Unit I, week 2 Flashcards
Tumors of the Appendix (3)
Neuroendocrine tumor (carcinoid) - most common
Epithelial tumors (adenocarcinoma)
Cystadenomas (mucinous tumor)
Appendix
arises off cecum (average 9 cm length), tubular structure
Types of watery diarrhea (2)
Osmotic
Secretory
Osmotic diarrhea
mOsm gap?
due to what 2 things?
type of watery diarrhea
gap > 50 mOsm
Carbohydrate malabsorption: Lactose intolerance, Sorbitol, Fructose
Osmotic laxatives: Magnesium containing laxatives
Secretory diarrhea
mOsm gap?
5 common causes
gap < 50 mOsm
1) Bacterial toxins (V. Cholera, E. Coli.)
2) Neuroendocrine tumors (Gastrinoma, VIPoma, Carcinoid)
3) Bile salt (e.g. terminal ileal resection)
4) Stimulant laxatives
5) Motility disorders (diabetes, IBS)
Differentiating osmotic vs. secretory diarrhea:
Normal stool osmolality = 290 mOsm
Osm gap = 290 - 2x(stool sodium + potassium)
→ greater than 50 mOsm → osmotic diarrhea
→ less than 50 mOsm → secretory diarrhea
Types of diarrhea (4)
1) Watery
2) Steatorrhea
3) InflammatoryExudative
4) Functional
Steatorrhea can be caused by what 2 main things?
(fecal fat+)
1) Malabsorption
2) Maldigestion
Diseases that cause steatorrhea via malabsorption (4)
1) Pancreatic insufficiency
2) Celiac
3) Whipple’s disease
4) Small bowel bacterial overgrowth
5) Short gut (small bowel) from surgery
Diseases that cause steatorrhea via maldigestion (2)
Pancreatic insufficiency
Biliary obstruction
3 main causes of inflammatory/exudative diarrhea
1) IBD - Crohn’s, UC
2) Ischemia
3) Invasive infections (colon)
Diagnosis of inflammatory diarrhea
Infection –> ?
Ischemia –> ?
Inflammatory –> ?
Infection → stool culture, PCR, ELISA, endoscopy with biopsy
Ischemia → CT scan, endoscopy-colon
Inflammatory → endoscopy
How does pancreatic insufficiency cause malabsorption and what kinds of malabsorption? (3)
1) → impaired lipolysis due to decreased lipase and colipase → fat malabsorption → steatorrhea
2) → decrease secretion of trypsinogen, chymotrypsinogen, proteases, pro carboxypeptidases A and B → protein malabsorption
3) → decreased pancreatic amylase → carbohydrate malabsorption
What are the pain causes of pancreatic insufficiency malabsorption
chronic pancreatitis, Cystic Fibrosis - insufficiency results when 90% of pancreas burned out
How does liver disease cause malabsorption?
alcoholic cirrhosis→, primary biliary cirrhosis, biliary obstruction
→ fewer hepatocytes with decreased function
→ decreased bile formation
→ lipid malabsorption
How does gastric bypass surgery cause malabsorption?
what deficiencies are common?
surgical rerouting results in inadequate mixing of food with biliary and pancreatic secretions
B12, Fe, Ca, Vit D deficiencies common
What causes predispose to small intestinal bacterial overgrowth (SIBO)? (5)
Hypomotility (scleroderma, diabetes, narcotics)
Partial intestinal obstruction
Small bowel diverticula
Decreased gastric acid secretion
Enterocolonic fistula (Crohn’s)
What problems to SIBO cause? (5)
1) Fat soluble vitamin and B12 deficiency
- Bacteria de-conjugate bile salts and consume B12
2) Folate levels will be normal to high
3) Catabolizing disaccharides in microvilli
4) Reducing effectiveness of enterokinase
5) Disrupting small bowel motility
How do you diagnose small intestinal bacterial overgrowth (SIBO) (3)
Aspiration of duodenum with culture
Glucose-Hydrogen breath test
Empiric treatment with abx (e.g. Ciprofloxacin)
What are the symptoms of SIBO? (6)
diarrhea, steatorrhea, abdominal pain, flatulence, bloating, weight loss
Deficiencies of fat soluble vitamins (A, D, E, B12)
Fat malabsorption vitamin deficiencies:
Vitamin A → ?
Vitamin D → ?
Vitamin E → ?
Vitamin K → ?
Vitamin A → night blindness, xerophthalmia
Vitamin D → osteomalacia (bone mineralization defects)
Vitamin E → hemolytic anemia (rare in adults)
Vitamin K → clotting dysfunction (PT/INR)
Celiac disease
inflammatory disease of small intestine
Immune response to peptides of gluten (gliadin) → loss of villi due to presence of increased intraepithelial lymphocytes and crypt hyperplasia leading to malabsorption
Mostly affects proximal small intestine → iron and folate deficiency
Symptoms of celiac disease
typical signs (8)
atypical signs (6)
steatorrhea, diarrhea, weight loss, bloating, abdominal pain, flatulence, failure to thrive, vomiting
Atypical signs: dermatitis herpetiformis, iron deficiency anemia, LFTs (AST, ALT elevations), cerebellar ataxia, osteoporosis, oral ulcers
Diagnosis of celiac disease
Intestinal biopsy (3 findings)
Serologic testing (what ab?)
What two HLA alleles?
Intestinal biopsy → villous flattening, intraepithelial lymphocytes, crypt hyperplasia
Serologic anti-tissue transglutaminase (tTg) IgA antibody test
HLA-DQ2, HLA-DQ8 → REQUIRED to have celiac disease (but not everyone with this will have celiac disease)
Tropical sprue
cause
presentation
Residents or visitors to tropics
Cause: bacterial toxins or colonization of aerobic coliform bacteria
Classic presentation: megaloblastic anemia (B12 and folate deficiency)
Tropical sprue
diagnosis
treatment
Diagnosis: intestinal biopsy with villous flattening and travel history
Treatment: abx, B12, folate
Symptoms of chronic vs. acute mesenteric ischemia
Chronic: 2-3 major vessels occluded
- Symptoms: postprandial abdominal pain, weight loss, sitophobia, malabsorption
- Causes: Atherosclerosis, clot, radiation stenosis of vessel
Acute: embolus, severe abdominal pain
Small Intestinal Tumors
VERY rare cause of primary tumors
Present with symptoms of obstruction: abdominal pain, distension, decreased stool output
Neuroendocrine tumor→ endocrine symptoms
Irritable Bowel Syndrome (IBS)
abdominal pain and altered bowel habits in absence of an organic cause
Pain improved with defecation
Pain onset with change in stool frequency
Pain onset with change in stool appearance
Constipation and/or diarrhea
10-15% of population in North America
Function of normal colon
resorption of water and electrolytes from chyme, bacterial fermentation of unabsorbed nutrients, storage and elimination of waste and indigestible materials
5 layers of normal colon
mucosa → muscularis mucosae → submucosa → muscularis propria → serosa (no villi)
Muscularis propria of colon and innervation of colon
Muscularis propria = inner circular smooth muscle + outer longitudinal smooth muscle layer
Muscle innervated by: afferent/efferent parasympathetic (stimulatory) and sympathetic (inhibitory)
Mucosa of colon
glandular epithelium with cylindrical indentations (crypts) with epithelial stem cells at base and columnar enterocytes, goblet cells, and neuroendocrine cells throughout
Anatomic pathway of the colon
ileocecal valve → cecum → ascending colon → hepatic flexure → transverse colon → splenic flexure → descending colon → sigmoid colon → rectum → anus
Blood supply to the colon
SMA → right colon (IC valve → distal transverse colon)
IMA → left colon
Inferior rectal and hemorrhoidal arteries → Distal rectum
*Splenic flexure and rectum = watershed areas (susceptible to ischemia)
Inflammatory Bowel Disease
disorderly immune function involving small and large intestines (immune dysregulation)
HLA-B27 associated with IBD
Chronic inflammation of mucosa and submucosa
Pathogenesis of Crohn’s and UC
immune dysregulation (not strictly autoimmune)
Can result from:
1) Host interactions with intestinal microbiota
2) Intestinal epithelial dysfunction with tight junction barrier dysfunction
3) Aberrant mucosal immune responses
- TH1 skewed response → Crohn’s disease
- TH2 skewed response → Ulcerative colitis
IBD and cancer?
IBD Increases cancer risk → adenocarcinoma
Increased risk with: duration of disease, extent of disease, family history, and extra-intestinal manifestations
Requires regular endoscopic surveillance for dysplasia
Ulcerative colitis has higher risk of colon cancer than Crohn’s
Defining features of Ulcerative colitis (6)
1) *Location limited to COLON, usually rectosigmoid
- -> Cure via surgical resection
2) Improves with tobacco use
3) Inflammation confined to mucosa/submucosa
4) *DIFFUSE inflammation (friability, edema, bleeding, punctate ulcerations)
5) Circumferential ulceration
6) Formation of pseudopolyps
- No strictures, no fistulae or abscess
- Increased risk of colon cancer
Defining features of Crohn’s (7)
1) *ENTIRE GI TRACT - Occurs from distal oropharynx to anus, most common in terminal ILEUM and right colon
2) *TRANSMURAL inflammation (extends to muscle and serosa)
3) → spread of disease outside GI tract → *FISTULA FORMATION
4) Can cause *marked FIBROSIS, narrowing, and *STRICTURES of small bowel common
5) *Patchy inflammation / ulceration with relative sparing of mucosa in between (“SKIP LESIONS”)
6) *Linear/focal ulceration - Deep ulcers
7) Exacerbated by tobacco use
Symptoms of Ulcerative Colitis (8)
1) *LOWER abdominal pain, crampy - LLQ > RLQ
2) *HEMATOCHEZIA
3) *MUCUS in stool
4) *Tenesmus
5) *Urgency
6) Chronic diarrhea, fatigue, weight loss
7) **No problems with malabsorption or obstruction
8) Extra-intestinal manifestations more common in UC than Crohn’s → *Primary sclerosing cholangitis
Symptoms of Crohn’s (5)
1) *LOWER OR MID abdominal pain
2) *Nausea/vomiting
3) *Steatorrhea
4) *FISTULA symptoms
5) Weight loss, chronic diarrhea, fatigue
Microscopic appearance of UC
Chronic inflammation restricted to mucosa
Bowel wall is thinned
Microscopic appearance of Crohn’s (4)
1) Transmural chronic inflammation and lymphoid aggregates
2) Bowel wall thickening
3) *Granuloma formation - NOT in UC
4) *Fissuring ulcers - UC has broad based ulcers
Extra-intestinal manifestations of IBD (6)
1) Uveitis: eye pain, redness
2) Pyoderma gangrenosum: large, painful, ulcerative condition over lower extremities
3) Erythema nodosum: painful raised erythematous nodules
4) Ankylosing spondylitis: stiffness and pain in lumbar spine
5) Primary sclerosing cholangitis
6) Osteoporosis and osteopenia
Primary sclerosing cholangitis
fibrosing condition of intra/extrahepatic bile ducts → cirrhosis or cholestasis
More common in UC
Ischemic colitis
inflammatory condition of colon that develops as a result of severely impaired regional blood flow (low CO or occlusive disease of vascular supply to bowel)
2 typical areas where ischemic colitis occurs
Typically occurs in watershed vascular areas (splenic flexure, rectosigmoid junction)
Risk factors predisposing to ischemic colitis
older individuals with peripheral vascular disease or CHF, or younger patients (long distance runners, oral contraceptive use)
Presentation of ischemic colitis
sudden onset crampy lower abdominal pain, diarrhea, and/or hematochezia
Weight loss or severe bleeding NOT present
Diagnosis of ischemic colitis
gold standard is colonoscopy or flexible sigmoidoscopy with biopsy
→ mucosal edema, friability, ulceration, hemorrhage
Infectious colitis
presentation? without what?
common cause of acute diarrhea
Inflammatory diarrhea caused by invasion or destruction of mucosa by microbe
Presentation: crampy lower abdominal pain, diarrhea, small volume, frequent, bloody or mucoid without caloric malabsorption
Diagnosis of infectious colitis
Leukocyte stain of stool (nonspecific)
Stool cultures or stool toxin assays
History: travel, undercooked beef, contaminated poultry, eggs, milk, lettuce, recent abx use (c.diff)
C. Diff/Pseudomembranous Colitis
results in formation of necrotic, mucopurulent debris adherent to inflamed colonic mucosa
Diverticulosis
outpouching of colon wall composed of mucosa and submucosal layers that herniate outward through muscularis propria but are contained by serosa
Benign in 80% of patients
VERY common - 60% in Western adult populations over 60
Pathogenesis of diverticulosis
low fiber diet → decreased stool bulk → increase peristaltic squeeze pressure and intra-colonic pressure → mucosal herniation through focal defects in bowel wall
What is a symptom of diverticulosis but not diverticulitis?
Diverticulosis → possible diverticular hemorrhage (diverticula can penetrate colon wall and vasa recta)
Painless hematochezia, often heavy, typically stops within 2-3 days
NOT a feature of diverticulitis
4 complications of diverticulosis
infection, perforation, abscess formation, hemorrhage
Diverticulitis
fecalith obstruction of diverticulum → distension from bacterial gas and neutrophils, micro perforation, abscess, or frank perforation with peritonitis
Infiltration of diverticulum with acute, then chronic inflammatory cells
Symptoms of diverticulitis
Typically occur in sigmoid → rapid onset, lower abdominal pain (LLQ), fever, nausea/vomiting
NO diarrhea, NO bleeding
Treatment of diverticulitis (uncomplicated vs. complicated)
Oral/IV abx for uncomplicated diverticulitis
Percutaneous drainage, surgery for complicated diverticulitis (perforation, stricture, recurrent disease)
Complications of diverticulitis (3)
1) Perforation: rupture of diverticulum due to multiplication and expansion of bacteria
2) Obstruction
3) Abscess formation
Microscopic colitis
autoimmune inflammatory condition of colon associated with mild-moderate diarrhea
Presentation of microscopic colitis (3)
Females > males, after age 50
Mild, chronic, watery, non-bloody diarrhea WITHOUT weight loss
Endoscopic and imaging normal
Diagnosis of microscopic colitis
Diagnosis by endoscopic biopsy → two types (lymphocytic or collagenous)
NORMAL on endoscopy, diagnosis on BIOPSY
Lymphocytic colitis (microscopic colitis) appearance on biopsy
increased intraepithelial lymphocytes
Strong association with celiac disease, lymphocytic gastritis, and other autoimmune diseases (thyroiditis)
Collagenous colitis (microscopic colitis) appearance on biopsy
thickened subepithelial collagen layer
Colonic hemorrhage
presentation
common causes
lower GI bleeding
Presentation: hematochezia (red/maroon blood per rectum)
Causes: diverticulosis (most common), AVMs, IBD, neoplasia, internal hemorrhoids
Symptoms of colonic obstruction (5)
1) Diffuse or upper abdominal discomfort
2) Distension
3) Nausea/vomiting
4) Emesis may be feculent
5) Absence of stool passage (obstipation) or low grade diarrhea
Diagnosis of colonic obstruction
Abdominal radiographs show dilated loops of colon and/or small intestine
Causes of colonic obstruction
adenocarcinoma of colon or rectum, volvulus, strictures, volvulus, foreign body
KEY POINTS - KNOW THESE!!!
Chronic abdominal pain and diarrhea → ?
Weight loss, new constipation → ?
Painless, heavy bleeding in otherwise healthy elderly patient → ?
Hematochezia after major surgery or MI → ?
1) Chronic abdominal pain and diarrhea → IBD
2) Weight loss, new constipation → Neoplasia
3) Painless, heavy bleeding in otherwise healthy elderly patient → Diverticulosis
4) Hematochezia after major surgery or MI → ischemic colitis
KEY POINTS - KNOW THESE!!!
Acute dysentery, travel, ill contracts, or abx use → ?
Chronic microcytic anemia → ?
NSAIDS → ?
History of pelvic radiation → ?
5) Acute dysentery, travel, ill contracts, or abx use → infectious diarrhea
6) Chronic microcytic anemia → AVMs or neoplasia
7) NSAIDS → drug induced colitis
8) History of pelvic radiation → radiation proctitis
Gliadin - what is it, what does it do to celiac people
(glycoprotein extract from gluten)
Effects:
Directly toxic to enterocytes
Stimulates lymphocyte mediated response and formation of autoantibodies
Pathophysiology of celiac disease
Gliadin deamidated by tissue transglutaminase (tTG)
→ deamidated gliadin presented by APCs via MHC class II to helper T cells → helper T cell mediated tissue damage
→ Villous atrophy, tissue damage, loss of mucosal and brush border surface area → malabsorption, diarrhea
*Typically involves duodenum
Presentation of Celiac disease
Bulky fat diarrhea, flatulence, weight loss, anemia, nutritional deficiencies, growth failure in children
Extra-intestinal complications of celiac disease
Dermatitis herpetiformis**
Other extra-intestinal complaints:
Fatigue, iron-deficiency anemia, pubertal delay, short stature, aphthous stomatitis
Lymphocytic gastritis, lymphocytic colitis
Dermatitis herpetiformis
small, herpes-like vesicles on skin that arise due to IgA deposition at tips of dermal papillae
What malignancies are associated with Celiac disease
Enteropathy-Associated T-Cell Lymphoma (EAT Lymphoma happens when you eat gluten)
Small intestinal adenocarcinoma
Both present as refractory disease despite good dietary control
Endoscopy and serology of Celiac disease
Endoscopy: loss of surface villi
Serology: IgA antibodies to tTG, anti-endomysial antibodies
Tissue biopsy: 3 characteristic findings
*****KNOW THIS
1) Villous blunting
2) Increased intraepithelial lymphocytes
3) Lymphoplasmacytosis of lamina propria
*Histologic severity does not always correlate with symptoms
Whipple’s Disease
Pathogenesis
gram (+) bacilli, Tropheryma whippelii (actinomycete) absorbed by lamina propria macrophages
Organism laden macrophages accumulate in small intestinal lamina propria and mesenteric lymph nodes → lymphatic obstruction
→ impaired lymphatic transport → malabsorptive diarrhea
Whipple’s Disease
Presentation
Triad: diarrhea, weight loss, malabsorption
- Arthritis, lymphadenopathy, neurologic disease
- Middle-aged/elderly white males
Whipple’s Disease
Diagnosis
tissue biopsy demonstrates presence of Tropheryma whippelii
PAS+ Macrophages filled with Whipple bacilli on biopsy
PCR based assay
Whipple’s Disease
Treatment
one year of abx
Giardia lamblia
what type of bug is it?
how do you get it?
incubation period?
causes what?
- noninvasive flagellated parasite
- can cause sporadic or epidemic diarrhea
- cysts present in stool
- Waterborne or food borne (cysts resistant to chlorine, need filter)
7-14 day incubation period
-diarrhea due to malabsorption / hyper-secretion with villous atrophy
Symptoms of Giardia Lamblia GI infection
chronic diarrhea, malabsorption, flatulence, weight loss
Sx may be intermittent
Can persist for years
Giardia Lamblia GI infection on duodenal biopsy
identification of organisms in lumen = “schools of fish”
Tear-drop shaped with two nuclei on each side of axoneme
Cyst in stool by immunofluorescence
villous atrophy
Giardia Lamblia GI infection microscopic findings
Villous blunting but no ulceration
Intraepithelial lymphocytes
Numerous protozoa bound to brush border, but no invasion
Bacterial infections and diarrheal illness
Mostly related to ingestion of contaminated water, food, foreign travel
Typically acute, self-limited colitis
Campylobacter spp diarrheal illness
gram negative, comma shaped, motile
-major cause of diarrhea worldwide
Inflammatory diarrhea - watery diarrhea at first –> progress to bloody
WBCs present in stool
Found in contaminated meat (poultry), water, and unpasteurized dairy
-complications: reactive arthritis, Guillan-Barre
Salmonella diarrheal illness
2 main types
gram negative bacilli, transmitted through food (uncooked chicken), reptiles (turtles), and water
Typhoid (enteric) fever = S. typhimurium
-or-
Non-Typhoidal Salmonella species
Typhoid (enteric) fever = S. typhimurium
Fever Abdominal pain Bacteremia "Pea soup" diarrhea "Rose spots" rash on trunk Hepatosplenomegaly
Peyers Patch hyperplasia –> perforation/intestinal bleeding
Abx treatment does not help
Non-Typhoidal Salmonella species:
Mild, self limited gastroenteritis
4 kinds of E. Coli diarrheal illness
1) Enteroadherent
2) Enterotoxigenic E. Coli (ETEC) and Enteropathic E. Coli
3) Enteroinvasive E. Coli
4) Enterohemorrhagic E. Coli
Enteroadherent E. Coli diarrheal illness
non-invasive, non-bloody diarrhea
Chronic diarrhea and wasting in AIDS
Form a coating of adherent bacteria on surface epithelium of enterocytes
Enterotoxigenic E. Coli and Enteropathic E. Coli diarrheal illness
Non-invasive, non-bloody diarrhea
Enterotoxigenic = major cause of traveler’s diarrhea
Enteropathic = infection of infants and neonates
Enteroinvasive E. Coli diarrheal illness
Invasive (similar to Shigella), non-bloody diarrhea, dysentery-like illness, bacteremia
Contaminated cheese, water, person-person contact
Cause of traveler’s diarrhea
Enterohemorrhagic E. Coli (EHEC) diarrheal illness
O157:H7 strain
Non-invasive, toxin-producing, bloody diarrhea
-Severe cramps, mild or no fever
From contaminated hamburgers
Sometimes renal failure = HUS
Deadly outbreaks
Rotavirus diarrheal illness
- most common cause of severe childhood diarrhea and diarrheal mortality worldwide
- Children 6-24 months most vulnerable
Selectively infects and destroys mature enterocytes → villus surface repopulated by immature secretory cells → loss of absorptive function → net secretion of water and electrolytes → osmotic diarrhea → DEHYDRATION = DEATH
Vaccines available
Protozoal infections of GI tract
1 example
typically in subtropical and tropical areas, dx via stool sample examination
Entamoeba histolytica
Entamoeba histolytica
infects 10% of world’s population
- Symptoms: abdominal pain, bloody diarrhea, nausea, vomiting
- can spread to liver –> elevated LFTs, liver abscesses
Cecum most commonly affected → “Flask shaped” ulcers in mucosa/fecal matter
cysts found in stool
Helminthic Infections of GI tract
1 example
Dx via stool examination for ova and parasites
Serious disease in nations with deficient sanitation systems, hot, humid, climate, and poverty
Can cause severe and life-threatening nutritional deficiencies
EX) Ascaris lumbricoides (roundworm)
Ascaris lumbricoides (roundworm)
In tropics, one of most common parasites in humans
Ingested from soil contaminated feces
Obstruction, perforation, growth retardation (malnutrition)
Giant worms up to 20 cm can be identified
Pathogenesis of pseudomembranous colitis
disruption of normal colonic flora by antibiotic allows C. difficile overgrowth → toxins released caused disruption of epithelial cytoskeleton, tight junction barrier loss, cytokine release, and apoptosis
Pseudomembranes
adherent layer of inflammatory cells and mucinous debris at sites of colonic mucosal injury
Eruption of neutrophils and mucinous debris attached to surface epithelium
Appendicitis
clinical features
treatment
Most common in adolescents and young adults
M > F
McBurney’s sign = tenderness located ⅔ of distance from umbilicus to R anterior superior iliac spine
Often presents as an acute abdomen
TX: appendectomy
Appendicitis
pathogenesis
luminal obstruction by stone-like mass of stool (fecalith) → ischemic injury and stasis of luminal contents → inflammatory response
Appendicitis
microscopic findings
Mucosal ulceration
Transmural acute and chronic inflammation
Extension of inflammation into mesoappendix
Bile
amphipathic liquid that contributes to excretion of various components (cholesterol, copper, medications) and lipid digestion within the small bowel
Synthesized by hepatocytes
Secreted into canaliculi → drain into peripheral intrahepatic bile ducts → right and left hepatic ducts → common hepatic duct
Main components = bile acids/salts, bilirubin, cholesterol
What happens to your bile in the fasting state
Storage and concentration of bile in gallbladder
Parasympathetic vagal tone and cholecystokinin levels decreased → sphincter of Oddi remains closed, gallbladder and bile duct peristalsis inhibited
- Bile flows proximally up cystic duct into gallbladder = reservoir
- Bile becomes 5-10x more concentrated during fasting
- -> Na+ actively transported from lumen into bloodstream
What happens to your bile in the fed state
Bile is released into duodenum
Cholecystokinin levels and vagal tone increased → gallbladder/bile duct peristalsis → transport of bile into duodenal lumen
Gallbladder
columnar epithelium, thin fibromuscular layer, and serosa
Stores and concentrates bile (fasting state)
Contracts to deliver bile to duodenum (fed state)
When is the pathogenesis of cholesterol stone formation
cholesterol supersaturation or decreased bile acid synthesis
Supersaturation of cholesterol → cholesterol crystals
When do cholesterol stones form (4)
Bile duct/gallbladder dysmotility (stasis)
Hereditary mutations in cholesterol chain structure
Bile acid hypersecretion
Inflammation of gallbladder
Cholesterol stones - composition, appearance
made up of cholesterol, bile acids, phospholipids, lecithin
White or yellow in color
Soft and greasy consistency
Develop within the gallbladder but may spill into bile duct/duodenum
Brown stones - develop when?
develop as a result of infection in patients with prostheses or downstream obstruction
Pigment stones appearance and composition
composed of calcium bilirubinate salts that coalesce around mucin nidus
Black and hard consistency
Risk factors for pigment stone formation (4)
Asian, rural
Chronic hemolytic syndromes (SICKLE CELL)
Biliary infection
Ileal disease
When do pigment stones form?
increased concentration of bilirubin in bile (hemolytic state), and obstructed gallbladder/bile duct as a result of stasis
Can also develop in Asia due to chronic inflammation within biliary tree, (parasitic infections, oriental cholangiohepatitis)
Risk factors for stone formation
5 F’s = Fat, Female, Fertile, Forties, Family hx
Others:
- rapid weight gain or weight loss
- Latin American or Native American ethnicity
- Estrogen/contraceptive use, pregnancy
Abdominal ultrasound and diagnosis of stones in biliary tree/organs
Abdominal ultrasound (>90% accuracy for cholelithiasis or cholecystitis)
Less accurate for bile duct stones (50%) → CT scan considered
Gallstone related complications (5)
1) Biliary Colic
2) Cholecystitis
3) Choledocholithiasis
4) Acute gallstone pancreatitis
5) Biliary Strictures
Biliary colic
gallstone can move downstream and obstruct gallbladder neck, cystic duct, or common bile duct
Intermittent gallbladder occlusion, e.g. after eating = Biliary colic
*complications of cholelithiasis
Presentation of biliary colic and treatment
Dull crampy pain in epigastrium or in RUQ which occurs within an hour of eating and resolves spontaneously within 3-5 hours
Timing corresponds to rise in cholecystokinin and decline
TX = cholecystectomy
Acute (calculous) cholecystitis
Pathophysiology
90% due to stone obstruction of neck/cystic duct → accumulation of toxic products in lumen → disruption of protective mucus layer
→ Severe inflammation and/or ischemia of gallbladder
Acute (calculous) cholecystitis
Symptoms and exam finding
Symptoms: Severe pain in RUQ, radiating to flank or shoulder, nausea, fever
Exam: focal tenderness to deep palpation during exhalation = Murphy’s sign
Acute (calculous) cholecystitis
treatment
admit, pain control, NPO, IV fluids, IV abx, cholecystectomy
Acalculous Cholecystitis
Pathophysiology
no obstructive stone, no infection, only inflammation and/or necrosis of gallbladder due to ISCHEMIA (vascular insufficiency)
Typically due to generalized hypoperfusion (sepsis, trauma, burns, MI)
Can be caused by vasculitis of cystic artery (Polyarteritis Nodosa)
Treatment of Acalculous Cholecystitis
drainage of gallbladder, or cholecystectomy if stable (typically since this is due to hypoperfusion, these patients are pretty sick and not surgery candidates)
Chronic cholecystitis
chronic inflammation in gallbladder, marked thickening and fibrosis of gallbladder wall
Clinically silent, follows repeated episodes of mild cholecystitis
*Increases risk of gallbladder cancer
Choledocholithiasis
stones travel into common bile duct, but too large to pass through ampulla → cause BILE DUCT OBSTRUCTION and/or acute pancreatitis
Choledocholithiasis
Symptoms
epigastric or RUQ pain, jaundice, dark urine
Liver chemistries elevated
Choledocholithiasis
Treatment
Possible complication?
ERCP with extraction or surgery
Ascending cholangitis
Ascending Cholangitis:
infection develops within bile duct above obstructing stone = LIFE THREATENING
Ascending Cholangitis:
presentation and treatment
Presentation:
- Charcot’s Triad: RUQ pain, jaundice, fever
- Progress to sepsis or death if untreated
Treatment: urgent IV abx and URGENT ERCP with stone extraction/stent
Biliary strictures
symptoms
causes
fixed narrowing or blockage of bile duct
Symptoms are more chronic and persistent - cholestasis (jaundice, dark urine/choluria, acholic stools, pruritus), RUQ pain, LFTs elevated
Can be benign or malignant causes
Benign biliary strictures (BBS)
what is it?
symptoms?
caused by edema and fibrosis, fixed narrowing or blockage of bile duct
Can cause cholestasis –>
Symptoms: jaundice, dark (bilirubin rich) urine, pruritus (from systemic retention of bile acids), acholic stool (gray/white color)
RUQ pain, fever
Causes of benign biliary strictures
1) Chronic chledocholithiasis (chronic inflammation of bile duct wall adjacent to stone or iatrogenic)
2) Chronic pancreatitis → narrowed distal common bile duct due to severe fibrosis of pancreatic head
3) Autoimmune pancreatitis
4) Primary sclerosing cholangitis (PSC)
Primary sclerosing cholangitis (PSC)
idiopathic intra/extra hepatic inflammatory disorder causing numerous BBS throughout biliary tree
- *Associated with IBD (UC)
- *High risk for cholangiocarcinoma (bile duct cancer) **KNOW THIS
- Progress to cirrhosis and liver fibrosis
- No medical therapy, treat symptoms only
Diagnosis of Biliary stricture
Ultrasound, CT → dilation of bile duct proximal to stricture
Confirm with MRCP or ERCP
Liver biopsy: assess decree of liver damage, may see concentric fibrosis around bile ducts (onion skinning)
Biopsy to determine if benign or malignant
Treatment of biliary strictures
ERCP, dilation of BBS
Sphincter of Oddi
muscular sphincter that regulates opening and closing of biliary orifice
Normal: sphincter relaxed during fed state (NO or B-adrenergic control) and contracts (cholinergic control) in fasting state
Sphincter of Oddi Dysfunction (SOD)
Clinical features (4)
- episodic epigastric or RUQ pain
- elevations in liver/pancreatic chemistries
- recurrent pancreatitis
- dilation of bile or pancreatic duct by imaging
DX confirmed by ERCP
Sphincter of Oddi Dysfunction (SOD)
treatment
ERCP guided biliary, pancreatic, or combined sphincterotomy
Gallbladder cancer
type?
prognosis?
treatment?
Typically adenocarcinoma
rare, but poor survival
Treatment:
Surgical removal of gallbladder and surrounding lymph nodes
Palliative with advanced disease (pain control, ERCP w/stent)
Gallbladder cancer histology
2 major risk factors?
Adenocarcinoma - gland forming epithelial cancer that usually develops in patients with *gallstones and *chronic cholecystitis (infection)
Produce desmoplasia (thick stroma of connective tissue)
Choledochal Cysts
congenital dilation of common bile duct
Typically discovered in infancy and early childhood
Increases risk for bile duct carcinoma
Bile Duct Carcinoma
prognosis, histology, 4 risk factors
nearly all adenocarcinomas, very rare, poor prognosis
Risk factors:
1) Choledochal cyst in older adults
2) Primary sclerosing cholangitis**
3) Infections (liver flukes)
4) Cholelithiasis
Pancreatic ductal adenocarcinoma
- most common form of pancreatic cancer
- Very poor prognosis
Appearance: Firm, white mass with irregular borders
Typically at head of pancreas and blocks common bile duct and pancreatic duct → painless jaundice
Pancreatic Endocrine Neoplasia
Better prognosis than ductal adenocarcinoma
Most clinically relevant tumor are: Nonfunctional and Well-differentiated
Functional tumors:
Insulinoma 42% → low blood sugar
Gastrinoma 24% → Peptic ulcers
Glucagonoma 14%
Appearance: well circumscribed fleshy tumor, arranged in “string of pearls” arrangement on histology
Ondansetron, Granisetron
mechanism
clinical use (3)
5HT3 antagonist
Clinical uses: greatest efficacy of antiemetic classes
- Prevention of chemo-induced N/V
- Post-op emesis
- N/V associated with post-op use of opioid analgesics
Side effects of Ondansetron, Granisetron
well tolerated, occasional GI upset (constipation, diarrhea) and headaches
Promethazine, Meclizine, Diphenhydramine
mechanism?
antihistamines
First generation H1 antagonist → good CNS penetration and muscarinic receptor blocking actions
Promethazine, Meclizine, Diphenhydramine
clinical use (2)
motion sickness, postoperative emesis
Scopolamine
mechanism? clinical uses (2)
anticholinergic
Clinical use: prevention and treatment of motion sickness, some post-op N/V prevention
Administered transdermally (duration of action 72h)
Metoclopramide, Prochlorperazine, Droperidol
mechanism?
D2 receptor antagonists
metocloparmide vs. prochlorperazine?
Botha re D2 receptor antagonists used as antiemetic
Metoclopramide: also blocks 5HT3 → used for N/V of chemo
Prochlorperazine: cross BBB poorly
- Less effective against emetic stimuli in gut which are mediated via 5HT3 receptors
- Additional block of M and H1 receptors increases utility in nausea with motion sickness
- Block a1 receptors increases potential for HTN
Side effects of Metoclopramide, Prochlorperazine, Droperidol (5)
Extrapyramidal symptoms, restlessness, fatigue, drowsiness, diarrhea
Best treatment of nausea/vomiting in pregnancy (2)
Pyridoxine (B6) and doxylamine (H1 antagonist) first line treatment
What are some causes of drug induced constipation (6)
1) Antimuscarinic agents
2) Drugs with antimuscarinic side effects (1st gen antihistamines, TCAs, typical antipsychotics)
3) Antacids: calcium carbonate, Aluminum
4) Ca2+ channel blockers (especially Verapamil)
5) Opioid analgesics
6) 5HT2 Antagonists (Ondansetron)
Management of simple constipation
proper diet (high fiber, 20-30g daily), exercise, adequate fluid intake (6-8 8oz glasses/day)
Types of laxatives (4)
1) Fiber/Bulk Forming Laxatives
2) Saline (osmotic) Laxatives
3) Stimulant/Irritant Laxatives
4) Stool-Wetting Agents and Emollients
Psyllium
Fiber/Bulk Forming Laxatives
First line treatment
Approximates physiological mechanism - facilitates passage, stimulates peristalsis via H2O absorption → bulk expansion
Effective in 12-24 hours to 3 days
May combine and interact with other drugs (digoxin/salicylates)
Saline (osmotic) Laxatives
4 examples
non absorbable ions → osmotic retention of intestinal water → increased peristalsis
Used for purging doses for food/drug poisoning
1) Milk of Magnesia, Magnesium Citrate
2) Phosphate enemas
3) Polyethylene Glycol
4) Lactulose
Milk of Magnesia, Magnesium Citrate:
most used for mild/moderate constipation
Avoid in renal dysfunction (can cause electrolyte imbalances)
Phosphate enemas
primarily used for fecal impaction
Polyethylene Glycol
Electrolyte solutions
High volume solutions → bowel cleansing prior to medical procedures, contain Na+/K+ salts to prevent net transfer of electrolytes
Small volume solutions → for difficult to treat constipation
-Excessive use may lead to electrolyte depletion
Lactulose
disaccharide metabolized by colonic bacteria to low MW acids → osmotic diarrhea → increased peristalsis
Alternate for acute constipation (useful in elderly)
Stimulant/Irritant Laxatives
3 examples
try if fiber/saline fail
1) Bisacodyl
2) Senna
3) Castor Oil
Bisacodyl
mechanism
side effects?
increased peristaltic activity via local irritation (PG-NO) → accumulation of water and electrolytes → increased motility
Potentially dangerous side effects = electrolyte/fluid deficiencies, severe cramping
Most widely abused class
Safe for chronic use in recommended doses
Castor Oil
mechanism of action?
contains triglyceride hydrolyzed in gut to ricinoleic acid
Acts primarily in small intestine → stimulate fluid/electrolyte secretion and speed intestinal transit
Castor bean also contains ricin an extremely TOXIC glycoprotein
Stool-Wetting Agents and Emollients
2 examples
Docusate
Lubricant (mineral oil, olive oil)
Docusate
mechanism
use
surfactant that acts as stool softener (facilitates admixture of aqueous and fatty substances)
Primarily used for prevention
Often combined with stimulant laxative during opioid therapy
Lubricant (mineral oil, olive oil)
mechanism?
coats fecal contents - prevents colonic absorption of fecal water
Potential for aspiration in very young/elderly
Treatment of opioid-induced constipation
stool softener (docusate)
+ stimulant laxative (bisacodyl-senna)
+ osmotic laxatives (milk of magnesia)
What are two peripherally acting opioid antagonists that can be used to treat opioid induced constipation?
Methylnaltrexone (does not cross BBB) - very expensive
Naloxegol (primarily binds opioid receptors in GI tract only) - cheaper
Activated charcoal
Prevention of Absorption-Chemical Adsorption
binds drug in gut to limit absorption
Effective without prior gastric emptying
Can even reduce elimination half-lives of drugs given IV
Given with Sorbitol 70%: recommended given with charcoal to prevent briquet formation
Treatment of watery diarrhea:
ETEC
EHEC
E. Coli (ETEC) → quinolones, azithromycin, rifamaxin
EHEC → DO NOT treat with abx (increases risk of HUS) or anti peristaltics (increase risk of systemic disease)
Treatment of watery diarrhea:
Giardia lamblia
C. diff
rotavirus
Giardia lamblia → metronidazole
C. Difficile → metronidazole, oral vancomycin
**Risk INCREASED with fluoroquinolones, clindamycina dn broad spectrum penicillin/cephalosporins
Rotavirus → rehydration
Loperamide
mechanism uses (2)
opioid receptor agonist affecting intestinal motility (mu), intestinal secretion (delta), and absorption (mu and delta)
Uses:
Anti-secretory activity against cholera toxin (blocks cAMP)
Effective against traveler’s diarrhea
Side effects of loperamide (3)
Low addiction potential (BUT can be injected IV)
CNS (euphoria)
Cardiac toxicity (increased QT)
Polycarbophil
antidiarrheal agent
binds free fecal water
Used for diarrhea and constipation
Avoid use of ________ in children under 12 years old
Avoid use of bismuth subsalicylate in children under 12 years old (salicylate risk for Reye’s Syndrome)
Drugs used to treat IBS (4)
1) TCAs
2) Drugs to improve bowel function (anti-diarrheals and anti-constipation)
3) 5HT-3 Antagonists
4) 5HT-4 Agonists
TCA use in IBS
TCAs → relieve abdominal pain and discomfort
Pain in IBD due to functional pain - abnormal operation of nervous system
Alosetron
mechanism
use?
side effects?
5HT3 Antagonists
→ reduces pain and inhibits colonic motility
*Used for severe IBS in women with diarrhea as prominent symptom
Can cause constipation
Tegaserod
mechanism?
use?
side effects?
5HT4 Agonists → increase release of NTs → peristaltic reflex → gastric emptying and intestinal motility
Used for IBS patients with predominant constipation
Can cause diarrhea and linked to heart attacks, strokes, and unstable angina
Leading causes of death from infectious disease worldwide
mainly effects who?
pneumonia and diarrhea
Mainly affects the young and old
Leading cause of morbidity and mortality with diarrhea?
what is the mainstay of therapy?
Dehydration: leading cause of morbidity and death associated with diarrheal disease
Rehydration is the mainstay of therapy
Pathogens that cause inflammatory diarrhea (6)
C. Jejuni Shigella Salmonella E. Coli O157:H7 C. Difficile E. Histolytica
**Campylobacter is #1 cause of diarrhea in children and adults in US
Composition of inflammatory diarrhea and where?
increase T cells, WBC, and RBC
in colon
Noninflammatory diarrhea pathogens (5)
Norwalk Rotavirus Giardia lamblia Vibrio cholerae Enterotoxigenic E. Coli (ETEC)
Composition of noninflammatory diarrhea and location
watery, in small bowel
Cholera
type of diarrhea?
mechanism?
non-inflammatory watery diarrhea that affects the small bowel
Once cholera toxin has infected, cells must slough off for them to stop secreting fluid due to cAMP → abx not very effective
Presentation of cholera
18h to 5 day incubation
Abrupt diarrhea (rice water stool), vomiting
NONBLOODY
Normal histology (noninflammatory)
Signs of dehydration
how do you rehydrate?
Decreased pulse volume, low BP
Poor skin turgor, sunken eyes, decreased urine, decreased MS
Metabolic acidosis, hypoglycemia, hypokalemia
Rehydration: give fluids with Na+ and glucose
ETEC
noninflammatory watery diarrhea
traveller’s diarrhea
Rotavirus
leading cause what?
Leading cause of: prolonged diarrhea, dehydration from diarrhea, hospitalization from diarrhea, and death from diarrhea (US and world)
Epidemiology of rotavirus
what ages are typically effected?
how is it transmitted?
incubation and duration of illness?
Epidemiology: sporadic cases, usually winter, occasionally epidemic
Age affected: infants, young children
Transmission: Fecal-oral
Incubation period: 1-3 days
Duration of illness: 5-8 days
Norwalk viruse (norovirus)
epidemiology?
what ages are typically effected?
how is it transmitted?
incubation and duration of illness?
Epidemiology: family and community epidemics, often winter
Age affected: older children, adults
Transmission: fecal-oral, contaminated shellfish and water
Incubation period: 1-2 days
Duration of illness: 1-2 days
Giardia Lamblia
typically caused by what?
presentation?
typically water contamination
-Protozoan
Diarrhea, fatigue, abdominal cramps, bloating (borborygmi), fat malabsorption
E. Coli O157:H7 (EHEC)
causes bloody inflammatory diarrhea
Causes vast majority of HEMORRHAGIC colitis (and HUS) in US
Can cause hemolytic uremic syndrome and thrombotic thrombocytopenic purpura (TTP)
Illness lasts 2-4 days (less than 7 days)
Highest rates in young children and elderly
Toxin involved in EHEC
verotoxin, Shiga-like toxin (SLT-I/II)
Binds especially to human renal endothelial cells
Inhibits protein synthesis
Where is EHEC typically found?
Reservoir in intestines of beef and dairy cattle
C. Difficile
presentation?
associated with what?
leading, and almost only cause of nosocomial infectious diarrhea
Most commonly associated with antibiotic use
Symptoms may be mild diarrhea, watery or bloody, or may have fever, leukocytosis with severe colitis
Salmonella typhi
risks of infection
enteric fever
Risks: fecal contamination, food/water (poor handling) contact with carrier
Where is free air/gas typically found on an abdominal XR
Free air: will always be located in the most non-dependent space
Upright CXR → look under diaphragm
cross table (left lateral decubitus) look → air is anterior, pushing against liver on right side
Systematic approach for interpreting abd XRs
Free air/Gas Bones Stones Calcifications Mass
Imaging modalities used to evaluate GI tract
1) Abdominal XR
2) Fluoroscopy
- Biphasic esophagram
- Upper GI
- Small bowel follow through (SBFT)
- Enteroclysis
- Barium enema
3) Ultrasound
4) CT
5) MRI
6) Nuclear medicine
7) Angiography/interventional radiology
Barium Swallow test
what is it?
what is it used to evaluate?
fluoroscopic-radiographic contrast exam of oral, pharyngeal, and/or esophageal swallowing
Used to evaluate: 3 phases of swallowing (oral, pharyngeal, esophageal), structural, and functional abnormalities of oral cavity, pharynx, and esophagus
Biphasic esophagram
Evaluates what 4 areas?
Evaluates: oropharynx, hypopharynx, esophagus, GE junction
Biphasic esophagram
looks at what pathology?
reflux (common), hiatal hernia (very common), aspiration, neoplasm, esophagitis, stricture
Upper GI
evaluates what 3 areas?
sees what pathology?
Evaluates: esophagus, stomach, duodenum
Pathology: gastritis/duodenitis, gastric or duodenal ulcers, diverticula, benign or malignant tumors
Small bowel follow through (SBFT)
evaluates what area of GI tract?
sees what pathology?
Evaluates: distal duodenum, duodenojejunal junction to ileocecal valve
Pathology: Crohn’s disease, lymphoma, TB, sprue, adhesions, partial/intermittent obstruction
Enteroclysis
gold standard of small bowel imaging, double contrast exam of jejunum and ileum (contrast + air)
Not well tolerated by patients, expensive, high radiation
Barium Enema
fluoroscopic-radiographic test to evaluate colon and rectum (single or double contrast)
Requires bowel prep - stool can obscure/mimic pathology
Contraindicated in acute perforation, toxic megacolon, or immediately after biopsy
Ultrasound used to evaluate what in GI tract?
evaluate abdominal organs and biliary system
Use: suspected appendicitis, cholecystitis, solid organ lesions (solid vs. cystic differentiation), vascular flow evaluation
Not widely used to evaluate GI tract
Computed Tomography (CT) used to evaluate what in GI tract?
with vs. without contrast
Without IV contrast → detection of renal stone or hemorrhage
With Iv contrast → ischemic, infectious, or inflammatory disease, trauma, or tumor
When is barium contraindicated?
DO NOT give orally upstream of a colon obstruction
Contrast agents
used to opacify the lumen and include air, thin (low density), thick (high density) barium, and water soluble contrast
air barium Iodinated water soluble contrast IV contrast Enteric contrast
When would iodinated water soluble contrast be given?
give if possible gut perforation
what are the risks of IV contrast?
what about gadolinium based IV contrast?
Risks: nephrotoxic, allergic reactions
Gadolinium-based: IV contrast agent used in MRI
- No nephrotoxicity
- allergic reactions rare
What is the composition of salivary gland secretions during HIGH FLOW RATES?
Saliva slightly hypotonic
- HIGH bicarb
- LOW Cl-
Moving too fast for significant exchange - limits action of duct cells on ionic/water content
Parasympathetic AND sympathetic input modifies secretion and changes in blood flow
What is the composition of salivary gland secretions during LOW FLOW RATES?
-Saliva highly hypotonic because striated duct has time to modify secretion
- Absorb Na+ and Cl- and secrete K+ and HCO3-
- *→ Decrease NaCl, increase KHCO3-
-Movement of water in ducts restricted by tight junctions, leaving saliva hypotonic
What is the composition of pancreatic juice in relation to flow rate?
Increase flow → increase [HCO3-], and decrease [Cl-] in pancreatic secretions, but Na+ (high) and K+ (low) always constant
**→ High NaHCO3-
Regulation of salivary secretions
Via SNS and PNS input
Parasympathetic regulation of salivary secretions
input from higher brain centers: vagal ACh
INCREASES acinar cell secretion and VASODILATION of blood vessels surrounding acini (results in protein rich and fluid/ion rich solution)
→ increased blood flow around acinus → increased fluid content of saliva by moving ions and water into acinar lumen
Sympathetic regulation of salivary secretions
increased sympathetic input –> increased acinar cell secretion (results in high protein, low fluid solution
Regulation of pancreatic secretion (3)
ANS input and hormonal input
1) ACh
2) CCK
3) Secretin
ACh regulation of pancreatic secretion
- released from where?
- stimulates release of what and from where?
released from vagus and ENS nerves, stimulates release of digestive enzymes from acinar cells
Cholecystokinin (CCK) regulation of pancreatic secretion
- released from where?
- stimulates release of what and from where?
released from endocrine cells in proximal small intestine in response to fat and proteins
Stimulates release of digestive enzymes from acinar cells
3 main effects of CCK release
1) Stimulates release of digestive enzymes from acinar cells
2) Causes gallbladder contraction and Sphincter of Oddi relaxation
3) Reduces stomach emptying
Matches nutrient delivery to digestive and absorptive capacity
Secretin regulation of pancreatic secretion
- released from where in response to what?
- stimulates release of what and from where?
released from endocrine cells in proximal small intestines in response to acid
Stimulates bicarb-rich fluid secretion from pancreatic duct cells
Acts by increasing cAMP levels in duct cells
Main components of saliva
1) Mucins - lubricate food, facilitate swallowing
2) Amylase, lingual lipase - begin digestion of starches and fats
3) NaHCO3 - maintain optimal pH for enzyme activity, reduce Ca2+ solubility
4) IgA, lysozyme (destroys bacterial cell walls), lactoferrin (chelates iron, preventing bacterial growth that requires iron) → innate and acquired immune protection
5) Water - facilitates taste and dissolution of nutrients, aid in swallowing/speech
Saliva
1-2 L of saliva secreted per day - 70% from submaxillary or submandibular gland, 25% from parotid gland, 5% from sublingual gland
Formed by passive filtration
Dependent on blood flow
Acinar cells of salivary gland do what?
make saliva
Contain leaky tight junctions that allow increased blood flow to move more ions and water into acinar lumen
Intercalated duct of salivary gland
between acinus and striated duct - contains myoepithelial cells to facilitate active secretion
Striated duct of salivary gland
modifies ionic composition of saliva as it exits
Main goals of striated duct of salivary glands
what channels and enzyme make this happen? (5)
Goal: NaCl reabsorption, K+ secretion, bicarbonate secretion
Cl-/HCO3- exchanger
+ H+/K+ exchanger
+ Na+/H+ cotransport
- Na+/K+ ATPase establishes concentration gradient
- Carbonic anhydrase uses H2O + CO2 to produce H+ + HCO3-
Acinar cells vs ductal cells of pancreas
Acinar cells: produce variety of enzymes
-Acinar cells produce and excrete full complement of pancreatic enzymes via secretory granules released via exocytosis
Ductal cells: produce bicarb solution to help liquefy and neutralized acidic chyme in duodenum
What is the aqueous component of pancreatic secretions
Aqueous component: water and bicarb
Produced by duct cells
Acid in small intestine triggers secretin release from duodenal endocrine cells → stimulus for NaHCO3 release
Secretin and CCK both inhibit gastric acid/fluid production and delay gastric emptying
Pancreas does NOT contain what? (as compared to salivary gland)
MYOEPITHELIAL CELLS
Similarities of pancreas and salivary gland
Both have acinar and ductal cells, both produces slightly hypertonic solution that is modified by ductal cells before release
Comparing regulation of secretion between pancreas and salivary gland
Salivary secretion regulated by ANS
Pancreatic secretion regulated by both ANS and hormones
How does increase in blood flow effect the salivary gland vs. pancreas
Salivary acinus is very vascular and increased blood flow results in a dilute saliva that is modified by duct cells
Pancreatic acini are not as vascular and respond to ACh and CCK
How would you compare the ducts of the salivary glands and pancreas?
Pancreas: Ductal cells actively secrete a water and bicarbonate rich solution in response to secretin
Salivary: Salivary ducts on the other hand are fairly impermeable to water
Saliva is rich in _______, where as pancreatic juice is rich in _______
**Saliva is rich in KHCO3-, whereas pancreatic juice is rich in NaHCO3-
Categories of Salivary gland diseases (5)
1) Reactive lesions
2) Infectious sialadenitis
3) Benign neoplasms
4) Malignant neoplasms
5) Rare tumors
Eight infectious/reactive diseases of salivary gland
1) Mumps
2) CMV Sialadenitis
3) Bacterial Sialadenitis
4) Sarcoidosis (granuloma)
5) Sjogren’s Syndrome
6) Salivary Lymphoepithelial Lesion
7) Xerostomia (dry mouth)
8) Halitosis
Benign neoplasms of salivary gland (4)
1) Mixed Tumor (pleomorphic adenoma):
2) Monomorphic Adenomas
3) Ductal papilloma
4) Warthin’s Tumor: Warthin’s has abundant lymphoid and epithelial components (WHALE)
Features suggesting malignancy in a salivary neoplasm (7)
Induration (hard) Fixed to overlying skin or mucosa Ulceration of skin or mucosa Rapid growth, growth spurt Short duration Pain, often severe Facial nerve palsy
Tracheo-esophageal fistula
connection of distal esophagus and trachea in setting of proximal esophageal atresia (ends in a blind pouch)
Presentation: polyhydramnios, choking with feeds, inability to swallow oral secretions
Infantile hypertrophic pyloric stenosis
hypertrophy and hyperplasia of smooth muscle of gastric wall at level of pylorus → narrowing of antrum → causes near complete obstruction
Symptoms: dilation of stomach, projectile nonbilious vomiting, olive mass in RUQ, presents around 3 weeks of life
Meckel diverticulum
what is it?
how do you diagnose it?
partial persistence of vitelline duct or yolk sac → blind pouch protrudes from terminal ileum
Wall may contain gastric mucosa → can cause gastric diseases (PUD)
Rule of 2’s: in 2% of population
Diagnosis: Technetium-99 scan (detects gastric mucosa) or other imaging (US/CT)
Omphalocele
failure of intestines to return from extraembryonic celom to abdominal cavity at 10 weeks of gestation
Defect in abdominal wall at attachment site of umbilical cord → large sac composed of amniotic membranes filled with loops of bowel
Intestines have peritoneal AND amniotic covering
Typically associated with other congenital malformations
Gastroschisis
bowel protruding from abdomen, but by different mechanism
Due to defect in anterior abdominal wall
NO amniotic covering
Usually an isolated defect, no other malformations
Omphalocele vs Gastroschisis
Omphalocele: intestines have peritoneal AND amniotic covering
-associated with other congenital malformations
Gastroschisis: intestines do NOT have amniotic covering
-Isolated defect
Intestinal malrotation
abnormal rotation and fixation of intestinal tract
Anomaly of large intestine during development
Typically occurs at 10 weeks when intestines returning to abdominal cavity
Present with volvulus of large bowel → obstruction (bilious vomiting)
Gastrointestinal duplications/cysts
saccular (cystic) or tubular structures containing all layers of normal bowel wall and gastrointestinal lining, which may or may not communicate with bowel
Intestinal stenosis
congenital narrowing of bowel
Intestinal atresia
associated with with what congenital abnormality?
complete failure of development causing a blind ending
Associated with down syndrome (duodenal atresia)
Imperforate anus/rectal agenesis
malformation ranging in severity from thin membrane of tissue covering the anus to complete agenesis of rectum
Hirschsprung Disease
Causes congenital megacolon (massive dilation of intestinal lumen) due to failure of bowel nerve plexi (both auerbach and Meissner) to form in a segment of the bowel wall → absence of ganglion cells (ENS neurons)
TX: surgical resection of segment of bowel
Necrotizing Enterocolitis
Complication of prematurity typically associated with hypoxemia
Blood shunted away from intestines to provide scarce oxygen to vital organs → ischemic damage to bowel wall → perforation and peritonitis
Symptoms and treatment of necrotizing entorcolitis
SX: abdominal distension and bloody stools, feeding intolerance
TX: bowel rest, abx, surgical resection if meds fail
Allergic esophagitis: aka eosinophilic esophagitis
what is it?
acid probe test results?
histology?
Immune reaction to dietary allergens
Normal pH probe testing, no response to acid block
Histology: severe eosinophilic infiltrate, typically involves entire length of esophagus with relative uniformity
Reflux Esophagitis
what is it?
acid probe test results?
histology?
inadequate gastroesophageal sphincter function
Abnormal esophageal pH probe testing due to reflux of gastric acid
-Responds to treatment with PPIs
Histology: typically in distal esophagus, mild intraepithelial infiltrate with eosinophils
Sessile vs. pedunculated polyp
Sessile → no stalk, flat base
Pedunculated → polyp on a stalk
Inflammatory polyps
benign or malignant?
how does it form?
How does it present?
benign
Present with bleeding
Cycles of injury and healing result in “polyp” formation = inflamed colonic mucosa with ulceration/erosion, epithelial hyperplasia
Not a precursor to malignancy
Hamartomatous polyps
benign or malignant?
associated with what?
how does it form?
benign - but can increase risk of future GI carcinoma
typically associated with syndromes (juvenile polyposis, Peutz-Jeghers) –> extra-GI symptoms
“tumor-like” overgrowth of mature or developing tissue where it is NORMALLY present
Juvenile polyposis
Type of hamartomatous polyp
sporadic and syndromic
Often have foci of dysplasia
Increase risk of future GI carcinoma
Onset at under 5 years old
Symptoms of Juvenile polyposis
associated with what other cancers?
Symptoms: arborizing polyps (small intestine > colon > stomach), colonic adenocarcinoma
Extraintestinal:
- mucocutaneous pigmented lesions
- increased risk thyroid, breast, lung, pancreas, gonadal and bladder cancers
Peutz-Jeghers Syndrome
increases risk of future GI carcinoma
Onset between 10-15 years
Symptoms: juvenile polyps with increased risk of gastric,small intestinal, colonic, and pancreatic adenocarcinoma
Extraintestinal: pulmonary AVMs, digital clubbing
Hyperplastic polyps
typical location and size?
need to distinguish it from what?
Location: left colon and rectum (90%)
Increased incidence with age
Small in size (less than 0.5 cm)
Need to distinguish from “sessile serrated polyp/adenoma” (SSP) which are premalignant**
Histology of hyperplastic polyps
delayed maturation with overgrowth of superficial epithelium (hyperplasia) resulting in SERRATED architecture
No dysplasia, NOT pre-malignant
Sessile Serrated Polyps/Adenomas
benign or malignant?
typical size and location?
genetic pathway to get these?
Premalignant - can progress to adenocarcinoma
Location: right side of colon most common, larger
Alternate pathway to carcinoma that the usual adenomatous polyp
–> Microsatellite instability pathway
Adenomas
Variable size (can be 10 cm or more)
VERY common - in 50% of Western adults by age 50
Precancerous lesion that can lead to adenocarcinoma
Signs of dysplasia in an adenoma
Increased number of cells piling up on each other Loss of basal-orientation of nucleus Reduced mucin production Reduced cytoplasm Increased mitotic activity
Risk of malignancy in an adenoma
_______ adenomas more invasive then ______ adenomas
_______ is the most important characteristic that correlates risk of malignancy overall
Villous adenomas contain foci of invasion more frequently than tubular adenoma
SIZE
Main molecular pathways associated with colon cancer (4)
1) WNT/APC/B-catenin
2) K-Ras/MAP kinase
3) K-Ras/PI3 kinase
4) Microsatellite Instability: defects in mismatch repair
WNT/APC/B-catenin pathway for colon cancer
classical adenoma-carcinoma sequence
WNT critical for development - WNT ligands drive proliferation of their target tissues/organs
WNT pathway regulates levels of cytoplasmic B-Catenin
Classic pathway from nothing to adenoma to colon cancer?
4 steps
1) Germline (inherited) or somatic (acquired) mutation in APC tumor suppressor gene
2) → 2nd APC inactivation
3) → KRAS proto oncogene mutation
4) → p53 tumor suppressor gene loss with overexpression of COX-2 → Cancer
Risk factors for colorectal carcinoma
Advanced age Obesity FAP/HNPCC Long standing UC Smoking Excessive alcohol
Familial Adenomatous Polyposis (FAP)
APC mutations that are hereditary (AD), Chr5 (polyp has 5 letters!)
APC = component of Wnt signaling pathway, “destruction complex” that turns over B-catenin in absence of WNT ligand signaling
-Mutation in APC –> constiutively active B-catenin –> polyp formation
- 100% develop invasive colon adenocarcinoma by age 30
- Numerous colon polyps
Treatment: preventative colectomy
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
(aka Lynch Syndrome), AD
-Develop colon cancer at an earlier age than sporadic forms - not associated with numerous polyps
Tend to be right sided
Inherit mutation of mismatch repair gene allele → acquire second allele mutation over time leading to MICROSATELLITE INSTABILITY
–> formation of sessile serrated polyps (adenomas) and eventually cancer
Detection of colon cancer (3)
Visualization +/- Biopsy: colonoscopy
Blood detection in stool
DNA/mutation detection in stool
Colorectal carcinoma
invasion of ________ cells beyond ___________
_______ is biggest risk for invasion
invasion of dysplastic epithelial cells into and beyond the lamina propria
SIZE is biggest risk (>4cm = high risk of invasive component in lesion)
Most important prognostic features for colorectal carcinoma
Depth of invasion
Presence or absence of lymph node metastasis
Distant metastasis -
MOST COMMONLY METS TO LIVER***
Cetuximab
EGFR receptor inhibitor that can be used to treat colon cancer with WILD TYPE KRAS tumors
-If KRAS is constitutively activated, inhibiting EGFR will have no effect
KRAS = signaling molecule downstream of EGFR tyrosine kinase receptor
Blood flow through liver (4)
- Hepatic portal vein supplies 75% of (DEOXYGENATED) blood and hepatic artery (branch from celiac trunk) supplies (OXYGENATED) 25% of blood
- Drained by hepatic vein into IVC
- All vessels enter/exit from porta hepatis (hilar region)
- Blood supply completely separated from biliary secretion via tight junctions
Lobes of the liver
Four lobes - each surrounded by fibrous connective tissue (Glisson’s capsule)
Each lobe maximizes contact with blood
Fibrous connective tissue that surrounds liver
Glisson’s capsule
Liver lobules
smallest functional unit within liver, generated by repeated branching of hepatic portal vein and hepatic artery
3 types of liver lobules
- Classic lobule
- Portal lobule
- Acinar lobule
Classic lobule
hexagonal-shaped arrangement of hepatocytes around central vein
Interlobular vessels between lobules carry incoming blood from hepatic portal vein and hepatic artery
- Each vertex has a bile duct and lymphatic space (space of Mall)
- Interlobular vessels + bile duct = portal triad
Portal lobule
triangular shape between three central veins, zone of tissue around a bile duct into which a group of bile canaliculi feed
Bile secretory functional unit
Acinar lobule
short axis between two portal triads and long axis between two central veins
- Defines liver tissue in terms of blood delivery
Distributing branches of interlobular vessels run along “edges” of classic lobule, but run along short axis of acinar lobule
Significance of acinar lobule (3)
- Toxin exposure → degeneration nearest to distributing vessels
- Lack of oxygenation or nutrients → affect hepatocytes nearest central vein
- Most glycogen accumulation in hepatocytes near central acinar lobule (nearest blood supply)
Function of liver
first organ receiving blood from GI system → gets nutrients and toxins
Synthesizes blood proteins, glycoproteins, and lipoproteins, stores glucose from gut (temporarily as glycogen), metabolizes lipid soluble molecules and toxins, involved in urea formation
Arrangement of hepatocytes
Arranged in anastomosing plates or sheets with two sides facing blood sinusoids → every hepatocyte exposed to plasma components
Components of hepatocytes
Contain rough/smooth ER, golgi network, and secretory vesicles + abundant lysosomes, peroxisomes, and lipid droplets
- Smooth ER hypertrophies upon exposure to toxins/alcohol
- Extensive microvilli aiding in absorptive process
Function of hepatocytes (4)
1) Take up glucose after a meal, store it as glycogen, convert glycogen to glucose during fasting periods for reentry into blood
2) Produce major blood proteins (albumin, clotting glycoproteins - fibrinogen/prothrombin, and lipoproteins)
3) Take up lipid soluble toxins, bilirubin from spleen, etc. → detoxify them by biochemically conjugating them
4) Excess cholesterol elimination in bile
Sinusoidal endothelial cells of liver
outside microvillar surface of hepatocytes facing sinusoids
Fenestrated, allow large plasma components and lipoproteins to pass freely
DO NOT permit RBCs to contact hepatocyte surface
Perisinusoidal space
(space of Disse) = space between endothelial cells and hepatocyte
Space contains fine meshwork of reticular fibers → support for sheets of hepatic cells + endothelial cells on top of them
Kupffer cells
derived from monocytes, part of fenestrated endothelial layer adjacent to hepatocytes
Large nuclei, rapidly phagocytose particulate materials
Key role in defense and general removal of particulate material from blood
Bile canaliculi (2)
Formed in between grooves of adjacent hepatocytes forming circumferential belt around each hepatocytes with microvilli extending into canaliculi lumen
Hepatocytes have tight junctions to prevent leakage of bile
Canals of Hering
Small bile ducts where bile canaliculi come together within liver lobule
Surrounded by cuboidal epithelial cells with microvilli projecting into lumen
Interlobular bile ducts
Formed by canals of Hering coming together at the portal triad
Has cuboidal epithelial lining initially → columnar epithelium as ducts fuse toward the porta hepatis to for lobar ducts which connect to form common hepatic duct
Gallbladder
attached to liver surface, connected to common hepatic duct via cystic duct
Common hepatic duct + cystic duct →
Common bile duct
2 bile sphincters
Sphincter chledochus (sphincter of Boyden) - controls bile before entry of pancreatic duct
Sphincter of Oddi - controls bile entry after pancreatic duct
Histology of gallbladder (4)
- Mucosa of the gallbladder: extensively folded
- Columnar epithelium: numerous microvilli, tight junctions, numerous mitochondria, folded basolateral surface (actively transport salt into space between cells, water follows by osmosis → concentration of bile)
- Lamina propria → lymphocytes and plasma cells, loose CT
- Muscularis externa → adventitia and adipose tissue
Jaundice (icterus)
yellowish pigmentation of skin/sclerae, due to abnormally high levels of bilirubin in blood (hyperbilirubinemia)
Normal bilirubin metabolism
RBCs broken down → heme → biburdin → bilirubin released into circulation from spleen
Bilirubin → carried in complex with albumin, into liver → conjugated in liver → makes bilirubin water soluble → excreted in feces
Physiologic jaundice
babies unable to adequately conjugate bilirubin before 2 weeks of age and increased breakdown of fetal RBCs → increased unconjugated bilirubin
Develops gradually in first week of life
Most common cause of neonatal jaundice
Tx of physiologic jaundice
Self-limited, phototherapy can be used to transform bilirubin into isomers that can be excreted in bile and urine
Kernicterus
toxic accumulation of unconjugated bilirubin in neonatal brain
Differential for neonatal jaundice
- Physiologic
- Metabolic disorders
Bile obstruction - Choledochal cyst
- Hereditary
- Idiopathic neonatal hepatitis
- Infection, medication
Metabolic disorders that can cause jaundice
(alpha-1 antitrypsin deficiency, CF, metabolic storage disorders)
Choledochal cyst
congenital dilation of biliary tree and bile stasis
Present before age 10 + jaundice ,abdominal pain, RUQ mass
4 types of hereditary hyperbilirubinemia
- Crigler-Najjar Syndrome
- Gilbert Syndrome
- Dubin-Johnson Syndrome
- Rotor Syndrome
Biliary atresia and two types
causes neonatal cholestasis, number one pediatric disorder requiring liver transplantation
- perinatal
- congenital structural anomaly of biliary tree
Perinatal form of biliary atresia
extrahepatic biliary tree normal at birth and undergoes progressive destruction, more common
Presentation of perinatal biliary atresia
late onset jaundice with progressively acholic stools
No associated anomalies
Diagnosis of perinatal biliary atresia
cholangiogram to assess patency of biliary tree
Treatment of perinatal biliary atresia
hepatoportoenterostomy (Kasai Procedure):
- Excise extrahepatic biliary system and loop of small bowel connected to hepatic hilum to allow for bile drainage
- Best if performed before 2 months
- No non-surgical therapeutic options - liver transplant only
Congenital structural anomaly of biliary tree
abnormal development of biliary tree, associated with other anomalies
Presentation: progressive jaundice immediately AT BIRTH
Hereditary disorders with increased unconjugated bilirubin (20
- Crigler-Najjar (type I and II)
2. Gilbert syndrome
Crigler-Najjar Syndrome
mutation leads to lack of Type I or decrease in Type II UDP-glucuronyltransferase (UGT1A1)
- UDP-Glucuronyltransferase typically conjugates bilirubin to glucuronic acid making water soluble bilirubin glucuronides that are excreted in bile
Type 1 = fatal without liver transplant, no functional enzymes
Type 2 = jaundice, normal life expectancy, decreased enzyme activity
Gilbert syndrome
mild, benign, fluctuating serum bilirubin due to decrease in UGT1A1 activity
Episodic jaundice during physiologic stress (e.g. illness)
Disorders causing increased conjugated bilirubin (2)
- Dubin-Johnson syndrome
2. Rotor syndrome
Dubin-Johnson syndrome
hereditary defect in excretion of bilirubin glucuronides across canalicular membrane due to absence of multidrug resistance protein 2
→ episodic jaundice, normal life expectancy
Benign neoplasms of liver (4)
1) Mesenchymal Hamartoma:
2) Teratoma
3) Hepatocellular adenoma
4) Focal nodular hyperplasia
Mesenchymal hamartoma
Nontender abdominal enlargement over days to months
Vomiting, decreased appetite, respiratory distress
Alpha fetoprotein levels NOT increased
Malignant neoplasms of liver (3)
- Hepatoblastoma
- Hepatocellular carcinoma
- Undifferentiated/embryonal sarcoma
Hepatoblastoma
tumor recapitulates hepatogenesis and arises in an otherwise NORMAL liver (unlike hepatocellular carcinoma)
Presentation of hepatoblastoma (4)
- Enlarged abdomen, anorexia, weight loss, nausea, vomiting, pain
- Elevated alpha-fetoprotein (unlike mesenchymal hamartoma)
- Presents before age 5
- **NOT associated with underlying liver disease
Activation of what pathway is seen in hepatoblastoma
Activation of Wnt/B-Catenin pathway present
Hepatoblastoma incidence increased in which two syndroms
Beckwith-Wiedemann Syndrome and FAP
Tx of hepatoblastoma
preop chemo and surgical resection
MOST important prognostic factor of malignant neoplasms of the liver
STAGE at time of resection
