GI

Lecture 1
Monday, August 8, 2016
2:56 PM
Be knowledgeable about the public health burden of gastrointestinal and liver disorders
Prevalent diseases
Diarrhea
Leading cause of death in children
IBS
Affect 10% of the US
GERD
2nd most prescribed drug (PPI)
Colon Cancer
3rd most common cancer in men and women
One of the most killing cancers
Recognize key elements in the history and physical exam of patients with gastrointestinal
and liver disorders
GI
Constitutional symptoms
Nausea, vomiting,
Changes in bowel habits
Liver
Jaundice, easy bruising and mucosal or GI bleeding
Abdominal swelling
Mental confusion
PE:
Distention, excavated abdomen, collateral veins

Auscultation
Bowel sounds
Arterial bruits
Palpation
Tone, tenderness, organomegaly
Percussion
Tympani (air) or dullness (fluid or organ)
Shifting dullness and fluid wave->ascites
Other:
Jaundice, pallor, telengiectasias, diffuse bruises (liver disease)
Understand the main diagnostic modalities utilized to evaluate patients with disorders of
GI and liver disease
Plain
Small bowel: plica circularis- stack of coins
Large bowel-haustral marks
Thumb printing-mucosal edema
Air fluid levels-distenstion of fluid filled intestines (obstruction)
Air under diaphragm-bowel perforation
Ultrasound
Liver, bilary tree (not good for gas), vascular structures
CT: rapid, but radiation and contrast (bad for kidneys)
MRI: longer, not good in emergency
Endoscopy
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Lecture 2
9:53 PM
List general functions of GI system and the relative roles of each component organ.
Digestion
Mouth, esophagus, stomach
Absorption
Stomach, small intestine, large intestine
Secretion
salivary glands, liver, gall bladder, and pancreas
Motility
smooth muscle layers and skeletal muscles located at the upper portion of the esophagus
and at the anal sphincters
Immune surveillance and tolerance
Regulation of energy homeostasis
Describe the organization and classification of nervous system control of the GI system.
Extrinsic NS (regulate functions of intrinsic NS)
Somatic NS-> higher centers to voluntary skeletal muscle
Mouth and external anal sphincter
Autonomic central nervous system
Parasympathetic-stimulates motor and secretory
Long preganglion fibers from high centers
Synapse w/ neuron of intrinsic system within GI
Vagus
Pelvic Nerves
Sympathetic-inhibits motor and secretory
Postganglionic fibers that arise from SC
Synapse directly on smooth muscle fibers, endocrine glands, or blood vessels
Intrinsic (enteric) NS [transmits local info to higher centers via afferent pathways)
Autonomic system entirely within GI system
At submucosal and myenteric levels of the tract
Synapse w/in and b/w plexi and often from complete functional circuits consisting of
sensory neurons, interneurons, and motor neurons
Sensory, motor, and interneurons
List the signaling systems that control GI function and describe their general mechanisms.
Neural- neuron to target cells
Endocrine-hormone through blood vessel
Paracrine-hormone to nearby target cells, no blood vessels
List the mechanisms by which substances are transported across the GI epithelium.
Primary active
Secondary active
Co-transport
Counter-transport (exchange or anti-transport)
Facilitated
Regulated channels
Proteins move by EXOCYTOSIS (secretion)
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Lecture 3 and 4
10:25 PM
Be able to recognize and identify the cells, subcellular structures and extracellular structures that comprise the digestive system. The
components that will be covered are:
Alimentary canal
i. Oral cavity including the salivary glands, tongue and tonsils
ii. Pharynx and esophagus
iii. Stomach
iv. Small intestine
v. Colon (large intestine) including the rectum
o Organs connected to the alimentary tract by excretory ducts
i. Liver/gallbladder
ii. Pancreas
Be able to assign function to individual structures and to describe how each structure
participates in the digestive process.
Lecture 3: Microanatomy of the Digestive System
What are the components of the alimentary canal?
What is the structure and function of mucosa of the alimentary canal?
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What is the structure and function of the submucosa of the alimentary canal?
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What is the structure and function of muscularis propria of the alimentary canal?
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What is the structure and function of the serosa/adventitia of the alimentary canal?
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What is the structure and function of the serosa/adventitia of the alimentary canal?
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What is the structure and function of the mucosal epithelium of the oral cavity?
What is the structure and function of the tonsils (lamina propria) of the oral cavity?
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What is the structure and function of salivary glands of oral mucosa?
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What are the types of salivary glands?
What is the structure and function of the tongue?
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What is the structure and function of the pharynx?
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What is the structure and function of the esophagus?
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What is the structure and function of the esophagus?
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What are the esophageal sphincters?
What are the divisions, gross features, and function of the stomach?
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What is the structure and function of the stomach mucosa?
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What is the structure and function of the muscularis propria of the stomach?
What structures of the small intestine help maximize surface area?

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What structures of the small intestine help maximize surface area?
What is the structure and function of the epithelium of the mucosa of the small intestine?
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What is the structure and function of the lamina propria of the mucosa of the small intestine?
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What is the structure and function of the submucosa of the small intestine?
What is the structure and function of the muscularis propria of the small intestine?
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What is the structure and function of the muscularis propria of the small intestine?
**Summarize the histologic differences in the sections of the small intestine.
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Describe intestinal neuronal dysplasia.
What are the divisions, general function, and distinguishing structural features of the colon?
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What is the structure and function of the mucosa of the small intestine?
What is the structure and function of the muscularis propria of the large intestine?
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What is the structure and function of the muscularis propria of the large intestine?
What is the structure and function of the rectum?
What is the structure and function of the appendix?
What is the function of the liver?
Describe the gross anatomy of the liver.
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Describe lobule microanatomy.
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What are the components of the biliary tree?
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What is the structure and function of the cystic duct?
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What is the structure and function of the gallbladder?
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What is the structure and function of the gallbladder?
What is the structure and function of the pancreas?
Describe the different pathways of bile flow.
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Lecture 5
Tuesday, August 9, 2016
12:30 PM
Understand and describe the functions of saliva.

Oral protection
Buffering extremes
Hydration of oral tissues
Lubrication
Swallowing
Oral hygiene
Bacteriostatic
Digestion
Breakdown of carbs and lipids
Know the mechanisms of saliva production.
Saliva is produced in the acinus and modified in the ducts
In the acinus it is isotonic, as it moves to the duct, the saliva is modified by having K+ and
HCO3- being secreted while NaCl is absorbed-->hypotonic saliva is produced
More NaCl is absorbed than K+ and HCO3- is secreted
Ducts are impermeable to water, so it can maintain a net movement of Cl Know how production of saliva is regulated.
Stimulators
Chewing, taste, smell, nausea
Inhibitors
Sleep, fatigue, dehydration, fear
These factors go to the salvatory nuclei in the medulla, which triggers parasympathetic nerves CN
IX and VII
Those fire at ACH and promote high volume/electrolyte rich secretion
ACH goes to muscarinic receptors and promote secretion
Water and electrolyte secretion by serous type salivary acinar cells
Alpha adrenergic and cholinergic will trigger IP3 and DAG--> Ca2+ protein kinase C-->
activate channel and transporter activation--> net movement of Cl- out into the lumen
Regulation of salivary protein secretion by mucus type acinar
Sympathetic/parasympathetic will trigger (beta adrenergic and alpha adrenergic)
(cholinergic m3) receptors, which will turn on cAMP and IP3 and DAG--> stimulate secretion
by exocytosis
Parasympathetic and sympathetic both increase salivary secretion by many routes
Beta adrenergic:
Low volume, transient, protein rich
Luminal vs membrane bound digestive enzymes
Luminal enzymes are synthesized by specific cells and secreted into
the lumen of the GI tract by exocytosis where they digest their dietary substrates.
Membrane bound digestive enzymes are synthesized by epithelial cells of GI tract (mainly in the
small intestine) and act on the apical surface of these cells as intrinsic membrane proteins.
The combined action of luminal and membrane-bound digestive enzymes prepares dietary
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The combined action of luminal and membrane-bound digestive enzymes prepares dietary
nutrients for absorption.
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Lecture 6
2:02 PM
Know and understand the mechanism of acid secretion by the parietal cell.
1. HK+ ATP ase pumps H ions out and bring K+ into the cell
2. H20 and CO2 are the source of H ions by carbonic anhydrase, forming H ions and bicarb
3. K+ is recycled out apical side by a channel to sustain the movement of K+ in by pump
4. K+ ions inside their cell are given their concentration by a Na+K+ ATP ase on the basolateral side
5. The bicarb produced in generating H ions begins alkalinating the cell, so it is moved out by a
HCO3- CL- exchanger, and CL- is pumped in
6. Cl- builds up in the cell, so it is channeled out the apical side into the lumen
7. H2O follows the CL- ions into the lumen
List regulators of acid secretion and understand their mechanisms.
1. Gastrin (endocrine)
a. In G cells in pyloric mucosa
i. Gastrin receptor is activated
ii. G protein coupled receptor is activated
iii. IP3 and DAG are activated-->activate a protein kinase C
iv. Sequestered H+/K+ pumps are brought to the cell apical surface to allow for more
pumping of H ions
2. Acetylcholine (neurocrine)
a. Intrinsic neurons in oxyntic mucosa
i. Ach receptor is activated
iii. IP3 and DAG are acivated-->activate a protein kinase C
pumping of H ions
3. Histamine (paracrine)
a. ECL cells in oxyntic mucosa
i. Histamine H2 receptor is activated
iii. cAMP is activated-> protein kinase A
pumping of H ions
4. The pathways are not linear, and in fact interact with each other
a. Enteric neurons can fire and release Ach directly onto the parietal cell to activate
i. Can activate G cells, to:
1) Activate gastrin receptors on parietal cell
2) Activate ECL cells to release histamine
a) Activate histamine receptors on parietal cells
ii. Act directly on ECL cells
1) release histamine onto parietal cells
b. G cells can activate via circulation and move to
i. Activate ECL cells (histamine receptors)
ii. Activate gastrin receptors directly on parietal cell
c. ECL cells can be activated
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c. ECL cells can be activated

i. Act on histamine receptors of parietal cells
Know how acid secretion from the parietal cell is inhibited.
Inhibitors of acid secretions:
Somatostatin
Prostaglandins
EGF (epidermal growth factor)
a. Somatostatin
i. Inhibits acid secretion by:
1) Preventing G cell from releasing gastrin
2) Acting directly on parietal cell
3) Preventing ECL from releasing histamine
ii. In response to a fast the vagus nerve no longer fires and
1) Prevents stimulatory enteric neurons from firing
a) Ceases gastrin release from G cells
2) Prevents inhibitory enteric neurons from firing
a) Allows somatostatin to fire on G cells and prevent G cells from releasing
gastrin
iii. As pH falls, turns somatostatin up and release
Know the phases of acid secretion, their relative importance, and the mechanisms that
regulate them.
Phases of gastric secretion
1. Cephalic-thought, sight, smell, taste, or chewing of food (30%)
i. Multi signal promotion of acid secretion driven by vagus
2. Gastric - distension in stomach or presence of AA (60%)
i. Distension sensed by mechano receptors
1) Can directly signal ECL activation or act directly on parietal cell
2) Vagal-vagal reflex afferent signal to vagus to reinforce the efferent signals
ii. AA and peptide presence
1) Bind to receptors on G cell and stimulate gastrin release
3. Intestinal - food in duodemum (10%)
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Lecture 7
4:02 PM
1. List and explain the composition and functions of pancreatic secretions.

a. Pancreas has endo and exocrine functions
i. Composition:
1) Luminal enzymes
a) Secreted by acinar cells
2) H2O
a) Released by duct cells
3) HCO3a) Release by duct cells
ii. Exocrine secretion
1) Aqueous componenet (duct cells)
a) Water
b) Bicarbonate
c) Function: acid neutralization
i) Small intestine like neutral or alkaline pH
2) Enzymatic component (acinar cells)
a) Proteases
b) Lipases
c) Saccharidases
d) Function: digestion
2. Know and understand the mechanism of bicarbonate secretion from the pancreas.
a. Na+K+ ATPase establish a NaK gradient
b. Na gradient is used to move HCO3- across membrane into the cell
c. Carbonic anhydrase converts H2O and CO2 into H ions and bicarb inside the cell
d. Na+H+ transporter gets rid of the H+ ions by using the Na gradient moving Na into the cell
e. The increased bicarb in the cell creates a gradient to move out the cell on the apical side in
exchange for CL ions by a HCO3-Cl- exchanger
f. Water and Na+ follows the bicarb into the lumen by traveling between duct cells
g. Now, there isn't a lot of Cl- in the lumen, so the cell uses a CFTR channel to allow Cl ions to
cycle out and recycle the supply
i. When this channel is broken (ie cystic fibrosis) then the lumen doesn't have a supply
of Cl ions to exchange for HCO3-, meaning that the lumen now has small amounts of
Na, H2O, and bicarb
3. Know and explain how pancreatic secretion is regulated.
a. Stimulators of secretions
i. Acetycholine (enteric neurons)
1) Vagal stimulation
2) ACH receptors on acinar cells fire, activating a G protein coupled receptor, then
causing PIP2 and IP3+DAG cascade to fire--> pancreatic enzymes are exocytosed
into the lumen
ii. Secretin
1) S cells in the duodenum
2) Secretin receptor caused adenylate cyclase to activate->cAMP->Protein Kinase
A-> exocytosis of enzymes into the lumen
3) Secretin regulates the opening of CFTR Cl- channels in pancreatic duct cells
a) Secretin causes CFTR channels to be phosphorylated in the duct cells,
allowing them to be opened and activated
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allowing them to be opened and activated

b) Bicarb secretion-> think secretin
b.
c.
d.
e.
iii. CCK
1) I cells in the dodenum
2) CCK receptors on acinar cells fire, activating a G protein coupled receptor, then
causing PIP2 and IP3+DAG cascade to fire--> pancreatic enzymes are exocytosed
into the lumen
Cephalic/gastric phases of pancreatic secretion
i. Through enteric neurons
1) Activate GRP, Ach, and VIP to promote secretion
Intestinal phase of pancreatic secretions
i. Components of chyme are providing the signals that will be driving the secretions
ii. Duodenal chemoreceptors respond to the chyme and signal the vagal-vagal reflex
iii. Reinforces the effect of secretion of enzymes and bicarb
Intestinal phase using CCK
i. Amino acids and peptides activate I cells in the duodenum
1) AA and FA promote release of CCK-RP from other cells
a) CCK-RP act on I cells to promote release of CCK
2) Monitor peptides promote the release of CCK from I cells
ii. CCK cells release CCK, which have a major effect on acinar cell
1) CCK acts primarily on the acinar cells
iii. I cells generate afferent pathways for vagal reflex
iv. Efferent pathways for vagal reflex
Intestinal phase using S cells
i. Acid acts on S cells to release Secretin
ii. Promotes the release of H2O and bicarb to neutralize the acid
iii. Secretin acts primarily on the duct cells
4. Know and understand the composition and functions of bile.

a. Composition
i. Bile acids/salts 70%
1) Conjugated so their pKa's are dropped, making them more soluble
ii. Phospholipids 20%
iii. Cholesterol 5%
iv. Bilirubin 1%
v. Everything else 4%
b. Functions
i. Emulsification of dietary lipids
1) Needed for lipid digestion (breakdown of FA into smaller droplets)
ii. Solulibization of lipid digestion products
1) Needed for lipid absorption
iii. Excretion of waste products
1) Bilirubin, cholesterol, organics, antibiotics
5. Know and understand how bile is secreted.
a. Bile is secreted on the apical side by means of protein mediated processes
i. Bile acids are made de novo from cholesterol, or reclaimed from the small intestine
(by means of a Na gradient on the BL side)
ii. The movement of organic components make an osmotic drive to move H2O and
electrolytes to the lumen by leaky gaps
iii. Secretion from the liver and gall bladder are not very regulated
1) Constitutive process-> happening all the time
b. For the concentration of bile in the gall bladder, the net movement is the extraction of
water from the gall bladder lumen into the blood
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water from the gall bladder lumen into the blood

c. Bile is secreted by means of contraction of gall bladder smooth muscle
i. CCK inhibits the closure and leads to the relaxation of the Sphincter of Oddi
1) Allows bile to go into the ileum
6. Know and explain the function and mechanisms of the enterohepatic circulation.
a. The bile acid pool is ~3g
b. Bile acid synthesis is ~0.5 g/day
c. Bile acid secretion is about 30g/day
i. This means that there must be a cycling of the bile acids
ii. Return of about 95% of what was secreted each day
d. Bile acids are absorbed in the ileum
i. Na+ K+ ATPase creates a Na gradient of lower NA inside the cell
ii. Na+ gradient into the cell drives bile acids into the cell by the ASBT symporter
iii. Bile acids either:
1) Move back into the ileum after intracellular binding protein
2) Move to the BL side in exchange for an anion
a) Go back to the liver
7. Know how proteins, lipids and carbohydrates are digested and absorbed in the small intestine.
a. Carbs:
i. Only monosaccharides can be absorbed
ii. Digestion of starch by salivary and pancreatic alpha-amylase
1) Most amylase comes from pancreatic amylase
2) Breaks down large sugars into trimers and dimers
iii. Membrane bound proteins can chew products of amylase down to monosacch
1) Ex: lactase, sucrase, isomaltase
iv. End up with glucose, galactose, and fructose
1) Glucose and galactose absorption
a) SGLT1 is a Na+ (glucose/galactose) symporter that uses Na+ gradient
generated from a BL Na+K+ ATPase to bring sugars into enterocyte
2) Fructose is transported by GLUT5 into the cell by facilitated diffusion
v. GLUT2 transports the monosacchs across BL side to blood
b. Proteins
i. Digestion
1) Combined action of endoproteases and exoproteases digest proteins to AA and
short peptides
a) Endo: makes cuts in the middle of proteins
b) Exo: chew from 1 end or the other
2) Most proteases come from the pancreas and are released by exocytosis
3) Luminal proteases are secreted as inactive precursors and are only active in the
duodenum
a) Except pepsin, which is active in stomach by pH
4) Trypsinogen in an inactive precursor and is activated by a membrane protein
called enteropeptidase
a) Trypsinogen-> Trypsin
b) Trypsin is the catalytic convertor of all other proteases being secreted
5) Pepsin and pancreatic proteases break down dietary proteins into smaller
chains of AA
ii. Absorption
1) Small chains of AA can be transported across the apical membrane
a) Doesn't have to be single AA to be absorbed
2) PepT1 is an important transporter of oligopeptides
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2) PepT1 is an important transporter of oligopeptides

a) Works well with dimers and trimers
b) Co-transports H+ ion with oligopeptides into the enterocyte
c) Transport is also linked to Na transport process
3) Peptidases inside the enterocyte break down the oligopeptides into AA
4) For single AA's in the lumen, there is a large variety of proteins that transfer
many AA across the apical side
a) There are also many proteins to transfer single AA across the BL into the
blood
5) Hartnup: mutation in B transporter, doesn't let trypsin across
c. Lipids
i. Digestion
1) Lipids are in the form of triglycerides (triacylglycerols), phospholipids (lecithin)
or cholesterol esters which are primarily insoluble
2) Enzymes break down the lipids into smaller components
a) Lipase (gastric) to remove FA from triacylglycerols
b) Phospholipase A2 for phospholipids
c) Lipase and cholesterol esterase to take FA off cholesterol esters
3) Digestion of lipids occurs in emulsions
a) Bile acids prevent phase separation back into big blocks
4) Co-lipase anchors lipase to bile acid coated droplets to help ensure breakdown
5) Bile acids package products of lipid digestion into mixed micelles for absorption
ii. Absorption
1) Products of lipid digestion experience phase transition into mixed micelle
2) Absorption occurs like a bubble of a lava lamp disappearing into solution as the
emulsification turn into mixed micelles
3) Mixed micelle are brought to unstirred water layer
4) There is protein mediated transport of cholesterol and FA's across apical side
into enterocyte
a) IE: NPC1L-1 for cholesterol and FAT/CD36 for FA
b) By blocking NPC1l-1 with ezetimibe, you can block cholesterol uptake
5) Enterocytes rebuild the broken down products into larger products like
chylomicrons for transport wither through blood or lymphatics
8. Know the motor functions of the small intestine.
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Lecture 9
Thursday, August 11, 2016
4:15 PM
1. List and draw the mechanisms for absorption of Na and Cl by the intestines.
a. Na
i. Solute piggy backing
1) Na comes in by a transporter with solutes, follows an electrogenic pull
ii. In the duodenum, get Na back by Na+H+ counter-transport mechanism
iii. Get Na by Na selective channels
1)
2)
b. Get Net NaCl reabsorption all along GI tract

i. Get Na by Na+H+ anti-transporter
ii. Get Cl- by HCO3- Cl- exchanger
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iii.
c. Cl absorption
i. All along the GI tract, occurs paracellularly by electrogenic nature
1) + charge in blood from Na-dependent nutrient absorption pulls Cl- in
2) Parallel Na/Cl mechanism
3) Exchange of Cl- in for HCO3- out
4)
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5)
2. Know and understand the mechanisms for absorption and secretion of K+ by the intestines.
a. Net absorption in SI and secretion in LI
b. Secretion from salivary glands, stomach, pancreas, and liver by both transcellular and
paracellular
c. Most reabsorption by paracellular
d. Mechanisms:
i. Solvent Drag
1) Gets caught up in water moving in and out like a flood
2) SI reabsorption
3) More distal, K+ can go either way, depending on gradient
ii. K+ secretion in LI by K+ channel
iii. In distal colon, can be reabsorbed by K+ H+ exchanger
1) Trying to neutralize the possible too basic contents of intestine
e.
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f.
3. Differentiate qualitative and quantitative roles of various GI system organs in the secretion and
absorption of water.
a. Crypt region is where the secretion of water takes place
b. Small intestine absorb 8500ml of water
c. Large intestine absorb 400 ml of waer
d. Secretion
i. Stomach-2l
ii. Bile-0.5L
iii. Pancreas-1.5L
iv. Intestine-1.5L
4. Differentiate roles of different cell types in the secretion and absorption of water.
a. Secretion:
i. Crypt cells
ii. Na+K+ ATPase creates gradient
iii. NA gradient of low Na inside moves Na and Cl inside from basolateral side
iv. Cl moves to lumen by CFTR that has been phosphorylated
1) Protein Kinase A regulates phosphorylation
2) Secretagogues like Ach, gastrin, secreting, serotonin promote secretion
a) Bind to signaling molecules on enterocytes that will activate protein
kinase to phosphorylate Chloride channels
b) Also move more sequestered Cl channels to the apical membrane to have
more possible channels open
v. Osmotic gradient generated by Cl- moving to lumen pulls Na and H2O into lumen
b. When you increase tone of GI smooth muscle, more secretion
c. Decrease tone, more absorption of water
5. List factors that influence water absorption and describe their mechanisms.
a. the absorption of water is dependent on and proportional to the absorption of solutes
b. As more solutes are absorbed, it creates a hypertonic area to the side of the enterocyte
i. This pulls water, with Na+, and K+ (from solvent drag) back from the lumen by means
of leaky tight junctions or aquaporins in the cell
c. Leaky epithelia (high permeability) allow for more water reabsorption
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c. Leaky epithelia (high permeability) allow for more water reabsorption

i. More proximal part of the tract
ii. As get more distal, tight junctions get tighter and don't allow as much water across,
aquaporins aren't enough to compensate change
d. When solutes aren't absorbed, get osmotic diarrhea
i. lactose
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Lecture 10
6:35 PM
1. List the four types of motility found in the GI system and explain their general roles
a. Propulsion
i. Net movement by peristalsis
b. Mixing
i. Digestion and absorption
ii. segmentation
c. Separation
i. Sphincters
ii. Tonic contraction
d. Storage
i. Decreased pressure
ii. Receptive relaxation
2. Identify the major types of motility in each organ of the GI system and describe their
importance
a. Esophagus
i. Peristalsis
ii. Tonic contraction
b. Stomach
i. Storage
1) Stomach initially undergoes receptive relaxation
ii. Mixing and grinding
iii. Regulated pumping
1) Optimal delivery rate of duodenum
2) Pinch off parts of food and move down towards pyloric valve
3) Pyloric valve initially contracts more
a) This shakes up and emulsifies the lipids and stuff
c. Small intestine
i. Mixing
ii. Migrating motor complex
1) Peristalic movement that occurs after food has cleared small intestine and the
stomach
a) Housekeeping function that gets rid of debris, sloughed epithelial cells,
and bacteria
b) Initiated by motilin
i) By endocrine signaling
iii. Vomiting
1) Can be induced centrally or peripherally
2) Can lead to dehydration, loss of H+ and Cl-, hypoK
iv. Peristalsis
1) Peristalsis and segmentation have mixing and matching in order
d. Large intestine
i. Mixing movements
ii. defecation
iii. Storage
iv. Peristalsis (mass movements)
3. Describe the regulation of motility in each organ of the GI system
a. Slow waves are generated by ICC pacemaker cells
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a. Slow waves are generated by ICC pacemaker cells

i. Affect the basal electrical rhythm "BER"
ii. Stimulated by
1) Stretch
2) Acetylcholine
3) Parasympathetics
iii. Lowered by:
1) Sympathetics
2) NO
3) VIP
b. Most smooth muscles in GI tract are normally relaxed (ileus)
i. Active inhibitor enteric neurons are ON when relaxed
1) In contracted smooth muscle, inactive inhibitory enteric neurons "OFF"
ii. Sphincter
1) Default state: inactive inhibitory enteric neuron
2) Relaxed state:
a) In presence of NO or VIP
b) Have active inhibitory enteric neurons
c. Esophagus:
i. Components of bolus are a driver to fire enteric neurons
1) Propulsive segment
a) Circular: contracted
i) Inhibitory motor is off
ii) Excitatory motor is on
b) Longitudinal: relaxed
i) Inhibitory motor is on
2) Receiving
a) Circular: relaxed
i) Inhibitory motor is on
ii) Excitatory motor is off
b) Longitudinal: contracted
i) Inhibitory motor is off
ii) Excitatory motor is on
ii. Upper esophagus has neurons directly fire on muscle cells
iii. Lower esophagus has muscle firing done by enteric neurons
iv. Happens by a rank order of firing of vagus nerves
1) Starts at top then moves down preferentially
v. Regulation of LES
1) Mostly neural
a) Tonic contraction at rest (myogenic)
b) Vagal mediation of relaxation (activation of inhibitory intrinsic neurons,
VIP, NO)
2) Hormonal
a) Not really any regulation
3) Environmental
a) Caffeine, alcohol, chocolate--> decrease resting LES tone
4) Mechanical
a) Obesity and pregnancy
d. Stomach
i. Mechanoreceptors sense distension and cause relaxation of smooth muscle by vagovagal reflex
1) Receptive relaxation
ii. Regulation of gastric emptying
1) Duodenal chemoreceptors sense many features of chyme
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1) Duodenal chemoreceptors sense many features of chyme

a) Acids, fats, hypertonicity, AA
b) Duodenal chemoreceptors can send hormonal effects to lead to
decreased gastric empyting
i) secretin, cck, gip, gastrin
2) Send back a feedback on gastric smooth muscles themselves and part of pyloric
valve
3) Goes to intrinsic nervous system
a) Can lead directly to decreased gastric emptying
4) Goes to chemoreceptor afferents to central NS
a) Through sympathetic/parasympathetic nerves lead to decreased gastric
emptying
e. Large intestine
i. Motility at ileocecal sphincter
1) Distension in ileum promotes sphincter contraction for efficient ileal absorption
2) Activation of ileal mechanoreceptors promotes peristalsis and sphincter
relaxation
3) Activation of cecal mechanoreceptors inhibits ileas peristalsis and promotes
sphincter contraction after bolus has moved to colon
ii. Pooping
1) Internal anal sphincter and rectum are controlled by enteric neurons
2) External anal sphincter (skeletal) are innervated directly from pelvic nerves
3) Rectosphincteric reflex
a) Rectal smooth muscle reflexively contracts to presence of poop
b) This sets up a reflex relaxation in internal anal sphincter
c) Also sets up a reflex contraction of external anal sphincter
iii. Long range reflexes for control of gastrointestinal motility
1) Gastroileal reflex
a) Gastric distension and motility increases motility in the ileum
2) Ileogastric reflex
a) Distension in ileum inhibits gastric motility
3) Coloncolonic reflex
a) Distension in one portion of colon decreased tension and motility in other
portion of colon
4) Gastrocolic reflex
a) Motility in stomach increases motility in distal colon and promotes
defecation
4. Describe the relative roles of the extrinsic and intrinsic nervous systems in GI motility
a. Extrinsic nerves can regulate peristalsis
i. Can speed mechanism up or down
Week 1 Page 49
Lecture 12
Sunday, August 14, 2016
2:47 PM
1. Know that there are two basic types of enteric pathogens: those that always cause disease
when they enter the human GI tract (e.g., Shigella species) and those that are usually harmless as
long as they remain in the GI tract (e.g., Klebsiella species) but which can cause serious infections
outside of the GI tract.
a. Primary Pathogens
i. Salmonella shigella
ii. Always cause disease when enter GI tract
b. Norml GI tract Flora
i. Opportunistic pathogens
2. Know that there are special selective and differential isolation media for enteric pathogens.
a. Identification is based on:
i. Lactose fermentation ability
a. MacConkey
i. Selective
1) Bile salts inhibit growth of non-enteric bacteria
ii. Differential
1) Contains lactose and pH sugar identifier
iii. Lactose positive: red/pink-> CAN ferment lactose
ii. Biochem test using metabolic reactions
iii. Serological typing (especially for Salmonella)
a. Antigens
i. O=LPS in outer membrane
1) Toxic part is the Lipid A moiety
ii. H=flagella
iii. K=capsule (usually polysaccharide)
3. Know that there are at least six different mechanisms by which E. coli strains can cause
diarrheal disease.
a. ETEC (enterotoxigenic)
i. Produce either enterotoxins
a. LT-heat liable
b. ST-heat stable
ii. Leading cause of traveler's disease
iii. Pathogenesis
a. LT enterotoxin- causes increased cAMP--> more fluid/electrolyte release
b. ST enterotoxin- causes increased cGMP-> more fluid/electrolyte release
b. EPEC (enteropathogenic)
i. Attach tightly to intestinal epithelial cells and cause EFACEMENT of microvilli
ii. Injects its own receptor into cells that rearrange cytoskeleton
iii. Have O antigens
iv. Fluid and electrolyte replacement is CRITICAL
v. Use type III secretion system to inject tir protien
a. Tir protein create pedestal of which bacteria become firmly attached
c. EIEC (enteroinvasive)
i. Closely related to shigella
Week 1 Page 50
d.
e.
f.
g.
h.
i.
i. Closely related to shigella

ii. Children in developing countries
EAEC (enteroaggregative)
i. Associated w/ persistent diarrheal disease, especially in people w/ AIDS
ii. Was second to Campylo as a cause of gastroenteritis
DAEC (Diffusely adhering)
i. Associated w/ relatively severe diarrheal disease in children
EHEC or Shiga toxin producing E. Coli (STEC)
i. Produce one or more Shiga toxins that are cytotoxic for endothelial cells
ii. Very low infectious dose, can be transmitted by contact
iii. Can cause HUS in kids or TP in adults
iv. Epidemiology
a. Have an animal reservoir, including healthy cattle
b. (hamburger bug)
v. Number of infections caused by non-O157 strains is larger than the number caused by
O17 strains
E. Coli is the most common cause of UTI in the country
e.coli from normal flora can cause bacteremia and RTI in debilitated persons
E.Coli K1 strains can cause neonatal meningitis
4. Understand that Salmonella species can cause typhoid fever, septicemia, and food-borne
disease and that the greatest incidence of Salmonella disease is in children under the age of 5.
a. ALL salmonella are pathogenic for humans
b. 99% of salmonella do NOT ferment lactose
c. S.Typhi produces a polysacch capsule designated as the Vi antigen
d. Typhoid fever
i. S.Typhi found only in humans, commonly international travel in dev. Countries
ii. Diagnosis: isolation of S.Typhi from specimen
iii. Prevention: live oral vaccine of Ty21a mutant
a. Parenteral vaccine of purified Vi capsular polysacch
e. Gastroenteritis
i. Nausea, vomiting, diarrhea 6-48 hours after ingestion
ii. Epidemiology
a. Most imp cause of bacterial food borne disease
iii. Diagnosis
a. Don't need antibiotics usually
f. Uses type III secretion system
5. Understand that shigellosis is the most communicable of the bacterial diarrheas.
a. Infectious inoculum can be as small as 10 organisms
b. Shigella do NOT produce ferment lactose
c. ALL shigella are pathogenic for man
d. Bloody, mucus, pus filled diarrhea
e. Treatment: fluid and electrolyte replacement is imp
i. Use of antibiotics is determined by severity of disease
f. Prevention: disrupt fecal-oral route
6. Know that Campylobacter jejuni is an important bacterial cause of diarrheal disease in this
country and that special isolation media and conditions are essential for the successful isolation of
C. jejuni.
a. Second most common acute bacterial diarrheal disease
Week 1 Page 51
a.
b.
c.
d.
Second most common acute bacterial diarrheal disease

Is a zoonosis-can be contracted by animals
ALL campylobacters are obligate micro-aerophiles that grow best at 42-43 degrees C
Pathogenesis:
i. Invades mucosa of colon and small intestine
ii. Resultant diarrhea might not contain blood, find leukocytes
e. CHICKENS!!
f. Has bimodal distribution in infants and young adults
g. Isolation of campylo requires special media and incubation conditions
Week 1 Page 52
Lecture 13
3:23 PM
1. Viral gastroenteritis
a. Summarize the epidemiology, clinical presentation, and pathogenesis of gastroenteritis due
to Rotaviral infection.
i. Epidemiology:
1) Infectious dose is less than 10 virions
2) Fecal-oral spread
a) Person-person
b) Fomites
c) Fecal contamination of foods
3) Secondary spread is common b/c of high # of virions
a) Day care centers
b) Adult caregivers
4) Seasonal distribution w/ winter peak
ii. Presentation:
1) Short vomiting (first day only or so)
2) Incubation is 1-3 days
3) Diarrhea is watery (up to 20 X / day)
4) Stool leukocytes are present in only a small # of patients
iii. Pathogenesis
1) Virus infects cells at villus tip in small intestine
2) Mechanisms for diarrhea
a) Lytic growth destroys mature absorptive cells
i) Fluid leakage from barrier disruption
b) Damaged cells on vili replaced by immature crypt
i) Inefficient absorption-->osmotic diarrhea
c) NSP4 is a secretogogue
i) Secretory diarrhea
iv. Diagnosis
1) ELISA
2) Latex agglutination
3) RT PCR
v. Criteria for IV
1) Unstoppable vomiting
2) Altered mental status
3) Loss of >10% body weight
vi. Other
1) Resistant to drying, acid, detergents, and disinfectants
a) Allows survival in environment
2) Major antigens are VP7 (surface glycoprotein) and VP4 (protease cleaved
protein)
a) Basis for classification
b. Summarize the epidemiology, clinical presentation, and pathogenesis of gastroenteritis due
to Norovirus infection.
i. Epidemiology
1) Infectious dose is 10 virions
2) First exposure as children
3) Cruise Ships!! (epidemics common, like hospitals and nursing homes)
Week 1 Page 53
ii.
iii.
iv.
v.
a) Raw or undercooked food
5) Secondary and tertiary spread common
Presentation
1) Incubation 1-2 days
2) Vomiting goes on for longer time
3) Less diarrhea (4-8 X / day)
4) Improvement within 2-3 days
Pathogenesis
1) Shortening and atrophy of villi in proximal small bowel
2) Carb malabsorption
3) Short lived immunity, strain specific, need repetitive exposure
Diagnosis
1) Distinguished from Rota by vomiting predominnace and by age of patients
2) No culture methods usually presumptive in sporadic cases
3) RT-qPCR
Treatment
1) No drug therapy
2) Rehydration
3) Symptomatic therapy
2. Nosocomial and antibiotic-associated diarrhea

a. Summarize the clinical and economic significance of nosocomial diarrhea in the United
States.
i. Noninfectious versus infectious
ii. Viral causes
iii. Antibiotic associated, NOT CAUSED BY C.DIFF
iv. Cost a lot and extends hospital stays
v. C.diff-associated disease is the most significant
b. Summarize the epidemiology and clinical spectrum of Clostridium difficile-associate colitis
(CDAD).
i. Epidemiology:
1) Spores can survive a long time
2) Outbreaks occur in closed settings
a) Hospitals, nursing homes
b) Carried on hands, shoes, etc
3) Disease requires presence of toxin
ii. Risk factors
1) Previous or concurrent antibiotic therapy
2) Older, severity of underlying disease
iii. Antibiotic associations
1) STRONG POSITIVE ASSOCIATIONS
a) Significantly increases risk
i) Clindamycin, ampicillin, amoxicillin, cephalosporins
iv. Pathogenesis
1) Two toxins, A and B
2) Mechanism
a) A is a cytotoxin and enterotoxin (causes secretory diarrhea)
b) B is a cytotoxin
v. Clinical manifestations
1) Psuedomembranous colitis
a) Yellow plaques
Week 1 Page 54
a) Yellow plaques
2) Toxic megacolon
3) Watery diarrhea (can be bloody)
4) Elevated peripheral WBC
5) Dehydration
vi. Caused by antibiotics vs C.Diff
1)
c. Summarize the diagnostics and specific therapies used to manage the patients with C.
difficile diarrhea.
i. Daignostics
1) PCR
a) Look for presence of toxic genes
2) Cytotoxin assay
ii. Treatment
1) Discontinue offending antibiotic
2) Oral metronidazol and oral vancomycin
a) NO IV vancomycin
3) Relapsed C.Diff
a) Stool transplant
iii. Controlling
1) Frequent hand washing w/ soap and water
iv. New Super C.Diff has deletion of repressor gene
Week 1 Page 55
Lecture 14
6:23 PM
1. Identify the most common protozoa and helminths that are associated with complicated
infections.
a. Protozoa
i. E. histolytica
ii. Dientamoeba fragilis
iii. Giardia lamblia
iv. Balantidium coli
v. Cyclospora Cayetanensis
vi. Microsporidia
1) Enterocytozoon bieneusi
2) Encehalitozoon species
b. Hemlinths
i. Ascaris lumbricoides
ii. Nectar americanus, Ancylostoma duedenale
1) Hookworm
iii. Strongyloidiasis stercorales
iv. Enterobius vermicularis
1) Pinworm
v. Trichuriasis trichiura
1) Whipworm
vi. Taenia solium
2. Identify the key histories that are important for the presumptive diagnosis of amebic dysentery,
and giardiasis.
3. E.Histolytica
a. History:
i. 7 day history of cramping abdominal pain
ii. Low fever
iii. Anorexia
iv. Intermittent diarrhea, sometimes blood
b. Complications
i. Intestinal disease (primary illness)
ii. Amebic liver abscess
iii. Peritonitis (2o to colonic bacterial infection)
c. Reservoir and mode of transmission
i. Human reservoir
ii. Transmission- ingestion of mature cysts in fecally contaminated food, water
d. Life cycle-fecal/oral cycle
e. Differnetiate E.histolytica from Amebae
i. Erythrophagocytosis for E. histolytica
f. Drugs
i. Metronidazole or tinidazole
ii. Paromomycin or tetracycline
4. Giardia
a. History
i. Child at daycare with subacute diarrhea
ii. Malabsorption
iii. Ab pain, vomiting
b. Complications
i. Asymptomatic carriage to severe diarrhea to malaborption
Week 1 Page 56
i. Asymptomatic carriage to severe diarrhea to malaborption

ii. Above symptoms
c. Reservoir and mode of transportation
i. Human reservoir
ii. Habitats-wild animals
iii. Transmission
1) Fecally contaminated water
2) Hand-mouth transfer of cysts among infancy and travelers
iv. Life cycle
1) Cysts deposited into the environment
a) Infective when ingested
v. Drugs
1) Metronidazole, tinidazole, quinacrine
d. Identify the tests to confirm the clinical diagnosis of protozoal infections, and know the
rationale to undertake serologic investigation in cases of disseminated amebic diseases.
i. Serology antigen test is highly specific for Giardia
ii. Upper endoscopy w/ aspiration of fluid
5. Ascaris lumbricoides
a. History
i. Child that immigrated to US from honduras
ii. Progressively worsening pain
iii. Nausea and vomiting
iv. Later projective vomiting
v. NO diarrhea
b. Complications
i. Very tender ab, no stool in rectal vault
ii. Low grade fever
c. Reservoir and mode of transmission
i. Human reservoir
ii. Ingestion of eggs in from soil contaminated with human feces
iii. Uncooked produce contaminate w/ soil w/ infective eggs
d. Drugs
i. Mebendazole or Albendazole
6. Strongyloidiasis
a. History
i. Immigrated from haiti
ii. Epigastric pain intermittent
iii. Unchanged bowels
iv. Ulcerations and sloughing of intestinal mucosa
b. Complications
i. Coughing, wheezing
ii. Dermatological manifestations like urticarial rashes
iii. Blood eosinophils may be present (except in immunosupressed)
c. DISSEMINATED STRONGYLOID OCCURS IN IMMUNOSUPPRESSED PATIENTS--POTENTIALLY
FATAL
d. Reservoir
i. Goes through skin from soil
ii. Transmission-human infective filariform larvae penetrate skin
e. Drugs
i. Ivermectin
ii. Thiabendazole
7. Enterobiasis (pin worm)
a. History
i. Peri-anal iching
Week 1 Page 57
i. Peri-anal iching
ii. Disturbed sleep
iii. Irritability
iv. Mild nausea or vomiting
b. Complications
i. Secondary infection of infected site
c. Reservoir
i. Humans
ii. Transmission-ingestion of infective eggs by hand from anus to mouth
1) Also indirectly through bedding, food, or other articles
d. Drugs
i. Pyrantel pamoate
ii. Mebendazole
iii. Albendazole
8. Trichuriasis (whip worm)
a. History
i. Worm removed during colonoscoy
b. Complications
i. Bloody diarrhea or mucoid diarrhea
ii. Weight loss and weakness
iii. Ab pain and tenderness
iv. Rectal prolapse (especially in children)
c. Reservoir
i. Humans
ii. Transmission-ingestion of eggs from fecally contaminated soil
d. Drugs
i. Mebendazole or albendazole
9. taeniasis
a. History:
i. Partial motor seizures
ii. Lives on a farm from peru
iii. Decreased level of consciousness
b. Complications
i. Nervousness
ii. Insomia
iii. Anorexia
c. Reservoir
i. Cattle are intermediate hosts for saginata
ii. Pigs are intermediate hosts for solium
iii. Humans are accidental hosts for both
iv. Transmission
1) Beef tapeworm
2) Saginata-GI infection of raw or indercooked beef
3) Undercooked pork for other one
v. Drugs
1) Remove lesions in brain
2) Steroids like mannitol to control inflammatory response
10. Cysticercosis
a. From Taeniasis
b. History:
i. Seen either ocular or subcutaneous
ii. CNS
1) Parenchymal cysts
2) Subarachnoid cysticercosis
Week 1 Page 58
2) Subarachnoid cysticercosis
c. Complications
i. Messed up head
d. Reservoir
i. Human accidental hosts
e. Treatment
i. Praziquantel
ii. Albendazole
11. Cystic hydatid disease
a. History
i. Develop in the liver
ii. Highest prevalence in sheep raising areas
b. Complications
i. Pain in liver
ii. Anahylaxis upon rupture
iii. Lung cysts
c. Reservoir
i. Humans are intermediate hosts
ii. Transmission
1) Ingesting eggs of parasite from dogs, or other animals
2) May be present on animal fur
d. Drugs
i. Surgery
ii. Albendazole
12. Schistosomiasis
a. History
i. Africa parasite
b. Complications
i. Many are asymptomatic
ii. CNS lesion
iii. Hepatosplenomegaly
iv. Ab pain
v. Diarrhea
c. Reservoir
i. Skin penetration
ii. Transmisison-eggs are eliminated through feces and urine
d. Drugs
i. Praziquantel
ii. Oxamniquine
e. Hard to get rid of because they can live a very long time asymptomatically
13. Have some understanding of the difficulty in eradicating schistosomiasis from Africa.
Week 1 Page 59
GI physiology review
1:19 PM
1. Describe the factors controlling the rate of gastric emptying and the physiologic rationale for
their actions.
2. Describe the intracellular molecular mechanism of HCl secretion of the parietal cell.
3. List and discuss the major neural and hormonal mechanisms for stimulating HCl secretion.
4. What are the mechanisms for protecting the epithelium of the stomach from the digestive
effects of pepsin and HCl?
5. List the phases of gastric secretion that are associated with eating and digesting a normal meal.
Discuss in detail the control of secretion in each of these phases.
6. What are the functions of the bile?
7. What is meant by enterohepatic circulation of bile acids/salts?
8. Describe the regulation of gastrin and HCl secretion by somatostatin.
9. Define potentiation and describe its importance in the mechanism of acid secretion.
10. Describe the role of cholecystokinin in gastrointestinal function.
11. What are the distinctions between luminal and membrane-bound digestive enzymes?
12. Summarize the steps involved in digestion and absorption of fat.
13. Briefly discuss the role of efferent nerves in the vagus in the three phases of gastric secretion
that follow a meal.
14. Describe the molecular basis for the absorption of water in GI epithelium. In what area of the
villus does this occur?
15. Describe the cross-sectional organization of the GI tract and identify important functions
associated with each area.
16. Identify four hormones that function in the GI system by endocrine mechanisms and describe
the physiologic functions of each.
17. What is the role of Na+ in normal absorption of amino acids and carbohydrates?
18. What are the differences among endocrine, neurocrine and paracine signaling mechanisms?
Give an example of each in the GI system.
19. Describe the roles of sensory neurons, interneurons, and motor neurons in the mechanism of
peristalsis.
20. Is it possible to have an active mechanism for the transport of water? Why or why not?
21. Describe the roles of fat and H+ in the duodenum with respect to the signaling of pancreatic
secretion.
22. How does cholera toxin cause diarrhea?
23. What is the mechanistic distinction between an osmotic diarrhea and a secretory
diarrhea?
24. Describe the general features of neural regulation of salivary secretion. What is the role of
endocrine signaling in acute regulation of salivary secretion?
25. How are H/K ATPase pumps activated during stimulated acid secretion in parietal cells?
26. What is the role of the migrating myoelectric complex?
27. Describe the general roles of parasympathetic innervation during defecation.
28. Why does it matter that cholesterol and other fats are absorbed by protein-dependent
transport mechanisms as opposed to simple diffusion through membranes based on
biophysical properties?
29. How can intestinal bacteria affect nutrient absorption?
1.
Week 1 Page 60
9:15 AM
3 day rule for stool

If in hospital for more than 3 days--> NO STOOL SAMPLE
Epidemiology-hospital acquired bloody diarrhea is unusual if in hospital for a while
Setting up a stool culture
Blood agar plate
Mcconkey
Normal is lactose positive
Shigella/salmonella
Whte
Sorbitol
E coli does not ferment sorbitol, so colorless on plate
Hektoen
Shigella-->green colonies
Salmonella-> black colonies
Campylobacter
Special growth characteristics
Campy agar
Microaerophilic
Seal plate in bag
Thermophilic 42 degrees celsius
GN broth
Enhances salmonella and shigella
1. Salmonella is an equal opportunity bug

2. Parasitic infection
a. Liquid look for
b. Mix some specimen with saline
i. Look for amoeba
c. Preserve sample with formalin and PVA
i. Formalin
ii. Concentrated ,add ethl accetate
iii. Can be stained
d. PVA
i. Smears
ii. Trichome stain
iii. Fast green and light green
1) cytoplasmic proteins
iv. Trimchome
1) Protazoan parasites
3. Giardai
a. Owls eyes
Week 1 Page 61
a. Owls eyes
b. Does not take up acid fast stain in the stool
4. Acid fast
a. Crypto
b. Cyclo
5. C.diff
a. At risk 6 months after
Week 1 Page 62
Lecture 15
1:56 PM
1. Learn the pathophysiology and clinical presentation and management of xerostomia

a. Pathophysiology of xerostomia
i. Meds
1) Anticholinergics (many anti-depressants)-->affect salivary output
2) Sympathomimetic that have central alpha-2 stimulant effects
a) Like amphetamines "meth mouth"
b) Directly decrease salivary output
ii. Cancer treatment
1) Cytotoxic chemo
2) Head and neck radiation
iii. Autoimmune - attack exocrine glands and salivary glands
1) Sjorgen's syndrome
a) Inflammatory process affecting various exocrine glands
i) Perimenopausal women
ii) Dry eyes and keratoconjunctivitis
2) IgG4 related disease
b. Clinical presentation
i. Difficult generating a food bolus
1) Difficulty swallowing, especially solid and dry foods
ii. Loss or protective immune functions of saliva
1) Gingivitis
2) Oral candidiasis (oral thrush)
iii. Tooth demineralization
1) From inability to regulate pH in the oral cavity
2) Caries and tooth decay
c. Management
i. Frequent water sips and saliva replacement
ii. Avoidance of foods w/ extreme pH ranges
iii. Treat nasal obstruction to avoid mouth breathing
iv. Methodical dental care
v. Stimulation of residual salivary function (gum)
vi. Drugs
1) Muscarinic agonists
a) Pilocarpine (m1,m2, m3 agonist)
b) Cevimeline (m1 and m3 agonist)
i) No heart stimulation
2) M2 receptor are expressed in heart
a) Bradycardia
3) M3 agonist basically
2. Learn the pathophysiology and clinical presentation and management of acid hypersecretion
a. Pathophysiology
i. Gastrin overproduction
1) Zollinger-Ellison syndrome
a) Caused by a gastrin producing tumor
b) 20% of cases assoc w/ genetic cancer syndrome MEN1 gene
week 2 Page 63
b) 20% of cases assoc w/ genetic cancer syndrome MEN1 gene

c) Leads to hypertrophic changes in gastric mucosa
2) Retained antrum syndrome (surgery)
ii. Histamine over production
1) Systemic mastocytosis
a) Urticaria pigmentosa
b. Clinical presentation
i. Peptic ulcers in duodenum or stomach
ii. Ulcers that are hard to treat, recurrent, recalcitrant (post bulbar) distal to stomach
iii. Diarrhea form acid hypersecretion
1) Caused by hypersecretory state
2) Inactivation of pancreatic enzymes due to large acid
3) Direct diffuse mucosal injury
iv. GERD
v. GI bleeding
vi. Weight loss
vii. Gastrin > 1000pg/mL and gastric pH<4
viii. Secretin stimulation test
c. Management
i. Anti-secretory therapies
1) H/K ATPase, or proton pump inhibitor
2) H2 histamine receptor antagonist
a) Responsible for parietal cell acid secretion
ii. So, pretty much PPI's and H2RA
iii. Surgery
1) Gastrinomas removed
iv. Somatostatic analogs for non resectable tumors
3. Learn the pharmacology of drugs that control acid secretion
a. PPI
i. Disulfide bond w/ cysteine 813--permanent inactivation
ii. Needs to be taken 30 minutes before a meal
iii. Typically once daily
1) Omeprazole 20-40 mg
2) Esomeprazole (20-40mg) least drug reactions
b. H2RA
i. Mechanism
1) Block H2 receptor on parietal cells, responsible for acid stimulation
ii. Main ones
1) Ranitidine
2) famotidine
week 2 Page 64
Lecture 16
4:02 PM
1. Understand the key defining features of malabsorption and maldigestion, and how these
disorders are distinguished from other forms of chronic diarrhea.
a. Maldigestion
i. Global macronutrient digestion is impaired
ii. Due to decreased pancreatic enzymes or bile
b. Malabsorption
i. Absorption is impaired due to loss of absorptive capacity in small intestine
ii. In the lumen, there is an increase in osmalarity b/c of the broken down sugar pulling
water (osmotic load)
iii. Symptoms
1) Weight loss from reduced caloric contribution
2) Diarrhea:
a) Osmotic
b) Resolves when patient fasts
3) Enteropathies linked to defects in water and electrolyte absorption
4) Fat excreted in stool, has oil droplets
5) Distension
6) Micronutrient deficiency in fat soluble vitamins ADEK
2. Understand what constitutes protein-losing enteropathy and its main causes.

a. Protein-losing enteropathy (PLE)
i. Loss of proteins into the intestinal lumen, leading to hypoprotenemia
b. Chronic diarrhea
i. Edema is very telling
1) Result of severe hypoproteinemia
2) Steatorrhea is due to obstruction of lymphatics
a) Established by stool Alpha 1 antitrypsin > 54
b) Qualitative stool fat +++ rating
3. Be able to outline the main diagnostic algorithm for malabsorption.

a. Established patient suffers from malabsorption
i. Fat malabsorption test
1) Quantitative stool fat determination
a) 3 days stool collection
b) Malabsorption is >13g/d
2) Qualitative stool fat determination and fecal concentration
a) Done on spot sample
3) Serum vit A levels
a) Deficiency of vit A
b. Discriminate b/w maldigestion and malabsorption
i. Pancreas
1) Stool elastase or chymotrypsin
a) These are naturally protease resistant and can be found in the stool. If low
quantities are found-->pancreatic exocrine insufficiency
2) Pancreatic exocrine function test
a) Endoscope is placed in duodenum to collect pancreatic juice
b) Measure bicarb or amylase in response to secretin stimulation
week 2 Page 65
b) Measure bicarb or amylase in response to secretin stimulation

3) Pancreatic imaging
a) Demonstrate pancreatic atrophy or pancreatic duct obstruction
ii. Small intestine
1) Endoscopic evaluation
a) Malabsorption involves diffuse enteropathies that affect most of small
intestine
2) Small bowel imaging
a) Patchy disease involvement is suspected
3) Other test
a) D-xylose test examines intestinal absorption
b) Pentose sugar is ingested and it's absorption is determined by blood levels
or urine excretion
i) Poor absorption is indicative of small bowel disorder
ii) If excretion in urine is below 1--> malabsorption
c. Summary
i. Establish patient suffers from malabsorption: focus on fat in stool
ii. Discriminate b/w maldigestion and malabsorption
1) Pancreas vs small intestine evaluation
iii. Consider PLE
1) Edema + hypoproteinemia
2) Check for stool alpha-1-AT
4. Acquire a general knowledge of the causes behind malabsorption and maldigestion.
a. Maldigestion
i. Impaired pancreatic exocrine function
1) Chronic pancreatitis
2) Cystic fibrosis
3) Pancreatic duct obstruction
ii. Decreased bile acid output
1) Bile duct obstruction
2) Poor bile excretion
b. Malabsorption
i. Enteropathy and decreased absorptive function
1) Celiac sprue
2) Infection
a) Giardia
b) Strongyloides
3) Malignancies
4) Bacterial overgrowth
week 2 Page 66
Lecture 17
4:02 PM
1. Acquire a general knowledge of the causes for dysphagia

a. Difficulty swallowing
b. Perceived as a sensation that food is "stuck" at the completion of swallowing
c. Causes
i. Mechanical obstruction
1) Long luminal narrowing
a) Tumor
b) Fibrous stricture in response to acute or chronic esophageal ulceration
c) Present with gradually progressive dysphagia to solid food and weight loss
2) Esophageal rings or webs
a) Short areas of luminal narrowing
i) Asymptomatic before severe lumen compromise
b) Intermittent solid food dysphagia
i) May present with acute food impaction
ii. Impaired motility of the esophagus
1) Disorders of skeletal muscle
a) Pharyngeal phase of swallowing is affected--> oropharyngeal dysphagia
b) Airway aspiration (coughing when drinking)
c) Nasal regurgitation of liquids
2) Neurological disorders
a) Something affecting the innervation of pharyngeal muscles
i) Stroke victims
ii) Diseases that affect the brainstem or CN
3) Disorders of smooth muscle and intrinsic esophageal neurons
a) Particularly of the myenteric plexus
b) Direct damage to smooth muscle of esophagus
i) Achalasia
ii) Psuedo-achalasia
One. Secondarily damage the plexus, like tumors or Chagas
iii) Scleroderma
One. Damages visceral smooth muscle
2. Be able to outline the main clinical differences between mechanical dysphagia and dysmotility
a. Gradually progressive dysphagia to liquids
b. Dysmotility:
i. First dysphagia to liquids, with gradual dysphagia to solids
week 2 Page 67
c.
3. Understand the general algorithm to investigate dysphagia

a. Asses if oropharyngeal dysphagia is present
i. Careful neuro exam
ii. Fluoroscopic eval of oropharyngeal swallowing
b. Examine esophageal lumen
i. Asses for mechanical causes of dysphagia
1) Upper endoscopy
2) Esophagram
a) Contrast exam can identify luminal compromise
b) Can detect alterations of motility
c. Assess motlity
i. Esophageal manometry
1) Catheter measures pressure waves
2) Achlasia
a) Absent or low amplitude non-peristaltic waves
b) Increased basal pressures at LES that fails to relax upon swallowing
i) If neurons arent there-->sphincter pressure stays high--> means
neurons have been lost
3) Scleroderma
a) Aperistalsis
b) Low amplitude esophageal contractions
c) very low resting P at the LES
i) Makes it different from achlasia
4) Other manometric findings
a) Nutcracker esophagus
i) High amplitude peristaltic contraction upon swallowing
b) Esophageal spasm
i) Simultaneous high amplitude contractions
week 2 Page 68
Lecture 18
7:33 PM
1. Understand the pathology and pathophysiology of GERD

a. Pathophysiology
i. Mechanisms that cause reflux
1) Hiatal hernia
a) Displacement of the EGJ above the diaphragmatic haitus
b) LES is placed in the (-) pressure of the thoracic cavity
c) Lose protective effect
d) Reduces the effective intraluminal sphincter in the lumen
2) LES pressure
a) Low LES P can potentiate reflux
i) Scleroderma
3) Transient lower esophageal sphincter relaxation (TLESR)
a) Involuntary mechanism to vent gas from stomach
b) Reflux to the esophagus in patients with GERD coincide with TLER
i) TLESR occur in normal individuals with same frequency
4) Acid pocket
a) Persistent acidity of proximal stomach despite buffering of food
5) Decreased reflux clearance
a) Esophageal motility is triggered by reflux episodes
i) With bicarb in saliva, imp in normalizing pH in esophagus
6) Delayed gastric emptying
a) Can potentiate the degree of reflux and symptoms
7) Obesity
a) Higher rates of hiatal hernia
8) Tobacco, alcohol, pregnancy, drugs
9)
ii. Mechanisms that cause symptoms

1) Acidity
a) Esophageal pH <4
2) Volume
a) More proximal extent and greater distention of esophagus
week 2 Page 69
a) More proximal extent and greater distention of esophagus

3) Mucosal disruption
a) Mucosal erosions can expose nociceptive nerve endings in the mucosa-->
more likely to elicit symptoms
b. Pathology
i. Non-erosive disease
1) Dilation of intercellular spaces in squamous epithelium (EM)
2) Thickening of basal layer
3) Elongation of papillae
4) Reduced maturation features of squamous epithelium adjacent to lumen
5) Neutrophils, lymphocytes, and some eosinophils may be recruited to mucosa
and to epithelium
ii. Erosive disease
1) Loss of epithelium
2) Inflammatory infiltration and cellular debris
iii.
2. Be able to outline the diagnostic evaluation and treatment of uncomplicated cases

a. Typical symptoms
i. Heartburn and regurg
b. No evidence of complications
c. Diagnosis of GERD is made on clinical grounds
d. Response to anti-secretory therapy (ie, proton pump inhibitors)-->diagnosis is most likely
accurate
e. GERD w/ assoc dysphagia or odynphagia
i. Rule out tumor, stricture, esophagitis
f. Disease refractory period
i. EGD: does patient have other cause for esophagitis?
ii. pH monitoring: pathological levels of acid exposure?
iii. Namometry: motility disturbances?
g. Atypical presentations
i. Endoscopy, manometry, pH studies, or therapeutic trials w/ PPI
3. Be knowledgeable regarding possible complication of GERD
a. Erosive esophagitis
i. Best diagnosed under endoscopy
ii. Classified according to severity (A-D)
iii. Typical symptoms: heartburn, dysphagia
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iii. Typical symptoms: heartburn, dysphagia

iv. Subacute upper GI bleed
1) Hematemesis
b. Strictures and rings
i. Fibrosis and stricture formation over time
ii. Mechanical obstruction and progressively dysphagia to solids
iii. Schatzki's ring
1) Formation of ring at the gastroesophageal junction
c. Barrett's
i. Metaplastic change in mucosa of distal esophagus
1) Squamous is replaced by columnar
a) Goblet cells present
2) White males over 50
ii. Short term
1) Segment of metaplastic tissue is less than 3 cm
2) Asymptomatic
iii. Long term
1) Tissue longer than 3 cm
2) 5-10 times less common than short term
3) More severe GERD
iv. Associated with risk of esophageal adenocarcinoma
week 2 Page 71
Lecture 19
8:12 PM
1. Learn the basic pathophysiology and clinical presentation of gastroparesis

a. Gastroparesis-diseases that affect the neuronal control or smooth muscle component of
gastric motility-->delayed gastric emptying
b. Pathophysiology
i. Vagus nerve
1) Ach stimulation
2) Most often surgical injury
3) Denervation of stomach and loss of vagal inputs
ii. Myenteric plexus neurons
1) Damage to NO producing neurons responsible for smooth muscle relaxation
a) NO vasodilator-->relax smooth muscles
iii. ICC cells
1) Without these cells pacemaker function--> gastric dysrrythmias
2) Lack of coordination of smooth muscle contraction
iv. Smooth muscle cells
1) Immune or infiltrative processes can lead to damage to gastric muscle fibers
2) Loss of contractile reserve
3) Will destroy contractility
c. Causes
i. DM
1) Apparent after other end-organ damage occurs, particularly neuropathy
ii. Post viral
1) More likely to resolve after a year
iii. Post surgical
1) Ulcer surgeries, bariatric procedures, fundoplication, lung or heart transplant
iv. Neuro disorders
1) MS, stroke, neurodegenerative disorders associated w/ autonomic
dysautonomia
v. Autoimmune
1) Anti-neural antibodies
vi. Smooth muscle damage
1) Scleroderma
2) Infiltration or amyloidosis
vii. Meds
1) Decreased motility
a) Anticholingergic drugs, CA channel blockers, dopamine agonist, narcotics
d. Presentation
i. Nausea
ii. Vomiting
iii. Abdominal fullness
iv. Distention
v. Early satiety
vi. Weight loss
vii. Abdominal pain
2. Understand the clinical presentation of chronic intestinal pseudo-obstruction
a. Poor motility
b. Diseases that affect neuronal or smooth muscle components required for small bowel
contraction
week 2 Page 72
contraction
c. Presentation
i. Slowly progressive symptoms
ii. Abdominal distension
iii. Nausea, vomiting
iv. Early satiety
v. Abdominal discomfort
vi. Diarrhea
vii. Malabsorption
viii. Weight loss and nutritional deficiencies
d. Causes
i. Neuronal loss
1) Autoimmune
2) Autonomic dysautonomia
a) Parkinsons
b) chagas
3) DM
ii. Smooth muscle myopathies
1) Scleroderma, amyloidosis, mito myopathies
iii. Meds
1) Same as above
iv. Genetic conditions
e. Additional dysmotility involving the esophagus, stomach or colon can occur
3. Learn the basic pathophysiology and clinical presentation of Hirschprungs disease
a. Congenital disorder due to failure of neural crest precursors to migrate to the developing
gut
i. Isolated neuropathic or myopathic injury to the colon
b. Caused by a number of genetic mutations
i. RET gene
ii. MEN2
c. Presentation
i. Colonic aganglionosis- lack of neurons from distal rectum to more proximal areas
1) 80% involve rectosigmoid
ii. Denervated distal colon is collapsed and obstructs-->proximal distension
iii. Urogenital abnormalities and anorectal malformations
iv. 90% of cases disease is evident at birth b/c can't pass myconium
1) Can progress to enterocolitis and sepsis if not relieved
d. Rectal balloon distension DOES NOT causes reflex inhibition of internal anal sphincter
week 2 Page 73
Lecture 20
8:12 PM
1. Define the following terms and use them in the proper context:
a. Leukoplakia
i. White plaque, fairly well delineated
ii. Benign hyperkeratosis-->severe dysplasia
iii. 1-25% malignant transformation
iv.
b. Erythroplakia
i. Red, granular area
ii. Usually harbor dysplasia
iii. >50% --> malignant transformation
iv.
c. pleomorphic adenoma
week 2 Page 74
c. pleomorphic adenoma
i. Benign mixed tumor
ii. Most common tumor of salivary gland
iii. 50 YO M or F
iv. Slow growing, asymptomatic
v. 20-45% recurrence rate--> need WIDE local excision
1) b/c of finger like projections-->psuedopodia
vi. Slight risk of malignant transformation
vii. Cartilage like matrix confers the gross glistening appearance
viii.
d. Warthin tumor
i. Second most common parotid tumor
ii. M>F; average age 60, smokers
iii. Bilateral
iv. Painless, cystic, swelling mass
v. Encapsulated, cut surface has cystic spaces oozing mucinous fluid
vi.
week 2 Page 75
2. Describe the development of squamous cell carcinoma of the oral cavity

In terms of:
a. - predisposing and risk factors
i. Leukoplakia and erythroplakia
ii. Tobacco
iii. HPV types 16 and 18 (cervical-> high risk for dysplasia)
iv. Alcohol
v. Prolonged sun exposure
b. - specific anatomic sites within the oral cavity
i. Lower lip
ii. Floor of mouth
iii. Lateral tongue
c. - clinical presentation and biologic behavior
i. presentation
1) Non-healing sores/ulcers
2) Pain
3) Earaches-->possibility of malignant tumor
4) Trouble swallowing->having trouble coordinating their swallowing
5) Lump in neck-> metastatic lymph node
ii. Behavior
1) Spread to regional lymph nodes
2) Metastases in 50-60% at original diagnosis
3) 5YSR is 40% w/out LN metastases
a) 20% when it IS present
d. - morphology (gross and microscopic)
i. gross
1) Exophytic
2) Endophytic->can be flat b/c bulk of tumor beneath surface
3) Ulcerated mass
4)
ii. Microscopic
1) Disorderly cellular arrangement
week 2 Page 76
1)
2)
3)
4)
5)
Disorderly cellular arrangement

Hyperchromasia
Incr N:C ratio
Mitotic figures
Keratin pearls
a) Specific for squamous
6) Desmosomes-intercellular ridges
7)
e. - patterns of metastasis
i. Spreads to regional (neck) nodes
3. Describe the salivary gland tumors pleomorphic adenoma and Warthin tumor
In terms of:
a. -relative frequency
i. Uncommon-> 2-4% of head and neck tumors
ii. Broadly grouped into benign, tumor-like, malignant
b. -location
i. Most (70%) in the parotid
ii. Submandibular 8%
iii. Minor salivary 22%
c. -clinical presentation and biologic behavior
i. Present
1) Slowly enlarging, painless mass
2) Parotid
a) Discrete mass
3) Submandibular
a) Diffuse enlargement of gland
4) Sublingual
a) Palpable fullness to floor of mouth
5) Facial paralysis
ii. The bigger the salivary gland, the lower the incidence of malignancy
iii. Incr in malignancy correlates with smaller glands
d. -morphology (gross and microscopic)
i. Gross
week 2 Page 77
i. Gross
1) Pleomorphic
a) Smooth, multilobular, encapsulated
2) Warthin
a) Smooth capsule
b) When cut, multiple cystic spaces
c) Contain mucus
ii. Microscopically
1) Pleomorphic
a) Presence of both epithelial and mesenchymal like elements
b) Varied appearance
i) Epithelial cells(cellular regions) and myoepithelial cells (stromal)
ii) Stromal
One. Myxoid, fibroid, or chondroid appearance
iii) Presence of psuedopodia
2) Warthin
a) Multiple papillae projection into cystic spaces
b) Papillae have double layered epithelium
i) Outer: granular oocytes w/ apical nuclei
ii) Inner: round-cuboidal eosinophilic cells
week 2 Page 78
Lecture 21
9:34 PM
a. Achalasia
i. failure of LES to relax
b. Barrett esophagus
i. Replacement of squamous epithelium by metaplastic columnar epithelium
ii. GOBLET CELLS
c. Dysphagia
i. Difficulty swallowing
d. Dysplasia
i. Abnormal epithelial maturation and cellular aberrations that may or may not precede
invasive carcinoma
e. Erosion
i. Portion of epithelium of a mucosal surface has been lost due to necrosis
ii. Has been little or no loss of underlying connective tissue
f. Esophagitis
i. Injury to the mucosa from any cause w/ subsequent inflammation
g. gastroesophageal reflux disease (GERD)
i. Inflammation of lower esophagus from regurg of acidic gastric contents
ii. Substernal pain usually due to malfunction of LES
h. hiatal hernia
i. Protrusion of part of the stomach into the chest cavity
i. intestinal metaplasia
i. Transformation (metaplasia) of epithelium to a type that bears some resemblance to
the intestine with the presence of goblet cells
j. Mallory-Weiss Syndrome
i. Longitudinal tears in the GEJ mucosa caused by violent retching/vomiting
1) Throwing up bright red blood
k. Odynophagia
i. Pain swallowing
l. Ulcer
i. Portion of epithelium AND some of connective tissue has been lost due to necrosis
2. Describe the following disorders of the esophagus:
a. Achalasia
i. Etiology
1) Inflammation of nerves in myenteric plexus
ii. Pathogenesis
1) Loss of adequate peristaltic contractions in response to swallowing liquids or
solids
iii. Presentation
1) Difficulty eating
2) Weight loss
3) Halitosis
4) Regurg of undigested food
5) Symptoms progress gradually for months to years
iv. Complications
1) Esophagus becomes dilated
2) Loss of peristalsis
week 2 Page 79
b. hiatal hernia
i. Etiology
1) Protrusion of stomach into chest cavity through opening in diaphragm
ii. Pathogenesis
1) Assoc w/ GERD
2) Twisting or torsion of the stomach
iii. Presentation
1) Sliding hiatus (most common)
2) Paraesophageal hiatus hernia
iv. Complications
1) Acute obstruction
2) Compromise blood supply to stomach
c. Mallory-Weiss Syndrome
i. Etiology
1) Violent vomiting or retching cause longitudinal tears in mucosa of GEJ
ii. Presentation
1) Upper gastrointestinal bleeding
2) Severe vomiting
iii. Complications
1) Might have through and through tear or rupture of lower esophagus and
contamination of mediastinum
d. esophagitis (reflux, infectious, eosinophilic)
i. Etiology
1) Infection
a) HSV esophagitis
i) 4 m's
One. Multi nucleation
Two. Molting
Three. Muddy chromatin
Four. Margination of the nuclei to the side
b) CMV esophagitis
i) Cytomegala cell
ii) Cmv lives in the granular tissue
iii) Owl's eyes
c) Candida esophagitis
i) White thrush plaque that wipes off
ii) Spaghetti and meatballs
2) Allergy (eosinophilic)
a) In older people
b) Family history of hyper sensitivity reaction like eczema and atopic dermitis
3) GERD
a) Replacement of squamous epithelium by metaplastic columnar
epithelium
ii. Pathogenesis
iii. Presentation
1) Eosinophilic
a) Odynophagia
b) Food doesn't go down
c) Heart burn
iv. Complications
v. Morphology
week 2 Page 80
v. Morphology
1) gross
a) Eosinophilic
i) Corrugated diffusely narrowed esophagus
ii) Ridged in esophagus
iii) Food impaction
2) Microscopic
a) Eosinophilic
i) Eosinophils, 100s of them
ii) Big pockets w/ microabscess
3. Describe the pathogenesis, morphologic features, clinical outcomes, and treatment of Barrett
esophagus and its relationship to GERD and adenocarcinoma.
a. Pathogenesis
i. Replacement of squamous epithelium by metaplastic columnar epithelium containing
goblet cells
ii. Consequence of severe reflux
b. Morphological
i. Salmon pink tongues of mucosa extending up from the GEJ and contributing to
irregular or jagged band at GE junction
c. Clinical outcomes
i. Iron deficiency
ii. Fibrosis of esophagus
iii. Slow GI bleeding
d. Treatment
e. Relationship to GERD and adenocardinoma
i. Increases risk of esophageal adenocarcinoma
ii. GERD sets the stage for metaplasia (BE)->dysplasia->carcinoma
4. Compare and contrast the two most common forms of esophageal malignancy (squamous cell
carcinoma and adenocarcinoma)
In terms of:
a. adenocarcinoma
i. Etiology and pathogenesis
1) BE is the only recognized precursor of adenocarcinoma
2) Intestinal metaplasia undergoes dysplastic changes that can progress to
carcinoma
ii. Presentation and biological behavior
1) Invade rich esophageal lymphatic network and adjacent structures early
2) Found in distal esophagus
iii. Morphology
1) Micro
a) A rise in glandular epithelium
b) Signet ring forms
c) Lumens
d) Cribriforming - Swiss cheese
e) Papillary growth
f) Mucin production
b. SCC
i. Etiology
1) Arise in stratified squamous epithelium
a) Native->skin, esophagus, mouth
b) Metaplastic->endocervix, bronchi
ii. Predisposing risk factor
week 2 Page 81
ii. Predisposing risk factor

1) Smoking and EtOH
2) Diet (nitrates, nitrosamines)
3) achalasia
iii. Presentation and biological behavior
1) Upper or middle third of esophagus
2) Black males
iv. Morphology
1) Micro
a) Disorderly cellular arrangement
b) Hyperchromasia
c) Incr N:C ratio
d) Apoptotic figures
e) Keratin
f) Keratin pearls
g) desmosomes
week 2 Page 82
Lecture 22
10:40 PM
a. coffee ground emesis
i. Gastric acid coagulates blood, turns it brown
b. gastritis:
i. Any inflammation, irritation, erosion/ulceration to the gastric mucosa
ii. Symptoms
1) Nausea, abdominal bloating, heartburn, epigastric pain
c. Acute-abrupt
i. Acute damage from any cause
ii. NSAIDs, EtOH, systemic abnormalities
d. acute erosive
i. Gastritis where there is necrosis of epithelial cells
e. Chronic
i. Lamina propia mononuclear inflammatory cell infiltrate
ii. Might have intestinal metaplasia
f. autoimmune
g. Helicobacter pylori
i. Helix shaped G(-) rod
ii. Linked to dyspepsia, chronic gastritis, peptic ulcers
h. Hematemesis
i. Vomiting blood
i. intrinsic factor
j. linitis plastica
i. Leather bottle stomach
ii. Morphological variant of diffuse, infiltrating gastric carcinoma
iii. Usually has signet ring cells
iv. Thick, rigid stomach wall
k. Melena
i. Diarrhea with black tarry stools and distinctive odor
ii. Produced by upper GI bleeding
l. peptic ulcer
i. Chronic, usually solitary, deep, penetrating ulcers that are the result of digestive
action of acid pepsin
m. stress ulcer
i. Usual acute erosions
ii. Small areas of loss of some of the mucosa
n. pernicious anemia
i. Type of megaloblastic anemia caused by loss of gastric parietal cells and inability to
absorb vitamin B12
o. signet ring cells/carcinoma
i. Malignant cell type seen predominately in stomach carcinomas
ii. Cell contain a large amount of mucin-->pushed nuclei to the periphery
2. Compare and contrast acute (erosive), autoimmune, atrophic, and chronic gastritis
3. In terms of:
a. Acute (erosive) gastritis
i. Etiology
1) Erosion from meds NSAIDS
2) bile reflux
week 2 Page 83
2) bile reflux
3) severe physical stress
4) EtOH
5) iron pill
ii. Pathogenesis
1) Compromise of mucosal defenses
2) Incr acid production
3) Decr bicarb production
4) NSAID's
5) Severe physical stress
6) Chemo
iii. Morphology
1) Neutrophil infiltrate
2) Finger like projections
3) Reactive process
iv. Clinical presentation and course
1) Erosions of gastric mucosa
b. Autoimmune gastritis
i. Etiology
1) Genetic, autosomal dominant
ii. Pathogenesis
1) Anti-parietal cell antibodies
2) Anti-intrinsic factor antibodies
3) NOT assoc w/ H. pylori
iii. Morphology
1) RBC's come out megaloblastic
1) No HCL--> 0 intrinsic factor produced
2) Hypergastrinemia
a) G cells recognize low acid content--> so become hyperplastic to try to spur
parietal cells to produce acid
c. Atrophic gastritis
i. Chronic atrophic gastritis
1) If lose too many glands, body will compensate through metaplasia
d. Chronic gastritis
i. Etiology
1) Increase in inflammatory cells in lamina propia
2) With or w/out activity (acute inflammation)
3) H.Pylori
ii. Pathogenesis
1) H.Pylori alkalinizes the pH with urease
2) Destroys the epithelium
iii. Morphology
1) Wall-to-wall mononuclear cells
2) Neutrophils->signify active inflammation
3) Awash in a sea of blue
1) Initially never seen nor felt
2) GI ulcers
3) Lymphoproliferative disease
a) MALT
4) Chronic atrophic gastritis
a) If lose too many glands, body will compensate through metaplasia
5) Can turn to dysplasia--> carcinoma
week 2 Page 84
5) Can turn to dysplasia--> carcinoma

4. Outline the role H.pylori plays in gastric pathology including its relation to chronic gastritis,
gastric carcinoma, and lymphoma.
a. Has 4 factors
i. Flagella
1) Allow it to bore down to mucosa
ii. Adhesions
1) Prevent it from being washed away
iii. Urease
1) Breaks down urea into ammonia
a) Alkalinizes pH
b) Destroys eithelium
iv. Toxins
1) Proteases and phospholipases
b.
5. Compare and contrast the pathogenesis, morphology, clinical complications, and outcomes of
stress ulcers and peptic ulcers in the stomach and duodenum.
a. Peptic
i. Pathogenesis
1) H.Pylori-->Inflammation damages the mucosa
2) exposure to gastric acid and pepsin
3) 70% are from H.Pylori in stomach
a) 99% in the duodenum
4) NSAIDS
ii. Morphology
1) Rarely have rolled borders
2) Single, sharply punched out mucosal defects 2-4cm
3) Have a clean base
4) Lack the rolled up borders of ulcers--> cancer
iii. Clinical complications
1) Pain temporarily relieved when stomach acid is neutralized
2) Gastrointestinal bleeding
week 2 Page 85
2) Gastrointestinal bleeding
3) Perforation
4) Gastric outlet obstruction
iv. Outcomes
1) Malignant transformation DOES NOT OCCUR with duodenal ulcers and is
extremely rare with gastric ulcers
b. Stress
i. Pathogenesis
1) Hyperacidity is not the problem
2) Vary with setting
3) Severe trauma
4) Chronic use of NSAIDS or corticosteroids
5) Extensive burns
6) CNS trauma
ii. Morphology
1) In stomach usually
2) More shallow, no penetration of muscularis propia
iii. Outcomes
1) Heal w/out scaring
6. Compare and contrast the typical gross and histologic features of the two morphologic types of
gastric carcinoma.
a. Intestinal type
i. Gross
1) Malignant glands resembling colonic adenocarcinoma
ii. Histological
1) Gastric surface mucus cells that have undergone intestinal metaplasia
2) Variously shaped invasive glands lined by tall columnar cell w/ ovoid nuclei
b. Diffuse infiltrative type
i. Gross
1) Sheets of single mucus-type cells
ii. Histological
1) Small glands made of polyhedral cells w. round, tame nuclei
2) Signet ring cells
7. Discuss the epidemiology and risk factors of gastric carcinoma and correlate the pathologic
findings and clinical symptoms of gastric cancer.
a. Epidemiology
i. Prevalence in US has decreased strikingly in recent decades
ii. Bad 5 ysr
iii. Intestinal:
1) Older males
iv. Diffuse
1) Younger females
b. Risk factors
i. Intestinal
1) Chronic gastritis
2) H.pylori
3) Diet
4) Partial gastrectomy
5) Pernicious anemia
ii. Diffuse
week 2 Page 86
ii. Diffuse
1) H.pylori
2) Rare germ-line mutation of E-cadherin
week 2 Page 87
Lecture 23
11:45 PM
a. Adhesion
i. Fibrous bridge between loops of bowel that create the opportunity for "internal"
hernias-->bowel obstruction ad subsequent ischemia
b. Diverticulum
i. Blind pouch leading off the GI tract
ii. Lined by mucosa that communicates with gut lumen
c. Hematochezia
i. Passage of fresh blood in or with stools
ii. Usually from lower GI bleeding
d. Hemorrhoids
i. Variceal dilations of the anal and perianal submucosal venous plexus
ii. From deterioration of connective tissue and smooth muscle that anchors anal
submucosal venous sinusoids
e. Hernia
i. Occurs when the contents of a body cavity bulge out of the area where they are
normally contained
f. Intussusception
i. Segment of intestine invaginates into adjoining intestinal lumen-->bowel obstruction
g. ischemic enteritis or colitis
i. Inflammation, ulceration, necrosis of parts or all of bowel wall
ii. Due to vascular insufficiency from:
1) Hypotension
2) Thrombosis
3) Vasculitis
4) Infection
h. Melena
i. Diarrhea with black tarry stools and a distinctive odor produced from upper GI bleding
i. Pseudomembranes
i. Colitis caused from C.diff overgrowth and toxin production
ii. Usually from antibiotic use
iii. Forms overlying exudative layer of fibrin, bacteria, and neutrophils
j. Volvulus
i. Twisting of bowel about its base of attachment
ii. Constricts venous outflow
iii. Results in bowel obstruction and ischemia
2. List the three major causes of ischemic enterocolitis and describe the gross and microscopic
levels of severity.
a. Causes
week 2 Page 88
a. Causes
i. Reduction
ii. Interruption
iii. Obstruction
iv. Acute
1) Thrombi/emboli
2) Hemorrhagic
a) Because the infarct occurs w/ occlusion of vessels in organs with collateral
circulation
v. Chronic
1) Atherosclerosis
b. Morphology
i. Mucosal infarct
1) No deeper than muscularis mucosae
2) Gross
a) Hemorrhagic
b) Edematous
c) Superficial necrosis
d) Lesions are often Patchy and segmental
e) Serosal hemorrhage and serositis are generally absent
3) Micro
a) Top-most layers affected
b) Psuedomembranes
c) May mimic IBD
ii. Mural infarct
1) Involves mucosa and submucosa
2) Gross
a) Hemorrhagic
b) Edematous
c) Superficial necrosis
d) Lesions are often Patchy and segmental
e) Serosal hemorrhage and serositis are generally absent
3) Micro
a) Top-most layers affected
b) Psuedomembranes
c) May mimic IBD
iii. Transmural infarct
1) Gross
a) Intensely congested
b) Dusky to dark purple-red
c) Blood tinged mucus or frank blood accumulates inn lumen
d) Wall becomes edematous, thickened, and rubbery
e) Involves ALL layers
f) Due to acute occlusion
g) Not reversible
h) Splenic flexure is site at greatest risk
2) Microscopic
a) Full thickness of wall
b) Possible perforation
c) Sloughing of mucosa
week 2 Page 89
3. Predict which areas of the colon will be affected most often by ischemic injury secondary to
vascular disorders.
a. Watershed zones
i. Superior and inferior mesenteric artery watershed
1) Splenic flexure
ii. Inferior mesenteric and hypogastric artery watershed
1) Rectosigmoid colon
iii. 75% of cases are left colon
b. Microvascular anatomy
4. Compare and contrast transmural ischemic injury to mural/mucosal ischemic injury
In terms of
a. Transmural ischemic injury
i. Clinical history
ii. Presentation
1) Sudden, severe ab pain and tenderness
2) Nausea, vomiting, bloody diarrhea, melatonic stool
3) May progress to shock and vascular collapse w/in hours
4) Diminished peristaltic sounds
iii. Prognosis and outcome
1) Severe-life threatening
2) Definite risk of perforation
3) Not reversible
4) Requires surgical resection of dead segment
b. Mural/Mucosal ischemic injury
i. Clinical history
ii. Presentation
1) Milder, usual gradual onset of pain/discomfort
2) May have GI bleeding
3) Unexplained ab distension
iii. Prognosis and outcome
1) Not fatal
2) If underlying cause of hypoperfusion is corrected--> lesions heal
3) If muscularis propia is spared--> completely reversible
5. Discuss diverticular disease

In terms of
a. Etiology
i. Congenital
1) Have all 3 layers of bowel wall
2) Includes muscle
ii. Acquired
1) Lack or have attenuated muscularis propia due to focal weakness in wall and
increased intraluminal P
iii. Exaggerated peristaltic contractions
1) w/ incr of intraluminal P
iv. Inherent anatomy of the colon
1) Incomplete outer longitudinal muscle layer gathered into taeniae coli and focal
defects
b. gross and microscopic morphology
i. Gross
week 2 Page 90
i. Gross
1) Multiple, small, flask like invaginations present along prominent taeniae coli
a) Often filled w/ mucin or stool
b) May bulge into serosa or into appendices epiplicae
2) Circular muscle of colon is thickened and corrugated
3) Accordion like mucosal folds
ii. Microscopic
1) No muscle layer around diverticula except for residual bundles
2) Inflammation may dissect into adjacent pericolic fat
3) Fibrotic thickening resembling colon carcinoma
c. Presentation
i. Cramping
ii. Discomfort
iii. Sensation of inability to completely poop
iv. Alternating constipation and diarrhea
d. Complications
i. Peritonitis
ii. Hemorrhage
iii. Perforation w/ resultant abscess resembling mass or forming a sinus tract
iv. Can mimic appendicits clinically
v. May resemble carcinoma radiologically
6. Identify and describe four major causes of mechanical obstruction in the small bowel.
a. Adhesion
i. Fibrous bridges develop b/w bowel loops when peritonitis heals
ii. Often caused by surgeries
b. Hernia
i. Content of a body cavity bulge out of area where they are normally contained
c. Intussusception
i. Segment of intestine invaginates into the adjoining intestinal lumen--> bowl
obstruction
ii. Intraluminal tumor
d. Volvulus
i. Compete twisting loop of intestine around its mesenteric attachment sire
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e.
7. List less frequent causes of bowel obstruction

a. Tumor
b. Inflammatory stricture (chron's)
c. Previous XRT
d. Obstructive gallstones
e. Congenital anomalies
week 2 Page 92
Lecture 24
11:45 PM
1. Define Celiac Disease (CD).

a. Immune mediated chronic sensitivity to gluten
i. In wheat, rye, and barley
b. Affects the small intestine in genetically susceptible patients
2. Understand the pathogenesis of Celiac Disease.
a. Eating gluten leads to damage to small intestine--> inability to absorb nutrients
b. Exposure of upper small bowel mucosa to gluten precipitates an immune mediated reaction
that involves both the innate and the adaptive immune responses
c. Tissue trans-glutaminase deamidates glutamine in gluten to form glutamic acid
d. Glutamic acid is recognized by antigen precipitating cells that express HLA-DQ2/DQ8
receptors for t cells
e. T cells are activated and begin to divide rapidly and secrete several immunomodlators
f. These cause damage to enterocytes and result in villous atrophy
3. Recognize the clinical manifestations of CD in children.
a. GI symptoms
i. Diarrhea
ii. Ab pain
iii. Constipation
iv. Vomiting
v. Bloating
vi. Poor weight gain or weight loss
b. Non-GI
i. Growth and puberty delay
ii. Iron deficiency anemia
iii. Fractures of thin bones
iv. Dermatitis herpetiformis
1) Itchy papular vesicular eruption
v. Dental enamel defects
4. Understand the histologic features of Celiac Disease.
a. Marsh classification
i. Normal 0
ii. Infiltrative 1
1) More blue cells
iii. Hyperplastic 2
1) Hyperplasia of microvilli
iv. Partial atrophy 3a
1) Villi starting to be flattened
v. Subtotal atrophy 3b
1) Almost completely slick
vi. Total atrophy 3c
1) Completely flat
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vii.
5. Recognize the risk factors and conditions associated with this disorder.
a. Family members w/ CD
b. Endocrine disorders
i. Type 1 DM: 4-5%
ii. Turner: 4-8
iii. Autoimmune thyroiditis 6.2
c. Down syndrome 4-19
d. Williams syndrome 8.2
e. IgA deficiency 7
6. Know how to screen for Celiac Disease and interpret the laboratory abnormalities.
a. Blood test
i. Anti-tissue transglutaminase antibody tTG
1) Highly sensitive and specific
2) Non-operator dependent
3) Cheap
4) Can monitor disease progression
5) FALSE NEGATIVES in children and IgA deficiency
ii. Anti-endomysial antibody (EMA)
1) High sensitivity and specificity
2) Can monitor disease progression
3) FALSE NEG in children and IgA deficiency
4) Operator dependent
5) expensive
iii. Total serum IgA level
1) Antibodies are against IgA, so if deficient, can't interpret it
iv. Anti-deamidated gliadin peptide (DGP)
1) Highly sensitive and specific
2) Less false pos than tTG
3) Trend compliance
4) Limited reliability in patients with lesser degree of villous atrophy
5) Less accurate <5 YO
v. Genetic screening is optional (HLA-DQ2 or DQ8)
1) Celiac is highly unlikely without these haplotypes
week 2 Page 94
1) Celiac is highly unlikely without these haplotypes

vi. Both tTG and EMA are highly accurate, but insufficient to make a diagnosis
7. Understand how to diagnose the disease.
a. Must be confirmed by finding changes in small intestine villi by biopsy
b. Testing on a gluten free-diet
i. May have normal results from antibody testing if on low gluten diet
ii. If begun a low gluten diet, resume diet for 2-12 weeks prior to drawing antibody titers
8. Learn the treatment for Celiac Disease.
a. Lifelong gluten free diet
b. Refractory
i. Persistent clinical signs and symptoms of CD and a persistently abnormal small bowel
biopsy despite adherence to a gluten free diet
c. Corticosteroids and immunosuppression
9. Know the long-term complications of CD.
a. Malabsorption/malnutrition
i. Micronutrient deficiencies
ii. Folate, iron, vit b12, Ca++
b. Osteopenia
c. Anemia
d. Hyposplenism
i. Need pneumococcal vaccine
e. GI malignancies
f. Ulcerative jejunoileitis
i. Recurrent episodes of small intestinal ulcerations and formation of strictures
g. Collagenous celiac disease
i. Large amount of scar tissue forms just under intestinal lining
10. Understand how to assess therapeutic success in pediatric CD patients.
a. Response to a gluten free diet is measured upon improvement in the patient's
manifestations of CD
b. Normalization of celiac serologies
i. A rise in antibody levels indicate non-compliance in diet
week 2 Page 95
Lecture 25
Friday, August 19, 2016
12:00 PM
1. Describe the incidence and pathophysiology of pediatric short bowel syndrome.

a. 24.5/100K live births
b. 5Y mortality rate is 25% still
c. Pathophysiology
i. Short bowel
1) Reduced absorptive mucosal surface
2) NEC
a) Most frequent indication for extensive intestinal resection
3) Intestinal artesia
a) Multiple atresias or apple peel deformity
b) Mucosal or mesenteric defect
4) Gastroschisis
a) Prenatal bowel ischemia or postnatal NEC
5) Midgut volvulus from malrotation
6) Hirschsprung's disease
a) Ganglionic SB<50cm
b) High probability permanent IF
7) Complicated meconium ileus
a) Resection required due to volvulus, necrosis, atresia
8)
week 2 Page 96
i. Intestinal fistula
1) Bypass of large areas of absorptive mucosal surface
ii. Intestinal dysmotility
iii. Mechanical obstruction
iv. Extensive small bowel mucosal disease
1) Inefficient absorption
1. Describe the medical and surgical management of pediatric short bowel syndrome
a. Explain the importance of nutrition support in short bowel syndrome
i. Initial phase
1) Period of intestinal ileus w/ high gastric output, diarrhea, and massive
electrolyte loss
a) PN is initiated
b) Give replacement solutions
c) Gastric secretions and serum gastrin levels are increased
i) Treat w. IV H2 blockers and PPI's
ii. Phase 2
1) Enteral feeding initiated
a) Continuous enteral feeding
i) Greater percentage of nutritional requirements
ii) Reduces tendency to vomit
iii) Stimulates increase in carrier protein saturation
iv) Maximized functional capacity
v) Reduce thermal energy loss
iii. Later phase
1) PN is weaned proportionally
2) Calorie requirements are 1.2-1.5 X normal
3) Oxalate restriction in persons w. colon
4) 5-6 meals per day
iv. Ideal nutrition
1) Breast milk
2) Hydrolysate formulas
a) Most proteins absorbed in form of di and tri peptides
3) Elemental formulas beneficial in reducing risk or protein intolerance
4) LCFA offer strong stimulus for adaptation--> more efficient and calorically dense
than proteins and CHO
b. Describe surgical options in pediatric short bowel syndrome
i. Re-anastomosis of ileostomy
ii. Bianchi-bowel lengthening procedure
1) 2 tubes that are smaller
iii. STEP procedure
1) Need 6 cm of dilation
iv. Small bowel / liver transplant
2. Review the pathophysiology of necrotizing enterocolitis
week 2 Page 97
2. Review the pathophysiology of necrotizing enterocolitis

a. Idiopathic coagulation necrosis and inflammation of intestine in a neonatal patient
b. Ischemia and/or reperfusion injury exacerbated by activation of proinflammatory
intracellular cascades
c. Prematurity is the single greatest risk factor for NEC
3. Define small bowel bacterial overgrowth
a. Overgrowth of more than 10^5 CFU/mL of bacteria in the proximal small bowel
b. Discuss the risk factors for bacterial overgrowth
i. Structural abnormalities and disorders that cause decreased gastric acidity
ii. Reduced peristaltic activity
iii. Mucosal damage or atrophy
c. Complications
i. Increased intestinal permeability
1) Bacteria compete for proteins and produce ammonia--> encephalopathy
2) D-lactic acidemia from gram + anaerobes
a) Altered mental status
ii. Nutritional consequences
1) Fat and CHO malabsorption
2) Vit b12 deficiency
3) Folate and vit K are normal or increased as a result of bacterial synthesis of
these vitamins
d. Summarize the symptoms of small bowel bacterial overgrowth
i. Bloating
ii. Flatulence
iii. Ab pain
iv. Diarrhea
v. Dyspepsia
vi. Weight loss
week 2 Page 98
Lecture 26
12:32 PM
1. Understand the epidemiology and growth of IBD throughout the world

a. US
i. CD=1million
ii. UC=800k
2. Understand the basic pathophysiology of IBD
a. Dysregulation of the inflammatory response to a luminal pathogen in genetically
predisposed patients
b. Key components
i. Environment
ii. Microbes
iii. Epithelia barrier
iv. Microbial sensing
v. Innate/adaptive immunity
vi. Leukocyte trafficking
vii. Pathophysiology
1) Environment, microbes, genetics, and host immune responses all play role
2) Bacteria play significant role
3) IBD patients are genetically predisposed to disease
4) Altered pattern recognition receptor function influences IBD
5) Autophagy is compromised in IBD
6) TH1,2,17,and Treg cells all have a role
7) A dysregulation of T cell balance contributes to IBD
8)
week 2 Page 99
viii.
3. Understand the characteristic features of the major subtypes of IBD

a. Ulcerative colitis
i. By location
1) Ulcerative proctitis: limited to rectum
2) Ulcerative proctosigmoiditis: limited to rectum and sigmoid colon
3) Left side UC: extends as far as splenic flexure
4) Extensive: extending more proximally than the splenic flexure but sparing the
cecum
5) Pancolitis: extends throughout the colon, including the cecum
ii. Severity
1) Mild:
a) Mild erythema
b) Decreased vascularity
c) Mild friability
2) Moderate
a) Marked erythema
b) Lack of vascular pattern
c) Friability
3) Severe
a) Spontaneous bleeding
b) Circumferential ulcerations
iii. Endoscopy
1) Mucosal involvement
a) Diffuse/continuous/superficial ulceration
2) Strictures
a) Rare
i) If present--> neoplastic
3) Rectal involvement
a) ALWAYS
iv. Histology
1) Superficial mucosal ulceration
2) Crypt abscesses
3) Chronic active inflammation
4) NO inflammation past epithelial layer
v. Diagnosis
1) Based upon clinical suspicion
week 2 Page 100
1) Based upon clinical suspicion

2) Based upon endoscopic findings and histological findings
vi. Complications
1) Iron deficiency anemia
2) Dysplasia and colorectal cancer
3) Toxic megacolon
4) Infections
a) C.diff and CMV
b. Intermediate colitis
c. Crohn's disease
i. Location
1) Mouth to stomach 6%
2) Colitis 32%
3) Ileocolitis 45%
4) Ileitis 22%
ii. 3 phenotypes
1) Inflammatory
a) Tenderness
b) Diarrhea
c) Treatable
2) Stricturing
a) Cramps
b) Distension
c) Vomiting
d) Narrowed to where almost anything gets stuck
3) Fistulizing
a) Diarrhea
b) Pain
c) Air/feces in urine
d) Types
i) Enteroenteric
ii) Enterovesical
iii) Retroperitoneal
iv) Enterocutaneous
iii. Severity
1) Discrete "punched out" apthae
2) Longitudinal ulcer
3) Irregular stellate ulcer
a) Looks like it was cut out by cookie cutter
4) Macroulcerations and psuedopolyps
a) In both CD and UC
b) Cobblestoning
iv. Endoscopy
1) Mucosal involvement
a) Focal/asymmetric/apthoid or linear ulcers or cobblestoning
2) Strictures
a) Common
3) Rectal involvement
a) Rectal sparing is common
v. Histology
1) Transmural inflammation
2) Submucosal fibrosis
3) Fissures
week 2 Page 101
3) Fissures
4) Granulomas
5) Chronic active inflammation
vi. Diagnosis
1) Based on clinical suspicion, endoscopic findings if possible, histological findings
if possible
vii. Complications
1) Malabsorption
2) Vit deficiencies
3) Phlegmons and abscesses
4) Fistulas
5) Bowel obstruction
4. Understand the main concepts in treatment of IBD
a. Goals for IBD therapy
i. Induce clinical remission
ii. Maintain remission
1) Pyramid w/ least aggressive topical 5-ASA at bottom and experimental at top
b. 5 ASA therapies
i. Effective in colon only b/c the AZO bond needs to be cleaved by intestinal bacteria
ii. Goals
1) Induce remission in MILD to MODERATE UC or chron's
a) Maintain
2) Controversial use in small bowel CD
c. Gluccocorticosteroids
i. Prednisone (oral) and solumedrol (IV)
ii. Indications
1) Induce remission for CD and UC
a) NOT FOR MAINTENANCE
d. Immunomodulators
i. 6-mercaptopurine and Azathioprine
ii. Induce remission in MODERATE to SEVERE UC
iii. Maintain remission in MODERATE to SEVERE CD
iv. Combo therapy w/ biological therapy
e. Anti-TNF therapies
i. Infliximab
ii. Adalimumab
iii. Certolizuman
iv. Screen for Hep B before this treatment
v. Indications
1) Induce remission MODERATE to SEVERE UC
2) Maintain remission MODERATE to SEVERE CD
3) Combo therapy w/ immunomodulators
f. Anti-integrin therapies
i. Blocks lymphocyte tracking to the gut and brain
ii. Indications
1) Induce remission MODERATE to SEVERE UC
2) Maintain remission MODERATE to SEVERE CD
week 2 Page 102
g.
h. Surgery
i. UC
1)
ii. CD
1)
2)
3)
Technically curative
Not curative
Disease recurrence at site of surgical resection
Repeat surgery 8-10 years
week 2 Page 103
Lecture 28
2:42 PM
1. Be able to characterize six types of diarrhea on a pathophysiologic basis and give examples of
each.
a. Secretory
i. Secretion into lumen>absorption
ii. Increase in secondary messengers (cAMP, cGMP) which activate apical membrane cl
channels
1) Ex: cholera
2) Bacterial toxin
3) Secretory tumors
4) Congenital causes
b. Osmotic
i. Abnormality of digestion/absorption-->malabsorption of osmotic substrate
1) Carbs (lactose)
ii. Ingestion of poorly absorbed substrate
1) Sorbitol
2) Polyethylene glycol
iii. Stops w/ fasting
iv. EX: lactose intolerance, excessive ingestion of fructose, sorbitol, laxatives, antacids
c. Inflammatory
i. Infectious
1) Viral,
a) Norovirus->mainly vomiting, diarrhea for little while
b) Rotavirus-->infants
c) Usually no blood
2) bacterial
a) Salmonella
b) Shigella
c) Campylobacter
d) e.coli
e) c.diff
f) Cholera
g) Stool often w/ blood or mucus
3) Parasitic
a) Giardia
b) Fat malabsorption w/ giardia
c) Crypto likes bile ducts
ii. Non-infectious
1) Inflammatory bowel disease
a) UC or CD
b) Diarrhea is usually chronic
2) Food allergy
a) IgE mediated-acute reactions w/ diarrhea occuring w/in 1-6 hours after
eating
b) Non-IgE mediated--> typically sub acute or chronic in nature
i) Involves only GI tract
d. Malabsorptive
i. Choleastatic liver disease
1) Decrease in bile flow
2) Decr enterohepatic circulation of bile acids
a) Ileal resection
week 2 Page 104
a) Ileal resection
b) Inflammation of terminal ileum
3) Exocrine pancreatic insufficiency
a) Loss of lipase and colipase -->steatorrhea
b) cystic fibrosis
c) Schwachman syndrome
d) Chronic pancreatitis
4) Celiac
a) Immune mediated reaction triggered by gluten results in villus blunting w/
significant malabsorption
5) IF
a) Decr in length of intestine secondary to intestinal resection
e. Iatrogenic
i. Involves both osmotic and secretory components
ii. Antibiotics
1) Erythromycin acts on motilin receptors in the GI tract to cause diarrhea
2) Alteration of intestinal microbiome
f. Functional
i. IBS
ii. Process causing symptoms w/out a specific disease process causing symptoms
iii. Factitious disorder
1) Laxative abuse
2. Describe the clinical and laboratory differences between secretory and osmotic diarrhea.
a. Osmolar gap
i. 290 mOsm/kg-2 X [stool Na + K]
ii. Normal <60
iii. Osmotic >100
iv. Secretory <60
b. Volume
i. Osmotic: moderate increase
ii. Secretory: large
c. Fasting
i. Osmotic: stops
ii. Secretory: continues
d. Stool Na+
i. Osmotic: normal or low <60mmol/L
ii. Secretory: elevated >60mmol/L
3. Provide a short differential of the most common infectious causes of acute diarrhea in the U.S.
a. Viral,
a) Norovirus
b) Rotavirus-->infants
c) Usually no blood
b. bacterial
a) Salmonella
b) Shigella
c) Campylobacter
d) e.coli
e) c.diff
f) Cholera
g) Stool often w/ blood or mucus
h) Preformed toxin
1) Staph
week 2 Page 105
1) Staph
i) Toxigenic organism
1) ETEC, cholera, yersinia
j) Enteroinvasive organism
1) Shigella, salmonella, EHEC
c. Parasitic
a) Giardia
b) Crypto
c) E.histolytica
d) Fat malabsorption w/ giardia
e) Crypto likes bile ducts
4. Know the key findings upon a stool analysis that are consistent with
a. i) carbohydrate
a) Carb malabsorption incr osmolarity due to colonic bacterial fermentation of
undigested sugars
b) Reducing substances are generated by colonic bacterial fermentation of unabsorbed
carbs
b. ii) fat malabsorption.
a) Rapid screen via stool steatocrit or sudan staining
b) Most accurate evaluation is a 72 hr stool collection w/ quantification of fat absorption
5. Identify four different conditions or abnormalities that may result in steatorrhea.
a. Exocrine pancreatic insufficiency
a) Cystic fibrosis
b) Shwachman syndrome
c) Chronic pancreatitis
d) Choleastatic liver disease
week 2 Page 106
Lecture 29
2:42 PM
1. Understand the main epidemiologic factors that affect colon cancer risk
a. Family history of CRC
i. Increases by 1.5-3.5 fold
b. Genetic syndromes (lynch FAP, MAP, Others)
i. High penetrance syndromes
ii. Lynch syndrome contributes 5% to CRC
c. IBD
i. Incr 3-10 fold
d. Demographic factors
i. Men > 60 YO, blacks
e. Dietary factors
i. Lower in developing countries
ii. High consumption of meat, low fiber, low calcium
f. Additional: acromegaly, smoking, alcohol, obesity
2. Learn the main pathologic and molecular pathways that lead to sporadic colon cancer
a. Molecular
i. Chromosomal instability
1) Large dissaray of chromosomal number and integrity
2) Mutation affecting APC
3) Lesions grow and turn into tubular adenomas--> display dysplasia
4) Incr expression of COX-2
5) Tumors grow and acquire KRAS mutations and transition from tubular to
villous architecture
6) Larger lesions get TP53 mutation-->carcinoma
7)
ii. Some sporadic tumors have a large # of genetic mutations due to defects in repair
iii. Microsatellite instability
1) Look at microsatellite length
2) BRAF mutations--> emergence of genomic DNA methylation
3) Number of genes are silenced
a) PTEN-tumor suppressor
week 2 Page 107
a) PTEN-tumor suppressor
b) MLH1-part of mismatch repair machinery
4)
b. Pathological
i. Precursor legion: polyps
1) Some inflammatory-psuedopolyps
ii. In CIN: adenoma
1) Precursor legions are tubular adenoma
a) Can turn into villous adenoma before being malignant
2) Lesions can be sessile (no stalk) or pedunculated (stalk of normal tissue)
3) Appear bluer than non-adematous mucosa on histology
4) Psuedostratification of nuclei
5) Nuclei more rounded and less pencil shaped
iii. In MSI pathway: Sessile serrated adenoma (SSA)
1) Precursor region is sessile serrated adenoma in colon
2) Crypts in these polyps are elongated w/ luminal saw tooth pattern
3) Have crypt branching, dilation, horizontal orientation, and crypt base
iv.
3. Understand the basic principles of tumor diagnosis and staging

a. Staging
i. Based on particular TNM combinations
1) Stage 1: small local tumor (T1, T2)
a) No lymph nodes
b) No metastasis
2) Stage 2: moderate to large local tumor (T3 and T4)
a) No lymph nodes
week 2 Page 108
a) No lymph nodes
b) No metastasis
3) Stage 3: various degrees of lymph node involvement
4) Stage 4: Metastasis, regardless of T/N stages
b. Diagnosis
i. Colonscopy
1) See and biopsy
2) Tumors appear as protruding polpoid or fungating masses
3) After obtaining biopsies, site is tattooed for future id
ii. Cross-sectional imaging
1) Staging for metastasis dependent on cross sectional imaging
2) CT or MRI of ab and pelvis
3) Chest CT
a) Patients w/ rectal cancer
iii. Tumor markers
1) CEA can be elevated in a subset of CRC
2) Not a helpful marker for early detection
3) Elevated CEA portends more advance disease and possibly poorer diagnosis
4) Normalization of CEA after resection is expected
4. Understand the main strategies for colon cancer screening and surveillance
a. Progression from a premalignant lesion to a tumor takes many years
b. Annual stool testing for occult bleeding
i. Average risk
ii. Fecal immunohistochemical testing (FIT) detection of hemoglobin
iii. FIT is replacing FOBT
c. Colonoscopy
i. See and resect
ii. Average risk individuals start screening at 50 and every 10 years after
iii. Advance lesions may be missed in 2-5% of cases
1) Operator viable
iv. Reduces risk for CRC by about 2/3
d. Annual stool DNA testing
i. Looks for tumor cells and gene mutations
ii. More expensive than FIT, but detection rate is higher
iii. Average risk
e. Other imaging
i. Can't do normal stuff
1) Flexible sigmoidoscopy
2) Double contrast barium enema DCEB
3) CT colonography CTC
5. Learn the basic approaches toward treatment of colon cancer
a. Treatment
i. Local
1) Surgical resection
2) Laproscopic operations achieve faster recovery and do NOT impact long
term cancer related outcomes
3) Generous margins (>5cm) and extensive lymph node (>12) recommended
4) Multivisceral resection:
a) Locally advanced should be resected w. attached organs
ii. Neoadjuvant chemotherapy
1) Use of radiation and chemo prior to surgery
2) Standard approach for large rectal tumors T3/T4
week 2 Page 109
2) Standard approach for large rectal tumors T3/T4

iii. Adjuvant chemo
1) Use of chemo after surgery to reduce risk of disease recurrence
2) Stage 3 node positive get most benefit
iv. Palliative chemo
1) Patients w/ metastatic, non-resectable disease
2) Lengthen median survival from less than 1 year to over 20 months
6. Learn about other major tumors in the GI tract
a. Lymphoma
i. 1-4% of GI malignancies
ii. 2/3 in the stomach
iii. Colonic lymphoma is extremely rare
b. Gastric lymphoma
i. Assoc w/ H. Pylori
ii. 2 types
1) MALT
a) Can respond to eradication of H. Pylor
b) Translocation tumors require local radiation
2) Diffuse large B cell
a) Requires chemo and resection
c. Small bowel lymphoma
i. Immunoproliferative small intestinal lymphoma
1) Alpha chain disease
2) Extranodal marginal zone lymphoma of MALT type that produces
monoclonal alpha heavy chains
3) Linked to campylobacter
4) May present as malabsorption w/ PLE
5) Antibiotic treatment may lead to regression in early stages
ii. Enteropathy associated T cell lymphoma
1) Tumor of intraepithelial lymphocytes
2) Only w/ celiac disease
3) Aggressive tumor
a) Needs combo chemo w/ autologous stem cell transplant
d. Small bowel adenocarcinoma
i. Rare
ii. Cancer genetic syndromes
iii. Tumor typically present w/ bleeding, obstruction, or both
e. Carcinoid tumors
i. Well differentiated neuroendocrine tumors
ii. Rare
iii. Rectum>small intestine> appendix> rest of colon or stomach
iv. Local disease=asymptomatic
v. Metastatic disease to the liver
1) Can cause carcinoid syndrome
f. Gastric carcinoids
i. Driven by high gastrin levels
ii. Autoimmune gastritis type 1
iii. Larger than 2 cm may become metastatic
iv. Typically multifocal, small, and indolent
g. Small bowel carcinoids
i. Most commonly from ileum
ii. Often symptomatic due to bulky local disease like lymph node and mesenteric
invasion
week 2 Page 110
invasion
iii. Can metastasize regardless of size
h. Appendical carcinoid
i. Limited to appendix unless >2cm
i. Rectal
i. Found during colonoscopy
ii. Asymptomatic and localized
j. Treatment
i. Resection
ii. Unresectable tumors treated w/ somatostatin
week 2 Page 111
Lecture 30
5:06 PM
1. Learn the clinical features and underlying mutations responsible for the main polyposis
syndromes
a. Mutations
i. FAP
1) Familial adenomatous polyposis APC gene, adenomas
2) Classical: >100 synchronous colonic adenomas
3) Attenuated: 10-100 synchronous colonic adenomas
4) Polyps evident by 10-15 YO
5) Cancer occurs by 50 YO: 100% in classical FAP
6) Variations
a) Gardner's: FAP + soft tissue tumors
b) Turcot: colon + brain cancer
c) Desmoid: benign monoclonal proliferation of myofibroblasts
i) Can be locally invasive
ii) Congenital hypertrophy of retinal pigmented epithelium (CHRPE)
One. Multiple bilateral lesions
d) Gastric polyps
i) Fundic gland polyps
7) On q arm 5q21
ii. MAP
1) MUTYH assoc polyp MUTYH gene, adenomas and SSA
2) Only recessive syndrome
a) Both arms damaged in the germ line to begin with
3) Develops adenomas and SSAs in the colon and duodenum
4) Cancer by ~50YO
5) Yearly colonoscopy from 20-25 age
6) On P arm 1p34
iii. PJS
1) Peutz Jeghers Syndrome STK11 gene, hamartomas (PJS polyps)
2) 2 or more typical hamartomatous polyps + pigmented spots
3) Polyps are hamartomas w/ arborizing infoldings and muscularis mucosae
extensions
4) Most common location: small bowel
5) Messed up mouth, finger tips, and bottoms of feet
6) Surveillance is complex
a) Frequent GI surveillance
b) Surveillance for breast and pancreas
iv. JPS
1) Juvenile polyposis syndrome SMAD4 or BMPR1A genes, hamartomas (juvenile
polyps)
2) 4 or more juvenile polyps in rectum
3) Polyps are hamartomas w/ cystic dilations of gland structures
4) Lack a smooth muscle core
5) Location: colon
6) Presentation
a) Extensive polyposis resulting in protein losing enteropathy
b) Unexplained anemia
7) Management
a) Surveillance for colon and gastric cancer starting at puberty
week 2 Page 112
a) Surveillance for colon and gastric cancer starting at puberty

v. Cowden syndrome
1) PTEN gene, hamartomas and other polyps
2) Multisystemic presentation
3) Skin and mouth have papules and tricholemmomas on face and hands
4) Macrocephaly
5) Developmental delay
6) Location: stomach then duodenum
2. Learn the clinical features and underlying mutations responsible for non-polyposis cancer
predisposition syndromes
a. Lynch syndrome
i. Mutations
1) Caused by mutations that disrupt expression of genes involved in DNA
mismatch repair
a) MLH1
b) MSH2
c) MSH6
d) PMS2
2) Code for MutS-alpha heterodimer formed by MSH2 and MSH6
a) Recognize small insertion/deletion loops
3) MUTl-alpha heterodimer formed by MLH1 and PMS2 binds to MutS-alpha
a) Part of excision of the mismatch
ii. Clinical features
1) Right sided colon cancers, large, mucinous
2) Immunohistochemistry staining
a) Loss of expression of MMR proteins
3) Elicit strong inflammatory response
4) MIS is common in these
5) Strong family history
a) Amsterdam 2 criteria
i) 3 relatives w/ lynch related tumor
ii) 2 generations involved
iii) One of the cases is under 50
6) Tumor based strategies
7) Genetic testing
b. Li-Frarmeni
i. Mutation
1) TP53
1) 80% cancer risk
2) Wide range of cancers
3) More than one malignancy is seen in affected individuals
c. Hereditary diffuse gastric center
i. Mutation
1) CHD1
2) 100 gastric cancer risk
1) Presents as multifocal signet cell diffuse gastric cancer
2) Prevention: phrophylactic gastrectomy
d. Pancreatic cancer
i. Mutations
1) Hereditary pancreatitis: PRSS1 mutation
week 2 Page 113
1) Hereditary pancreatitis: PRSS1 mutation

2) Familial atypical mole and multiple myeloma syndrome FAMMM
a) CDNK2A mutation
ii. Clinical
1) Familial breast cancer
2) BRCA2 mutations
e. Neuroendocrine tumor syndromes
i. Mutations
1) MEN1
a) Pituitary, parathyroid, pancreatic
2) MEN2
a) Medullary thyroid cancer and pheochromocytoma
b) Men2A parathyroid hyperplasia
c) MEN2B: hirschprung's
3. Understand the cancer risk and surveillance strategies for each condition
a. FAP
i. Cancer risk
1) Colon 100%
2) Duodemum 3-10%
ii. Surveilance
1) Yearly colonoscopy from puberty until total colectomy at 20
2) Lifetime watching duodenal and small bowel cancer (EGD) and thyroid
(ultrasound)
b. MAP
i. Cancer risk
1) Colon 40-60%
2) Duodenum 3-10%
ii. Surveillance
1) Yearly colonoscopy from 20-25
2) Periodic surveillance for duodenal polyps
c. PJS
i. Risk
1) Colon 39%
2) Stomach 29%
3) Small bowel 13%
4) Breast 32-54%
ii. Surveillance
1) Frequent GI
2) EGD, colonoscopy, and capsule endoscopy every 3 years starting at 18
3) Surveillance for breast and pancreas yearly and for uterine
4) Testicles yearly too
d. JPS
i. Risk
1) Colon 70%
2) Stomach 30%
ii. Surveilance
1) Colon and gastric cancer starting at puberty and every 1-3 years after
2) Periodic small bowel imaging
e. Cowden
i. Risk
1) Breast 50-80%
2) Endometrium 13-28%
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3) Thyroid 3-38%
ii. Surveillance
1) Annual breast and thyroid cancer starting at 18-25
2) Colon at 35
3) Possible renal cancer at 40
f. Lynch
i. Risk
1) Colon 80%
ii. Surveillance
1) Yearly colonoscopy starting at 20-25
2) Aspirin daily \
3) Yearly screening urine cytology
g. Li-fraumeni
i. 90% risk
h. Hereditary diffuse gastric
i. Gastric 100%
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Lecture 31
Saturday, August 20, 2016
7:19 AM
1. Understand the presentation, etiology, evaluation and treatment of upper, mid and
lower GI bleeding
a. Upper gi bleeding
i. Presentation
1) Epigastric tenderness
2) Low hemoglobin, hematocrit
3) Bright red blood vomiting
4) Epigastric pain
5) Hematemesis
6) Coffee ground emesis
7) melena
ii. Etiology
1) Mouth to ligament of treitz
2) Ulcer (gastric or duodenal)
a) h.pylori
b) NSAID
3) Esophasgitis
4) Dieulafoy's lesion
5) Mallory-weiss tear
6) GAVE
a) Watermelon stomach
7) Cameron's lesion
8) Hemobilia
9) Esophageal varices
iii. Evaluation
iv. Treatment
1) Acid blockade
a) PPI to decrease gastric acid secretion and intragastric pH
i) High low pH prevents platelet aggregation
2) IV octreotide if portal htn present
3) IV antibiotics if portal HTN present
4) Endoscopy
a) Intubate
b) Diagnostic
i) EGD, small bowel capsule endoscopy
ii) Colonoscopy
c) Theraputic
i) Heat (heater probe)
ii) Mechanical
One. Endoscopic clips
iii) Injection therapy
One. Saline
Two. Epi
iv) Variceal therapy
One. Sclerotherapy/glue
Two. banding
b. Mid GI bleeding
i. Presentation
1) Sub acute, occult
ii. Etiology
week 2 Page 116
ii. Etiology
1) Ligament of treits to ileocecal valce
2) Angioectesia
3) Blue rubber bleb nevus syndrome
4) Meckel's diverticulum
a) Rule of 2's
i) 2%
ii) 2 feet from IC valve
iii) 2 years old
5) NSAID induced erosion/ulcer
6) Neoplasm/polyp
iii. Evaluation
1) Capsule endoscopy
2) CT
3) MR
4) Tagged red blood cell scan
5) Enteroscopy
a) Capsule
b) Push
c) Push and pulll
d) spiral
iv. Treatment
c. Lower GI bleeding
i. Presentation
1) Maroon
2) BRBPR
ii. Etiology
1) Cecum to anus
2) Typically painless
3) Diverticulosis
4) Colon cancer/polyps
5) Colitis
a) Infectious
b) Ischemic
c) IBD
6) Angioectasia
7) Post-polypectomy
8) Rectal ulcer
9) Hemorrhoid
10) Fissure
11) Radiation colitis
iii. Evaluation
iv. treatment
2. Identify warning signs and red flags that might signify urgent therapy is indicated
a. Acute GI bleeding
b. Upper gi bleeding
c. Volume
d. Access
e. Shock or orthostatic hypotension
f. Decrease in hematocrit to at least 6%
g. Decrease in hgb of at least 2g/dL
3. Describe various endoscopic techniques used to identify and treat GI bleeding
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3. Describe various endoscopic techniques used to identify and treat GI bleeding

a. Endoscopy
a) Intubate
b) Diagnostic
i) EGD, small bowel capsule endoscopy
ii) Colonoscopy
c) Theraputic
i) Heat (heater probe)
ii) Mechanical
One. Endoscopic clips
iii) Injection therapy
One. Saline
Two. Epi
iv) Variceal therapy
One. Sclerotherapy/glue
Two. banding
4. Understand the physiologic differences between variceal and non-variceal GI bleeding
a. lesions that arise by virtue of portal hypertension, namely gastroesophageal varices
and portal hypertensive gastropathy
a) Treat with fluid replacement colloids or albumin
b) Veins are affected
c) esophageal or gastric varices were present
d) signs of acute bleeding or recent bleeding (fibrin clot) were detected
b. non-vericeal includes lesions seen in the general population (peptic ulcer, erosive
gastritis, reflux esophagitis, MalloryWeiss syndrome, tumors, etc.)
week 2 Page 118
Lecture 32
Saturday, August 20, 2016
8:00 AM
1. Define acute abdomen and peritonitis

a. Acute abdomen
i. Pain < 1 week
ii. Typically seen by PCP or ER
iii. Presentation=need for prompt diagnosis
iv. Does NOT imply need for surgical intervention
b. Peritonitis
i. Inflammation of the peritoneum
ii. Clinical diagnosis
1) Physical exam
iii. Often implies need for surgical intervention BUT not always
2. Summarize the pathophysiology of acute abdominal pain
a. Anatomy
i. Sensory neuroreceptors in ab organs
1) w/in mucosa and muscularis of hollow organs
2) On serosal structures like peritoneum and w/in mesentery
ii. Sensory neuroreceptor involved in regulation of
1) Secretion
2) Motility
3) Blood flow
b. Stimulants of pain
i. STRETCH is the principal stimulant of pain
1) Cutting, tearing, or crushing viscera does NOT result in pain
c. Types
i. Visceral
1) Neuroreceptors in hollow or solid organs
2) Crampy, achy, diffuse, colicky
3) Poorly localized
4) Classic presentation of someone that can NOT stay still
5) Ex: kidney stones
ii. Parietal
1) Involves parietal peritoneum
2) Sharp pain that is well localized
3) Causes tenderness and guarding
a) Progress to rigidity and rebound
4) Ex: perforated gastric ulcer
5) Classic presentation: motionless in bed, knees bent
iii. Referred
1) Overlap of fibers from other locations-->produce SYMPTOMS not signs
3. Be able to describe the approach to a patient with acute abdominal pain - Discuss the
components of a complete history and physical exam
a. History
i. OLD CAARS
1) Onset
a) Acute--> can mean perforation or rupture
b) Gradual-->inflammatory/infectious process
2) Location
week 2 Page 119
2) Location
a) Conditions tend to occur in specific abdominal quadrants
3) Duration
a) 1 week of severe pain unlikely to represent ruptured AAA
4) Character
a) Dull, sharp, intermittent, constant, worst in life, burning?
b) Colicky pain-->obstructive process
c) Continuous pain--> underlying ischemia or inflammation
5) Alleviat/aggrevating factors
a) Peritonitis->relief when lying still with their knees bent
b) Kidney stones-> constantly shifting and adjusting to find more
comfortable position
6) Associated symptoms
a) Chronology of nausea is important
b) Vomiting that starts after onset of ab pain is more likely to be a surgical
diagnosis
7) Radiation
a) Patients w/ pancreatitis often have abdominal pain radiating to their back
8) Severity
a) Pain out of portion to exam can be a symptom of mesenteric ischemia
ii. Past medical history
1) Surgical
a) Intestinal obstruction w/ previous ab surgery likely adhesions
i) No previous surgery--> tumor
b. Physical exam
i. Palpation
1) Rebound tenderness
2) Voluntary guarding
3) Involuntary guarding
a) Rigid abdomen as the muscles guard involuntary
4. Develop a differential diagnoses for patients presenting with acute abdominal pain
a. Cullen's sign
1) Bluish periumbilical discoloration
a) Retroperitoneal hemorrhage
b. Kehr's sign
1) Severe left shoulder pain
a) Splenic rupture
b) Ectopic pregnancy rupture
c. McBurney's sign
1) Tenderness located 2/3 distance from anterior iliac spine to umbilicus on right side
a) Appendicitis
d. Murphy's sign
1) Abrupt interruption of inspiration on palpation of right upper quadrant
a) Acute cholecystitis
e. Iliopsoas sign
1) Hyperextension of right hip causing pain
a) Appendicitis
f. Obturator's sign
1) Internal rotation of flexed right hip causing ab pain
a) Appendicitis
g. Grey-turner's sign
1) Discoloration of the flank
a) Retroperitoneal hemorrhage
h. Chandelier sign
week 2 Page 120
h. Chandelier sign
1) Manipulation of cervix causes patient to lift buttocks off table
a) Pelvic inflammatory disease
i. Rovsing's sign
1) Right lower quadrant pain w/ palpation of the left lower quadrant
a) appendicitis
5. Explain the rationale for diagnostic modalities in the evaluation of abdominal pain.
a. Ab x-ray
1) Greatest utility in diagnosis of perforated viscus by detection of pneumoperitoneum
a) Only seen in 30-50% of bowel perforations
b) Best series is an upright chest x-ray
c) Upright ab x-ray and supine ab x-ray
b. Ultrasound
1) Lower cost
2) No radiation
3) Choice
a) Hepatobiliary pathology
a) 90% sensitive for gallstone
b) Obstetrical and/or gynecologic pathology
a) Ectopic pregnancy
c. CT
1) Sensitivity for most acute abdomen
d. MRI
1) Lack of universal availability
2) Less ideal for practical daily use
6. Identify specific considerations in special patient populations what should you consider in the
extremes of age, immunocompromised, pregnant women, and the morbidly obese
a. Elderly
1) Do not have typical symptoms and signs
a) Lack of febrile response and leukocytosis--> age dependent decline in immune
function
b) Little to no pain compared to expected->delay in perception
2) Atypical presentation
a) Comorbidities alter presentation: diabetes
b) Meds
c) Memory or neurologic deficits
3) High incidence of complications, morbidity and mortality
a) Incidence of acute appendicitis is lower compared to younger patients
a) Rate of perforation is significantly higher-->up go 70%
b. Infants and children
1) Diagnosis difficult in preverbal or uncooperative children
2) Etiologies from trivial to potentially life-threatening w/ little to no difference in their
presentation
a) Higher rates of misdiagnosis and complications
b) Perforation rate in appendicitis in children: 30-65%
c. Immunocompromised
1) Delayed onset of fever & other typical symptoms
2) Experience less pain
3) Underwhelming leukocytosis
4) Diagnosis often delayed until development of overwhelming sepsis, multisystem
organ failure and death
5) Should have a high index of suspicion for acute ab process
week 2 Page 121
5) Should have a high index of suspicion for acute ab process

a) Even if symptoms or physical exam underwhelming
b) Need prompt diagnostic imaging
c) Early operative intervention
d. Pregnant
1) Delay in diagnosis or intervention
a) Increased morbidity and mortality
2) Delays in presentation, diagnosis, and treatment because presenting signs and
symptoms of acute ab pain mimic those normally observed in pregnancy
3) Vital signs and lab findings difficult to interpret b/c of physiologic changes in
pregnancy
a) Physiologic anemia
b) Mild leukocytosis
c) 10-15 bpm incr in pulse rate
d) Relative hypotension
e. Gravid female
1) Upward displacement of gravid uterus and subsequent intra-ab organs
2) Classic example in acute appendicitis->tenderness palpated in RUQ
f. Morbidly obese
1) Challenging to diagnose an acute abdomen in obese
a) Subtle changes in vital signs, atypical symptoms, and underwhelming physical
exam findings
a) Tachycardia and hypoxia most common findings
b) Ab exam is normal or benign
b) Obese body may prevent ability to obtain some imaging studies or result in poor
quality studies
2) Presentation of peritonitis is a late finding
3) Obese patients at high risk for sepsis, multi-organ failure, and death
week 2 Page 122
Lecture 33
10:28 AM
1. Understand the vocab associated w/ operations and procedures on the GI tract

a. prefix
i. Colo-/colono- Colon
ii. Entero- small intestine
1) Duodeno- duodenum
2) Jejuno- jejunum
3) Ileo- ileum
iii. Esophago- esophagus
iv. Gastro- stomach
v. Pancreatico- pancreas
vi. Hepato- liver
vii. Choledocho- common bile duct
viii. Cholangio- bile duct
ix. Recto- rectum
x. Laparo-/celio- abdomen
xi. Ano- anus
b. suffix
i. -centesis -surgical puncture or drainage
ii. -rrhapy -to repair or strengthen
iii. -desis -fusion of 2 structures
iv. -ectomy -surgical remocal
v. -oscopy -to view w/ a scope
vi. -otomy -incise surgically
vii. -pexy -to fix or secure
viii. -plasty -to modify or reshape
ix. -graphy -to view, usually w/ x-rays
2. Understand various surgical approaches to abdominal operations
a. Endoscopic
b. Open
i. Greater access
ii. Increased wound complications
iii. Tactile feedback
iv. Multi-quadrant surgery
v. Shorter OR time
c. Laproscopic
i. Hand assisted
ii. Robotic-assisted
iii. Traditional laproscopy
iv. Limited field
v. Less pain, faster recovery
vi. Instrumentation limitations
vii. Magnified view
viii. Longer OR times
1) Absolute contraindications
a) Surgeon's lack of skills
b) Inadequately equipped OR
c) Compromised cardiopulmonary status
d) Markedly increased intracranial pressure
week 2 Page 123
d) Markedly increased intracranial pressure

e) Retinal detachment
2) Relative contraindications
a) Pregnancy
b) Previous surgery
c) Large mass
d) obstruction
3. Describe the categories of indications for surgical operations
a. Timing: emergent or elective
b. Curative or therapeutic
c. Diagnostic
d. Therapeutic
4. Understand how disease process, indications for surgery and anatomy dictate the conduct of
surgical operations
a. Bariatric
i. Restriction
1) Limit caloric intake by reducing capacity
ii. Malabsorption
1) Decrease effectiveness of nutrient absorption by shortening the length of
the functional small intestine
2) Lots of weight loss
b. Roux en Y gastric Bypass
i. Combo of restriction and malabsorption
1) Gut hormone mod contributes to improved weight loss
2) Rhoux limb length allows for the ability to increase malabsorptive properties
of operation
c. Sleeve Gastrectomy
i. Restrictive procedure
1) Less operative risk
2) Decreased hormonal changes--> promotes less hunger
3) Not assoc w/ dumping syndrome
d. Laparoscopic Adjustable Band
i. Restrictive
1) Minimal operative risk
2) Compartmentalizes the upper stomach by placing a tight, adjustable band
around entrance to stomach
3) reversible
e. PUD
i. H.pylori eradication
ii. NSAID cessation
iii. Smoking cessation
iv. PPI
v. Repeat endoscopy
vi. Complications
1) Hemorrhage
2) Perforation
3) Obstruction
f. Gastrectomy, Types and Complications
i. Types
1) Total
2) Subtotal
3) Distal
week 2 Page 124
3) Distal
4) Partial
ii. Complications
iii. leak
iv. Persistent weight loss
v. Dumping syndrome
1) Rapid entry of hyperosmolar chyme into the small intestines causing release
of vasoactive peptides
2) Early-hyperosmolar
3) Late-hypoglycemia
vi. Vit deficiencies
g. Gastric Cancer
h. HPB
i. Painless jaundice=malignancy until proven otherwise
i. Pancreaticoduodenecomy
i. Early
1) Bleeding
ii. Late
1) Pancreatic fistula
2) Delayed gastric emptying
3) Psuedo aneurysm
iii. Sequelae
1) Dumping
2) diabetes
week 2 Page 125
Lecture 34
11:51 AM
1. Briefly review normal Liver Morphology

a. Divided into 3 zones
i. 1 around portal tract
ii. 3 around ventral vein
iii. 2 in between zones 1 & 2
iv. Hepatocytes in these zones have differing enzyme expression profiles
1) Interface w/ different nutrient and oxygen profiles
2) Differentially susceptible to injury
b. Lobule
i. Multiple portal tracts surrounding a central vein
c. Acinus
i. Portal tract and adjacent central vein
ii. Enzyme expression, oxygenation, and nutrient and metabolite gradients
d. Blood from portal veins and hepatic arteries mix in the sinusoids
i. Travel countercurrent to the flow of bile in the canniculus
e. Normal sinusoidal endothelium is fenestrated
i. numerous microvilli
f. Space of disse has type IV collegen
i. Stellate cells here function as storage cells
g. Intestinal collagens limited to the portal tracts
2. Describe morphologic patterns of hepatic Injury
a. Ballooning and feathery or foamy degeneration of hepatocytes
i. 2 forms
1) Ballooning degeneration common to liver disease
a) Fatty liver
2) Feathery or foamy degeneration->cholestasis
b. Lipid accumulation in hepatocytes
i. Steatosis->can be macrovesicular w/ large droplet of fat filling hepatocyte
1) Displace the nucleus
c. Lipofuscin pigment and metals (iron and copper)
i. Accumulation in hepatocytes, kupfer cells, endothelial cells, and bile duct epithelial
cells
ii. Prussian blue->hemosiderin
1) iron
iii. Rhoadanine-strain for copper
d. Bile
i. Cholestasis
1) Bile accumulates in hepatocytes-->feathery degeneration
a) Bile canalicular plugging
b) Kupffer cell clogging
c) Metaplastic ductules
2) Loss of secretion of bile into canaliculi
e. Apoptotic hepatocytes
i. Rate of apoptosis can be incr in liver disease
ii. Shrunken, hypereosinophilic cells
f. Necrosis
i. Cell loss
ii. Random in parenchyma, zonal, bridging, or submassive
week 3 Page 126
ii. Random in parenchyma, zonal, bridging, or submassive

g. Inflammation
i. Hepatitis
1) Mononuclear
2) Acute
3) "mixed"
4) Granulomatous
h. Bile ductular reaction
i. Oval cells in canals of Hering serve as a reserve cell compartment for liver cell
regeneration and for metaplastic ductular reaction
ii. Metaplastic ductules or neo-ductules proliferate in response to both acute and
chronic liver injury
i. Fibrosis
i. Portal, pericellular anywhere in the acinus
ii. Bridging w/ eventual development of cirrhosis
j. Ductopenia
i. Loss of small or interlobular bile duct
1) Seen in primary biliary cirrhosis
a) Chronic rejection of liver transplant allografts
2) Normally bile duct should be paired up w/ hepatic artery
3. Review of Laboratory Liver Function Tests
a. Bilirubin
i. Jaundice when bilirubin exceeds 2-3 mg/dl
ii. Total bilirubin measures both conjugated and unconjugated fractions of bilirubin
1) Direct=conjugated portion
a) Eliminated in kidneys
2) Indirect=Total bilirubin-direct fraction
iii. Most diseases=rise in both total and direct
iv. Gilbert's syndrome
1) Need to measure both total and direct
b. Aspartate aminotransferase (AST) and aminotransferase (ALT)
i. Cystolic and mito enzymes that are released into circulation w/ hepato damage
c. Alkaline phosphatease and gamma-glutamyl transferase (GGT)
i. Canilular enzymes elevated w/ biliary tract disease
ii. Alkaline phosphate is present in liver, bone, placenta, and intestine
iii. GGT production may be induced by alcohol
4. Describe Hereditary Hyperbilirubinemias
a. Dubin-Johnson and Rotor syndrome
i. Hereditary
ii. Conjugated hyperbilirubinemia
b. Craig-Najjar and Gilbert Syndromes
i. Present w/ unconjugated hyperbilirubinemia
1) Gilbert->hereditary hyperbilirubinemia
a) b/c of decr hepatocyte, bilirubin UDP-glucuronyl transferase activity
b) Mild fluctuating
c) Benign course
5. Describe the microscopic features of cirrhosis
a. Diffuse disruption of liver architecture
b. Extensive bridging fibrosis
c. Regenerative hepatic parenchymal nodules
d. Result of ongoing cellular damage resulting in fibrosis or scar formation and repeated
week 3 Page 127
d. Result of ongoing cellular damage resulting in fibrosis or scar formation and repeated
attempts at cellular regeneration
e. Loss of microvilli on sinusoidal surface of hepatocytes
f. Conversion of sinusoids into vascular channels that have lost normal solute exchange
mechanisms
6. Describe the pathology of Viral Hepatitis
a. Viruses
i. Epstein-Barr virus
ii. CMV
iii. Herpes
iv. Yellow fever
v. Rubella
vi. Adenovirus
vii. Enterovirus
b. Outcomes
i. Asymptomatic infection
ii. Symptomatic acute infection
1) Anicteric and icteric disease
a) Portal in location
b) Inflammation
c) Kupffer cell activation and proliferation
d) Cellular degeneration
e) +- cholestasis
f) Hepatocyte loss
g) Lobular disarray
h) Cellular regeneration
2) Fulminant hepatitis
a) Large areas of necrosis w/ parenchymal collapse
iii. Resolution and recovery
iv. Chronic hepatitis w/ or w/out progressive liver disease
1) Progressive fibrosis w/ fibrous expansion of portal tracts
2) Pericellular fibrosis in areas of interface hepatitis
c. Chronic viral hepatitis
i. Symptomatic, biochemical, and/or serologic evidence of continued or relapsing
disease for 6 months or more
ii. Primary determinant of disease progression is etiologic agent
week 3 Page 128
Lecture 35
1:42 PM
1. Define and identify determinants of acute and chronic liver disease

a. Determinants of whether liver disease is only acute or becomes chronic include both
host and disease factors
i. Host
1) Immune response to viruses
a) Hep B or Hep c
2) Idiosyncratic responses to viruses (pharmacogenetics)
3) Autoimmunity
a) Primary biliary cholangitis
b) Primary sclerosing cholangitis
c) Autoimmune hepatitis (immunogenetics)
4) Genetics
a) Hemochromatosis
b) Wilson disease
c) Alpha-1 anti-trypsin deficiency
d) ALD and non-alcoholic fatty liver disease
ii. Disease
1) Hep A-acute
2) Hep C-chroinic
iii. Co-factors
1) Alcohol and obesity can be promoting factors for progression of chronic
liver diseases
b. Acute=abnormalities < 6 months
c. Chronic=abnormalities for > 6 months or evidence of fibrosis from chronic inflammation
d. Always acute and resolve (unless fatal)
i. Hep A, ischemic liver damage, treatable microbial diseases, benign mechanical
obstruction
e. Acute or chronic
i. HBV, HCV, HDV, HEV
ii. Recognized drug and toxin injury
f. Always chronic
i. Genetic and autoimmune liver disease
g. Chronic but resolve w/ abstinence
i. Fatty liver
2. Given abnormal liver tests, identify the pattern and the 5 most likely etiologies in the U.S.
a. Aminotransferases>alkaline phosphatase=hepatitis
i. AST and ALT>500 = HepatitiC
1) Acute viral hepatitis
a) HAV, HEV, HBV, HCV, and HDV
2) Ischemia
a) Hypotension
3) Drugs
a) Acetaminophen
4) Acute obstruction of common bile duct
5) Autoimmune hepatitis
ii. AST and ALT abnormal but <500
b. Alkaline phosphatase fold elevation>aminotransferase fold elevation
week 3 Page 129
b. Alkaline phosphatase fold elevation>aminotransferase fold elevation

i. Cholestasis
c. Mixed
i. Neither hepatitis nor cholestasis
3. Given the clinical presentation of any patient with hepatitis and aminotransferases > 500
U/L, be able to make the diagnosis when one of the following etiologies is most likely:
a. o viral hepatitis;
i. NO Hypotension or heart failure, NO heat stroke, NO cocaine
ii. Positive:
1) IgM anti-HAV
2) IgM anti-Hbcore
3) Anti-HCV new
b. o drug-induced hepatitis;
ii. YES: New drug or old drug
iii. YES Hepatotoxic or Compatible pattern
iv. Viral Hepatitis is excluded
c. o autoimmune liver disease;
ii. NEGATIVE IgM anti-HAV, IgM anti-Hbcore, anti-HCV
iii. On sonogram
1) Positive antibodies
d. o ischemia;
i. YES: Hypotension or heart failure, NO heat stroke, NO cocaine
ii. POSITIVE lactate dehydrogenase very elevated
e. o obstruction
ii. NEGATIVE IgM anti-HAV, IgM anti-Hbcore, anti-HCV
iii. On sonogram
1) Pain and tenderness
2) Visible gallstones
3) Visible obstruction
f. Algorithm
i. Is acetaminophen contributing to the clinical presentation?
1) Commence N-acetylcysteine no matter what
ii. Is hepatic injury immune related?
1) Lactate dehydrogenase is NOT elevated when injury is immune-mediated
iii. Ask specific questions to one or other potential diagnosis
week 3 Page 130
Lecture 36
2:28 PM
1. For a given hepatitis virus, identify

a. a. Mode of transmission and identify related host and viral factors.
i. HAV
1) Transmission
a) Food and water
b) Contact w/ another person
2) Host factors
a) Household contacts
i) Asymptomatic children
b) Sexual contacts
c) No chronic disease
3) Viral factors
a) Outer coat doesn't contain any lipid components
b) Detergents do NOT destroy infectivity
c) RNA genome w/ 3 major domains
ii. HEV
1) Transmission
a) Contaminated water
b) Food
c) Percutaneous transmission is rare
2) Host factors
a) No sexual contacts
b) No chronic disease
3) Viral factors
a) Not lipid enveloped
b) RNA genome
b. b. Distinguishing virion and genome properties, particularly related to above key features.
i. HAV
1) Not lipid enveloped
2) RNA genome
a) 3 major domains
ii. HEV
1) Not lipid enveloped
2) RNA genome
2. Identify major clinical findings (symptoms, signs and laboratory test results) for patients with
acute viral hepatitis and use serologic test results to identify type of viral hepatitis present.
a. Symptomatic disease
i. Jaundice in older children and adults w/ acute HAV
1) Older men w. HEV
b. HAV Acute
i. Positive
1) IgM HAV ab
2) Total HAV Ab
c. HEV acute
i. Positive
1) IgM HEV Ab
2) IgG HEV Ab
week 3 Page 131
2) IgG HEV Ab
3. In any given patient without clinical findings of viral hepatitis, use serologic test results to:
a. a. Identify those previously exposed to viral hepatitis.
i. HAV
1) Negative IgM
2) Positive IgG
ii. HEV
1) Negative IgM
2) Positive IgG
b. b. Identify those at risk for viral hepatitis.
i. HAV
1) Negative
a) IgM Ab
b) Total HAV Ab (IgG)
ii. HEV
1) Negative
a) IgM HEV Ab
b) IgG HEV Ab
4. List the threshold for alcoholic liver disease for men and women and give examples of this
threshold in terms of beer, wine, and 80-proof liquor.
a. Women
i. 10g EtOH/day
1) 1 glass of wine
2) ~1 beer a day
3) <1oz of liquor
b. Men
i. 20g EtOH/day
1) ~2 glasses of wine
2) ~2 beers
3) ~2 oz liquor
5. Define chronic liver disease and describe the sequelae. List the five most common etiologies
(broad categories) of chronic liver disease and be able to diagnose and manage alcoholic liver
disease.
a. Chronic liver disease
i. Process of progressive destruction and regeneration of the liver parenchyma-->
leading to fibrosis and cirrhosis
b. Causes
i. Viral
ii. Toxic and drugs
iii. Metabolic
iv. Autoimmune
v. Other
c. Diagnose ALD
i. Diagnosis of exclusion
1) Based off alcohol history and liver biopsy confirmation
2) Exclude
a) Hemochromatosis
b) Wilson disease
c) Chronic viral liver
d) Autoimmune liver disease
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d) Autoimmune liver disease

e) Drug-induced liver disease
ii. Normal Alpha 1 T w/ bilirubin of 12--> ALD
d. Manage ALD
i. Abstinence
ii. Improve nutritional support
iii. Corticosteroids for the depressed
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Lecture 38
5:09 PM
1. Understand the definitions for cholestasis and jaundice; and describe the differences as well as
the inter-relationship between each term.
a. Cholestasis
i. A decrease in bile flow
ii. May be result of intrinsic liver or biliary disease, genetic disease, or bile duct
obstruction
iii. Assoc. w/ hyperbilirubinemia
iv. Assoc. w/ elevation of "biliary" obstructive liver enzymes
1) Bilirubin
2) GGT
3) Alkaline phosphatase
v. Assoc. w/ elevations of serum bile acids and may be assoc. w/ elevation of serum
cholesterol
b. Jaundice
i. Yellow discoloration of the skin, sclera, and mucus membranes due to elevation of
bilirubin
ii. Degree of discoloration is directly related to amount of bilirubin deposition
1) 4-5mg/dl in adults and 3mg/dl in children
iii. An elevated bilirubin should be fractioned into unconjugated or conjugated bilirubin
c. Differences
i. Cholestasis describes a process
ii. Jaundice is a condition caused by cholestasis
2. Describe the clinical manifestations of cholestatic liver disease.
a. Incr in blood levels of main constituents of bile
i. Bile acids
ii. Bilirubin
iii. Cholesterol
b. Symptoms
i. Jaundice
ii. Pruritis
1) Maybe due to elevation of serum bile acids acting on central or peripheral nerve
receptors
iii. Xanthomas
1) Elevation of serum cholesterol
iv. Fat malabsorption
1) Loss of intestinal bile acids--> inability to form miscelles
2) Fat soluble vitamin deficieny
a) Night blindness (vit A)
b) Rickett's (vit D)
c) Neurological defects, ataxia (Vit E)
d) Coagulopathy, bleeding (vit K)
3. Recognize the laboratory abnormalities that may signify the presence of cholestatic liver
disease.
a. Liver enzyme pattern: "obstructive pattern"
i. Incr GGT
ii. Incr Alk Phos
iii. Icr Bili
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iii. Icr Bili

b. Incr in serum bile acids and serum cholesterol
4. Be able to outline a pathway for the evaluation of a patient presenting with jaundice.
a. History
i. Jaundice in infancy is normal
1) In older infant, child, and adult-->always pathologic
ii. Direct (conjugated) hyperbilirubinemia is always abnormal
iii. History of drug or medicine exposure
iv. Associated symptoms
1) Fever
2) RUQ pain
b. Physical
i. Jaundice
1) Excessive carrot eating can cause yellow discoloration of skin
ii. Xanthomas
iii. Spider angioma
iv. Bruising
v. Hepatomegaly
vi. Splenomegaly
vii. Ascites
viii. Collateral veins
a. Tests
i. Blood work
1) Liver enzymes (LFTs)
a) Aminotransferases (AST, ALT)
b) Cholestatic or obstructive enzymes:
i) Bilirubin (total and direct)
ii) GGT
iii) Alkaline phosphatase
2) Test of liver synthetic function
a) Prothrombin time (PT)
b) Albumin
3) NH3, glucose
a) Liver function
ii. Ultrasound/imaging
1) Evaluate liver, gall bladder, bile ducts, vascular structure
a) Detect obstruction of bile duct, gall stones, liver mass
2) Doppler-evaluate blood flow in portal vein
a) Hepatopedal=normal (toward liver)
b) Hepatofugal=abnormal (away from liver)
i) Signifies portal hypertension or thrombus in portal vein
3) MRCP
a) Magnetic resonance cholangiopancreatography
4) ERCP
a) Endoscopic retrograde cholangiopancreatography
iii. Liver biopsy
1) Cholestatic liver disease
a) Bile duct injury
b) Portal inflammation
c) Bile duct plugs
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c) Bile duct plugs

d) Cholestasis
b. Genetic testing
i. Microarray sequencing
ii. Most common forms of cholestasis
5. Understand the pathway involved in bilirubin metabolism and describe 3 different genetic
disorders of bilirubin metabolism.
a. Metabolism of bilirubin
i. Bilirubin is the end result of breakdown of heme
1) Heme oxygenase converts heme to biliverdin
2) Biliverdin reductase changes biliverdin to bilirubin
ii. Bilirubin is NOT water soluble-->bound to albumin w/in bloodstream
iii. Conjugated w/ glucuronides by UDP-glucuronyl transferase
iv. Conjugated bilirubin is water soluble->transported from canalicular hepatocyte
membrane by MRP2
v. Conjugated bilirubin is excreted into the lumen of small intestine
1) Some is changed into urobilinogen and excreted into feces by bacteria
2) Some resorbed into ileum by enterohepatic circulation
b. Genetic disorders of bilirubin metabolism
i. Gilbert's
1) Inherited decr in UDP glucuronyl transferase activity
2) Heterogeneous disorders
a) 50% decr in hepatic bilirubin UDP glucuronyl transferase (UGT1A1) activity
3) Affect 8% of pop
4) Mild jaundice may occur during fasting/dehydration/stress
5) Serum total bilirubin 1-4mg/dl
6) Benign condition
ii. Crigler-Jajjar syndrome
1) Glucuronidation defect resulting in severe unconjugated hyperbilirubinemia
2) Occurs in neonatal period w/ high risk of kernicterus
3) Autosomal recessive
4) Genetic defect:UGT1A1
a) Absent BUGT activity (Cn type 1)
b) Decr BUGT activity (CN type 2)
5) Total bilirubin 20-45
6) Response to phenobarb
a) Type 1=No
b) Type 2=Yes
7) Treatment
a) Exchange transfusion
b) Phototherapy (life long)
c) Liver transplant
8) Kernicterus
a) Unconjugated bilirubin can cross immature blood brain barrier
i) Brain injury, developmental delay, mental retardation, death
iii. Dubin-Johnson syndrome
1) Defect of hepatic excretion of bilirubin and non-bile salt organic ions at the
apical canalicular membrane by the ABC transport system (MRP2/ABC2)
2) Autosomal recessive
3) Elevation of both conjugated and unconjugated serum bilirubin fractions
a) Total bilirubin: 1.5-6mg/dl >50% conjugated
4) Brown-black pigmentation of liver
5) Usually diagnosed after puberty, though may occur in neonates
week 3 Page 136
5) Usually diagnosed after puberty, though may occur in neonates

6) Jaundice is lifelong
7) No specific therapy is needed
week 3 Page 137
Lecture 39
11:31 AM
1. Understand some basic mechanisms of cellular injury within the hepatocyte

a. Drug-induced liver injury (DILI)
i. Liver damage caused by over-the counter and prescription drugs
b. Acute liver failure (ALF)
i. Severe, rapid onset hepatocyte dysfunction results in hepatic encephalopathy and
coagulopathy
ii. ALI
1) INR>2.0 w/out HE
c. Hepatocyte injury
i. Loss of cell integrity results in a leak of liver contents into circulation
ii. Acetaminophen (APAP) is most common cause of severe injury
iii. Drugs are small, fat soluble chems that pass intestinal mucosal border and converted
into water-soluble forms that can be distributed
iv. Drug metabolism results in highly reactive intermediate compounds
1) Can disrupt intercellular function-->display of immunogens on cell surface
a) Pulls response of cytolytic T cells->damage hepatocytes that display these
immunogens
v. Idiosyncratic drugs can also cause injury w/out immune system
1) Can disable transport proteins at canalicular membrane
2) Can extract toxic metabolites into bile
3) Alter mito DNA
a) Disruption of fatty-acid oxidation and energy production
i) Triggers oxidative stress and accumulation of triglycerides
vi. APAP
1) Through cytochrome P450, liver metabolizes APAP to unstable NAPQI
a) NAPQI requires sufhydral donor group to be detoxified
i) w/ glutathione, NAPQI is converted to mecrapturic acid
ii) w/ overdose glutathione is depleted--> NAPQI forms covalent
bonds w/ other intracellular proteins
One. Disrupt hepatocytes protein structure and functions-->cell
lysis and release of these contents
vii. Cytochrome P450 system creates unstable intermediates
1) APAP yields direct injury/necrosis
viii. Other drugs, indirect->haptenization, traffic to cell surface
1) Immune response ensues
2. Recognize the biochemical patterns of injury associated with each type of drug/toxin
a. Direct APAP injury
i. Hepatocyte necrosis
ii. Predictable and dose dependent
iii. Occurs uniformly across a wide variety of species
b. Idiosyncratic toxicity
i. Immunological response to drug-protein adducts or haptens involving apoptosis
ii. Vary greatly in severity and timing of reaction
iii. Unrelated to dosage given
1) Usually over 100mg
iv. Drugs w/ a relative low potency will have more off-target effects and more likely to
week 3 Page 138
iv. Drugs w/ a relative low potency will have more off-target effects and more likely to
cause injury to skin, liver, or GI tract
3. Understand the degrees of severity of injury associated with drug-induced liver injury
a. Asymptomatic elevation of liver function
b. ALF
c. Common, nonspecific symptoms
i. Anorexia, nausea, ab pain, vomiting, fatigue
ii. Hypersensitivity reaction
1) Rash, fever, eosinophilia, joint pain, lymphadenopathy
iii. Cholestatic injury
1) High bilirubin levels w/ absence of aminotransferases elevations
d. Direct toxins (APAP)
i. Hyperacute
1) Onset of injury is w/in 36 hours, resolution w/in 7 days
e. Idiosyncratic drugs
i. Subacute
1) Latency 2-3 weeks
2) Duration of illness continuing for at least 2 weeks
ii. 10% become chronic, w/ evidence of injury lasting >6 months
f. Spectrum of severity
i. Percent w ALT elevations higher than comparators
1) 3X ULN
2) 5X ULN
3) 10X ULN
ii. Occurrence of Hy's law cases (jaundice)
iii. Occurrence of acute liver failure
4. Recognize the symptoms, signs and biochemical indications of acute liver failure
a. ALF symptoms
i. Young person is disorientated, confused, occasionally agitated
ii. Can be mistake as a reaction to illicit drug use like cocaine or PCP
iii. Increased susceptibility to infection, kidney injury
b. ALF signs
i. Presence of any degree of hepatic encephalopathy
1) Mild cognitive slowing, mildly drowsy but not asleep
2) Easily rousable, converse in short phrases, demonstrates asterixis
3) Asleep unless stimulated, can't converse, occasional short phrases
4) Unarousable, may move to deep pain, semi-purposefully
5) Totally comatose, does not respond to any stimuli
ii. Cerebral edema
iii. Elevated PT time
iv. Presence of elevated INR and elevated ammonia levels
v. Low systemic vascular resistance
vi. High cardiac output and vascular collapse
c. Biochemical Indicators
i. Detection of NAPQI-protein adducts
1) Test for APAP hepatotoxicity
a) Aminotransferases are often extremely elevated (3-20k IU/L)
b) Bilirubin is near normal (2-6 mg/dL)
c) Severe and sudden centrilobar necrosis
2) DILI
week 3 Page 139
2) DILI
a) Apoptosis that is panlobular and incremental
i) Lower aminotransferases levels (400-1.2K)
ii) Higher bilirubin levels (15-25mg/dL)
5. Understand the physiologic basis for some treatments for acute liver failure
a. IV NAC will prevent toxicity if given <12 hours
b. Osmotic measures: mannitol/hypertonic saline can be used
c. Target ammonia
i. Lowering ammonia can prevent hepatic encephalopathy
ii. Can also bring down brain edema
iii. OPA treatment
1) Traps ammonia and allows renal excretion
6. Recognize the components of prognostic scores in acute liver failure.
a. Presence of any degree of hepatic encephalopathy
1) Mild cognitive slowing, mildly drowsy but not asleep
2) Easily rousable, converse in short phrases, demonstrates asterixis
3) Asleep unless stimulated, can't converse, occasional short phrases
4) Unarousable, may move to deep pain, semi-purposefully
5) Totally comatose, does not respond to any stimuli
week 3 Page 140
Lecture 40
12:37 PM
1. Recognize the typical clinical presentation (symptoms, liver tests, autoantibodies, histology) of
Autoimmune Hepatitis (AIH), Primary Biliary Cholangitis/Cirrhosis (PBC), and Primary Sclerosing
Cholangitis (PSC)
a. Autoimmune Hepatitis
i. Symptoms
1) Relapsing and remitting disease
2) Females
3) Middle aged or teenager
4) Family history of autoimmune disease
5) Concurrent autoimmune disease
a) Thyroiditis
b) rheumatoid arthritis
c) ulcerative colitis
d) Diabetes
e) Vitiligo
f) alopecia
ii. Liver tests
1) Elevated transaminases
2) Elevated gamma globulins (IgG)
a) >16g/l =1 point
b) >18.5g/l =2 points
3) Autoantibodies 90%
iii. Autoantibodies
1) Primary
a) ANA,SMA, or LKM>1:40 = 1 point
b) ANA 60-80%
i) Most ANA positive liver disease is NOT AIH
c) smAB 60-80%
d) LKM
2) Secondary
a) 1:80 or SLA/LP positive = 2 points
b) Anti-actin 60%
c) pANCA 90%
d) SLA/LP 10-30%
e) ALC 90%
iv. Histology
1) Compatible w/ AIH = 1 point
2) Typical of AIH = 2 points
3) Interface hepatitis
a) Jagged edge around portal
4) Plasma cell infiltration
5) emperipolesis
b. Primary Biliary Cholangitis/Cirrhosis (PBC)
i. Symptoms
1) Middle aged females
2) Fatigue (50%)
3) Pruritis (33%)
week 3 Page 141
3)
4)
5)
6)
7)
8)
9)
Pruritis (33%)
Dry eyes and mouth
Arthritis
Hyperpigmentation
Hepatomegaly
Xanthelasma
Jaundice
a) Most important prognostic marker
10) osteoporosis
ii. Liver tests
1) Alk Phos: 3-10X normal
a) Chronic cholestasis
2) ALT, AST < 5X normal
3) Bilirubin
a) Bili>10 corresponds w/ an average 2 year survival
iii. Autoantibodies
1) >95% Anti-mitochondrial antibody positive
2) 45% ANA positive
iv. Histology
1) Florid duct lesion
a) Granulomatous destruction of inflamed bile duct w/out necrosis
c. Primary Sclerosing Cholangitis
i. Symptoms
1) 2/3 male, around 40
2) 60-80% have IBD
3) Increased risk of cancer
4) Fatigue
5) Itching
6) Hypercholesterolemia
7) Osteoporosis
8) Fat soluble vit deficiency
9) Hepatomegaly
10) Splenomegaly
11) jaundice
ii. Liver tests
1) Elevated alkaline phosphatase
2) Cholangiography
3) Exclusion of secondary sclerosing cholangitis
iii. Autoantibodies
1) 75% pANCA
iv. Histology
1) Onion skinning of bile ducts
a) Concentric fibrosis
2) Radiology
a) MRI
i) Multiple dilations and strictures
One. Beading of bile ducts
2. Understand the natural history of AIH, PBC, and PSC
a. AIH
i. History
1) AIH is a relapsing and remitting disease
2) Left untreated-> mortality is high
week 3 Page 142
2) Left untreated-> mortality is high

a) Only 25% 5 ysr
b. PBC
i. Chronic cholestatic liver disease
ii. Begins as inflammation of small to medium sized intrahepatic bile ducts
iii. Progressive destruction of ducts
1) Cholestasis ensues
2) Fibrosis develops and evolves into fibrosis
iv. Diagnosis to fibrosis = 10 years
c. PSC
i. Fibrotic stricturing of extrahepatic or intrahepatic bile ducts-->chronic cholestasis and
cirrhosis
ii. Punctuated by episodes of recurrent cholangitis
iii. Have high lifetime risk of developing cholangiocarcinoma, gall bladder cancer, or colon
cancer
3. Describe the currently used treatment approach to AIH, PBC, and PSC
a. AIH
i. Induction
1) Prednisone to induce remission
2) Budesonide can reduce remission in non-cirrhotic patients
ii. Maintenance
1) Azathioprine
2) Mycophenolate mofetil
3) Gradual withdrawal of steroids
iii. Liver transplant
1) AIH that has progressed to decompensated cirrhosis
2) Post-transplant immunosuppression
b. PBC
i. UDCA (ursodeoxycholic acid) improves biochemical tests
1) Delays histological progression
2) Prolongs expected survival w/out liver transplant
3) Increased bile secretion
4) Decreased ability of bile to enter hepatocyte membranes and cause damage
ii. OCA (obeticholic Acid)
1) Stimulates nuclear hormone receptor to upregulate bile acid excretion from
liver into bile
2) Decrease re-absorption of bile acids in ileum
iii. Liver transplant
1) Definitive therapy for advanced PBC w/ complications of cirrhosis
c. PSC
i. No clinically proven medical treatment
ii. Antibiotics may be effective in children
iii. Endoscopic dilation of benign dominant strictures to maintain long term patency of
bile ducts helps survival
iv. Liver transplant
1) Recur in 20-40% of transplants
week 3 Page 143
Lecture 41
1:30 PM
1. Describe the basic mechanisms, the histologic patterns, and common causes of drug and toxin
induced liver disease
a. Mechanisms
i. Drug or toxin induced direct hepatocyte toxicity
1) Acetaminophen in a dose dependent manner
ii. Hepatic injury induced inflammatory responses
1) Alcohol
iii. Hepatic conversion of drugs to active toxins
iv. Immune mediated injury
1) Granulomatous liver injury
v. Can be dose dependent
1) APAP
2) Chemo
3) Amanita toxin
vi. Can be unpredictable amount
1) Antibiotics
2) Isoniazid
vii. Can be impacted by concurrent liver disease, drug administration, or nutritional status
b. Histologic patterns
i. Hepatocellular damage
1) Cholestatic liver injury
a) Oral contraceptives, estrogen
2) Hepatitis
a) Alcohol
3) Hepatocellular necrosis
a) APAP, amanita
i) Zone 3 preference necrosis (around the central vein)
4) Steatosis
a) Alcohol, methotrexate
5) Steatohepatitis
a) Alcohol, steroids
6) Fibrosis
a) Alcohol, methotrexate
7) Granulomatous inflammation
c. Common causes
i. Vascular disease
1) Sinusoidal obstruction syndrome
a) High dose chemo
2) Budd-Chiari syndrome (hepatic vein thrombosis)
a) Oral contraceptives
3) Peliosis hepatitis
a) Steroids and tamoxifen
b) cystically dilated spaces filled w/ blood in the liver
ii. Tumors
1) Hepatic adenoma
a) Oral contraceptives and anabolic steroids
2) Hepatocellular carcinoma
a) Aflatoxin and thorotrast
week 3 Page 144
a) Aflatoxin and thorotrast

3) Cholangiocarcinoma
a) Thorotrast
4) Angiosarcoma
a) Thorotrast and vinyl chloride
2. Describe the pathology, morphologic manifestations and basic mechanisms of Alcoholic Liver
Disease
a. mechanism
i. Hepatocytes take up fatty acids alcohol mobilizes from adipocytes
ii. Hepatocyte oxidation is reduced
iii. Assembly and secretion of lipoproteins by VLDL is impaired
b. Morphology
i. Alcoholic steatohepatitis
1) Steatosis
2) Ballooning degeneration of hepatocytes
3) Peri-cellular fibrosis
4) Mallory-denk bodies:
a) Tangles of intermediate filaments and proteins
b) Highlighted by ubiquitin
5) Progression to cirrhosis
a) Lose steatosis and mallory bodies
6) Immunohistochemical stain for cytokeratins 8 and 18
c. Pathology
i. Steatosis
1) Bland fatty liver
ii. Alcoholic hepatitis
1) Steatohepatitis
iii. Cirrhosis
1) Progressive liver injury
2) Hepatocellular carcinoma in some patients
3. Describe nonalcoholic Fatty Liver Disease (NAFLD) Steatosis and non-alcoholic steatohepatitis
(NASH)
a. NAFDL
i. Triglycerides accumulate in hepatocytes by:
1) Impaired oxidation of fatty acids
2) Increased synthesis and uptake of fatty acids
3) Decreased hepatic secretion of VLD and cholesterol
4) Fat laden hepatocyte is sensitive to lipid peroxidation products
a) Damages mito and plasma membranes
b. Non-alcoholic steatosis and NASH
i. Associated w/ metabolic syndrome
1) Obesity
2) T2DM
3) HTN
4) Dyslipidemias
ii. Insulin resistance
iii. Most frequent cause of elevation of serum aminotransferases
4. Discuss the diagnostic criteria of autoimmune hepatitis and associated autoimmune diseases and
antibodies
a. Diagnosis
week 3 Page 145
a. Diagnosis
i. Exclusion of other known causes of liver disease
b. Antibodies
i. Elevated IgG levels
ii. ANA
iii. Anti-smooth muscle
iv. Anti liver/kidney
c. Associated immune diseases
i. Rheumatoid arthritis
ii. Thyroiditis
iii. Sjorgen syndrome
iv. Ulcerative colitis
d. Interface hepatitis
e. Portal inflammatory infiltrate, MANY PLASMA CELLS
5. Discuss pathology related to primary and secondary Hemochromatosis
a. Secondary
i. Parenteral iron overload from multiple transfusions and renal failure
ii. Ineffective erythropoiesis
iii. Increased oral intake of iron
1) Bantu siderosis
iv. Chronic liver disease
b. Primary
i. Autosomal recessive disease of adult onset caused by HFE mutations
ii. Adults have hepatic iron conc. Over 10,000 micrograms/g dry liver
iii. Cirrhosis develops w/ iron conc. > 20K microg
iv. Risk of hepatocellular carcinoma is 200X greater than normal pop.
v. Can display
1) Endocrine insufficiency
2) DM (bronze diabetes)
3) Cardiac disease
4) Arthritis
5) Skin pigmentation
c. Very dark and brown
d. Iron pigment w/in macrophages
i. Seen easily w/ prussian blue
6. Describe the biochemical abnormalities, hepatic morphology, neurologic changes, and ocular
changes seen in Wilson disease.
a. Mutation of trans-membrane copper transporting ATPase gene (ATP7B)
i. Increased copper accumulation
ii. Increased urinary excretion
b. Biochemical abnormalities
c. Hepatic morphology
i. Steatosis
ii. Acute and chronic hepatitis
iii. Cirrhosis
iv. Nuclear glycogenation of hepatocytes
v. Mallory bodies
d. Neurologic changes
i. Copper accumulates in the brain
e. Ocular changes
i. Krayser-Fleischer rings
1) Copper accumulates in the cornea
week 3 Page 146
1) Copper accumulates in the cornea

7. Describe the pathology and physiologic basis of the liver disease associated with alpha1
antitrypsin deficiency.
a. AAT is an autosomal recessive disorder
b. Misfolded Z proteins stay in liver--> inability to secrete AAT
i. Increased lysosomal degradation of peptide in hepatocytes
c. Patients are diagnosed w/ low serum AAT and confirmed by Pi protein electrophoresis
d. Accumulated AAT is visible as eosinophilic, cytoplasmic, globular material in lysosomes in
the cytoplasm of hepatocytes
i. Stains positive in PAS stain
e. Pathology
i. Chronic hepatitis, cirrhosis, and emphysema in older children
ii. Cirrhosis later in life possibly
8. Hepatic tumors
a. o Know the pathogenesis and pathology of the most common benign and malignant liver
tumors
i. Benign
1) Hemangioma
a) Single localized tumors of benign vascular channels separated by
collagenous stroma
b) Well circumscribed
c) Not infiltrative
2) Focal nodular hyperplasia
a) Mass w/ a stellate, fibrous scar from center throughout the mass
b) Separates nodules of benign hepatocytes surrounded by fibrous tissue
c) Bands of fibrous tissue contain abnormal vessels and bile reaction
d) Assoc. w/ sickle cell disease
3) Hepatic adenoma
a) Localized proliferation of benign hepatocytes
b) Usually assoc. w/ hormonal use in women
c) May regress on discontinued use of exogenous drug
d) No portal tracts
e) Hepatocytes w/ isolated arteries
f) Rarely harbor hepatocellular carcinomas
4) Bile duct adenomas
a) Small lesions, single
i) Consist of proliferation of small ductules b/c of previous injury
b) Well circumscribed/demarcated
c) No infiltration
d) Benign bile duct structures in fibrous background
e) Peribiliary gland harmatoma
5) Bile duct hamartomas
a) Small lesions, multiple
b) Contain multiple small dilated bile ducts in expanded portal tracts
c) Von Meyenberg complex
ii. Malignant
1) Hepatocellular carcinoma
a) # of structural and chromosomal abnormalities
b) DNA damage b/c of chronic liver--> ongoing cell death, hepatocyte
replication and inflammation
c) Likely arise form high-grade dysplactic nodules
week 3 Page 147
c) Likely arise form high-grade dysplactic nodules

d) May be unifocal, multifocal, or diffusely infiltrative
e) Vary cytologically from well to poorly differentiated
f) Often have psuedoglandular structures and can produce bile
g) Thickened cords
h) Lots of bile (sometimes) solid appearing tumor
2) Cholangiocarcinoma
a) Assoc. conditions
i) Chronic biliary tract infection
ii) Primary sclerosing cholangitis
iii) Fibrocystic diseases of bile ducts
b) Histology
i) Well-formed glands
ii) Abundant fibrous stroma
iii) Mucin production
iv) Cause jaundice early-->bile duct obstruction
v) No histology of cirrhosis
vi) Malignant duct structures
vii) Anastamosis and infusing
viii) Can spread more than hepatocellular carcinoma
b. o Know the distinction between macroregenerative and high-grade dysplastic nodules in
cirrhosis
i. High grade dysplastic nodules
a) Considered pre-neoplastic lesion
b) Can have same genetic aberrations as carcinomas
c) Thick cords
ii. Macroregenerative nodules in cirrhotics (low grade dysplastic nodules)
a) Can be confused for hepatocellular carcinomas
b) Less risk for hepatocellular carcinoma
9. Discuss the pathology of Transplantation-related Liver Disease

a. Bone marrow transplants
i. Graft vs host disease
a) Injury and loss of bile ducts
ii. Sinusoidal obstruction syndrome
a) Endothelial injury
b) Extensive central venous occlusion
c) Can be caused by pre-transplant chemo
iii. Nodular regenerative hyperplasia
a) Multiple regeneration nodules w/out fibrosis
b) Long term complication
iv. Mixed portal inflammatory infiltrate
b. Liver transplants
i. Acute cellular rejection (T cell mediated)
a) Portal inflammation
b) Endothelialitis
a) Chronic inflammatory cells lifting up the endothelial lining of the vein
c) Bile duct destruction
ii. Chronic rejection
a) Ductopenia
b) Obliterative arteriopathy
a) Lumen taken over by foaming macrophages
week 3 Page 148
a) Lumen taken over by foaming macrophages

10. Describe the pathology of the liver associated with circulatory disturbances
a. Portal vein obstruction/thrombosis
i. Extrahepatic causes
a) Pylephlebitis from thrombosis of portal vein
b) Portal hilar adenopathy
c) Propagation of splenic vein thrombosis
a) pancreatitis
d) Post-surgical
a) Hypercoagulable states
ii. Intrahepatic diseases
a) Cirrhosis
b) Carcinoma
b. Hepatoportal sclerosis (non-cirrhotic portal HTN)
c. Hepatic vein disease
i. Passive congestion
ii. Cardiac cirrhosis
a) Nutmeg liver
iii. Large veins
a) Hepatic vein thrombosis/Budd-Chiari syndrome
a) Spiderman looking red and black
b) Hepatomegaly severe centrolobular congestion w/ necrosis and ascites
c) Causes
a) Polycythemia vera
b) Factor deficiencies
c) Tumors
d) Pregnancy
e) Hormones
iv. Small veins
a) Sinusoidal obstruction (veno occlusive diseases)
a) Cells appearing in a vessel type structure surrounded by fibrosis
b) Causes
a) Chemo agents
b) Toxin mediated
11. Describe the liver pathology associated with pregnancy
a. HELLP syndrome
i. Complicated preeclampsia and eclampsia
a) Hemolysis
b) Elevated liver enzymes
c) Low platelets
ii. Acute fatty liver of pregnancy
a) Rare, patients can develop fulminant hepatic failure and encephalopathy
iii. Microvesicular steatosis
week 3 Page 149
Lecture 42
10:21 AM
1. For each of the hepatitis viruses, understand:

a. o Modes of transmission
i. Hep B
1) Body fluids
a) Blood> semen, vaginal secretions, > saliva
b) Remains infectious for 7+ days on surfaces
2) Low prevalence regions, pre-hep b vaccination
a) Sexual transmission
b) IV drug use
c) Healthcare exposures
d) Post adolescence
ii. Hep C
1) Efficiently spread by exposure to blood, blood products, or organ/tissue
transplant
2) Vertical transmission or sexual intercourse transmission is very rare
3) Majority of infections by blood transfusions prior to 1990 or during IDU in early
adulthood
4) Poor sterilization of re-used syringes, needles, and other medical equipment
are the most common cause in infection in Africa, Asia, and E. Europe
iii. Hep D
1) Parenteral via IDU
2) Inapparent household contact
b. o Geographic differences in epidemiology and disease presentation

i. Hep B
1) Low prevalence regions, pre-hep b vaccination
a) Sexual transmission
b) IV drug use
c) Healthcare exposures
d) Post adolescence
2) High prevalence regions
a) Vertical transmission from mother to child
b) Horizontal transmission from playmates, household contacts
c) Africa and south central Asia
ii. Hep C
1) Genotypes 1, 2, 4, and 5 in low prevalence infections in Africa
2) Types 3 and 6 in South and Southeastern Asia
3) 1b and 2 and 1a in N America
iii. Hep D
1) Genotype:
a) 1/3 in S america
b) 5-8 in africa
c) 1 in europe and w asia
d) 1 in india
e) 1/2/4 in east asia and indonesias
week 4 Page 150
e) 1/2/4 in east asia and indonesias
c. o Relative frequencies of disease outcomes

i. Hep B
1) Risk of chronic infection >90% in infants and declines w/ age
2) 20-40% of persons w/ chronic hep B destined to suffer life threatening
complication
ii. Hep C
1) Initial infection asymptomatic or assoc. w/ short lived symptoms w/out
evolution to acute liver failure
2) No IgM test to distinguish acute from chronic
3) Typically chronic
a) Spontaneously resolves 15-40%
4) Rate of progression to cirrhosis slower than Hep B, but lifetime risk of fatal
complications is same
iii. Hep D
1) Occurs in 2 patterns
a) Co-infection at time of acute HBV infection
i) Same chronicity rate as HBV mono-infection
ii) Incr risk of fulminant hepatic failure
b) Superinfection in persons w/ chronic hep B infection
i) HDV infection usually chronic
ii) 3X increase risk of cirrhosis and chronic liver failure
d. o Distinguishing virion and genome properties related to above key features

i. Hep B
1) Produce very high levels of both viral proteins and infectious virions
a) Not directly cytopathic and elicits only a very weak innate immune
response
2) Hepatotropic DNA virus w/ open circular DNA genome of 4 genes
a) S: 3 forms of surface proteins/envelope
b) C: core protein and e-antigen
c) P: encodes DNA polymerase that has reverse transcriptase activity
d) X: trans-activating protein that enhances viral replication
3) Produces intact virions (double shelled spheres) and smaller spherical particles
and tubular structures made up of surface antigen HBsAg
a) Noninfectious HbsAg outnumber intact virions by a lot
b) HBeAg is not essential for formation of infectious virions or for successful
replication of virus
i) Marker of HBV replication
ii) More efficient at eliciting T cell tolerance and promoting chronicity
of infection
iii) Can cross placenta--> induce tolerance to both HBeAg and HBcAg
cell epitopes prior to exposure to infectious HBV virions at birth
c) HBcAg
i) Nucleocapsid protein
ii) Shares T cell epitopes w/ HBeAg but elicits distinct Ab response
iii) Target of CTL responses responsible for hepatocellular injury
4) cccDNA
a) Resistance to degradation/humoral immunity
week 4 Page 151
a) Resistance to degradation/humoral immunity

b) Not eradicated by current antiviral drugs
c) Lifelong persistence
ii. Hep C
1) No protective antibody response
a) Patients that clear an HCV infection can be re-infected
b) No vaccine
c) No immune globulin preparations
2) Genome: + sense ssRNA
3) Genes: single open reading frame
4) Virion: Coat contains host lipid
5) Genotypes
a) Extensive diversity w/ 7 genotypes and 50 subtypes
i) Difficult to develop directly antiviral drugs against all genotypes
6) Elicits a vigorous host innate immune response but less vigorous adaptive
immune response
7) HCV NS5B RNA-dependent polymerase lacks proof reading function
a) Simultaneous infection w/ large number of genetically related but distinct
variants
iii. Hep D
1) Genome: circular ssRNA
2) Genes:
a) Single gene encodes short (S) and long (L) form of HDAg
3) Lifecycle: replicated by host RNA polymerases and utilizes HBsAg as envelope
protein
2. Use laboratory test results to:
a. o Identify type(s) of viral hepatitis infection present
i. Hep B
1) HBsAG
2) HBeAg
3) HBV DNA
ii. Hep D
1) Anti-HDV test
b. o Determine the stage of disease
i. Hep B acute
1) Blood high concentrations of HBsAg and HBV DNA containing viral particles
2) Detectable levels of HBeAg
3) Antibody response to HB core (HBcAb) --> IgM during early months
a) IgG after months
4) HBsAg (+)
5) Anti-HBc (+)
6) IgM anti HBc (+)
7) Anti HBs (-)
ii. Hep B Chronic
1) Presence of HBsAg and HBV DNA persists for years or decades
2) No IgM
3) Continued presence of HBeAg, HBsAg, and HBV DNA in serum after resolution of
acute IgM anti HBc response
4) HBsAg (+)
week 4 Page 152
4) HBsAg (+)
5) Anti-HBc (+)
6) IgM (-)
7) Anti-HBs (-)
iii. Hep C
1) No single test to distinguish acute from chronic
a) At all times of infection IgG and IgM don't really change
iv. Hep D
1) Total anti-HDV
a) Appears early in infection and resolves after acute self-limited infection
but persists throughout course of HBV and HDV chronic co-infection
c. o Identify those previously exposed to viral hepatitis
i. Hep B
1) HBsAg (-)
2) Anti-HBc (+)
3) Anti-Hbs (+)
d. o Identify subjects at risk for viral hepatitis
i. Hep B
1) HBsAg (-)
2) Anti-HBc (-)
3) Anti-HBs (-)
ii. Hep C
1) Individuals who spontaneously or after antiviral therapy clear HCV infection
remain vulnerable to re-infection
3. Understand the differences in clinical outcomes that can be achieved with currently available
antiviral therapies for each hepatitis virus.
a. Hep B
i. Multiple viral polymerase inhibitors have been developed
1) Tenofovir and entecavir > 95% efficacy in control of HBV proliferation and
normalization of serum ALT levels
ii. Current anti-viral therapies suppress viral replication and prevent disease
manifestations but do not "cure" HBV infections
b. Hep C
i. No effective vaccine for prevention of HCV infection
1) Therapy is effective and curative
c. Hep D
i. HBV suppression has no significant effect on rates of HDV viremia or clinical course of
chronic HDV
ii. Only option is liver transplant
week 4 Page 153
Lecture 43
12:10 PM
1. Understand the normal regulation of copper metabolism and describe the defects
responsible for copper overload in Wilson Disease
a. Normal copper metabolism
i. Dietary intake
1) Transported into intestinal epithelial cells
a) Bound by metallothionein
b) Intracellular copper may be transported across BL membrane of
intestinal epithelial cells by ATP7A-->circulation
i) Circulation copper-->from albumin to hepatocytes
2) Minimal amounts of copper reach the kidney--> <40mcg/24 of copper
excretion
ii. Hepatocyte uptake leads to:
1) Biliary copper
2) Ceruloplasmin-Cu
b. Second copper transporter ATP7B is required in hepatocytes for copper metabolism
i. Transport copper from trans-golgi system to apo-ceruloplasmin to create
active ceruloplasmin enzyme
ii. Excretion of excess copper into bile
1) Excretion of 1-2g/day
c. Wilson's disease-> polymorphism of ATP7B (mutation)
i. Copper overload occurs first in liver-->hepatocyte necrosis and release of free
Cu in the blood
ii. Free Cu in high levels--> hemolysis
d. Wilson's pathogenesis
i. Due to failure of biliary Cu excretion, hepatic Cu levels are greatly elevated
1) Hepatocellular injury and eventually cirrhosis
2) Hepatic Cu release into circulation
a) RBC injury-hemolysis
b) Urinary Cu excretion
c) Cu deposition in brain and eye
3) Failure of Cu incorporation into apo-ceruloplasmin leads to decr levels
of serum ceruplasmin
2. Understand the normal regulations of iron metabolism and describe the defects
responsible for iron overload in Hemochromatosis.
a. Body lacks any regulated mechanism for excretion of excess iron
b. Iron stores controlled by regulation of iron absorption and by regulation of iron
release from stores in tissue macrophages
c. Hepcidin
i. Major regulator of iron transport out of intestinal epithelial cells into systemic
circulation
ii. Binding to ferroportin at cell surface--> internalization and degradation
1) This post-translational downregulation of ferroportin expression causes
cessation of iron transfer to blood stream
d. Hepcidin regulation
i. Suppress
1) Anemia and hypoxemia--> increase iron absorption
ii. Increased
1) External IL6 signaling during inflammation
2) Oxidative stress from alcohol abuse or chronic liver disease
week 4 Page 154
2) Oxidative stress from alcohol abuse or chronic liver disease

iii. Major point of feedback
1) Hepatocyte receptors that sense levels of transferrin saturation in blood
e. Hemochromatosis
i. Caused by genetic mutations that impair mechanisms involved in feedback
response to high levels of circulating or tissue iron stores
ii. Mutation 945G-A
1) Results in Cys282Tyr change in HFE gene product
a) Loss of cysteine critical to assembly of mature forms of HFE
i) Loss of ability to sense high levels of transferrin bound Fe in
circulation
iii. Mutations in other genes that regulate iron absorption or transport
1) Juvenile onset genetic hemochromatosis
a) Rare form of hepcidin or hemojuvelin
i) Signaling protein involved in sensing both transferrin bound
circulating and tissue iron stores
ii) Leads to initial elevation in transferrin saturation
iii) Increases in ferritin bound iron and parenchymal tissue iron
stores
iv. Ferroportin disease
1) Dominant
2) Gain of function mutation in ferroportin-->unregulated iron absorption
3) Initial elevation of excess iron in macrophages and kupffer cells
4) Elevation in blood ferritin levels--> increase in transferrin saturation
3. Be able to describe the differences in pathogenesis of lung vs. liver disease in patients
with alpha-1-antitrypsin (A1AT) deficiency
a. Liver
i. Z form of A1AT
ii. Substitution of lysine for glutamate -> alteration of mature glycoprotein
iii. Abnormal protein product spontaneously polymerizes and is trapped in ER of
hepatocytes
1) Intrahepatic polymerization leads to:
a) Failed secretion
b) Deficiencies in blood levels of serpin activity
c) Sets off cascade of inflammatory responses
i) Development of cholestatic liver disease and cirrhosis
iv. Homo for Pi-ZZ
1) Can present in infancy or late adulthood
b. Lung
i. Risk of disease is proportional to decrease in serum anti-trypsin activity
ii. Null mutation (severe Pi mutation) is highest risk of emphysema
1) No increased risk of liver disease
iii. Manifest b/w 25-45 in patients homo for Pi-Z
iv. Measurement of alpha-1 antitrypsin function of the blood is best approach for
detection
4. List at least two tests used in screening for and making a diagnosis of:
a. o Wilson Disease
i. Ceruloplasmin level
1) >95% exhibit depressed blood levels of ceruoplasmin
ii. 24 hour urine Cu
1) Have high levels of urinary copper excretion (>100mcg/24)
2) >2.5 fold elevated
b. o Hemochromatosis
week 4 Page 155
b. o Hemochromatosis
i. Fe/TIBC X 100 = 100 Transferrin Saturation
1) Elevated transferring saturation is the initial abnormality in HFE C282Y
patients
2) Higher specificity than ferritin testing
ii. Ferritin
1) Values >1000 associated w/ hepatic fibrosis in HFE C282Y patients
2) Multiple causes of hyperferritinemia, low specificity
3) Genetic testing for HFE mutations
4) Hepatic iron content
c. o Alpha-1-Antitrypsin Deficiency
i. A1AT level
ii. A1AT phenotype (liver)
1) Distinguished common polymorphism (Z,S) from normal (M)
iii. Liver biopsy
1) PAS +/- immunohistichemical stains detect A1AT polymers
week 4 Page 156
Lecture 44
12:11 PM
1. Recognize key radiologic and clinical features of non-malignant liver masses including
cavernous hemangioma, focal nodular hyperplasia, and hepatic adenomas
a. Hemangioma
i. Most common benign liver lesion
ii. Females, 30-50s
iii. Collection of irregular vascular spaces separated by thin fibrous stroma
iv. Radiological findings
1) Contrast enhanced imaging
a) Peripheral arterial enhancement w/ central filling on venous and delayed
images
2) CT usually sufficient
a) MRI: usually definitive
3) Histology
a) Well circumscribed collection of vascular spaces w/ endothelial cell lining
v. No needed follow up
b. Focal Nodular Hyperplasia
i. 2nd most frequent benign liver tumor
1) 30-50 females
ii. Solitary, and smaller than 5 cm
iii. Radiological findings
1) Contrast enhanced imaging
a) Can have nearly 100% specificity when typical imaging features are seen
in combo
b) Intense homogenous enhancement in arterial phase
i) Followed by isointense venous phase and enhancement of CENTRAL
SCAR in later phases
ii) Lack of capsule w/ lobulated contours
2) Histology
a) Benign hepatocytes w/ central scar containing bile duct proliferation and
abnormal blood vessels
c. Hepatic adenomas
i. 40s, females
ii. Risk factors: Oral contraceptives, pregnancy, steroids, glycogen storage disease
iii. Solitary but can be multifocal
iv. Radiological findings
1) biopsy required in many cases
2) Contrast enhanced MRI
a) Well demarcated lesions, often lipid-rich
b) Early hyperenhancement w/ delayed images showing iso- or
hypoenhancement
c) Areas of hemorrhage, necrosis, or calcifications possibly
3) Histology
a) Sheets of benign hepatocytes in cords 1-2 cells thick
i) Unpaired arteries and no portal tracts
v. Risk of hemorrhage and risk of malignant transformation
2. Describe the evaluation and treatment regimens for non-malignant liver masses including
cavernous hemangioma, focal nodular hyperplasia, and hepatic adenomas
a. Hemangioma
week 4 Page 157
a. Hemangioma
i. Evaluation
1) Lesions are benign w/ no malignant potential
ii. Treatment
1) NO routine follow up is required
2) Intervention only is symptomatic
a) Surgical resection
b) Kasabach Merritt syndrome
i) Large hemangioma, thrombocytopenia, and consumptive
coagulopathy
3) Do NOT need to discontinue birth control
b. Focal Nodular Hyperplasia
i. Evaluation
1) Do not have malignant potential and no routine follow up is required
2) Most lesions remain stable in size over time
ii. Treatment
1) Only if symptomatic
a) Surgical resection
b) Don't need to stop birth control
c. Hepatic adenomas
i. Evaluation
1) Typically remain stable in size
2) There is a risk of hemorrhage (25%)
3) Risk of malignant transformation (4%)
a) Risk of rupture is increased in lesions > 5cm, exophytic, subcapsular
position
b) Malignant transformation higher in lesions > 5cm or w/ beta-catenin
mutations
ii. Treatment
1) Treatment:
1) Discontinuation of oral contraceptives
2) Surgical resection for symptomatic lesions > 5cm
i) Or increasing size despite discontinuation of birth control and
steroids
3. Identify the most common risk factors for primary liver cancer worldwide and in the United
States
a. Risk factors
i. HEP B infection
ii. In US, cirrhosis from any etiology
1) Hep c, b, alcohol, nonalcoholic steatohepatitis, hemochromatosis
4. Describe the characteristic radiologic features of hepatocellular carcinoma and the role of liver
biopsy in its diagnosis
a. Radiological features
i. Contrast enhanced imaging shows lesions w/ arterial enhancement and delayed
washout (4 phase MDCT/dynamic contrast enhanced MRI)
1) Arterial hypervascularity AND venous or delayed phase washout
2) HCC lesion is brighter than surrounding liver in arterial phase
3) Liver is brighter than HCC lesion in portal venous and delayed phases
week 4 Page 158
3) Liver is brighter than HCC lesion in portal venous and delayed phases
4) Appearance related to dual blood supply to liver
1) Liver get blood from portal vein
2) HCC gets most from hepatic artery
ii. Serum tumor marker alpha fetoprotein (AFP)
1) Diagnosis 200 ng/mL
iii. Biopsy
1) Rarely required (only after initial MRI is negative)
2) Histology
1) Increased cell density w. increased nuclear to cytoplasm ration
2) Psuedoglandular formation
3) Diffuse fatty changes
4) Unpaired arteries
3) PET not really used
week 4 Page 159
Lecture 45
3:08 PM
1. 1. Given a clinical presentation of a patient with NAFLD, list the risk and protection factors
pertinent to a diagnosis of NAFLD.
a. Risk
i. Obesity
ii. T2DM
iii. Hyperlipidemia
iv. Insulin-resistance
v. Secondary
1) Inborn errors
2) Surgical procedures
3) Drugs/toxins
4) miscellaneous
b. Protection factors
i. Low triglyceride content
ii. Caloric restriction
2. 2. Given a patient with hepatic steatosis list three physiological changes contributing to fat
accumulation in liver.
a. Metabolic alterations
i. Increased FFA release from adipose tissue
1) Increased hydrolysis of triglycerides and release of free fatty acids into the
blood
2) Rate of hepatic FFA uptake is unregulated--> proportional to plasma FFA
concentrations
3) Increased insulin resistance in adipose tissue results in increased fatty acid
release and delivery to the liver
ii. Secretion
1) Reduced fatty acid secretion from the liver
iii. Increased Fatty Acid synthesis
1) High insulin and glucose levels stimulate triglyceride synthesis
2) High plasma insulin levels present in obese and insulin resistant states activated
SREBP-1c and triglyceride synthesis
3. 3. Given a clinical presentation, to make a diagnosis of hepatic steatosis or nonalcoholic
steatohepatitis and identify three pathological differences between hepatic steatosis and
nonalcoholic steatohepatitis.
a. Hepatic steatosis
i. Prerequisite for subsequent events that lead to liver injury
ii. Presence of excess fat in liver can be documented by ultrasound, CT, or MRI
iii. Mortality was not increased in subjects w/ steatosis alone
b. NASH (non-alcoholic steatohepatitis)
i. More severe form of NAFDL and requires biopsy to diagnose
ii. Diagnosis of NASH requires:
1) Presence of steatosis
2) Hepatocyte ballooning degradation
3) Diffuse mixed acute and chronic inflammation
4) perivenular, perisinusoidal collagen deposition
iii. Mortality significantly increased in subjects w/ nash
week 4 Page 160
4. 4. Given a clinical presentation of a patient with NAFLD, list two genetic factors contributing to the
pathogenesis and progression of NAFLD.
a. PNPLA3
i. First risk factor identified for disease progression in NAFDL
ii. Member of family of proteins that usually have phospholipase activity
1) Hydrolyze and remove fatty acid from phospholipid
2) Polymorphism of PNPLA3 destroys the proteins catalytic activity
a) Triglycerides accumulation
iii. Only a factor when obese or insulin resistant
b. TM6SF2
i. Adenine to guanine sub at residue 167
ii. Carriers of TM6SF2 had elevated liver TG's, higher ALT's, lower plasma TGs
iii. Have a block in VLDL secretion from liver
week 4 Page 161
Lecture 27
4:28 PM
1. Define what constitutes a functional GI disorder

a. Heterogeneous group of chronic conditions that are characterized by persistent and
recurring GI symptoms
i. Considered to have no structural or biochemical abnormalities that account for
the symptoms
b. Abnormality of function not structure
c. Can affect any part of GI tract, even biliary tract
d. 3 primary features
i. Motility-ability to move spontaneously and actively
1) In FGID, abnormal like spasms
ii. Sensation - how nerves of GI tract respond to stimuli
1) So sensitive that even normal contractions can bring pain or discomfort
iii. Brain gut dysfunction
1) Regulatory conduit b/w brain and gut function may be impaired
2. Know the prevalence and economic burden of functional GI disorders
a. 3-20%
b. IBS 10% of population
i. $1.7 billion direct cost
3. Describe the pathophysiology of functional GI disorders
a. Brain gut axis
i. Bidirectional communication b/w central and enteric NS
ii. Links emotional and cognitive centers of brain w/ peripheral intestinal function
iii. Disruption in brain-gut axis
1) Stress
a) Alteration in behavior, cognition, emotion, nociception
b) Abnormal gut function
c) Increased levels of inflammatory cells/mediators intestinal dysbiosis
4. Summarize types and classifications of functional GI disorders
a. ROME III
i. Functional esophageal disorders
ii. Functional gastroduodenal disorders
iii. IBS
iv. Functional abdominal pain syndrome
v. Functional gallbladder and sphincter of oddi
vi. Functional anorectal disorders
5. Identify commonly used criteria for diagnosing functional GI disorders such as ROME III
a. Diagnosing criteria
i. IBS
1) Recurrent abdominal pain or discomfort at least 3 days/month
a) w/ 2 of the following
i) Improvement w/ defecation
ii) Onset assoc. w/ a change in frequency of stool
iii) Onset assoc. w/ a change in form (appearance of stool)
week 4 Page 162

6. Describe diagnostic testing and treatment options Irritable bowel syndrome
a. Diagnostic
2) Clinical diagnosis
3) PE aimed at assessing for any alarm signs or red flags
4) ABC's
a) Ab pain or discomfort
b) Bloating
c) Change in bowel habit
b. Treatment
1) Identify and remove stressors on gut
2) Enable GBA to reduce stress via cognitive behavior therapy (CBT)
3) "numbing"/reducing signals going from the gut to the brain
4) IBS
5) Explain pathophysiology in easy words to the patient
6) Placebo effect of up to 70% in all IBS treatments
7) Treatment should depend on symptom subtype
8) Goal
1) Relieve ab pain and discomfort
a) Anticholinergic drugs
i) Block M receptors
b) Relieve distention/bloating
c) Improve bowel function
i) Diarrhea:
One. Anti diarrheal
ii) Constipation
One. laxatives
7. Summarize diagnostic testing and treatment options for functional constipation other
functional disorders of defecation.
a. Must include 2 or more of the following
1) Straining during at least 25% of poops
2) Lumpy or hard stools in a least 25% of defecations
3) Sensation of incomplete evacuation for at least 25% of defecations
4) Sensation of anorectal obstruction/blockage for at least 25% of defecations
5) Manual maneuvers to facilitate at least 25% of defecations (digital, support of
pelvic floor)
6) Fewer than 3 poops/week
b. Loose stools are rarely present w/out use of laxatives
c. Insufficient criteria for IBS
d. Child constipation
1) 2 or more poops in the toilet/week
2) At least one episode of fecal incontinence per week
3) History of retentive posturing or excessive volitional stool retention
week 4 Page 163
3) History of retentive posturing or excessive volitional stool retention

4) History of painful or hard bowel movements
5) Presence of a large fecal mass in the rectum
6) History of large diameter stool that may obstruct the toilet
e. Treatment
1) Education of family and child
2) Disimpact using osmotic laxatives (polyethylene glycol)
3) Daily maintenance laxatives
4) Diet
5) Toilet behavior
f. Other disorders
1) Slow transit
2) Outlet dysfunction
3) Assoc. w/ the feeling of incomplete poop, excessive straining and digital help of
bowel movements
4) Diagnosing
1) Constipated
2) During repeated attempts to poop, must have at least 2:
a) Evidence of impaired evacuation
i) Balloon expulsion test or imaging
b) Inappropriate contraction of pelvic floor muscles
c) Inadequate propulsive forces assessed by manometry or imaging
week 4 Page 164
Lecture 46
2:41 PM
1. Be familiar with the history of liver transplantation

a. First performed in 1963
i. Patient bled to death
ii. First 5 patients died
b. 1967, first transplant to survive more than one year
c. 1979 cyclosporin heralded new era in OLT
d. 1983 liver transplantation approved as therapy for ESLD by NIH
2. Identify indications for liver transplantation
a. Decompensated cirrhosis: most common indication for liver transplant
i. Variceal hemorrhage
ii. Ascites
iii. Encephalopathy
iv. Jaundice
b. Liver function declines to give a MELD>10
c. Patients w/ HCC
d. Patients w/ acute liver failure
e. Metabolic liver diseases
i. Wilson's, hemochromatosis
f. Vascular diseases of liver
i. Budd Chiari syndrome
g. Cholestatic liver disease
i. Primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia
h. Other:
i. Adult polycystic liver disease
ii. Amyloidosis
3. Describe selection for liver transplantation based on MELD score
a. MELD score = severity of illness
i. Highest score gets first choice of available organ
b. Livers are allocated w/in a specific geographic region
c. MELD<35
i. Access to local organs
d. Share 35
i. Anyone w/ MELD 35 or higher has access to all organs w/in the region
e. MELD score
i. Predicts 3 month mortality
ii. Ranges from 6-40
iii. MELD = 3.78 X ln[serum bilirubin (mg/dl) + 11.2 X ln[INR] + 9.57 X ln[serum creatinine
(mg/dl)] + 6.43
4. Understand and describe the complications of liver transplantation
a. Immediate Complications
i. Surgical
ii. Medical
iii. Graft dysfunction
iv. Rejection
v. Infection
b. Acute
week 4 Page 165
b. Acute
i. Hepatic Artery thrombosis
1) 2-9%
2) Most common in first 3 weeks after transplant
3) Results in organ dysfunction and abnormal LFTs
4) 50% mortality or need for re-transplantation
a) w/in 7 days
5) Late presentation (usually liver abscess)
ii. Hepatic artery stenosis
1) 5-11%
2) Angiographic evidence of >50% reduction in arterial lumen caliber
3) Majority occur at surgical anastomosis
4) DX:
a) US w/ doppler, CT, angio
5) TX:
a) PTA =/- stenting successful > 90%
b) Surgical revision
iii. Biliary Leak/stricture
1) 25%
2) Presents w/ pain, jaundice, and abnormal LFT's
3) 80% successfully managed w/ ERCP or percutaneous drains but 20% need
surgical revision
iv. Hepatic outflow obstruction
1) 1-5%
2) Presents w/ ascites, renal dysfunction, lower extremity edema
3) Managed by angioplasty +/- stents
v. Infections
1) Higher risk of opportunistic infections for 1-6 months
2) CMV most common opportunistic infection
a) Other:
i) EBV
ii) PJP
iii) Fungal
vi. Rejection
1) 30% of patients in first 6 weeks
2) T cell driven and treated w/ steroids
3) Long term graft function is not needed
c. Long term complications
i. Chronic rejection
ii. Renal insufficiency
1) 80%
2) Due to CSA, tacrolimus
3) Electrolyte disorders
a) Hyponatremia
b) hyperK
c) hypoMg
d) Metabolic acidosis
4) Therapy
a) Reduction of immunosuppressive doses
iii. Obesity
1) 20-40%
2) Due to
a) Prednisone
b) Sense of well-being
week 4 Page 166
iv.
v.
vi.
vii.
viii.
ix.
b) Sense of well-being
3) Therapy: diet and exercise
Hyperlipidemia
1) 30%
2) Due to
a) Obesity
b) CSA, sirolimus
c) Pre-OLT risk factors
3) Therapy
a) Diet and exercise
b) HMG-CoA inhibitors
c) Niacin-glucose intolerance, hyperuricemia
d) Bile acid binders-CSA malabsorption
HTN
1) 55-85%
2) Due to:
a) CNI, steroids
b) Pre-OLT risk factors
3) Therapy
a) Salt restriction
b) Immunosuppressive dose reduction
c) Calcium channel blockers
d) Additional beta blocker
e) Additional ACE-I or ARB
DM
1) 13-30%
2) Due to:
a) Weight gain
b) Tacrolimus > cyclosporin
c) Steroids
d) HCV
3) Therapy
a) Diet and exercise
b) Insulin or oral agents
c) Immunosuppression dose reduction
Osteoporosis
Malignancy
Disease recurrence
5. Understand the mechanism of action of immunosuppressive agents used for liver

transplantation
a. Signal I
i. Antigen presentation by APC to the T cell receptor
b. Signal II
i. Costimulation-binding of additional APC ligands to specific T cell receptors
c. Signal III
i. Newly synthesized IL-2 and growth factors feedback on T cell membrane receptors,
causing clonal expansion of newly activated T cells
d. Goals
i. Early
1) Prevent graft dysfunction long enough to permit adaptation
ii. Long term
1) Stabilize adaptation while preventing damage to the transplanted organ
2) Likelihood of rejection falls after 6-8 weeks due to host-graft adaptation
week 4 Page 167
2) Likelihood of rejection falls after 6-8 weeks due to host-graft adaptation

e. Target T cell/APC interaction and early T cell Activation-signal 1/2
f. Immunosuppressive agents targeting later stages of T cell differentiation and proliferation
and selected cytokines--signal 3
i.
week 4 Page 168
Lecture 47
3:34 PM
1. Discuss the pathology of Intrahepatic Biliary Tract Diseases

a. Pathogenesis
i. Mitochondrial protein alterations leading to states of immunologic tolerance and
immune mediated mechanisms
ii. Females 90%
iii. Assoc. other autoimmune diseases like Sjogren syndrome, scleroderma, autoimmune
thyroiditis
iv. Serological distinctions
1) >90% mitochondrial antibody (AMA)
2) 20% ANA positive
v. Distinctive features
1) Florid duct lesion
a) Chronic inflammatory destruction of small, intrahepatic bile ducts
eventually resulting in ductopenia
vi. Primary sclerosing cholangitis
1) Assoc. w/ inflammatory bowel disease
a) Ulcerative colitis (70%)
b) ANA positive 80%
c) Progressive, segmental fibrotic narrowing and destruction of intra- and
extrahepatic ducts
d) beaded appearance on contrast radiographic imaging of biliary tree
2. Discuss the pathology of Extrahepatic Biliary Tract Diseases

a. Pathogenesis
i. Choledocholithiasis
1) 20 million in US
2) Stones
a) Cholesterol or mixed (80%)
i) <5% under 40 and females
ii) Native Americans
iii) Family history, hyperlipidemia, impaired bile salt synthesis and
secretion
iv) Acquired/environmental
One. Estrogen, pregnancy, rapid weight loss, drugs, post-vagotomy,
spinal cord injury, and diabetes
b) Pigment (20%)
i) Non-western countries
ii) Acquired/environment
One. Chronic hemolytic anemias
Two. Distal small intestinal resection
Three. Pancreatic insufficiency
iii) Biliary tract infection
3) Cholecystitis
a) Acalulous
i) Occurs due to ischemic injury of gallbladder from vasculitis, bile
sludge, major surgical postoperative states, post partem state,
severe trauma/burns, and sepsis
ii. Biliary atresia
1) 20-30% of neonatal jaundice
week 4 Page 169
b.
c.
d.
e.
1) 20-30% of neonatal jaundice

2) Destruction of majority of extrahepatic biliary tree
3) Leads to cholestatic liver disease
4) Develops into biliary cirrhosis in first 3-6 months if not treated
5) One of most common reasons for OLT in infancy and childhood
iii. Biliary stricture
iv. Tumors/mass lesions in the bile duct, adjacent to the bile ducts, causing compression
of bile outflow
1) Gallbladder adenocarcinoma and extrahepatic cholangiocarcinomas
(extrahepatic bile duct carcinomas)
a) Cholelithiasis present in 60-90% of gallbladder carcinomas
b) Fibrocystic diseases of bile ducts
i) Site for chronic inflammation and repair
c) Biliary tract infections
i) Chronic inflammation and repair
d) IBD and primary sclerosing cholangitis (chronic inflammation of bile ducts)
e) Thorotrast (toxic/carcinogenic)
Clinical course
i. Progressive
Both genders
No serological distinctions
Distinctive features
i. Diseases affect the extra- and intrahepatic biliary tree
3. Discuss Disease of the Exocrine Pancreas

a. Acute Pancreatitis
i. Results from tissue damage due to exposure to inappropriate activated pancreatic
enzymes
ii. Risk factors
1) Alcoholism and biliary tract disease (stones) 80%
2) Infection/inflammation
3) Ischemia
4) Drugs
5) Metabolic
6) Congenital anomalies
7) Trauma
8) Hereditary PRSS1 (trypsinogen) and SPINK1 (trypsin inhibitor) gene mutations
iii. Test
1) Amylase
a) Pancreatitis, pancreatic psuedocyst, perforated peptic ulcer
2) Lipase
a) More specific for pancreatitis, but less sensitive
iv. Complications
1) Hypocalcemia and electrolyte imbalance
2) Multisystem organ failure
3) Disseminated intravascular coagulation
4) Pancreatic psuedocyst
a) Not true cyst b/c not lined by epithelium
b) Result of localized collections of liquefied tissue and blood that get walled
off by fibrotic tissue
5) Pancreatic abscess
b. Chronic
week 4 Page 170
b. Chronic
i. Results from repeated pancreatic injury and is commonly due to alcohol abuse
ii. Extensive fibrosis w/in pancreas
1) Causes
a) Chronic hypercalcemia
b) Hypertriglyceridemia
c) Hereditary causes
i) CFTR
One. Decreased bicarbonate secretion and proteinaceous plugging
of ducts
ii) PRSS1
One. Affect trypsinogen and trypsin making them resistant to
inactivation
2) Can develop into
a) Exocrine pancreatic insufficiency
b) DM
c) Pancreatic psuedocyst formation
d) Pancreatic carcinoma in cases of hereditary causes of pancreatitis
4. Describe the pathology and pathogenesis of pancreatic adenocarcinoma and other, less
common pancreatic tumors
a. Nonneoplastic
i. Psuedocyst
b. Neoplastic
i. Pancreatic ductal adenocarcinoma
ii. Serous neoplasms
1) Contain multiple microcysts or slightly larger cysts lined by serous type
epithelium
2) Thin yellowish fluid
iii. Mucinous cystic neoplasms
1) Serous and mucinous cystic neoplasms can be benign or malignant
2) Uni- or multilobular tumors containing benign or malignant mucinous type
epithelium
iv. Intraductal papillary mucinous neoplasms
1) Arise in main pancreatic duct growing intraluminally
v. Acinar carcinoma
vi. Endocrine tumors
1) Low grade functional or non-functional tumors and small cell and large cell
neuroendocrine carcinoma
2) Can secrete hormones like insulin, glucagon, somatostatin, and vasoactive
intestinal polypeptide
vii. Solid-psuedopapillary neoplams
1) Usually benign in adolescent and young women
2) No vessels
viii. Pancreaticoblastoma
c. Pancreatic ductal adenocarcinoma
1) Pathogenesis
1) Development is the consequence of a series of genetic alterations that are
initially manifest as pancreatic intraepithelial neoplasia
a) Telomere shortening
b) K-ras gene mutations
i) Oncogene
c) Inactivation of tumor suppressor gene p16 CDKN2A
i) Loss of normal cell cycle control
week 4 Page 171
2)
3)
4)
5)
i) Loss of normal cell cycle control

d) SMAD4 - tumor suppressor gene inactivation
i) Role in growth inhibitory and pro-apoptotic TGF-beta signals
e) P53 tumor suppressor gene inactivation
Associations
a) Smoking 2 X risk
b) Chronic pancreatitis and diabetes
c) Hereditary disorders
i) Tumor syndromes
One. PJS, BRCA2, HNPCC, and FAP
ii) CFTR mutation
Location
a) Head of pancreas 60%
b) Body 15%
c) Tail 5%
d) Diffuse 20%
CEA and CA19-9 tumor markers
Histology
a) Angulated ductules in background of desmoplasia
week 4 Page 172
Lecture 48
4:43 PM
1. Describe the normal anatomy and physiology of the biliary tree

a. Liver secretes bile continuously
i. About 1 L /day
b. Bile becomes more concentrated the longer it remains in gallbladder
c. Release of CCK by duodenum triggers dilation of hepatopancreatic sphincter and
contraction of gallbladder
i. Ejects bile into duodenum through duodenal ampulla
d. In the lumen of digestive tract, bile salts break lipid droplets apart by emulsification
e. Biliary drainage
i. Bile secreted by liver
ii. Flows from liver through hepatic ducts into gallbladder
iii. Exits gallbladder
iv. Flows from cystic duct into common bile duct-->small intestine
1) When sphincter of oddi is relaxed
v. In small intestine, aids digestion by breaking down fatty foods and fat soluble
vitamins
2. Understand factors which contribute to the development of gallstones
a. Age
b. Female
c. Oral contraceptives
d. Pregnancy
e. Obesity
f. Rapid weight reduction
g. Gallbladder stasis
h. Disorders of bile acid metabolism
i. Hyperlipidemia syndromes
j. TPN
k. F rule
i. Fat
ii. Forty
iii. Fertile
iv. Female
v. Fair (white)
l. Types
i. 2 main types
1) Cholesterol
a) Pure
b) Mixed
i) 50-90% cholesterol/remainder is pigment and calcium/bile
2) Pigment stones occur in brown and black
a) Both types of pigment stones result from abnormalities in
metabolism of bilirubin
b) In general, bile of patients w/ both types of pigment stones
contains an excess of unconjugated bilirubin
i) Black
One. Formed in uninfected gallbladders
ii) Brown
One. Formed in gallbladder and other portions of biliary
week 4 Page 173
One. Formed in gallbladder and other portions of biliary

tract (intrahepatic)
Two. Formation requires presence of structural or
functional stasis of bile assoc. w/ biliary infection
3. Recognize the clinical presentation of different biliary tract disorders related to
gallstones
a. Biliary pain
i. Severe poorly localized epigastric or RUQ visceral pain
1) Grows intensely over 15 minutes
2) Remains constant for 1-6 hours
ii. Nausea
iii. Frequency of attacks varies from days to months
iv. Gas, bloating, flatulence-->NOT RELATED TO STONES
b. Acute Cholecystitis
i. 75% of cases preceded by attacks of biliary pain
ii. Visceral epigastric pain gives way to moderately severe localized pain in RUQ,
back, right shoulder, or chest
iii. Nausea w/ some vomiting
iv. Pain lasting > 6 hours
c. Choledocholithiasis
i. Often asymptomatic
ii. Symptoms indistinguishable from biliary pain
iii. Predisposed to cholangitis and acute pancreatitis
d. Cholangitis
i. Charcot's triad
1) Pain
2) Jaundice
3) Fever
ii. Pain may be mild and transient
1) Often accompanied w/ chills
iii. Mental confusion
1) Lethargy, and delirium suggest sepsis
e. Acute biliary pancreatitis
i. Several hour history of epigastric pain
1) Radiating to the back
2) Assoc. w/ emesis
4. Understand the management of biliary tract disease related to gallstones
a. Biliary Pain (Colic)
i. Elective cholecystectomy
b. Acute Cholecystitis
i. Analgesia
ii. Intravenous antibiotics
iii. Cholecystectomy, possibly w/ IOC
c. Choledocholithiasis
i. Stone removal at time of ERCP
ii. Laproscopic cholecystectomy
d. Cholangitis
i. Volume resuscitation
ii. Antibiotics
iii. Emergent biliary decompression
1) ERCP vs percutaneously
week 4 Page 174
1) ERCP vs percutaneously
e. Acute biliary pancreatitis
i. Cholecystectomy
ii. Clearing bile duct of stones
iii. Supportive care
1) Pain control
2) IV fluids
3) Correction of electrolyte and metabolic abnormalities
week 4 Page 175
Lecture 49
11:00 PM
1. Understand the presenting signs and symptoms of patients with acute and chronic
pancreatitis.
a. Adult
i. Epigastric pain, may radiate to the back
ii. Vomiting
iii. Elevated enzymes >3 Xs upper limit normal
iv. US/CT edema, fluid, stranding
v. Signs
1) Ill appearing, tachycardic, shallow respirations
2) Epigastric tenderness
3) Grey Turner's sign (ecchymosis in one or both flanks)
4) Cullen's sign (ecchymosis in periumbilical area)
b. < 3 years of age
i. US abnormal in 51 %
ii. CT abnormal in 46%
iii. Vomiting most common
iv. Abdominal pain, irritability, and distension also noted
v. Enzymes may NOT be elevated
c. Chronic
i. Abdominal pain c/w pancreatic origin and imaging findings suggestive of
pancreatic damage
ii. Evidence of exocrine PI AND imaging findings
iii. Evidence of endocrine PI AND imaging findings
iv. Sequela of long standing inflammation and destruction
v. Clinical diagnosis
1) Pain
a) Constant or intermittent
b) Epigastric/radiate to back
c) "deep and penetrating"
i) Obstructed duct
ii) Inflammation/acute on chronic
iii) Perinueral
iv) Pain "imprinting"
d) Malabsorption
e) jaundice
2. Describe etiologies of and risk factors for acute and chronic pancreatitis
a. Acute
i. BADHITS
1) Biliary
2) Alcohol/Autoimmune
3) Drugs/meds
4) Hereditary/Hypertriglyceridemia
5) Infection
6) Trauma/Tumor
7) Scorpion Bite
ii. Adults
1) Mainly alcohol, biliary
iii. Children
week 4 Page 176
iii. Children
1) Mainly multisystem disease
2) Systemic infection
3) Idiopathic
b. Chronic
i. Alcohol
1) FAEEs have direct negative effects on pancreatic acinar cells by
activating IP3R leading to sustained intracellular Ca++
2) EtOH stimulates pancreatic stellate cells
ii. Tobacco
1) Predisposes to more rapid calcification
2) Increases risk of pancreatic cancer
iii. Obstruction (Necrosis-Fibrosis hypothesis)
1) Stricture
2) Stones
3) tumors
iv. Tropical Pancreatitis
1) Mean Age 24
2) Manifest as pain, malnutrition, exocrine and endocrine insufficiency
3) Stones in 90%
v. Genetics
1) PRSS1
2) CFTR
3) SPINK1
4) CTRC
vi. Autoimmune pancreatitis
1) More common in men
2) Presents as biliary obstruction and confused w/ pancreatic mass
3) Diagnosis IgG 4 elevated
3. Understand the role of genetic mutations in the development of acute, recurrent and
chronic pancreatitis
a. PRSS-1
i. Hereditary pancreatitis
ii. Dual gain of function mutation
1) Increased autoactivation
2) Decreased autodegredation
iii. Extensive lipomatous atrophy
iv. High lifetime likelihood of exocrine and endocrine insufficiency
v. Lifetime cancer risk > 40%
b. SPINK1
i. Serine protease inhibitor Kazal Type 1
ii. 25-45% of patients w/ CP carry mutation on at least 1 allele
iii. Inactivates intrapancreatic trypsin
c. CFTR
i. Decreased Cl- and HCO3- secretion
ii. Heterozygous w/ mild CFTR mutation are at increased risk of AP and CP
iii. CF patients w/ pancreatic insufficiency do not appear to be at risk of acute
pancreatitis
d. CTRC
i. Chymotrypsin C gene
ii. Loss of protective trypsin degradation
e. CPA1
week 4 Page 177
e. CPA1
i. ER stress due to misfolding
4. Understand the intracellular changes and messengers involved in pancreatic

inflammation
a. Normal pancreatic intracellular activity
i. CCK or Ach
ii. Inositol Triphosphate (IP3)
iii. Short burst of Ca++
iv. Triggers zymogen granule fusion w/ cell membrane
v. Enzyme excretion into duct, and activation in duodenum
vi. CRAC opens (STEMI) to allow influx
b. Pathogenesis
i. Starts w/ conversion of trypsinogen to trypsin W/IN acinar cell
1) Trigger/inciting event
2) SUSTAINED elevations of Ca++ in cytoplasm
3) Initiates trypsin activation INSIDE zymogen granules
4) Vacuolization occurs w/ release of activated trypsin and more Ca++ in
the cell
ii. Incr trypsin overwhelms innate protective mechanisms
1) Innate protective mechanisms
a) Synthesis of trypsin as inactive enzyme
b) Production and activation of trypsin in different sites
c) Autolysis of activated trypsin
d) Ductal secretions (HCO#- rich)
e) Serine protease inhibitor, Kazal type 1 (trypsin inhibitor)
f) Low intra-acinar Ca++ concentrations
2) Protective mechanisms can be ineffective in some genotypes
iii. Trypsin catalyzes conversion or proenzymes to active enzymes
iv. Active enzymes autodigest pancreas
v. Systemic inflammation occurs in local injury unchecked
5. Describe the approach to treatment of patients with acute, recurrent or chronic

pancreatitis
a. Acute
i. Pain control
ii. IVF (volume?)
iii. Diet? Advance as tolerated
b. Chronic
i. Pain control
1) Oral therapy
2) Endoscopic or IR celiac plexus block
ii. Pancreatic enzyme replacement therapy (oral)
iii. ERCP to relieve obstruction
iv. Total pancreatectomy w/ islet auto transplant
v. Calmodulin
1) Cytosolic calcium binding protein
2) Prevents release of intracellular Ca++
a) Particularly by ethanol
3) Addition of CALP-3 in citro can prevent toxic effects of high ethanol
conc.
vi. Caffeine
week 4 Page 178
vi. Caffeine
1) Interferes w/ opening of IP3R channels
2) Reduce cytosolic calcium signal generation in response to FAEEs and bile
acids
3) Low affinity for IP3R--> only moderate effect
vii. CRAC channel blockade
1) Novel compound
2) Reduces sustained elevation of Ca++ due to influx via CRAC channel
following intracellular calcium release
week 4 Page 179
Lecture 50
Wednesday, August 31, 2016
5:33 PM
1. Identify the common tumors which occur in the pancreas and biliary tree.
a. Pancreatic ductal adenocarcinoma
b. Cystic tumors of the pancreas
i. Mucinous Cystic Neoplasm
ii. Intraductal Papillary Mucinous Neoplasms
1) Main Duct IPMN
2) Side Branch IPMN
c. Cholangiocarcinoma
d. Gallbladder Carcinoma
2. Understand factors which contribute to the development of pancreaticobiliary tumors
i. Risk factor
1) Genetics
a) BRCA2/BRCA1
b) TP16 (CDKN2A)
i) FAMMM syndrome
c) PRSS1
i) Hereditary pancreatitis
d) STK11/LKB1
i) PJS
e) MLH1, MSH2, others
i) HPNCC
f) FANC-C, FANC-G
i) Young age onset PC
g) Palladin
i) Family x
2) Environmental
a) Cigarette Smoking
i) Contribute to 20-25% of all pancreatic tumors
b) DM
b. Cholangiocarcinoma
i. Other cholangiopathies
1) Caroli's disease
2) Choledochal cysts
a) Types 1 and 4
c. Gallbladder Carcinoma
i. Cholethiasis
1) 65-90%
ii. Adenomatous polyps of gallbladder
1) Correlates w/ size, type, and growth rate
a) EX: greater than 1cm, sessile, and associated w/ gallstones, rapid
increase in size, arterial flow, or symptomatic-->increased
malignancy
d. Definite
i. Smoking
ii. Hereditary pancreatitis
iii. Other syndromes
week 4 Page 180
iii. Other syndromes

iv. Diabetes
v. Obesity
e. Possible
i. Diet
1) Fat, dairy, red meat, soda
ii. Chronic inflammation
iii. EtOH
iv. Low vitamin D
v. Chemical exposures
3. Recognize the clinical presentation of the different pancreaticobiliary tumors.
i. Only a small number of patients present w/ a resectable tumor at the time of
diagnosis
ii. Only experience symptoms late in course
iii. Tumors in head
1) Produce symptoms earlier
iv. Distal tumors
1) Silent presentation
v. Jaundice 1st sign
vi. Pancreatic exocrine insufficiency
1) Steatorrhea
2) Malabsorption
vii. Pain
1) Low intensity, dull, vaguely localized to upper abdomen
2) Advanced
a) May be localized to middle and upper back
3) Postprandial
a) Lead to reduced caloric intake
viii. Nausea, fatigue, anorexia, and weight loss
ix. New onset DM
x. Glucose intolerance
1) Women
2) In pancreatic body and tail
3) Almost always solitary
4) asymptomatic
1) Main Duct IPMN
a) Slow dilatation of main pancreatic duct >5mm
2) Side Branch IPMN
a) Communication of cystic lesion w/ main duct definable by
MRI/MRCP imaging
3) Fish mouth deformity
a) Secondary to mucin overproduction and extrusion
i. Non-specific symptoms
1) Ab pain
2) Weight loss
ii. Jaundice
week 4 Page 181
ii. Jaundice
iii. Cholangitis
iv. #1 risk factor is PSC
4. Understand the management of pancreaticobiliary tumors.
i. Resection is only chance for a cure
ii. Unresectable patients may benefit from chemo
iii. Metastatic disease may benefit from chemo or other palliative treatments
1) Prognosis is excellent if MCN is removed prior to invasion
1) Main Duct IPMN
2) Side Branch IPMN
i. Complete resection
ii. Outcomes after R0 resection
1) 5 YSR 25-40%
2) Few
iii. Few patients resectable
iv. Palliating effects of biliary obstruction is often primary treatment objective
i. Surgical resection is the only potentially curative treatment
ii. Only a small # of patients are surgical candidates
week 4 Page 182
Lecture 51
Saturday, September 3, 2016
6:13 PM
1. Define process of nutrition and recognize variability of nutritional requirement in health and in
disease states
a. Process
i. Mouth: chew food w/ saliva
ii. Esophagus: transport
iii. Stomach: mix acidic fluid w/ proteolytic/lipolytic enzymes
iv. Small Intestines: most of digestion (except alcohol)
v. Colon: absorb electrolytes and scant residual nutrients
1) Fiber/resistant starch is fermented at brush border
vi. Large intestine: storage for waste, defecation, controlled by distal colon, rectum, and
anus
b. Normal varaition by stage in life/age
2. Perform clinical assessment of nutritional status

a. Clinical history
b. BMI
i. Measure of adiposity, as indicatory of total body fat
ii. Body mass index (kg/m2) = weight (kg) / height (m)^2
1) <18.5 = underweight
a) <16= eating disorder
2) 18.5-24.9 = -6.4 healthy
3) 3--34.9 = 37.9 obese
4) >40 = morbidly obese
3. Identify and know the difference between food allergy and food intolerance
a. Allergy
i. Immune mediated reaction (IgE mediated)
1) Acute onset symptoms: targets skin, GI, respiratory tract, CV system
2) Mild to life threatening
a) Eggs, milk, peanut, soy, wheat, and fish
b. Intolerance
i. Abnormal physiological response to ingested food or food additive
1) Toxic: histamine in scombroid fish poison, toxins of salmonella or shigella
2) Pharm: caffeine or tyramine in aged cheese
3) Idiosyncratic: lactase deficiency
4) Additives: MSG, FD&C yellow #5, BHA, BT
4. Awareness of cultural nutritional habits and appropriate food proportions

a. Cultural differences
i. Availability of type and quantity of food
ii. Domestic vs 3rd world countries food proportion/allotment
iii. Perception of health and beauty
5. Discuss health policy changes to modify dietary behavior toward better nutrition
a. Soda tax
b. Low fat lunch options for public schools
week 5 Page 183
b. Low fat lunch options for public schools

c. Required "nutrition fact" listing by vending machines/major restaurants
6. Know the difference between additives and adulterants
a. Additive
i. Substance w/ the intended use of which results in its becoming a component affecting
the characteristic of any food
1) Direct: added for a specific purpose in that food
a) Xantham gum, chocolate milk, bakery fillings, puddings
2) Indirect: becomes part of the food in trace amounts due to its packaging,
storage, or other handling
a) Small amounts of packaging substances in foods during storage
b. Adulterant
i. When an ingredient is replaced partially or fully w/ something different w/out
knowledge of the consumer
1) Vanilla extract, maple syrup, grape wine, coffee, apple juice, saffron, honey,
milk
7. Know how to interpret food labels
a. Components
i. Calories / serving
ii. Fats
iii. Carbs/fiber
iv. Sugars
v. Vitamins
vi. Ingredients
vii. % daily value
b. GMO
i. Food that contains ingredients made from plants that were genetically engineered
1) Usually grains, like corn syrup, soybean, canola, flours, and rice
c. Terms
i. 100% natural
1) Meats and stuff that must be minimally processed and contain no artificial
ingredients
a) Doesnt define artificial, so can have chemical sweeteners, preservatives,
antibiotics
ii. Naturally raised
a) Livestock raised w/out growth promotants, antibiotics and have never
been fed animal byproducts
d. Organic
i. Raw, fresh products and processed products that contain organic agricultural
ingredients
1) Meets:
a) Made w/out excluding methods
i) Antibiotics, genetic engineering, ionizing radiation, or sewage
sludge
b) Made using allowed substances
c) Oversaw by USDA national organic program
ii. USDA has 3 label categories
1) 100% organic - 100% organic ingredients
2) Organic - 95% organic
3) Made w/ organic products - 70% w/ strict restrictions on remaining 30%
including non GMO
e. Flavors
week 5 Page 184
e. Flavors
i. Natural
1) Essential oil, essence, or extract which contains the flavoring constituents
derived from a spice, fruit, vegetable, herb, meat, etc whose significant function
is flavoring rather than nutritional
ii. Artificial
1) Come from ingredients that are not edible (petroleum)
2) Sometimes contain the exact same chemicals as natural flavors, BUT produced
through different methods
iii. Natural flavor is NOT necessarily healthier or purer than an artificial one
week 5 Page 185
Lecture 52
6:47 PM
1. Discuss the role of macronutrients in the diet

a. Chemical compounds consumed in large quantities that provide bulk energy to an organism
for its metabolic needs
2. Identify specific sources of macronutrients in the diet
a. Carbs:
i. Sugars, starches, and fiber
1) Sugars:
a) Fructose - main sweetener in US. Found in high fructose corn syrup, lead
to weight gain
2) Starches: multiple linked glucose units
a) Potatoes, grains (rice, oats, wheat, corn) or legumes (beans & peas)
3) Fiber:
a) Dietary: non digestible carb and lingin
i) Fruits, veggies, breads, pastas, nuts, oatmeal
b) Functional: extracted from either natural sources or made synthetically
and added to foods and beverages
b. Proteins
i. Animal proteins: meat/seafood, eggs,
ii. Legumes: beans, nuts, and seeds and cereals
iii. Powders: whey or casein or soy
c. Lipids
i. Fatty Acids: vegetable oils (mainly saturated/unsaturated)
1) Monounsaturated: canola/olive oil
2) Unsaturated: peanut, cotton, and corn oil
3) Mixed: sunflower oil
ii. Trans/saturated: mainly from animal proteins
1) Mediterranean diet: high in monounsaturated fats
3. Interpret the meaning and range of glycemic index

a. Measurement of the impact of carb containing foods on blood glucose levels
b. Determined by measuring the rise in blood glucose after consuming 50g of carbs w/ a
reference food (white bread) that has a glycemic index of 100%
i. Low GI - 55 or less
1) Peanuts, apple, wheat tortilla
ii. Medium - 56-69
1) Coke, honey, banana
iii. High GI 70 or more
1) Gatorade, graham cracker
iv. Mixed meals
1) Fat and protein ingested during a meal may alter the glycemic response, but
higher glycemic foods will still lead to a higher glycemic response than lower
ones
c. Food temp alters GIi. Cold potatoes and pasta are lower than when warm
ii. Al dente pasta has a lower GI than when well cooked
4. Recall states of protein deficiency and increased requirement
week 5 Page 186
4. Recall states of protein deficiency and increased requirement

a. Decreased caloric intake, protein is used for glucose production and oxidation
b. Marasmus
i. Occurs after prolonged starvation in which all body fat mass is depleted, in absence of
inflammation
1) Cachexia - loss of lean body mass in presence of chronic inflammation
a) Cancer, pulmonary disease
ii. Develops over months to years
iii. Starved appearance, reduces triceps skin fold, midarm muscle circumference
iv. Albumin is normal in ,marasmus but decreased in cachexia
v. Low risk of death
c. Kwashiorkor
i. Occurs in acute disease such as trauma, or sepsis where there are increased protein
and energy requirements and intake is limited
ii. Occurs acutely over course of weeks
iii. BMI is normal, easy hair pluckability, edema
1) Characteristic lab findings
a) Serum albumin < 2.8g/dl
b) Total iron binding capacity < 200 ug/dl
c) Lymphocytes < 1500/uL
d) Anergy
e) High risk of mortality
5. Understand the role of fats in the diet and associated health effects
a. Lipids are required for multiple functions including hormone synthesis and cell membranes
and tissues
b. Vegetable oils in the diet provide essential fatty acids- linoleic and linolenici. help w/ digestion of fat soluble vitamins
c. Trans fats:
i. Negative effects on LDL and HLDL
1) May disrupt desaturation of omega 3 fatty acids
d. Saturated fatty acids
i. Replacing w/ polyunsaturated fats may decrease heart disease risk
e. Vitamin E
i. Decreased uptake of oxidized LDL by decreasing the expression of CD36 receptors
(take up LDL in macrophages)
f. Plasmalipoproteins
i. Fiber can decrease LDL
1) Every gram increase in fiber can decrease LDL by 2.2 mg/dL
g. Essential fatty acid requirements
i. Linoleic and linolenic acid are required for synthesis of other fatty acids needed for
skin and cell membrane functions, prostaglandin, and leukotriene function
week 5 Page 187
Lecture 53
8:04 PM
1. Know the major vitamins, minerals and trace elements with an awareness of nutritional sources
a. Vitamins
i. Fat soluble:
1) A: liver, dairy products, dark (yellow/orange) fruits, green leafy veggies
2) D: sunlight (UV), fortified foods (milk, grains), fatty fish and fish oil, plants and
grains
3) E: veggies, grains, nuts, oils, milk products, fish, meat, fortified cereal,
supplements
4) K: intestinal flora, diet (widely available), recycled
ii. Water soluble
1) C: plant and animal sources (citrus fruits, milk, liver)
2) B1 (Thiamine): diet, deficient in "refined foods" liked polished rice, white flour,
and white sugar
3) B2 (Riboflavin): milk products, green leafy vegies, liver, meat, fortified foods,
coloring agent (yellow-orange)
4) B3 (Niacin): grains, legumes, seed oils, meats (coloring agent in meats), can be
synthesized from tryptophan
5) B6 (Pyridoxine): diet, so deficiency is rare
6) B9 (Folic Acid): whole-wheat flour, beans, nuts, green leafy veggies, liver
7) B12 (Cobalamin): meat and milk products, fortified foods
b. Minerals:
i. Sodium
ii. Potassium
iii. Calcium
iv. Magnesium
v. Phosphorus
c. Trace Elements:
i. Zinc
ii. Iron
iii. Iodine
iv. Copper
v. Fluoride
vi. Selenium
2. Recognize the signs and symptoms associated with deficiencies of vitamins and trace elements.
a. Vitamins
i. Fat soluble:
1) A:
a) Follicular dermatosis
b) Night blindness (earliest manifestation)
i) Bitot spot-small opaque plaques of built-up keratin debris
ii) Keratomalacia-softening and destruction of the cornea
c) Xerophthalmia
d) Squamous metaplasia of respiratory and urothelial mucosae
e) Immune deficiency
2) D:
a) Excess un-mineralized osteoid
i) Rickets:
One. Frontal bossing
week 5 Page 188
One. Frontal bossing

Two. Rachitic rosary
Three. Harrison's groove
Four. Kyphoscoliosis
Five. Genu valgus/varus
Six. Greenstick fractures
Seven. Widened wrists and ankles
ii) Osteomalacia (adults)
One. Bone is weak and vulnerable to fractures, most likely vertebral
and femoral necks
Two. Deranged bone remodeling
3) E: deficiency rare
4) K:
a) Fat malabsorption syndrome, biliary tract disease
b) Destruction of endogenous K synthesizing flora w/ antibiotics
c) Neonatal period: liver reserves are small, bacteria not well developed
i) Bleeding diathesis (hemorrhagic disease of the newborn)
ii. Water soluble
1) C:
a) Hemorrhages
i) Purpura and ecchymoses on skin and gingival mucosa
ii) Subperiosteal hemorrhages and hemarthroses
iii) Retrobulbar, subarachnoid, intracerebral hemorrhages
b) Skeletal
i) Poor formation of osteoid matrix-->cartilaginous overgrowth and
widening of epiphyses
ii) Bowing of long bones of legs
iii) Sternal depression
c) Perifollicular, hyperkeratotic, papular rash, ringed by hemorrhages
d) Impaired wound healing
2) B1:
a) Chronic alcoholics
b) Dry beriberi (polyneuropathy)
i) Myelin degeneration
ii) Motor and sensory neurons
iii) Toes and foot drop, wrist drop
c) Wet beriberi (CV syndrome)
i) Dilated cardiomyopathy
ii) Heart failure, peripheral edema
d) Wernicke-Korsakoff syndrome
i) Retrograde amnesia w/ confabulation
ii) Inability to acquire new info
iii) DOES NOT respond to thiamine administration
3) B2:
a) Angular stomatitis/cheilosis, glossitis
b) Interstitial keratitits w/ neovascularization
c) Dermatitis of cheeks, scrotum, and vulva
4) B3:
a) Pelagra
i) Diarrhea
One. Atrophy & ulceration of GI mucosa
ii) Dermatitis, glossitis
One. Casal's necklace
iii) Dementia
week 5 Page 189
iii) Dementia
5) B6:
a)
b)
c)
d)
6) B9:
a)
7) B12:
a)
b)
c)
d)
Dermatitis
Cheilosis, glossitis
Peripheral neuropathy
convulsions
Megaloblastic anemia
Megaloblastic anemia
Sore tongue, taste bud atrophy
Small bowel atrophy, diarrhea, weight loss
Subacute combined degeneration
b. Trace Elements
i. Zinc
1) Rash around eyes, mouth, nose, anus
2) Anorexia and diarrhea
3) Growth retardation in children
4) Depressed mental function
5) Depressed wound healing and immune response
6) Impaired night vision
7) infertility
ii. Iron
1) Hypochromic, microcytic anemia
iii. Iodine
1) Goiter and hypothyroidism
2) Poor neurodevelopment, poor growth, cretinism
iv. Copper
1) Hypochromic anemia resistant to iron
2) Muscle weakness
3) Neurologic defects
4) Abnormal collagen cross-linking
v. Fluoride
1) Dental caries
vi. Selenium
1) Myopathy
2) Cardiomyopathy (keshan disease)
3) Fingernail-bed abnormalities
4) Psuedoalbinism, alopecia, growth retardation,
3. Identify signs and symptoms associated with toxicities of fat-soluble vitamins.
a. Vitamins
i. Fat soluble:
1) A:
a) Teratogenic effects
i) Cleft palate, ear defects
ii) Cardiovascular defects
iii) Renal defects
iv) Limb defects
v) Thymic agenesis
vi) Embryonic lethality
2) D:
week 5 Page 190
2) D:
a) Anorexia, nausea, and vomiting
b) Polyuria, polydipsia
c) Weakness, nervousness, pruritus,
d) Impaired renal function
e) Metastatic calcification
3) E: toxicities rare
4) K:
a) K1 is safe
b) K2 is questionably safe
c) K3 is toxic
i) Banned from supplements
ii) Causes allergic reactions
iii) Hemolytic anemia
iv) Cytotoxicity in liver cells
4. Recognize that supplements can have interactions with food and prescription
a. Specific to drug/supplement/herb taken
b. Recognize that each situation has the potential for possible interaction or side effects
5. Awareness regarding regulation of vitamins/supplements

a. Dietary supplements have variable quality standards
i. FDA delegates responsibility to the manufacturer to ensure safety
ii. No direct FDA regulatory requirements like prescription drug/OTC drugs
b. 2 nonprofits perform testing on manufacture's who voluntarily submit to their evaluation of
purity and quality
week 5 Page 191
Lecture 54
Wednesday, September 7, 2016
12:34 PM
1. Describe how members of the healthcare team screen patients for malnutrition in an acute
care setting
a. Clinical Nutrition Assessment
i. Use of history, PE, biomarkers, etc to determine risk of malnutrition for the purposes
of prevention and treatments
b. PE
i. Low body fat stores
ii. Muscle wasting
iii. Ulceration of the skin or mucosa
iv. Various skin rashes
v. BMI
1) <18.5 moderate
2) <16 severe
3) <13 lethal in males
4) <11 lethal in females
c. Nutrition risk scores
i. SAG (subjective global assessment): validated method that includes factors like weight
change, dietary intake, GI symptoms, functional status and exam findings
1) NRS and NUTRIC score are used for risk-stratification of patients in ICU
a) Determine both nutritional status and disease severity
2. Identify patients who may be at risk for malnutrition and determine their energy requirements
a. Estimating nutrition requirements
i. Predictive equations
1) Harris-Benedict
a) Estimate an individual's BMR
i) Men: 66.5 + (13.75 X wght kg) + (5.003 X cm) - (6.755 X age)
ii) Women: 655.1+(9.563Xweight(kg)+(1.850Xheight(cm))-(4.676Xage)
b) BMR is multiplied by activity factor to estimate maintenance needs
c) Confounding factors:
i) Temp-fever
ii) Inflammation-cytokines
iii) Weight-edema
iv) Losses-wound exudation
v) Accuracy 40-75% in critically ill patients
2) Ireton-Jones
3) Emperic
a) 25-30 kcal/kg/day
ii. Indirect calorimetry
1) Most accurate method
2) Respiratory quotient = CO2 eliminated / O2 consumed
3) Production of chemical energy is proportional to gas exchange
b. Obese:
i. High-protein hypocaloric feeding
3. Summarize the indications for enteral and parenteral nutrition therapy, modes of
administration and complications
a. Used when patient's ability to ingest and/or absorb nutrients is impaired
i. Most commonly seen during recovery from acute illness
week 5 Page 192
i. Most commonly seen during recovery from acute illness

1) Systemic response to infection
2) Inflammation or injury in extended critical illness
3) Loss of bowel function or length
ii. EN (enteral): in critically ill patients
1) Preserve mucosal immunity of the gut
2) Prevent infectious morbidity
3) Reduce length of stay in ICU
4) Started 24-48 hrs after admission to ICU
b. Enteral routes:
i. Depends of length or therapy, risk of aspiration, if planned surgery, and volume and
viscosity of formula to be administered
ii. Nasal:
1) Short-term <4 weeks
2) Easy to initiate early
3) Can cause nasal irritation
4) Contraindicated
a) Maxillofacial trauma/infections
b) Confusion
5) Nasogastric:
a) Normal gastric motility and a low risk of aspiration
6) Nasoduodenum/jejunum:
a) Disordered gastric motility, nausea and vomiting, or esophageal reflux
iii. Percutaneous
1) Long term > 4 weeks
2) Planned/post-surgery
3) Wider bore (less clogs)
c. Enteral Complications
i. Feeding tube issues
1) Irritation: nostril, sinusitis, ab wall
2) Dislodgement: confused patient, breakage
ii. Aspiration
1) Position patient at 45 degrees
2) Monitor for signs: cough, coarse lung sounds, fever
3) Check residual gastric volumes: but not in ICU
iii. Diarrhea
1) Multifactorial: antibiotics, dysmotility, malabsorption, bacterial overgrowth
2) Fiber helps or consider changing formula
d. Parenteral nutrition
i. When oral and enteral nutrition not possible
ii. Short bowel, bowel obstruction, GI fistula, post-GI surgery
iii. Routes:
1) Peripheral parenteral
a) PPNM administered via smaller peripheral vein
b) Osmolality needs to be < 900 mOsm/L: pain, infiltration and thrombosis
c) Requires larger volumes of fluid-can overload
d) Addition of hydrocortisone may help reduce irritation
2) Total parenteral nutrition
a) Administered via central vein or peripherally inserted central catheter
iv. Complications
1) Bloodstream infection
a) Prevent w/ hand hygeine, eductaion, tunneled catheter w/ fewer
ports/lumens
2) Metabolic effects
week 5 Page 193
2) Metabolic effects
a) Hyperglycemia
b) Electrolyte abnormalities
c) Macro-/Micro- nutrients deficiencies
d) Refeeding syndrome
e) Fatty lvier
f) Hypertriglyceridemia
3) Vascular problems
a) Bleeding and vascular injury
b) Thrombosis
c) Cather dis-/mis- placement
d) pneumothorax
4. Discuss that nutritional support in palliative and terminal situations may not be indicated
a. Provision of artificial nutrition and hydration to patients who are expected to die w/in
days/weeks is not usually beneficial
b. Voluntary cessation of nutrition intake is a medically and legally acceptable step for patients
at end of life
week 5 Page 194
Lecture 55
Wednesday, September 7, 2016
1:20 PM
1. Compare the commonly used bariatric surgeries and their anatomical differences
a. Jejuno-ileal bypass
i. Surgical excision of 50% of distal SB caused 50% weight loss in 24 weeks
ii. Calories lost due to fat malabsorption
b. Adjustable gastric band
i. 15%
ii. Around upper aprt of stomach
c. Sleeve gastrectomy
i. Most popular surgery in US
ii. 75% of stomac is removed
iii. No diversion of nutrients
iv. Metabolic improvements (eg, DM curing) not as profound
v. "restrictive" procedure
vi. 21.1%
d. Roux-en-Y gastric bypass
i. Proximal stomach is made into a small pouch
1) Distal end of pouch is attached to the jejunum
ii. Restrictive and malabsorptive
iii. Malabsorption proportional to common channel length
iv. 24.5%
e. Biliopancreatic diversion w/ duodenal switch
i. 33.82%
ii. Sleeve gastrectomy
1) Duodenum is divided distal to the pylorus and attached to the small intestine
around 150 cm proximal to the ileocecal valve
2. Discuss the mode of action and complications of commonly used bariatric surgeries
a. Jeuno-ileal bypass
b. Adjustable gastric band
i. Esophageal dilatation
ii. Band slippage
iii. erosion
c. Sleeve gastrectomy
i. Leakage from staple line
ii. Gastric stricture
iii. GERD
d. Roux-en Y gastric bypass
i. Diversion of nutrients increases risk of nutritional deficiencies
ii. Dumping syndrome
iii. Diarrhea
iv. Ulceration
v. Anemia
vi. Strictures
vii. leakage
e. Biliopancreatic diversion w/ duodenal switch
i. Highest rates of complications
ii. Nutritional deficiencies (esp fat soluble vitamins)
iii. Anemia
iv. Diarrhea
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iv.
v.
vi.
vii.
viii.
Diarrhea
Dumping syndrome
Leakage
GERD/vomiting
strictures
f. Mechanism of action
i. Restricts food intake, calorie and nutrient absorption
ii. Metabolic improvements
1) Increased incretin hormones
a) Glucagon-like peptide
2) Circulating bile acids
a) Facilitate improvements in glucose control
iii. Changes in apetite
iv. Nutrient sensing
v. White and brown adipose tissues
vi. Alteration in the gut microbiota
3. Review approved weight loss devices and their modes of action

a. Gastric balloon devices
i. Action
1) Single chamber Orbera and double-chamber reshape
b. Vagus nerve stimulator
i. Emulate vagal interruption that occurs as part of bariatric surgery
ii. Battery powered stimulator is inserted laparoscopically w/ leads attached to the
anterior and posterior vagus nerve trunks
iii. Decrease food intake by decreasing gastric accommodation
c. Aspire assist gastrectomy
i. Endoscopically placed gastrostomy port
1) Aspirate meal contents from the stomach 20-30 minutes after mealtimes
2) Causes weight loss by calorie removal
4. Identify newer weight loss procedures that are undergoing evaluation
a. Mini gastric bypass (single anastomosis gastric bypass)
b. Duodenal-jujunal bypass liner (DJBL)
i. Polymer sleeve inserted into proximal duodenum and allows bypass of undigested
food through upper small bowel
c. Duodenal mucosal resurfacing (DMR)
i. Heated balloon causes thermal injury to duodenal mucosa
ii. Altered absorption of nutrients and hormonal changes in proximal small intestine
week 5 Page 196

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Lecture 1

Monday, August 8, 2016

Distention, excavated abdomen, collateral veins

Lecture 3: Microanatomy of the Digestive System

What are the components of the alimentary canal?

What is the structure and function of mucosa of the alimentary canal?

What is the structure and function of salivary glands of oral mucosa?

What are the types of salivary glands?

What is the structure and function of the tongue?

What is the structure and function of the pharynx?

What is the structure and function of the esophagus?

What is the structure and function of the esophagus?

What are the esophageal sphincters?

What is the structure and function of the stomach mucosa?

What structures of the small intestine help maximize surface area?

What structures of the small intestine help maximize surface area?

**Summarize the histologic differences in the sections of the small intestine.

Describe intestinal neuronal dysplasia.

What is the structure and function of the rectum?

What is the structure and function of the appendix?

What is the function of the liver?

Describe the gross anatomy of the liver.

Describe lobule microanatomy.

What are the components of the biliary tree?

What is the structure and function of the cystic duct?

What is the structure and function of the gallbladder?

What is the structure and function of the gallbladder?

What is the structure and function of the pancreas?

Describe the different pathways of bile flow.

Understand and describe the functions of saliva.

c. ECL cells can be activated

1. List and explain the composition and functions of pancreatic secretions.

allowing them to be opened and activated

4. Know and understand the composition and functions of bile.

water from the gall bladder lumen into the blood

2) PepT1 is an important transporter of oligopeptides

b. Get Net NaCl reabsorption all along GI tract

c. Leaky epithelia (high permeability) allow for more water reabsorption

a. Slow waves are generated by ICC pacemaker cells

1) Duodenal chemoreceptors sense many features of chyme

i. Closely related to shigella

Second most common acute bacterial diarrheal disease

2. Nosocomial and antibiotic-associated diarrhea

i. Asymptomatic carriage to severe diarrhea to malaborption

Tuesday, August 23, 2016

3 day rule for stool

1. Salmonella is an equal opportunity bug

1. Learn the pathophysiology and clinical presentation and management of xerostomia

b) 20% of cases assoc w/ genetic cancer syndrome MEN1 gene

2. Understand what constitutes protein-losing enteropathy and its main causes.

3. Be able to outline the main diagnostic algorithm for malabsorption.

b) Measure bicarb or amylase in response to secretin stimulation

1. Acquire a general knowledge of the causes for dysphagia

3. Understand the general algorithm to investigate dysphagia

1. Understand the pathology and pathophysiology of GERD

ii. Mechanisms that cause symptoms

a) More proximal extent and greater distention of esophagus

2. Be able to outline the diagnostic evaluation and treatment of uncomplicated cases

iii. Typical symptoms: heartburn, dysphagia

1. Learn the basic pathophysiology and clinical presentation of gastroparesis

2. Describe the development of squamous cell carcinoma of the oral cavity

Disorderly cellular arrangement

ii. Predisposing risk factor