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Ischemic Bowel Disease
- can be caused by anything that ↓ intestinal blood flow
- an infarcted bowel is edematous & diffusely purple
- extensive hemorrhage is seen in the mucosa & submucosa; is especially prominent in VENOUS occlusions
- ischemic injury usually begins in the mucosa & spreads outward
- within 18 to 24 hours there's a thin, fibrinous exudate over the serosa (most outer layer)
- mucosal surface (most inner layer) shows irregular white sloughs, the wall becomes thin & distended, & bubbles of GAS may be present in the bowel wall & mesenteric veins
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After 24 hours of decreased blood flow to the bowl, what is taking place?
- intestinal bacteria produce outright gangrene & sometimes perforation of the bowel
- the serosal surface is cloudy & COVERED by inflammatory cells
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Adynamic Ileus
- term for when the bowel proximal to the lesion is dilated & filled w/ fluid
- it's smooth muscle cell function is compromised & therefore peristalsis is unable to occur
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Are the boundaries between infarcted & normal tissue more distinct when caused by arterial or venous occlusions?
- boundaries are MORE distinct w/ arterial occlusion
- it's more difficult to differentiate between the 2 tissue types when the ischemia is caused by a venous occlusion
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What is the most common cause/type of Ischemic Bowel Disease?
- acute intestinal ischemia
- occlusion of the Superior Mesenteric artery is the MOST common cause of acute intestinal ischemia
- this is associated w/ injury ranging from mucosal necrosis to transmural bowel infarction
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Why might gradual or unnoticed loss of 1 of the 3 major vessels of the intestine not cause an effect (i.e. Ischemic Bowel Disease)?
because rich anastomoses exist between the Celiac artery, Superior Mesenteric artery, or Inferior Mesenteric artery (the 3 vessels)
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What are the severity 3 levels of Ischemic Bowel Disease?
- 1. mucosal infarction
- 2. mural infarct
- 3. transmural infarction
- mucosal & mural infarcts are secondary to acute or chronic hypoperfusion
- damage to the mucosa & submucosa are less severe in mural & mucosal infarctions
- transmural infarction is generally caused by acute occlusion of a major mesenteric artery
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What are some conditions that can predispose acute arterial obstructions?
- Atherosclerosis
- Aortic aneurysms
- hypercoagulable states
- Oral contraceptive use
- Embolization of cardiac vegetations
- Aortic atheroma (plaques)
- other conditions associated w/ hypoperfusion & bowel ischemia: cardiac failure, shock, dehydration, vasoconstrictive drugs, systemic vasculitides, portal hypertension, compression by masses such as tumors, etc.
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Possible Outcomes of Ischemic Bowel Disease
- recovers w/ complete repair of the lesions OR granulation tissue & fibrosis
- this second way eventually leads to stricture formation
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Celiac Disease (Celiac Sprue, Gluten-sensitive Enteropathy)
- an immune response to gluten in cereals characterized by:
- 1. Generalized malabsorption
- 2. Small intestine mucosal lesions
- 3. Prompt clinical & histopathologic response to the withdrawal of gluten-containing foods from the diet
- found in 0.5–1% of Caucasians w/ European ancestry
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Cells of Celiac's
- dense plasma cell infiltrates in the lamina propria
- T lymphocyte infiltration of the surface epithelium

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General Celiac Characteristics
- blunting or total disappearance of villi
- crypt hyperplasia
- villous atrophy
- leaky epithelium
- ↑ in intraepithelial CD8+ T cells (lymphocytosis)
- ↑ plasma cells, mast cells, & eosinophils in the lamina propria but NOT in deeper layers
- full blown celiac's is characterized by malabsorption
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Major Histocompatibility Complex (MHC)
- cell surface molecules that mediate interactions between T cells & antigens
- also called human leukocyte antigens (HLA) & determine whether a donated organ is compatible for transplant
- genes for the molecule found on the short arm of chromosome 6, Class II (DP, DQ, DR) & Class I (B, C, A)
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What HLA/MHC genes are found in 90% of patients with Celiac Disease?
- HLA-B8
- HLA-DR8
- HLA-DQ2
- these HLA molecules display gluten fragments (gliadin) to immune cells which then direct an attack on the intestinal lining where many of them are lodged
- concordance (the presence of the same trait) in 1st-degree relatives ranges from 8–18%
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What contains most of the disease-producing components?
- Gliadin, a fraction of gluten
- gliadin particles interact w/ the immune system → killing of enterocytes & damage to the mucosal epithelium
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What is the hypothesis behind gluten's activation of an immune response against the small intestine mucosa?
- 1. indigestible fragments of gluten induce enterocytes to release zonulin → LOOSENS tight junctions between mucosal cells
- 2. gluten may move through now opened spaces between cells & accumulate underneath
- 3. enterocytes secrete IL-15 in response to deposited gluten → intraepithelial leukocytes squeeze through mucosa to target area
- 4. tissue transglutaminase (tTG) modifies the gluten, which is now picked up by APCs, presented to T cells, initiating an immune response
- 5. T cell activation occurs, B cells make Ig's to gluten, & damage mucosal enterocytes in the destruction process
 - both innate & adaptive immune mechanisms are involved in the tissue responses to gliadin
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Pseudomembranous Colitis
- infection of the large intestine (colon) by an overgrowth of Clostridium difficile bacteria
- is a type of infectious enterocolitis
- cytotoxin-producing strains of C. diff may overgrow in the gut after use of antibiotics (eg. clindamycin) – is usually a normal gut organism
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leads/manifests as a bare surface epithelium & superficial lamina propria filled w/ NEUTROPHILS
(+ the occasional capillary fibrin thrombi)
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When released, what do C. diff toxin proteins TcdA & TcdB cause?
- disruption of the intestinal epithelial cytoskeleton
- loss of tight junction barriers
- cytokine release
- apoptosis of intestinal epithelial cells
- the production of a DISTINCTIVE PSEUDOMEMBRANE
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C. diff Pseudomembrane
- superficially damaged crypts are distended by a mucopurulent exudate (MUCUS + NEUTROPHULS) that forms a volcano-like ‘eruption’
 - the released exudate coalesces to form the pseudomembrane, a plaque-like adhesion of fibrinopurulent debris & mucus to the damaged superficial mucosa
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Diverticular Disease (Nutrition)
- high intracolonic pressure can cause colonic outpouchings, called Diverticulosis
- if in addition you have poor intestinal transit, things such as food, stool, or bacteria can get stuck in the outpouchings
- DiverticuLITIS: infection & inflammation due to impaction of stool or food particle in colonic outpouchings
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DiverticulOSIS (Diverticular Disease)
- an acquired herniation/diverticulum (outpouching) of the mucosa & submucosa through the muscular layers of the colon
- are generally asymptomatic
- ENVIRONMENTAL factors are primarily responsible for the disease, as shown by how varied its prevalence of is
- ~10% of persons are affected in Western countries
- it increases in frequency w/ age
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What part of the colon is affected in 90% of cases?
- the SIGMOID colon

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Layers of the Intestinal Wall (Inner → Outer)
- 1. Mucosa (Epithelium, Lamina propria, Muscularis Mucosae)
- 2. Submucosa
- 3. Muscularis (Circular, Longitudinal Muscle)
- 4. Serosa (Areolar CT, Epithelium)

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What layers of the intestine are involved in the outpouchings (diverticulum)?
- only the mucosa & submucosa are herniated through the muscle layer (should really be called a pseudodiverticula)
- the base of the diverticulum is the serosal connective tissue
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DiverticuLITIS
- inflammation of the BASE of a diverticulum
- results from irritation caused by retained fecal materials
- is seen in 10–20% of patients w/ diverticulosis
- such infection increases the risk of outpouching perforation
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Crohn's Disease
- chronic, segmental, transmural inflammation of the intestine
- occurs mainly in the DISTAL SMALL INTESTINE but may involve any part of the digestive tract (eg. the colon, esp. the right colon)
- appears in adolescents or young adults, most common among persons of European origin
- has a higher frequency in the JEWISH population
- slight female predominance (1.6 : 1)
- a type of IBD (Inflammatory Bowl Disease, which is also a type IV hypersen rxn)
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What factors play a part in the pathogenesis of Crohn's Disease?
1. Genetic: a family history of IBD, mutation of NOD2/CARD15 gene
2. Immunologic: chronic/recurrent inflammation, mucosal immune response, immunosuppression
3. Epithelial: defective trans-epithelial transport
4. Microbial: not well understood
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What layers of the intestine wall are usually involves in Crohn's Disease?
- it's a TRANSmural inflammatory disease, so inflammation usually involves ALL layers of the bowl wall
- mucosal damage is SHARPLY delimited
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Is involvement of the intestine continuous or discontinuous with Crohn's Disease?
- DISCONTINUOUS
- segments of inflamed tissue are separated by apparently normal intestine (SKIPPED lesions)
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The presence of what inflammatory processes is indicative of Crohn's Disease?
- Non-caseating Granulomas
- are present in 40–60% of cases
- can be present anywhere in the GI tract, even if the disease is limited to one bowel segment
- also Crohn's Disease can exist w/o granulomas present
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4th Important Characteristic of Crohn's Disease
fissuring (linear tear) & the formation of fistulae (abnormal connections between two epithelium-lined organs or vessels)
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Gross Description of Crohn's Disease
- thickened bowl wall
- edema & fibrosis of ALL (transmural) layers
- “creeping fat”: mesenteric fat often wraps around the bowel
- a NARROWED intestinal lumen due to the edema & fibrosis
- “cobblestone” appearance b/c of the nodular swelling, fibrosis, & mucosal ulcerations
- early lesions = aphthous ulcers (canker sores)
- ulcers later become deeper & appear as linear clefts or fissures

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Microscopic Description of Crohn's Disease
- 1. NEUTROPHIL infiltration into epithelium & accumulation in crypts → crypt abscesses
- 2. ULCERATION
- 3. CHRONIC MUCOSAL CHANGE: distortion, atrophy, & metaplasia
- 4. transmural, nodular LYMPHOID aggregates
- 5. GRANULOMAS
 - blue = lymphoid aggregates btwn the mucosa & submucosa
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Symptoms of Crohn's Disease
- 1. Abdominal pain & Diarrhea: these are the MOST frequent symptoms (are in 75% of patients)
- 2. Fever (50% of patients)
- 3. Malabsorption
- 4. Colonic Bleeding
- are highly variable
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What are the most common complications of Crohn's Disease?
- intestinal obstruction
- fistulas (abnormal connections between two epithelium-lined organs or vessels)
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What types of cancers are people with Crohn's Disease prone to?
- Small Bowel Cancer is 3x more common in people w/ Crohn's
- Colorectal Cancer
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Ulcerative Colitis (AUTOIMMUNITY) UC
- a chronic superficial inflammation of the colon & rectum
- characterized by chronic diarrhea & rectal bleeding
- presents as a pattern of exacerbation & remission
- can have serious local & systemic complications
- cause is UNKNOWN but most of the factors implicated in Crohn's Disease are implicated in UC
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What 3 major pathologic features characterize UC & help differentiate it from other inflammatory conditions?
- 1. it's a diffuse disease: extends from the distal part of the rectum for a variable distance proximally
- • it almost always involves the rectum
- • therefore it rarely only involves the right side of the colon ALONE

- 2. inflammation is generally limited to the colon & rectum
- • it rarely involves the small intestine, stomach, or esophagus
- 3. it's essentially a mucosal disease
- • deeper layers are rarely involved (only in EXTREME cases or w/ Toxic Megacolon)
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General UC Symptoms
- most patients (70%) have intermittent attacks w/ partial or complete remission in between
- symptoms are VERY variable
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Clinical Features of Mild Ulcerative Colitis
- rectal bleeding
- rectal pressure
- discomfort
- 50% of patients w/ UC have mild colitis
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Clinical Features of Moderate Ulcerative Colitis
- loose bloody stools
- some anemia (from the chronic fecal blood loss)
- crampy abdominal pain
- low-grade fever lasting days or weeks
- 40% of patients w/ UC have moderate colitis
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Clinical Features of Severe Ulcerative Colitis
- severe or fulminant episodes, often during a flare of activity
- may be more than 6 & sometimes more than 20 bloody bowel movements daily, often w/ fever and other systemic manifestations
- dehydration, anemia, & electrolyte depletion from blood and fluid loss
- massive hemorrhage may be life threatening
- 10% of patients w/ UC have severe colitis
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Toxic Megacolon
extreme dilation of the colon & an associated risk of perforation that is a dangerous complication of Ulcerative Colitis
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Fulminant Ulcerative Colitis
- a medical emergency that requires immediate intensive therapy & possible colectomy
- affects the entire colon
- ~15% of patients w/ Fulminant UC die of the disease
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People with long-standing (Advanced) Ulcerative Colitis have a higher risk of what disease than the general population?
Colorectal Cancer :(
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Early Ulcerative Colitis
- a raw, red, & granular mucosal surface that's frequently covered w/ a yellowish exudate & bleeds easily
- superficial erosions or ulcers may be present
- mucosal congestion
- edema
- microscopic hemorrhages
- diffuse chronic inflammatory infiltrate in the lamina propria
- damage & distortion of the colorectal crypts, which are often surrounded & infiltrated by NEUTROPHILS
- suppurative necrosis of the crypts → crypt abscess: appear as dilated crypts filled w/ NEUTROPHILS
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Crypt Abscess
- typical of Ulcerative Colitis (& mentioned in Crohn's Disease)
- a collection of pus in in the mucosa of the large intestine
- causes swelling & inflammation around it

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Progressive Ulcerative Colitis
- Inflammatory Polyps: formed from crypt abscesses joining (this undermines the mucosa leaving areas of ulceration adjacent to hanging fragments of mucosa)
- NO strictures
- granulation tissue develops in denuded (bare) areas
- loss of mucosal folds; atrophic mucosa
- tortuous & branched colorectal crypts
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Advanced (Long-standing) Ulcerative Colitis
- shortened large bowel, esp. the LEFT side
- mucosal folds are indecipherable → have been replaced by a granular or smooth mucosa
- the mucosa is atrophied & there's a chronic inflammatory infiltrate in the mucosa + superficial submucosa
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HOW TO TELL THE DIFFERENCE BETWEEN CROHN'S DISEASE & ULCERATIVE COLITIS
- Crohn's: lesions skip around, don't affect a part of the colon uniformly
- also inflammation is TRANSMURAL (affecting ALL layers of the intestine), includes ulcerations & fissures
 - Colitis: there is continuous, chronic involvement that starts in the rectum → proceeds up the left (descending) colon
- inflammation manifests as pseudopolyps (b/c not all layers are involved) & also ulcers
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Crohn's v. Ulcerative Colitis Distribution Pattern
- Crohn's
- • distr. pattern: lesions happen discontinuously/non-uniformly throughout the small or large intestine & cause STRICTURES
- • ulcer conformation: LINEAR (fissures through most layers)
- • wall thickenings: transmural inflammation (all layers thicken)
- Ulcerative Colitis
- • distr. pattern: lesions happen continuously starting in the rectum & are generally in the large (left) colon
- • ulcer conformation: SUPERFICIAL (only in mucosa mostly)
- • wall thickenings: pseudopolyps that only really involve the mucosa (& submucosa if advanced)

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Non-neoplastic Polyps of the Small & Large Intestine
most of intestinal polyps occur sporadically, particularly in the colon, & ↑ in frequency w/ age
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What percentage of all epithelial polyps in the large intestine are non-neoplastic?
- 90%
- are found in more than half of all people 60 or older
- are found in more than half of all people 60 or older
- MOST are hyperplastic polyps, small (<5mm dia.), nipple-like, hemispherical, smooth protrusions of the mucosa found in the rectosigmoid region
- these generally have no malignant potential

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However what kind of hyperplastic polyps may HAVE malignant potential?
- Sessile Serrated Adenomas
- these tend to be found on the Right side of the colon & may be precursors of Colorectal Carcinomas
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Adenomatous Polyps
- premalignant lesions that arise from the mucosa
- 50% are found in the RECTOSIGMOID region
- appearance varies from a barely visible nodule, a small, pedunculated adenoma, or a large, sessile (flat) adenoma
- classified as Tubular, Villous, or Tubulovillous

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Tubular Adenomas
- smooth-surface lesions, often have a stalk covered by normal colonic mucosa
- head is composed of neoplastic epithelium, forming branching glands lined by tall, hyperchromatic, somewhat disorderly cells, which may or may not show mucin secretion
- DYSPLASIA may be encountered, ranging up to cancer confined to the mucosa (intramucosal carcinoma) or invasive carcinoma extending into the submucosa of the stalk
- risk of invasive carcinoma is correlated to the size of the tubular adenoma

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Villous Adenomas
- are large, broad-based, elevated lesions w/ a shaggy, cauliflower-like surface found predominantly in the rectosigmoid region
- most are larger than 2 cm in diameter
- 10% of colonic adenomas belong to these type
- composed of thin, tall, finger-like processes that superficially resemble the villi of small intestines
- there can be variable degrees of dysplasia

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Which contains foci of carcinomas more often, Tubular or Villous adenomas?
- VILLOUS adenomas do
- more than 1/3 of all resected villous adenomas contain invasive cancers
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Tubulovillous Adenomas
- have both tubular & villous features (duh)
- polyps w/ more than 25% & less than 75% villous architecture are termed tubulovillous
- such polyps have an intermediate risk of developing invasive carcinoma between tubular & villous adenomas
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Risk Factors for Colorectal Cancer
- increasing age
- chronic Inflammatory Bowel Disease
- prior colorectal cancer
- diet
- genetics: persons w/ 2 or more 1st or 2nd degree relatives w/ colorectal cancer constitute 20% of all patients that develop the disease
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What percentage of all colorectal cancers are inherited as autosomal dominant traits?
5 – 10%
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Adenocarcinomas of the colon & rectum are an example of what type of carcinogenesis?
- MULTISTEP
 - APC = tumor suppressor gene (makes Adenomatous polyposis coli proteins)
- DCC = Deleted in Colorectal Carcinoma, a protein encoded by the DCC gene
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Colorectal Cancers
- tend to be polypoid & ulcerating or infiltrative and may be annular & constrictive
- majority of cases are adenocarcinomas
- 10 – 15% secrete large amount of mucin & are called Mucinous Adenocarcinomas
 - adenocarcinoma of the colon presents as an ulcerated mass w/ enlarged, firm, rolled borders
- can also present w/ malignant glands that have prominent cribriform pattern & frequent central necrosis
- these can infiltrate into the muscle wall
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How is Colorectal Cancer spread?
- by direct extension or vascular/lymphatic invasion
- the LIVER is involved in its metastasis in most patients
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What is the MOST common sign of Colorectal Cancer?
- occult (hidden) blood in the feces
- there also may be obstructive symptoms, especially w/ cancers on the left side of the colon
- cancers on the right side can grow to a large size W/O causing symptoms
- also due to the chronic asymptomatic bleeding, Iron-deficiency Anemia* can be a first indication of colorectal cancer
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Appendicitis
- inflammatory disease of the wall of the vermiform appendix → transmural inflammation & perforation w/ peritonitis (if untreated)
- acute = obstruction of its orifice w/ secondary distention of the lumen & bacterial invasion of the wall
- the organ is congested, tense, & covered by a fibrinous exudate
- its lumen often contains purulent material
- a fecalith (hardened feces) may be present
- the entire wall becomes infiltrated w/ NEUTROPHILS, which eventually reach the Serosa
- perforation of the wall releases the luminal contents into the peritoneal cavity
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