Unit 3 Pathology

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Gastric Pathology

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Unit 3, Week 21 (2)

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Acute Gastritis

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transient mucosal inflammatory process. In more severe cases may be mucosal erosion, ulceration, hemorrhage, hematemesis, melena, or rarely, massive blood loss

M: surface epithelium inftact
signs of inflammation (neutrophils, moderate edema, slight vascular congestion)

Front 3

Curling Ulcer

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Acute Gastric ulceration
occurs in proximal duodenum
associated w/ severe burns or trauma
Present w/ chest pain or epigastric pain

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Cushings Ulcer

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Acute Gastric Ulceration
Gastric, duodenal, and esophageal ulcers arising in persons w/ intracranial disease (stroke)
high incidence of perforation

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Stress Ulcers

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common in individuals w/ shock, sepsis, or severe trauma

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Causes of Mild Gastric Injury
(acute and chronic gastritis)

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H. pylori infection
NSAID
Aspirin
Cigarettes
Alcohol
Gastric hyperacidity
Duodenal-gastric reflux

Ischemia
Shock
Delayed Gastric Emptying
Host Factors

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NSAID - induced ulcers

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cyclooxygenase inhibition
prevents synthesis of prostaglandins (which enhance bicarbonate secretion, inhibit acid secretion, promote mucin synthesis, and increase vascular perfusion)

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Ulcers associated w/ intracranial injury

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caused by direct stimulation of vagal nuclei (which causes hypersecretion of gastric acid)
Frequently find systemic acidosis, causing mucosal injury by lower intracellular pH of mucosal cells

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Hypoxia and reduced blood flow ulcers

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Stressed induced splanchnic vasoconstriction

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Acute Gastric Ulcers

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Rounded
Less than 1 cm in diameter
Base stained brown/black by acid digestion or extravasated blood
May be associated w/ transmural inflammation and local serositis
Sharply demarcated
Normal adjacent mucosa
Found anywhere in stomach (often multiple in stomach and duodenum)

Front 11

Chronic Gastritis
due to H. pylori -> Peptic Ulcer Disease

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long-standing gastric mucosal inflammatory process secondary to H. pylori (number 1 cause of chronic gastritis)

predominantely antral gastritis
Increased to slightly decreased Acid production
Normal to decreased Gastrin

G: erythmatous and nodular, punched out lesions

M: spiral shaped bacilli concentrated w/in surface mucus and pits, neutrophils, lymphocytes, macrophages

Dx w/ serologic test for H. pylori antibodies, fecal bacterial detection, urea breath test, gastric biopsy

Tx w/ combo of antibiotics & proton pump inhibitors, bismuth

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H. pylori
4 virulence features

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Flagella - allow bacteria to be motile in viscous mucus
Urease - generates ammonia f/ endogenous urea & thereby elevates local gastric pH
Adhesins - enhance bacterial adherence to surface foveolar cells
Toxins - involved in ulcer/cancer development (eg CagA)

Front 13

Urea Breath Test

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considered in pts <55 yo presenting w/ dyspepsia w/ suspicious features suggestive of upper GI malignancy
Very sensitive and Specific for presence of active H. pylori infection
PPIs, bismuth, and antibiotics can interfere w/ test

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Chronic Auto-immune Gastritis

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Caused by Antibodies (CD4+T) to parietal cells (secretes gastric acid & intrinsic factor). Results in hypergastrinemia and hyperplasia of antral gastrin-producing G cells. No intrinsic factor disables ileal vit B12 absorption (pernicious anemia), Reduced serum pepsinogen I concentration results from chief cell destruction.
Decreased Acid production
Increased Gastrin

G: diffuse mucosal damage of oxyntic (acid-producing) mucosa w/in body & fundus, loss of rugae

M: lymphocytes, macrophages, plasma cells. glandular atrophy

PTs may also exhibit other auto-immune disorders like Hashimoto thyroiditis, insulin-dependent (type 1) diabetes mellitus, Addison ds, primary ovarian failure, primary hypoparathyroidism, Graves ds, vitiligo, MG, Lambert-Eaton

Front 15

Peptic Ulcer Disease

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Defects in GI mucosa that extend thru muscularis mucosae

Developes on the background of chronic gastritis

common in 1st portion of duodenum and gastric antrum, may also occur in esophagus as a result of GERD.

G: round to oval, sharply punched out lesion
commonly solitary
smooth base

M: < 0.3 cm in diameter
base may have a thin layer of fibrinoid debris underlaid by a neutrophilic inflammatory infiltrate and beanth this an active granulation tissue infiltrated w/ mononuclear leukocytes and a fibrous/collagenous scar

CF: epigastric burning/aching pain, anemia, hemorrhage, performation. pain 1-3 hours after meals, worse at night. relieved by alkali or food. nausea, vomiting, bloating, belching, and significant weight loss

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Gastritis cystica

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exuberant reactive epithelial proliferation associated w/ entrapment of epithelial-lined cysts.
In submucosa - gastritis cystica polyposia
In deeper layers of gastric wall - gastritis cystica profunda
Risk factors - chronic gastritis, trauma, prior surgery (partial gastrectomy)

variable age, stomach body, affects mucous & cyst-lining, neutrophils & lymphocytes, Chronic gastritis Sxs

No association w. adenocarcinoma

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Zollinger Ellison syndrome

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caused by gastrin-secreting tumors (gastrinomas) in small intestine or pancreas
50 yo
fundus
preital cells
neutrophils
Peptic ulcers
Risk factors - multiple endorine neoplasia (pancreas)
No association w/ adenocarcinma

Front 18

Menetrier Disease

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Hypertrophic gastropathy - lots of rugal folds due to epithelial hyperplasia w/o inflammation
Caused by excessive secretion of TGF-a
30-60 yo
body & fundus
affects mucous
lymphocytes
Sxs: hypoproteinemia, weight loss (mal-absorption), diarrhea
No risk factors
Associated with ADENOCARCINOMA

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Inflammatory & Hyperplastic Polyps

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50-60 yo
antrum > body
affects mucous
neutrophils & lymphocytes
Chronic gastritis Sxs
Risk factors - chronic gastritis, H. pylori
Occasionally associated w/ adenocarcinoma

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Hyperplastic polyp

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small gastric polyps
proliferation of gastric epithelium
sometimes stalk is present w/ fibrovascularization
corkscrew shaped foveolar glands

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Inflammatory polyp

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M: nests of lymphocytes, fibrosis, and eosinophils
G: bright red rugae

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Fundic Gland Polyp

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50 yo
body and fundus
affects parietal and chief cells
no infammatory cells
Sx: none or nausea
Risk factors - PPI use (possible increased gastrin secretion in response to reduced gastric acidity), Familial adenomatous polyposis
M: well-circumscribed lesions w/ a smooth surface. may be single of multiple. cystically dilated glands lined by parietal, chief, and foveolar cells

Front 23

Gastric Adenoma

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50-60 yo
Antrum > Body, solitary lesions less than 2 cm in diameter
M: epithelial dysplasia, intestinal-type columnal epithelium
Risk factors: Familial adnenomatous polyposis, chronic gastritis

Front 24

Gastric Adenocarcinoma

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most common malignancy of stomach, associated w/ low fiber diet and dietary carcinogens (preservations). Reduce risk by eating green, leafy veggies and citrus fruits (antiox, vit C & E & beta carotene)

Diffuse gastric cancer: loss of E-cadherin fx (endoded by CDH1 gene mutations), also BRCA2 mutations.
Familial Intestinal-type Gastric Cancer: interaction b/w host genetic background and environmental factors
Sporadic Intestinal-type Gastric Cancer: Mutations in B-catenin; microsatellite instability and hypermethylation of several genes incl TGFBRII !!!, BAX, IGFRII, & p16/INK4a

M: Intestinal (bulky tumor) or Diffuse (infiltrative growth pattern)

Associate w/ Virchow's nodes (palpable L supraclavicular lymphnode)

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Intestinal type Adenocarcinoma

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G: bulky, exophytic mass, ulcerated tumor. Multilobular (non-polyp looking, no defined border). Exofidate (coming outward)
M: columnar, gland-forming cells lacking stroma in b/w. Blue zone of mytotic activity

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Signet-ring (diffuse) adenocarcinoma

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Diffuse: plastic texture, rugal flattening, "leather bottle" appearance (linitis plastica)

Diffuse: Signet-ring cells w/ large cytoplastic mucin vacuoles and cresent-shaped peripheral nuclei

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Carcinoid

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well-differentiated neuroendocrine carcinomas arising f./ diffuse components of the endocrine sys.

E/P: endocrine cell hyperplasia, chronic atrophic gastritis, and Zollinger Ellison

G: Commonly in appendex and small intestine. Tracheobronchial tree and lungs next most common sites.
Intramural/submucosal masses that create small polypoid lesions. Yellow/tan

M: islands/clusters of small blue cells sep by thin stronma, angular cells w/ lots of nucleus

CF: wheezing, recurrent watery diarrhea, colicky abdominal pain

Front 28

Gastro-intestinal stromal tumors

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mesencymal neoplasms of the stomach.
60 yo
gain of fx mutations of gene encoding tyrosine kinase c-KIT
G: large, solitary, well-circumscribed, fleshy mass covered by ulcerated or intact mucosa, star, whorled texture
M: elongated cells

PT w/ unresectable, recurrent, of metastatid ds often repond to Imatinib (tyrosine kinase inhibitor)
related to Carney triad - nonhereditary syndrome seen primarily in young females that incl gastric GIST, paraganglioma, and pulmonary chondroma

Front 29

Gastroparesis

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slowing of GI movement
common in diabetics w/ peripheral neuropathy.

Front 30

Immunology of Diarrhea
(chronic diarrhea)

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Unit 3, Week 22 (3)

Front 31

Define Diarrhea

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Daily stool production in excess of 250 mg, containing 70-95% water, resulting in an increase amount of stool volume, fluidity, and/or frequency.

Front 32

Define Dysentery

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painful, bloody diarrhea that usually shows low stool volume.

Front 33

Small bowel histology
Name the layers from inside to out

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Mucosa - villous, lamina propria, crypts
Submucosa
Muscularis Propria - Circular and long
Serosa

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Large bowel histology

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same as small bowel except doesn't have villi

Front 35

Secretory Diarrhea

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Diarrhea that occurs w/ net intestinal fluid secretion > 500 ml/day.
“watery” diarrhea - Can be watery or bloody or both
Isotonic w/ plasma.
Persists during fasting.

Etiologies: Viral infectious enterocolitis, Bacterial enterocolitis (enterotoxin mediated), or Neoplastic (tumor secreting diarrhea causing hormones, neuroendocrine tumors)

Usually due to intrinsic intestinal secretions.

Front 36

Secretory Diarrhea
Viral enterocolitis

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Examples: Rotavirus, Norwalk viruses, enteric adenoviruses, Caliciviruses, and Astro viruses.
Morphology:
Small intestine show modestly shorter villi.
Lamina propria inflammation (mostly lymphocytic).
Virus particles sometimes are seen by electron microscopy.
Clinical features:
Diarrhea, anorexia, headache, and fever.
Symptoms may start from hours to several days.
Acute illness lasts one to seven days (depending on virus).

Front 37

Secretory Diarrhea
Bacterial enterocolitis (enterotoxin mediated)
3 mechanisms of producing GI diseases

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1.) Preformed toxin (Staphylococcus aureus & vibrios).
Explosive diarrhea, abdominal pain within hours.
Secretory diarrhea - watery
2.) Make toxins (enterotoxigenic E. coli - traveler’s diarrhea).
Acute / chronic diarrhea, abdominal pain within day(s).
Secretory diarrhea – watery, may be bloody
3.) Invade and destroy mucosal epithelial cells (Shigella)
Acute / chronic diarrhea, abdominal pain w/in day(s).
Exudative diarrhea – bloody, purulent and painful

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Osmotic Diarrhea

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occurs when osmotic forces exerted by luminal solutes lead to > 500 ml stole/day.
Mucosa functions normally
Stops during fasting.
“watery” diarrhea
exhibits an osmotic gap (stool osmolality electrolyte [ ] >50 mOsm).

Front 39

Disaccharidase deficiency (lactose intorerance)

results in osmotic diarrhea

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Deficiency of apical membrane enzyme of surface absorptive cells that cleaves lactose
inability to absorb lactose
CP: After intake of dairy products develop: abdominal bloating, abdominal cramps, diarrhea, floating stools, foul smelling stools, gas (flatulence), malnutrition, nausea, slow growth (children), and weight loss.
Tx: Remove dairy products from diet; lactase enzymes can be taken in capsule or chewable tablet form.

Front 40

Exudative Diarrhea

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Occurs w/ purulent, bloody stools.
Persist even after fasting.
Presents with frequent stools w/ variable volume.

Etiologies
Idiopathic Inflammatory Bowel Disease and Infectious Diarrhea (Shigella, Salmonella, Campylobacter, Entamoeba histolytica)

Front 41

Inflammatory bowel disease (IBD) refers to what two chronic inflammatory diseases of GI tract ?

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Ulcerative colitis & Crohn's disease.

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Ulcerative Colitis
IBD

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Affects Large Intestine (rectum and extends proximally)
Involves Inner mucosal & submucosal of bowel wall
Painless
bloody diarrhea, chronic diarrhea (or both), lower abdominal pain, fecal urgency and extraintestinal manifestations.
Toxic megacolon can occur with associated risk of perforation. Bowel adenocarcinoma is a complication in 3% to 5% of patients.
Radiologic Features: loss of haustral folds, lead-pipe appearance, pseudopolyps
Strong Risk: FHx, HLA-B27, Infection (enteritis due to pathogens causes 50% of relapses)
Weak Risk : NSAIDs

Front 43

Crohn's Disease
IBD

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Affects Small Intestine
Transmural involvment (entire bowel wall)
Provokes irritation of bowel wall nerves -> PAIN
Presents as chronic diarrhea, weight loss, and right lower quadrant abdominal pain (mimic acute Appendicitis)
Radiologic Features: Cobblestone mucosa, assymetric involvement (string sign), Fistulas, Skip lesions
Strong Risk: American Jewish and those w/ family Hx
Weak Risk: cigarette smoking, oral contraceptives, not breastfed, NSAIDS

A fat granny and an old crone skipping down a cobblestone road away from the wreck

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Extraintestinal involvement (A PIE SAC) of Crohn's disease

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Aphthous ulcers (canker sores in mouth)
Pyoderma gangrenosum (inflammation in legs)
Iritis (Uveitis)
Erythema nodosum (red nodules under skin, commonly on shins)
Sclerosing cholangitis
Arthritis
Clubbing of fingertips

Front 45

What 4 events contributes to increased bacterial exposure in PTs w/ intestinal inflammation

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1) disruption of the mucus layer
2) dysregulation of epithelial tight junctions
3) increased intestinal permeability
4) increased bacterial adherence to epithelial cells

Front 46

What was the 1st identified susceptibility gene for Crohn's Disease?

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Nucleotide binding oligomerization domain NOD2 (CARD15)
'intracellular' pathogen recognition receptor

CARD15 mutations result in defective clearance of intracellular bacteria and impiared immune responsiveness to bacterial components in human intestinal epithelium

Front 47

In Inflammatory bowel disease, what do innate cells produce increased levels of?

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TNF-a, IL-1B, 6, 12, 23, and chemokines

Front 48

Describe the cycle of inflammation seen in IBD seen w/in the expanded lamina propria of the intestinal epithelia.

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increased CD4+T cells -> secrete increased levels of cytokines and chemokines, -> recruitment of additional leukocytes -> cycle of inflammation

Front 49

Anti immunologic therapeutic approaches to inflammatory bowel disease are by inhibiting_(3)_ also _(3)_

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1) proinflammatory cytokines
2) entry of cells into intestinal tissues
3) T-cell activation and proliferation

1) blockade of costimulatory signals that enhance interactions between innate cells and adaptive cells
2) administration of epithelial
growth factors
3) enhancement of tolerance

Front 50

Prevalent serological marker in Crohn's Disease

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ASCA+
(Si Crohn's)

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Prevalent serological marker in Ulcerative colitis

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p-ANCA+
(nay Crohn's)

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Less specific IBD treatments include _(4)_?

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dietary changes,
antibiotics and anti-inflammatory medications,
surgeries to relieve fistulas

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infliximab

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monoclonal antibody against TNF-a

Front 54

Deranged motility of GI tract
Definition

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altered motility of bowel (increased to decreased peristalsis),
variable stool content and frequency (diarrhea or constipation),
diagnosed after the other types of diarrhea are excluded

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Etiologies
(4 types)

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Irritable Bowel syndrome,
Post GI intestinal tract surgical procedures cause less time to transit thru bowel (Short bowel syndrome, Hemigastretectomy, Blind loop syndrome, Ileo-cecal valve resection)
Diabetic neuropathy & Hyperthyroidism affect nerves
Carcinoid syndrome affect hormones

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Irritable Bowel Syndrome (IBS)
Definition and clinical presentation

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functional bowel disorder characterized by chronic abdominal pain & discomfort that occurs for at least 3 days of the week for a period of 3 months.
Abdominal discomfort in the absence of any detectable organic cause.
Relieved by defecation through diarrhea or constipation or both

Front 57

IBS
Epidemiology

Back 57

prevalence of disease highest in Mexico (45%)
US (15%)
lowest in Canada (5%)

Front 58

IBS
Etiology & pathogenesis

Back 58

Unkown cause, but may be related to stress
Usually doesn't progress to serious complications

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IBS
Morphologic features and Treatment

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M: No radiographic or pathologic abnormalities identified
TX:
No cure for IBS
Attempt to relieve SXs by dietary adjustments, medications & psychological interventions.
Patient education & a good doctor-patient relationship are also important.

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Malabsorption Diarrhea

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an inability to absorb nutrients from the GI lumen b/c Mucosa is NOT functioning properly.
Results in voluminous, bulky stools with excess fat (yellow and floats) and osmolarity
Can have bloating, flatulence, & foul smelling stools
Better with fasting

Front 61

Etiologies for malabsorption
(7)

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Gluten-sensitive enteropathy
Whipple’s disease
Eosinophilic gastroenteritis
Pancreatic Insufficiency
Intraluminal bile salt deficiencies
Parasitic infestation
Drug induce

Front 62

Gluten-Sensitive Enteropathy (Celiac Sprue)
Definition, Clinical Features, and Epidemiology

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Def: autoimmune disorder of small intestine occuring in genetically predisposed people of all ages, caused by a reaction to GLIADIN (a protein found in wheat, barley, and rye).
Leads to malabsorption of nutrients, minerals and fat-soluble vitamins A, D, E and K
CF: abdominal pain/distention, vomiting, diarrhea, weight loss (or stunted growth in children, progressive cachexia), fatigue after ingestion of gliaden containing products, iron-deficiency anemia, osteoporosis, dermatitis herpetiformis, neuological dysfunction
Epi: African, Japanese & Chinese descent are rarely diagnosed

Front 63

Celiac Sprue
Diagnosis, Morphology, and Treatment

Back 63

DX:
serology shows (+) IgA antibodies to gliaden & endomysium (EMA, a structure of the smooth m ct), & autoantibodies to transglutaminase 2 (TG II)
Must be confirmed by duodenal biopsy and histology
Endoscopic Morphology: scalloping of the small bowel folds; paucity in the folds; mosaic pattern to the mucosa (described as a "cracked-mud" appearance); prominence of the submucosa blood vessels, and a nodular pattern to the mucosa
Microscopic: lymphocytes, proliferation of crypts of Lieberkuhn, and partial/complete villous atrophy

TX: gluten-free diet

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Celiac Sprue Risk Factors

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Strong:
FHx
IgA deficiency
Type 1 diabetes
Autoimmune thyroid disease

Weak: Inflammatory bowel disease (mores so in PTs w/ Crohn's than Ulcerative colitis)

Front 65

Whipple’s Disease

Back 65

Caused by gram(+) bacillus Tropheryma whipplei
CP: diarrhea, steatorrhea, abdominal pain, weight loss, bloating, fever, fatigue, arthralgia (periodic joint pain), CNS (neurologic SXs), and cardiac problems
M:
Endoscopic findings: internal sores & thickening of villi, which takes on an abnormal, clublike appearance.
Pathology: Lamina propria of small bowel is expanded by “foamy” histiocytes; PAS stain shows macrophages containing organisms (also outside macrophages is indicator of active disease); EM & PCR studies can also be used.
TX: long-term antibiotics
outcome for most PTs are good, but fatal if left untreated
most SXs disappear in ~1month, but relapse is common

Front 66

Eosinophilic Gastroenteritis (EG)

Back 66

Def: heterogeneous condition characterized by patchy or diffuse eosinophilic infiltration of gastrointestinal (GI) tissue.
Possible Food allergy & IgE response to food substances (hypersensitivity)
Epi: rare, more in males (30-50yo)
Etiology/Path: unkown
possibly parasites, allergies, drugs, neoplasm
affect mostly stomach > small intestine > colon
CP: abdominal pain, nausea, vomiting, diarrhea, weight loss
DX: exclude parasites via stool samples, somtimes see peripheral blood eosinophilia & elevated serum IgE
TX: corticosteroids, 90% response rate but relapses are often seen

Front 67

How can HIV and AIDs can cause Inflammation & Diarrhea

Back 67

HIV infects CD4+T cells -> lack of immune cells to fight of pathogens in GI tract -> opportunistic pathogens attack