Unit 1- GI Flashcards
Histo info
digest things “outside” of body/cells then absorb
Histo GI layers
mucosa (incl epithelium, lamina propria, then muscularis mucosa)
submucosa
muscularis propria
adventitia
mucosa layer mucins glands lamina propria muscularis mucosa
wavy epithelial surface on top of basal lamina
-barrier is selective for certain molecs
surface: mucins
heavily glycosylated (Ser; Thr) w/ sugars and -OH groups (hydrated) and disulfide bonds
-highly resistant to digestion
glands: mucosal glands (and submucosal glands) accessory glands (ex pancreas) completely outside of mucosa/submucosa
Loose CT- lamina propria
- lots of capillaries
- lots of lymphocytes around the capillaries (even more toward colon)- mostly producing IgA
smooth muscle layer- muscularis mucosa
thickness depends on where you are in GI
demarcates mucosa and submucosa
submucosa
muscle layers
serosa
nerve plexi
more dense CT
can have glands
outside: most of the GI has smooth muscle layers- “inner circular” and “outer longitudinal” layers
- stomach has additional oblique muscular layer
very outside: serosa: adventitia w/ large blood vessels and large nerves; has mesothelial layer around it; (all places except esophagus have serosa)
Meissner’s plexus: nerve plexus running in here to stimulate the muscularis mucosa and glandular secretions
Auerbach’s plexus: runs between inner circular and outer longitudinal layers
M cells
enteroendocrine cells
M cells:
survey things in gut- lots of sampling components (antigens, nl flora)
-fast response w/ macrophages and local immune responses if epi layer or integument is compromised
Enteroendocrine cells:
secrete into the local blood supply
-secrete Gastrin, Polycystikinan, and Secretin
stomach mucosa histo
gastric gland cells
thick mucosa that has GLANDS that come in and branch deep into mucosa
ascinar cells at the end of the branches
glandular
gastric gland-
3 main types of cells here
runs all the way down to the muscularis mucosa
1 cell in neck at top: goblet (mucus secreting cell)
another cell- parietal cell (fried egg; prod HCl)
- large canaliculi
- proton pump to acidify stomach
- large SA; lots of mito
chief cells- at bottom; prod pepsinogen (zymogen); activated in low pH
enteroendocrine cell- not much contact w/ luminal surface; secretes into blood via basolateral side (prod gastrin)
this is all within the lamina propria
muscularis mucosa squeezes to help glands move things out as it contracts
intestine histo
SI vilar surface lined by epithelium large SA for abs at the ends we have small microvillar surface called enterocytes- large SA for Na/K ATPase to take up molecs
Crypts:
Crypts of Lieberkuhn (esp defined in SI)
-special Paneth cells (granular); prod Defensins- antibacterial and lysozyme; primarily involved in preventing bac growth if it makes it alive to duodenum
extend into submucosa via Brunner’s glands- primarily prod NaHCO3- only found in duodenum
intestinal ridges: plicae circularis (inc SA by 2-3 fold)
Jejunum has plicae circularis and crypts of Lieberkuhn
Ileum has peyer’s patches (lymphoid aggregates)
Colon:
thick mucosa
number of linear, highly regular crypts filled w/ mucus secreting cells (test tube rack)
goblet cells for lube
absorb water and salts
conc fecal matter
still have muscularis mucosa, and lamina propria and lymphocytes
-layer underneath: adipose cells mixed/ w/ some muscle strands
serous demilune- help flush water material into duct
can have myoepithelial cells arranged in web around individual acinar cells- contract to help force components out of individual acinar cells
esophagus histo
transition to stomach
has mucosal layer- mainly protective (not digestion)
inner circular and outer longitudinal muscle layers
skeletal muscle at top 1/3 and smooth muscle at bottom 1/3; mix in between
transition to stomach:
contraction of diaphragm mainly keeps the separation largely constricts; not really a sphincter there
stomach regions sphincters reservoir and pump funcs nl HCl acid secretion protection injury
cardia, corpus, pylorus
true sphincter- pyloric sphincter (to duodenum)
allows stomach to have low pH to denature proteins and prevent unwanted flow to duodenum
Reservoir and pump function o receptive relaxation ♣ fundus o solid emptying ♣ vagally-mediated contractions o residual solids emptied ♣ During non-fed state by MMC every 90-120 min
nl HCl acid secretion o Acid secretion: ♣ Denature proteins ♣ Protect from infection ♣ Aids in abs of iron and vit B12 o Mediated by ♣ Neural, hormonal, and paracrine pathways
protection
surface mucus secretion, bicarbonate secretion into mucus; mucosal blood flow; epithelail barrier func; epi regenerative capacity; elaboration of prostaglandins
Injury, ischemia, shock, NSAIDs can alter the protective mech’s of the stomach
lymphatic channel
in the center of lamina propria and going into submucosa- lymphatic channel called lacteal
all throughout villus and mucosa
-lots of capillaries for large blood flow
water goes into lacteal
any fats we take up to into lacteal as chylomicrons
enterocytes are involved in syn as those triglycerides as the monoglyceride fats come across the cell
-have to digest then rebuild triglycerides to not clog things up
enzyme proteins at surface
enterokinase- proteolytic enzyme (not a phosphorylizer as the name implies) acts on trypsinogen from the pancreas converted to trypsin and activates the other zymogens that are also coming from pancreas
pancreas enzymes0 usually optimal at pH 7
lactase:
converts lactose to glucose and galactose
maltase-
breakdown of maltose into glucose
sucrose-
breaks down sucrose into fructose and glucose
these are cell surface proteins because don’t want to lose sugar proteins to bac
transport sugars, AAs, and other things to lacteals
bile salts from gallbladder/liver
important for emulsifying fats
wedge-shaped
polar ends, fit into lipid regions
lipases can degrade the lipases
what causes GI motility disorders
4 things
ENS-
missing, immature, damaged by infection, influenced by chem sub’s (inside and outside) = neuropathic
neurons
Diseased GI muscles
genetic defect (muscular dystrophy) or acquired (progressive systemic sclerosis) = myopathic
muscles
Abnormalities of intestinal cells of Cajal
pacemaker (Stims baseline contraction)
CNS disorders
-signals from CNS are impaired
esophageal manometry
used to dx esophageal disease
-visually highlight disorders
-esophageal pressure waves during swallowing- measure func
-swallow repetitively to measure P transmitted throughout;
looking at contraction/relaxation of UES and LES
esophagus-
dysphagia and heartburn
achalasia
no LES relaxation
absence of peristalsis
achalasia- hallmark of esophageal motility disorder (get dysphasia)
esophagus-
scleroderma/progressive systemic sclerosis PSS
multi sys disorder:
- obliterative small vessel vasculitis
- CT proliferation w/ fibrosis of multiple organs
GI manifestations 80-90%
-principal path’s are SM atrophy and gut wall fibrosis (predominately myopathic process)
characteristic “weakness of esophageal muscle disorder”
esophageal manifestations:
SM atrophy- weak peristalsis - dysphagia
SM atrophy- weak LES- GERD
unrepentant GERD- esophagitis - stricture
see nl high pressure in UE (striated, not smooth muscle); then absence of peristalsis and weak LES
esophagus- spastic disorders
uncertain etiology;
peristalsis preserved
symptoms usually chest pain and dysphagia
pathophys related to overactivity of excitatory nerves (an impairment of inhib innervations or overactivity of SM response)
gradient of excitatory/cholinergic and inhib/noncholinergic nerves in SM portion of esophagus
-greater conc of inhib nerves distally; overtime of activity or absence of inhibition
jackhammer esophagus on imaging
stomach- gastric motility
gastric pacemaker
interstitial cells of Cajal
proximal body along greater curvature
funds and proximal body
storage
low P to receive food- relaxation
distal body and antrum
-processing/grinding
emptying
stomach- emptying and reservoir func
emptying: receptive relaxation (vagally mediated inhib of body tone)
liquid emptying by tonic P gradient
solid emptying by vagally-mediated contractions
residual solids emptied during non-fed state by MMC every 90-120 min
reservoir:
receptive relaxation
-swallowing-induced vagal response
accommodation
-SM relaxation elicited by mechanical distention of stomach (gastric mechanoreceptors)
vasovagal response
gastroparesis
clinical manifestations
major causes
Dx
management
stomach paralysis
impaired transit of food from stomach to duodenum
(mechanical obstruction of gastric outlet excluded)
clinical manifestations: N/V early satiety postprandial abdominal distention postprandial abdominal pain
major causes
idiopathic (post infectious?)
post surgical (vagal nerve injury)- gastric, esophageal, thoracic surgeries: lung tx
diabetic
med-related (opiates)
others (rheum, paraneoplastic, neuro, myopathic- scleroderma!)
dx
gastric emptying study
Gastric scintigraphy: low fat EggBeaters radio labeled w/ Technetium 99
abnl: retention >60% at 2 hr or >10% at 4 hrs
management lifestyle/dietary (small and freq meals; low fat and low-residue diet; glucose control in diabetes) meds (pro kinetics; antiemetics) gastric electric stim surgery (2%)
SI nl
fed state
fasted state
~21 ft long; ~1 in diameter
fed state: primary motility is segmentation
9-12 contractions/min (pacemaker cells)
total transit time 3-5 hrs
fasted state: migrating motor complex sequential orderly short peristaltic waves stomach--> caudally sweep gut between meals
small bowel motility disorders
neuropathic
myopathic
CIPO
neuropathic:
nl amplitude of contractions but sustained bursts of uncoord phasic contractions
early return of MMC (migrating motor complex)
inc freq of MMC
myopathic
dec amplitude of contractions or complete lack of any motor activity
some diseases have feature of both
chronic intestinal pseudo-obstruction- CIPO
signs/symptoms of mechanical obstruction of SI without a lesion obstructing flow of contents
characterized by presence of dilation of bowl on imaging
major manifestation of SI dysmotility
SI bac overgrowth is a complication of CIPO: stasis –> bac overgrowth–> fermentation and malabs
symptoms:
N/V 83%
abd bain 74
distention 57
constipation 36
diarrhea 29
urinary Sx 17
etiologies of small bowel motility disorders and CIPO
neuropathic
mixed myopathic and neuropathic
CIPO (child vs adult)
neuropathic: degenerative neuropathies (Parkinson) paraneoplastic autoimmune (anti-Hu Ab) Chagas disease: parasite Trypanosome Cruzi Diabetes assoc (neuropathy)
Mixed myopathic and neuropathic
- infiltrative conditions (Scleroderma*, amyloidosis, eosinophilic gastroenteritis)
- idiopathic
CIPO- diff for children/adults
child:
mostly congenital
mostly primary condition (visceral neuroapthy/myopathy)
absent MMC predicts need for IV nutrition
-1/3 infants die w/in 1st yr of life
colon func
transport, store, and expel stool after absorbing majority of luminal fluid
2 types of motor activity
low amplitude tonic and phasic contractions for mixing luminal contents (Haustra)
high amplitude propagated contractions (HAPCs) for propelling
colonic motility inc after meal (gastrocolonic response) and on awakening
causes of constipation
drugs
mechanical
metabolic (DM*, hypoK, hyperCa, hypoMg, hypothyroid)
MYOPATHY: AMYLOID, SCLERODERMA
NEUROGENIC (Parkinson, spinal cord injury, MS, autonomic neuropathy, HIRSCHSPRUNG’s)
other (pregnancy, immobility)
IBS-C
Nl transmit, slow transmit, DYSSNERGIC DEFACATION
colonic transit studies
sitz marker
scintigraphy
wireless motility capsule
Sitz marker
-24 radiopaque markers in capsule given Day 1
abdominal Xray Day 5
<5 markers nl
>5 in recto-sigmoid suggests defactatory disorder
>5 scattered throughout colon = slow transit
scintigraphy
isotope in delayed-release capsule dissolves in alkaline pH of distal ileum
-gamma cameras scans in 4,24,48 hrs to show colonic distribution
wireless motility capsule
get measurements of pH, temp, and P
anal manometry
eval of incontinence: resting and volitional squeeze, cough reflex test, rectal sensation testing
eval of constipation:
anal resting P
attempted defecation lying left lateral
stim defecation on commode w/ 50 cc balloon
recto-anal inhibitory reflex (absent in Hirschsprung’s**)
rectal sensation testing
Hirschsprung’s disease
congenital absence of myenteric neurons of distal colon (neuropathic motility disorder)
no reflex inhibition of the IAS following rectal distention (no recto-anal inhib reflex)
anal manometry: pressure tracings; deganglionated, distended
pelvic floor dysfunc
define
signs
dx
tx
failure to coordinate the abdominal, rectoanal, and pelvic flow muscles during defecation
anismus (high anal resting pressure) incomplete anal relaxation paradoxical contraction of pelvic floor and external anal sphincters (dyssnergia) rectal hyposensitivity excessive perineal descent rectocele
causes:
bad toilet habits, painful defecation, obstetric or back injury, brain gut dysfunc
dx: dyssnergia
abnl anorectal manometry
reveals: paradoxical contraction of pelvic floor and external anal sphincters
tx:
biofeedback therapy is effective (PT?)
important nl GI motility patterns altered in disease:
esophageal peristalsis LES relaxation LES tonic contraction Gastric emptying Small bowel peristalsis colonic transit sphincter dysfunc
esophageal peristalsis:
achalasia, scleroderma
LES relaxation
achalasia
LES tonic contraction
scleroderma
Gastric emptying
gastropharesis
functional dyspepsia
Small bowel peristalsis
CIPO (scleroderma)
colonic transit
slow transit constipation (scleroderma)
sphincter dysfunc
Hirschsprung’s
dyssnergic defecation
2 types of GI motility
mixing- segmentation
jostled back and forth
constant movement
no progress
propulsive- peristalsis
coord movement along GI to force food from esophagus to anus
aboral to oral peristaltic wave- vomit
smooth muscle in GI
muscle contractility
min 4 diff layers of SM
- 2 longitudinal (push along)
- 2 circular (push down)
muscle contractility mediated by EC influx via VG Ca channels or intracellular Ca release from SR
-Ca binds to calmodulin
Calmodulin phosphorylates myosin
cross bridge cycling
unitary (single unit) cell type
held together w/ adherens junc
communicates electrically via gap junc’s
pacemaker cells w/ spontaneous activity
intrinsically prod BER and muscle tone w/o tension (myogenic properties)
-tension comes from NTs acting on muscles- role of the ANS
ANS innervation of GI tract
parasympathetic-
rest and digest; sit and shit,etc
Vagus nerve and pelvic nerve
sympathetic:
works on C, SM, IM
innervation of the gut wall: ENS
signaling process is bidirectional
basic electrical rhythm
cyclical changes in potential difference; not enough to cause a contraction itself
if you add ACh, the combo of the 2 elicits a contraction during the original waves, even if the ACh is there the whole time
BER is different as you move along GI tract- as you move distally, your BER goes up
stomach BER- 3 cylces/min
duodenum BER- 12 cycles/min
3 phases of digestion
cephalic phase- neural control
gastric phase- neural (early) and hormonal
intestinal- mostly hormonal, some neural
mastication and digestion
chewing and swallowing
3 stages-
1- voluntary (oral cavity then bolus pushed by tongue to oropharynx)
2- involuntary (glottis covers trachea; UES relaxes)
3- involuntary (esophageal peristalsis)
esophagus
func and peristalsis
LES
transports and adjusts food temp
UES and LES
muscular walls transition from skeletal to smooth muscle
thick muscular walls prod strong peristaltic waves
peristalsis-
bolus movement causes wall distention where there’s relaxation below it and contraction above it
LES-
b/w esophagus and stomach
failure to relax due to damage/loss of enteric nerves= achalasia; can cause dysphagia
-more so thickening of muscle wall- not quite sphincter
stomach
func
HCl/gastric acid pepsin pyloric sphincter gastric motility patterns rate of emptying
stores food 3-4 L
HCl/gastric acid disinfects food, denatures, and digests proteins and produces intrinsic factor (Vit B12 abs)
-pepsin req a low pH to work; used in combo w/ HCl to break down
resulting chyme released in peristaltic spurts into duodenum
pyloric sphincter serves as sieve (prevents passage of things >1-2 mm)
gastric motility patterns-
mixing and churning w/ retropulsion and receptive relaxation
rate of emptying:
carbs leave in few hrs
proteins leave more slowly
fats even slower
emesis
steps
vomiting
centrally regulated by vomiting center in brain
steps:
salivation (HCO3) and sensation of nausea
reverse peristalsis from upper SI to stomach
abdominal muscles contract and UES and LES relax
gastric contents are ejected
SI func key hormones digestion, abs motility
liquification: pH adjustment, release of hormones and addition of enzymes in response to food entry
key hormones: CCK, Secretin, GIP
enzymatic digestion of food in lumen and at the enterocyte surface
abs of nutrients, water, and ions occurs via cellular and paracellular pathways
both peristaltic and segmentation motility
intestinal reflexes
gastroileal reflex
gastrocolic reflex
mediated by both ENS and external innervation
gastroileal reflex- stomach activity stim’s movement of chyme through ileocecal sphincter
gastrocolic reflex- food in stomach stim’s mass movement in colon
migrating motor complex MMC
location
phases 1-3
occurs in the absence of feeding (during fasting)- housekeeping
every 90-100 min w/ 3 phases starting from stomach and propagating aborally to ileocecal valve
Motlin (hormone) appears to initiate, but also some neural component
only in SI- not LI
Phase 1-
quiescence occurs 40-60% of the 90 min duration
phase 2-
motility inc but contractions are irregular
fails to propel luminal content
lasts 20-30% of MMC duration
phase 3-
5-10 min of intense contractions
from body of stomach to pylorus to duodenum to ileocecal valve
pylorus FULLY OPENS
ileocecal valve
local reflexes
ileocecal sphincter (Valve) is normally closed (to prevent reflux of bac from colon to ileum)
opened by distention of end of ileum (local reflex)
closed by distention of proximal colon (local reflex)
Large intestines
taenia coli semilunar folds haustra func 2 types of movement evacuation plan
Taenia coli
-small folds to prevent kinking
semilunar folds
-helps conc bolus
haustra
contract bolus into manageable/pinch off pieces easy to elim)
serves as reservoir for undigested foodstuff
main func is to reabsorb water and ions
elim of waste is controlled by 2 sphincters-
internal (involuntary) and external (vol) anal sphincters
2 types of movement- haustration -similar to segmentation; but more marked and in anatomically pre-defined locations of circular muscle layer mass movements -strong peristaltic waves 1-3x/day wave of contraction that usually follows a meal that moves content over larger distance than w/ reg peristalsis; colon is contracted for a while overall slow movement (5-10cm/hr) (NO MMC!)
evacuation plan
filing of rectum causes relaxation of internal anal sphincter via release of VIP and NO from intrinsic nerves
at same time, external anal sphincter contracts- retroanal inhibitory reflex
defecation/evacuation occurs when external anal sphincter is voluntarily relaxed and is enhanced by an inc in intra-abdominal pressure
secretion general properties
tightly regulated process (receptors)
enzymes usually released in pro-enzyme/zymogen form
involved in both maintenance and integrity or inner GI surface (Cl, mucus, HCO3-, etc) in addition to digestive processes
chloride secretion via CFTR channel is one mech for water/ion secretion in the SI and colon
secretory activity in stomach
acid secretion- HCl
kills bac (disinfects at pH 1.0)
begins protein digestion- denatures
activates pepsinogen (active=pepsin)
acid prod parietal cells also secrete intrinsic factor when secreting acid (Vit B12 abs; pernicious anemia)
E consuming process- H//K ATPase pumps across the luminal surface against a sig gradient
mucosal defenses in stomach
HCl secretion is risky, so there are mech’s to confine acidity to stomach as much as possible
mucus layer and alkaline (bicarb) layer at cell surface (mucus cells) protects stomach lining- prostaglandins can inc mucus production
tight junctions between cells prevent acid from infiltrating wall layers
rapid cell turnover maintains cell surface integrity
parietal cell (oxyntic) products
intrinsic factor and Vit B12 abs
produces HCl and intrinsic factor
Vit B12 abs:
dietary proteins contain Cobalamin- important in RBC prod
B12 binds salivary R protein in stomach
IF from stomach then binds B12 in duodenum
IF/B12 complex binds to receptor in terminal ileum for abs (the receptor is for IF)
phases of HCl secretion
regulation
interdigestive (basal) phase- between meals following circadian rhythm (highest in evening and lowest in morning prior to wake)
cephalic phase- mostly neural regulation
gastric phase- initially neural followed by endocrine (gastrin) and neural regulation
intestinal phase- mostly neural reg
regulation of acid production and secretion
parietal cell receptors- amplification of apical surface area is accompanied by and inc density of H/K ATPase molecs
ACH and gastrin signal via Ca
Histamine signals via cAMP
ion transport proteins of parietal cells- protons are generated in cytosol via Carbonic anhydrase II (CA2)
bicarb ions are exported from basolateral pole of cell either by vesicular fusion or via chloride/bicarb exchanger
Peptic ulcer disease risk factors
NSAID use (aspirin, ibuprofen)
turmors (Zollinger Ellison Syndrome)
Helicobacter pylori
Physiologic secretion of Cl
hormones and NTs have “AC”- activate cAMP to transport Cl out of cell via CFTR
cholera toxin activates this too much
SA of virus is greater than than of crypts
digestion and abs of carbohydrates
enterocyte enzymes
enterocyte uptake
SGLT1 transporter
regulation of carb abs
true for everything: some digestion happens at mouth and stomach but majority of final digestion occurs in the intestinal lumen or at surface of enterocytes (absorptive cells)
carbs ~50% western diet
plan starch amylopectin is largest single carb source
amylase is major enzyme in saliva and pancreatic secretions
other dietary sugars (fructose, lactose, etc) can be digested at surface of enterocytes
-only simple monomeric sugars can be abs
-products of amylase/amylopectin digestion: maltose, maltotriose, and alpha-limit dextrin
final step in carb digestion occurs at enterocyte for all dietary carbs
enterocyte surface enzymes:
isomaltase (alpha dextrine)- converse alpha-limit dextrin to glucose
maltase- maltose and maltotriose to glucose
lactase- lactose to glucose and galactose
sucrase- sucrose to glucose and fructose
trehalase- trehalose to glucose
enterocyte uptake of sugar monomers:
Na binding facilitates abs
SGLT1 transporter:
-req Na as co-transporter
transporters glucose and galactose across apical membrane of enterocyte
fructose transport across apical surface via GLUT5 (Na dependent)
glucose and galactose use same transporter as fructose on basolateral surface (GLUT2- NOT Na-dependent)
SGLT1 can operate in the string of secretory diarrhea (inc cAMP/cholera) so is important in oral rehydration
regulation of carb abs:
inc carb consumption up regulates transporters and inc the uptake of simple sugars
dec carb consumption down regulates transporters and dec uptake of simple sugars
lactose intolerance
missing brush border enzyme lactase
causes gas and diarrhea due to clonic bac digestion of lactose
areas where dairy isn’t staple (Asia) have higher prevalence
digestion and abs of proteins
sources
digestion locations
uptake pathways
protein sources: food, digestive secretions (recycled mucus, enzymes), exfoliated cells
digestion:
stomach: pepsin breaks down 15% proteins to small peptides
SI (lumen): pancreatic proteases (trypsin, chymotrypsin, carboxypeptidase, elastase) break down proteins to oligopeptides, di/tri-peptides and AAs
brush border: peptidase break down oligopeptides to AAs, di/tripeptides
intracellular peptidases: peptidases in enterocyte can break down di/tri’s to AAs
protein uptake pathways:
Na dependent co-transporters that utilize Na/K ATPase gradient are major route for diff classes of AAs (water follows)
-Na independent transporters of AAs
-Specific carriers for small (di/tri) peptides linked to H uptake (co transporter; ex PEP T1)
-pinocytosis of small peptides by enterocytes (infants)
liver basic composed of functions injury
central organ of metabolic homeostasis
large functional reserve
high regenerative capacity
composed of
hepatocytes
bile ducts
blood vessels
functions: lipid, carb,a nd protein metabolism albumin production bile processing and secretion coagulation factor prod detoxification storage of vitamins and glycogen reticuloendothelial system
injury
can be minimal–> massive
subclinical–> liver failure
most acute injuries –> resolution
digestion and abs of fats
diet
essential fatty acids
challenges
bile acids
30-40% of caloric intake
essential for cell membranes, hormones, bile acids, etc
triglycerides are most abundant fat in diet
body can make most lipids EXCEPT linoleic acid (omega 6 fatty acid) converted to arachidonic acid and alpha-linoleic (omega-4) acid “essential fatty acids”
our GI is water based so challenges w/ water abs
bile acids and bile salts- micelles help with fat breakdown
lipid digestion summary
dietary fats
lingual and gastric lipase
pancreatic lipase- hydrolyzes triglycerides into FFAs
bile salts solublize fats into micelles. FFAs are transported to enterocytes
triglycerides are resynthesizes and chylomicrons form
released into lacteal
bile acids
primary, secondary
bile salts
advantage
primary bile acids are prod in liver from cholesterol- cholic acid and chenodeoxycholic acid
secondary bile acids- formed by bac in SI/LI
bile acids are complexed w/ glycine or taurine to make bile salts
bile is recycled during a meal by uptake in distal ileum- enterohepatic circ
bile salt advantage- micelles; high SA allows breakdown of fats
vitamin abs
fat soluble
water soluble
fat soluble vitamins (A,E,D,K) are abs along length of SI and carried in micelles
form chylomicrons similar to dietary lipids
water soluble vit’s either enter enterocyte by simple diffusion (biotin, folic acid) or via specific transporters (Vit B12)
fluid abs and secretion
movement of water
~9L fluid is put into gut each day
100-200mL lost
water follows solutes (requires a solute gradient or active transport)
after stomach, SI contents become iso-osmotic w/ respect to blood
water/ions move paracellularly and/or transcellularly depending on loc
net fluid secretion from cells in intestinal crypts and a net fluid abs from enterocytes on villi
Villi SA > crypt SA
secretion:
stomach: diet 2L, saliva 1L, gastric 2L
duodenum: pancreatic 2L, bile 1L
jejunum: 1L
abs:
jejunum: 4.5L
ileum: 3.5L
colon: 0.9L
movement of water
paracellular water permeability dec from proximal to distal in SI
colon has lowest paracellular perm to water- trying to solidify water and needs to link water movements to transcellular ion movement
Na abs
absorbed all along intestine, w/ most abs in jejunum (60-80%)
dependent on gradient eat by Na/K ATPase
water abs is critically linked to Na abs
mech is via Na/glucose and galactose or Na/AA cotransport, Na/Cl cotransport, Na/H exchange, or passive diffusion
Cl abs
passive in proximal intestines (due to loose Tight junc’s)
offsets Na charge in intercellular space
in distal ileum and colon, w/ less leaky junctions, Cl is exchanged for HCO3- that is offsetting the acids prod by bac (HCO3- is generated b action of carbonic anhydrase)
Hepatitis define etiology causes \_\_ histo
inflammatory injury and death of hepatocytes
results from variety of etiologies
is a common cause of chronic liver disease
histo:
hepatocyte swelling/degernation; injured hepatocytes lose correct osmotic balance (reversible injury)
apoptosis (lobular or interface) hepatocytes (irreversible)
bridging necrosis or geographic coagulative necrosis- confluent death of hepatocytes
Fe abs
regulated abs in proximal intestines
transported across apical membrane as either heme or Fe2+ (receptor mediated)
2 possible fates:
- binds to apoferritin to form ferritin that stays in the cell and is lost when cell dies
- binds to transferrin (carrier protein), leaves cell, goes into blood
diarrhea and motility disorders
osmotic diarrhea
secretory diarrhea
osmotic diarrhea:
caused by impaired digestion or defects in abs
-lactase deficiency
-ileal resection- bile salts not abs
-Celiac disease (Sprue) w/ gluten sensitivity (gliaden-induced destruction of villi)
secretory diarrhea:
may be caused by Vibrio cholera
-inc cAMP levels in cells and this activates the CF Cl channel, and (thus water) on the luminal surface
chronic hepatitis
define
common causes
micro findings
long-standing, on-going hepatocyte injury and inflamm (>6 mo)
common causes:
chronic viral hepatitis, autoimmune hepatitis, drug injury
micro:
less prominent inflamm and injury, preponderance of portal tract-based inflamm, fibrosis
general features of liver injury
cytoplasmic accumulations
- fat: steatosis
- bile: cholestasis
- iron: hemosiderosis/genetic hemochromatosis
- copper: Wilson disease/chronic cholestasis
- viral particles: viral hepatitis (viral inclusion/ground glass hepatocytes)
degernation, necrosis, and apoptosis
inflamm
regeneration, fibrosis, and cirrhosis
regeneration of fibrosis
cycle
progression to cirrhosis tracking
chronic cycles of injury and regeneration–>
activated stellate cells deposit collagen –>
architectural and vascular reorganization –>
cirrhosis
pathologic fibrosis stains blue- type 1 collagen wrapping around hepatocytes
-portal fibrosis (rounded), periportal fibrosis (fingerlike projections), bringing fibrosis
then cirrhosis
tracking
-biopsy surveillance
serial liver biopsies track disease progress
-grade- amount of inflamm and injury
-stage- amount of fibrous tissue deposition
viral hepatitides
types
characteristics
hepatotropic viruses = hepatocyte is primary target
5 types- A through E
other viruses also uncommonly cause hepatitis
important characteristics:
Hep A-
transmitted fecal-oral (contaminated water)
never progresses to chronic liver disease
Hep B-
partially dsDNA (all others are RNA)
10% freq of chronic liver disease
Hep C-
80% freq of chronic liver disease
Hep E:
fecal-oral transmission
Never progresses to chronic liver disease
Hep C virus infections
genetics
transmission
HCV risk factors
histo
major cause of chronic liver disease in US
genetically unstable- multiple genotypes and subtypes
-anti-HCV antibodies made, but antibodies are not neutralizing
transmission mostly by blood and bodily fluids
range of clinical outcomes/presentations
-most common is a chronic hepatitis (85%)
HCV risk factors: IV drug abuse 54% multiple sex partners 36% recent surgery 16% needle stick injury 10% multiple contacts w/ HCV-infected pts employment in medical or dental fields unknown
outcomes:
only small portion will have a progressive enough of a disease to develop cirrhosis
histo:
rarely caught in acute phase, so usually see chronic
-lymphoid aggregates
-spotty inflamm injury
-inflammed portal tract; injury between portal tract and lobule
portal hypertension
nl portal flow
consequence of
signs/symptoms
portal blood flow comes from intestines
usually a low P sys from intestines to liver
consequence of cirrhosis
results from vascular reorg from cirrhosis
abnl porto-systemic shunts
inc in BP
inc hemorrhoids
prominent umbilical veins
esophageal varicose (ominous)
ascites (hypoalbuminemia and P black flow)
splenomegaly
abnl shunts and stuff that should be cleared isn’t cleared- you get hepatic encephalopathy
Hep D virus
replication of incompetent, completely dependent on HBV confection
potentiates effects of HBV: increased risk of fulminant hepatitis, inc activity, and faster progression to end stage liver disease
IV drug use most common mode of transmission in US
Hepatitis
define
etiology
causes __
inflammatory injury and death of hepatocytes
results from variety of etiology
is a common cause of chronic liver disease
inflamm in hepatitis
cells
types characteristic but not pathognomonic
lymphocytes- many hepatitides, common in viral
neutrophils- common in steatohepatitis
eosinophils- common in drug injury
plasma cells- common in autoimmune hepatitis
acute hepatitis
define
common causes
micro findings
new onset (<6 mo) of symptomatic disease and lab evidence of hepatocyte injury
common causes: acute viral hepatitis and drug injury
micro findings:
lobular disarray, marked inflamm throughout, widespread hepatocyte injury, no fibrosis
chronic hepatitis
define
common causes
micro findings
long-standing, on-going hepatocyte injury and inflamm (>6 mo)
common causes:
chronic viral hepatitis, autoimmune hepatitis, drug injury
micro:
less prominent inflamm and injury, preponderance of portal tract-based inflamm, fibrosis
general features of liver injury
cytoplasmic accumulations
- fat: steatosis
- bile: cholestasis
- iron: hemosiderosis/genetic hemochromatosis
- copper: Wilson disease/chronic cholestasis
- viral particles: viral hepatitis
degernation, necrosis, and apoptosis
inflamm
regeneration, fibrosis, and cirrhosis
regeneration of fibrosis
cycle
chronic cycles of injury and regeneration–>
activated stellate cells deposit collagen –>
architectural and vascular reorganization –>
cirrhosis
viral hepatitides
hepatotropic viruses = hepatocyte is primary target
5 types- A through E
other viruses also uncommonly cause hepatitis
important characteristics:
Hep A-
transmitted fecal-oral (contaminated water)
never progresses to chronic liver disease
Hep B-
partially dsDNA
10% freq of chronic liver disease
Hep C-
80% freq of chronic liver disease
Hep E:
fecal-oral transmission
Never progresses to chronic liver disease
Hep C virus infections
major cause of chronic liver disease in US
genetically unstable- multiple genotypes and subtypes
-anti-HCV antibodies made, but antibodies are not neutralizing
transmission mostly by blood and bodily fluids
range of clinical outcomes/presentations
-most common is a chronic hepatitis (85%)
Hep B viral infection
genetics
transmission
outcomes
major cause of chronic liver disease worldwide but not US
can integrate into genome
transmission by blood and bodily fluids;
also VERTICAL transmission is important
range of clinical outcomes and presentations-
-most recover; only ~5% progress to chronic hepatitis
outcomes:
most pts will recover from acute infection, whether it’s subclinical or symptomatic
-only 5% dev chronic hepatitis, and minority of those have further complications
histo:
ground glass hepatocytes (viral inclusions)
sanded nucleus
oral rehydration therapy for diarrhea
antibiotics plus KHCO3 to prevent hypokalemia and metabolic acidosis
glucose (or AAs) with NaCl to facilitate the abs of electrolytes and water
digestion and abs of fats
diet
essential fatty acids
challenges
bile acids
30-40% of caloric intake
essential for cell membranes, hormones, bile acids, etc
triglycerides are most abundant fat in diet
body can make most lipids EXCEPT linoleic acid (omega 6 fatty acid) converted to arachidonic acid and alpha-linoleic (omega-4) acid “essential fatty acids”
our GI is water based so challenges w/ water abs
bile acids and bile salts- micelles help with fat breakdown
lipid digestion summary
dietary fats
lingual and gastric lipase
pancreatic lipase- hydrolyzes triglycerides into FFAs
bile salts solublize fats into micelles. FFAs are transported to enterocytes
triglycerides are resynthesizes and chylomicrons form
released into lacteal
bile acids
primary, secondary
bile salts
advantage
primary bile acids are prod in liver from cholesterol- cholic acid and chenodeoxycholic acid
secondary bile acids- formed by bac in SI/LI
bile acids are complexed w/ glycine or taurine to make bile salts
bile is recycled during a meal by uptake in distal ileum- enterohepatic circ
bile salt advantage- micelles; high SA allows breakdown of fats
vitamin abs
fat soluble
water soluble
fat soluble vitamins (A,E,D,K) are abs along length of SI and carried in micelles
form chylomicrons similar to dietary lipids
water soluble vit’s either enter enterocyte by simple diffusion (biotin, folic acid) or via specific transporters (Vit B12)
fluid abs and secretion
movement of water
~9L fluid is put into gut each day
100-200mL lost
water follows solutes (requires a solute gradient or active transport)
after stomach, SI contents become iso-osmotic w/ respect to blood
water/ions move paracellularly and/or transcellularly depending on loc
net fluid secretion from cells in intestinal crypts and a net fluid abs from enterocytes on villi
Villi SA > crypt SA
secretion:
stomach: diet 2L, saliva 1L, gastric 2L
duodenum: pancreatic 2L, bile 1L
jejunum: 1L
abs:
jejunum: 4.5L
ileum: 3.5L
colon: 0.9L
movement of water
paracellular water permeability dec from proximal to distal in SI
colon has lowest paracellular perm to water- trying to solidify water and needs to link water movements to transcellular ion movement
primary sclerosing cholangitis
define presentation dx prognosis histo
presumed immune-mediated obliterative fibrosis of intrahepatic and extra hepatic bile ducts (generally large caliber bile ducts*)
clinical presentation
Men > women
70% have UC (but not vice versa)
asymptomatic w/ persistent alk phos elevation
progressive fatigue, pruritus, and jaundice
dx
cholangiography= alternating biliary strictures and dilation
-no specific serologic findings
prognosis
-variable clinical course
inc risk for cholangiocarcinoma
histo
periductal “onion skin” fibrosis
fibrous obliteration of bile ducts
Cl abs
passive in proximal intestines (due to loose Tight junc’s)
offsets Na charge in intercellular space
in distal ileum and colon, w/ less leaky junctions, Cl is exchanged for HCO3- that is offsetting the acids prod by bac (HCO3- is generated b action of carbonic anhydrase)
Ca and Mg abs
Vit D in Ca abs
Ca and Mg compete for uptake by cells
Ca enters enterocyte passively down ECM gradient in proximal intestines
uptake of Ca in intracellular Ca stores maintains the gradient
Ca ATPase pumps Ca out of blood
Vit D role in Ca abs
Vit D is syn in skin or abs by intestine; hydroxylated in liver
25-OH Vit D is 1-hydroxylated in kidney, pin presence of PTH
Vit D binds to cytoplasmic receptor, activating transcription/translation
Vit D stimulates the uptake of Ca by inc Ca binding proteins and Ca ATPase molecs
metabolic liver disease in adults
steatosis
steatohepatitis
alcoholic:
steatosis -accum of fat in hepatocytes -metabolic derangement of hepatocytes -many causes: metabolic syndrome, alcohol, drug effect, Wilson disease, viral infection -histo: fat droplets in hepatocytes lipid influx > lipid clearance
steatohepatitis
-hepatocellular injury in assoc w/ steatosis
+/- overt inflamm
causes: alcohol, metabolic syndrome, drug injury
-not all causes of steatosis also cause steatohepatitis
-histo: balloting denigration, inflamm, and steatosis; pericentral, pericellular fibrosis (chicken wire around central vein); neutrophilic infiltration; Mallory bodies
-alcohol can shut off beta oxidation in cells and inhibits exporting lipids; all lead to accum of lipids in hepatocyte (high carbohydrate load causing de novo lipogenesis)
non-alcoholic:
fatty liver disease assoc w/:
obesity, DM2, hypertriglyceridemia
inc prevalence in US
-accum of fat in hepatocytes is mostly due to delivery of peripheral/visceral fat to liver for lipolysis
metabolic liver disease in adults
hereditary hemochromatosis
Wilson disease
A1A deficiency
hereditary hemochromatosis
- genetic iron overload disease, throughout body
- manifests as liver disease, diabetes, HF
- “Bronze diabetes”
- auto recessive inheritance- usually HFE gene mutation (abnl reg of Fe abs)
- N european common
- histo: Fe deposits, iron staining- blue
Wilson Disease genetic copper overload, throughout body liver disease and neuropsychiatric problems mutations in ATP7B gene -auto recessive inheritance transporter involved in bile excretion of Cu histo: Cu staining- brown/red -test Ceruloplasmin levels
Alpha-1-Antitrypsin deficiency genetic dec excretion of A1A A1A is a protease inhibitor -auto recessive inheritance PiMM is nl phenotype; PiZZ is common disease phenotype -protease inhibitor levels less than 10% nl in PiZZ -in PiZZ: -most pts have pulm emphysema -only 10% of pts develop liver disease histo: PASD stain (pink globules= A1A)
oral rehydration therapy for diarrhea
antibiotics plus KHCO3 to prevent hypokalemia and metabolic acidosis
glucose (or AAs) with NaCl to facilitate the abs of electrolytes and water
liver masses in liver disease
hepatocellular carcinoma
cholangiocarcinoma
hemangioma
focal nodular hyperplasia
hepatocellular adenoma
malignant:
hepatocellular carcinoma HCC
-neoplasia differentiating towards hepatocytes
most common primary malignant liver tumor
occurs mostly in pts w/ chronic liver disease (HCV, HBV, alcohol), and CIRRHOSIS
-in vernal, dismal long-term survival unless liver transplant
-histo: proliferation of hepatocytes; arterial enhancement
cholangiocarcinoma
- bile ducts all throughout liver giving rise to malignant tumor
- may be intrahepatic or extra hepatic
- major risk factor is primary sclerosing cholangitis
- in general, dismal long-term survival
- histo: desmoplastic fibrous tissue; malignant glands (firm grossly)
benign:
-hemangioma
-tumor of blood vessels
-common- 2%; 4/1 F/M
usually small and asymptomatic
-larger ones may req resection
-vague RUQ pain, early satiety, nausea, vomiting
-histo: bloody sponge; dilated vascular spaces
-focal nodular hyperplasia
-quasi-neoplastic proliferation of hepatocytes and weird vessels
-arises due to local vascular flow anomaly
-old term = “focal cirrhosis”
-second most common primary hepatic mass
-F/M 4/1
usually asymptomatic
histo: abnl large arteries in fibrous septa
gross: characteristic “central scar”
- hepatocellular adenoma
- mostly women in childbearing age
- assoc w/ oral contraceptive use
- usually no underlying chronic liver disease
- asymptomatic or RUQ abdominal pain
- risk of rupture into abdomen w/ hemorrhage
- extremely low risk of malignant transformation
histo: benign proliferation of hepatocytes
gross: well circumscribed mass; non-cirrhotic liver background
autoimmune liver diseases
3 kinds
autoimmune hepatitis
primary biliary cirrhosis PDC (cholangitis)
primary sclerosing cholangitis
autoimmune hepatitis
define
presentation
serology
histo
immune-mediated attack directed at hepatocytes
clinical presentation:
78% women
often present in assoc w/ other autoimmune diseases
has variable course: indolent to severe
serology (major role in dx)
- autoantibodies (ANA, ASMA, Anti-LKMB)- 80%
- elevated IgG
histo:
chronic hepatitis pattern
-plasma cell rich at interface
oropharyngeal dysfunc symptoms
♣ Oropharyngeal (transfer) dysphagia- inability to initiate a swallow or transfer food bolus into esophagus
♣ May occur w/ obstruction or neuromucsuclar disease (leading to dysfunc of oropharyngeal musculature read propulsive/motility disorder)
♣ Nasal regurgitiation may occur
♣ Aspiration- food or liquids passing into airway or lungs
♣ Cough after attempted swallows
♣ Airway obstruction-choking, stridor, wheezing, cyanosis
♣ Aspiration pneumonitis- lung injury from acidid or lipophilic properties food
• SOB or hypoxia
♣ Pneumonia if bac coloniczation occurs
• SOB, fever, white count, consolidation on CXR
oropharyngeal diseases
neurologic
muscular
structural
-benign; malignant
dx
tx
Neurologic ♣ Stroke ♣ Amytorphic lateral sclerosis ALS ♣ Parkinson’s ♣ MS ♣ Polio
Muscular
♣ MG, muscular dystrophy
♣ Muscle injury (surgery, radiation therapy)
Structural
Benign
• Zenker’s diverticulum- outpouching of esophagus leading to food regurg or bac colonization (halitosis)
• Crycopharyngal bar
• Other: thyromegaly, fibrosis (radiation)
Malignant
• Squamous cell carcinoma of tongue, oropharynx, soft palate, or upper larynx (head and neck cancers)
Dx
♣ History, PE— most helpful
♣ (modified) Barium swallow- X rays of mouth and throat under direct observation while the pt chews and swallows various consistencies of radio-opaque barium
♣ neurology consultation may be needed for tx
Tx
♣ Depends on etiology
♣ Modification of diet
♣ Radiation or surgical resection for tumor, ring, or diverticulum
♣ Speech/PT- cornerstone of tx for neuromuscular disease
♣ Percutaneous endoscopic gastrostomy PEG tube may be needed for feeding and prevent aspiration
drug induced liver injury
a relatively common cause of liver injury
many patterns of injury (mimics other diseases)
-necrosis, cholestasis, bile ducts, autoimmune like hepatitis, steatosis, steatohepatitis, acute hepatitis, or chronic hepatitis
intrinsic or idiosyncratic
- intrinsic (often dose related)- eg acetaminophen
- idiosyncratic (unpredictable)
acetaminophen liver injury
major cause of ACUTE liver failure that leads to liver transplant in US
intrinsic hepatotoxin (dose related)
centrilobular necrosis (zone 3)
metabolic liver disease in adults
steatosis steatohepatitis hereditary hemochromatosis Wilson disease A1A deficiency
steatosis -accum of fat in hepatocytes -metabolic derangement of hepatocytes -many causes: metabolic syndrome, alcohol, drug effect, Wilson disease, viral infection -histo: fat droplets in hepatocytes lipid influx > lipid clearance
steatohepatitis
-hepatocellular injury in assoc w/ steatosis
+/- overt inflamm
causes: alcohol, metabolic syndrome, drug injury
-not all causes of steatosis also cause steatohepatitis
-histo: balloting denigration, inflamm, and steatosis; pericentral, pericellular fibrosis (chicken wire around central vein)
hereditary hemochromatosis
Wilson Disease
Alpha-1-Antitrypsin deficiency
metabolic liver disease in adults
hereditary hemochromatosis
Wilson disease
A1A deficiency
hereditary hemochromatosis
- genetic iron overload disease, throughout body
- manifests as liver disease, diabetes, HF
- “Bronze diabetes”
- auto recessive inheritance- usually HFE gene mutation (abnl reg of Fe abs)
- N european common
- histo: Fe deposits, iron stain
Wilson Disease
Alpha-1-Antitrypsin deficiency
abnormalities in blood flow in liver disease
3 problems
leads to
caused from
is the problem w/ blood coming into liver (hepatic artery and portal vein)
abnl flow within liver? (via sinusoids)
abnl outflow? blockage in hepatic vein or vena cava
lead to ascites, hepatomegaly, ascites, other signs of portal hypertension
cirrhosis is a major cause
liver masses in liver disease
malignant
bengin
malignant:
hepatocellular carcinoma HCC
-neoplasia differentiating towards hepatocytes
most common primary malignant liver tumor
occurs mostly in pts w/ chronic liver disease (HCV, HBV, alcohol), and CIRRHOSIS
-in vernal, dismal long-term survival unless liver transplant
-histo: proliferation of hepatocytes; arterial enhancement
cholangiocarcinoma
- bile ducts all throughout liver giving rise to malignant tumor
- may be intrahepatic or extra hepatic
- major risk factor is primary sclerosing cholangitis
- in general, dismal long-term survival
- histo: desmoplastic fibrous tissue; malignant glands (firm grossly)
benign:
-hemangioma
-tumor of blood vessels
-common- 2%; 4/1 F/M
usually small and asymptomatic
-larger ones may req resection
-vague RUQ pain, early satiety, nausea, vomiting
-histo: bloody sponge; dilated vascular spaces
-focal nodular hyperplasia
-quasineoplastic proliferation of heapotcyes and weird vessels
-arieses due to local vascular flow anomaly
-old term = “focal cirrhosis”
-second most common primary hepatic mass
-F/M 4/1
usually asymptomatic
histo: abnl large arteries in fibrous septa
gross: characteristic “central scar”
-hepatocellular adenoma
-mostly women in childbearing age
-assoc w/ oral contraceptive use
-usually no underlying chronic liver disease
-asymptomatic or RUQ abdominal pain
-risk of rupture into abdomen w/ hemorrhage
-extremely low risk of malignant transformation
histo:
dysphagia
oropharyngeal and esophageal causes:
obstructive
propulsive/motility
oropharyngeal: obstructive: • Head and neck cancers • Zenker’s diverticulum • Radiation therapy • Choking, cough, nasal regurg, aspiration • Evaluation: barium swallow ♣ Propulsive/motility • Neurologic conditions o Stroke, ALS, MS, Parkinson’s, • MG, Muscular dystrophy • Transfer dysphagia, cough, nasal regurg, aspiration • Barium Swallow
esophageal: ♣ Obstructive • Esophageal stricture • Esophageal rings • EoE • Extrinsic compression • Esophageal cancer • Dysphagia to solids, food impaction (EoE), weight loss, vomiting, regurg • Evaluation: EGD, esophagram ♣ Propulsive/motility • Achalasia o Scleroderma, spastic disorders (Jackhammer) • Solid and liquid dysphagia, chest pain • Evaluation: esophagram, EGD (to exclude), esophageal manometry
structural disorders of esophageal-luminal narrowing/obstruction
Eosinophilic esophagitis EOE general dx prevalence clinical features demographics tx
Chronic immune/antigen-mediated esophageal disease
caused by allergic and immunologic factors
Clinicopathologic dx:
• Symptoms of esophageal dysfunc
• Eosinophilic infiltrate in the esophagus
• Absence of other potential causes of esophageal eosinophilial
Rapidly emerging disease; exponential inc in prevalence;
Clinical feats
• In adults and adolescents- dysphagia almost universally present
• ~50% of cases of acute food impaction
• food avoidance
• maybe heartburn
vomiting, pain, dysphagia, progressing to odynophagia and stenosis; assoc w/ food allergies and atopic symptoms
• in children, more non-specific (feeding intolerance, failure to thrive, abdominal pain)
-“ringed esophagus”
o numerous intraepithelial eosinophils (15-20 per hpf or more) often forming eosinophilic “microabscesses”
o present in proximal and distal esophagus (a biopsy from the proximal esophagus is needed to exclude GERD)
demographics
• most common <40 yo
• white males classic (but being dx more freq in minority pop’s)
• commonly assoc w/ other allergic diseases (asthma, atopic dermatitis, seasonal allergies, food allergies
tx
best outlook if dx and tx early; may lead to severe esophageal strictures (req dilation) if confused w/ reflux
3 D’s: drugs, diet, dilation
drugs
o exclusively steroids; topical»_space;> systemic
o asthma preparations that are subsequently swallowed
o several randomized trials revealing decreased esophageal eosinophilica and improved symptoms
diet
o elemental diet (allergen free) effective in children
o more practical: 5 food elimination died (SFED)
o eliminates 6 most common food allergens
♣ milk, eggs, wheat, soy, seafood, nuts
dilation
oropharyngeal dysfunc symptoms
♣ Oropharyngeal (transfer) dysphagia- inability to initiate a swallow or transfer food bolus into esophagus
♣ May occur w/ obstruction or neuromucsuclar disease (leading to dysfunc of oropharyngeal musculature read propulsive/motility disorder)
♣ Nasal regurgitiation may occur
♣ Aspiration- food or liquids passing into airway or lungs
♣ Cough after attempted swallows
♣ Airway obstruction-choking, stridor, wheezing, cyanosis
♣ Aspiration pneumonitis- lung injury from acidid or lipophilic properties food
• SOB or hypoxia
♣ Pneumonia if bac coloniczation occurs
• SOB, fever, white count, consolidation on CXR
Barrett's esophagus general histo risk factors low grade vs high grade tx
Long term sequele of acid reflux disease
Chronic injury- you undergo metaplasia; and intestinal type epithelium in the distal esophagus cells replace the squamous epithelium
Salmon pink color, velvet
Presence of goblet cells on biopsy
Consequence of GERD
(Chronic mucosal injury causes the squamous mucosa to change into intestinal-type mucosa w/ goblet cells (“intestinal metaplasia”/”specialized metaplasia”)
characterized by intestinal glandular metaplasia
confers inc risk for esophageal cancer- adenocarcinoma (pts w/ >3cm of BE have 30-40x inc risk of cancer) (but only 1-5% with BE will dev esophageal cancer)
♣ Metaplasia leads to dysplasia; dysplasia leads to adenocarcinoma
Risk factors
♣ Male, white, central adiposity, advancing age (plateau in 60s)
♣ Chronic GERD
♣ Sig in risk of dev esophageal adenocarcinoma
Previously thought to be higher risk, currently est at ~0.1-0.5% per yr
Pts may benefit from endoscopy w/ biopsies every 3-5 yrs to assess for dysplasia
Presence of dysplasia is a much greater risk for the dev of esophageal cancer
Low-grade dysplasia merits even closer surveillance
High grade dysplasia is ominous and merits tx
Tx
♣ Esophagectomy: previously for HGD or any cancer
♣ Endoscopic tx: now for HGD and early esophageal adenocarcinomas
♣ Endoscopic txs incl:
• Ablation of barrett’s tissue
• Endoscopic resection of visible lesions
• BE w/o dysplasia- at 1 yr then at 3 yr intervals
• BE w/ low grade dysplasia: at 1 yr intervals until neg for dysplasia
• BE w/ high grade dysplasia: although HGD is not cancer, there is a high likelihood that there may be cancer elsewhere in the Barrett’s segment
o Aggressive surveillance every 3 months
o Resection (esophagectomy)
o Ablation/endoscopic mucosal resection
• BE w/ “intramucosal adenocarcinoma”. Since lymphatics are present within the mucosa, tx aggressively- esophagectomy or ablation/endoscopic mucosal resection
esophageal cancer
general
symptoms/signs
tx
squamous cell carcinoma
adenocarcinoma
Progressive dysphagia to cells lipids
Weight loss, sometimes profound
♣Rare: hemoptysis, chest pain, or anemia
♣Does not cause symptoms unitl advanced
Preferred tx is surgical resection, If deteted early…
♣Chemotherapy/radiation initially in advanced cases (most)
♣Metal stent placement or feeding tube for palliation
squamous cell carcinoma
♣ Risk factors- age, alcohol/tobacco, diet, caustic injuries
M/F 4/1 and African american (8/1 w/ whites)
♣ Declining incidence in US and Europe (more common worldwide- Asia and Africa)
♣ May arise anywhere in esophagus
squamous cell epithelial malignancy
adenocarcinoma
♣ Risk factors: age, smoking, obesity, radiation exposure, GERD, and Barrett’s esophagus**
M/F 7/1
♣ Rising incidence in US and Europe
♣ Nearly always in distal esophagus or gastric cardia
glandular epithelial malignancy
-glands infiltrating stroma
esophageal dysfunc
achalasia symptoms types pathophys primary vs secondary
“no relaxation” Cardinal motility disorder of esophagus- most important Impaired relax of LES Absence of nl peristalsis Idiopathic Both genders, all races, adults (25-60yo) Loss of peristalsis in distal esophagus Failure of LES to relax w/ swallowing
Symptoms • Dysphagia to solids and liquids • Weight loss • Regurg • Chest pain, difficulty breathing, heartburn, hiccups
Types (manometry findings) Type 1 (Classic) o Swallowing no sig change in esophageal pressurization
Type 2
o Swallowing simultaneous pressurization spanning entire esophagus length
o Botox injections, pneumatic dilation, surgical myotomy work best
Type 3 (spastic)
o Swallowing abnl, lumen obliterating contractions/spasms
o Botox injections, pneumatic dilation, surgical myotomy have poor outcomes
Pathophysiology
Nl: LES pressure and relaxation reg by excit/inhib NTs
♣ Selective loss of inib neurons in the myenteric plexus resulting in relatively unopposed excitatory (cholinergic) neurons hypertensive nonrelaxed esophageal sphincter
Primary (idiopathyic)—vast majority
Secondary (pesudoachalasia) <2% of all achalasia
♣ Direct mechanical obstruction of LES
♣ Infiltrative submucosal invasion
• Primary esophageal or gastric malignancy
• Infiltrative metastatic malignancy (pancreatic, breast, neurofibromatosis, bladder, prostate, etc)
♣ Paraneoplastic
• Small cell lung cancer, pancreatic, prostate
• Tumor expresses neuronal Ag (non-self) also expressed in neurons T cells, Ab attacking neurons of myenteric plexus
♣ Chagas disease
common liver chemistry tests
AST, ALT Bilirubin Alk Phos Albumin Prothrombin time
AST, ALT
markers of hepatocellular damager
bilirubin
cholestasis, impaired conjugation or biliary obstruction
alkaline phosphatase
cholesatasis, infiltrative diseases, or biliary obstruction
albumin
synthetic dysfunc
prothrombin time (INR)- coagulation factors made in liver synthetic dysfunc -assesses extrinsic clotting pathway w/ serum albumin can assess synthetic func prolongation of PT: -significant hepatocellular dysfunc -Vit K deficiency --prolonged jaundice --malabsorption **dysfunc vs deficiency? admin SC Vit K and assess response -no correction---> liver dysfunc -normalization --> Vit K deficiency
scleroderma/PSS
Smooth muscle atrophy and gut wall fibrosis
Myopathic (predominantly) process
Esophageal manifestations?
• SM atrophy weak peristalsis dysphagia
• SM atrophy–> weak LES–> GERD
• Unrepentant GERD–>esophagitis–> stricture
• Dx of Esophageal disease?
• Esophageal manometry
spastic disorders of esophagus
general info
symptoms
tx
Conditions of uncertain etiology
Peristalsis preserved!
Symptoms usually chest pain and dysphagia
Postulated pathophysiology related to overactivity of excitatory nerves or overactivity of SM response
Tx Limited Meds • CCBs, Sildenafil Botox ? POEM
AST and ALT elevation etiologies
mild
work up
severe
etiology of mild (<5x nl) AST and ALT elevations -hepatic: chronic HBV and HCV acute viral hepatitis (A-E, EBV, CMV) steatohepatitis alcohol-related liver injury (AST predominant) hemochromatosis autoimmune hepatitis A1A deficiency Wilson's disease Celiac disease cirrhosis --Non-heptaic: hemolysis myopathy thyroid disease strenuous exercise
H&P, discontinue hepatotoxic meds
look at alk pos, Bilirubin, INR, Albumin, viral hepatitis serologies, Fe studies
-asymptomatic/neg serologies: lifestyle modifications
-symptomatic/neg serologies: US, ANA, anti-smooth muscle Ab, ceruloplasmin, A1A;
then liver biopsy
—repeat liver chemistries in 3-6 months
etiology of severe (>15x nl) AST and ALT elevations acute viral hepatitis (A-E, herpes) medications/toxins (esp acetaminophen, amphetamines) ischemic hepatitis autoimmune hepatitis Wilson's disease acute Budd-Chiara syndrome hepatic artery ligation or thrombosis
alkaline phosphatase general presence acute obstruction elevation? elevated in: hepatobiliary vs nonhepatobiliary origin GGT causes of elevation how to asses an elevated alk phos
hydrolase enzyme responsible for removing phosphate groups from nucleotides, proteins, and alkaloids
present in nearly all tissues: liver, localized to microvilli of bile canaliculus bone placenta intestine
alk phos has to be generated in response to obstruction- the first thing that will go up in an acute obstruction will be AST/ALT; alk phos goes up more slowly (days?)
elevated in: cholestatic or infiltrative diseases of liver obstruction in biliary system bone disease pregnancy
hepatobiliary vs nonhepatobiliary origin
-isoenyzme determination
5’ nucleotidase
-sig elevated only in liver disease, highest levels in cholestatic diseases
gamma-glutamyltransferase (GGT)
- not present in bone
- elevated after alcohol consumption and almost all types of liver disease
causes of elevation \_\_-hepatobiliary bile duct obstruction* primary biliary cirrhosis PBC AKA Primary biliary cholangitis PSC meds hepatitis cirrhosis infiltrating disease of liver* ---nonhepatic bone disease pregnancy chronic renal failure lymphoma and other malignancies CHF infection and inflamm
elevated alk phos:
H&P
liver chemistries:
nl AST and ALT–> look at gammaGGT or 5’nucleotidase; if nl, etiology is not hepatobiliary
Abnl AST/ALT or elevated GGT/5’ –> RUQ US to assess for biliary duct obstruction:
yes–> ERCP or MERCP
no–> AMA
AMA positive–> PBC
AMA neg–> eval for elevated ALT, liver biopsy, and/or ERCP/MRCP
infiltrating diseases of liver causing elevation in alk phos
sarcoidosis tuberculosis fungal infection other granulomatous diseases amyloidosis lymphoma metastatic malignancy hepatocellular carcinoma
Bilirubin
nl general
unconjugated vs conjugated
processing
nl heme degradation product
excreted from body via secretion into bile
insoluble in water
req conjugation (glucuronidation) into water-soluble forms before biliary excretion
–unconjugated (indirect) bilirubin
–conjugated (direct) bilirubin
bilirubin is (unconjugated) bound to albumin; gets into liver; UDP enzyme converts to conjugated Bilirubin and actively secreted into bile canaliculus
esophageal cancer
general
symptoms/signs
tx
squamous cell carcinoma
adenocarcinoma
Progressive dysphagia to cells lipids
Weight loss, sometimes profound
♣Rare: hemoptysis, chest pain, or anemia
♣Does not cause symptoms unitl advanced
Preferred tx is surgical resection, If deteted early…
♣Chemotherapy/radiation initially in advanced cases (most)
♣Metal stent placement or feeding tube for palliation
squamous cell carcinoma
♣ Risk factors- age, alcohol/tobacco, caustic injuries
♣ Declining incidence in US and Europe
♣ May arise anywhere in esophagus
adenocarcinoma
♣ Risk factors: age, smoking, obesity, GERD, and Barrett’s esophagus
♣ Rising incidence in US and Europe
♣ Nearly always in distal esophagus or gastric cardia
serum liver chemistries
general
checked when:
often termed liver function tests LFTs -tests don't assess actual liver func not solely of hepatic origin nl values don't exclude disease -think of them as chemistries; not LFTs
checked when: suspected liver disorder periodic health screening insurance physical hospitalization unrelated to hepatic disorder
Bilirubin DDx
unconjugated/indirect hyperbilirubinemia
conjugated/direct hyperbilirubinemia
indirect is predominant:
Gilbert’s syndrome
Hemolysis (inc heme breakdown)
Crigler-Najjar syndrome
Direct (either 50/50 or more conjugated): Extra hepatic obstruction of bile flow intrahepatic cholestasis hepatitis cirrhosis
initial evaluation of abnl liver chemistries
patterns
assess pt symptoms
look for risk factors for liver disease
-esp viral hepatitis, alcohol use
concomitant conditions
meds or drug use (incl prescribed and oral meds)
H&P
pattern of liver chem abnormalities
- hepatocellular injury or necrosis: predominantly AST and ALT elevation
- cholestatic pattern: predominately alk pos elevation
- can be mixed pattern
AST and ALT general, func location expressed in ratio
aminotransferases
-catalyze transfer of AA groups to form hepatic metabolites
AST:
location in hepatocytes: cytosol and mito
expressed in liver, heart, muscle, blood
ALT:
location in hepaotcyes: cytosol
expressed in liver only
AST/ALT ratio
typically <1
ratio >1 seen in cirrhosis
ratio >2 suggestive of alcoholic liver disease*
-lower ALT from hepatic deficiency of pyridoxine (B6) in alcoholics which is cofactor for enzymatic activity of ALT
-preferential alcohol-induced injury to mito enriched in AST
AST and ALT elevation etiologies
mild
severe
etiology of mild (<5x nl) AST and ALT elevations -hepatic: chronic HBV and HCV acute viral hepatitis (A-E, EBV, CMV) steatohepatitis alcohol-related liver injury (AST predominant) hemochromatosis autoimmune hepatitis A1A deficiency Wilson's disease Celiac disease cirrhosis --Non-heptaic: hemolysis myopathy thyroid disease strenuous exercise
H&P, discontinue hepatotoxic meds
look at alk pos, Bilirubin, INR, Albumin, viral hepatitis serologies, Fe studies
-asymptomatic/neg serologies: lifestyle modifications
-symptomatic/neg serologies: US, ANA, anti-smooth muscle Ab, ceruloplasmin, A1A;
then liver biopsy
—repeat liver chemistries in 3-6 months
Hepatitis C virus infection
goal of HCV tx
genotypes
tx options
goal of tx:
chronic HCV defined as presence of HCV RNA in blood >6mo after infection
goal of antiviral therapy is to clear HCV RNA such that remain HCV RNA negative 12 weeks after stopping therapy*
-sustained virological response (SVR)= cure
genotype and viral load in US Genotype 1 HVL 50% Genotype 1 LVL 24% Genotype 2 and 3 22% Genotype 4,5,6 4%
Genotype 1 tx options
1 pill w/ 2 meds inside taken or 8-12 weeks can cure 95% of HCV w/ essentially no side effects
-costly, but incredibly effective
hereditary hemochromatosis general tx anemic pts genetics discourage
inherited disorder resulting in inc intestinal Fe abs
tx: therapeutic phlebotomy
500 mL of whole blood = 200-250 mg Fe
endpoint is serum ferritin 50 ng/mL
maintenance phlebotomy to keep ferritin 50-100 ng/mL
for anemic pts not able to tolerate phlebotomy, chelation therapy w/ desfuroxamine
genetics: classic homozygote C282Y
discourage: Vit C supplements (helps Fe abs)
autoimmune hepatitis genearl tx relapse flair risk serology histology
chronic hepatitis characterized by immunologic and autoimmune features
tx based on immune suppression
- corticosteroids
- azathioprine
relapse typically occurs if tx stopped after liver enzymes normalized
50% chance of flair w/ cessation of therapy 2 yrs after achieving remission
serology: ANA postive
AST and ALT go down while bilirubin increases despite getting steroids, liver failure
histo: bridging necrosis; residual islands of hepatocytes, lymphoid aggregates
primary biliary cirrhosis AKA primary biliary cholangitis general tx benefits of tx serology screen for
immune mediated disease causing damage to small intrahepatic bile ducts
tx:
ursodeoxycolic acid UDCA
secondary bile acid, metabolic byproduct of intestinal bac
improves bile acid transport, “detoxifies” bile and provides cytoprotection
benefits of UCDA
improved liver biochemistries
improve survival
reduce need for liver transplantation
serology:
anti-mitochondrial antibody positive
screen for:
osteoporosis
classifications of cholestasis (dec bile flow
site of lesion
detection
common examples
canaliculus or biliary ductules:
detect via lab tests or liver biopsy
ex: cholestatic drug rxns, PBC, pregnancy
intra- and/or extra hepatic bile ducts
detect via imaging (US, ERCP, MRCP)
ex: biliary atresia (child born w/o bile duct), PSC, gallstones, malignancy of pancreas or bile duct
Wilson disease general presentation tx maintenance therapy
auto recessive disorder- young person’s disease
dec hepatocellular Cu excretion resulting in hepatic Cu accum and injury
presentation
splenomegaly, cirrhotic liver, portal HTN, Kayser-Flesher rings (in eyes)
can also present as acute liver failure, others
tx: copper chelation
- D-penicillamine
- Trientine
maintenance therapy w/ Zn
non-alcoholic steatohepatitis NASH general tx investigational therapies serology
NASH is presence of hepatic steatosis and inflamm w/ hepatocyte injury (ballooning w/ or w/o fibrosis)
tx focused on modifying risk factors
obesity
DM2
dyslipidemia
investigational therapies
Diabetes meds- even if not diabetic
Vit E- antioxidant
serology: can be all nl
Hepatitis B Virus nomenclature
HBsAg HBsAb (or anti-HBs) HBcAb HBeAg HBeAb (or Anti-Hbe) HBV DNA
- HBsAg: Hep B surface antigen*
- marker of active infection
- presence for >6 mo defines chronic hepatitis B infection
HBsAb (or anti-HBs): antibody to HBsAg (IgM will decline but IgG will always stay pos)
- marker of immunity to Hep B
- you got infected with Hep B and got rid of it, or you got vaccinated
HBcAb: Hep B core antibody
-marker of active or prior infection
only seen in pts who have been exposed at some point
HBeAg: Hep B “e” antigen
- surrogate marker of high viral load
- marker of infectivity
HBeAb (or anti-Hbe): antibody to hep B “e” antigen
-assoc w/ lower viral load
HBV DNA: presence means active viral replication
Wilson disease general presentation tx maintenance therapy
auto recessive disorder
dec hepatocellular Cu excretion resulting in hepatic Cu accum and injury
presentation
splenomegaly, cirrhotic liver, portal HTN, copper depositions in eye (Kayser-Flesher rings)
tx: copper chelation
- D-penicillamine
- Trientine
maintenance therapy w/ Zn
non-alcoholic steatohepatitis NASH
general
tx
investigational therapies
NASH is presence of hepatic steatosis and inflamm w/ hepatocyte injury (ballooning w/ or w/o fibrosis)
tx focused on modifying risk factors
obesity
DM2
dyslipidemia
investigational therapies
Diabetes meds- even if not diabetic
Vit E- antioxidant
epidemiology of suicide doc rates med student rates males females estimates risk factors
occupational hazard #3
doc suicide rates 2-4x that of the general pop (350-400 per yr in US)
after accidents, most common cause of death among med students
male docs, rates are 40% higher than for men in general pop
female docs, rates are 130% higher than for women in general pop
conservative estimates
- death certificates don’t always reveal suicide
- suicides may be attributable to “accidental” overdose/drowning/MVA
risk factors: single/divorced chronic illness stress/overwork career dissatisfaction conflicted relationships at home losses- personal/professional conflict- personal/professional financial problems family of origin issues (serious psychosocial problems, abuse, neglect) FHx (depression/suicide, sub abuse, psychiatric problems)
physician suicide unique risk factors higher ratio of suicide completions knowledge of lethal means access to lethal drugs identify themselves as healers not pts (shame about being ill, fear of losing control)
high degree of work stress
–occupational hazard #1
anticipated demands:
long hours, lifelong learning, responsibility, sacrifice
matrix of physician stress:
vicariously upsetting experiences
mistakes
pt complaints, threats of suits/professional discipline
insufficient training in business/policitcs
MOC
EMRs
needs of pt/staff/family
needs of self (often ignored until burn out sets in)
work stress ratio:
mental workload** (responsibility/weight of decision making) vs Decision latitude** (Degree of control over work environ)
high mental workload in combo w/ low decision latitude = sig stress
depression epidemiology
signs
CC
depression in med students
occupational hazard #2
signs:
less friendly
withdrawn
irritable
negative/pessimistic
less available
less spontaneous
loss of humor
-preoccupied
distracted
one feels less connected to doc ("back off" vibe)
change in physical appearance
physical complaints
"Just stress" assumption can delay dx
CC = “stress”
depression in med students 15-30% of med students meet criteria for major depression barriers to pursuing tx: lack of time 48% lack of confidentiality (perceived) 37% stigma 30% cost 28% fear of documentation on academic record 24%
poor physical health
occupational hazard #6
our health is not better than the general population and worse in certain areas sleep deprivation sustained stress vicarious trauma every day beeper trauma
physician vulnerability training: adaption to extreme conditions other directness little stress management education -suppression of feelings; intellectualization
poor physical health: circadian rhythm disruption sustained stress is not benign -sympathetic NS hyper-arousal -atrophy of the hippocampus elevated cortisol levels: irritability, insomnia, weight gain/diabetes, osteoporosis, HTN/stroke, toxic to neurons (dec BDNF)
addiction general characterized drug of choice workaholism process addictions
occupational hazard #4
primary, chronic, neurobiologic disease w/ genetic, psychosocial, and environmental factors influencing its dev and manifestations
characterized by >=1 behaviors: impaired control over use compulsive use continued use despite harm craving
physician drug of choice: alcohol
new trends? marijuana
workaholism- very much like sub abuse
disrupts sleep
creates multiple fam problems and destroys marriages
dec your efficiency and ability to concentrate
makes you irritable and fatigued
inc your risk of back problems, GI disorders, heart disease, and stroke
process addictions compulsive viewing of prog gambling sexual addiction work addiction social media
physician burnout
occupational hazard #5
depersonalization
detachment from others
protective defense mech
emotional exhaustion
diminished sense of personal accomplishment
work loses meaning
no longer feeling sense of efficacy
burnout correlates w/ self-reported medical error
-not related to hours worked, setting, methods of compensation, or nights on call
unhealthy interpersonal relationshps
occupational hazard #7
traditionally high divorce rates in medical school and residency
married physicians prior to Gen X and Gen Y
- 10-20% higher divorce rate than general public
- tend to be less happy in their marriages
more recent studies show greater marital satisfaction among physicians
“thinking like a doctor” doesn’t work at home
nature of the profession:
compulsive, perfectionist, preoccupation w/ being right, obsessive, used to be being in charge
physicians in relationships and families:
stress resilience
-promoted by establishing and maintaining caring relationships
floundering personal relationships
-inc risk of professional disillusionment
professional disillusionment
-threatens marriage and home life
professional boundary maintenance
occupational hazard #8
ubiquitous
boundary maintenance isn’t easy
failure to maintain boundaries can threaten professional and personal lives
failure to maintain boundaries can cause pt harm
background conditions:
pts must mobilize trust in pts
borders on faith, a product of the role of the doc and the adaptive suspension by pts of their usual behavior rules
pts’ adaptation born of need- for help and care
the essence of pt vulnerability
potential boundary issues: sexual contact physical contact physical exam verbal interaction self-disclosure collateral contact fees appointment times and locations dual relationships (friends, business transactions, professional transactions) prescribing workplace behavior (inappropriate touching, dating subordinates, profanity)
prevention: boundary awareness
boundary problems normally confront physicians
-dev a view of work in which boundaries are an everyday consideration
-dev and use a sys of consultation with an expert when significant boundary concerns arise (inexerpt colleagues don’t give good advice)
-participate in continuing medical education int he area of professional boundaries
poor health care for physicians
warning signs of deteriorating health
tx barriers in practice
difficulty crossing threshold to becoming a pt
less likely to have personal physician
less likely to see a personal physician
more likely to self-prescribe (not only meds)
“curbside consultation” model of care
warning signs: absenteeism- emotional, physical change in attitude/mood troubled relationships professional boundary issues decline in appearance physical symptoms or illness other (financial problems, staff turnover)
tx barriers: concerns about: discrimination in medical licensing hospital privileges being jeopardized health insurance being denied malpractice and disability inc premiums peer disapproval -Colorado Physician Health Program- Safe Haven Revised Medical Practice Act: confidential agreements, illness is not considered unprofessional conduct
unhealthy interpersonal relationshps
occupational hazard #7
traditionally high divorce rates in medical school and residency
married physicians prior to Gen X and Gen Y
- 10-20% higher divorce rate than general public
- tend to be less happy in their marriages
more recent studies show greater marital satisfaction among physicians
“thinking like a doctor” doesn’t work at home
nature of the profession:
compulsive, perfectionist, preoccupation w/ being right, obsessive, used to be being in charge
physicians in relationships and families:
stress resilience
-promoted by establishing and maintaining caring relationships
floundering personal relationships
-inc risk of professional disillusionment
professional disillusionment
-threatens marriage and home life
professional boundary maintenance
occupational hazard #8
ubiquitous
boundary maintenance isn’t easy
failure to maintain boundaries can threaten professional and personal lives
failure to maintain boundaries can cause pt harm
background conditions:
pts must mobilize trust in pts
borders on faith, a product of the role of the doc and the adaptive suspension by pts of their usual behavior rules
pts’ adaptation born of need- for help and care
the essence of pt vulnerability
potential boundary issues: sexual contact physical contact physical exam verbal interaction self-disclosure collateral contact fees appointment times and locations dual relationships (friends, business transactions, professional transactions) prescribing workplace behavior (inappropriate touching, dating subordinates, profanity)
prevention: boundary awareness
boundary problems normally confront physicians
-dev a view of work in which boundaries are an everyday consideration
-dev and use a sys of consultation with an expert when significant boundary concerns arise (inexerpt colleagues don’t give good advice)
-participate in continuing medical education int he area of professional boundaries
esophagitis
general
etiologies
o Inflammation and injury of esophageal mucosa
o Results from variety of etiologies
♣ In which injury is followed by inflamm
♣ Or in which inflamm leads to injury
o Is an extremely common disease (5% US adults)
o Etiology ♣ Chemical • Reflux of gastric contents • Acids, alkalis (lye), alcohol, tobacco • Medications (pill esophagitis and chemotherapeutics) ♣ Inefection • Fungal (Candida) • Viral (Herpes simplex virus, CMV, adenovirus ♣ Immune related diseases • EoE • Dermatologic diseases (lichen planus) ♣ Radiation ♣ Trauma ♣ GVHD
reflux esophagitis
general
clinical features
prognosis and therapy
o Injury and inflamm that results from reflux of gastric contents into the esophagus
o Results in gastroesophageal reflux disease
o Clinical features
♣ Heartburn and regurg are the typical
♣ Atypical presentation incl angina-like pain, hoarseness, asthma, and hiccups
♣ Some are asymptomatic
o Prognosis and therapy
♣ Prognosis depends on degress of LES pressure
♣ Early detection prevents complications
♣ If left untreated, severe ulcerations, strictures, barrett’s, and adenocarcinoma may develop
♣ Tx incl lifestyle modifications, PPIs, and surgical procedures (Nissen fundoplication) in severe cases
infectious esophagitis
herpes esophagitis
candida esophagitis
o Herpes esophagitis
♣ Punched out ulcers, viral inclusions
o Candida esophagitis
♣ White plaques, fungus (with PAS stain)
esophageal obstruction
functional
♣ nutcracker esophagus
♣ diffuse esophageal spasm
♣ hypertensive lower esophageal sphincter
♣ achalasia
♣ motility disorders
• diseases that affect nl coord of swallowing
• general
o repetitive high amplitude nonperistaltic contractions
♣ diffuse esophageal spasm (ganglionitis, hypertrophy of the inner muscle layer)
o peristaltic high amplitude peristalsis
♣ nutcracker esophagus (extensive hypertrophy of the inner muscle layer)
o diffuse esophageal spasms
♣ corkscrew esophagus
♣ aperistalsis, lack of LES relaxation and inc IRP
• achalasia (chronic ganglionitis w/ myenteric plexus destruction)
♣ dec muscular activity
• muscular dystrophies, scleroderma, Chagas, amyloidosis
gastric mucosal diseases- 2
large gastric fold syndrome
gastritis
esophageal laceractiosn
o severe retching or vomiting, often assoc w alcohol intoxication
o Mallory-Weiss tears
o Boerhaave syndrome (rupture)
vascular disorders
esophageal varices
esophageal varices
♣ Dilated submucosal veins due to partial HTN and shunting of blood from the portal to systemic venous sys (collateral circ)
♣ Inc pressure causes the tortuous esophageal veins to bludge into the lumen (varicies)
♣ The overlying mucosa may ulcerate and bleed
♣ Clinically: can cause massive GI bleeding and hematemesis and lead to death
♣ Dev in 90% of cirrhotic pts. Worldwide, hepatic schistosomiasis is the 2nd most common cause of variceal bleeding
Gastritis- autoimmune lymphocytic eosinophilic gastritis assoc w/ systemic disease
gastropathy vs gastritis
Autoimmune
• Autoimmune atrophic gastritis
o Attack on parietal cells
♣ Achlorhydria; can’t prod H+ ions
♣ Pernicious anemia from Vit B12 deficiency
♣ Parietal cells secrete H+ and make intrinsic factor;
o Can develop intestinal metaplasia- then go on to dev dysplasia, etc. I think she said any type of gastritis, not just autoimmune
o Higher risk of gastric cancer
•Corpus restricted chronic atrophic gastritis
o CD4+ T cells against parietal cells (eg H+ K+ ATPase)
•Anti-parietal cell and anti-intrinsic factor antibodies
•Pernicious anemia
•Scandinavian and northern European descent
lymphocytic
Assoc w/ celiac disease
eosinophilic Allergic disease (eg cow’s milk) and parasitic infection)
(granulomatous) gastritis assoc w/ systemic disease
Crohn’s disease, sarcoidosis, infection
non-H pylori infection cause of gastritis is generally uncommon
♣Immunosuppressed
• CMV, candidiasis, aspergillosis, strongyloides
♣Eosinophilic
• Can have ulceration
• Early satiety, nausea, vomiting, inc eos in blood
• Rare, cause unknown
another lecture: Common causes: drugs/NSAIDs, alcohol, tobacco, H pylori, “chemical” injury (bile, strong acids, bases)
**gastropathy= non-inflamm injury gastritis= inflamm + injury
gastropathies
ethanol NSAID protective mech's erosions Ulcer PUD
Non-inflammatory epithelial cell injury
♣Gastroduodenal injury in the absence of sig inflamm
♣Causes
•Ethanol, NSAIDs, stress ulceration, cocaine, bile reflux
Ethanol gastropathy ♣ Disrupts mucosa ♣ Inc acid secretion ♣ PUD: high conc (>10%) ♣ High amounts of use ♣ Concurrent NSAID use
NSAID gastropathy
♣ NSAID-related GI side effects
• Heart burn, N/V, abdominal pain
♣ Mucosal lesions/gastropathy
• 20% after 3 months of use
♣ GI complications: PUD and GI bleeding
MOA: Inhib both COX1 and COX2; COX’s make PG
COX1 makes PG that has mech’s that protect mucosa, and hemostasis
COX2 makes PGs that are thought to be assoc w/ systemic inflamm process (pain, fever, inflamm)
Gastric protective mechanisms ♣ All PG dependent • Mucous layer thickness • Cell membrane hydrophobicity • Bicarbonate secretion • Mucosal blood flow • Epithelail cell • Migration/proliferation
Erosions- not penetrating beneath the muscularis mucosa; no bleeding
Ulcer- deeper erosions that give you hemoptysis and black stools
PUD- separate card
Peptic Ulcer Disease PUD incidence/prevalence stress ulcers PUD complications tx
♣ Lifetime prevalence 5-10%
•Most asymptomatic
♣ Gastric ulcer prevalence male=female
♣ Duodenal ulcer prevalence M >F
♣ Inc incidence in COPD, cirrhosis, chronic renal failure, post-transplantation, smokers
♣ Decreasing incidence of non-NSAID ulcers
Pathogenesis of PUD
• Due to insult- H pylori or NSAIDs; smoking or other factors also contribute
• Disruption of mucosal integrity; acid/pepsin contribute to injury
• Ulceration
Stress ulcers •ICU pts o CNS injury (Cushing’s ulcer) o Burns (curling’s ulcer) o Prolonged mechanical vent >48 hrs o Coagulopathy •Fundus and body •Impaired mucosal protection •Inc acid secretion
PUD complications •Abdominal pain •Anemia, acute or chronic o Iron deficiency from chronic blood loss o Bleeding: hematemesis or melena ♣ Incidence 60/100,000 ♣ Mortality 5-10% •Perforation o Acute abdominal pain •Gastric outlet obstruction o Nausea, vomiting, abdominal pain
•Tx for PUD oPPI therapy ♣ Ulcer healing 4-8 weeks oH pylori test and treat ♣ Confirm clearance if H pylori positive oRisk factor avoidance ♣ NSAIDs, smoking ♣ Chronic PPI if NSAID necessary
•Tx of severe PUD oAcute bleeding ♣ IV resuscitation restore intravascular vol ♣ Acid suppression with IV PPI • Improves clotting ♣ Endoscopy ♣ Angiography ♣ Surgery oPerforation ♣ surgery
other lecture:
♣ Acid mediated ulceration of stomach and duodenum
♣ Bleeding 15%; perforation 5%; obstruction 2%
♣ Mucus hangs over the edge and ulcer has a “clean” base
♣ Necrotic debris in ulcer bed
gastropathies
ethanol NSAID protective mech's Ulcer PUD
Non-inflammatory epithelial cell injury
♣Gastroduodenal injury in the absence of sig inflamm
♣Causes
•Ethanol, NSAIDs, stress ulceration, cocaine, bile reflux
Ethanol gastropathy ♣ Disrupts mucosa ♣ Inc acid secretion ♣ PUD: high conc (>10%) ♣ High amounts of use ♣ Concurrent NSAID use
NSAID gastropathy
♣ NSAID-related GI side effects
• Heart burn, N/V, abdominal pain
♣ Mucosal lesions/gastropathy
• 20% after 3 months of use
♣ GI complications: PUD and GI bleeding
MOA: Inhib both COX1 and COX2; COX’s make PG
COX1 makes PG that has mech’s that protect mucosa, and hemostasis
COX2 makes PGs that are thought to be assoc w/ systemic inflamm process (pain, fever, inflamm)
Gastric protective mechanisms ♣ All PG dependent • Mucous layer thickness • Cell membrane hydrophobicity • Bicarbonate secretion • Mucosal blood flow • Epithelail cell • Migration/proliferation
Erosions- not penetrating beneath the muscularis mucosa; no bleeding
Ulcer- deeper erosions that give you hemoptysis and black stools
PUD- separate card
Peptic Ulcer Disease PUD incidence/prevalence stress ulcers PUD complications tx
♣ Lifetime prevalence 5-10%
•Most asymptomatic
♣ Gastric ulcer prevalence male=female
♣ Duodenal ulcer prevalence M >F
♣ Inc incidence in COPD, cirrhosis, chronic renal failure, post-transplantation, smokers
♣ Decreasing incidence of non-NSAID ulcers
Pathogenesis of PUD
• Due to insult- H pylori or NSAIDs; smoking or other factors also contribute
• Disruption of mucosal integrity; acid/pepsin contribute to injury
• Ulceration
Stress ulcers •ICU pts o CNS injury (Cushing’s ulcer) o Burns (curling’s ulcer) o Prolonged mechanical vent >48 hrs o Coagulopathy •Fundus and body •Impaired mucosal protection •Inc acid secretion
PUD complications •Abdominal pain •Anemia, acute or chronic o Iron deficiency from chronic blood loss o Bleeding: hematemesis or melena ♣ Incidence 60/100,000 ♣ Mortality 5-10% •Perforation o Acute abdominal pain •Gastric outlet obstruction o Nausea, vomiting, abdominal pain
•Tx for PUD oPPI therapy ♣ Ulcer healing 4-8 weeks oH pylori test and treat ♣ Confirm clearance if H pylori positive oRisk factor avoidance ♣ NSAIDs, smoking ♣ Chronic PPI if NSAID necessary
•Tx of severe PUD oAcute bleeding ♣ IV resuscitation restore intravascular vol ♣ Acid suppression with IV PPI • Improves clotting ♣ Endoscopy ♣ Angiography ♣ Surgery oPerforation ♣ surgery
take home points for gastric diseases
gastric mucosal diseases
PUD
gastric neoplasms
Gastric mucosal diseases can be inflamm or non-inflamm
♣ H pylori most common cause of gastritis
♣ NSAIDs most common cause of gastropathy
PUD
♣ Most common causes NSAIDs and H pylori
♣ Tx dependent on underlying cause and acid suppression to heal mucosa
♣ Complciatons: bleeding, perforation, GOO
Gastric neoplasms ♣ Polyps (benign) ♣ Adenocarcinoma ♣ GIST (stromal tumor) ♣ Carcinoid (NET) ♣ MALT-oma (check and tx for H pylori)
stromal turmors/GIST
gastric carcinoid
mucosa associated lymphoid tumor MALT lymphoma
GIST
♣distinctive stromal tumor
• most common gastric mesenchymal tumor (60%)
• leiomyomas, etc are NOT GISTs
♣worse prognosis than other GI stromal tumors
♣cell of origin: interstitial cell of cajal (pacemaker)
♣histology: positive for c-kit (CD117) mutation in transmembrane receptor tyrosine kinase RTK
♣10-30% malignant
♣tx: surgery, Imatinib (Gleevac): small molec RTK inhibitor
gastric carcinoid ♣neuroendocrine tumor (1:1 million) ♣found in fundus/body ♣predisposing factors: •autoimmune atrophic gastritis o hyphcholorhydria elevated gastrin stimulates ECL cells •ZE syndrome/gastrinoma o MEN1 o Elevated gastrin stimulates ECL cells •Sporadic o More dangerous
MALT lymphoma
♣H pylori in gastric lymphoma
•Low grade B cell lymphomas arise in gastric MALT
o Stimulated by H pylori infection
•Eradication of H pylori can sometimes induce regression of lymphoma
take home points for gastric diseases
gastric mucosal diseases
PUD
gastric neoplasms
Gastric mucosal diseases can be inflamm or non-inflamm
♣ H pylori most common cause of gastritis
♣ NSAIDs most common cause of gastropathy
PUD
♣ Most common causes NSAIDs and H pylori
♣ Tx dependent on underlying cause and acid suppression to heal mucosa
♣ Complciatons: bleeding, perforation, GOO
Gastric neoplasms ♣ Polyps (benign) ♣ Adenocarcinoma ♣ GIST (stromal tumor) ♣ Carcinoid (NET) ♣ MALT-oma (check and tx for H pylori)
congenital abnormalities of upper GI
causes
hypertrophic pyloric stenosis
tx
Duplication, stenosis (incomplete atresia), ectopia (eg pancreatic ectopia)
Hypertrophic pyloric stenosis
♣ Hyperplasia of pyloric muscularis propria obstructive gastric outflow
♣ M/F 4/1
♣ Presents in 2-3rd week of life w/ regurg and persistent projectile non-vilious vomiting
♣ Firm ovoid abdominal mass
♣Tx: surgical splittling of the muscularis propria (“myotomy”)
stress related injury to upper GI
Morphologically resembles acute gastritis
• Injury mediated by vasoconstriction/ischemia
• Erosion and ulceration may be widespread
Occurs in 75% of critically ill pts
• Trauma, shock, or sepsis (stress ulcers)
• Severe burns (curling ulcers)
• Intracranial disease (Cushing ulcers)
upper GI mass-like inflammatory lesions
hypertrophic gastropathies
Mass-like inflammatory lesions
♣ Gastritis cystica
♣ Gastritis polyposa
Hypertrophic gastropathies
♣ Menetrier disease
♣ Zollinger-Ellison syndrome
benign neoplastic diseases
inflammatory/hyperplastic polyp
fundic gland polyp
adenomatous polyp
Inflammatory/hyperplastic polyp
• Assoc w/ Helicobactoer and other chronic gastritides
• Cystically dilated foveolae and inflamm and edema histo
Fundic gland polyp
• FAP associated and sporadic (usually PPI associated)
• Cystically dilated oxyntic glands histo
Adenomatous polyp (adenoma)
• Common progression to cancer; inc incidence in FAP, Helicobacter gastritis, and other chronic gastrides
• Dark, atypical cells histo; display dysplasia- neoplastic, non-invasive (precancerous)
malignant or malignant potential gastric neoplasms
adenocarcinoma
lymphoma
carcinoid (neuroendocrine) tumor
gastrointestinal stromal tumor GIST
carcinoid tumor
AKA proliferation of behavior assoc w/ histo
Carcinoid (neuroendocrine) tumor- malignant
•epi tumor derived from neuroendocrine cells; variable behavior from indolent to malignant; some tumors are sporadic and others are assoc w/ gastric arophy (eg autoimmune gastritis) or a genetic synrodme (eg MEN1)
aka well differentiated endocrine neoplasm
neoplastic proliferation of ECC in body/fundus
variable behavior
o sporadic: higher rate of malignant behavior
o atrophy associated: typically indolent
associated with gastric atrophy and MEN-1
histo: nests and trabeculae of monomorphic cells
GIST cell origin mutation therapy clinical course risk assessment histo
gastrointestinal stromal tumor GIST- malignant
•stromal trumor derived from interstitial cells of Cajal; variable behavior from indolent to malignant; tumros harbor activating mutations in the typrosine kinase CKIT, PDGFRA, or (rarely) SDHB
mesenchymal neoplasm derived from intestinal cells of Cajal (pacemaker cells controlling peristalsis)
most contain a mutation in the CKIT oncogene
o used as a diagnostic aid on tissue
o targeted therapy w/ tyrosine kinase inhibitor imatinib
variable clinical course- indolent to malignant
risk assessment: location, mitotic rate and size
histo: spindle cell proliferation; c-kit immunohistochemical stain
summary of upper GI diseases
o inflammatory gastric diseases occur when there’s a mismatch between protective and damaging forces
o stress-related gastritis very common in sick pts
o Helicobacter infection is a huge player in gastric disease
o Adenocarcinoma is the most common cancer in the stomach, is decreasing in incidence in the US, and typically presents at an advanced stage
o Many gastric lymphomas can be cured with antibiotics
o Gastrointestinal stromal tumors have a variable behavior and many are driven by CKIT mutations
GIST
gastrointestinal stromal tumor GIST
• stromal trumor derived from interstitial cells of Cajal; variable behavior from indolent to malignant; tumros harbor activating mutations in the typrosine kinase CKIT, PDGFRA, or (rarely) SDHB
• mesenchymal neoplasm derived from intestinal cells of Cajal (pacemaker cells controlling peristalsis)
• most contain a mutation in the CKIT oncogene
o used as a diagnostic aid on tissue
o targeted therapy w/ tyrosine kinase inhibitor imatinib
• variable clinical course- indolent to malignant
o risk assessment: location, mitotic rate and size
• histo: spindle cell proliferation; c-kit immunohistochemical stain
summary of upper GI diseases
o inflammatory gastric diseases occur when there’s a mismatch between protective and damaging forces
o stress-related gastritis very common in sick pts
o Helicobacter infection is a huge player in gastric disease
o Adenocarcinoma is the most common cancer in the stomach, is decreasing in incidence in the US, and typically presents at an advanced stage
o Many gastric lymphomas can be cured with antibiotics
o Gastrointestinal stromal tumors have a variable behavior and many are driven by CKIT mutations
pancreas
exocrine endocrine 2 major funcs acinar cells zymogens
Exocrine
♣Synthesis of enxymes needed for digestion of fats, proteins, and carbohydrates
♣Neutralizes gastric gastric acid and chime
Endocrine
♣Synthesis and secretes hormones (insulin, glucagon) that regulates glucose and lipid metabolism
2 major funcs:
♣makes bicarbonate and water to neutralize gastric acids and bile acids; in response to secretin in blood from duodenum release
♣inc cholescytokinin to stim gall baldder emptying and pancreatic enzyme secretion
pancreatic acinar cells secrete many diff proteins that break down everything
♣when they’re made- they’re zymogens so the enzymes don’t act on the pancreas
zymogen activation- duodenal lumen and enterokinase activate the zymogens; trypsin aslo helps activate zymgogens
♣you also have physical separation, enterokinase in duodenum, and trypsin inhbitors in the duct to inactivate an accidentally activated zymgogen before it reaches the duodenum to protect the pancreas
ACUTE pancreatitis general alcohol obstruction etiologies gallstone (biliary) pancreatitis presenting features standard dx tests management
♣ acute inflamm
♣ acute abdominal pain
♣ elevated pancreatic enzymes in serum
♣ self-limited
♣ trypsinogen and other pro-enzymes are prematrurely activated within the pancreas
♣ auto-digestion of gland
♣ leakage of enzymes around pancreas may lead to local complicatons
♣ imflammm cascade may result in organ failure or death when systemic
♣ most common causes are alcohol abuse or obstruction pancreatic duct from a gallstone
alcohol
•premature release and activation of zymgogens
•proteinaceous plugs within pancreas duct
abrupt ductal obstruction or disruption (stone, trauma, ERCP, etc)
•bile reflux or retention of enzymes
etiologies
• gallstones 40-50%
• alcohol 40-50%; worldwide most common; US is gallstones
• idiopathic- 5%; others- 5% (drugs, hyperlipidemia, congenital, any obstruction/penetration, etc)
gallstone (biliary) pancreatitis • #1 cause in America • clues to diagnsos o risk factors for gallstones o gallstones seen on imaging (in gallbladder or bile duct) o elevated liver chemistries o dilated bile duct o absence of other risk factors
♣presenting features- not typically subtle; severe pain • abdominal pain- epigastric pain radiating to the back • nausea/vomiting • tachy • low grade fever • abdominal guarding • loss of bowel sounds • jaundice- if severe/necrosis
♣standard diagnostic tests
• amylase and lipase blood serum enzyme test
o highly sensitive; moderately specific; >3x nl increases specificity
• US- best for gallbladder stones
• CT- detects edema, calcifications, fluid collections
• CT w/ IV contrast- detects necrosis
♣Management
• Admit to hospital (usually)
• NPO, then slow advancement in diet
• IV narcotics for pain
• IV fluids- mainstay of therapy
• Surgery consultation if gallstones are present
• Consider ERCP for bile duct stone removal
• Sever disease feeding tube, IV nutrition, pancreatic debridement, pseudocyst drainage, etc.
complications of ACUTE pancreatitis ileus intra-abdomen hemorrhage pseudocyst formation severe diseases
- Ileus (paralysis of the gut)
- Intra-abdomen hemorrhage
•Pseudocyst formation
o Collection of pancreatic fluid, debris surrounded by wall of granulation tissue- lacks epithelial lining
o Results from ductal disruption, necrosis, or both
o Develop in 10-30% of cases of acute pancreatitis
o Majority 60-70% will resolve w/ time, others may persisit or lead to crhonic pain, infection, or obstruction of viscera
o Not a true cyst- no epithelium
Severe diseases:
Pancreatic necrosis
♣Presence of one or more diffuse focal areas of nonviable pancreatic parenchyma
♣Necrotizing pancreatitis- higher risk of infection, mortality; it’s a big deal
Bowel or bile duct obstruction
Shock
Resp or renal failure ♣ARDS- delayed onset ♣Assoc w/ pancreatic necrosis ♣Commonly leads to resp failure ♣Fully reversible ♣Tx= support
Death
CHRONIC pancreatitis general pathophys and features causes in US spectrum symptoms steatorrhea B12 abs dx tx
♣ chronic inflamm
♣ ductal obstruction
♣ chronic pain or malabsorption
♣ permanent loss of pancreatic func
♣ permanent destruction of the pancreatic parenchyma with replacement by fibrosis (scar tissue)
♣ may lead to ductal stricutres, ductal or parenchymal calcifications (stones), or chronic pseudocysts
may be assoc w/ prior episodes of acute pancreatitis
pathophysiology and features
• ductal strictures/stones pain, exocrine failure
• pancreatic pseudocysts pain, N/V (depending on wha’ts compressed)
• acinar destruction exocrine failure
• diabetes endocrine failure (late)
causes In US
• alcoholic- 60-70%
• idiopathic- 15%
• other 15%- cystic fibrosis, hereditary pancreatitis, hyperlipidemia
have to functionally lose about 85% before you get the fat in the stool, 95% before you get diabetes
clinical spectrum
• abdominal pain
o chronic epigastric pain, radiates to back; worse after meals
• steatorrhea
o oily stools, large vol, light colored, foul smelling; gas, bloating
• hypo- or hyperglycemia
brittle diabetes from loss of islets
pancreatic insufficiency- symptoms**** • weight loss- fat malabsorption • steatorrhea- fat • bleeding problems- Vit K • anemia- Vit B12 • weakness, edema- protein • watery diarrhea- CHO, protein
steatorrhea mechanisms •dec lipase and colipase in duodenum •dec duodenal pH o inactivation of pancreas enzymes o bile acid precipitation
B12 absorption and the pancreas- can’t cleave the compd, and B12 will stay bound and not abs
Dx
• History, PE
• Plain x-ray calcifications in pancreas
• CT dialted duct, atrophy, calcifications, psuedocysts
• Secretin test, ERCP, or endocscopic ultrasound more accurate, but invasive
Tx
• ETOH avoidance
• Pancreas enzyme replacement (pills) for steatorrhea
• ERCP and dilation, stent placement, or stone removal for duct obstruction
• Celiac nerve block for pain
• Surgical resection if refractory and severe
• Pancreatectomy w/ islet cell transplant
o Young pts, refractory disease
autoimmune pancreatitis AIP general cells epidemiology assoc w/ symptoms dx tx
Diffuse or focal enlargement of pancreatic parenchyma; not autoimmune?
Infiltration by IgG-4 + plasma cells and lymphocytes
Males, typically 40-70 yo
Association w/ other autoimmune dieases- RA, Sjogren’s, IBD, SLE
o May masquerade as pancreatic cancer!!
Symptoms
♣Abdominal pain, jaundice, weight loss, (rarely) acute pancreatitis
o Imaging
♣Diffuse or focal enlargement of pancrease w/ narrowing of pancreatic duct +/- bile duct
Dx ♣ CT/MRI, serum IgG-4, EUS, ERCP, and occasionally FNA/biopsy o Tx ♣ PO corticosteroids x 6 weeks ♣ Biliary stenting for symptom relief
pancreatic neuroendocrine tumor NET growth prognosis cell origin presentation dx detect lesions
Slow growing
Prognosis favorable
Islet cell origin
May present w/ symptoms of hormone excess
•Insulin, glucagon, somatostatin, gastrin, VIP
Diagnosis, tx, same as for adenocarcinoma
Octreotide scan may be used to detect lesions not seen on CT or EUS
autoimmune pancreatitis AIP general cells epidemiology assoc w/ symptoms dx tx
Diffuse or focal enlargement of pancreatic parenchyma; not autoimmune?
Infiltration by IgG-4 + plasma cells and lymphocytes
Males, typically 40-70 yo
Association w/ other autoimmune dieases- RA, Sjogren’s, IBD, SLE
o May masquerade as pancreatic cancer!!
Symptoms
♣Abdominal pain, jaundice, weight loss, (rarely) acute pancreatitis
o Imaging
♣Diffuse or focal enlargement of pancrease w/ narrowing of pancreatic duct +/- bile duct
Dx ♣ CT/MRI, serum IgG-4, EUS, ERCP, and occasionally FNA/biopsy o Tx ♣ PO corticosteroids x 6 weeks ♣ Biliary stenting for symptom relief
GI side effects assoc w/ NSAID use
tNSAID side effects
safety comparison son NSAIDs
o Symptoms: heartburn, nausea, vomiting, and abdominal pain
o Mucosal lesions 20% in 3 months
o GI complications; eg perforated ulcers or gastrointestinal bleeding
o interfere w/ gastric cytoprotection by inhibition of COX-1 PGE synthesis dyspepsia and gastric ulceration
o relative contraindication in pts at high risk for PUD
o advanced age
o history of PUD or prior NSAID gastropathy
o concurrent glucocorticoid anti-inflamm use
o food or antacids can help manage lesser dyspepsia
o PPIs (omeprazole) will protect against gastroduodenal toxicity
safety comparisons
oGI risk (COX-1 inhibition > COX-2 inhibition)
♣NSAIDS pose inc risk if male- hx of ulcer- existing CVD
♣Lowest risk w/ ibuprofen, celecoxib an option, highest risk w/ naproxen
oCV risk (cox-2 inhibition > cox-1 Inhibition ♣NSAIDs can inc risk of MI, stroke, death ♣Naproxen is safest- high doses of ibuprofen and celecoxib carry greatest risk
oRenal risk (cox-1 inhibition = cox-2 inhibition)
♣NSAIDs pose inc risk if older age, Diabetes, renal insufficiency, HF
♣Recommendation to avoid NSAIDs in pts w:
• HTN, diabetic or other CKD, HF
• But risk is low for short-term, low-dose use
♣Consider NSAID alternatives: acetaminophen, tramadol, opioids for acute pain
celecoxib side effects- GI tract
o Less gastroduodenal toxicity relative to the non-selective NSAIDs at doses that provide equal pain relief
o Celecoxib is an option for pts requiring chronic NSAID tx at high risk for gastric complaints
♣ Age >65 yo
♣ Use of anticoagulant
♣ Prior GI bleed
♣ Active peptic ulcer disease
♣ Concurrent use of oral glucocorticoid
o Other safe options incl: tNSAID plus PPI or tNSAID plus misoprostol (prostaglandin analog- poorly tolerated)
PUD and GERD pharmacotherapy
Tx of H pylori infection
o Gram neg bacilli- facultative anaerobe
o Triple therapy- 1st line
♣ PPI + 2 antibiotics x 14 days
♣ Clarithromycin and amoxicillin (metronidazole if PCN-allergy)
o Quadruple therapy- 1st line alternative OR salvage therapy
♣ PPI + bismuth + 2 antibiotics x 14 days
♣ Metronidazole and tetracycline
o Sequential therapy if resistance is concern
♣ PPI + amoxicillin x 7 days then PPI + clarithromycin + metronidazole (or tinidazole) x 7 days
o Confirm eradication (Stool antigen)
GI drugs- PUD
o Anti-secretory ♣ Omeprazole ♣ Esomeprazole ♣ Lansoprazole ♣ Pantoprazole ♣ Rabeprazole- all of these are PPIs ♣ Ranitidine, Famotidine, Cimedidine- H2 antagonists
o Cytoprotective
♣ Sucralfate
♣ Misoprostol
cytoprotective agents
sucralfate
misoprostol
Sucralfate
♣ Sulfated disaccharide Aluminum salt binds necrotic tissue forming protective barrier
♣ Activated acidic pH- give on empty stomach- 2-4 x/day
♣ Not absorbed- few side effects- constipation
♣ Dimishing use
Misoprostol
♣ Prostaglandin analog- acts on epithelial cell dec H+ secretion to inc mucus-bicarbonate
♣ Indicated for NSAID induced ulcers
♣ Side effects limit use- diarrhea, uterine cramping, contraindicated in pregnancy
H2 receptor antagonists mech pharmacokinetics uses ADRs, DDIs
o Competitive reversible block of H2 receptors- basolateral membrane
o Less efficacious than PPIs- generally req bid dosing
o More rapid onset of action than PPIs in acute gastritis
o Better at block of nocturnal (H2) than meal-stimulated (ACh-gastrin) acid secretion
Pharmacokinetics
♣ Rapidly abs (advantage in acute gastritis)
♣ Major route of elim is renal excretion
♣ Dosage reduction in renal dysfunc (esp in elderly)
Uses
GERD
• If infrequent managed w/ antacids, prn H2 antagonists
• Freq w/ bid H2 antagonists
• Severe erosive esophagitis- PPIs
PUD- largely replaced by PPIs
Stress-related gastritis- IV H2 antagonists
ADRs, DDIs
♣ Generally well tolerated- OTC
♣ CNS dysfunc- mental status change
• Seen w/ cimetidine, or high doses, or elderly w/ renal dysfunc
• Endocrine effects- gynecomastia w/ chronic high dose cimetidine
DDI- cimetidine inhibition of CYP450 metabolism
Tolerance- with continued use??
cytoprotective agents
sucralfate
misoprostol
Sucralfate
♣ Sulfated disaccharide Aluminum salt binds necrotic tissue forming protective barrier
♣ Activated acidic pH- give on empty stomach- 2-4 x/day
♣ Not absorbed- few side effects- constipation
♣ Dimishing use
Misoprostol
♣ Prostaglandin analog- acts on epithelial cell dec H+ secretion to inc mucus-bicarbonate
♣ Indicated for NSAID induced ulcers
♣ Side effects limit use- diarrhea, uterine cramping, contraindicated in pregnancy
gastric antacids ideal properties Calcium Aluminum Mg
Properties of ideal antacid
♣Rapid raise pH of stomach contents to 4
♣Should be nonabsorbalbe
• NAHCO3- high systemic abs, generally avoid
• Al, Mg, Ca- less complete abs, not accumulated w/ nl renal func
♣Should be long-acting
• Hard to attain- emptying time shortened w/ ulcer
• Must be given every 2 hrs
♣No adverse effects- but diarrhea-constipation common
♣No DDIs- generally avoid by spacing dose around other drugs
Calcium (as carbonate = Tums)
♣ Rapid, prlonged neutralization rebound secretion
♣ Safe- not for chronic use (but OK as Ca supplement)
♣ Constipation, hypercalcemia, renal calculi possible
Aluminum (hydroxide, carbonate)
♣ Widely used, binds phosphate in gut (used in CKD)
♣ Main side effect is constipation
♣ Chronic intake may lead to CNS toxicity
Mg (as hydroxide- milk of magnesia)
♣ Osmotic diarrhea- used to counteract Al or Ca induced constipation
♣ Avoid if renal disease retention of Mg ions
pro kinetic agents for GERD and gastroparesis
metoclopramide
tegaserod cisapride
Tx gastroparesis w/ prokinetic agents and antiemetics
Metoclopramide
♣Dopamine antagonist blocks presynaptic inhibition of ACh release
• Inc in coordinated contractions enhance transit
• Approved for not >12 weeks
♣Additional benefit of antiemetic effect at chemoreceptor trigger zone (weak 5HT3 antagonist) relief of n/v
♣Somnolence, dystonic rxns, tardive dyskinesias (boxed warning)
Tegaserod, Cisapride
♣5HT4 receptor agonists direct stimulation of ACh release
• inc coordinated contractions- transit in esophagus, stomach
• reduces bloating of irritable bowel syndrome IBS
♣cisapride life threatening arrhythmias (inc QT interval)- restricted
♣tegaserod linked to strokes, MI, angina- restricted
serotonin (5-HT) subtyes
1B, 1D, 4
5HT3 antagonists
pharmacokinetics
side effects
clinical use
Alosetron pharmacodynamics pharmacokinetics clinical use adverse rxns
Serotonin 5-HT4 agonists- Tegaserod
1B Gi/o receptor presynaptic inhibition (pulmonary vasoconstriction) Agonist: Ergotamine (anti-migraine)
1D Gi/o receptor presynaptic decreased release (pulm vasoconstriction) Agonist: Sumatriptan (anti-migraine) Antagonists: Ergotamine (pAg)
4
PNS neuronal excitation
(inc GI motility)
Agonist: Tegaserod (IBS-constipation)
Serotonin receptor 5HT3 antagonists
o Ondansetron; granisetron, alosetron
Pharmacokinetics
♣ Well abs from BI- IV formulations available
♣ Heaptic CYP metabolism- anti-emetic effects remain after disappearance of parent drug from plasma
Side effects
♣ Very Well tolerated, occasionally GI upset (diarrhea, constipation*), and headaches
Clinical use
♣ Greatest efficacy of anti-emetic classes
♣ Prevention-tx of chemotherapy-induced n/v
♣ Post-op emesis
♣ N/V assoc w/ post-op use of opioid analgesics
Alosetron
o Pharmacodynamics
o Block of 5-HT3 receptors on sensory and motor neurons reduces pain and inhibits colonic motility STOP
o Pharmacokinetics
o Rapid oral absorption (bioavailability 50-60%)
o P450 metabolism (t1/2 1.5 h), longer duration of effect
o Clinical Use - restricted due to risk of ischemic colitis
o Severe IBS in women with diarrhea as the prominent symptom if non-responding (50-60% efficacy)
o Adverse Reactions
o Constipation in 30% of patients (10% discontinue)
Tegaserod
oPharmacodynamics
o 5-HT4 agonist at release of NTs peristaltic reflex gastric emptying and intestinal motility GO
oPharmacokinetics
o Low oral bioavailability (10%) - take before meals
o Renal excretion (66%) and hepatic metabolism (33%)
oClinical Use - use restricted to women under 55
o IBS patients with predominant constipation
oAdverse Reactions
o Some diarrhea (10%) early that resolves
o Linked with heart attacks, strokes, and unstable angina leading to restricted use
appendix general appendicitis -clinical features, pathogenesis, micro tumors
o Arises off cecum, avg 9cm
true diverticulum of cecum
Function has been debated ♣ Vestigial remnant ♣ “education” of lymphocytes ♣ reservoir of commensal (“good”) bac ♣ endocrine func during dev
appendicitis- 7-9% lifetime risk in US
♣ caused by non-specific obstruction of the appendiceal orifice- impaction of fecal material, lymphoid aggregate, tumor, positioning, etc
Clinical features
o Most common in adolescents and young adults
o Lifetime risk for appendicitis is 7%
o M>F
o Classic finding is McBurney’s sign; tenderness located 2/3 of the distance from the umbilicus to the R anterior superior iliac spine
o Often presents as an acute abdomen
o Appendectomy is tx of choice; often laparascopic
Pathogenesis
o Luminal obstruction by stone-like mass of stool “fecalith” ischemic injury and stasis of luminal contents inflammatory response
Microscopic findings
o Mucosal ulceration
o Transmural acute and chronic inflamm
o Extension of inflamm into the mesoappendix
tumors of the appendix ♣ carcinoid (1% will have a tumor, about half of those will be carcinoid) ♣ benign tumors • mucinous cystadenoma • villous adenoma ♣ malignant tumors • adenocarcinoma • lymphoma ♣ secondary tumors (mets)
SI anatomy lengths nl bac distribution absorptive capacity absorption and transport of fluids small bowel diseases
Total length 6 m
♣ Duodenum 5%
♣ Jejunum 40%
♣ Ileum 55% length
The “nl” distribution of bac in the GI tract
o Microbial load per mL inc from stomach down to colon; 10^2ish all the way to 10^12; much more diversity in colon
Absorptive capacity is inc by expanding the surface area of the small intestine
o Surface area: est 250 m^2 – tennis court
o You have folds and villi to amplify SA and microvilli; 600 fold amplification of SA of intestinal mucosa
Absorption and transport of fluids
o 9 L secreted/ingested
o 8.9 L absorbed* in SI and colon; SI absorbes about 8.5 L
o 100 mL excreted
small bowel diseases characterized by malabsorption +/- maldigestion
o syndromes of disordered or inadequate abs of nutrients
o clinical sings: weight loss, diarrhea, steatorrhea, vitamin deficiencies
o pale, bulky, malodorous stool
♣ float, difficult to flush, oily residue
causes of malabsorption
determination of fat malabs
malabs dx tests
surgery
♣ gastric bypass surgery
♣ small bowel resection
bacterial overgrowth
medication
♣ cholestyramine-ADEK
♣ phenytoin-folate
pancreatic insufficiency
liver disease
intestinal inflamm/villus flattening
♣ celiac sprue, Whipple’s disease, tropical
sprue
♣ ulceration
ischemia
infiltration
♣ amyloidosis
determination of fat malabs
o qualitative determination of fecal fat
♣ Sudan fat stain of fecal sample
o qualitative determination of a timed (72 hr) stool collection
malabs diagnostic tests o focused testing- clinical scenario o fecal fat o vit levels o CBC, albumin o CT- small bowel, liver, pancreas, bile ducts o Endoscopy
pancreatic insufficiency general when? malabs causes
Pancreatic digestive enzymes
♣ Pancreatic lipase (fats)
♣ Pancreatic amylase (carb)
♣ Trypsin, chymotrypsin, carboxypeptidase (protein)
Insufficiency results when 90% of pancreas is burned out
Maldigestion leads to malabs
♣ Lipid maldigestion first
♣ Protein malabs
♣ Carbohydrate malabs rare
Causes:
♣ Chronic pancreatitis
♣ Occurs in cystic fibrosis
liver disease causing malabs
Bile necessary for the abs of lipids
Cirrhosis
♣ Dec func of hepatocytes
♣ Dec bile func
Biliary obstruction
surgery causing malabs
cause
vit deficiencies
gastric bypass
Surgical re-routing results in inadequate mixing of food with biliary and pancreatic secretions
Gastic bypass vitamin deficiencies ♣ B12, Fe, Ca, Vit D deficiencies the most common ♣ Vit C, Cu rare ♣ Prevention: multivitamin ♣ Monitoring recommended
small intestinal bacterial overgrowth SIBO
nl bac vs SIBO
causes
clinical signs
Nl bac abundance: <10^5 organisms/mL
o SIBO: >10^5
Causes
♣ Anatomic abnormalities
• Diverticula, blind loop (BII), IC valve resection
♣ Hypomotility: Diabetes, scleroderma, narcotics
♣ Partial intestinal obstruction
♣ Dec acid secretion
♣ Enterocolonic fistula (Crohn’s)
Clinical signs: diarrhea, steatorrhea, abd pain, bloating, weight loss
bacterial overgrowth
general
dx
tx
Fat soluble vit and B12 deficiency
♣ Bacteria de-conjugate bile salts
♣ Bacteria consume B12
Folate levels will be nl-high
♣ Bac production
Dx
♣ Aspiration of duodenum w/ culture
♣ Glucose-hydrogen breath test
♣ Empiric Tx with antibiotics
Tx: antibiotics (eg Ciprofloxacin)
fat malabs Vit deficiencies
Vit A
♣ Night blindness; xerophthalmia
Vit D
♣ Osteomalacia
• Bone mineralization defects
Vit E
♣ Rare in adults
♣ Hemolytic anemia
Vit K
♣ Clotting dysfunc
• PT/INR
celiac sprue general histo changes typical celiac sprue signs/symptoms atypical celiac sprue signs/symptoms pathogenesis host factors dx tx future other clinical notes
tropical sprue genearl cause presentation dx tx
Celiac sprue
oGluten-sensitive enteropathy
♣ Wheat, barley, rye
o Inflamm disease of SI
o Loss of villi, crypt hyperplasia, IE lymphocytes**
o 0.5-1% of US pop; 80% asymptomatic
o incidence inc w/ age
o Gluten has a gliadin glycoprotein in it, which can be either directly toxic to epi cells lining SI (duodenum) or it can excite an immune response w/ T cells once it passes through the epi, and immune-mediated w/ auto-antibodies
o 1- directly toxic to enterocytes
o 2- stimulates lymphocyte-mediated response and formation of autoantibodies (mediated by TG)
o distinguished from wheat allergy and gluten sensitivity
how much gluten causes histologic changes in pts w/ CD?
o One average slice of bread ~5g of gluten
o Daily intake 50mg will cause changes
Typical celiac sprue signs and symptoms o Abdominal distention o Abdominal pain o Anorexia o Bulky, sticky, pale stools (steatorrhea) o Diarrhea o Flatulence o Failure to thrive ♣ Weight loss, fatigue o Vomiting bulky fatty diarrhea, flatulence, weight loss, anemia, nutritional deficiencies, growth failure in children
Atypical celiac sprue sings/symptoms o Iron deficiency anemia o Dermatitis herpetiformis* o Liver func tests (AST, ALT elevations) o Cerebellar ataxia o Osteoporosis o Oral apotheosis ulcers • some minor GI complaints but other problems: anemia, dental enamel defects, infertitlity, arthritis
Celiac pathogenesis
o Assoc w/ autoimmune diseases (eg thyroiditis, type 1 DM; F/M 2/1
o HLA-DQ2, HLA-DQ8 (40% US), and TTG antibodies
♣ APC-MHC-II, present gluten peptides
♣ 2-5% gene carriers dev disease (other genes + environ)
o CD4+ T cell response (IELs)
o All have antibodies to tissue transglutaminase
♣ cytotoxic and autoAb formation inflamm (inc T lymphocytes) villous atrophy tissue damage loss of mucosal and brush-border surface area malabsorption, diarrhea
host factors
♣ Class II HLA-DQ2 or HLa-DQ8 allele (don’t need to memorize)
Assoc w/ other autoimmune diseases: type 1 DM, thyroiditis, Sjogren syndrome
Celiac sprue
Dx: serology, SI biopsy
o Serologic tests: anti-tissue transglutaminase anti-endomysial antibodies, anti-gliadin IgA and IgA
♣ Endoscopy: loss of surface villi
♣ Serology: IgA antibodies to tissue transglutaminase; anti-endomysial antibodies * important to know
♣ Tissue biopsy: 3 characteristic findings
• Villous blunting (extreme is villous atrophy)
• Inc intraepithelial lymphocytes- vey likely to be celiac disease- lots of dark blue dots
• Lymphoplasmacytosis of the lamina propria- generalized, chronic inflamm
♣ Histologic severity doesn’t always correlate w/ symptoms
Tx: gluten free diet
♣ Corn, rice, soy, millet…
Future: wheat without gluten epitopes, degradation of epitopes, oral tolerance, inhibitors of the innate immune response
Other clinical notes
♣ Celiac disease often presents w/ extra-intestinal complaints
• Fatigue, iron deficiency anemia, pubertal delay, short stature, aphthous stomatitis
♣ Assoc w/ dermatitis herpetiformis blistering skin disease
♣ Inc incidence of lymphocytic gastritis, lymphocytic colitis
♣ Celiac-disease assoc malignancies incl enteropathy-assoc T cell lymphoma (EAT lymphoma), and small intestinal adenocarcinoma
Tropical sprue
o Residents or visitors to tropics
Cause: bac toxins or colonization of aerobic coliform bac
Classic presentation: megaloblastic anemia from B12 and folate deficiency
Dx: intestinal biopsy with villous flattening and travel history
Tx: antibiotics, B12, and folate
Whipple’s Disease
general
signs
tx
Rare <1/1 million
Gram pos antinomycete: T whippelii
Pathogenesis
♣ Caused by gram-pos bacilli tropheryma shippelii
♣ Bacilli absorbed by lamina propria macrophages
♣ Organism-laden macrophages accumulate within the SI lamina propria and mesenteric lymph nodes lymphatic obstruction
♣ Impaired lymphatic transport causes malabsorptive diarrhea
Clinical signs: fever, joint pain, diarrhea, abdominal pain, CNS-neurologic symptoms
♣ Triad of diarrhea, weight loss, malabsorption
♣ Other common symptoms: arthritis, lymphadenopathy, neurologic disease
Typically presents in middle-aged or elderly white males
dx
PAS+ Macrophages (TRIGGER WORD) on biopsy, PCR
♣ Villi distended by macrophages
♣ Macrophages filled w/ whipple bacilli (PAS stain)
♣ Tissue biopsy demonstrates the presence of the organisms
Tx: one yr of antibiotics
mesenteric ischemia
general
chronic
acute
o Atherosclerosis, clot, radiation
Chronic: 2 of 3 major vessels occluded
♣ Post-prandial abdominal pain, weight loss, sitophobia, malabs
Acute: embolus, severe abdominal pain
SI tumors
general
%
presentation
Very rare cause of primary tumors (despite 90% of gut SA) ♣ <5% of primary GI tumors ♣ 47% of adenocarcinomas- most duodenum • Crohn’s disease ♣ 28% carcinoid ♣ 13% sarcoma (incl GIST) ♣ 12% lymphoma
metastasis
present w/ symptoms of obstruction
♣ abd pain, distention, dec stool output
diarrhea
2 main causes
classification based on stool characteristics
2 main causes of diarrhea
dec abs of fluid and electrolytes
• inhibitied or defective abs of fluid +/- electrolytes
• luminal osmotic agents
• inc motility w/ dec contact time
inc secretion of fluid and electrolytes
• stimulated anion secretion
• inc crypt secretion
classification based on stool characteristics
- fatty= steatorrhea
- watery
- inflamm/exudative
- functional
steatorrhea
2 causes
fatty diarrhea
malabsorption
o mucosal diseases (Celiac, Whipple’s)
o short-bowel syndrome
o small bowel bac growth
maldigestion/malabsorption
o pancreatic insufficiency
o inadequate luminal bile sald conc (chronic liver disease, biliary obstruction)
watery diarrhea
osmotic
secretory
lactose intolerance
osmotic o carbohydrate malabs ♣ lactose ♣ sorbitol (Chewing gum) ♣ fructose (non-diet drinks and many commercial foods- high fructose corn syrup_ o osmotic laxatives ♣ Mg-containing ♣ Phosphate, sulfate (colonoscopy bowel preps)
Secretory
o bacterial toxins (V cholera, E coli enterotoxins
o neuroendocrine tumors
♣ gastrinoma, VIPoma, carcinoids, calcitonin
♣ ileal bile salt malabsorption
♣ stimulant laxatives
♣ disordered motility/regulation
• diabetic neuropathy, postvagotomy, IBS
o bile acid-induced diarrhea results from ileal dysfunc
♣ ileum is the only site of active bile acid absorption
Osmotic vs secretory o Measure stool sodium + K o The nl stool osmolality is 290 mOsm o Osm gap = 290 – 2 (stool Na + K) o If the diff is >50 mOsm, then the diarrhea is osmotic; if <50, the diarrhea is “secretory”
lactose intolerance
o >50% world down-regulates lactase after weaning
o lactose ingestion leads to diarrhea (osmotic), flatulence (colonic bac)
o mutations in lactase promotor resulting lactase persistence in ~80% Northern European and nomadic pop’s
inflamm/exudative diarrhea
general
dx
IBS
infection
inflamm bowel disease
o crohn’s
o ulcerative colitis
ischemia
Dx
Infection
♣ Traditionally stool culture- now PCR or ELISA based tests
♣ Endoscopy w/ biopsy
Ischemia
♣ CT scan
♣ Endoscopy-colon
IBD
♣ Endoscopy
Irritable Bowel syndrome IBS
Abdominal pain altered bowel habits in the absence of an organic cause
♣ Pain improved w/ defacation
♣ Pain onset w/ change in stool freq
♣ Pain onset w/ change in stool appearance
Constipation and/or diarrhea
10-15% of the pop in North America
possible mechs
♣ visceral hypersensitivity
♣ carb malabs
• FODMAPS fermentable oligo-, di-, and monosaccharides and polyols
o Fructose, fructans (wheat polymers eg inulin), sorbitol, lactose
♣ Low grade inflamm
colon anatomy
functions
o 5 ft long
o tubular structure w/ all 5 layers
o inner circular, outer longitudinal smooth muscle layers
o ileocecal valve, internal and external anal sphincters
o no vili
functions
o abs of water and ions
o bac fermentation of nonabsorbed nutrients
o storage of waste and indigestible materials
o elimination of waste and indigestible materials
IBD general diagnosing- when and how IBD management colon cancer risk
chronic, dysregulated inflammation of small and/or large intestine
IBD pathogenesis
♣CD and UC result from immune dysreg, commonly thought of as “autoimmune” but not strictly classically autoimmune
♣Colitis results from a combination of defects
• Host interactions w/ intestinal microbiota
• Intestinal epithelial dysfunc
• Aberrant mucosal immune responses
♣Mucosal immune response
• T cell mediated disease
o Th 1 type in crohn’s
o Th 2 type in UC
• Dysreg of immunoregulation: pro and anti-inflamm cytokines
♣Epithelial defects
• Defects in intestinal epithelial tight junc barrier func
• Crohn’s disease: NOD2 polymorphisms (intracellular receptor for microbes)
• Ulcerative colitis: ECM2 polymorphisms (extracellular matrix protein)
♣Microbiota
• Recents studies indicate that antibiotics can reduce disease severity, although specific organism not identified
Diagnosing IBD
♣When
• Suggestive symptoms (diarrhea, crampy abdominal pain, bleeding), lasting >=2 weeks
• Negative work up for other causes of enteritis (infection, ischemia, medications)
• Extra-intestinal symptoms
♣How
• Imaging may be suggestive
• Endoscopy and biopsy= gold standard
♣10-20% of pts are indeterminate, with features of both Crohn’s and UC
IBD management
♣ Corticosteroids (topical or abs) for flares only
♣ 5-aminosalicylates, PO or PR
♣ immunomodulators
♣ TNF-alpha antagonists (IV or SC)
• Infliximab, adalimumab, natalizumab
♣ Surgery- colectomy, partial SB resection, or stricturoplasty
• Refractory disease, obstruction, fistula, HG dysplasia, or cancer
Colon cancer is inc in IBD, esp UC o Colon cancer surveillance o Risk inc w/ disease duration o Yearly colonoscopy after 7-8 yrs o Biopsies frome every segment o LG dysplasia is common o HG dysplasia or cancer colectomy
Risk of adenocarcinoma is similar in CD (colonic disease) and UC (25-year cumulative risk approx 10%) and is related to:
• Duration of disease
• Extent of disease (pancolitis vs localized involvement)
• Family history
• Extra-intestinal manifestations (i.e. primary sclerosing cholangitis)
Endoscopic surveillance includes assessment of disease activity and dysplasia, the precursor to adenocarcinoma
UC vs Crohn's signs and symptoms macroscopic pathologic genetics other features extra intestinal manifestations
UC signs/symptoms • Chronic diarrhea, weight loss, fatigue • Lower abdominal pain • Hematochezia • Mucus in stool • Tenesmus • Urgency • Bloody diarrhea or loose stools w/ lower abdominal pain, cramps o Symptoms relieved by defecation
macro • Bowel region: colon • Fistulate or abscesses: no • Strictures: no • Distribution: diffuse
pathologic • Inflammation: mcusus +/- SM • Ulcers: superficial, confluent • Fibrous: mild to none • Granulomas: no
Rectal involvement w/ retrograde continuous diffuse disease (no skipping)
• No ileal involvement (except “backwash ileitis”)
• Disease worse distally
• Mucosal inflamm only- no transmural disease
• No fissures, sinuses, fistula tracts
genetics
HLA-A11, HLA-A7
HLA-DR2 (Japanese)
DRB103, DRB12 (Western)
micro: inflamm: limited to mucosa pseudopolyps: marked ulcers: superficial, broad-based lymphoid rxn: moderate fibrosis: mild-none serositis: mild-none Granulomas: NO fistulae/sinus tracts: no
other feats ♣ UC= hamburger meat blood colon • Obstruction: no • Malabs: no • Malignant pot: yes • Recurring after colectomy: no • Toxic megacolon: yes
Extraintestinal manifestations
o Primary sclerosing cholangitis *** PSC
• Inc risk of colonic adenocarcinoma
Crohns signs and symptoms • Chronic (non bloody) diarrhea, weight loss, fatigue • mid or lower abdominal pain • nausea/vomiting • steatorrhea • fistula symptoms variable- intermittent attacks, relapsing remitting
macro • bowel region: Entire GI tract • fistulae or abscesses: Yes • strictures: Common • pattern: “skip lesions”
♣Disease characteristics***
• Skip lesions
• Ileal involvement (“regional enteritis”)
• Transmural chronic inflammation
• Inflammatory strictures
• Fissuring ulcers, sinus tracts, fistulae
pathologic • inflamm: Transmural • ulcers: Deep, linear • fibrous: Marked • granulomas: Yes- 20-35%
genetics
NOD2 Chr 16
IBD5 on Chr 5
IL23R on Chr 1
micro: inflamm: transmural pseudopolyps: moderate ulcers: deep, knife-like lymphoid rxn: marked fibrosis: marked serositis: marked granulomas: YES (35%) fiestulae/sinus tracts: yes
other feats: obstruction: yes malabs: yes malignant pot: w/ colonic involvement recurring after colectomy: common toxic megacolon: no
Crohns fistulas: ♣Types • Entero-cutaneous • Entero-enteral • Entero-gastric • Entero-vesical • Entero-vaginal ♣May be disabling and/or embarrassing ♣Usually req aggressive tx or surgery
Extraintestinal manifestations
o Uveitis, migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum
• Increased risk of colonic adenocarcinoma
microscopic colitis general presentation biopsy subtypes assoc w/ prognosis dx
o 2-5 per 100k individuals o ages 50-80, female/M 15:! o Autoimmune, trigger unknown o Salt and water loss in colon o Chronic non-bloody watery diarrhea without weight loss o Endoscopy normal***
Presentation: mild chronic secretory diarrhea ♣ Watery, non-bloody ♣ 4-10 stools per day ♣ no bleeding ♣ minimal to no weight loss ♣ Chronic watery diarrhea ♣ Presents primarily in middle aged and older women ♣ NSAIDs implicated
Mucosal inflammation on biopsy
♣Collagenous colitis- thickened sub epithelial collagen layer
♣ Lymphocytic colitis- inc intraepithelial lymphocytes
2 subtypes, based on histology
♣ lymphocytic colitis
♣ collagenous colitis
assoc w/ celiac disease (and lymphocytic gastritis and other autoimmune diseases (thyroiditis)- strong assoc in lymphocytic colitis)
prognosis is good
♣ no bleeding, dehyrdration, or other complications
♣ no inc in cancer risk or mortality
dx
♣colonoscopy- usually nl
♣biopsy is definitive***
• lymphocytic infiltration of mucuosa and SM (LC)
• thickened collagenous band (CC) in submucosa
Tissue biopsy shows characteristic lymphocytic inflamm +/- a thickened subepithelial collagen layer
♣histology
• lymphocytic colitis: chronic inflamm w/ lymphocytic infiltration
• collagenous colitis: thickened subepithelial collagen band +/- lymphocytic surface injury
ischemic colitis pathophysiology triggers presentation imaging findings dx
recovery
causes
o 90% of pts >60 yo
o fundamental insult = acute compromise in colonic blood flow (hypoxia)
♣Lack of blood flow due to
• Low CO
• Occlusive disease of vascular supply to bowel
triggers
♣ vasospasm
♣ dehydration, hypotension, or cardiopulmonary insult (MI, PE, ex)
o most commonly in watershed vascular areas (splenic flexure, rectosigmoid junction)
presentation
♣ abrupt onset, crampy, lower abdominal pain
♣ urgent need to defecate
♣ mild diarrhea and/or hematochezia
♣ Older individuals w/ co-existing cardiac or vascular disease
♣ Young pts: long-distance runners, women on oral contraceptives
♣ Mechanical obstruction: hernias, volvulus
imaging
CT or endoscopic findings: inflamm, ulceration, +/- bleeding confined to a single vascular region
dx
♣Clinical presentation
• Acute transmural infarction: severe abdominal pain, tenderness, nausea and vomiting, bloody diarrhea and blood in stool
• Peristaltic sounds disappear, rigid abdomen, shock, sepsis
♣Histologic findings
• Varies from focal acute mucosal necrosis to full-thickness necrosis
• Regeneration: if pt doesn’t have full obstruction but diffuse lack of perfusion: withered, atrophic crypts and lamina propria fibrosis; these cells are trying to regenerate; they’re very dark
Complete recovery within 1-2 weeks is typical
Other causes
♣ Vasculitis- lupus (SLE), polyarteritis nodosa (PAN), Henoch-schonlein
♣ Substance abuse- cocaine, amphetamines
♣ Meds- estrogens, migraine meds
♣ Mesenteric thrombosis- protein C/S deficiency, factor V leiden def, etc
♣ Rare: marathon running, extreme dehydration
infectious colitis
general
presentation
cause
Acute inflamm diarrhea
Lower abdominal cramping +/- hematochezia
♣ Mucosal invasion
• Toxin-related injury
♣ Hx- short duration, travel, ill contact,s, dietary indiscretion, antibiotic use
Acute <4 week) diarrhea- think infection
♣Travel to developing countries
• Traveler’s diarrhea GNR
• Amoebiasis
♣Undercooked beef
• E coli
♣Contaminated poultry, eggs, milk, lettuce
• Salmonella/shigella, campylobacter, Yersinia
♣Antibiotic use, recent hospitalization
• C diff
♣Anal intercourse
• Syphilis, gonorrhea, HSV proctitis
“other” colitis
o Hx is a paramount!
♣ Meds, XRT
o Dx is via endoscopy (location, appearance)
Diverticulosis
general
prevalence
diverticular hemorrhage
acute diverticulitis
Diverticulosis (out pouchings from inc intra colonic pressure) o >50% in the elderly o western > developing countries ♣inc intra-colonic pressure ♣low fiber diet o 80% are asymptomatic o 20% diverticulitis, hemorrhage
diverticular hemorrhage
o 5% of pts with diverticulosis
o usually from R colon
o vasa recta within the dome of diverticulum
o painless hematochezia, often heavy, typically stops within 2-3 days
o not a feature of acute diverticulitis
acute diverticulitis o 10-15% of pts with diverticula o fecolith obstructs a diverticulum ♣ distention form bac gas and neutrophils ♣ microperforation, abscess ♣ frank perforation w/ peritonitis o symptoms: lower abdominal pain, nausea fever; not diarrhea, not bleeding o management dx: CT or MRI tx: • oral or IV antibiotics • abscess drainage • surgery o refractory or recurrent disease o stricture o perforation
lower GI bleeding general causes etiologies historical cues dx tx
bleeding distal to ligament of Treitz
colon is most common site
usually hematochezia (less commonly, melena)
mortality 1%
ceases in 90% without intervention
may recur if cause is not identified
LGIB- etiologies
♣ Diverticulosis- most common
♣ Arteriovenous malformations
♣ Colitis (IBD most common)
Lower GI bleed- historical clues
♣Chornic abdominal pain and diarrhea
• IBD
♣Weight loss, new constipation
• Neoplasm
♣Painess, heavy bleeding in o/w healthy, elderly pt
• Diverticulosis
♣Hematochezia after major surgery or MI
• Ischemic colitis
♣Acute dysentery, travel, ill contacts, or antibiotic use
• Infectious diarrhea
♣Chronic, microcyitc anemia
• Neoplasia or AVMs
♣NSAIDs
• Drug induced colitis
♣Hx of pelvic radiation
• Radiation proctitis
Dx of choice: endoscopy (colonoscopy)
♣Also tagged RBC scan, or angiography
Tx
♣ Support and endoscopic therapy
♣ Also angiography therapy, surgical resection (refractory bleeding, recurrent bleeding, cancer)
colon obstruction causes presentation dx tx
Causes
♣ Malignancy
♣ Benign- adhesions, stricturs, volvulus
♣ Foreign body- inserted or ingested
presentation
N/V, abdominal distention, constipation, or obstipation
Dx
♣ Tentative- plain x ray
♣ Confirmed and defined with CT
Tx ♣ Admission to hospital, NPO ♣ NGT tube decompression ♣ Colonoscopy in select cases ♣ Surgical resection is standard ♣ Metal stent for select cancer pts
Giardiasis
o Giardia lamblia: parasitic enterocolitis
♣ Protozoan parasite causing sporadic or epidemic diarrhea, waterborne and foodborne in US, water is a major source of transmission
♣ Cysts are resistant to chlorine filter necessary
♣ 7-14 day incubation period
♣ chronic diarrhea, malabsorption, flatulence, weight loss, may cause intermittent symptoms
Large bowel- infectious and non-infectious causes of colitis
infectious causes of colitis ♣ bacterial enterocolitis ♣ pseudomembranous colitis ♣ viral gastroenteritis ♣ parasitic enterocolitis
non-infectious causes of colitis
♣ ischemic colitis
♣ microscopic colitis
infectious enterocolitis- bacterial infections general presentation Campylobacter spp salmonella E coli Pseudomembranous colitis
o mostly related to ingestion of contaminated water, food, or foreign travel
o these infectious typically create an acute self-limited colitis
pts typically present several weeks after onset of symptoms, therefore tissue biopsy rarely sots classic acute infectious findings ♣ cholera ♣ campylobacter spp ♣ shingellosis ♣ salmonellosis ♣ enteric (typhoid) fever ♣ Yersinia spp ♣ Escherichia coli ♣ Mycobacterial infection
Campylobacter spp
♣ Gram neg bac; major cause of diarrhea worldwide
♣ A leading cause of bac foodborne illness in US
♣ Produces a watery diarrhea +/- blood
♣ Found in contaminated meat (poultry), water and unpasteurized dairy
♣ C jejuni commonly assoc w/ food-borne gastroenteritis
♣ C fetus more often seen in immunosuppressed pts
Salmonella
♣ Gram-neg bacilli transmitted through food and water
♣ Important cause of food poisoning and traveler’s diarrhea
♣ Typhoid (enteric) fever (S typhimurium)
• Abdominal pain, headache, fever
• Abdominal rash and leukopenia
• Diarrhea (not until 2nd week of infection) initially watery then bloody
• Characteristic pathology most commonly seen in the ileum, colon, appendix, and peyer’s patches
• Perforation and toxic megacolon possible
♣Non-typhoid salmonella species
• Mild self-limited gastroenteritis
• Endoscopy: mucosal redness, ulceration and exudates
Escherichia coli
♣Enteroadherent E. coli
• Non-invasive → nonbloody diarrhea
• Similar to enteropathogenic E. coli → chronic diarrhea and wasting in AIDS
• Form a coating of adherent bacteria on surface epithelium of enterocytes
♣Enterotoxigenic E. coli and enteropathogenic E. coli
• Non-invasive → nonbloody diarrhea
• Enterotoxigenic E. coli is a major cause of traveler’s diarrhea
• Enteropathogenic E. coli is an infection of infants and neonates
♣Enteroinvasive E. coli
• Invasive (similar to Shigella) → non-bloody diarrhea, dysentery-like illness, bacteremia
• Transmitted via contaminated cheese, water, person-to-person contact
• A cause of traveler’s diarrhea
♣Enterohemorrhagic E. coli (O157:H7 is the most common strain***)
• Non-invasive, toxin-producing, contaminated hamburgers
• Bloody diarrhea, severe cramps, mild or no fever, sometimes renal failure (HUS)
• On endoscopy: edema, erosions, ulcers, hemorrhage (right colon mostly)
• Deadly outbreaks
Pseudomembranous colitis
♣Clinical features
• Most often caused by C difficile but not always infection-related
• Colitis often occurs after course of antibiotic therapy (antibiotic-assoc colitis”)
• Most freq implicated antibiotics are third-generation cephalosporins
• Common in hospitalized pts (up to 30%)
• Presents w/ fever, leukocytosis, abdominal pain, cramps, watery diarrhea
♣Pathogeneiss
• Disruption of nl colonic flora by Antibiotic allows C diff overgrowth toins released cause disruption of epitheial cytoskeleton, tight junction barrier loss, cytokine release and apoptosis
♣Histologic findings
• Pseudomembranes
o Adherent layer of inflammatory cells and mucinous debris at sites of colonic mucosal injury
• Surface epithelium denuded, mucopurulent exudates
• A “volcano-like” eruption of neutrophils and mucinous debris attached to the surface epithelium
infectious enterocolitis- VIRAL infections
o Cytomegalovirus (mouth-anus)
o Herpesvirus (esophagus and anorectum)
o Enteric viruses
♣ Rotavrius
• Most common cause of severe childhood diarrhea and diarrheal mortality worldwide
• Children b/w 6-24 mo are most vulnverable
• Selectively infects and destroys mature enterocytes villus surface repopulatd by immature secretory cells loss of absorptive function net secretion of water and electrolytes osmotic diarrhea DEHYDRATION = DEATH
• 2 vaccines now available, previous vaccine inc risk of intussusception
infectious enterocolitis- PARASITIC
protozoal infections
entamoeba histolytica
helminthic infections
protozoal infections
♣ prevalanet pathogens in tropic and subtropical countries
♣ dx is primarily by examination of stool samples
Entamoeba histolytica
♣ 10% of world’s population is infected w/ E histolytica parasite
♣ assoc w/ severe dysentery-like, fulminant colitis
♣ can disseminate to other sites (liver)
♣ cecum most commonly affected; “flask shaped” ulcers in mucosa
Helminthic infections
♣ Most common method of diagnosing is by examination of stool for ova and parasites
♣ Worldwide distribution, many people multiply infected
♣ Cause of serious disease in nations with deficient sanitation systems, poor socioeconomic status and hot, humid climates
♣ Seen in immigrants, patients who travel to endemic areas
♣ Nutritional problems can be severe or life-threatening, especially in children
♣ Ascaris lumbricoides (roundworm)***
• One of most common parasites in humans
• Most common in tropics
• Ingested from soil contaminated with feces
• Obstruction, perforation, growth retardation
• Giant worms (up to 20cm) can be identified
diverticular disease general pathogenesis clinical features micro complications appendix
A diverticulum is an outpouching/herniation of the mucosa and submucosa
Pathogenesis
♣ Results from dec dietary fiber dec stool bulk elevated intraluminal pressure mucosal herniation through focal defects in the bowel wall
Clinical features
♣ Most common in sigmoid colon
♣ Prevalence approaches 60% in Western adult populations over 60 yo
♣ Asymptomatic or intermittent cramping, lower abdominal discomfort
♣ Diverticulosis = presence of diverticula
♣ Diverticulitis= inflamm of the diverticula, usually secondary to obstruction
Microscopic findings
♣ Diverticular outpouching lined by mucosa, submucosa, and variable amounts of muscularis propria= diverticulOSIS
♣ Mucosa is compressd/flattened
♣ In diverticulITIS, the diverticulum becomes infiltrated w/ acute, then chronic inflamm cells, and as the inflamm extends, the mucosa ulcerates and pericolonic abscesses, or sometimes fistula form
Diverticulitis complications
♣ Incl obstruction, perforation, abscess formation, bleeding
The appendix
♣ True diverticulum of the cecum
gallbladder
bile ducts
normal bile
Gallbladder-
♣ Stores and concentrates bile (fasting)
♣ Contracts to deliver bile to duodenum (fed)
Bile ducts
♣ Conduct
♣ Route of bile flow for digestion
♣ Route of excretion for cholesterol, minerals, certain drugs
Normal bile- sits in liver and bile ducts, and is conc in gallbladder
♣ Made of water, bile acids/salts, bilirubin, cholesterol, lecithin, ions
gallstones general locations types pathophysiology of formation pigment stones risk factors complications
Usually multiple causes- passes through and/or gets lodged in ampulla and causes obstruction- know that
o Pebble-like accretions that form in the gallbladder
o Are assoc w/ gallbladder inflamm (cholecystitis)
o Causes 9/10 of cases of acute cholecystitis
o Are major cause of pancreas inflamm (pancreatitis)
o Causes 4/10 cases of acute pancreatitis
o 10% of pop has gallstones, and of those 10%, 20% are symptomatic; asymptomatic - symptomatic at rate of 2%/yr
Almost always dev within the gallbladder
♣ Biliary colic
♣ Acute cholecystitis
May spill into bile duct
♣ Obstruction of CBD
♣ Pancreatitis
Numerous risk factors, both genetic and acquired, contribute
Types
♣ Cholesterol- most common
♣ Brown- bacterial infection
♣ Pigment stones- bile stasis
Cholesterol stones- mechanisms ♣ Cholesterol supersaturation ♣ Bile acid deficiency ♣ US, northern Europe, native americans ♣ Advancing age ♣ Female sex hormones- female gender, oral contraceptives, pregnancy , obesity- Female, Fat, Fertile ♣ Rapid weight loss
Pathophysiology of stone formation
♣ Gallbladder stasis
♣ Gallbladder inflamm
♣ Cholesterol hyper secretion by liver
♣ Over-abs of water within the gallbladder
♣ Nidus such as mucin plug or foreign body
o You have cholesterol supersaturation that causes crystallization
♣ Supersaturation is either due to inc cholesterol output or dec bile acid synthesis
♣ Crystallization is exacerbated then by gallbladder hypomotility and excessive mucus- viscous
Pigment stones ♣ Chief constituent= calcium bilirubinate ♣ Risk factors: • Biliary obstruction • Excess bilirubin excretion (hemolysis) • Asian ancestry • May develop in gallbladder or bile duct ♣ Asian, rural ♣ Chronic hemolytic syndromes ♣ Biliary infection ♣ Ileal disease
Gallstone risk factors
♣ Obesity, female, age >30, FHx, estrogen use - 5 F’s
♣ Latin American or native American ethnicity
♣ Rapid weight loss
♣ Biliary obstruction
Complications BILIARY COLIC acute cholecystitis (calculous) acalculous cholecystitis choledocholithiasis ascending cholangitis biliary stricture sphincter of Oddi dysfunc SOD gallstone pancreatitis gallbladder carcinoma
complications of gallstones
BILIARY COLIC acute cholecystitis (calculous) acalculous cholecystitis choledocholithiasis ascending cholangitis biliary stricture sphincter of Oddi dysfunc SOD gallstone pancreatitis gallbladder carcinoma
Biliary colic- know this
• Intermittent pain in epigastrium or RUQ
• After meals, particularly fatty foods
• Peaks within an hour, remits 3-8 hrs later
• Caused by movement of stone into cystic duct or gallbladder neck
•Management
o May persist for months or yrs
o Laparoscopic cholecystectomy is curative
o Non-lithogenic bile acid supplement (ursodeoxycholic acid) may be considered in special cases
Acute cholecystitis (calculous)
• More common than acalculous variety
• Stone in cystic duct or gallbladder neck
• Bac colonization (GNRs, enterococci)
• Transmural inflamm
• GB, perforation, sepsis or death may result if untreated
Presentation
o Severe pain in RUQ, nausea, fever
Tx
o NPO (gallbladder rest)
o IV fluids
o IV antibiotics
o Surgical removal of the gallbladder (cholecystectomy) when stable
o Percutaneous drainage of gallbladder in pts too ill for surgery
Acalculous cholecystitis (acute cholescystitis that occurs independent of stone formation)
• Nonobstructive cholecystitis
• Usually from ischemia of gallbladder
• Risk factors= sepsis, recent surgery, trauma/burns, hypotension
• Vasculitis
- Symptoms, disease otherwise similar to ACC
- Tx: drainage of gallbladder or cholecystectomy, but these pts are typically sicker than ACC so drainage is a little more common
Choledocholithiasis • Stones In bile duct/s • Vast majority migrate from gallbladder • ~10% form de novo in CBD • jaundice, dark urine, and abd pain • may also cause acute pancreatitis
•dx
o liver chemistries will probably be abnl
o ultrasound
o MRCP or ERCP
•Management
o ERCP with extraction and/or lithotripsy*
o Surgery if refractory
Ascending cholangitis
• Bacterial infection of bile duct
• Almost always a complication of choledocholithiasis **
•Symptoms= Charcot’s triad*
o Fever, RUQ pain, jaundice (choledocholithias + fever)
• Sepsis or death may occur if untreated
o Reynold’s pentad = Charcot’s triad + hypotension + altered MS
•Initial management
o Admit to hospital
o NPO broad spectrum IV abx
o IV fluids
•Dx
o History, labs, US are usually suggestive
•Definitive dx and management
o URGENT ERCP
Biliary stricture
• Fixed narrowing or blockage of bile duct
• Intra- or extrahepatic
• Intrinsic or extrinsic
• Benign or malignant
• Symptoms are more chronic and persistnet than stones
•Causes o Benign ♣ Iatrogenic- surgery, radiation ♣ Primary sclerosing cholangitis PSC ♣ Chronic pancreatitis ♣ Autoimmune pancreatitis o Malignant ♣ Pancreatic cancer ♣ Cholangiocarcinoma ♣ Gallbladder cancer ♣ Ampullary cancer
Presentation o RUQ pain o Cholestasis: ♣ Jaundice, dark urine (choluria), alcoholic stools, pruritis o LFTs elevated in cholestatic pattern: ♣ Alk phos/GGT, bilirubin >>ALT/AST
Dx
o Us or CT –> dilated ducts
o MRCP or ERCP for confirmation**
o Biopsy to differentiate bengin vs malignant w/ cholangioscopy
Management
o ERCP with dilation or stenting *
o Biopsy to rule out malignancy, if applicable
o Surgery for refractory or malignant cases
Primary sclerosing cholangitis PSC
o Assoc w/ inflamm bowel disease (UC > Crohns)
o RUQ pain, jaundice, fevers
o Most get cirrhosis of liver
o Disease course independent of colitis (if you tx bowel disease, PSC doesn’t improve)
o Inc risk of cholangiocarcinoma- colon cancer and bile duct cancer
o Alk phos/GGT > AST/ALT
o Bilirubin rises late
o Dx= MRCP or ERCP
o No effective tx except liver transplant
o Consider biliary stent if jaundiced
o Close surveillance for cholangioCA is essential (bile duct cancer)* know that
Sphincter of oddi dysfunction SOD
• Motility disorder of Sphincter of Oddi (young, nervous females)
• Typically intermittent
• Symptoms, labs, imaging may mimic choledocholithiasis
• Types 1,2,3 depending on severity
Presentation
o Recurrent RUQ pain
o Dynamically elevated ALT/AST/alk phos
o Dilated bile duct on US
Dx: ERCP with sphincter of oddi manometry
Tx: Biliary sphincterotomy
Abdominal ultrasound • Cheap, safe, readily available • 95% sensitive and specific for gallbladder stones • >80% accuracy for cholecystitis • 50% sensitive for choldocholithiasis
other complications: Gallstone pancreatitis Gallbladder carcinoma -rare- 0.5%; poor survival- 1% alive at 5 yrs o major risk factors ♣ gallstones (70% have stones) ♣ chronic infection o almost all adenocarcinoma; and much smaller is adenosquamous; squamous; small cell, other
acute vs chronic cholecystitis
Inflamm of gallbladder
Descriptors: acute vs chronic; calculous (assoc w/ stones) vs acalculous (not assoc w/ gallstones)
Acute cholecystitis
♣ 90% due to gallstone obstruction of the neck/cystic duct
♣ other less common causes: trauma, majory surgery, sever burns, postpartum
♣ process
• accumulation of the toxic products in lumen
• disruption of protective mucus layer
• distention ischemia more inflamm
chronic cholecystitis
♣ histopathologic term for inflamm and fibrosis of the gallbladder w/ poor correlation to clinical symptoms
♣ pathogenesis is not well est but, 95% are assoc w/ gallstones
♣ ? recurrent attacks of mild acute cholecystitis
• but most pt’s clinical histories don’t support this notion
♣ ? repetitive mucosal trauma from gallstones
• bu there is a poor correlation w/ the vol of gallstones
♣ ? genetics of bile composition or inflamm response
• but there is as of yet no supporting evidence
extra hepatic bile ducts
choledocholithiasis
choledochal cyst
bile duct carcinoma
choledocholithiasis
♣ stones (choledocholiths) within the biliary tree
♣ major cause of ascending cholangitis (gram neg bac infection going from intestines up through biliary tree)
♣ 90% from gallbladder; 10% primary
choledochal cyst
♣ congenital dilatation of the common bile duct
bile duct carcinoma ♣ very rare; nearly all are adenocarcinomas ♣ risk factors • choledochal cyst in older adults • primary sclerosing cholangitis • infections (liver flukes) • ? cholelithiasis ♣ very poor prognosis, too
pancreatitis
general
sequelae
acute vs chronic
inflamm of the pancreas
sequelae • pseudocysts • abscesses • pancreas insufficiency • secondary diabetes
acute
• gallstones 45%; alcohol 35%; other 20%
• gallstones: pathogenesis
o not simply mechanical obstruction
o inc intraductal pressure
o leakage of enzyme-rich fluids back into the pancreas (digestive fluids)
o tissue injury, inflamm, edema, ischemia more injury
•alcohol pathogenesis
o not simply toxic injury
o defective packaging of enzymes in the acini; released into ducts; cause activation too early in the pancreas (auto-digestion)
o secretion stimulation of the enzymes
o sphincter of oddi contraction
o alcohol might just be an exacerbation of chronic pancreatitis from alcoholics
chronic
• irreversible parenchymal destruction and fibrosis
• multiple causes
o most common identifiable cause is alcohol abuse
o long-standing duct obstruction
o hereditary forms of pancreatitis
o large proportion (40%) are idiopathic
• chronic duct obstruction by concretions
o abnl pancreatic secretions plug ducts
• direct toxic effects on acinar cells
• inducing oxidative stress on acinar cells
• necrosis-fibrosis
o acinar cell necrosis and replacement by fibrous tissue
pancreatic neoplasia
ductal carcinoma
endocrine neoplasia
other tumors
ductal carcinoma- 95%
• top 10 new cases per yr; despite being #9 for men and not even make the list for women, it accounts for the 4th highest death rate in cancer for both sexes
endocrine neoplasia- 2%
• most clinically relevant tumors are:
o nonfunctional; well-differentiated
• behavior is difficult to predict on appearance
• functional tumors
o insulinoma 42%; gastrinoma 24%; glucagon 14%
other tumors- 3%; acinar cell carcinoma, solid-pseudopapillary neoplasm, pancreatoblastoma, etc
dopamine receptor D2 antagonists
side effects
clinical uses
Metoclopramide (also blocks 5HT3), prochlorperazine
Side effects: due to block of D2 receptors at other sites
♣ Extrapyramidal symptoms (movement disorders)
♣ Restlessness, fatigue, drowsiness, diarrhea
Clinical uses
♣Metoclopramide- used for n/v of chemotherapy
♣Prochlorperazine- crosses BBB poorly
• Less effective against emetic stimuli in gut which are mediated via 5HT3 receptors)
• But additional block of M and H1 receptors increases their utility in nausea with motion sickness
• Blocking on alpha1 receptors inc potential for hypotension
antihistamines
first generation agent info
Meclizine, promethazine, diphenhydramine (dimenhydrinate)
First generation agents
♣ Good CNS penetration
♣ Additional muscarinic receptor blocking actions
♣ Available orally- promethazine also IV and rectally
♣ Primary use for motion sickness and post op emesis
anticholinergic agents
primary use and others
admin route
o Scopolamine
Primary use: prevention and tx of motion sickness
o Some efficacy in post op nausea and vomiting
o Administered transdermally with duration of action of 72 h
PACU post op orders- anesthesiology
post op N/V
Post op N/V: drugs are listed in order of suggested use for rescue
Select an anti-emetic that affects different receptors than medications already given for post op N/V prophylaxis
♣ Ondansetron- 5H3 antagonist
♣ Droperidol (consider black box warning and movement disorders)- D2 antagonist
♣ Promethazine- H1-D2 antagonist
♣ Metoclopramide (caution in pts w/ movement disorders)- D2 antagonist
anti-emetic regimens for cancer chemo
1-5
Emetic class; acute vomiting (estimated incidence w/o anti-emetics); pre-treatment regimen
o 1: minimal: prn anti-emetics (lorazepam, prochlorperazine plus diphenhydramine, metoclopramide plus diphenhydramine) o 2: low: dexamethasone (Dex) o 3: mild: ondansetron + Dex o 4: moderate: Granisetron + Dex o 5: high: Granisetron + Dex
N/V of pregnancy
nonpharmacologic
pharmacologic
Nonpharmacologic: dietary-lifestyle modifications, acupuncture, acupressure, ginger
Pharmacologic agents (not assoc w/ inc fetal risk)
♣ First line: pyridoxine (B6) + H1 antagonist (doxylamine)
♣ If N/V persists add diphenhydramine or meclizine
♣ No improvement D2 antagonist (prochlorperazine) or metoclopramide (effective but 2nd line- movement disorders)
♣ If dehydration requiring hospitalization 5HT3 antagonists (ondansetron) – inc QT interval caution if cardiac disease
♣ Glucocorticoids (methylprednisolone) reserved for refractory n/v (2nd trimester)
constipation
prescription vs non prescription considerations
drug-induced constipation
Prescription vs non-prescription
Considerations
• Is the condition the drug is to be used for self-diagnosable and self-treatable?
• What is the products toxicity? Habit forming? High dose safety profie.?
• Do the benefits of OTC availability outweight the risks?
• Do methods of use preclude OTC availability?
• Can directions for use/warnings be written and understood by ordinary person?
Drug-induced constipation
♣ Antimuscarinic agents
• Antispasmodic agents, overactive bladder agents
♣ Drugs w/ antimuscarinic side effects
• 1st gen antihistamines
• TCADs
• Typical antipsychotic agents (Esp low potency)
♣ Antacids
• Calcium carbonate
• Aluminum
♣ CCBs (esp verapamil)
♣ Opioid analgesics
♣ 5HT3 antagonists
management of simple constipation fiber/bulk forming laxatives saline/osmotic laxatives stimulant-irritant laxatives stool wetting agents and emollients
♣ proper diet (high fiber)
♣ exercise (esp abdominal m)
♣ adequate fluid intake
fiber/bulk forming laxatives: Psyllium
♣ usually recommended first
♣ approximates physciological mechanism (facilitates passage-stimulates peristalisis via H2O abs bulk expansion
♣ effective in 12-24 hrs to 3 days; take w/ fluids
♣ may combine and interact w/ other drugs (Digoxin/salicylates), so space dosing
saline (osmotic) laxatives
♣ added to fiber as second step
♣ general
• non absorbable ions osmotic retention of intestinal water inc peristalsis
• also used in purging doses for food/drug poisoning
♣milk of magnesia (Mg(OH2), magnesium citrate
• most used for mild to mod constipation
• avoid in renal dysfunc as long term use can lead to electrolyte imbalances
♣phosphate enemas: primarily reserved for fecal impaction
♣polyethylene glycol- electrolyte solutions (PEGs)
• high vol solutions
o bowel cleansing prior medical procedures
o contain Na/K salts to prevent net transfer of electrolytes
• smaller vol solns
o for difficult to tx constipation
o daily dose for tx <2 weeks duration
o excessive use may lead to electrolyte depletion
♣lactulose
• dissacharide metabolized by colonic bac to low MW acids osmotic diarrhea inc peristalsis
• alternative for acute constipation; useful in elderly
stimulant-irritant laxatives
♣ try if fiber/saline fail
♣bisacodyl
• inc peristaltic activity via local irritation (PG-NO) accumulation of water and electrolytes inc motility
• usually active w/in 6-10 hrs po or 15-60 min pr
• effective, potentially dangerous side effects electrolyte/flid deficiencies, severe cramping
• most widely abused class- but safe for chronic use in recommended doses
• wide interindividual variation in the effective dose
♣senna- also commonly used stimulatnt laxative
♣castor oil
• contains a triglyceride that is hydrolyzed in the gut to ricinoleic acid
• acts primarily inn the small intestine stimulate fluid/electrolyte secretion and speed intestinal transit
• castor bean also contains ricin, an extremely toxic glycoprotein
stool wetting agents and emollients
♣docusate- dicotyl sodium sulfosuccinate (Colace)
• a surfactatnt that acts as s stool –softener (Facilitates admixture of aqueous and fatty sub’s)
• role is primary prevention- used in pts w/ CV disease/hernia/postpartum pts
• often used in combo w/ stimulant laxative when initiating opioid analgesic therapy
♣lubricant (mineral oil, olive oil)
• coats fecal contents preventing abs of fecal water
• use w/ caution in very young/elderly due to potential for aspiration into lungs
opioid analgesic-induced constipation
♣ constipation: managed w/ stool softeners (docusate), stimulant laxatives (bisacodyl-senna), osmotic laxatives (PEG (miralax), milk of magnesia)
♣ tolerance to constipation does not dev to same lelve as tolerance to analgesia or resp depression
♣ option for pts taking opioids for non-cancer pain that have failed laxative therapy
• peripherally acting antagonists
methylnaltrexone
♣ given SC, doesn’t cross BBB
♣ expensive ($700/day)
naloxegol
♣ new pegylated derivative of naloxone given orally
♣ extensive first-pass metabolism, primarily binds opioid receptors in GI tract only
♣ $10/day
tx of diarrhea
activated charcoal
sorbitol
o prevention of abs- chem abs
o activated charcoal: efficacy > MgO-tannic acid
♣ binds drug in gut to limit abs (wil also bind ipecac)
♣ effective w/o prior gastric emptying
• can even reduce elim half-lives of drugs given IV
• back-diffusion of drug from blood with ion-trapping in stomach
o sorbitol 70%: recommended, given with charcoal to prevent “briquet” formation
antimicrobial therapy for watery diarrhea-
C diff
risk inc w/ antibiotic use
♣C difficile- diarrhea/colitis
• Metronidazole*, vancomycin, rifaximin
♣Risk inc w/ antibiotic use:
• Fluoroquinolones, clindamycin, broad spectrum penicillins and cephalosporins
drug-induced diarrhea causes
o Antibiotics (esp broader spectrum agents): super infection
o Colchicine (anti-inflammatory agent for gout)
o Digoxin: parasympathomimetic action
o Magnesium antacids: osmotic laxative action
o Misoprostol: prostaglanding analog stimulates intestinal musculature
o Muscarinic agonists: inc parasympathetic tone
o Reserpine: sympathyolytic agent allows parasympathetic dominance in GI tract
o SSRIs: elevated synaptic 5HT levels stimulates GI motility
antidiarrheal agents
general
symptoms
sudden onset diarrhea
♣Products are available to tx: • Cause (bac): covered in ID block • Effects (loss of fluids and electrolytes)- in severe cases principal concern in infants, children, and elderly o Primary tx is oral rehydration therapy o Covered next hr
♣Symptoms
• Agents discussed provide symptomatic relief of mild cases of acute diarrhea (majority avail OTC)
♣Sudden onset diarrhea is often benign, self-limiting illness that req no tx or eval
opioids
loperamide
side effects
p-glycoprotein membrane transporters [T]
polycarbophil
adsorbents
probiotics
opioids
Loperamide (also diphenoxylate and paregoric)
♣ Opioid receptor agonist affecting instinal motility (mu), intestinal secretion (delta), and abs (mu and delta)
♣ Anti-sectretory activity against cholera toxin
♣ Effective against traveler’s diarrhea, alone or w/ antibiotics- discontinue if no improvement in 48 hrs
Side effects
♣ Low addiction liability for acute use due to low water solubility (difficult to dissolve and then inject) BUT:
• Doses of 70-200 mg cross BBB (2 mg capsule) CNS (euphoria dec RR), cardiac toxicity (inc QT)
♣ Few adverse effects but overdosage can cause CNS depression (esp in children) and paralytic ileus
P-glycoprotein membrane transporters [T]
o Transporter “pumps” loperamide out of CNS- use w/ the inhibitor omeprazole inc CNS levels
Polycarbophil
o Recognized by FDA as safe and effective (marked capacity to bind free fecal water)
o Useful in diarrhea (Absorbs 60x weight in H2O) and constipation (prevents fecal desiccation)
Adsorbents
o Kaolin, pectin, attapulgite, charcoal, bismuth subsalicylate
o Rationale to absorb “toxins” that cause irritation
o Taken after each loose bowel movement until controlled
♣ Manages mild to moderate diarrhea
♣ “formed stools” and perception of dec fluidity, but small effect on fluid vol excreted
o avoid use of bismuth subsalicylate in children under 12 yo (salicylate risk for Reye’s syndrome)
probiotics
o most commonly Lactobacilus species
♣ Rhamnosus CG
♣ Acidophilus
♣ REuteri
♣ Yogurt (“live and active cultures”)
o Suppress growth of pathogenic organisms restore normal flora possible role in antibiotic-associated, viral, or traveler’s diarrhea
o To be clinically useful, bacterial agent must:
♣ Survive production and storage process
♣ Survive low pH of stomach
♣ Reach the colon and adhere to intestinal cells
pharm tx of IBS
mild
moderate
severe
o Aimed at relieving abdominal pain and discomfort
o Low dose tricyclic antidepressants**
o Improve bowel function
o Diarrhea: antidiarrheal agents [loperamide]**
o Constipation: osmotic laxatives**
mild
diet, loperamide for diarrhea
moderate:
pain/discomfort: ANTISPASMODICS, dicyclomine, hyoscyamine
constipation: laxatives
diarrhea: loperamide
severe:
pain/discomfort: ANTIDEPRESSANTS, despiramine, nortriptyline
constipation: TEGASEROD
diarrhea: ALOSETRON
antipsychotic agents- adverse rxns
o Muscarinic block** – with typical-low potency o Dry mouth o Blurred vision o Urination difficulty o Constipation o Tachycardia o Sedation
o Alpha-1 adrenergic block** – with typical-low potency
o Orthostatic hypotension
o H1 Histamine block** – with typical-low potency
o Sedation
o Weight gain–> risk of Type 2 diabetes*
diarrhea morbidity and mortality infectious gastroenteritis in US anatomy of diarrhea enteric infections pathogens prod watery diarrhea cholera
♣ Diarrhea is 2nd leading cause of death worldwide- due to dehydration?? Or maybe just 5.8% and he cut off the rest of the chart
Morbidity and mortality: developing couuntries (1980); higher deaths than resp infections?
♣ Diarrheal disease in young and old
o Dehydration is the leading cuase of morbidity and death
o Rehydration is the mainstay of therapy
Infectious Gastroenteritis in the US
o Viral 30-40%
o Bacterial/parasitic 20-30%
o Unknown 40%
Anatomy of diarrhea
o Non-inflammatory (watery)- small bowel
o Inflammatory (inc T, WBC, RBC)- colon
♣ Enteric infections
o Non-inflammatory
♣ Site: upper small bowel
♣ Pathogens: Norwalk, Rotavirus, Giardia, Cholera, ETEC
o Inflammatory
♣ Site: colon
♣ Pathogens: C jejuni, Shigella, Salmonessa, E coli, C diff, E histolytica
Pathogens producing watery diarrhea o Vibrio cholera o Enterotoxigenic E coli o Rotavirus o Norwalk virus o Giardia lamblia
Migration poverty igrnorance politics pathobiology o Water (Salt, warm, communal, untreated)
Cholera is a disease of lethal history, wanton epidemics, universal fear
♣ To die of cholera is to die in suspicious circumstances
♣ Therapy of cholera- 1832
o Bloodletting, calomel cathartic, mercury, laudanum, beeswax rectal plug, tobacco smoke enema, IV saline
cholera toxins
dehydration
o Structure: A:5B o Molec weight 30:11.6 o Receptor: ganglioside; GM1 o Mech: cAMP o Rice water stool
o Dehydration ♣ Dec pulse vol ♣ Low BP ♣ Poor skin turgor ♣ Sunken eyes ♣ Dec urine ♣ Dec Mental status ♣ Metabolic acidosis- not perfusing well, losing bicarb in bowel ♣ Hypoglycemia ♣ Hypokalemia o Oral rehydration soln ♣ WHO; common juice/soft drink plus heaping teaspoon sucrose
pathogens producing watery diarrhea (non-inflamm)
♣Vibrio cholera
♣Enterotoxigenic E coli- “turista”- enterotoxigenic E coli; traveler’s diarrhea
♣Rotavirus • Epidemiology o Leading cause of: ♣ Prolonged diarrhea ♣ Dehyrdration from diarrhea ♣ Hospitalization from diarrhea ♣ Death from diarrhea (US and world) ♣ Poorest countries= 82% of deaths (
pathogens producing inflammatory diarrhea
♣ Campylobacter jejuni
♣ Salmonella sp
♣ Shigella sp
♣ E coli 0157:H7
• Causes vast majority of hemorrhagic colitis (and HUS) in US
• Illness lasts 2-4 days (<7d)
• Highest rates in young children and elderly
•Reservoirs
o Intestines of dairy cattle, beef cattle, ? role of other animal reservoirs
•Spectrum of illness o Asymptomatic infection o Non-bloody diarrhea o Hemorrhagic colitis o Hemolytic uremic syndrome (HUS) o Thrombotic thrombocytopenic purpura TTP
•Toxin
o Verotoxin; Shiga-like toxin (SLT-I/II)
o Binds esp to human renal endothelial cells
o Inhbitis protein synthesis
•Therapy o TMP/SMX- all sensitive ♣ No benefit in 47 childrne ♣ May inc toxin production/release* ♣ ? IV immunoglobulin ♣ prevention (food, cooking)
♣E histolytica
leading cause of acute bacterial diarrhea in US, all ages
campylobacter jejuni
predominant cause of nosocomial diarrhea
o C diff is the leading, and virtually the only, cause of nosocomial infectious diarrhea
o Culturing for other agents in this setting is not indicated
o Most commonly assoc w/ antibiotic use
o Symptoms may be mild diarrhea, watery or bloody, or may have fever, leukocytosis w/ severe colitis
o Nosocomial: >3 days in hopstial
♣ >50% of stool specimens
♣ routine culture- 1/191 of positives
♣ parasite xam- 0/90 of positives
o antibiotics are important- clear out gut and replace w/ good bac (fecal transplants)
enteric infections ♣ I. Non-inflammatory Site: Upper small bowel Pathogens: Cholera, ETEC, Giardia, Norwalk, Rotavirus ♣ II. Inflammatory Site: Colon Pathogens: Shigella, Salmonella, C. jejuni, C. difficile, E. histolytica ♣ Enteric Fever Site: Nodes; Blood;Gallbladder Pathogens: Salmonella typhi,S. paratyphi, ± Yersinia
salmonella enteric serotype type
♣ Salmonella enteric serotype typhi (Typhoid fever)
o Gram neg rod; human only
o <50 cases/yr in US; 12-33 million worldwide
o 600,000 deaths/yr (SE asia)
o risks: fecal contamination; food/water (poor handling), contact w/ carrier (Typhoid mary)
infectious diseases ex cases
♣ College student goes to Mexico for summer vacation, acute, non-inflammatory diarrhea (watery stool, no blood, no fever)
o Enterotoxigenic E coli- noninflammatory diarrhea
♣ Embassy official travels to Peru; enjoys ceviche at a state dinner; does not enjoy acute abd. pain, profuse watery diarrhea (20/day) which develops 2 days later; No fever, blood. Several others ill.
o Vibrio cholera; noninflammatory
♣ American trekker in Nepal develops acute abd. pain, bloating, gas, foul-smelling diarrhea. No blood, fever. Does not respond to quinolones; loses 10 lbs.
o Giardial lamblia?
♣ Embassy official, well-recovered, arrives in Seattle, kisses ground, and, craving real American food, takes family to Jack-in-the Box. Four days later, develops abd. pain, grossly bloody diarrhea. No fever.
o E coli 0157:H7 (enter-hemorrhagic E coli EHAC- O- oligosaccharide; H- flagellum)
♣ Spectrum of illness • Asymptomatic infection • Non-bloody diarrhea • Hemorrhagic colitis • Hemolytic uremic syndrome HUS • Thrombotic thrombocytopenic purpura TTP
systemic approach to viewing imaging studies
pt data
study image data (incl projection, position, technical info, etc)
image quality and adequacy
detection of abnormality
ABCs for bone X-rays
-alignment, bone, cartilage, soft tissue
-ABCED for CXR
airway, bones, cardiac, diaphragm, everything else
description of abnormality (size, shape, number, borders, location)
DDx (correlate w/ Hx and PE)
assess for change (prior studies)
abdominal radiograph xrays general bones stones calcifications gas hallmark of obstruction mass
projections usually supine (KUB- kidney, ureter, bladder) and upright, or left lateral decubitus
indications: after tube placement, central line, eval for obstruction, free air, foreign bodies
bones- look for fractures, dislocations, etc for unexplained abdominal symptoms
stones- gallstones, kidney stones
calcified gallstones- laminated due to formatting for long time and faceted due to multiple and rubbing against one another; only 10% gallstones appear calcified and visible on plain films
calcifications:
wall or capsule of organ (or artery wall)- eggshell appearance
phleboliths- round calcifications w/ lucent centers, often in pelvis (calcifications in a vein- generally no clinical sig but difficult to tell from a uterus stone)
gas- stomach air bubble- LUQ above diaphragm if pt has hiatal hernia supine: air rises to anterior body of stomach prone: posterior fundus
small bowel- nl to have scattered air-fluid levels
-valvulae conniventes (numerous, narrow spacing, cross lumen from one side to other)
large bowel: haustral indentations/folds, sacculations (from tania coli and circular muscles)- should not cross entire lumen diameter
bowel obstruction: proximal bowel will be distended and dilated** (hallmark of obstruction)- nl is 3-6-9 rule (SI, transverse colon, cecum)
-if bowel is dilated all the way to anorectal junction, it’s a functional obstruction
mechanical obstruction:
compensatory inc in peristalsis and eventually clearing of air distal to obstruction
mass:
2 different densities will show interface/contour/silhouette borders
mass effect- displacement of structures away from nl locations (due to tumors or enlarged organs)
fluoroscopy
specialized X-ray technique
images in real time on video monitor for dynamic processes
higher radiation dose than plain film
¥ Barium swallow ¥ Esophagram ¥ Upper GI ¥ Small bowel follow through (SBFT) ¥ Enteroclysis ¥ Barium enema
highest indication for iodinated water-soluble contrast is possible gut perforation
extravasation of water-soluble agents into peritoneum and retroperitoneum is safer than barium
avoid high osmolality in pts w/ proximal GI obstruction- aspiration can lead to life threatening pulm edema
barium swallow
can eval 3 phases of swallowing- oral, pharyngeal, and esophageal (structural and functional abnormalities)
pharyngeal dysphagia- food sticking to throat/lump in throat, coughing, choking, nasal regard, food dribble
retrosternal dysphagia- esophageal motility disorders or structural abnormalities (esophagitis, rings, strictures, tumors)
-do a biphasic esophagram
Upper GI fluoroscopy
-esophagus, stomach, duodenum w/ simple and double contrast (air, barium)
air- swallow carbon dioxide producing crystals
small bowel follow through SBFT
- jejunum, ileum, terminal ileum
- often combo w/ upper GI
- radiographs obtained at timed intervals (15-30min) until Ba reaches colon
contrast or Barium enema BE
evaluate colon and rectum
enema tube w/ rectal tip and balloon in rectum
single or double contrast
adequate bowel prep needed (stool can mimic/obscure pathology)
-shouldn’t be performed immediately after endoscopic biopsy or in toxic megacolon- danger of perforation or in pt w/ suspected acute perforation
if there’s a risk for perforation- water soluble contrast can be used
enteroclysis
gold standard of small bowel imaging
not well tolerated by pts
more costly
higher radiation exposure than SBFT
allows for double contrast exam of jejunum and much of ileum
tube placed in jejunum and after Ba is injected, methyl cellulose or air is then instilled
reserved for situations when superior anatomic info is needed
ultrasound of GI CT IV contrast MRI nuclear medicine angiography/interventional radiology
US-
typically eval organs and biliary sys, esp for suspected appendicitis and specific pediatric indications
sound waves (not ionizing radiation)
air produces “dirty shadowing) and poor/no visualization to posterior structures of air
operator dependent
body habitus dependent
CT
widely used to eval pain and other indications
Barium is superior to CT/MRI for eval motility, intraluminal, and mucosal disease, but advancements are being made (ex CT enterography and CT enteroclysis)
–don’t use Barium if suspected perforation
CT is better for eval intraluminal component of bowel
allows eval of adjacent mesentery, momentum, retroperitoneum, peritoneal cavity, and viscera
assess hepatobiliary and pancreatic ductal systems for eval of strictures, stones, and neoplasms
IV contrast
eval of bowel wall, solid organs, vascular structures
can mask renal stones, subtle calcifications, or hemorrhage
—-extremely important to give radiologist the Hx
risks- nephrotoxic, allergic rxn
need to get baseline serum Cr and GFR before injection in pts at risk for nephrotoxicity
–indiations:
>60yo
Hx of renal dx (dialysis, transplant, single kidney, cancer, surgery), hx of HTN, DM, metformin drugs (metformin can rarely lead to lactic acidosis)
MRI
no ionizing radiation
mainly eval solid organs and biliary tract for strictures, stones, neoplasms
not limited by overlapping bowel loops
IV contrast agents- gadolinium based (no nephrotoxicity, but risk for nephrogenic systemic fibrosis NSF)
nuclear medicine used in eval of practically every GI problem, but other imagining has limited application to specific clinical problems inject radioactive dose/swallow spatial resolution is low imaging times can be long (hr or more)
angiography/interventional radiology use is more widespread for therapeutic purposes, but sometimes dx GI bleed biliary obstruction image-guided biopsy abscess drainage feeding tubes portal HTN IR oncology
salivary glands saliva secretory unit of salivary gland CNS regulation ANS reg
Salivary glands
o 3 pairs of glands: parotid, submandibular, and sublingual
o produce a serous (proteinaceous) or mucus product, or both
constituents of saliva and their funcs
o water- Facilitates taste and dissolution of nutrients; aids in swallowing and speech
o bicarb- neutralizes refluxed gastric acid
o mucins- lubrication
o amylase- starch digestion
o lysozyme, lactoferrin, IgA- innate and acquired immune protection
o epidermal and nerve growth factors- assumed to contribute to mucosal growth and protection
secretory unit of the salivary gland- acinus
o division of labor: acinar cells make the saliva and striated duct cells modify its ionic content
CNS regulation of salivary secretion- parasympathetic input from higher brain centers
o Salivary nuc parasympathetic 2 divisions
♣ Otic ganglion ACh parotid gland inc salivary secretion via effects on acinar secretion and vasodilation
♣ Submandibular ganglion ACh submandibular gland inc salivary secretion via effects on acinar secretion and vasodilation
o Parasympathetic- inc acinar cell secretion and vasodilation of blood vessels surrounding the acini (results in protein rich and fluid/ion rich soln)
o Sympathetic- inc acinar cell secretion (results in high protein/low fluid soln)
salivary secretion- key points
o acinar secretions are close to isotonic. TJs allow movements of ions and water from blood
o in duct cells, Na/K ATPase establishes a conc gradient. Carbonic anhydrase uses H2O and CO2 to prod H+ and HCO3-
o at a low rate of flow, duct cells absorb Na and Cl and secrete K and HCO3-
o the movement of water in the ducts is restricted by the TJs, leaving the saliva hypotonic
o faster flow rate limits the action of duct cells on ionic/water content
o secretion is modified by ANS (parasympathetic and sympathetic) and the changes in blood flow
exocrine pancreas secretions regulation thematic structure acinar secretion control of CCK release trypsin
pancreas and pancreatic secretions
♣ acinar cells prod variety of enzymes (proteases,lipases and amylases)
♣ ductal cells prod a bicarb soln to help liquefy and neutralize acidic chime int ehduodenum
♣ endocrine organ
proteases trypsinogen chymotrypsinogen proleastase procarboxypeptidase A and B
amylolytic enzyme:
amylase
lipases:
lipase
nonspecific esterase
phospholipase A2
nucleases:
deoxyribonuclease
ribonuclease
others:
proclipase
trypsin inhibitors
monitor peptide
regulation of pancreatic secretions
o ACh- released form the vagus and ENS nerves; stims the release of digestive enzymes from acnar cells (mostly cephalic stage)
o Secretin- released from endocrine cells in the proximal small intstines in response to acid; stim’s the release of a bicarb-rich soln from pancreatic duct cells
o Cholecystokinin CCK- released from endocrine cells in the proximal SI in response to fats and proteins; stims the releases of digestive enzymes from acinar cells but has other effects in the duodenum
schematic structure of exocrine pancreas
o Division of labor: acinar cells make the enzymes and duct cells secrete a water/bicarb rich soln
o NO MOEPITHELIAL CELLS- EXAM QUESTION
Secretion from the pancreatic acinar cells
o Effects of cholecystokinin cluster unit in the duodenum
o CCK: gallbladder contraction
♣ Pancreas- acinar secretion
♣ Stomach- reduced emptying
♣ Sphincter of oddi- relaxation
o Protein, carbohydrate, lipid abs and digestion
o Matching of nutrient delivery to digestive and absorptive capacity
Control of CCK release from “I” cells
o As long as there’s enough protein in sys, trypsin isn’t going to act here; until you get to no protein left, so trypsin targets I cell process and shuts it down
o As long as protein is in lumen, trypsin will target protein and not the monitoring peptide/I cell
Trypsin
o The bulk of the enyzmes released by the pancreas are proteases
o Trypsin is secreted from the pancreas in an inactive, pro-enzyme form called trypsinogen. Also released is a trypsin inhbitior
o Trypsin becomes activated in the duodenal lumen when trypsinogen is cleaved by enzymes (enterokinases) located on the surface of enterocytes
o Activated trypsin then autoactivates more trypsinogen along w/ most of the other pancreatic enzymes
Secretion from the pancreatic duct cells
o Effect of secretin
o Secretin acts by inc cAMP levels in duct cells. The release of secretin is enhanced by CCK
Ionic composition of pancreatic juice as a func of flow rate
o Flow rate inc- K doesn’t change/low
o Cl dec, HCO3 gets high, and Na stays the same/high
Pancreatic vs salivary secretion summary
o Salivary secretion is regulated by the ANS. Pancreatic secretion is regulated by both ANS and hormones.
o The salivary acinus is very vascular and increased blood flow results in a dilute saliva that is modified by duct cells. Salivary ducts, on the other hand, are fairly impermeable to water.
o Pancreatic acini are not as vascular and respond to ACh and CCK. Ductal cells actively secrete a water and a bicarbonate rich solution in response to secretin.
o Saliva is rich in KHCO3 whereas pancreatic juice is rich in NaHCO3.
salivary gland pathology
o Salivary gland diseases ♣ Reactive lesions ♣ Infectious sialadenitis ♣ Benign neoplasms ♣ Malignant neoplasms ♣ Rare tumors
o 8 diff infection/immunological salivary gland diseases ♣ Mumps ♣ Cytomegaloviral Sialadenitis ♣ Bacterial Sialadenitis ♣ Sarcoidosis ♣ Sjögren’s Syndrome (venus Williams- extraoral manifestations incl joint pain) ♣ Salivary Lymphoepithelial Lesion ♣ Xerostomia or dry mouth ♣ Halitosis
o Benign neoplasms
♣ Mixed tumor (pleomorphic adenoma)
♣ Monomorphic adenomas
♣ Ductal papilloma- can be pedunculated (on the tongue ligament?) or cessile
hallmarks of pleomorphic adenoma in mouth
monomorphic adenoma
pleomorphic adenoma
o Diverse microscopic pattern
o Islands of cuboidal cells arranged in ductlike structures
o Loose chondromyxoid stroma, CT, cartilage (arrows) and even bone-like tissue
o Typically encapsulated, although tumor islands may be found within the fibrous capsule
Monomorphic adenoma
o Similar to pleomorphic adenoma except no mesenchymal stromal component
♣ Predominantly an epithelila component
o More common in minor salivary glands (upper lip)
o 12% bilateral
o rare malignant pot
otypes
♣ basal cell adenoma, canicular adenoma, myoepithelioma adenoma, clear cell adenoma, membranous adenoma, glycogen-rich adenoma
warthin’s tumor
o Warthin’s tumor (benign papillary cystadenoma lymphomastosum)
o The second most common benign tumor of the parotid gland
o It accounts for 2-10% of all parotid gland tumors
o Bilateral in 10% of the cases
o May contain mucoid brown fluid in FNA
o Preferentially effects smokers/men
Epithelial component
♣ Consists of papillary fronds which demonstrate 2 layers of oncocytic epithelial cells
♣ Cytoplasm stains deep pink and shows granularity because of an abundance of mito
♣ Occasionally undergoes squamous metaplasia (may mistakenly diagnose SCC on FNA
Lymphoid component
♣ An abudndance of this is presence- lymphoid aggregate
♣ Occasional germinal centers will be seen
♣ Lymphoid tissue forms the core or papillary structures
♣ Both lymphoid and oncoytic epithelial elements mus be present to dx warthin’s
WHALE- warthrin’s has abundant lymphoid and epithelail components ***
features suggestive of malignancy
staging for major salivary gland cancer
o induration/hardness o fixed to overlying skin or mucosa o ulceration of skin or mucosa o rapid growth; growth spurt o short duration o pain, often severe o facial nerve palsy
staging
o T2 is about 2 cm; and from that you can back and forward- calculate all the other stages
malignant neoplasms mucoepidermoid carcinoma polymorphous low grade adenocarcinoma adenoid cystic carcinoma clear cell carcinoma acidic cell carcinoma
Mucoepidermoid carcinoma (mucin+) ♣ MECs contain 2 major elemetns: mucin-producing cells and epithelail cells (epidermoid and mucinous components)- PAS staining ♣ MEC is div into low-grade (Well differentiated) and high grade (poorly differentiated)
Polymorphous low-grade adenocarcinoma
Adenoid cystic carcinoma
♣ Adenoid cystic carcinoma with Swiss cheese pattern
♣ It is the 2nd most common malignant tumor of the salivary glands
♣ ACC is the most common malignant tumor found in the submandibular, sublingual, and minor salivary glands
♣ Nerve invaded by adenoid cystic carcinoma; spread may oocur by emboli along nerve lymphatics
Clear cell carcinoma
Acinic cell carcinoma (no glycogen, fat at mucin, 3% malignant and bilateral); this list was increasing in freq
pancreatic cancer
general
endocrine
exocrine
♣ classified as either exocrine or endocrine
♣ only 3% will survive because of late dx
♣ most will die within 4 to 6 months
endocrine pancreatic cancer
♣ gastrinoma (Zollinger Ellison Syndrome)
♣ Glucagonoma- usually large, often mets, 70% malignant
♣ Insuloma- the most common pancreatic neuroendocrine tumors
♣ Nonfunctional islet cell tumors NICT- usually malignant and hard to detect; metastasis somewhere else is how they’re detected
♣ Somatostatinoma- occur anywhere in the pancreas or duodenum
♣ VIP-releasing tumor- usually in the body and tail of the pancreas
Exocrine pancreatic cancer
♣ Acinar cell carcinoma- rare leads to overproduction of lipase
♣ Adenocarcinoma- 90% of all pancreatic cancer starts in duct
♣ Adenosquamous carcinoma- forms glands that flatten as it grows
♣ Intraductal papillary-mucinous neoplasm- fingerlike projection into the duct, prelude to malignancy
♣ Mucinous cystadenocarcinoma- rare malignant spongy cystic tumor
♣ Pancreatoblastoma- rare, occurs in kids <10yo AKA “pancreatic cancer of infancy”
♣ The papillary cancers are more likely to be metastatic- break off and go somewhere else
trachea-esophageal TE fistula demographics embryo presentation/dx tx
o Demographics: 1/3k to 1/10k live births; half to 2/3 have other assoc anomalies (esp cardiac defects)
Embryo: failure of nl separation of intestinal and respiratory tracts; most cases also have esophageal atresia
Presentation/dx:
♣ Prenatal: polyhydramnios (too much amniotic fluid)
♣ Postnatal: choking with feeds, inability to swallow GI secretions, H+P, passage of feeding tube into upper GI tract
tx: surgery
infantile hypertrophic pyloric stenosis demographics presentation dx tx
o demographics: 4M/1F; overall about 1/1000 births
o very classic presentation: non-billous, projectile vomitin 70% assoc w/ upper abdominal mass 60-80%; usually presents around 3 weeks of life
♣ if vomit is bilious- the obstruction is distal to bile duct
♣ can usually feel olive shaped mass
o dx: H and P; ultrasound
o tx: surgery: pyloromyotomy
Meckel diverticulum demographics embryo histo presentation dx tx rule of 2's
Demographics: most common malformation of the SI – 2% of population
Embryo: abnl remnant of vitelline (omphalomesenteric) duct (connection between yolk sac and intestine)
Histology: contains heterotrophic gastric or pancreatic tissue in 50%
Presentation: most common symptoms
♣ Obstruction 35% (most common in neonates)
♣ Bleeding 40% (usually older children
♣ Inflamm 17%
Dx: technetium-99 scan (detects gastric mucosa) and/or other imaging US/CT
Tx: surgical resection
Rule of 2’s: 2% of population; 2 feet from ileocecal junction, most freq presents around 2 yo; 2 inches long; 2 types of epithelia (gastric/pancreatic); 2 times as likely in males
omphalocele demographics embryo assoc's dx tx
gastroschisis
Demographics: 1/2000 live births; assoc w/ advanced maternal age; m/F 1.5:1
Embryo: failure of intestines to retun to abdomen following physiologic herniation at weeks 6-10 of development (stuck in umbilical stump) peritoneal and amniotic covering
Associations: 30-50% assoc w/ other congenital anomalies
Dx: often prenatal (ultrasound)
Tx: surgery—return of contents to abdominal cavity and abdominal wall closure (may need to be staged/gradual procedure)
Gastroschisis:
o Paraumbilical abdominal wall defect (rectus muscle); no amniotic covering***, no associated malformations
intestinal malrotation
gastrointestinal duplications
intestinal atresia
imperforate anus/rectal agenesis
Intestinal malrotation
o Demographics: roughly 1/500 live births
o Embryo: abnl rotation and fixation of intestinal tract
o Can occur in isolation or complicate omphalocele, gastroschisis, and other conditions
o Presentation: most common- midgut volvulus and obstruction (bilious vomiting)
o Dx: H and P; imaging; surgical exploration
o Tx: surgery
Gastrointestinal duplications
o Embryo: saccular (cystic) or tubular stricture containing all layers of normal bowel wall and gastrointestinal lining, which may or may not communicate with bowel
o Presentation:
♣ Many found incidentally
♣ May cause bowel obstruction
o Dx: H and P; imaging; surgical exploration
o Tx: surgery
o Frequent sites of duplication:
♣ SI 44%; colonic 15%; gastric 7; duodenal 5; rectal 5; thoracic/thoracoabdominal 4; pyloric rare; cervical rare
Intestinal atresia
o Demographics: 1/3000
o Duodenal atresia most common; up to 40% have Down Syndrome
o Pathobiology: presumed vascular (ischemic) etiology
o Presentation: polyhydramnios, obstructive symptoms (bilious vomiting)
o Dx: h and P; imaging
o Tx: surgery
Imperforate anus/rectal agenesis o Demographics: 15000 o Varying degree f severity, freq assoc w/ fistula formation (perineum, bladder/urethra, vagina); up to 50% assoc w/ other anomalies o Dx: PE o Tx: surgery
Hirschsprung disease demographics embryo presentation dx tx complications gene
Demographics: 1/500 live births; 4M/1F
Embryo: defect of enteric NS; development resulting in absence of ganglion cells (ENS neurons)
Presentation: failure to pass meconium/poor stooling
♣ If unrecognized, can progress to life-threatening megacolon
Dx: H and P; imaging; biopsy (no ganglion cells)
Tx: surgical resection of aganglionic segment
Complications: short bowel syndrome for long-segment disease
Mutations in RET gene (GDNF receptor) found in 50% of cases of HD
neonatal necrotizing enterocolitis demographic presentation pathogenesis tx complications
Demographics: typically occurs as a complication of prematurity (up to 10% of infants <1500 g)
Presentation: feeding intolerance, abdominal distention, bloody stools
Pathogenesis: multifactorial
♣ Enteric feeds; bacterial flora; immune immagureity; bowel hypoperfusion/ischemia (abnl circulation- eg patent ductus arteriosis- is risk factor)
Tx:
♣ Medical: bowel rest, antibiotics
♣ Surgical: resection
Complications: bowel strictures, short bowel syndrome
reflux vs allergic (eosinophilic) esophagitis etiology pH probe histo tx
Reflux esophagitis
♣ Etiology: incompetent GE sphincter/hiatal hernia
♣ pH probe: positive
♣ histology:
• mild intraepithelial eosinophilic infiltrate
• reactive epithelail changes
• predominantly distal esophageal involvement
♣ tx: acid blockade
allergic esophagitis
♣ etiology: immunologic reaction to dietary allergen; incompletely understood
♣ pH probe: negative
♣ histology: marked intraepithelial eosinophilic infiltrate
♣ reactive epithelial changes
♣ freq submucosal inflamm with fibrosis
♣ distal and proximal esophageal involvement
tx: dietary modification; steroids
GI polyps
adenoma-carcinoma sequence general
♣ polyp- translates too “morbid excrescence”
♣ adenoma-carcinoma sequence: general
o polyp- sessile vs pedunculated (polyp on stalk for pedunculated; sessile has flat base), neoplastic vs non-neoplastic
o adenoma (precursor to malignancy)
o adenocarcinoma (invasive)
non-neoplastic polyps
inflammatory
hamartomatous
hyperplastic
keep in mind that non-neoplastic type polyps are frequently “syndromic”, ie assoc w/ genetic syndrome that overall predisposes to cancer dev
inflammatory polyps
♣ often present w/ bleeding
♣ often due to mucosal prolapse (very common in rectum)
♣ cycles of inury and healing result in “polyp” formation= inflamed colonic mucosa with ulceratin/erosion, epithelail hyperplasia
Hamartomatous polyps
♣ Distinct subset of polyps, most occurring in childhood (pre-pubertal)
♣ Hamartoma: tumor-like overgrowth/mature tissue/developing where it is normally present (eg colonic tissue developing in the colon)
♣ Juvenile (sporadic and syndromic) and Peutz Jeghers (syndromic)
♣Key points
• Polyps: variable locations in lower GI system
• Benign features histologically but syndromic juvenile polyps often have foci of dysplasia
• May portend
o Risk of future GI carcinoma (inc freq of screening)
♣ Both peutz-jeghers and juvenile polyposis= 40% cumulative risk for CA
o Extra-GI manifestations
o Need to consider familial screening (Genetic counseling) in some cases
♣ juvenile
♣ Peutz-Jeghers
♣ Others: Cowden, Cronkhite-Canada
Hyperplastic polyps
♣ Left colon incl rectum 90%
♣ Inc w/ age
♣ Usually <0.5cm
♣ Histo: delayed maturation w/ overgrowth superficial epithelium in SERRATED architecture
♣ No dysplasia
♣ But: need to distinguish from “sessile serrated polyp/adenoma” SSP which ARE pre-malignant
♣ Smooth, nodular lesion w/ flat base sessile
♣ Need microscopic eval to definitively distinguish
• Hyperplastic polyp
• Adenomatous polyp
♣ Serrated polyps
serrated polyps
non pre-malignant
pre-malignant
Not pre-malignant
Hyperplastic polyps (generally)
♣ Left side of colon: very common
♣ Sessile
♣ Architecture: crypts w/ “star shaped” / serrated appearance
♣ Cytology: not dysplastic
♣ Have been considered for decades “non neoplastic”… now there is a question about this assumption. Some genetic alterations identified
Pre-malignant
Sessile serrated polyps/adenoma alternate pathways to carcinoma than the usual adenomatous polyp
♣ Microsatellite instability pathway
♣ DNA hypermethylation pathway (CpG island methylation)
♣ Right side of colon (proximal) most common
♣ Right side: solitary/sessile/flat usually
♣ Left side/distal: uncommon
♣ Architecture: looks like serrated knife
♣ Cytology: dysplastic epithelium may or may not be present
♣ Pre neoplastic: DEFINITELY can progress to adenocarcinoma
adenomas
adenomatous changes
villous adenoma
Adenomas
o Site is variable- range from a few mm to several cm >10cm
o Present in nearly 50% of western adults by 50 yo
o Present throughout the colon
o Have epithelial cytologic dysplasia ranging from low grade to high grade (Carcinoma in situ)
o Villous adenomas contain foci of invasion more frequently than tubular adenomas but SIZE MATTERS (size is most important characteristic that correlates w/ risk of malignancy overall in the pt)
o Presence of high grade dysplasia inc risk of malignant transformation in that polyp but not in the rest of the colon
Adenomatous changes o Cells: Piing up on each other (no respect!) o Nuclei: darker (hyperchromasia) ♣ Progressive loss of basal-orientation o Cytoplasm ♣ Reduced compared to nucleus (inc N:C ratio) ♣ Reduced mucin production o Mitotic figures ♣ Inc mitotic activity
Villous adenoma
o Endoscopy: villi vaguely discernable
o Villi: finger-shaped; Fibrovascular core underlies epithelial layer; inc SA
o Lesion is sessile (but not always)- no stalk
o Architecture: multiple, slender villi (finger like projections)
o Cross section: no evidence of thickening of the bowel wall to suggest an invasive component
carcinoma GI cancers adenomas to cancer factors assoc w/ colorectal cancer molec basis of CRC risk
Gastrointestinal cancers
♣ Males and females: 8% of cancers are colorectum
♣ Males: 3% are liver and intrahepatic bile duct
♣ Females: 3% are pancreas cancer
Adenomas to cancer: gene mutaitons common are APC and beta-cakenin; K-RAS; p53
Factors associated with CRC (colorectal cancer)
Risk factors
• Advanced age, country of birth, FAP/HMPCC, long standing UC
• Body fatness, abdominal fatness, red meat, processed meat, alcohol (men), smoking
• Probably inc risk: alcohol (women)
Dec risk: physical activity, foods with high fiber
• Probable decrease risk: milk, Ca, garlic
Molecular basis of CRC risk
65-85% sporadic; familial 10-30%; HNPCC 2-3%
main molec pathways- know these
• WNT/APC/beta-catenin- classical adenoma-carcinoma sequene
• K-Ras/MAP kinase/PI3 kinase signaling pathways- activating mutations
• Microsatellite instability- defects in mismatch repair proteins
• Also: epigenetic events such as methylation-induced gene silencing; enhances progression along these pathways
WNT pathway
o Wnt protein ligands are critical for dev
o Animals lacking Wnt homologs fail to dev entire organs. The fly homolog of human wnt-1 is wingless
o Wnt ligands drive proliferation of their target tissues/organs
o The wnt pathway regulates the levels of cytoplasmic beta catenin
o Without wnt signal- beta catenin is made and then destroyed
o With wnt signal: beta-catenin stays active, stabilized, migrates to nucleus, and causes transcription of wnt response genes
o Adenoma formation
♣ There is no inc in the rate of cell proliferation in the early stage of polyp formation
♣ Polyps represent an inc in size of the proliferating crypt compartment, not the villous itself
FAP: familial adenomatous polyposis
• APC mutations can run in families, prod FAP
• FAP pts have inc risk of colon cancer, but these account for small fraction of the total cases of colon cancer (~5%)
• Most people who acquire colon cancer without FAP acquire spontaneous somatic mutations in APC
tx of GI cancers
usefulness of molec characterization
o 60 yo M dx w/ colon cancer metastatic to liver and lung
♣ testing performed on biopsy of the colon tumor is KRAS wild type
♣ tx w/ FOLFOX + cetuximab (EGFR inhibitor) is initiated
o receptor tyrosine kinase/Ras/MAPK/PI3K signaling
♣ EGFR can signal thorugh the Ras pathway or PI3K
♣ An antibiody to EGFR will take care of either pathway mutations if they’re wild type Ras
♣ If they’re Ras mutated- don’t give cetuximab because it’s downstream
he does research in this -_-
Hereditary non-non-polypopsis colorectal cancer
AKA Lynch Syndrome
o Dev colon cancer at an earlier age than sporadic forms
o Tend to be right sided
o Inherit mutation of mismatch repair gene allele, acquire the second allele mutation over time leading to microsatellite instability
The autosomal dominant DNA repair disorder prediposes patients to three cancers
Colorectal non polyposis cancer
Endometrial cancer
Ovarian cancer
so the CEO of Lynch
colon cancer numbers
familial (FAP and HNPCC)
sporadic (adenomas and cancers)
Familial:
♣ FAP
• 1/7000
• >90% APC mutation (germline)
• ND MMR gene mutations
♣ HNPCC
• 1/500
• ND APC mutation
• >70% MMR gene mutation
sporadic
♣ sporadic adenomas
• 1 in 2 incidence in population
• >80% (somatic) APC mutation
• ND MMR gene mutation
♣ Sporadic cancers
• 1 in 20
• >80% (somatic) APC mutation
• ~65% MMR gene mutations
colon carcinoma: symptoms/presentation early advancing R/ascending L/descending
early colon carcinoma
♣ no symptoms most often
♣ nonspecific findings: fatigue, weight loss, anemia
advancing colon carcinoma:
♣ change in bowel habits and indicators (constipation, urgency)
♣ narrowing of stool
♣ cramping/pain
♣ blood loss (blood in stool or bleeding from rectum (BBBPR))
♣ unexplained weight loss
R/ascending colon: stool is semi liquid:
♣ can pass partial obstruction
♣ can develop large lesions without obstruction until late
L/descending colon: stool progressively well formed/solid:
♣ Difficulty passing partial obstruction
goal: detect neoplasm methods
Goal: detect neoplasms
Visualization +/- biopsy
♣ Colonoscopy, barium enema, other options
Blood detection in stool
♣ Hemorrhage of ulcerated lesion
DNA/mutation detection in stool
♣ Shed neoplastic cells vs nl colonic epi cells
carcinoma
defintion
adenomas at risk
invasive adenomas typical prognosis distant metastasis therapy
Definition:
♣ Invasion of dysplastic epi cells into and beyond the lamina propria
Adenomas at risk:
• <1 cm: very low risk of invasive adenocarcinoma in lesion
• >4 cm: high risk (40% in one study) of identification of invasive component within lesion
invasive adenocarcinoma
“typical adenocarcinoma”
♣ most colon adenocarcinomas have this appearance w/ well defined “gland” formation
♣ a variable amount of mucin is produced by the cels “adenocarcinoma”
♣ scant mucin production
♣ dirty necrosis
♣ neoplastic glands (adenocarcinoma) invading into muscularis propria, inciting a “desmoplastic” (fibrotic) response. There is “dirty necrosis” in the lumen of some of the glands, a failry common finding in colon carcinoma
prognosis
most important prognostic factors:
• depth of invasion
• presence or absence of lymph node metastasis
• distant metastasis
distant metastasis
♣ colon cancer most commonly metastasizes to the LIVER
therapy ♣ surgery • local excision- eg polypectomy • colonic resection ♣ radiofrequency ablation ♣ cryosurgery ♣ chemotherapy • only treatment = palliative • adjunctive treatment (pre or post op) ♣ radiation therapy • not really used for colon, but for rectal cancer ♣ targeted therapy • monoclonal antibodies • angiogenesis inhibitors
functional histology of liver
basics
♣ liver has 4 lobes
♣ surrounded by capsule called glisson’s capsule; just outer layer of CT
♣ hilar region is called porta hepatis
♣ coming into liver at hilar region- hepatic portal vein (carrying 75% of blood coming into liver; deoxygenated); hepatic artery (branch from celiac trunk; oxygenated)
♣ coming out of liver: hepatic vein; bile (hepatic) duct which will join w/ pancreatic duct to form common bile duct; lymphatic
♣ these come in, branch; form lobar arteries, interlobar arteries, to interlobular arteries (same as urinary); arteries and heaptic portal vein
♣ individual lobules are arranged like parallel sausages; connected at ends to ducts/vessels; running at vertices is portal triad/tract
♣ all blood that’s draining from liver will come from central veins in the middle of lobules
♣ plates of hepatocytes are coming in towards central vein
♣ triad: bile duct (surrounded by cuboidal cells), portal vein, hepatic artery; also running in this region is lymphatic space- space of Maal
♣ blood travels from the triad along perlobular regions and dumps into sinusoids then central veins of the sausages/lobules
♣ Kupfer cells- macrophages involved in phagocytizing debris in blood; situated adjacent to hepatocytes on blood sinusoid side of cells
liver detoxification of blood
o Lots of drugs are activated and taken out by liver
o Things w/ double bonds can be epoxified than can be converted to hydroxyl group then sulfated then glucuronylation
basic structure of hepatocyte
ito or stellate cell
canals of Hering
Basic structure of hepatocyte:
o Central Channel w/ bile canaliculus- sealed off within the center of hepatocytes
o On one side a microviliar surface in contact w/ blood, and the other has a microvilar surface in contact w/ blood
o Endothelial cells on one side- fenestrations and discontinuities on outsie of microvilli; attached to reticular fibers that are forming the meshwork outside of microvilli; the space iwthin this area is Space of Disse
♣ Plasma can come in through the fenestrations and spaces and come in contact w/ Space of Disse; 10fold inc in SA
o Another cell type right up against fibers; the fibers intercalate w/ microvilar surface and the Kupffer cell sits on top of these fibers; kupfer cell is like a permanent macrophage resident; but not an adaptive immune response (that’s spleen)
Another cell type that sits among these plates is called ito or stellate cell
o The ito cells sit under endothelium of hepatocyte; sits wedged in between sets of hepatocytes; somewhat sparse; won’t be asked to identify these
o Contain a lot of lipid droplets; storage for lipids and esp Vit A or retinol (converted to retinal, attached to opsins, crucial for vision)
o Also seem to be involved in cirrhosis of liver
When you get to cuboidal ducts you get canals of Hering; and they join the duct that runs along hepatic triad; and these cells form a continusous duct
neonatal jaundice general classification nl bilirubin metabolism etiologies
Jaundice (icterus): yellow discolartion of tissues (PE skin, sclerae, mucous membranes) due to abnl deposition of bilirubin
Classification:
♣ Pre hepatic (before liver)/hepatic (abnl to bil metabolism in liver)/post-hepatic (distal to liver)
♣ Blood chemistry:
• Unconjugated/indirect bilirubinemia
• Conjugated/direct bilirubinemia
Normal bilirubin metabolism:
♣ RBC carries oxygen in bodies, rapidly turn over, esp in spleen, broken up, byprocuts are processed by body; Hb consists of protein and cofactor Heme, which is metabolized ultimately to bilirubin spleen; very insoluble in aqueous solns; carried in complex w/ albumin; conjugated in liver hepatocytes to make bilirubin water soluble, excreted through bile duct into intestine, and into feces
Etiologies physiologic jaundice pathologic jaundice infection ED total parenteral nutrition obstruction metabolic disease hereditary hyperbilirubinemia idiopathic neonatal hepatitis
pediatric physiologic vs pathologic jaundice onset presentation mech concern? grading etiology and tx
Physiologic jaundice*
• Most infants affected
• Onset in first week of life (but not in 1st 24 hrs)
• Inc unconjugated (indirect) bilirubin
Mechs incl:
o Inc RBC turnover
o Immaturity of system for bilirubin conjugation
o Deconjugating enzymes in breast milk
Generally benign, resolving in 10 days to 1 month, although some cases may req phototherapy to prevent kernicterus (toxic accum of unconjugated bilirubin in neonatal brain)
Grading through from face down; only jaundiced in face is correlated w/ lower grade, etc
Etiology and tx
o Light shines on skin, so bilirubin can be converted into photoisomers that can be excreted in urine
Pathologic jaundice • Onset in 1st 24 hrs or >14 days after birth • Rapid inc in total bilirubin • Very high total bilirubin • Inc direct bilitrubin
Classified into
Unconjugated
♣Hemolytic
• Intrinsic (eg sickle cell disease)
• Extrinsic (ex Rh disease(
♣Nonhemolytic
♣Crigler-Najjar Syndorme
• Mutation in bilirubin-UDP-glucuronosyltransferase (UGT1A1) which conjugates bilirubin
• Type 1 (AR): no functional enzyme; req phototherapy/transplantation (markedly elevated bilirubin levels in neonates result in neurotoxicity)
• Type 2 (AD): decreased enzyme activity; less severe
♣Gilbert syndrome
• Variably reduced expression of UGT1A1; recurrent, stress-induced hyperbilirubinemia, common (5-10% of pop)
Conjugated
♣Hepatic
♣Post hepatic
♣Dubin-Johnson syndrome
• Hereditary defect in excretion of conjugated bilirubin due to mutation in multi-drug resistance protein 2 (MRP2); variable hyperbilirubinemia, esp in setting of stress
♣Rotor syndrome
• Exact biochem defect unknown; variable hyperbilirubinemia, esp in setting of stress
obstructive causes of pediatric jaundice
congenital
choledochal cyst
biliary atresia**
Congenital malformations
Choledochal cyst
o Congenital anomaly of intrahepatic/extrahepatic bile ducts characterized by ductal dilation and bile stasis
o Presentation:
♣ Usually by 10 yo
♣ Classic tria (40%): pain, jaundice (conjugated/direct bilirubinemia), RUQ mass
o Dx: imaging, surgical exploration
o Tx: surgery
o Complications if untreated:
♣ Gallstones (Stasis), cholangitis, stenosisi/stricture, pancreatitis, obstructive biliary complciations
♣ If persist until adult, inc risk of cholangiocarcinoma
Biliary atresia
o Incidence: 1 in 8-12k
o Pathology: obstruction of extrahepatic biliary tree
o Blood chem: conjugated/direct bilirubinemia
o 2 main forms:
♣ Embryonic/fetal form (Congential): 10-35%
• Jaundice at birth
• Abnl dev of biliary tree
• Genetic abnormality; assoc w/ other anomalies
♣ Perinatal form: 65-90%
• Nl at birth; new onset, progressive jaundice 1-6 weeks after birth
• No assoc anomalies
• Histopathology: progressive destruction of biliary tree
• Etiology remains unknown: predisposed, but unproven, disease mechs incl: viral, toxic, autoimmune, vascular, genetic
o Pathologc findings (postnatal form)
♣ Liver
• Cholestasis in hepatocytes, canaliculi, and ducts (bile plugs)
• Reactive bile duct proliferation
• Variable inflamm and fibrosis
♣ Biliary remnant
• Fibroinflammatory obliteration of biliary tree
o Tx
♣ “Kasal procedure”
• hepatoportoenterostomy
• better prognosis if performed before day of life 60
♣ transplantation
• BA is most common indication for transplantation in pediatric age group
♣ At this time, no non-surgical therapeutic options
metabolic disease cause of pediatric jaundice
• Liver involved in many metabolic storage disease
Carbohydrate metabolism
♣ Glycogen storage disease, galactosemia and fructosemia
Lysosomal storage
♣ Wolman, niemann-pick, gaucher disease
Amino acid metabolism
Iron (hematochromatosis) and copper (wilson disease) storage
Path findings:
♣ Abnl storage product (diagnostic), usually in hepatocytes
♣ Liver damage (inflamm, fibrosis, etc)
idiopathic neonatal hepatitis pop dx types prognosis transformation
can cause jaundice
- 25-40% of cases of neonatal cholestasis
- diagnosis of exclusion (exclude known infectious, metabolic, anatomic, genetic disorders)
- 85-90% sporadic; 10-15% familial
• prognosis
o sporadic form: 75% recovery, 7 chronic liver disease, 19 fatal
o familial form: 22% recovery, 16 chronic liver disease, 63 fatal
• giant cell transformation (AKA giant cell hepatitis)
primary hepatic neoplasms in kids
benign
malignant
benign ♣ mesenchymal hamartoma ♣ teratoma ♣ hepatocellular adenoma ♣ focal nodular hyperplasia
malignant
♣hepatoblastoma (usually <5 yo)
• demographics: 90% present before 5 yo; 60% < 2 yo
o M/F 2/1
o NOT assoc w/ underlying liver disease (unlike most cases of hepatocellular carcinoma)
•Presentation
o Anorexia, weight loss, nausea, vomiting, pain; abdominal enlargement/mass; 90% have markedly elevated serum alpha-fetoprotein level (useful tumor marker)
•Pathobiology:
o Largely unknown; Wnt/beta-catenin pathway activated in 80%
•Inc incidence in a number of syndromes
o Beckwith-Wiedemann syndrome
o FAP (Wnt/Beta-catenin mutations)
•Pathologic findings
oTumor histology recapitulates features of hepatic development
oHistology
♣ Epithelial
• Feat and embryonal-type differentiation most common
♣ Mesenchymal
• Primitive mesenchyme, bone, cartilage, muscle
♣ Mixed
• Epithelial and mesenchymal differentiation
•Tx
o Chemotherapy and surgical resection
o Liver transplant is option in unresecteable cases without metastasis
o Overall survival 65-70%
STAGE at time of resection is most important prognostic factor
o Stage 1: 100% survival (complete resection)
o Stage 2: 75-80% survival (microscopic residual tumor)
o Stage 3: 65% survival (gross residual tumor, lymph nodes pos, tumor spill into abdomen)
o Stage 4: 0-27% survival (metastatic disease)
hepatocellular carcinoma (usually >5 yo)
undifferentiated/embryonal sarcoma
liver cirrhosis
general
2 types
natural history
o Late state of progressive hepatic fibrosis
o Characterized histologically by regenerative nodules surrounded by fibrous tissue
o Generally irreversible
o Clinically there are 2 types
♣ Compensated (no complications
♣ Decompensated (complications)
o Natural history
♣ Chronic liver disease- compensated cirrhosis- complications (variceal hemorrhage, ascites, encephalopathy, jaundice)- decompensated- death or liver transplant
complications of cirrhosis
Complications of cirrhosis result from portal HTN or liver insufficiency
♣ Portal HTN- most complications
• Variceal hemorrhage, ascites (SBP, HRS), encephalopathy
• Mech
o P inc results from interaction of R and F; portal HTN can result from inc R to portal flow or inc in portal venous flow
o Inc intrahepatic R is the initial mech leading to portal HTN
o Distorted sinusoidal architecture leads to inc R- blood starts backing up
o Inc hepatic R in cirrhosis is not only structural (sinusoidal fibrosis and regenerative nodules) but also functional (active vasoconstriction)
o Vasoconstriction-
♣ Normally NO plays a major role in regulating intrahepatic R
♣ In cirrhosis, NO activity is reduced and vasoconstrictors (VCs) are inc
o In portal HTN, splanchnic vasodilation results from an inc in NO
♣ Portal HTN- shear stress in splanchnic vasculature- inc NO- splanchnic vasodilation- inc portal blood flow- inc P in the liver w/ a fixed R
♣ Then ascites develops, causing bacterial translocation, leading to more NO, and more splanchnic vasodilate, more portal blood inflow, etc
o Summary:
♣ Inc intrahepatic R
• Structural (fibrosis, regenerative nodules)
• Active vasoconstrictors (dec NO, inc vasoconstrictors)
♣ Inc portal venous inflow
• Splanchnic vasodilation (inc NO)
Causes
o Cirrhosis is most common cause of portal HTN
o The site of inc R in cirrhosis is sinusoidal
o Others are classified according to site of inc R (ex. pre-hepatic, pre-sinusoidal, post-sinusoidal, post-hepatic)
o Sinusoidal obstruction syndrome (formerly Hepatic Venoclusive disease)
♣ Condition in which small hepatic veins are obstructed
♣ Occurs most commonly as a complication of myeloablative regimens used to prepare pts for bone marrow transplant
♣ Clinical presentation of RUQ, ascites, hepatomegaly, and jaundice
o S mansoni eggs
o Hepatic venous outflow obstruction (Budd-Chiari Syndrome)
♣ Obstruction of hepatic veins
• Small hepatic veins, large hepatic veins, IVC
♣ Obstruction most often from thrombosis in hypercoagulable conditions
• Also malignancy and venous webs)
♣ Clinical features: abdominal pain, ascites, edema
Portal pressure measurements
o Definitive method to est the dx of portal HTN
o Direct methods (percutaneous, transjugular) are cumbersome and may be assoc w/ complciations
o The safest and most reproducible method is measurement of hepatic venous pressure gradient HVPG
o HVPG = WHVP – FHVP (FHVP internal zero- corrects for extravascular, intraabdominal P inc- eg ascites)
♣ Nl HVPG is 3-5 mmHg
♣ HVPG is nl in presinusoidal portal HTN, and post-hepatic portal HTN (heart failure, ex- no gradient across the liver, but P can still be high)
♣ HVPG is inc in sinusoidal portal HTN and post-sinusoidal
♣ Liver insufficiency
• Encephalopathy, jaundice
clinical presentation of cirrhosis
♣ Stigmata of chronic liver disease on routine physical exam
• Spider angioma, jaundice,
♣ Incidentally covered
• Lab testing (elevated liver enzymes)
• Radiologic testing (ascites, splenomegaly)
• Unrelated surgical procedure (cholecystectomy)
♣ Complications
• Ascites, encephalopathy, variceal hemorrhage
suspect liver cirrhosis in:
♣ Any pt w/ chronic liver disease
♣ Chronic abnl ALT and/or Alk phos
♣ Scleral icterus, jaundice, spider angioma, pectoral alopecia, enlarged L Liver lobe, caput medusa, umbilical hernias, white nails/clubbing, female escutcheon, edema, muscle wasting, gyenecomastia, splenomegaly, ascites, testiclular atrophy, palmar erythema/Dupuytren’s contracture, purpura/petichiae
♣ Labs • Low Alb • Prolonged prothrombin time (big INR) • High Bilirubin • Portal HTN (low plts)
♣ Imaging • Nodular liver • Caudate hypertrophy • Ascites • Splenomegaly • Venous collaterals • Hepatocellular carcinoma (unusual unless you have cirrhosis)
etiologies of cirrhosis
♣ Viral (Hep C, B)
♣ Alcoholic liver disease*
♣ Autoimmune (PBC, BSC, autoimmune hep)
♣ Metabolic (hemochromatosis- iron; Wilson Disease- Cu; A1A deficiency)
♣ Vascular (Budd-Chiari syndrome; CHF)
♣ Non-alcoholic fatty liver disease (NASH)
cirrhosis
dx
assessing mortality
organ allocations
Dx
♣ Confirmatory liver biopsy is not always necessary in cirrhosis in presence of either:
• Decompensated cirrhosis (variceal hemorrhage, ascites, encephalopathy)
• CT scan diagnostic of cirrhosis
Assessing mortality in cirrhosis
♣ Child-Turcotte-Pugh CTP score; 1-3 based on severity of categories
♣ Child A: 5-6
♣ Child B: 7-9
♣ Child C: 10-15
♣ Model for end-stage liver disease MELD score
• Math survival model created from data on pts undergoing TIPS
• MELD score est risk of 3-month mortality
• Uses 3 lab values (Serum total bil, serum Cr, INR)
• Serum Na predicts risk of dying if you have cirrhosis; Na <135 has inc RR of death; now incorporated in MELD
Organ allocation for liver tx
♣ Fulfillment hepatic failure has highest priority
♣ MELD score determines priority in cirrhosis
• Amongst pts w/ same blood type, high MELD score determines priority
cirrhosis varices cause predictors of hemorrhage rupture risk endoscopy
Varices
♣ Result from inc portal Pressure and inc R to portal flow
♣ Small veins flatten, and large varices don’t flatten (at risk for hemorrhage)
♣ Can be 40% prevalence; as Child score inc your likelihood of having (large) varices inc in esophagus
Predictors of hemorrhages
• Variceal size
• Red signs
• Child B/C (measure of disease severity)
Dec portal pressure dec the risk of rupture
• By dec varix radius or inc wall thickness; or dec HVPG
Endoscopic variceal band ligation • Bleeding controlled in 90% • Rebleeding rate 30% • Compared w/ sclerotherapy: o Less rebleeding, lower mortality, fewer complications, fewer tx sessions
tx for cirrhosis and varices and portal HTN
Vasoconstrictors- OCTREOTIDE** if you suspect a variceal bleed to dec splanchnic flow and somewhat dec portal P
o Inhbitis release of vasodilator hormones such as glucagon causing splanchnic vasoconstriction
Venodilators- somewhat dec intrahepatic resistance and somewhat dec portal pressure
Vasoconstrictors plus venodilators- somewhat dec splanchnic flow and intrahepatic resistance, and really dec portal P
TIPS/shunt surgery- really really dec heaptic reistance and portal P
ascites from cirrhosis general NO renal failure natural history detection initial workup serum-ascites albumin gradient tx refractory ascites
Cirrhosis is most common cuase of ascites (80%); others are peritoneal malignancy, heart failure, peritoneal tuberculosis, others
Vasodilation and ascites result from an inc in NO
♣ Portal HTN shear stress inc NO vasodilation (dec SVR) activation of neurohumoral systems (renin, angio, Aldo) sodium and water retention ascites bacterial translocation inc NO cycle
Ascites w/ renal failure will have very high levels of renin and aldo vs pts w/o ascites or without cirrhosis
Natural history of ascites
♣ Portal HTN (no ascites) HVPG <10mmHg, mild vasodilation
♣ Uncomplicated ascites- HVPG >10, moderate vasodilation
♣ Refractory ascites- >10 and severe vasodilation
♣ Hepatorenal syndrome- >10 and extreme vasodilation
US is the most sensitive method to detect ascites- hyperechoic spot above a lumpy bumpy liver
Initial workup of ascites- diagnostic paracentesis ♣Routine • PMN count culture (? SBP) • Protein/albumin (? Cirrhotic ascites) ♣Optional • Glucose, LDH (secondary infection) • Amylase (pancreatic ascites) • Cytology (malignant ascites) ♣Ascites fluid analysis • Routine o Albumin, protein, PMN cell count, cultures • Optional o Glucose, LDH, amylase, RBC, TB smear and culture, cytology, triglycerides
Serum-ascites albumin gradient- TESTABLE
♣ Calculation: serum album MINUS ascites albumin; note- should be obtained at/near the same time
♣ Serum-ascites albumin gradient SAAG correlates w/ sinusoidal pressure
♣ Pts w/ cirrhosis- SAAG is almost always >1.1 (heart failure or cirrhosis)
• Total protein <2.5- cirrhotic ascites; >2.5 cardiac ascites
Tx of ascites
♣ Portal HTN (no ascites) – no specific therapy; consider salt restriction
♣ Uncomplicated ascites- salt restriction + diuretics; large vol paracentesis (LVP) w/ tense ascites
♣ Refractory ascites- LVP + albumin; TIPS (helsp dec sinusoidal P and inc effective arteral blood vol- TIPS, but inc risk of encephalopathy)
♣ Hepatorenal syndrome
Refractory ascites
♣ Occurs in ~10% of cirrhotic pts
♣ Diuretic-intractable ascites 80%
• Therapeutic doses of diuretics cannot be achieved because of diuretic-induced complications
♣ Diuretic-resistant ascites 20%
• No response to maximal diuretic therapy (400 mg spironolactone + 160 mg furosemide/day)
hepatorenal syndrome from cirrhosis general types major dx criteria 2 things always present pathogenesis management
o Renal failure in pts w/ cirrhosis, advanced liver failure, and severe sinusoidal portal HTN
o Absence of significant histological changes in the kidney (“Functional” renal failure)
o Marked arteriolar vasodilation in the extra-renal circulation
o Marked renal vasoconstriction leading to dec glomerular filtration rate GFR
o Neurohormonal systems are maximally activated in hepatorenal syndrome
o 2 types
♣ Type 1
• Rapidly progressive renal failure (2 weeks)
• Doubling of Cr to >2.5 or halving of Cr clearance CrCl to <20mL/min
• Lower survival
♣ Type 2
• More slowly progressive
• Cr >1.5 or CrCl <40
• Assoc w/ refractory ascites
Major criteria in dx of HRS
♣ Advanced heaptic failure and portal HTN
♣ Cr >1/5 or CrCl <40
♣ Absence of shock, bac infection, or nephrotoxic drugs
♣ Absence of excessive GI or renal fluid loss
♣ No improvement in renal func after plasma vol expansion w/ 1.5 L isotonic saline
♣ Urinary protein <500 and nl renal ultrasound
♣ Urine Na and urine vol are minor criteria in Dx of HRS
• Pts usually have very low urinary Na excretion <10
Ascites and hyponatremia are always present in HRS
♣ Besides renal failure, pts w/ HRS have Na and water retention
♣ Ascites is universal in pts w/ HRS**
• If ascites is absent, renal failure is more likely due to other causes
♣ Hyponatremia is almost universal in HRS**
• If serum sodium is nl, dx of HRS is unlikely
Ascites, HRS, and hyponatremia have a common pathogenesis in cirrhosis
♣ Cirrhosis dec arteriolar resistance (Vasodilation)
♣ Dec effective arterial blood vol
♣ Activation of neurohormonal systems (aldo, renin, angio, epi, ADH)
♣ Na retention: ascites
♣ Renal vasoconstriction- HRS
♣ Water retention- hyponatremia
Management of HRS ♣Proven efficacy • Liver tx ♣Under investigation • Vasoconstrictor + albumin • Transjugular intrahepatic portosystemic shunt TIPS • Vasoconstrictor (Terlipressin) • Extracorporeal albumin dialysis (ECAD) ♣Ineffective • Renal vasodilators (prostaglandin, dopamine) • Hemodialysis
spontaneous bacterial peritonitis SBP general bacterial translocation clinical characteristics early dx tx
• Spontaneous bacterial peritonitis (SBP) complicates ascites and can lead to renal dysfunc
o SBP is most common infection in cirrhotic pts; next is UTI
Bacterial translocation BT: main mech implicated in SBP
♣ BT is the migration of variable microorganisms form the intestinal lumen to mesenteric lymph nodes and other extraintestinal organs and sites
♣ BT inc in conditions assoc w/ a high risk of infection by gram neg organisms (ex burn, shock, trauma)
♣ BT doesn’t inc in pre-hepatic portal HTN
♣ Mechs: intestinal bac overgrowth, intestinal permeability, impaired immunity
Clinical characteristics ♣ Fever, jaundice >80% ♣ Abdominal pain ♣ Confusion ♣ Abdominal tenderness ♣ Hypotension ♣ No signs or symptoms (33%)
Early dx of SBP
♣ Diagnostic paracentesis:
• If symptoms/signs of SBP occur
• Unexplained encephalopathy and/or renal dysfunc
• At any hospital admin
♣ Dx is based on ascitic fluid- PMN count >250/mm^3
• Or a positive culture
Tx
♣ Recommended antibiotics for initial empiric therapy
• IV cefotaxime, amoxicillin-clavulanic acid
• Oral ofloxacin (uncomplicated SBP)
• Avoid aminoglycosides**
♣ Min duration: 5 days
♣ Re-evaluation if ascitic fluid PMN count has not decreased by at least 25% after 2 days of tx
♣ Albumin dec renal dysfunc and short term mortality in spontaneous bacterial peritonitis
• Albumin dec plasma renin activity in SBP
• Resolution of SBP w/ antibiotics + albumin albumin 98%
♣ SBP has poor prognosis; 38% survival at 1 yr
♣ Recurrence of SBP is common (almost 80% at 2 yrs)
• Norfloxacin reduces recurrence of SBP
♣ SBP is more likely in pts w/ low-protein ascites
hepatic encephalopathy from cirrhosis general results in overlying problem morphology changes pathophysiology clinical dx stages minimal hepatic encephalopathy abnormalities on testing PPTs tx
o Neuropschiatric complication of cirrhosis
o Results of both:
♣ Portosystemic shunt (spontaneous, surgical or radiographic)
♣ Chronic liver failure
o Failure to metabolize neurotoxic substances
♣ Hyperammonemia results in glutamine accumulation
o Alterations of astrocyte morphology and function (Alzheimer type 2 astrocytes)
♣ Astrocytes only cell cells in brain that can metabolize ammonia
Pathophysiology
♣ Inc ammonia- crosses BBB
♣ Upreg of astrocytic peripheral benzodiazepine receptors (PBR)
♣ Neurosteroid production
♣ Modulation of GABA A receptor which results in cortical depression
♣ Hepatic encephalopathy
Clinical diagnosis
♣ Clinical findings and hx are important!
♣ Ammonia levels are unreliable- poor correlation w/ dx and measurement is NOT necessary
♣ Number connection test
♣ Slow dominant rhythm on EEG
Stages
♣ 1-4 from mild confusion to coma
♣ neuro sings go from incoordination, tremor, impaired handwriting to no response to pain, decerebrate posture
minimal hepatic encephalopathy
♣ occurs in 30-70% of cirrhotic pts w/o overt hepatic encephalopathy
♣ detected by psychometric and neuro-psychological testing
♣ may improve w/ lactulose or synbiotics (probiotics and fermentable fiber)
abnormalities on testing ♣ attn and cognitive deficits ♣ visual-spatial perception impaired ♣ defects in visual constructive ability ♣ impaired driving ability ♣ evoked potentials and spectral electro-encephalography abnl
PPTs
♣ Excess protein, TIPS, GI bleeding, infections, sedatives/hypnotics, diuretics (dec serum K plasma vol azotemia)
Tx
♣ Identify and tx PPT factor
• Infection, GI hemorrhage, prerenal azotemia, sedatives, constipation
• Lactulose (Adjusts to 2-3 bowel movements/day)
• Protein restriction, short term (if at all)
♣ Inc ammonia fixation in liver
• Ornithine aspartate, benzoate)
♣ Shunt occlusion or reduction
♣ Dec ammonia production in gut
• Lactulose, antibiotics, adjustment in dietary protein
T cell immunology review
• T cell immunology review
o Beginning of immune response- always start w/ innate immune response, local disturbance activates local cells and makes innate immune mediators, made of chemokines and cytokines, and PAMPs are recognized by PRRs
o Dendritic cells phagocytize and most of the time an innate response is all you need for a small invasion, but then if you need adaptive immunity the dendritic cell is of utmost impprtance- it stops being immature, goes to lymphatics and matures in the process
o When the dendritic cell arrives at lymph node, it’s matured into an APC rather than just a phagocyte
♣ Comes in through afferent lymph at periphery, then percolate through body of node, and usually ends up in enterface between deep cortex (mostly T cells) and inner cortex (mostly B cells) show it can show its antigens findings to as many cells as possible
♣ The first cell to see it is an uncommitted Th0 helper cell; interaction w/ APC makes the T cell activated, proliferate rapidly, and differentiate into something depending on what the dendritic cell’s past history is
• Th0 can become- Th1, Th2, Treg, Th17, or Tfh; can leave lymph node when they’re mature to circ
Th1 Th17 Th2 Th1 vs Th2 vs Treg T cells interacting w/ antigens
Th1
♣ At the sites of antigen, activated Th1 cells release cytokines, esp IFN-gamma*- strongly chemotactic for macrophages called M1 macrophages (aggressive, phagocytosis, and good at killing)
• Need to have Th1’s and M1 macrophages to get better from TB- they’re able to eat AND kill a mycobacterium
o M1 and Th1 cell infiltrations cause “mononuclear infiltrate”
♣ Th1’s in pathological case- lots of hemorrhage and inflammatory cells (there by mistake, everyone’s best guess is UC- inflamm rxn where pt is making an immune response to commensal bac)
Th17 is like a Th1- a highly pro-inflammatory cell; mostly involved in really tough organisms (ex candida) and very prominent in their ability to cause pathology (esp psoriasis, but antigen is unknown)
Th2
♣ At the sites of antigen, activated Th2 cells release cytokines incl IL-4** and IL-13
♣ IL-4 is chemoattractive for macrophages (M2 macrophages)
♣ Also attract eosinophils- the cell for getting rid of parasites
• Ex Schistosoma worm egg in tissue will be encapsulated by M2 macrophages
o Initially a Th1 response, but assume it doesn’t clear everything because there’s Th2/eosinophil response, too (comes a few days later)
o Th2 response also builds scar around Schistosoma to wall off in case the eosinophil can’t kill it- contain it in the fibrous capsule
Th1 vs Th2 vs Treg
♣ Th1 is an “inflammatory” T cell
• Typical target: TB
• Mistakenly activated in inflammatory bowel disase, RA, T1D, MS…
♣ Th17 is a very strong inflamm T cell
• Typical target: candida
• Activated in IBD, psoriasis…
♣ Th2 is the alternative inflamm helper
• Typical target: Helminths (worms)
• Mistakenly activated in asthma and allergy
♣ Treg: also a helper
• Helps others stay calm and not get activated
T cells interacting w/ antigens
♣ T cell receptors have alpha and beta chain
♣ Alpha and beta chains interact w/ both the MHC class 2 antigen presenting molec and the antigenic peptide
♣ In general, 4/6 complementary regions engage the MHC and 2 engage the peptide- typical pattern
Th0 destinations
Th0 in thymus
Th0 in gut- 2 cases
Th0 cell in the thymus that binds peptide/MHC with HIGH affinity:
♣ Dies by apoptosis, or
♣ Turns into a Treg cell (called a tTreg)
A Th0 cell in the gut that binds peptide/MHC in the presence of TGFbeta only turns into a Treg (iTreg- induced)
♣ TGFbeta is normal cytokine in the gut- cells die by apoptosis all the time, and nearby macrophages engulf it, and then becomes an anti-inflamm macrophage (inflamm during apoptosis would be too much inflamm happening too frequently in the gut, so it makes a squirt of TGFbeta to create conditions to prod Tregs to keep things calm)
A Th0 cell in the gut that binds peptide/MHC in the presence of TGFbeta AND IL-6 turns into a Th1, Th2, or Th17
♣ Il-6 is made when gut is exposed to a stressor/invasion, so you’re getting tissue damage- need innate immune response
lumen of gut immunology
• Lumen of gut- has up to 10^12/mL organisms; high conc
o IgA in mucus layer keeps the bugs outside the barrier
o Nl gut organsism create a TGFbeta environment that favors Treg
o Aggressive invaders create an IL-6 + TGFbeta environment that turns on Th1 and Th2 in the peyer’s patches
IBD immunology
old friends
genetics
o Might something have been missing while you were growing up so clean?
♣ Old friends: (hygiene hypothesis)
• When we were hunter-gatherers, we had diff gut makeups (missing them now)
o Lactobacilli
o Saprophytic mycobacteria
o Helminths (parasitic worms)- nl hormones near equator have Helminths
• w/ missing stimulation by old friends, there are not enough Treg
o nl bac and harmless things may then be responsed to by Th1, Th17, and Th2
o IBD genetic causes
♣ GWAS have identical 30 risk loci in Crohn disease and 23 risk loci in UC
♣ 110 risk loci exhibit shared assoc’s between the 2 conditions, for a total of 163 IBD loci (so far) based on comparing almost 75k genomes
♣ these loci do a lot of things related to IBD- ex epithelial barrier and leaky gut allowing antigens across, healing, solute tx, innate defenses, etc.
♣ studies show there is no diff in Th subgroup involvement between UC and CD
♣ Th1/Th17 related expression, w/ little Th2 differentiation, dominated both diseases
• IBD: Pt responds to commensal bac as if its pathogenic
• Too much leakiness in gut puts pt at risk for IBD- barrier breakdown
celiac disease immunology
Based on immune response to Gliadin peptides- HLADQ2 and DQ8, the peptide that pts preferentially respond to
♣ Enormous side groups makes this peptide impossible to fit into most MHCs
♣ But DQ2s and DQ8s have deep pockets can accommodate it and present this antigen
♣ You present gliadin (foreign) and make Th1/Th17 cells against it
♣ Tx by avoiding antigen to not get response
The dominant immunopathology is “chronic frustrated immune response” against gliadin
Autoantibody to TTG2- this would be true autoimmunity
♣TTG2 self-reactive B cells, but without Tfh against TTG2 peptides + MHC class 2, they don’t become activated unless:
• Since TTG2 interacts w/ gliadin, you get a molec that is part foreign part self (Gliadin-TTG2)
• Formation of hybrid self-foreign antigen on B cells
• Only DQ2/DQ8 people can do this; and these people can make Tfh cells to activate B cells to make Ab against TTG2 (hybrid antigen help)
• The Ab is useful for dx- don’t need biopsy anymore
• Over time, anti-TTG2 mutates to also be reactive w/ TTG3 (in skin) and cause dermatitis herpetiformis
• DQ2/DQ8 people are also at highest risk for juvenile Diabetes
♣T cells responding to gluten is responding to foreign food and innocent bystander gut
lone star tick immunology
o People find they’re suddenly allergic to meat
o Syndrome overlaps the range of this tick
o Tick’s drool that bites you contains sugars that aren’t found in you but in many of the animals you eat
o You get an IgE response to the tick and then allergic rxns to the animals afterwards
o Avoid meat until immunity eventually fades
