Between mucosa and inner circular muscle Innervates secretory, endocrine, blood vessels in mucosa and submucosa Intrinsic primary afferent neurons project from submucosal plexus to myenteric plexus |
|
|
Neurons of the enteric NS
|
Type II - several axons
Type I and III - uniaxonal Most have multiple NTs, with one predominant |
|
|
Excitatory NTs in enteric NS
|
ACh
Substance P tachykinins |
|
|
Inhibitory NTs in enteric NS
|
NO
VIP |
|
|
Serotonin in enteric NS
|
Important in motor, sensory, endocrine fnc
Found in many interneurons |
|
|
Interneurons in enteric NS
|
Interposed between sensory and motor neurons and linked together
Amplify and distribute signals in the gut |
|
|
Afferent neurons of GI tract
|
Sense stretch, distention, chemicals
Transmit locally to myenteric plexus and back to brain Activated by 5HT from enterochromaffin cells |
|
|
Normal gut peristalsis
|
Automatic and not perceived
Afferent neurons (IPANs) sense distention and communicate via interneurons to motor neurons up and downstream |
|
|
Reflexes in the enteric NS
|
Peristalsis
Mucosal secretion Vasodilation |
|
|
Enteric NS and accessory organs
|
Increase bile and pancreatic secretions
Prevent reflux through sphincter of Oddi |
|
|
Interstitial cells of Cajal
|
Pacemakers of GI contraction
Generate rhythmic, spontaneous slow waves If these coincide with an AP then a contraction results Small cells located in muscular layer Rates in stomach (3 cpm) are different than intestine (12 cpm) |
|
|
Disorders involving the enteric NS
|
Achalasia
Gastroparesis Chronic pseudo-obstruction IBS Functional dyspepsia Chronic constipation Hirschprung's disease |
|
|
Nausea as a symptom
|
Vague unpleasant feeling in epigastric area
Usually accompanied by feeling that vomiting could occur Typically preceeded by anorexia |
|
|
Nausea objectively
|
Associated with decreased gastric peristalsis and tone
and increased small bowel tone |
|
|
Retching
|
Similar to vomiting with no expulsion of gastric/small bowel contents
Antral contraction, fundus/cardia relaxation, mouth and glottis closed Abdominal wall contraction with spasmodic inspiratory efforts |
|
|
Vomitting
|
Retrograde small bowel contractions, antral contractions propel contents into esophagus through relaxed LES, then out the mouth
Typically preceeded by anorexia, nausea Typically with autonomic symptoms (tachy, diaphoretic, pallor, hypersalivation) |
|
|
Gagging
|
Nonspecific
Hypersensitive pharyngeal reflex or Early vomiting being voluntarily suppressed |
|
|
Regurgitation
|
Sudden, effortless, involuntary movement of small amounts of solid/liquid into esophagus/mouth
|
|
|
Rumination
|
Food is chewed, swallowed, then voluntarily regurgitated
|
|
|
Prevalence of n/v in pregnacy
|
70% of women experience
25-55% experience recurrent vomiting 0.35% hyperemesis gravidum |
|
|
Functions of the stomach
|
Accommodation
Trituration (mixing) Emptying |
|
|
Muscular layers of the stomach
|
Inner oblique
Middle circular Outer longitudinal |
|
|
Role of vagus in gastric motility
|
Inhibits proximal tone for increased accommodation
Increases antrum contractions to increase trituration, emptying |
|
|
Fundus motility
|
High tone
Little phasic activity Acts as a reservoir with receptive relaxation and accomodation |
|
|
Antrum motility
|
Contracts in response to electrical slow waves
Responsible for process of trituration Empties food into duodenum when <1mm |
|
|
Trituration
|
Mixing/grinding based on antrum contraction
Can generation 300-400 mmHg against closed sphincter |
|
|
EGG
|
Electrogastrography
Noninvasive measurement of gastric electrical activity This evaluates the gastric slow wave |
|
|
Interstitial cells of Cajal
Embryology Gastric location |
Neural crest cell derivatives
Greater curvature of the stomach |
|
|
Normal gastric motility phases
|
Fed state -- Persistent, irregular contractile action
Fasting - Migratory motor complex I - quiescence II - irregular contractions III - short period of intense contractions |
|
|
MMC
|
Migratory motor complex
Peristaltic wave that sweeps through the gut about once a day to get rid of bacteria, shed cells, etc |
|
|
Erythromycin and gut motility
|
Stimulates antral contractions
Gives feeling of nausea, can be taken advangtage of |
|
|
Difference between nausea and vomiting
|
Thought to have same neurologic mechanisms, difference is from degree of stimulation
|
|
|
Vomiting triggers
|
Vomiting center in medulla receives input from vagal/sympathetic afferents from GI tract, heart, vestibular system
afferents from chemoreceptor trigger zone in area postrema afferents from higher brain centers sense noxious smells, etc |
|
|
Chemoreceptor trigger zone
|
Area postrema, where there is no BBB, to sample blood for potential toxins
Chemically induced vomiting is supressed with ablation of this zone (via apomorphine a DA receptor antagonist) |
|
|
Vomiting physiology
|
Coordinated action mediated by vagus, phrenic, and spinal nerves
Large amplitude small bowel contractions Retrograde movement of bile and secretions into stomach Pylorus contracts, stomach relaxes Abdominal wall muscles, diaphragm contract LES relaxes, esophagus relaxes and dilates Glottis closes, soft palate rises, mouth opens |
|
|
What exam to preform w/ n/v
|
VS
Abdominal Neurologic Skin Rectal/pelvic |
|
|
N/V DDx
|
Obstruction
Colonic disease Post-op ileus Pyloric stenosis Pseudoobstruction Ischemia Infections Pancreatitis Peritonitis Hepatobiliary disorders PUD/gastritis Gastroparesis Appendicitis Diverticulitis Toxins |
|
|
Labs in N/V
|
CBC
Electrolytes Ca, Mg, Phos LFTs glucose amylase/lipase bHcG Urinalysis Drug levels SPEP/UPEP ESR Hormone levels |
|
|
N/V radiologic studies
|
KUB
EGD, UGI series RUQ US Gastric emptying scan MRI of head |
|
|
Common causes of acute n/v
|
INFECTIONS (viral)
toxins metabolic disorders cns disorders oculovestibular disorder pregnancy meds |
|
|
Weirder causes of acute n/v
|
MI
CHF Excessive vitamin intake Excessive fasting/starvation |
|
|
Common causes of chronic n/v
|
Gastroparesis
Pseudoobstruction Psychogenic vomiting |
|
|
Metabolic of N/V
|
Metabolic:
Low K Low Na Low Cl Low H (alkalosis) Volume depletion Malnutrition |
|
|
Complications of emesis
|
Mallory Weiss tear
Boerhaave's syndrome GI bleeding Dental problems Aspiration pneumonia Purpura |
|
|
Acute N/V treatment
|
Remove precipitants
IV fluids Oral rehydration (salt, water) Full liquids Complex starches Anti-emetics |
|
|
Treatment of chronic n/v
|
Antiemetics
Pysch eval Alternative remedies Hyperalimentation Gastric pacing Surgery |
|
|
Meds used in treatment of N/V
|
Antihistamines
Anticholingerics Phenothiazines Butyrophenones Dopaminergic agonists Serotonin receptor antagonists |
|
|
Gastroparesis
|
Impaired transit of luminal contents from stomach to duodenum in the absence of mechanical obstruction
|
|
|
Symptoms of gastroparesis
|
N/V
Early satiety Epigastric pain Anorexia, weight loss Gastroesophageal reflux Bloating Pain (neuropathic) |
|
|
Diagnosis gastroparesis
|
r/o mechanical obstruction w/ endoscopy or UGI series
Gastric emptying scan w/ less than the normal 90% emptying of radiolabeled meal at 4 hours |
|
|
Gastroparesis etiologies
|
Idiopathic - 50%
DM Post surgical Post viral Neurologic Ischemia Radiation Metabolic Vaccinations Collagen-vascular Pseudoobstruction Inflammatory Infiltrative Prior transplant Cirrhosis |
|
|
Gastroparesis pathogenesis
|
Pacemaker dysrythmias (DM, trauma)
Hypomotility Antroduodenopyloric spasm Excessive inhibition by CCK (fatty foods) |
|
|
Complications of gastroparesis
|
Bezoar (high mortality if large)
GERD Unnecessary cholecystectomy Metabolic derangements Mallory Weiss Need for TPN, J-tube |
|
|
Treating gastroparesis
|
Meds
Diet Gastric stimulation J-tube, TPN rarely surgery |
|
|
Motility disorders
|
Dysfunction of the muscles and nerves of the GI tract
Neuropathic, myopathic, or both |
|
|
Intestinal embryology
|
Gut tube - 4th week lateral folding around yolk sack
Forgut - up to bile duct in proximal duodenum Midgut - distal duodenum to splenic flexure Hindgut - splect flexure - anus Umbical herniation at 6 weeks Counterclockwise rotation Return to abdomen at week 10 |
|
|
Malformations of the midgut
|
Omphalocele
Malrotation Volvulus Umbilical hernia Intestinal stenosis and atresia |
|
|
Ileocecal valve function
|
Prevents colonic bacteria from entering small bowel
Braking mechanism Not a true sphincter, but slows things down so as to avoid the constant urge to defecate |
|
|
Venous drainage of the midgut
|
Ileal and Jejunal veins join to form
Superior mesenteric vein SMV joins with the splenic to form portal |
|
|
Small bowel electrical activity
|
ICC cells are deep to the circular muscle layer
Rhythm is 9-12 cpm Contraction occurs when electrical spike burst coincides with a slow wave Contractions are lower amplitude that stomach |
|
|
Antroduodenal manometry
|
Specialized catheter with transducers
Measures neurologic and muscular activity Performed only at specialized centers |
|
|
Octreotide and motility
|
Small bowel stimulator
|
|
|
Colonic embryology
|
Hindgut forms distal transverse, descending, rectum, proximal anal canal
Terminal portion of hindgut is divided in week 6-7 by the urogenital septum creating the ventral urogenital sinus and dorsal rectum/anal canal |
|
|
Imperforate anus epi
|
M>W
1:5000 |
|
|
Anal sphincter
|
Internal -smooth muscle
- responsible for 70% of continence External - skeletal muscle |
|
|
How long is the colon?
|
4-5 feet
|
|
|
Venous drainage of the colon
|
Rectosigmoid, sigmoid, left colic vein join to form inferior mesenteric vein
|
|
|
Functions of the colon
|
Absorption -- fluid and electrolytes, nutrients, bacterial fermentation products
Formation of residue -- mixing, retention, formation Storage of material - reservoir - especially left side Transport conduit |
|
|
Motor patterns in the colon
|
Segementing contractions -- promotes mixing
Propagating contractions -- Low amplitude -- short distances, either direction High amplitude -- long distance, caudally, associated with defectation |
|
|
Hirschprung's disease
|
1/5000
Failure of neural crest cell migration to the enteric NS Aganglionic section of the colon Inability to relax to accommodate stool, pass stool Dilation above Can affect just anorectum or more Diagnosed perinatally because of lack of stool Treat with myotomy |
|
|
Diarrhea epi worldwide
|
1 billion cases/year
Contributes to 2.2 million deaths Third leading cause of death |
|
|
Normal range of stool frequency in US
|
3/day to 3/week
<200 gms/day 70-85% water |
|
|
Defining diarrhea physicians vs patients
|
Physicians define diarrhea as > 200 gms/day
Patients may complain of diarrhea when increase in stool frequency or change in consistency |
|
|
What part of the bowel is most important for absorbing nutrients?
|
Small bowel
|
|
|
Stool and water balance
|
9 L of water enter GI tract (1.5 L from diet)
90% of water is absorbed in small intestine (mostly jejunum) 90% of what's left is absorbed in large intestine |
|
|
How does small intestine absorb water?
|
Water follows salt (electrolytes) and travels mostly in paracellular pathway
Na-glucose co transporter Na-H exchanger Electrogenic Na pump (jejunum) |
|
|
What is specifically reabsorbed in duodenum, ileum?
|
Duo - Ca, Fe
Ileum -- bile salts, B12 |
|
|
What drives the concentration gradient allowing for absorption of water in the colon
|
Na/K ATPase on basolateral side
Oubain sensitive (diarrhea is a digitalis toxicity) |
|
|
SGLT-1
|
Sodium glucose co transporter
Carrier protein on apical membrane of enterocytes Moves Na and glucose from lumen into cell |
|
|
Intestinal secretion
|
Crypts and villus have different transport proteins
In crypts: Na/K-2Cl transporter on basolateral, CFTR chloride channel on apical --Allows for rapid egress of Cl (and water) |
|
|
Regulation of GI secretion
|
cAMP increases mean more secretion
and less absorption High cAMP levels result in phosphorylation of CFTR and increased activity |
|
|
Categories of mechanisms for diarrhea
|
Osmotic
Secretory Inflammatory Dysmotility |
|
|
Osmotic diarrhea
|
Poorly or non-absorbable solute in lumen results in water retention and watery stool
Sorbitol (gum) or lactulose |
|
|
Lactulose clinical application
|
Help move bowels
Especially in liver failure |
|
|
Hallmarks of an osmotic cause to diarrhea
|
Fasting stops the diarrhea
Increase in stool osmotic gap (290 - 2(Na + K)) > 100 indicates osmotic |
|
|
Causes of osmotic diarrhea
|
Ingestion of sorbitol, lactulose, poorly absorbed cations (milk of magnesia)
Lactose intolerance Malabsorption of fat (intestinal failure, pancreatic exocrine insufficiency) |
|
|
Secretory diarrhea
|
GI tract secretion overwhelms GI tract absorption
Normal mechanisms out of balance Example: cholera |
|
|
Effect of cholera toxin
|
Increase cAMP
Which results in increased CFTR action and decreased N/H, Cl/HCO3 action Na/glucose cotransporter is unaffected |
|
|
Secretory diarrhea hallmarks
|
Not relieved by fasting
No stool osmotic gap |
|
|
Causes of secretory diarrhea
|
Cholera
Endocrine tumors (VIP, gastrinoma, carcinoid) Laxatives (senna, phenolphthalein, bisacodyl) Lubiprostone - constipation med |
|
|
Lubiprostone
|
Activates apical chloride channels on intestinal cells
Oral bycyclic fatty acid FDA approved for treatment of chronic constipation |
|
|
Inflammatory diarrhea
|
Mucosal ulceration and inflammation leads to exudate of blood, lymph, mucus
Epithelial cells that regulate are destroyed |
|
|
Clinical findings in inflammatory diarrhea
|
Blood, mucoid diarrhea
Fever if infectious Increase in fecal leukocytes |
|
|
Causes of inflammatory diarrhea
|
Inflammatory bowel disease
Infections Toxin-mediated-- EHEC, C diff Invasive -- Shigella, Campylobacter, Salmonella, Yersenia |
|
|
Dysmotility diarrhea
|
Abnormal bowel transit time leads to diarrhea
Archetype -- post surgical |
|
|
Dumping syndrome and diarrhea
|
Dysmotility - large vols of fluid/solid enter the duodenum rapidly, stimulate motility
Osmotic - lack of reabsorption leads to hyperosmotic chyme Secretory - rapid distention leads to release of vasoactive substances promoting secretion |
|
|
Causes of dysmotility diarrhea
|
Surgery
Slow intestinal transit and bacterial overgrowth leading to problems with enterohepatic circulation, bile acids |
|
|
What makes diarrhea acute vs chronic?
|
< or > than 3 weeks in duration
|
|
|
Causes of acute diarrhea
|
Most common
Norovirus in adults Rotovirus in kids Others: ETEC from South America Salmonella, Shigella, Campy -- Asia Giardia from streams C diff w/ hospital or antibiotics |
|
|
Cause of diarrhea when returning from South America
|
Enterotoxigenic E coli
|
|
|
Cause of diarrhea when returning from Asia
|
Invasive organism: shigella, samonella, campylobacter
|
|
|
Cause of diarrhea after a camping trip
|
Giardia
|
|
|
Cause of diarrhea after hospitalization/antibiotic us
|
C. Difficile
Antitbiotics: cephs, clinda, PCN |
|
|
Cause of diarrhea in a patient with AIDS
|
Cryptosporidium, microsporidia, cyclospora, isospora
|
|
|
Diarrhea after a hamburger?
|
E. coli
Enterohemorrhagic |
|
|
Parasites that can cause diarrhea
|
G. lamblia
E. histolytica cryptosporidium isospora |
|
|
Infectious diarrhea, always inflammatory?
|
No
If in small bowel, likely a water, non-bloody diarrhea |
|
|
Acute diarrhea warning signs
|
Dehydration
Severe abdominal pain (toxic megacolon is a worry) |
|
|
What can you tell from the stool in acute diarrhea?
|
Fecal leukocytes
+ = bacterial or IBD - = viral Giardia antigen C diff toxin |
|
|
Treating acute diarrhea
|
Oral rehydration
ORS if severe Recommend fluids high in salt, K, carbs Antidiarrheal agents, cautiously (can make inflammatory worse) Antibiotics if toxic appearing |
|
|
IBS
|
Disordered bowels with abdominal pain
No weight loss, no noctural diarrhea |
|
|
Medications that can cause diarrhea
|
Digoxin
Mg containing antacids Sweeteners (fructose, sorbitol) |
|
|
Dermatitis herpetiformis
|
Skin finding in Celiac's disease
|
|
|
Best evaluation for chronic diarrhea?
|
48 stool
Check amount to r/o pseudo/IBS Check osmotic gap r/o laxative abuse |
|
|
Celiac's disease
|
Gluten sensitivity w/ villus atrophy
Diagnose w/ serum tissue transglutaminase Fe deficiency |
|
|
Differentiating between UC and Crohn's
|
Mucosal vs transmural inflammation
Always starts at rectum and only involves colon vs anywhere |
|
|
Ulcerative colitis histology
|
Intense, diffuse infiltrate in mucosa
Distortion and destruction of colonic glands Gland lumens filled with inflammatory cells |
|
|
Where is IBD found?
|
Developed nations have highest prevalence
With increased sanitation see rise in UC then Crohns |
|
|
Onset of IBD?
|
Can happen at any time but most common in adolescence, young adulthood
Small bowel Crohn's usually has earlier onset than colonic Crohn's |
|
|
Genetics and IBD?
|
Twin studies show some genetic component, much higher concordance in Crohn's than UC
|
|
|
Smoking and IBD
|
Improves UC
Worsens Crohn's |
|
|
Protective factors in ulcerative colitis
|
Smoking
Appendectomy Maybe breast feediing |
|
|
Risk factors in Crohn's
|
Smoking
High sanitation in childhood High intake of refined carbs Perinatal infection |
|
|
Etiologic hypothesis for IBD
|
Persistent infection
Defective mucosal integrity Dysbiosis (change in commensals) Dysregulated immune response |
|
|
Persistent infection theory of IBD
|
Candidates for infectious agent include
Mycobacterium Helicobacter ETEC Listeria Measles/mumps None have been proven |
|
|
Dysbiosis etiology of IBD
|
Loss of lactobacillius and bifidobacterium
Increase in Bacteriodes, entetrococcus, invasive E. Coli |
|
|
IBD
|
Inflammatory bowel disease
Chronic, relapsing immune mediated intestinal inflammation |
|
|
Normal mucosal defenses
|
Tight junctions
Mucus Intestinal trefoil factor Defensins IgA Restitution |
|
|
Intestinal trefoil factor
|
Increased viscosity of mucus
Stimulates epithelial restitution |
|
|
NOD2/CARD15
|
Two copies of mutant increases risk of Crohn's by 15-40x
One copy by 1.5-4x Increased prevalence in patients with Crohn's disease but only 1/10 who have gene develops Crohn's |
|
|
Environmental factors that promote onset or flare of IBD
|
Change commensals : antibiotics, diet
Change mucosal barrier fnc: NSAIDs, acute infections, stress (smoking in Crohn's) |
|
|
Bacterial role in the pathogenesis of IBD
|
There is one
Sterile animals do not develop IBD Can get varieties of colitis depending on the introduced bacteria (cecal -- aggressive colitis, lactobacillus -- protective) |
|
|
Luminal contents role in pathogenesis of IBD
|
Segmental resections with reanstamosis always lead to recurrence
Crohn's could be recapitulated by introduction of luminal contents |
|
|
Pattern of disease in ulcerative colitis
|
Always starts with rectum
Progresses contiguously No skip lesions |
|
|
Ulcerative colitis symptoms
|
Rectal bleeding (hematochezia)
Diarrhea Abdominal pain Tenesmus and urgency Systemic complaints Extraintestinal manifestations |
|
|
Tenesmus
|
Sense of incomplete rectal emptying
"dry heaving of the rectum" Sign of rectal inflammation |
|
|
Assessing severity of ulcerative colitis
|
Mild <4 stools day, no systemic comp, ESR wnl
Moderate <4 stools day, min systemic complaints Severe > 6 stools /day w/blood, fever, HR>90, anemia |
|
|
Diagnosing ulcerative colitis
|
Clinical picture
Chronic presentation Endoscopic appearance Colonic biopsies R/o other causes |
|
|
What differentiates IBD from IBS
|
Lots of things.
Acute phase-- increased plts, esr, decreased albumin Weight loss Fever Bloody stool, tenesmus Perianal disease Fecal blood, WBCs |
|
|
Colitis DDx
|
Crohn's
Ulcerative colitis Infectious colitis Ischemic colitis Microscopic/collagenous colitis STD Post xrt Vasculitis NSAID induced |
|
|
Differentiating between infections and IBD
|
Duration (<2 weeks vs > 4 weeks)
Onset of symptoms (acute vs slow) HCT (normal vs low) Plts (Normal vs high) Biopsy w/ PMN vs mixed infiltrate with architectural changes |
|
|
Cryptitis
|
PMN infiltrating crypt
Sign of active mucosal inflammation |
|
|
Crypt abscess
|
Crypt lumen filled with PMNs
Progression of cryptitis Surrounding epis are injured |
|
|
How does crypt architectural distortion occur?
|
Ulceration or erosion damaging basement membrant
and then re-epithelialization Result is branched, distorted crypts |
|
|
Potential courses for ulcerative colitis
|
Recurring episodes of mild/mod severity (most)
Fulminating Chronic active Proctitis -- may be difficult to treat |
|
|
Complications of ulcerative colitis
|
Hemorrhage
Toxic megacolon Perforation Colon cancer |
|
|
Toxic megacolon
|
Dilated colon which is late presentation of toxic colitis (complication of ulcerative colitis)
Penetrating inflammation results in paralytic ileus and build up of gas By megacolon stage, high risk of perf, peritonitis |
|
|
Early sign of bowel perforation?
|
Air dissecting subserosally
|
|
|
Risk of CRC in IBD
|
0.5% per year after first 10 years
20x increase over baseline |
|
|
How do colon cancers arise in IBD patients?
|
Out of dysplasia not polyps
|
|
|
Microscopic colitis
|
Inflammatory bowel diseases where mucosa appears normal endscopically
Watery, non-bloody diarrhea Collagenous and lymphocytic colitises |
|
|
Lymphocytic colitis
|
Microscopic colitis, IBD
Watery diarrhea Middle aged adults, M=F Usually normal endoscopy May be associated with celiacs/autoimmunity |
|
|
Collagenous colitis
|
Microscopic colitis, IBD
Watery diarrhea Usually normal endoscopy Predominantly in older women Thickened subepithelial layer of collagen is histologic differentiation from lymphocytic |
|
|
Consequences of transmural inflammation of Crohn's disease
|
Obstruction -- edema, fibrosis, spasm all combine to narrow lumen
Fistula -- deeply penetrating sinus tracts |
|
|
Microgranulomas in bowel wall
|
Crohn's disease
|
|
|
IBD without bleeding?
|
Much more likely to be Crohn's than UC
|
|
|
IBD with perianal lesions?
|
Crohn's
Happens in about 1/3 patients |
|
|
Where is most Crohn's found?
|
Small bowel
|
|
|
Apthous ulcer appearance
|
Punched out ulcer
Filled with exudate Charaterisic erythematous halo surrounds |
|
|
Crohn's appearance endoscopically
|
Nodular
Exudate Ulceration Luminal narrowing |
|
|
Crohn's presentation
|
Pain (often RLQ)
Tenderness Diarrhea Low grade fever Weight loss (anorexia) |
|
|
Confined perforation
|
Crohn's disease complication
Can mimic appendicitis or diverticulitis |
|
|
Symptoms of Crohn's related to strictures
|
transmural inflammation can lead to fibrosis/strictures
Obstruction Distention Borborygmi Vomitting Weight loss (food avoidance) |
|
|
Fistulas and Crohn's
|
Complication of transmural inflammation
Enterovesicular - recurrent UTIs, pneumaturia Retroperitoneal-- psoas pain Enterocutaneous -- drainage through scar Perianal -- pain, drainage Rectovaginal -- drainage of feces, air |
|
|
Gall bladder and Crohn's
|
Bile-salt wasting, depletion
Gall stones |
|
|
Osteopenia and IBD
|
Happens with both UC and Crohn's
50% prevalence Mediated by inflammation and IBD medications (steroids) |
|
|
IBD in childhood
|
Fever
Anemia Arthritis Growth retardation Extraintestinal complaints can dominate |
|
|
Mouth finding with IBD
|
Oral apthous ulcers
|
|
|
Eye findings in IBD
|
Episcleritis -- injection of deep cilliary vessels
parallels disease Anterior uveitis painful, synechiae and opacity in anterior chamber independent course |
|
|
Most common extranintestinal manifestation of IBD
|
Arthritis
|
|
|
Arthritis of IBD
|
Peripheral arthritis
Monoarticular Assymetric Large joints > small joints No nodules No synovial damage Seronegative Parallels disease course Central arthritis SI or ankylosing Independent of disease status |
|
|
Skin finding of IBD
|
Erythema nodosum
more common in Crohn's correlates with disease Pyoderma gangrenosum more common in UC less likely to correlated with disease mechanical trauma can contribute |
|
|
Liver complications of IBD
|
UC associated with PSC
unrelated to disease colectomy not protective Liver lesions that looks like hepatitis |
|
|
What types of treatment are used in IBD
|
Amiosalicylates
Corticosteroids Immunomodulators Antibiotics |
|
|
IBD pregnancy
|
Try to conceive during remission
Males should switch of sulfasalizine if infertile 5-ASAs, sulfasalizine, corticosteroids all safe 6-MP, azathioprine probably fine |
|
|
When to do surgery for UC?
|
Always w/ big hemorrhage, perforation, cancer, unresponsive acute disease
Consider w/ chronicity, steroid dependence, growth retardation, systemic complications |
|
|
Surgical options w/ UC
|
Ileostomy
+/- pouch Ileorectal anastomosis +/- pouch |
|
|
Malabsorption
|
Failure to absorb simple nutrients and products of digestion
|
|
|
Maldigestion
|
Failure to break down complex nutrients
|
|
|
What is required for successful carbohydrate/protein digestion
|
Intraluminal digestion
Brush border digestion Brush border transport |
|
|
What is required for successful fat digestion
|
Intraluminal digestion
Incorporation into micelles Brush border digestion Brush border transport Mucosal resynthesis Packaging in lippoproteins |
|
|
Pancreatic insufficiency and carbohydrate digestion
|
Disordered based on lack of intraluminal digestion by amylase
|
|
|
Gastrectomy and carbohydrate digestion
|
Disordered 2/2 poor mixing of carbohydrates and amylase
|
|
|
Celiac disease and carboydrate digestion
|
Disordered 2/2 poor absorption
|
|
|
Lactase deficiency
|
Oligo and disaccharides are digested at brush border by enterocyte enzymes
Lactase deficiency occurs with age, GI infections/inflammation Leads to osmotic diarrhea based on unabsorbed lactose and FA products of bacterial metabolism of lactose |
|
|
Pancreatic insufficiency and protein digestion
|
Disordered 2/2 decreased intraluminal digestion by pancreatic proteases
|
|
|
Hartnup disease
|
AR genetic defect in absorption of Na-linked neutral amino acids
--and niacin Symptoms are of niacin deficiency: photosensitive scaly rash cerebellar ataxia pyschosis, |
|
|
Cystinuria
|
AR recessive defect in absorption of dibasic AAs in gut and kidney
Manifests as cystine kidney stones --cysteine is the lease soluble of these AA in acidic urine |
|
|
Why don't patients with AA-transporter genetic deficiency become protein malnurished
|
Small peptides have their own brush border transport system
|
|
|
Etiologies of fat maldigestion
|
Decreased emulsification
Rapid gastric emptying Decreased salivary/gastric lipase Decreased pancreatic lipases Inmpaired secretin/CCK Lipase inactivation |
|
|
Pancreatic insufficiency clinical picture
|
Steatorrhea, ADEK malabsorption, insulin dependent diabetes
Metabolic bone disease, B12 deficiency, oxalate kidney stones |
|
|
Why B12 deficiency in pancreatic insufficiency?
|
Lack of pancreatic proteases leave glycoproteins in lumen (R factors) that compete with intrinsic factor for B12
|
|
|
Why metabolic bone disease from chronic pancreatic insufficiency?
|
Vit D malabsorption (fat soluble)
Calcium malabsorption If alcohol is cause, this also has direct effect on bones |
|
|
Etiologies of fat malabsorption
|
Impaired micelle formation
Decreased absorption of lipolytic products Impaired intracellular fat esterification Decreased chylomicron/lipoprotein formation Impaired chylmicron transfer |
|
|
How does lipid from micelles get absorbed?
|
Micelles with bile acid rims and FA/monolglyceride cores traverse the unstirred water layer to get to brush border
Enterocytes absorb lipid from core Empty micelles recycled |
|
|
Where does fat absorption occur?
|
Proximal small intestine
|
|
|
Ilitis and fat absorption
|
Causes malabsorption 2/2 lack of enterohepatic circulation of bile acids
|
|
|
Lipid metabolism within enterocyte
|
Esterification
Packaging into chylomicron/VLDL Secretion into lacteal |
|
|
Abetalipproteinemia pathogenesis
|
AR disorder of reduced levels of ApoB
Defect in microsomal triglyceride transfer protein Liver/enterocytes unable to make VLDL and chylomicrons Enterocytes fill with lipid, stop being able to take up...steatorrhea |
|
|
Abetalipporteinemia presentation
|
Lack of ability to deliver lipids
Ataxia RBC acanthocytosis Retinitis pigmentosa |
|
|
Whipple's disease
|
Rare infection w/ tropheryma whippeli
Gram + intracellular in macrophages --lamina propria, mesentery, LNs Steatorrhea, fat malabsorption, protein loss (edema, ascites, pleural effusion, lymphpenia) |
|
|
Who gets Whipple's disease?
|
Rare
Middle aged white construction workers |
|
|
Lymphangiectasia
|
Obstruction/damage to intestinal lymphatics or mesenteric duct
Congenital or acquired (cancer, retroperitoneal fibrosis, xrt( Protein losing enteropathy (edema, ascites, lymphopenia) Treat: low fat diet, ADEK |
|
|
Most common panmalabsorption in US?
|
Celiacs aka Gluten Sensitive Enteropathy
|
|
|
What is gluten?
|
Protein in wheat, barley, rye, oats
Seed storage protein w/ high concentration of glutamines Upon digestion -- gliadins and glutenins -resistant to pancreatic proteases |
|
|
Who get's celiacs?
|
Required to have DQ2 or DQ8
|
|
|
Presentation of celiacs
|
Diarrhea
Fe deficiency Metabolic bone disease Autoimmune disorders Migrane Infertility |
|
|
Celiacs pathogenesis
|
Immune destruction of enterocytes
Tissue transglutaminase converts the glutamine in gliadin to glutamic acid This complex binds with DQ2/8 on macros/DCs Activation of CD4, Th1 cells Elaboration of TNF, fibroblast MMP, CD8 activation, Th2 activation Th2 make anti-ttg |
|
|
Results of celiacs
|
Destruction of neuroendocrine GI cells -- no CCK/secretin -- impaired pancreatic fnc
Decreased brush border enzymes -- malabsorption Loss of tertiary villus structure -- loss of SA Increased inflammation -- intestinal secretion Fatty diarrhea |
|
|
Explain fatty diarrhea in celiacs
|
Disruption of enterohepatic circulation, pancreatic secretion, increased osmotic load from poor carbohydrate/lipid/protein absorption
|
|
|
Endoscopic appearance of celiacs
|
Scalloping of duondenal mucosa
|
|
|
Causes of B12 malabsorption
|
Lack of intrinsic factor --
pernicious anemia, gastrectomy Increased R factors pancreatic insufficiency Increased B12 uptake bacterial overgrowth Decreased ileal absorption Crohn's, bowel rxn |
|
|
Calcium, zinc, magnesium absorption
|
Duodenum - so celiacs and gastrectomy inhibit
Form insoluble soaps with fats, so increased loss with fat malabsorption (Ca and Mg) Also increased loss with diarrhea |
|
|
Iron malabsorption
|
Impaired reduction of Fe3+ to Fe2+ in achlorhydria, post-gastrectomy
Decreased absorption in celiacs, postgastrectomy |
|
|
Bacterial overgrowth syndrome risk factors
|
Achlorhydria
Stasis (reduced motility) Fistulas Surgery |
|
|
Bacterial overgrowth syndrome
|
10^6 bacteria/ml in small intestine
|
|
|
Bacterial overgrowth consequences
|
Fat malabsorption -- bile acid deconjugation
Diarrhea -- hydroxylation of FAs Bloating -- products of bacterial metabolism Tropical sprue - mucosal damage from toxins Megaloblastic anemia -- bacterial uptake of B12 |
|
|
Testing for bacterial overgrowth syndrome
|
Quantitative small bowel culture
Breath testing for hydrogen, methane after ingesting carbohydrate --happens faster if bacteria are in small intestine not just colon |
|
|
Oxalate kidney stones in fat malabsorption, why?
|
Oxalate is a metabolic end product
Normally Ca and Mg in lumen precipitate oxalate With fat malabsorption, Ca and Mg are bound to FAs and oxalate is absorbed Forms insoluble calcium oxalate stones in the kidney |
|
|
Carcinoid tumors histologically
|
Nests of atypical cells
Nuceli are bland, uniform, w/ salt and pepper chromatin |
|
|
Paneth cell
|
Cell of intestinal crypt
Apical granules -- defensins |
|
|
Appearance of endocrine cells in crypts
|
Granules of hormones at base (away from lumen)
|
|
|
Carcinoid tumors of the bowel complications
|
Kinking and obstruction
Secrete serotonin which results in fibrosis |
|
|
Possible histologic patterns of endocrine tumors in the bowel
|
Nests -- most commone
Trabecular Anaplastic |
|
|
Benign tumors of the small bowel
|
Present with pain (intermittent), nausea, vomitting, bleeding
M=F adenoma, lipomas, GIST, carcinoid, leimyomas, hemangiomas |
|
|
What diagnostic test when suspecting small bowel tumor?
|
With pain: CT/MRI enterography
Bleeding: endoscopy/colonoscopy, videocapsule endoscopy |
|
|
Treatment of small bowel tumors
|
For carcinods, adenomas, unclear
En bloc segemental resection Endoscopic treatment sometimes |
|
|
Carcinoid tumors of the bowel complications
|
Kinking and obstruction
Secrete serotonin which results in fibrosis |
|
|
Possible histologic patterns of endocrine tumors in the bowel
|
Nests -- most commone
Trabecular Anaplastic |
|
|
Benign tumors of the small bowel
|
Present with pain (intermittent), nausea, vomitting, bleeding
M=F adenoma, lipomas, GIST, carcinoid, leimyomas, hemangiomas |
|
|
What diagnostic test when suspecting small bowel tumor?
|
With pain: CT/MRI enterography
Bleeding: endoscopy/colonoscopy, videocapsule endoscopy |
|
|
Treatment of small bowel tumors
|
For carcinods, adenomas, unclear
En bloc segemental resection Endoscopic treatment sometimes |
|
|
Small bowel malignancy presentation
|
M slightly > female
Signs of obstruction -- pain, nausea, weight loss bleeding perforation 25-35% - palpable mass |
|
|
Risk factors for malignant tumors of the small bowel
|
Familial polyposis
HNPCC Peutz-Jeghers Crohn's Celiac's (esp lymphoma) Environmental exposures |
|
|
Treating small bowel malignancy
|
Chemo for primary lymphoma
En bloc rxn for most Whipple for duodenal No confirmed role for adjuvant Screen for FAP, HNPCC and survey rest of bowel |
|
|
Small bowel malignancy prognosis
|
20-50% survival for non-lymphoma
25-90% for lymphoma 50-60% have advanced disease at time of diagnosis |
|
|
Carcinoid tumors
|
Neuroendocrine cell tumors
Terminal ileum is most common site fore/midgut secrete serotonin, others do not 30% of patients have multifocal small bowel carcinoids |
|
|
Estimating malignant potential of a carcinoid tumor
|
Appendiceal and rectal -- usually benign
Depth of penetration <1/2 mucosa is usually benign Size < 2cm is usually benign |
|
|
What to monitor with a carcinoid tumor
|
Chromogranin A levels, urinary 5HIAA, octreotide scans
|
|
|
Symptoms of carcinoid tumor
|
Pain is most common
90% of symptomatic patients are metastatic Penetration into mesentery produces intense desmoplastic rxn Carcinoid syndrome |
|
|
Carcinoid syndrome
|
Occurs in <10% of malignant carcinoids, usually with liver mets
Release of serotonin into the systemic circulation: skin flushing/cyanosis diarrhea/cramps bronchospasm R ventricular subendocardial fibrosis (pulmonary/tricusp valve stenosis) |
|
|
Most common cancers of the small bowel
|
Carcinoid
Adenocarcinoma |
|
|
Most frequent site of small bowel adenocarcinoma?
|
Duodenum
Prox jejunum Crohn's related - terminal ileum |
|
|
GIST
|
Gastrointestinal stromal tumors
Tumors of the interstitial cells of Cajal Mesenchymal tumors resembling modified smooth muscle Ckit positive (CD117) Spectrum from benign to malignant |
|
|
Spindle cell histologically
|
Elongated nuceli with fasiculated cytoplasm
Usually mesenchymal origin |
|
|
GI lymphoma risks
|
MALT -- h pylori
T cell -- celiacs AIDS, IBD, transplant |
|
|
GI lymphomas
|
Most common site of extranodal lymphomas
50% in stomach, 37% in small intestine Single invasive cells Large nuclei, coarse chromatin, many mitoses |
|
|
Site of hematologic mets in small bowel
|
Submucosal area, where the blood vessels are
|
|
|
Tubular adenoma structure/histology
|
Pedunculated polyp
Stalk is normal mucosa, just stretched out Tightly packed tubules/glands with columnar cells lining |
|
|
What is the most common visceral malignancy?
|
Colon cancer
|
|
|
Falling colon cancer incidence?
|
Seen US Caucasians
Success of screening? |
|
|
Precursor lesion for colon adenocarcinoma
|
Adenoma
Not possible to distinguish which are going to progress to cancers 5-12 year natural history to progression |
|
|
Lifetime risk of colon cancer?
|
5-6%
|
|
|
Where in the colon are cancers?
|
30% in rectum
42% proximal to splenic flexure |
|
|
Epi of colon cancer
|
Incidence: Black>White>Asian>Hispanic>Indian
Mortality Indian>>Black>White>Hispanic>>Asian Increased rates in Jews Exposure to synthetic fiber production, dyes, organic solvents, asbestos, firefighting |
|
|
Risk factors for colon cancer
|
Diabetes
cholecystectomy pelvic xrt calorie intake/obesity red meat alcohol smoking |
|
|
Suggested tumor promoting factors in colon
|
Fecal bile acids
Heterocyclic amines (protein breakdown products) Fecapentenes - produced by anaerbes breaking down FA 3-ketosteroids -- oxidation product of cholesterol |
|
|
Colon cancer prevention
|
NSAIDs
Ca/D Folic acid b6 Omega 3s Increased fiber Physical activity |
|
|
Familial CRC
|
Pt has a family history of CRC but not syndromal
RR of having 1 first degree relative -1.7 History of advanced/many polyps is also bad |
|
|
Consistent feature of CRC syndromes
|
Patients get CRC at a young age
|
|
|
Personal risk of CRC
|
FAP - 95%
HNPCC IBD Personal h/o CRC cancer General pop -6 % |
|
|
HNPCC
|
Hereditary Nonpolyposis Colon Cancer
Lifetime risk 75% AD inheritance Mutation in mismatch repair gene Accelerated poly-->carcinoma Polyps more likely, more like to be villous, larger Right sided tendency |
|
|
Lynch syndromes
|
HNPCC
Lynch 1 -- CRC only Lynch 2 - CRC, pancreatic, endometrial, ovarian, gastric, small bowel, transitional |
|
|
HNPCC colon cancers
|
Tend to be proximal
Moor likley poorly diff, muscinous Better cancer-specific survival 45% chance of second primary |
|
|
Metachronous cancer
|
second primary
|
|
|
Diagnosing HNPCC
|
Screen family history
3-2-1 rule (3 members, 2 generations, 1<50) Look for microsatellite instability IHC for mismatch repair proteins if pt has cancer already |
|
|
Familial adenomatous polyposis
|
AD transmission
Germline APC mutation Hundreds of polyps in rectum/colon, stomach, small bowel 25% of probands have no family history |
|
|
FAP extraintestinal manifestations
|
Desmoids
Osteomas Brain tumors CHRPE Hepatobiliary tumors Thyroid tumors Adrenal tumors Epidermoid cyts |
|
|
What causes death in FAP?
|
duodenal tumors
desmoids |
|
|
Course of FAP
|
Symptomatic at 33
Cancer at 39 symptoms are bleeding and pain |
|
|
Polyp
|
A lesion that protrudes above surrounding mucosa
|
|
|
Adenoma
|
neoplastic polyp
|
|
|
Non-neoplastic polyps
|
90% of colonic polyps
Hyperplastic Hamartomatous Inflammatory pseudopolyps |
|
|
Normal colonic mucosa
Adenoma Carcinoma Histology |
Single layer of cells in gland, well defined goblet mucin
Adenoma -- stratification, depletion of mucin, cytologic atypia Malignant - invasion through basement membrane, branching of glands, lots of cytologic atypia |
|
|
Risk of malignancy in a polyp
|
Bigger is worse (>2cms)
Villous> Tubovillous > tubular High grade dysplasia Mutliplicity |
|
|
Villous adenoma
|
rare, worse prognosis (1/3 holds cancer)
Sessile adenomas Fronds of mucosa with fibrovascular core Velvety |
|
|
Treatment of polyps
|
Excise adenomas completely
Controversy about the right thing to do with polyps with malignancy-- do have risk for mets |
|
|
Hyperplastic polyp
|
Small, sessile polyps
Most commonly in rectum, sigmoid Elongated and serated, stellate crypts lined with hypermature goblet cells No malignant potential |
|
|
Juvenile polyp
|
Hamartomatous malformations
Mostly in rectum, children Dilated glands with inflamed lamina propria No malignant potential |
|
|
Peutz-Jeghers polyp
|
Hamartomatous polyp
Branching smooth muscle and glands lined by goblet cells Inherited, ser/thry kinase of unknown significance Increased risk of cancer of the pancreas, breast, lung, ovary, uterus --not arsing out of polyps |
|
|
Dirty debris
|
Necrosis of PMNs in gland lumen in colon
Characteristic of colon ca |
|
|
Left sided colon cancer pattern of growth
|
Annular, circumfrential ulcerated masses
"napkin ring lesions" Obstructive symptoms at presentation |
|
|
Right sided colon cancer pattern of growth
|
Polypoid, exophytic masses
Obstruction uncommon Often detected later w/ melena |
|
|
Tumor staging in colon cancer
|
Depth of invasion indicates risk of mets
pTis -- carcinoma in situ -- no risk carcinoma limited to mucosa -- low risk Submucosa 1 Into muscularis 2 Through muscularis 3 Penetration of serosa or into adjacent -- 4 |
|
|
Treatment of colon cancer
|
Segemental en bloc colon resection
removal of regional lymphatics metastatic disease in incurable (except maybe liver resections) |
|
|
Who has to have a colostomy permanently because of colon cancer?
|
distal rectal cancers invasive of the pelvic floor muscles
|
|
|
Adjuvant chem in colon cancer?
|
Proven to reduce cancer mortality (30%) stage III (postive nodes)
Unclear benefit in stage II |
|
|
Special concerns with rectal cancer
|
Need for colostomy
Difficult getting an adequate margin because of anatomy Preop chemo/xrt used to reduce the risk of local recurrence |
|
|
Metastatic disease in colon cancer
|
Can use lymphatic, peritoneal, hematogenous routes
80% hematogenous Major cause of colon cancer death Resistant to treatment 2/2 heterogeneity |
|
|
Oligometastatic liver disease in colon cancer
|
Resection w/ a 25% 5 year survival
|
|
|
Risk stratification for colon cancer
|
High: FAP, HNPCC, IBD
Increased: h/o crc, polyps, first degree relative with h/o crc, polyps |
|
|
How often to screen for colon cancer?
|
Avg risk: begin @ 50
Increased risk @ 40 or ten years prior FAP -- 12 HNPCC --25 IBD - q2 years 10 years into disease |
|
|
FAP management
|
Screening from age 12
Take out colon in 20s |
|
|
Options for colon cancer screen
|
Colonoscopy q 10
Year FOB w/ colonscopy if + Year FOB, FFS q 3 FFS and barium enema q5 |
|
|
Advantages/Disadvantages of using colonscopy has screening tool
|
Sensitivity 95%
does not miss many large polyps Cecum is reached 90+% of time Expensive, requires sedation time, IV access, invasive Complications: 1/1000 perfs, 3/1000 hemorrhage, 5/1000 resp distress |
|
|
Virtual colonoscopy
|
Not quite as good
Used in patients with incomplete colonscopies, obstruction, medical comorbidities |
|
|
How much does the liver weigh?
|
1400-1800 g
|
|
|
What is on the outside of liver?
|
Capsule except in bare areas (continuous with retroperitoneum)
Peritoneal reflections --support liver coronary left and right triangular ligaments Falciform ligament Hepatoduodenal ligament |
|
|
What's the falciform ligament?
|
Obliterated umblical vein
Contains the round ligament |
|
|
Hepatoduondenal ligament contents
|
Hepatic artery
Portal vein Common bile duct Nerves Lymphatics |
|
|
What divides the liver?
|
Falciform looks like it does
But its really the Cantlie's line (IVC to gallbladder Segments -- each contain a pedicle of portal vessels, ducts, drained by hepatic vein segment --can be divided |
|
|
Splenic vein tributaries
|
Short gastrics
Pancreatics Left gastroepiploic IMV |
|
|
SMV tributaries
|
Infterior pancreatoduodenal
Right gastroepiploic |
|
|
Portal vein tributaries
|
Splenic
SMV Inferior pancreatoduodenal Left gastric |
|
|
Normal hepatic arteries
|
Celiac -- common hepatic -- left and right hepatic
Cystic off right hepatic alt: Right hepatic off SMA Left hepatic from left gastric |
|
|
Hepatic veins
|
Central veins form three major veins: left, middle, right
Mid+Left, Right -> IVC BUT -- vein from Caudate goes directly to IVC --compensatory hypertrophy in Budd-Chiari or cirrhosis |
|
|
Portal HTN
|
Portal vein flow immediated by cirrohosis or thrombosis
Dilation of collaterals: Stomach, esophagus, Small intestine, retroperitoneum, stomal, umbilical --prone to rupture Also spleen enlargement |
|
|
Lymph and liver
|
Forms is space of disse, portal tract, hepatic veins
Drain to LN of hilum, cava Also capsule lymphatic drain the ligaments, cross diaphragm to esophageal, xiphsternal nodes |
|
|
Why can ascites lead to a pleural effusion anatomically?
|
Transdiaphragmatic lymphatics
|
|
|
Nerve supply of liver
|
Sympathetic and parasympathetic
Celiac plexus Vagus Right phrenic Function unclear |
|
|
Bile path out
|
Canals of Hering
Bile ductules Terminal bile ducts Segmental bile ducts R and L lobular ducts Common hepatic duct Common bile duct |
|
|
Hepatic acinus
|
Function unit of the liver
Hepatocytes supplied by one portal branch and on central vein |
|
|
Lobule
|
Hepatocytes encircled by a set of portal triads
|
|
|
Hepatic microcirculatory unit
|
Hepatocytes supported by a signle venule
Includes choleon and hepaton |
|
|
Major functions of the liver
|
Bilirubin and bile metabolism
Modification/detoxification Processing/redistribution of metabolic fuel Production of critical substances |
|
|
Ammonium metabolism and different liver zones
|
Periportal:
Urea cycle (ammonia -->urea) Amino acid metabolism (ammonium is a byproduct) Pericentral: Glutamine synthetase -- scavenges ammonium and converts to glutamine |
|
|
Stellate cell functions
|
AKA Ito cell
Vitamin A storage Synthesis of extracellular collagen Fibrogenic response to liver injury |
|
|
Source of billirubin
|
Heme from RBCs
pigments from macros/monos in spleen and bone marrow cytochrome enzymes in liver |
|
|
Bilirubin metabolism
|
Heme
Bilverdin Bilirubin Bilrubin-albumin travels to liver Simple and facilitated diffusion Bound to glutathione-S-transferase Conjugated by UDP-glucuronosyltransferase Water soluble Transported to bile ducts by MRP2 |
|
|
Bile constituents
|
Conjugated bilirubin
Cholesterol Bile salts Phospholipids (lecithin) |
|
|
What happens to conjugated bilirubin
|
Intestinal bacteria change to urobilinogen -- which can be reabsorbed
Converted to stercobilin -- excreted in stool Kidney can excrete urobilinogen, conjugated bilirubin Or liver can take them back up |
|
|
Etiology of unconjugated hyperbilirubinemia
|
Liver cell damage
Hemolysis -- increased production Decreased conjugation -Gilbert, Crigler-Najjar, acquired Vascular -- decreased flow to liver Starvation |
|
|
Etiology of conjugated hyperbilirubinemia
|
Obstruction
Hepatocyte defect leading to MRP2 failure acquired damage Dubin-Johnson, Rotor |
|
|
Measuring bilirubin
|
Van de Bergh reaction
Measure total Diazo reaction separates in a way that the conjugated can be DIRECTly measured Unconjugated in INDIRECTly calculated |
|
|
Phase I liver metabolism
|
CYP system
Oxidation, reduction, hydrolysis, hydration, decarboxylation, isomerizaiton |
|
|
Phase II liver metabolism
|
Non-cyp enzymes
Glucoronidation, sulfation, methylation, acetylation, glutathione conjugation |
|
|
Pentose phosphate pathway purpose
|
Generates reducing equivalents necessary for anaerobic glycolysis, fatty acid synthesis,
|
|
|
What about hepatic metabolism of carbohydrates other than glucose?
|
Fructose and galatcose enter glycogen synthesis pathway
|
|
|
Where are cholesterol and lippoproteins made?
|
Liver
|
|
|
What is the fnc of cholesterol?
|
Membrane structure
Precursors for steroid hormones |
|
|
Acute phase reactants
|
Group of proteins expressed during acute and chronic inflammation
Play a role in host defense against tissue damage Ex fibrinogen -- clots Anti-proteases - protect normal cells form the proteases that arise in necrotic tissue |
|
|
Potential reasons for lower serum protein levels
|
Hepatic insufficiency
Genetic mutations in serum proteins Depleted by disease (wilson's) Starvation (proteins --> energy) |
|
|
Albumin
|
Produced in liver
Binding protein Osmotic regulator Decreased in chronic liver disease Decreased in acute phase rxn |
|
|
Alpha feta protein
|
Made by liver
Binding protein Increased in HCC, testicular cancer Decrease in acute phase rxn |
|
|
Alpha1 antitrypsin
|
Made by liver
Inhibitor of elastase Missense mutations associated with liver disease, emphysema Increased in acute phase reaction |
|
|
Ceruloplasmin
|
Made by liver
Ferroxidase Decreased in Wilson's disease Increased in acute phase rxn |
|
|
Fibrinogen
|
Made by liver
Precursor to fibrin in clotting process Decreased in chronic liver disease Increased in acute phase rxn |
|
|
Transferrin
|
Made by liver
Iron-binding protein Increased in iron deficiency Decreased in acute phase rxn |
|
|
Complement C3
|
Made in liver
Immune function Increased in acute phase rxn |
|
|
Complement C4
|
Made by liver
Immune function Increased in acute phase rxn |
|
|
Alpha1 Acid glycoprotein
orosomucoid |
Made by liver
Inhibits proliferating response of peripheral lymphocytes to mitogens Increased in acute phase rxn |
|
|
Antichymotrypsin
|
Made in liver
Inhibits chymotrypsin-like serine protease Increased in acute phase rxn |
|
|
Haptoglobin
|
Made in liver
Binds hemoglobin released by hemolysis Increased in acute phase rxn |
|
|
C-reactive protein
|
Made in liver
Binds foreign pathogens/damaged cells to initiate their elimination Increased in acute phase rxn |
|
|
Serum amyloid A
|
Made in liver
Unknown function Increased in acute phase rxn |
|
|
Ferritin
|
Made in liver
Intracellular iron storage Increased in hemochromatosis Increased in acute phase rxn |
|
|
LFTs
|
Liver function tests
These are really liver injury tests |
|
|
Aminotransferase levels
What in liver elevates? Sources other than liver |
ALT/SGPT, AST/SGOT
Leakage from damaged hepatocytes Viral, autoimmune, toxic, wilsons, ischemic Muscle (skeletal and cardiac) |
|
|
AST/ALT ratio >2
|
Alcoholic liver damage
|
|
|
Alkaline phosphotase levels
What in the liver elevates Sources other than liver |
Overproduction is induced by
Extra/intrahepatic cholestasis, diffuse infiltrative process Bone, placenta --levels 3x higher in kids |
|
|
Gamma glutamyl transpeptidase
|
GGT
Overproduction is induced Drugs, alcohol Kidney, spleen, pancreas |
|
|
GGT/Alk phos > 2.5
|
Suggestive of alcoholic liver disease
|
|
|
5-Nucleotidase
What elevates in liver Sources outside of liver |
Overproduction/leakage
Cholestasis, infiltrative disease Liver specific |
|
|
LDH
What elevates in liver Sources outside of liver |
Overproduction/leakage
Very high in ischemic hepatitis, cancer, and infiltrative disease Skeletal/cardiac muscle, hemolysis, stroke, renal infarct |
|
|
Causes of low albumin
|
Chronic liver failure
Nephrotic syndrome Proetin-losing enteropathy Vascular leak Malnutrition Malignancy Inflammatory states |
|
|
Monoethylglycinexylidide
(MEGX) assay |
Lidocaine metabolism test
Tests liver detoxifying ability May predict death/complications in transplant |
|
|
Churg-Tucott-Pugh score
|
System designed to predict lifespan in cirrhosis so transplant list could be ordered
Based on presence of encephalopathy, ascites, bilirubin, INR, albumin |
|
|
MELD score
|
Prediction of surviving an intervention--including transplant with cirrhotic disease
Uses INR, Tbili, serum creatinine |
|
|
Carcinoembryonic antigen
|
CEA
Elevated in cholangiocarcinoma |
|
|
CA 19-9
|
carbohydrate antigen 19-9
elevated in cholangiocarcinoma |
|
|
Primary sclerosing cholangitis antibody
|
pANCA
|
|
|
Liver US
|
Primary screening exam for liver disease
Limited by obesity, recent food consumptom |
|
|
HIDA scan use
|
Gall bladder fnc/bile flow abnormal
|
|
|
Imaging to confirm hemangioma
|
Liver scintigraphy
99m Tc-labelled RBCs |
|
|
Percutaneous transhepatic cholangiography
|
Fluroscopy with dye injection into biliary tree transcutatneously
Allows visualization with ERCP is not possible Can place drains/ stents Complications: bleeding, perf, cholangitis |
|
|
Viruses that can cause acute hepatitis in healthy adults
|
HepA-E
|
|
|
Viruses that can cause hepatitis in children/immunosuppressed
|
Measles
Rubella CMV EBV Mumps Herpes Adenovirus Varicella zoster |
|
|
Which Heps increase risk of HCC
|
B, C, D
|
|
|
Which Heps have the potential for chronicity
|
B, C, D
E |
|
|
What kind of virus is hep
A B C D E |
A - RNA - picornavirus
B- DNA - hepadnavirus C - RNA - flavivirus D - RNA - satellite E - RNA - calcivirus |
|
|
Consequences of chronic infection with hepatitis?
|
20% cirrhosis
5% HCC |
|
|
Important cofactor for cirrhosis/hcc caused by chronic hepatitis?
|
Alcohol
|
|
|
Most common presentation of chronic hepatitis?
|
Asymptomatic, incidental finding
|
|
|
Symptoms of hepatitis infection
|
Jaundice
RUQ pain Fatigue Decreased exercise tolerance Anorexia Arthralgias Malaise Weakness Depression |
|
|
Regions with high rates to HepA
|
Middle East
medium: Central, South America, South and SE Asia, Subsaharan Africa |
|
|
Development of HepA antibodies with age?
|
Universal by age 5 in developing world
Much slower in developed |
|
|
How is HepA transmitted
|
Fecal oral
a little percutaneous |
|
|
Course of HepA symptoms and immunity
|
Symptoms, enzyme elevations, fecal excretion -- weeks after exposure
IgM -- on the rise a month after exposure, peaks at month 2 IgG -- peaks at month 4 |
|
|
Who gets jaundice with HepA infection and who doesn't?
|
Younger (<6) unlikely
Older than 14 likely |
|
|
Prognosis in HepA
|
99% recover w/o complication
Can get relapsing self-innoculating infection (which clears eventually), protracted course, cholestasis Fulminant hepatitis and death -- small percentage, older people, more likely with underlying liver disease |
|
|
HepA pooled immunoglobulin uses
|
Rapid short term pre-exposure prevention
Post-exposure prophylaxis -- decreasing frequency and severity of infection Passive immunity -- does not provide long term protection |
|
|
Who gets HepA vaccine?
|
Travelers
Children Military Homosexual men Patients with underlying chronic liver disease |
|
|
Hep A vaccine
|
Formalin killed whole virus
Give at 0, 1, 6 months 95% lifelong immunity --less if patient is immunocompromised |
|
|
World distribution of Hep E
|
Mostly Northern Africa, Southern Asia
<2% of acute hep cases in US |
|
|
Hep A transmission
|
Fecal oral
Household contact -- small percent ?percutaneous Vectors: deer, pigs |
|
|
Sequence of symptoms and immune response in HepE
|
HEV RNA -- 20 - 40 days
Fecal HEV -- 25-35 days ALT and symptoms -- 30 days IgM peaks at 45 days IgG rising until 120 |
|
|
What to look for in acute vs past HepE infection
|
Acute -- viral RNA or IgM
Past - IgG |
|
|
Course in HepE infection
|
Acute hepatitis --> resolution for majority
A few have fulminant hepatitis and death 20% mortality in 2-3 trimesters of pregnancy |
|
|
HepE treatment/prevention
|
Avoid infection through sanitation, fully cooking meat
Don't drink the water or eat salads when traveling |
|
|
Does HepB cause much mortality
|
9th leading cause of death the world
|
|
|
Why is there more chronic hepatitis in Asia/Africa?
|
More neonatal transmission
|
|
|
Where is more than 8% of pop with chronic hep B?
|
Africa, China, Brazil
|
|
|
How does hepB replicated
|
Integration into nucleus
|
|
|
HepB variations
|
Seven genotypes
C - more cirrhosis, HCC B - immune faster A, B -higher response rate IFN US/Europe - A, G, D Asia -- B, C, D Africa -- E, F |
|
|
HBV-2
|
Pre-core mutant
Ability to replicate without e antigen Less likely to have neonatal transmission |
|
|
HBV viral markers
|
HBsAg - first marker, shows HepB disease
Anti-HBs - antibody against surface antigens -- shows immunity Anti-HBc - antibody against core antigens -- shows past infection (rather than vaccination) HBeAg - marker of replicative ability Anit-HBe -- appears after seroconversion to non-replication HBV DNA -- best marker for replicative stage -- found in active infection |
|
|
Co vs Superinfection with Hep D and B
|
Co-infection: Acquiring the two viruses at same time
-- likely to result in acute hepatitis Superinfection: HBVsAg+ patient getting HepD -- likely to result in chronic hepatitis |
|
|
Hep B sequence of symptoms and immunity in cleared infection
|
HBsAg rises (day 4)
Jaundice, symptoms, increase ALT anti-HBc anti - HBe anti- HBs |
|
|
Hep B viral markers in chronic disease
|
Rise HBsAg, which never falls
IgG against HBc arises, but not anti-HBs HB DNA in serum and liver HB e in serum |
|
|
Risk of developing chronic disease after acute infection in HepB is determine by?
|
Age
Neonates - 80% Adults - 5% Neonates naive immunity recognized integrated HepB as self |
|
|
Risks of neonatal infection with HepB based on maternal status
|
With chronic state, having HBeAg in serum is worse
With acute infection, third trimester is worse |
|
|
Transmission of HepB
|
Blood and body fluids
STD |
|
|
Potential courses with chronic HepB
|
Asymptomatic carrier
Chronic hepatitis Cirrhosis HCC NB -- do not have to have chronic hepatitis to develop HepB related HCC But viral load increases chances of HCC and Cirrhosis |
|
|
Risk factors for cirrhosis in Hep B
|
EtOH
Cigarette smoking HepC, D, HIV coinfection Immune suppression Genotype C Frequent ALT flares Increased inflammation on biopsy Core/precore promotor mutaitons |
|
|
Extrahepatic manifestations of Hep B infection
|
Rash
Glomerulonephritis Arthritis Vasculitis Angioneurotic edema |
|
|
Biggest worldwide cause of HCC?
|
Hep B
Greatest incidence of HCC is in endemic HepB nations (China, subsaharan africa) |
|
|
Potential pathogenesis of HepB causing HCC
|
Chronic inflammation/regeneration
Integration near oncogenes HBx protein transcriptional regulation effects |
|
|
How to screen for HCC in patients with chronic HepB?
|
AFP and US every 6 months - year
|
|
|
When to treat chronic HepB patients
|
Viral loads (HBV DNA > 2000)
Increased ALT Consider biopsy if one is positive |
|
|
Treatment goals in chronic HepB
|
Long term prevention of cirrhosis, HCC, liver failure
Short term Clear HBV DNA Clear HBeAg Normalize enzymes Improve histology |
|
|
How long to treat in chronic HepB
|
If HBeAg +, treat until 6 months after seroconversion to HBeAg -
If HBeAg -, treat until HBsAg changes to HBsAb |
|
|
Drugs used to treat chronic hepatitis
|
Interferon -- high SEs
Lamivudine, telbivudine -- high resistence Adefovir Entecavir Tenofovir |
|
|
Only hepatitis drug to not have documented resistance with long term therapy?
|
tenofovir
|
|
|
What should HepBsAg + patients do to prevent transmitting the disease
|
Have sexual partners vaccinated or barrier protection
No sharing toothbrushes/razors Cover open cuts/scratches Clean blood spills with bleach Do not donate blood |
|
|
Vaccine protection in HepB
|
Slight decline in Anti-HBs over time, but immunity intact, only a few subclinical infections reported
|
|
|
How to protect neonates of HBsAg positive mothers?
|
HepB pooled Igs and vaccination
Active and passive protection |
|
|
What to use for post-exposure prophylaxis in HepB
|
Acute -- vaccinate and Ig sexual partners
Chronic -- vaccinate sexual partners, ?household |
|
|
HepD
|
RNA satellite virus that depends on HepB for its replication
|
|
|
HepD epidemiology
|
Endemic to Mediterranean, Middle East, Africa, S America
--transmisison is person to person, sexual contact, familial Rare in North America, Europe --transmission is percutaneous (transfusion, drug use) |
|
|
Preventing HepD
|
Prevent Hep B (get vaccine)
Prevent exposure if you already have Hep B (don't do drugs) |
|
|
Hep C outcomes
|
10-20% of chronically infected develop cirrhosis
1-5% develop HCC Leading need of liver transplant Leading cause of death in HIV |
|
|
Risks for having HepC
|
Transfusions before 87
IV drug use Long-term hemodyalsis Multiple sexual partners Healthcare worker Incarceration, homelessness, military |
|
|
Pattern of labs in HCV
|
ALT and HepC RNA rise at 1 month
ALT spikes up and down ALT normalizes and first generation antibodies are made -- if disease is cleared |
|
|
Extrahepatic manifestations of HCV infection
|
Sjogren's
Urticaria Glomerulonephritis Cryoglobinemia Neuropathy Eryethma nodusm Vasculitis |
|
|
Hepatitis C natural history
|
70-80% progression to chronic infection
75% of chronic infection leads to chronic hepatitis Cirrhosis develops at a higher rate (20-30%) of patients with chronic hepatitis HCC Death This is a 30 year time course |
|
|
What predicts cirrhosis development in HepC chronic infection?
|
Age at infection
Duration of infection Male gender Hight ALT Baseline fibrosis Steatosis Alcohol HepB, D |
|
|
What is liver and bile duct cancer incidence rising in US?
|
Hep C infections increasing 20-30 years ago
|
|
|
Screening and diagnosing HepC
|
Screen for Antibody
Confirm diagnosis with viral RNA |
|
|
Treatment goals in HepC
|
Primary goal eradicate HCV
Secondary goals: improve histology, slow progression to end stage liver disease |
|
|
HCV genotypes
|
1 has worse response to therapy than 2 and 3
|
|
|
Common SE of pegalated interferon treatment
|
Flu-like
Neuropsychiatric (dep, anxiety, insomnia) Pruitis Alopecia N/V/D Anorexia Endocrine dysfunction Cytopenias |
|
|
What predicts response to HepC treatment?
|
Genotype and Viral load
Host factors |
|
|
Mainstays of treatment in HepC
|
Interferon
Ribivarin |
|
|
Fulminant hepatitis
|
Hepatic failure w/in 8 weeks of onset of illness
Encephalopathy and a prolonged prothombin time Massive hepatic necrosis |
|
|
Major complications of fulminant hepatitis
|
Cerebral edema
Bleeding Sepsis Renal failure Respiratory failure Hypoglycemia Pancreatitis |
|
|
Fulminant hepatitis course
|
Usually death
Transplantation increases survival |
|
|
What area of liver is at risk during shock?
|
Zone 3
Centrilobular |
|
|
Acute vs chronic hepatitis histology
|
Acute- inflammatory infiltrate distributed throughout the lobule
Chronic - inflammatory infiltrate portal area and fibrosis |
|
|
Acute hepatitis histology
|
Diffuse lobular inflammation and necrosis
Lymphocytes, macrophages, Kuppfer cells Hydropic/ballooning degeration of hepatocytes Regeneration of hepatocytes |
|
|
Causes of acute hepatitis
|
Hep Viruses
Non-hep viruses as part of systemic illness, immunosuppressed hosts Drugs |
|
|
Drug induced hepatitis frequency
|
10% of apparently hepatitis
>40% in patients over 50 25% of fulminant |
|
|
Histology in drug induced hepatitis?
|
Widely variable
|
|
|
Chronic hepatitis
|
>6 months
Elevated transaminases Chronic inflammation of portal area Interface Heptocellular necrosis Lobular inflammation Often fibrosis |
|
|
Causes of chronic hepatitis
|
Autoimmune
B virus C virus Drugs Ethanol Wilson's A1AT deficiency |
|
|
Histology of chronic hep C
|
Lymphoid follicle in portal tract
Damaged interlobular bile ducts Apoptotic bodies in acini Large droplet steatosis Lymphocytes in sinusoids |
|
|
Histology of chronic hep B
|
Lymphoid follicle in portal tract
Damaged interlobular bile ducts Apoptotic bodies in acini Lymphocytes in sinusoids Variation in hepatocytes Ground glass hepatocytes |
|
|
Grading and staging chronic hepatitis
|
grading -- histologic change
inflammation, necrosis, apoptotic bodies staging -- structural change fibrosis |
|
|
Pathologic feature of autoimmune hepatitis?
|
Plasma cells
|
|
|
NASH on biopsy
|
Steatosis +
2 of these in zone 3 Necro-inflammatory foci w/ mononuclear cells + PMNs Ballooning degeneration Pericellular fibrosis |
|
|
Mallory Denk hyalin
|
Clumping of cytoskeletal structures
Associated with alcoholic and NASH |
|
|
Hemochromatosis
|
Mutation in an iron related protein
Lethargy and arthralgias Cirrhosis, HCC, diabetes, heart problems Treat with regular phlebotomy |
|
|
Hematochromatosis histology
|
Iron in hepatocytes and kupffer cells
|
|
|
Difference between hematochromatosis and secondary iron overload on histology
|
In iron overload the iron is only in the kupffer cells
In hemo, its in hepatocytes too |
|
|
Wilson's disease
|
Steatohepatitis in a young patient
Cu in hepatocytes |
|
|
A1AT deficiency liver histology
|
Neonatal hepatitis
Older patients -- cirrhosis In periportal hepatocytes, PAS positive globules |
|
|
Where are stem cell hepatopcytes?
|
Near bile duct
|
|
|
What type of collagen is found in the liver
|
Types I and II in portal tracts and central veins
Types IV |
|
|
Change to liver capillaries in cirrhosis
|
Closing of fenestrations by fibrosis produced by stellate cells
Increased material in space of Disse |
|
|
Interface necrosis/inflammation of liver
|
Inflammation/necrosis at border between portal tract and liver parenchyma
|
|
|
Liver response to hepatocyte injury
|
Hepatocellular proliferation, ductular proliferation
--but this does not follow the normal patterns (stratified growth, rather than single row with blood supply) --works well to compensate initially, but after a threshold cannot Fibrosis -- irreversible |
|
|
Blood flow in cirrhotic liver
|
Flows through withouth interacting with hepatocytes
A shunt, not a machine |
|
|
Staging chronic hepatitis (fibrosis) of liver
|
A - no fibrosis
B - fibrosis but not much bridging C - lots of bridging fibrosis D - annular fibrosis |
|
|
Cirrhosis on histology
|
Bridging fibrous septa
Parenchymal nodules (micro <3mm, macro > 3mm) Disruption of architecture of entire liver Vascular architecture is reorganized |
|
|
Etiology of cirrhosis
|
Hard to determine once cirrhotic on histology
Alcholic liver disease Viral hepatitis NASH Biliary diseases Hemochromatosis Wilsons A1AT Cryptogenic |
|
|
Gross pathology of hemochromatosis
|
Gives organ a brownish discoloration
|
|
|
Clinical features of liver failure
|
Jaundice
Hypoalbuminemia Coagulopathy Hyperammonium ---> encephalopathy Palmar erythema Spider angiomata Hypogonadism Gynecomastia |
|
|
What kills you in cirrhosis?
|
Liver failure
Portal HTN complications HCC |
|
|
Hepatocellular adenoma
|
Benign tumor of hepatocytes
Potential for degeneration to malignancy, rupture during pregnancy (>5cm) Presents as abdominal mass, pain, hemorrhage Resect |
|
|
Hepatocellular adenoma epi
|
Women 30,40s
Often associated with OCPs Also: androgenic steroids, glycogen storage disease (Ia and IV), MODY3 |
|
|
Hepatocellular adenoma histology
|
Normal looking hepatocytes
Well vascularized, but without normal vascular structure Lack of bile ducts |
|
|
Focal nodular hyperplasia of liver
|
Hepatocyte hyperplasia around a stellate scar
Usually an incidence finding M=F, all ages Most likely secondary to vascular abnormalities |
|
|
Hepatoblastoma
|
Childhood tumor of the liver
Presents as an enlarging abdominal mass Fever, n/v/d, jaundice -less common Can see precocious puberty (HCG) Elevated AFP |
|
|
Hepatoblastoma epidemiology
|
M 2: 1 F
Most occur <2 years, almost all <5 years Associated with Downs, Beckwith-Wiedemann, FAP, nephroblastoma |
|
|
Heptoblastoma treatment and prognosis
|
Surgery
Chemo Prognosis is based on stage, not histologic subtype |
|
|
Hepatocellular carcinoma epi
|
aka hepatoma
90% of primary liver cancers 80% related to HepC or HepB infection Male predominance, which is higher in endemic Hep areas |
|
|
Etiologies of HCC
|
HepB
HepC Alcohol NASH aflatoxin Vinyl chloride Metabolic diseases Steroids |
|
|
Major etiology of HCC in US
|
Chronic hep C infection
Alcohol + Hep C -- 60% |
|
|
Potential findings in HCC histology
|
Bile
Mallory hyalin A1AT granules Cytoplasmic pale bodies |
|
|
HCC cause of death
|
Metastasis seems to be late event
Most patient succumb to liver failure from replacement with tumor |
|
|
Tumor marker in HCC
|
AFP
|
|
|
Fibrolamellar HCC
|
1-5% of HCC
Mean age is 23 M=F No association with cirrhosis or AFP Favorable prognosis |
|
|
Histology of fibrolamellar HCC
|
Laminar fibrous tissue
Malignant hepatocytes |
|
|
Cholangiocarcinoma
|
Adenocarcinoma of the bile ducts
Location based on site of origins (small ducts peripheral) Hypovascular |
|
|
Cholangiocarcinoma related conditions
|
Things that inflame the biliary system
Liver flukes Hepatholithiasis Fibrocystic liver disease Chronic HepC Thorotrast |
|
|
Marker in cholangiocaricnoma
|
CEA, CA19.9
|
|
|
Immunostaining of HCC and cholangiocarcinoma
|
HCC - heppar 1, AFP, poly CEA
Chol -- CK7+, CK20- |
|
|
Most common benign tumor of the liver?
|
Hemangioma
|
|
|
What cells are targeted in immune rejection of transplanted liver
|
Endothelium
Cholangiocyte |
|
|
Possible courses of Hep B
|
Immune tolerance
Acute hep and then clearance Fulminant hepatitis and then transplant or death |
|
|
Hep B and renal failure
|
may reduce effectiveness of vaccine
|
|
|
HIV infection and Hep B
|
Immune tolerance (chronic infection) often occurs
|
|
|
Chemotherapy in HBV infection
|
May lead to reactivation
|
|
|
Autoimmune hepatitis
|
Genetically predisposed host
Environmental exposure Self-reactive T cell expansion Directed against liver antigens Progressive necroinflammatory and fibrotic process |
|
|
Genetics and autoimmune hepatitis
|
Classically -- HLA-DR3
Late onset -- HLA-DR4 |
|
|
Non-specific autoantibodies associated with autoimmune hepatitis
|
ANA
SMA - smooth muscle (actin, desmin, myosin, vimentin) Liver-kidney microsomal (antiLKM1) Probably markers and not central to pathogenesis, not diagnostic or exclusionary |
|
|
Autoimmune hepatitis clinical presentation
|
Heterogenous--ranging from asymptomatic to fulminant hepatic failure
Fatigue, lethargy, malaise, anorexia, nausea, abdominal pain, itchy arthralgia |
|
|
Labs in autoimmune hepatitis
|
Transaminases 500-1000
Often low albumin, prolonged PT ANA and/or SMA positive Polyclonal gammopathy (G > M > A) |
|
|
Who gets autoimmune hepatitis
|
Women > men
Those with other autoimmune illnesses |
|
|
Autoimmune hepatitis histology
|
Interface necrosis
Plasma cells Bridging necrosis Rosettes Bile ducts preservation |
|
|
Treatment of autoimmune hepatitis
|
Prednisone daily for a few months
Azathioprine for a few years or life if recurrent Other immunosuppressant if failure (6MP, cyclosporine, tacrolimus, mycophenolate mofetil, budesonide, ursodeoxycholic acid, rapamycin) |
|
|
Outcomes in autoimmune hepatitis
|
Remission in 65% at 18 months
10 year life expectancy 93% of age matched controls 80% 5 tear surivival post oltx |
|
|
Enzymes elevated with hepatocyte damage
|
AST, ALT
|
|
|
Enzymes elevated in cholestasis
|
Alk phos
GGT |
|
|
How to examine the synthetic capacity of the liver?
|
Albumin
PT |
|
|
Causes of hepatic cholestasis
|
PBC
Sepsis TPN Viral hepatitis Some medication NASH Alcoholic steatohepatitis |
|
|
Primary Biliary Cirrhosis
|
Granulomatous destruction of interlobular bile ducts
Progressive ductopenia Slowly progressive cholestasis Eventual cirrhosis and liver failure Presumed autoimmune Middle aged women |
|
|
Conditions associated with primary biliary cirrhosis
|
UTIs
Osteoporosis Hypercholesterolemia Other autoimmune diseases Fat soluble vitamin malabsorption with severe disease |
|
|
Primary biliary cirrhosis clinical presentation
|
Incidental finding or
Fatigue Pruritis (not from bili) Hyperpigmentation of skin (from melanin not bili) Rheumatologic symptoms arthritis Sjogren's CREST Jaundice late Xanthomas from hypercholesterolemia |
|
|
Labs in PBC
|
Cholestatic LFTs
AMA positive almost always 98% specific ANA positive mostly Hyperlipidemia |
|
|
Histology of PBC
|
Inflammatory cells attacking ducts
|
|
|
Pathogenesis of PBC
|
Autoimmune, T-cell mediated damage to bile duct cells
Cholestasis leads to inflammation and fibrosis |
|
|
Treating PBC
|
Ursodeoxycholic acid (UCDA)
--improves LFTs, survival, not osteoprosis Immune suppression has not been shown effective |
|
|
Complications of PSC
|
Cholestasis w/ metabolic bone disease, pruitis, ADEK malabsorption
Bacterial cholangitis Cholangiocarcinoma Cirrhosis Increased risk of colon cancer compared with just having UC |
|
|
What determines prognosis in alcoholic cirrhosis?
|
Continued drinking and onset of complications
|
|
|
What determines risk of alcoholic liver disease?
|
Amount
Type Drinking behavior Gender Ethnicity |
|
|
How much drinking to get liver injury
|
80 gms daily for 10-20 years
80 gms -- liter of wine, 8 beers, 1/2 pint liquor Of these people only 7% got liver disease |
|
|
Effect of type of alcohol
|
Wine is not as bad
|
|
|
Effect of drinking behavior
|
Increased risk with drinking outside of mealtimes
Increased (5x) risk with binge drinking --greater hypoxia and reperfusion damage |
|
|
Race and cirrhosis
|
Hispanic>Black>White
US males |
|
|
Alcoholic liver disease and hep C
|
More likely to develop
Disease will onset younger Disease will be more severe Increased risk of HCC More than an additive effect No alcohol is safe for pt with hepC |
|
|
Alcoholic and hemochromatosis
|
Alcoholics who are C282Y homozygotes have very high rates of cirrhosis
Carriers do not have increased risk |
|
|
Alcoholic liver disease and obesity
|
2-5 fold increased risk of liver injury
|
|
|
Alcohol metabolism
|
At low concentrations,
Mostly alcohol dehydrogenase/acetate dehydrogenase --> acetate At higher, CYP2E1 predominates, making acetaldehyde This CYP is induced -faster ETOH clearance in chronic drinkers, also risk with acetaminophen |
|
|
Gastric metabolism of EtOH
|
A little ADH (isoenzyme) is in the stomach
This alcohol never reaches the portal system Women have less gastric ADH |
|
|
Pathogenesis of alcoholic liver damage
|
Centrilobular hypoxia/ischemia
--oxygen metabolism is consuming the oxygen PMN infiltration and activation --reactive oxygen species -- proinflammatory and pro-fibrotic Acetaldehyde-protein adducts stimulate collagen synthesis |
|
|
Alcohol and infection
|
Ethanol promotes the translocation of LPS from GI tract to portal circulation
LPS in liver causes widespread inflammation |
|
|
Natural history of alcoholic liver disease
|
Fatty liver -- acute, reversible
Alcoholic hepatitis Cirrohsis Can skip the hepatitis step |
|
|
Symptoms of alcoholic hepatitis
|
Anorexia
Malaise Fever Jaundice Hepatomegaly 30% have ascites Severe alcoholic hepatitis is a poor prognostic |
|
|
Alcoholic fatty liver
|
Microvesicular steatosis, usually peripheral
Happens after acute consumption Totally reversible, does not predict cirhosis Maybe hepatomegaly Increased GGT if anything |
|
|
Alcoholic hepatitis histology
|
Steatohepatitis
Steatosis plus ballooning degeneration or hepatic necrosis |
|
|
Labs in alcoholic hepatitis
|
AST 2x ALT (both <300)
Elevated bili, alk phos, GGT, INR Decreased albumin Leukocytosis Mild anemia with increased MCV Increased uric acid, decrease K, Mg, Phosphorus Thrombocytopenia possible |
|
|
Prognosis with alcoholic hepatitis
|
Takes into account the PT and serum bili
Can also use MELD score |
|
|
Treating alcoholic hepatitis
|
Supportive care: fluid, lytes, vitamins, treatment of withdrawl
Corticosteroids in severe cases --biggest benefit in sickest pts Pentoxifylline Investigational: s-adensyl methionine, antioxidants |
|
|
Pentoxifylline
|
TNFalpha synthesis inhibitor
Small study showed in hospital mortality reduced Mainly 2/2 less hepatorenal syndrome |
|
|
Nutritional therapy in alcoholic hepatitis
|
Decreased mortality with increase caloric consumption
Total enteral feeding was as good as steroids in study |
|
|
Survival post transplant in pts with alcoholic liver disease
|
Good survival compared with other indications
Alcoholic damage does not recur if you abstain |
|
|
Non-Alcoholic Fatty Liver disease stages
|
NAFL -Fatty liver-- steatosis
NASH - steatohepatitis -- steatosis and increase hepatocyte death Cirrhosis |
|
|
NAFLD prevalence
|
5-30%
5 - by increased enzymes 30 - by imaging Much higher in obesity Probably cause of unexplained elevated LFTs in population |
|
|
NAFLD in patients undergoing gastric bypass
|
Steatosis - 30-90%
Steatohepatitis -- 30-40% Portal fibrosis -- 33% Advanced fibrosis -- 15% |
|
|
Risk factors for cirrhosis in non-drinking popoulation
|
Age > 45-50
Obesity Diabetes |
|
|
Prognostic significance of NAFL
|
3% cirrhosis in over 10 years
With NASH and fibrosis, 30% cirrhosis in 5-10 years |
|
|
Metabolic syndrome and cytokines
|
Too much of the inflammatory (TNFalpha) and not enough of the anti-inflammatory (adiponectin)
TNFalpha is proapototic, recruits WBCs, insulin resistance Adiponectin - reduces FA uptake, stimulates FA oxidation, enhances insulin sensitivity |
|
|
Diagnosing fatty liver
|
Confirm fatty liver
Etiology (alcoholic or non) Establish severity |
|
|
Who might have NAFLD
|
Metabolic syndrome
Elevated AST or ALT Cryptogenic cirrhosis |
|
|
Labs in NAFLD
|
AST/ALT <10 ULN, can be normal
Negative serologies, hemochromatosis, wilson's pbc, aih Hyperglycemia (A1C), hyperlipidemia |
|
|
Establish severity of NAFLD
|
Liver biopsy is gold standard
LFTS can be normal even in advanced AST/ALT ratio higher in cirrhosis Thrombocytopenia, increased bili, decreased albumin Stigmata of portal HTN Imaging for HCC |
|
|
Recommendations for therapy in NAFLD
|
Weight loss
Avoid high fructose corn syrup, transfats Treat metabolic syndrome Bariatric surgery in morbidly obese VitE in patient with no cardiac problems Follow for HCC and portal HTN |
|
|
Drug possibilities in NAFLD
|
Metformin ? not enough histo data
Pigalitizone ? weight gain Vit E - data to support improved histology Ursodeoxycholic acid -- might add to Vit E |
|
|
Symptoms of NAFLD
|
Often asymptomatic
|
|
|
Presentation of inborn metabolic disease of the liver
|
Acute life threatening disease of the liver
Chronic liver disease, presenting in adolescence or adulthood and progress to cirrhosis |
|
|
Hereditary liver disease and transplant
|
5% of transplants
|
|
|
Symptoms of metabolic liver disease
|
Hyperammonemia
Hypoglycemia Acidosis Coagulopathy Ketosis Acute liver failure Recurrent vomiting Growth failure Neurologic or motor skill deterioration Coma Seizures Developmental Delay |
|
|
Signs of metabolic liver disease
|
Short stature
Dysmorphic features Unusual odors Cataracts Hepatomegaly Splenomegaly Cardiac dysfunction Ascites Abdominal distention Hypotonia Jaundice Cholestasis Bruising Rickets |
|
|
What amount of blood loss makes you orthostatically hypotensive?
|
20-25%
|
|
|
Signs of potential hereditary metabolic liver disease
|
Family h/o cosanguinity, miscarriages, early infant deaths
Close relatives with weird liver disease, progressive neuromuscular Food exposures correlate with symptoms |
|
|
Diagnosing metabolic and storage disease of the liver
|
Labs may be abnormal only during acute episodes
Liver biopsy can be helpful |
|
|
Angiodysplasia
|
Small vascular malformation of the gut
Cecum or ascending colon Development related to age and bowel strain Similar to telangectasia Cause of unexplained GI bleeding |
|
|
A1AT epidemiology
|
AR with codominant expression
1 in 1500 (carriers 1 in 30) Higher in caucasians |
|
|
A1AT defect
|
Mutation in a serpin
(serine protease inhibitor) A1AT is responsible for more than 90% of anti-elastase activity Normal allele - PiMM Common mutation: PiZZ glutamine to lysine |
|
|
Most common A1AT mutation
|
PiZZ mutation
Glutamine to lysine at position 342 < 15% activity in anti-elastin |
|
|
Where does the bad anti-trypsin end up?
|
Misfolding and polymerizing cause retention of protein in ER
|
|
|
Other serpin protease inhibitor deficiencies
|
C1 inhibitor -- leads to angioedema
antithrombin III - thrombosis A1 antichemotrypsin -- COPD These can be inherited with A1AT because they are all close to each other on chromosome 14 |
|
|
How does A1AT deficiency harm the liver?
|
Unclear
|
|
|
What confounds the diagnosis of A1AT?
|
Its an acute phase reactant
So stress, injury, pregnancy, neoplasia can make the levels normal |
|
|
A1AT and liver disease
|
10% present neonatally with cholestasis
5% of older kids have clinical evidence of disease 50% have elevated LFTS |
|
|
A1AT deficiency presentations
|
Neonates -- jaundice, slow weight gain, irritability, lethargy, acholic stools, bleeding
Later -- Heptosplenomegaly, cirrhosis, ascites, UG bleed With null phenotype, emphysema but no liver disease |
|
|
Risks of A1AT for your liver as an adult
|
40% cirrhosis at autopsy
high rates of HCC, cholangiocarcinoma |
|
|
Histology of A1AT
|
Infant -- intracellular cholestasis, PAS positive diastase resistant globules
Older - cirrhosis |
|
|
Treating A1AT deficiency
|
Don't smoke
Breastfeed Ursodeoxycholic acid (decreased cholestasis) Liver transplant (also stops progression of lung disease) Lung replacement therapy (increase anti-elastase in bronchial fluid) |
|
|
Hereditary hemochromatosis epi
|
1 in 100-400 in whites
Carrier 12-40 |
|
|
What causes secondary iron overload
|
Repeated blood transfusions
Disorders of ineffective erythropoesis Increased oral intake Congenital atransferrinemia |
|
|
Hereditary hemochromatosis pathophysiology
|
HFE gene mutation -- looks like an MHCI, associates with B2 microglobulin
Senses iron in blood to regulate GI absorption Sensation by HFE in duodenal crypts Transport by divalent metal transporter-1 on villus tip |
|
|
Hereditary hemochromatosis mutations
|
C282Y: cysteine- > tyrosine at 282, less presentation at membrane
H63D: Histidine-->aspartate at 63 S65C --less bad |
|
|
Hereditary hemochromotosis mechanism of liver damage
|
Iron overload in hepatocytes
Iron-dependent lipid peroxidation Kuppfer cells activated to produce pro-fibrogenic cytokines Cytokines activate stellate cells |
|
|
Hereditary hemochromatosis other organs affected
|
Heart
Pancreas Joint Brain Endocrine glands Mechanism unknown |
|
|
Hereditary hemochromotosis presentation
|
Asymptomatic, with routine iron studies
4-5th decade M>F Women later then men Weakness, lethargy, arthralgias, abdominal pain, loss of libido/potency in men Arthropathy of 2 and 3 MCP joints |
|
|
Hereditary hemochromotosis physical exam
|
Hepatosplenomegaly
Ascites Edema Jaundice Bronzed/gray skin |
|
|
Hereditary hemochromatosis extrahepatic manifestations
|
Primary testicular failure
Hypothyroid Diabetes Cardiomyopathy, arrythmias, CHF Arthropathy of 2 and 3 MCPs joint space narrowing, chondrocalcinosis Increase in: yersina, vibrio, listeria infections |
|
|
Diagnosing hemochromatosis
|
Iron studies: high transferrin saturation, ferritin, serum iron
Biopsy with high Pearls Prussian blue staining in hepatocytes, especially periportal |
|
|
Treating hemochromatosis
|
Phlebotomy to deplete and then maintain
Deferoxamine: FE chelator, for patients who cannot tolerate phleb, cardiac manifestations Avoid FE rich foods and Vit C |
|
|
Hereditary hemochromatosis prognosis
|
Normal if start treating before cirrhosis
Reduced life expectancy from cirrhosis, HCC, Diabetes Liver transplant is not a fixall -- cardiac/infections |
|
|
If you ID an HFE mutation by genetic screen
|
C282Y/C282Y-- just treat once overloaded
C282Y/H63D -- just treat once overloaded H63D/H63D - unclear |
|
|
Menkes disease
|
X-linked defect in the transport of copper into intestine
|
|
|
Wilson's disease
|
AR
Copper overload Inadequate biliary copper excretion leads to accumulation in liver, brain, kidney, cornea |
|
|
Wilson's disease epi
|
1 in 30K
Carrier 1 in 90 |
|
|
Copper intake
|
Exceeds metabolic needs
Only some gets absorbed in intestine Carrier to liver by albumin There it is used to make enzymes |
|
|
Copper containing enzymes
|
Lysyl oxidase - CT crosslinking
Superoxide dismutase - free oxygen scavenger Tyrosinase - pigment production Dopamine B-mono-oxygenase - NT |
|
|
Wilson's disease gene
|
ATP7B
Mostly kidney and liver Facilitates the excretion of copper via bile |
|
|
Presentation of Wilson's disease
|
Variable
Typically young Chronic or fulminant liver disease hepatitis, jaundice, splenomegaly Progressive neurologic disorder Isolate acute hemolysis Psychiatric illness |
|
|
More common childhood presentation of Wilson's disease
|
Hepatic
|
|
|
Early feature of neuropsychiatric involvement in Wilson's disease
|
Hypophonia
|
|
|
Eye finding in Wilson's
|
Kayser-Feischer rings on slit lamp exam
Copper deposition in Descemet's membrane Not specific to Wilsons (other hepatic) |
|
|
Neurologic presentation of Wilson's
|
Usually in 20-30s
Movement disorder: tremors, poor coordination, loss of fine motor fnc or Rigid dystonia: mask-facies, rigidity, gait disturbance, dysarthria, drooling, swallowing difficult Intellect is not impaired |
|
|
Psychiatric presentation of Wilson's
|
Adults
20% of patients present purely psychologically Depression is common Phobias or compulsive behavior Aggressive or antisocial |
|
|
Extrahepatic manifestations of Wilson's disease
|
Hemolytic anemia
Fanconi syndrome (Renal) Large joint arthritis Cardiomyopathy/arrythmias Osteporosis/malacia, rhabdomylsis, pancreatitis, hyperparathyroidism, amenorrhea, testicular problems |
|
|
Wilson's disease histology
|
Copper staining primarily in hepatocytes
Steatosis, focal necrosis, glycogenated nuclei, Mallory hyalin Changes to mitochondria |
|
|
Wilson's disease labs
|
Low serum ceruloplasm
Increased urinary copper Serum copper low |
|
|
Fanconi syndrome
|
Microscopic hematuria
Aminoaciduria Phosphaturia Defective acidification of the urine |
|
|
Provocative test for Wilson's
|
Pencillamine increases urinary copper excretion in 24 hour
|
|
|
Are genetic tests helpful in Wilson's
|
Limited due to a large number of mutations with the disease
|
|
|
High copper content on liver biopsy
|
Indicative but not diagnostic of Wilson's
|
|
|
Treating Wilsons
|
Reduce intake: organ meats, shellfish, nuts, chocolate, mushrooms, drinking water
Chelation Pencillamine - SE: cytopenias Trien - SE: cytopenias Zinc - infections |
|
|
Prognosis of Wilsons
|
Treating before liver disease -- good
Neurodisease may not completely resolve Stopping chelation = decommpensation |
|
|
Type I glycogen storage disease
|
Deficiency of glucose 6 phosphate
Most common glycogen storage disease IA - total LOF IB - deficient transport to ER IC - deficient transport out of ER IB -- also neutropenia and impaired phagocytosis -- bacterial infections, Crohn's |
|
|
Clinical features of type I glycogen storage disease
|
Hypoglycemia, hepatomegaly, FTT in infancy
Acidosis Xanthoma Nephromegaly, HTN Hyperlipidemia Hepatic adenomas |
|
|
Diagnosing glycogen storage disease
|
Direct enzyme analysis
fasting glucose/lactic acid |
|
|
Treating glycogen storage disease type I
|
Liver transplant
Old: shunts around liver, IV nutrition, oral uncooked carbs |
|
|
Glycogen storage disease Type III
|
Deficiency in amylo-1,6-glucosidase debranching enzyme
Accumulation of dextrin Restricts glucose release Not as severe as I IIIa -- liver and muscle IIIB -- liver only |
|
|
Clinical presentation of Type III glycogen storage disease
|
Hypoglycemia, hepatosplenomegaly, growth failure
Some enzyme elevations in advanced Progressive weakness |
|
|
Treating Type III glycogen storage disease
|
High protein, low carb diet
Refractory may require addition of night time IV feeding, corn starch |
|
|
Type IV glycogen storage disease
|
AKA amylopectinosis
Deficiency in branching enzyme Accumulation of glycogen and amylopectinosis |
|
|
Type IV glycogen storage disease presentation
|
FTT, hepatosplenomegaly
3 to 15 months 50% hypotonia, atrophy, decreased deep tendon reflexes Labs pretty normal, no hypoglycemia |
|
|
Treatment and prognosis of Type IV glycogen storage disease
|
High protein/low carb
Transplanation Untreated, most patients die by 3 Treatment improves |
|
|
Tyrosinemia
|
Fumaryl acetoacetate hydolase deficiency
Cannot degrate tyrosine |
|
|
Porphyrias
|
Inherited defects in heme synthesis
|
|
|
Ornithine trancarbamylase (OTC) deficiency
|
Most common urea cycle defect
|
|
|
Progressive familial intrahepatic cholestasis (PFIC) syndromes
|
Defect in bile acid synthesis and transport
|
|
|
Gaucher's disease
|
Deficiency in glucocerebrosidase
Defect in lipid metabolism |
|
|
Portal HTN definition
|
An increase in the pressure of the portal venous system exceeding 5 mmHg
|
|
|
General mechanisms of portal HTN
|
Increase resistance
Increase flow |
|
|
Portal HTN mechanism
|
Pre-hepatic:
Thrombus of portal vein Compression of portal vein by tumor Splenic vein compression (pancreatic) Intrahepatic Post - hepatic hepatic vein blockage (Budd Chiari) right sided heart failure |
|
|
Etiologies of intrahepatic increase in portal pressure
|
Pre-sinusoidal:
Schistosomiasis, PBC, PSC, Infiltrative disease Sinusoidal: Parenchymal liver disease: ETOH, viral, autoimmune Post-sinusoidal: toxins causing occlusion of central vein |
|
|
Budd-Chiari
|
Occlusion of hepatic veins
|
|
|
Cirrhosis and portal HTN
|
Passive increased pressure from parenchymal damage
Active from myofibroblast deposition of collagen -- contractions |
|
|
Hemodynamic changes in liver disease
|
Diseased liver produces increase NO, glucagon, cytokines, endothelin, VIP, Epi, NE, changes renin-angio
Results in: Increased resistance Vasodilation of splanchnic circulation Peripheral vasodilation Central vasoconstriction Water and sodium retention Things go from bad to worse |
|
|
Hemodynamic changes in portal HTN
|
Hyperdynamic circulation
High cardiac output Systemic hypotension Central vasoconstriction Can result in hepatorenal syndrome, hepatopulmonary syndrome |
|
|
When do bad things start happen in portal HTN
|
>12 mmHg
|
|
|
Consequences of portal HTN
|
Collateral circulation (varices)
Ascites Spontaneous peritonitis Hepatorenal syndrome Hepatic hydrothorax Umblical hernais Diminished detox Portosystemic encephalopathy Hepatopulmonary Hypersplenism Hemodynamic changes |
|
|
Portal HTN and collateral circulation
|
Get from portal to systemic
Esophageal Caput medusa -->intercostals Hemorrhoidal -->iliac veins Retroperitoneal-->pariteal peritoneum veins Ectopic -- surgical sites |
|
|
Chances of developing an esophageal varice with cirrhosis? it bleeding?
|
35-80% chance of varices
25-40% chance of those bleeding in two years |
|
|
Higher risk of bleeding varices
|
Larger
Endoscopic: red whales, cherry red signs Worse cirrhosis Portal pressure gradient >12 |
|
|
What is a Child's score
|
Predicts life span in cirrhosis, used for transplant rankings
Encephalopathy, ascites, bilirubin, INR, albumin |
|
|
Portal HTN and varices, what drug to start?
|
Beta blocker
Non selective Also reduces rate of rebleeding |
|
|
Active variceal hemorrhage treatment
|
Protect airway
Aspirate gastric contents Hemodynamic rescussitation (up to 9-10) Antibiotics Octreotide - reduce portal HTN Metabolic support |
|
|
Somatostatin/Octreotide in esophageal varices
|
Decrease portal venous pressure and collateral blood flow
Helps control acute bleeding Initial, temporizing measure |
|
|
Endoscopic ligation of varices
|
Bleeding control in 90%
Rebleeding in 30% |
|
|
Sclerotherapy in varices
|
Endoscopic injection of a procoagulant
Does not work as well, higher complications than banding |
|
|
Indications for TIPS
|
Refractory portal HTN bleeding
Ascites Hepatorenal syndrome |
|
|
TIPS
|
Transjugular Intrahepatic portal shunt
Controls acute bleeding in 90%, rebleeding in 70% 20-30% develop encephalopathy 40% occlude stent |
|
|
Non-selective portal shunts
|
Portal vein into IVC
Also a selective-- splenic vein into IVC Better than TIPS for a non-compliant patient |
|
|
Portal HTN gastropathy
|
Occult blood loss
Oozing Not associated with portal pressure gradient Somtimes seem after sclerotherapy |
|
|
Ascities define
|
Free fluid in peritoneal cavity
|
|
|
Etiology of ascites
|
80% chronic liver disease
Cancer Heart Failure Infection Other stuff |
|
|
PE in ascites
|
Increase in abdominal circumference
Fullness in flanks Shifting dullness Fluid wave |
|
|
What diagnostic test in new onset ascites?
|
Diagnostic paracentesis
Culture, cell count, protein, albumin SAAG to see if its portal Serum albumin - ascites albumin High -- portal HTN |
|
|
What things have a high serum asicties albumin gradient?
|
Portal HTN
Cardiac disease |
|
|
Initial therapy of portal HTN related ascites
|
Sodium restriction
Diuretics (spironolactone, furosomide) Paracentesis Treat underlying disease Begin transplant assessment |
|
|
Treatment of refractory portal HTN ascites
|
Large vol parecentesis
TIPS Periteneovenous shunt Liver transplant |
|
|
Complications of ascites
|
Spontaneous bacterial infection
Umbilical hernia Hydrothorax |
|
|
Spontaneous bacterial peritonitis
|
Translocation of colonic bacteria
Can be asymptomatic Happens in about 20% of patients who have ascites Mostly patients with high bilis, low protein in their ascites Negatively effects survival |
|
|
Symptoms of spontaneous bacterial peritonitis
|
Fever
Jaundice Abdominal pain Confusion Abdominal tenderness Hypotension |
|
|
Most common organism for spontaneous bacterial peritonitis?
|
E Coli
|
|
|
Treating SBP
|
Initiate with high PMNs in ascitic fluid
Broad spectrum Avoid aminoglycosides 5 days Antibiotic prophylaxis |
|
|
Hepatic hydrothorax
|
Mostly right sided
Fluid get through the diaphragmatic fenestrations |
|
|
Umbilical hernia complications
|
Ulceration of skin
Incarceration Rupture |
|
|
Hepatorenal syndrome
|
Progressive kidney failure caused by cirrhotic liver (from chemicals produced)
Risk goes up with duration of cirrhosis Very poor prognostic |
|
|
Hepatorenal syndrome labs
|
Low urine sodium
High urine/plasma creatinine High urine/plasma osmolality Does not respond to plasma expansion No casts |
|
|
Treating hepatorenal syndrome
|
Midrione and octreotide
Restrict sodium/water Consider dialysis Evaluate for renal transplant |
|
|
Hepatic encephalopathy
|
A - acute liver failure
B - portal-systemic bypass C - cirrhosis Increase in nitrogenous substances, including ammonium which alters astrocyte fnc Tremor - asterixis -- hyperreflexia -- coma |
|
|
Diagnosing hepatic liver encephalopathy
|
Ammonia can be helpful sometimes
Psychometric Encephalopathy score EEG -- decrease of frequency, increase of amplitude, delta waves |
|
|
Precipitants of hepatic encephalopathy
|
Excess protein
GI bleeding Surgery TIPS Infections HCC Alcohol Sedative hypnotics Diuretics |
|
|
Treating hepatic encephalopathy
|
Nonabsorbable disaccharides, antibiotics
Lactulose is mainstay Acid from bacterial metabolism of lactulose draws in basic ammonia to gut Rifaxamin |
|
|
Leading cause of acute liver failure in US?
|
Drug toxicity
|
|
|
Drugs known to cause acute liver tox
|
Tons
Acetaminophen Amioderone AZT Bactrim Rifampin Penicillin Sulfa |
|
|
Acetominophen toxicity
|
Zone 3 of liver
Glutathione stores depleted NAPQ1 metabolite of CPY2E1 is toxic Treat with N-acetylcysteine, transplant |
|
|
How much acetominphen to get toxicity
|
>4 grams dangerous, usually >15 to really see acute hepatic necrosis
>300 mcg/ml at 4 hours = toxicity |
|
|
Amiodirone and liver
|
Bad
10-50% of patients have liver tox Lysosomal phospholipid deposition Alcohol like pattern of damage |
|
|
Drugs that cause cholestatic pattern of injury
|
Augmentin
ACE inhibitors Chlorpromazine Erythromycin Haloperidol Cimetidine/Rantidine Imipramine OCPs |
|
|
Hormones that reduce intake of food
|
CCK
GRP Leptin Ghrelin |
|
|
Cephalic phase of digestion
|
Visual, olfactory, auditory senses mediate response in GI organs
Vagally mediated Salivary secretion, gastric secretion, pancreatic secretion, gallbladder contraction, relaxation of sphincter of Oddi |
|
|
Oral phase of digestion
|
Chewing and saliva mixing
Tasting -- vagally stimulated changes in the GI tract Swallowing (voluntary the involuntary) |
|
|
Fives stages of pharyngeal swallowing
|
Elevation of soft palate
Anteriosuperior displacement of larynx Epiglottis and vocal cords close Relaxation of UES Pharyngeal contraction |
|
|
Swallowing and the esophagus
|
Swallowing initiates pharyngeal/esophageal peristalsis
and LES relaxation Neurally mediated ACh - peristalsis VIP and NO for LES relaxation |
|
|
Belch physiology
|
Mostly to release air that you've swallowed during eating (aerophagia)
Relaxation of LES Relaxation of UES |
|
|
Function of LES/cardia
|
Secretes mucus and HCO3
Prevents GE reflux Allows entry of food Regulates belching |
|
|
Function of fundus/body
|
Secretes HCL, intrinsic factor, mucus, HCO3, pepsinogen, lipase
Reservoir for food Tonic force durng emptying |
|
|
Function of antrum/pylorus
|
Secretes mucus and HCO3
Mixing, grinding, sieving, regulation of emptying |
|
|
Surface cell fnc
|
Secrete mucus
Lubrication |
|
|
Neck cells fnc
|
Secrete HCO3, trefoils
Protection |
|
|
Parietal cells fnc
|
Secrete HCL, intrinsic factor
Protein digestions, B12 absorption |
|
|
Chief cells fnc
|
Secrete gastric lipase, pepsinogen
Trigylceride digestion, protein digestion |
|
|
CCK
|
Released by entero endocrine cells when nutrients are in small bowel
Signal vagus |
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Neurotransmitters from vagal efferents and their action in gut
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ACh - gall bladder contraction, pancreatic enzyme secretion,
NO - relaxation of proximal stomach, sphincter of Oddi VIP - relaxation of proximal stomach, sphincter of Oddi, pancreatic enzyme secretion Somatostatin -- decreased enzyme secretion Gastrin releasing peptide - pancreatic enzyme secretion |
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Gas
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50% from swallowed air
50% produced during digestive process |
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Hematochezia
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BRB in stool
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Presentation of chronic GI bleeding
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Iron deficiency anemia
Occult blood in stool |
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Acute GI bleeding presentation
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Hematemesis
Hematocheza Melana Hemodynamic instability |
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Initial management of acute GI bleed
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Trendelenburg
Large bore IV access Infusion of isotonic/blood CBC, coags, type and cross |
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Where is the GI bleed?
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Hematemesis, bloody NG tube - def upper
Melena, elevated BUN -- prob upper Hematochezia -- likely lower |
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Upper GI bleed etiologies
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PUD
Portal HTN Mallory weiss mucosal erosive disease vascular anomalies neoplasms |
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High risk ulcers
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High on lesser curvature -- left gastric artery
Posteriorinferior duodenal bulb -- gastroduodenal |
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Cause of isolate gastric varices?
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Splenic vein thrombosis
Treat with splenectomy |
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Congestive gastropathy
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50% of portal hypertensives
Mucosal edema, small vessel ectasia, vascular congestion w/o mucosal inflammation Chronic bleeding |
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Working up hematochezia
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If resolved, colonscopy soon
If current, NGT washout with immediate colonoscope or angiography |
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Most common cause of acute lower GI bleeding
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Diverticulosis
Angiodysplasia |
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Bleeding and diverticulousis
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3% bleed
Mostly right sided ones bleed 80% self-limited (25% recur) Segmental resection in persistent |
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Angiodysplasia
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Degenerative vascular lesions associated with aging
Cecum and right colon Acute, chronic bleeding cause |
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Meckel's diverticulum complication
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Bleeding
Ectopic gastric mucosa -- gastrin -- ulcer Obstruction |
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Chronic GI bleeding
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Iron deficiency anemia, occult blood
Colon cancer! Work up: colonoscopy followed by upper gi endoscopy if neg |
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Bilious emesis in newborn
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Emergency
Get an upright abdominal film |
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Duodenal atresia
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Failure of the lumen to recanalize during 8-10th week gestation
Newborn with bilious emesis Double bubble sign on XRT |
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Duodenal atresia epi
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30% are associated with other anomalies
25% are preemies 20% have Downs |
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When is jaundice worrisome in baby?
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After two weeks
New onset |
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Biliary atresia
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Failure to form adequate biliary tree
Jaundiced, icterus in 2-3 weeker Elevated conjugated bili Acholic stool, dark urine FTT |
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Biliary atresia epi
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1 in 10000
More often a problem with extrahepatic than intrahepatic ducts Girls > Boys Asians have highest rate Etiology unknown |
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Labs in biliary atresia
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Elevated direct bili
Elevated Alk phos, GGT, AST, ALT |
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Biliary atresia treatment
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Kasai procedure
Hepatoportoenterostomy connect Gi tract to bile duct rements Better success if < 2 months |
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Biliary atresia prognosis
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High mortality by age 2 from cirrhosis if untreated
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Tracheoesphageal fistual presentation
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Polyhydraminos
Excessive salivary, drooling Choking, coughing, cyanosis with feed Regurgitation Aspiration Respiratory distress |
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Tracheoesophageal fistula frequencey
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1 in 3K-5K births
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Most common kind of tracheoesophageal fistula
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Esophageal atresia and distal fistula
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Associated with tracheoesphageal fistula
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40% have associate abnormalities
Cardiac -- PDA, ring, coarct, VSD Imperforate anus Intestinal malrotation Duodenal anomalies VACTERL |
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Tracheoesophageal fistula treatment and complications
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Primary surgical repair
Leak - 10% Strictures Esophageal dysmotility Abnormal LES fnc |
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Volvulus
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Problem with the reentery of bowel into abdominal cavity embryologically
Small intestine not fixed in abd Becomes suspended by mesenteric stalk containing SMA Midgut ischemia and infart |
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Symptoms of volvulus
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Adominal distension and bilious obstruction
Blood stools Perforation Peritonitis |
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What to do when someone has a volvulus
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Rush them to OR
Surgical emergency |
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Gastroesophageal reflux in babies
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Common problem
Most outgrow by 18 months Usually no treatment necessary Can: thicken feeds, burp, change positioning Rare: H2 blocker |
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Pyloric stenosis
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Tight pyloric sphincter
Nonbilious emesis starting at 2-4 weeks Emesis increases and becomes projetile Hypokalemia, metabolic alkaosis, dehydration |
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Treating pyloric stenosis
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Not an emergency
Fix metabolic disturbances Surgical pyloromyotomy |
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Colic
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Periods of paroxysmal crying in a healthy well fed infant
>3hrs/day, >3days week, >3 weeks Typically from 2 weeks to 4 months 15-25% of babies |
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Introducing solid food
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4 months, baby able to sit assisted, track
Meat at 9 months |
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When to start cows milk
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12 months
Avoid iron deficiency, potential colitis |
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Failure to thrive
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Inadequate growth rate in kids
Symmetric: weight, height, head Asymmetric: weight first, heigh second, head circumference often spared |
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Obesity in kids
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Hypernutrition leads to accelerated growth
But premature closure of growth plates... Short, fat adult |
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Constipation in kids
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Delay or difficulty in defecation for >2 weeks
Causing distress |
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What is normal stooling kids?
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Huge variation
Breast fed baby: 7/day - 1/week 1-3 yo :4-21/week |
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With lack of meconium passing, wory about
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CF
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DDx childhood constipation
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Painful defecation
Diet Illness Stress To busy Travel Inperforate anus Anal stenosis Hypotheyroid Hyper Ca Hypo K CF DM Gluten enteropathy Spinal dysraphism |
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Worrisome signs in constipation in kid
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FTT
abdominal distension Anatomic abnormality (spinal dysraphism) |
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Encoresis
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Involuntary resistance of stooling
Distended sigmoid Result of long standing constipation Requires repeated cleanout, takes a while to get back |
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Signs of encoresis
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Overflow incontinence
Bowel incontinence More boys than girls |
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Not potty trained by 5?
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Developmentally delayed
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Treating encoresis
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Eduction
Meds: miralax Modify diet (no milk, apple juice) Push practice Psyche |
