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)