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Flashcards in Diarrhea Quiz Lectures Deck (195):
1

secretory diarrhea

characterized as an infection of the proximal small bowel marked by watery diarrhea that does NOT contain fecal leukocytes. Viruses that cause gastroenteritis do not infect the colon

2

Rotavirus Clinical presentation:

gastroenteritis

3

Norwalk Virus (Norovirus) Clinical presentation:

gastroenteritis

4

Adenovirus Clinical presentation:

gastroenteritis (do not confuse with other serotypes of adenoviruses that cause respiratory tract infections)

5

Rotavirus Pathology:

transmitted via the fecal to oral route. After ingestion of the virus it travels in the GI tract (the virus particle is stable within the low pH of the gastrointestinal system) to eventually infect the villus cells of the proximal small intestine. Here the virus replicates within these cells eventually lysing these cells which leads to the impaired adsorption of carbohydrates and other nutrients. This can lead to vomiting followed by watery diarrhea.

6

Norwalk Virus (Norovirus) Pathology:

fecal to oral transmission usually through direct contact or through contaminated food and water. Causes a local infection and inflammation in the proximal small intestine.

7

Adenovirus Pathology:

fecal to oral transmission. Causes a local infection and inflammation in the proximal small intestine. If inhaled into the lungs some respiratory symptoms can be present.

8

Rotavirus Diagnosis:

stool specimen, serology for the virus. Electron microscopy and RT-PCR also possible.

9

Norwalk Virus (Norovirus) Diagnosis:

not typically done. When done it is through visualization of the virus in stool specimens or PCR/serology of stool and/or vomit specimens.

10

Adenovirus Diagnosis:

PCR detection of the viral genome within a stool sample

11

Rotavirus Treatment:

rehydration (supportive). There is a rotavirus vaccine (live oral attenuated).

12

Norwalk Virus (Norovirus) Treatment:

usually not required because it is self-limited. When done, treatment consists of rehydration (supportive) if there is severe fluid loss. Outbreaks can be minimized through proper food handling, clean water supplies, and hand washing.

13

Adenovirus Treatment:

self-limiting infection in immunocompetent individuals. Supportive care only.

14

Rotavirus

because rotaviruses cause no inflammation, diarrhea has no blood. Infection before 6 months of age is uncommon due to passive IgA immunity from the mother’s colostrum. However, by age 3, almost every individual worldwide (~95%) has been infected and develops lifelong immunity. Virus particle contains a double-layered capsid.

15

Norwalk Virus (Norovirus)

this virus is a major cause of group-related or institutional diarrhea.

16

Adenovirus

major cause of acute infantile gastroenteritis. These serotypes of adenoviruses rarely cause fever or respiratory tract symptoms.

17

bifidobacteria

are among the first colonizers in breast-fed infants

18

Staphylococcus aureus

Gram +
Cocci
Catalase +
Coagulase +
Also a common infectious agent of surgical wounds and cause of scalded skin syndrome

in food that sits around for a while
no need for antibiotics for a food borne infection

19

Bacillus cereus

Gram +
Large Bacilli
endospore-forming
Facultative anaerobe
Mostly motile
β hemolytic
Box-car shaped

Also frequently found on skin and is a threat in hospitals as it produces biofilms that adhere easily to invasive devices. This produces chronic persistent infection, as the biofilm can periodically release B. cereus into the bloodstream

B. Cereus spores are commonly found in the soil and sometimes in plant foods that are grown close to the ground – such legumes, cereals, spices etc..
Spores can survive rice cooking process

Duration for both only about 24 hrs

Because of its ubiquity, B. cereus often is ignored or dismissed as a contaminant when found in a culture specimen.
B. cereus in food and vomitus or feces of same serotype
Large numbers of B. cereus of serotype known to produce endotoxin
Only necessary when tracking outbreaks

20

Clostridium botulinum

Gram +
Bacilli
Spore-forming
Obligate anaerobe
Motile
Spores or toxin are the important issues for transmission of botulism

21

Staphylococcus aureus Symptoms:

Symptoms:
nausea, vomiting, stomach cramps, and diarrhea for 1-3 days
Appear 1-7 hrs following ingestion of food
Self-limiting, once toxin is gone, illness is gone

22

Staphylococcus aureus diagnosis

Positive diagnosis:
Toxin-producing S. aureus can be identified in stool or vomit
Most conclusive test is the linking of an illness with a specific food, or in cases in which multiple vehicles exist, detection of pre-formed enterotoxin in food sample(s).
Only necessary when tracking outbreaks

23

Bacillus cereus infection

Infection takes two forms:
Emetic (vomiting):
Diarrheal:

Duration for both only about 24 hrs

24

Bacillus cereus Emetic infection

Emetic (vomiting):
1 to 6 hours incubation
Nausea and vomiting
resembles the vomiting illness caused by Staphylococcus aureus enterotoxins
Caused by preformed enterotoxin that forms holes in membranes
Self limiting

25

Bacillus cereus Diarrheal infection

Diarrheal:
6-15 hours incubation
clinically similar to the symptoms of Clostridium perfringens infection
Watery diarrhea and abdominal cramps
Mechanism: Caused by large molecular weight enterotoxin that causes intestinal fluid secretion, probably by several mechanisms
This toxin is not likely pre-formed!
Ingestion of large amounts of bacteria cause it to generate the toxin in the small intestine
Vulnerable populations might get sicker and require antibiotics
Poor outcomes for systemic infection

26

Bacillus cereus diagnosis

Because of its ubiquity, B. cereus often is ignored or dismissed as a contaminant when found in a culture specimen.
B. cereus in food and vomitus or feces of same serotype
Large numbers of B. cereus of serotype known to produce endotoxin
Only necessary when tracking outbreaks

27

Botulism

Food borne botulism: ingesting toxin
Wound botulism: producing toxin
Infant botulism: ingested spores

Not really a GI illness, diarrhea not prominent

28

Botulism Diagnosis

Symptoms and history, results of physical exam indicate botulism
Tests to exclude other causes of the illness
Organism or toxin in stool sample only indirect evidence

29

Treatment for foodborne botulism

Ventilator if respiratory failure and paralysis
Antitoxin if paralysis is not yet complete
Remove contaminated food if still likely in gut

30

Botulism toxin

neurotoxin
irreversibly blocks the release of acetylcholine from the motoric end plate which results in muscle weakness and paralysis
Toxin is absorbed from GI tract to bloodstream

31

Symptoms, botulism

Toxin already produced, symptoms can begin when toxin hits GI tract
double vision, blurred vision, drooping eyelids, slurred speech, difficulty swallowing, dry mouth, and muscle weakness

32

Symptoms, infant botulism

Incubation period, spores have to produce toxin-forming bacteria
lethargic, feed poorly, are constipated, and have a weak cry and poor muscle tone
Can lead to paralysis of respiratory system and other muscles

33

Clostridium perfringens

Gram +
Bacilli
Spore-forming
Obligate anaerobe
Non-motile

Enterotoxin binds to receptors in endothelial cell junctions, then generates pores in host mucosa cells.

“C. perfringens infection often occurs when foods are prepared in large quantities and kept warm for a long time before serving”

34

Clostridium perfringens Symptoms

Symptoms:
Diarrhea and abdominal cramps
Incubation 6 to 24 hours (typically 8-12)
Symptoms last for less than 24 hours
Usually NO fever or vomiting
The illness is not passed from one person to another

35

Clostridium perfringens Positive diagnosis

Positive diagnosis:
Detection of toxin or high amounts of bacteria in feces
C. perfringens normally present in the GI tract, the problem is when you ingest a C. perfringens load high enough to produce enough toxin to generate symptoms

36

Clostridium perfringens Treatment

Treatment:
Usually self-limiting, but more serious, longer-lasting cases in immunocompromised individuals should be treated to avoid complications

37

Campylobacter jejuni

Gram -
Bacilli (Spirilli)
microaerophilic
Motile
Cold sensitive (often leads to false negatives)

get it from poultry
One unique feature is that campylobacter cannot usually multiply in food.

Symptoms:
diarrhea, cramping, abdominal pain, and fever
2-5 day incubation
Symptoms can last a week
Can have vomiting, diarrhea can be bloody
Mechanism: Symptoms are an inflammatory response to cell invasion

Positive Diagnosis: stool culture
Possible complication: Guillain-Barré syndrome

38

Salmonella enterica

Gram -
Bacilli
Non spore forming
H2S positive & lactose negative
Motile, flagellated

39

Salmonellosis

Symptoms:
diarrhea, fever, and abdominal cramps
12 hr to 3 day incubation
Symptoms typically last 4 to 7 days
Most persons recover without treatment
Remember: reactive arthritis as a possible complication

Diagnosis: we know for sure with a stool culture
Treatment: Hydration. Antibiotics only necessary if infection spreads beyond gut

40

Vibrio parahaemolyticus

Gram (-)
Vibrio (curved rod)
facultative anaerobes
Flagellated, motile
Oxidase +
water loving

Diagnosis: Vibrio may be isolated from cultures of stool, wound, or blood.

Form pores in red blood cells but also in epithelial cells, disrupting gut homeostasis

sushi and shellfish

41

Vibrio parahaemolyticus Symptoms

Fairly mild bloody diarrhea, stomach cramps, fever, nausea, and/or vomiting,
Symptoms last less than a week.
In the immunocompromised, it can spread to the blood and cause serious or deadly infections in other parts of the body

42

Listeria monocytogenes

Gram positive rod-shaped bacteria
Although a rare illness, a leading cause of death by foodborne illness

Gram (+)
Bacillus
Non-fastidious!!!
Flagellated, motile
Non spore forming
Oxidase -

Diagnosis:
Stool sample ID inappropriate
Positive ID is the bacterium found in a normally sterile site

Immune cells spread Listeria to other organs
Trojan horse
Liver is a major target
milk, cheese, seafood, deli

43

Listeriosis

Mild GI infection for most
More vulnerable are older adults, pregnant women, newborns, and adults with weakened immune systems OPPORTUNISTIC
Fever and muscle aches or stiff neck, or if you develop while pregnant: fever and chills
Meningitis and sepsis in vulnerable populations

44

Shigella

Gram (-)
Bacillus
Facultative anaerobe
nonmotile (distinguishes from e. coli)
Non spore forming
Mainly lactose negative, H2S (-) (distinguishes from e. coli)

Shigella sonnei: most Shigella-caused GI illnesses
Shigella flexnori: causes bacillary dysentery
Shigella dysenteriae: rarest but most severe dysentery

invade through m cells
Since Shigella is invasive, if not treated it can spread beyond the GI tract and cause complications
Antibiotics for more severe cases, most usually resolve without antibiotics
Possible complication: hemolytic uremic syndrome (HUS)

45

What is dysentery

Frequent, small bowel movements with blood and mucus, accompanied by rectal pain and spasms (tenesmus)

46

Shigella Transmission

Transmission: Mostly bacterium passing from stools or soiled fingers of one person to the mouth of another person.

47

Shigella Symptoms:

Symptoms:
diarrhea (often bloody)
fever
stomach cramps
Symptoms start 1-2 days following exposure
Usually resolves in 5 to 7 days.

48

E. coli

Gram (-)
Bacillus
Facultative anaerobe
motile
Non spore forming
Mainly lactose positive

Diarrhea
Urinary tract infection
Neonatal sepsis
Gram-negative sepsis

ETEC
STEC

Treatment: antibiotics generally not recommended (decaying bacteria release toxins)
Tracking outbreaks: commercial PCR and antibody-based kits.

49

ETEC

Traveler’s Diarrhea, diarrhea in children
activates adenylate cyclase, end result water into lumen, NO bacterial penetration.

50

STEC

penetrates like Shigilla toxin.
hemorrhagic colitis (HC) and/or HUS can result as a complication; children more vulnerable

51

E. coli Symptoms:

profuse watery diarrhea and abdominal cramping
Can progress to bloody diarrhea for STEC
Fever, chills
Nausea with or without vomiting, loss of appetite
Less common: headache, muscle aches and bloating
Incubation:1-3 days ETEC, 3-8 for STEC
Illness typically lasts 3-4 days, less than 10.

52

cholera toxin

Activates adenylate cyclase
 cAMP →  Na+ absorption,  Cl- excretion
Water moves into lumen

53

typhoid fever

Only fecal-oral contaminant, no other host, so water is a big source of contaminaton
Drinking water, unwashed fruits/veggies
Travelers are vulnerable
Vaccine available

Life-threatening illness
In GI tract and then to bloodstream
High fevers (103-104 °F)
Weakness and headache
Stomach pains, loss of appetite, diarrhea or constipation
Sometimes, a rash of flat, rose-colored spots
After symptoms clear, person could become a carrier
Antibiotic treatment is recommended

54

High inoculum organisms

Tens of thousands or more needed
Examples: Vibrio cholerae, C. perfringens

55

Clostridium difficile

Gram +
Bacilli
Spore-forming
Obligate anaerobe
Motile
Makes exotoxins
antibiotic diarrhea

Toxins produced by C. difficile result in apoptosis of the colonic epithelium, and in the case of pseudomembranous colitis, produce a mucosal surface exudate of necrotic epithelial cells, neutrophils, mucin, and fibrin.

Diagnosis is established by detecting toxin producing strains of C. difficile, typically with a stool PCR assay.

56

Giardia lamblia

Also most common intestinal parasite in US
Giardiasis (aka Beaver Fever) is the foe of backpackers/hikers
Symptoms for 1-2 weeks or more, may seem to resolve and then come back
Mechanism: presence of parasite causes loss of epithelial absorptive surface area.
Trophozoites: Attachment but not penetration
Foul-smelling diarrhea
Filter water in areas where Giardia cysts are likely to exist. Water does not need to be contaminated with human sewage. Wildlife can deposit cysts.

57

Cryptosporidium parvum

Often seen when a sanitation system fails
Pool/waterpark chlorination/UV treatment
Storms or issues with drinking water
Diarrhea symptoms for 1-2 weeks to ~30 days, may seem to resolve and then come back
Mechanism: Absorption impaired and secretion enhanced when intestinal epithelial cells are infected by Cryptosporidium
“Crypto” is opportunistic
HIV/Immunocompromised individuals
Chronic Diarrhea/fluid loss
Can be fatal
Watery, frequent, non-bloody stool
Disrupts epithelial microvilli, slides into host
cells, enveloping itself in the host cell membrane
Oocysts to sporozoites and back
Coccidia subclass

58

Entamoeba histolytica

Amebiasis
More prevalent in tropical/subtropical climates
Only 10-20% of infected individuals will become ill (CDC)
Of US population, male homosexuals most vulnerable
Bloody, mucus-ey loose stool
Relatively mild symptoms but
Can invade the liver and form an abcess
X-ray/ultrasound to detect abscess or tissue damage
Cysts in stool sample. Must differentiate from non-pathogenic entamoeba, takes a specialist.
cytotoxic

59

Metronidazole, Tinidazole

Tissue antiparasitic- low concentration in intestine, oral dose almost completely absorbed with high bioavailability
Despite this, it is the drug of choice to treat symptomatic Giardia infection, even though organism that does not penetrate the epithelium!!
Reminder: all about metronidazole/Tinidazole in lectures relating to treatment of H. pylori
Disulfiram reaction, avoid alcohol
Disturb normal GI flora

breaks down into toxic metabolites, damages DNA

60

Nitazoxanide

Mechanism: Interferes with pyruvate::ferredoxin oxidoreductase enzyme dependent electron transfer, essential to anaerobic energy metabolism protein
Selectivity: Species difference in electron transfer

Distribution: Rapidly metabolized to tizoxanide. Parent compound is not detected in plasma. Moderately absorbed (33%), primarily luminal.

For Crypto, used in combination with retroviral therapy for AIDS patients if at all, because of ineffectiveness

61

Iodoquinol

Mechanism: Unknown
Toxicity:
loss of visual acuity
Use with caution in patients with thyroid disease – its use interferes with certain thyroid tests
Distribution: only 10% of the drug is absorbed so it works locally on the protozoa including cysts in the GI tract, luminal antiparasitic (amebicide)

62

Paromomycin

Mechanism: Aminoglycoside- targets 30S subunit ribosome
Toxicity: Diarrhea, other GI effects including issues with intestinal flora because it has activity against some bacteria.
Distribution: Luminal antiparasitic- Minimal absorption after oral administration
Ototoxicity, nephrotoxicity

63

TMP-SMX

Spectrum: Broad spectrum, many bacteria, but also effective against apicomplexans including Toxoplasma and Cystoisospora (formerly Isospora), and Cyclospora
hits folic acid system

64

Enterobius vermicularis

Staple-sized worms
pinworms
Worldwide distribution, most common helminth infection in US
Prevalence can reach 50% in children, caregivers of infected children, and institutionalized individuals.
Symptom: perianal pruritis
Acquired by ingestion of pinworm eggs
Eggs can remain viable on surfaces for 2-3 weeks

65

Necator americanus/Ancylostoma duodenale

Pruritic Papular Erythematous Rash
Hookworms are bloodsuckers…
Major symptom is iron-deficiency anemia
¼ ml/day/worm

66

Strongolides stercoralis

Autoinfection possible, especially with Immunosuppressed individuals
Stomach and GI complaints
Respiratory
dry cough
throat irritation
Skin
an itchy, red rash that occurs where the worm entered the skin
recurrent raised red rash typically along the thighs and buttocks.

67

Trichuris trichiura

Diagnosis:
Eggs in feces have a characteristic barrel-shaped appearance
Finger clubbing best indicator of
severity of infestation
Bloody diarrhea = iron
deficiency anemia
Heavy cases:
Frequent, painful stools with mucus, water and blood, tenesmus
Rectal prolapse

68

Ascaris lumbricoides

Disease: ascariasis
Disease: IF symptoms are experienced, abdominal discomfort
If a severe case, intestinal blockages
Ultrasonography and radiology to determine
Has a lung stage of life cycle, may cause cough
Diagnosis: eggs w/thick shells

69

Albendazole and Mebendazole

Broad-spectrum benzimidazole drugs
Roundworms and tapeworms
Distribution: Limited oral absorption, albendazole is better absorbed if targeting tissue-migrating larvae is important
Broad-spectrum benzimidazole drugs
Mechanism: Binds to parasite β-tubulin and inhibits the formation of microtubules
Death can take several days, for some helminths more than one dose may be necessary
Specificity: differences in tubulin
Toxicity:
Systemic toxic affects on liver/bone marrow rare
Abdominal pain, nausea, dizziness, headache
Embryotoxic and teratogenic in pregnant rats
Evidence suggests safe for use in children when warranted

70

Pyrantel pamoate and Levamisole

Mechanism:
Levamisole selectively opens a restricted subgroup of nematode acetylcholine receptor (AChR) ion channels in nematode nerve and muscle. depolarization entry of calcium through the opened channels, and an increase in sarcoplasmic calcium, producing spastic muscle contraction the parasite is then unable to maintain its location (often in the intestine) and is then swept away, effecting the cure.

Toxicity: Causes nausea, vomiting, diarrhea
Distribution: Poorly absorbed

71

Ivermectin

Mechanism: Binds to glutamate-gated chloride channels in invertebrate nerve and muscle cells, causing deactivation of channel: worm paralysis and death by starvation
Resistance: efflux transporters
Toxicity:
Generally well-tolerated
Itching, swollen lymph glands and rarely dizziness
Inflammatory reaction due to death of adult worms
Specificity: This type of channel restricted to phyla Nematoda and Arthropoda. in humans are only in the CNS , Doesn’t cross blood-brain barrier
Spectrum: Nematodes- Ascaris, Strongyloides and Onchocerca

72

Initial upper GI bleed management

Remember ABC’s
Airway?
CPR?

IV access
At least 2 large bore IVs

Infusion
Crystalloid
Blood products

73

Varices

Presentation: Dramatic bleeding, usually hematemesis
Causes: Portal hypertension
Associated with: Liver disease/cirrhosis

Treatment:
Octreotide or Vasopressin
Proton Pump inhibitor
Non-selective Beta-blocker
Variceal band ligation

74

Responsible for tolerance

Treg cells

75

NSAIDs and Peptic Ulcer Disease

Direct injury effects
Systemic effects
COX inhibition and  prostaglandin production
Prostaglandins in the gut regulate mucus secretion and basal bicarbonate secretion
Prostaglandins are trophic for gastric epithelia and play role in feedback inhibition of gastric acid secretion
COX-2 selective inhibitors still pose risk for PUD

76

Intraepithelial Barrier

Intraepithelial Lymphocytes (IEL) promote barrier repair and are rapidly recruited
Majority of IELs express CD8 (recognize MHC class I Ag)
Two types of TCR
αβ, thymus derived
γδ, non-thymic derived
15% of small intestine IEL
40% of colonic IEL
Produce keratinocyte growth factor

77

Lamina Propria

Reservoir to 70-80% total lymphocytes
Predominate T cells are CD4, recognize MHC class II Ag

78

M Cells

Some bacteria and viruses cross the epithelial barrier via M Cells

79

α-Defensin

Neutrophils, NK cells, Paneth cells

80

β-Defensin

Leukocytes and Epithelial cells

81

Paneth Cells

Small intestine is lined with villi interspersed with Crypts.
Paneth cells harbor pro-defensin 5
Degranulation occurs following bacteria penetration

82

Type 1 Interferons

(IFN-α/β)
Induces MHC Class I expression
Kill Infected Host Cell

83

Natural resistance-associated macrophage proteins

remove mn to starve bacteria

84

Calprotectin

Broad spectrum scavenger of divalent cations is Calprotectin, S100 protein that sequesters Ca, Fe, Zn and Mn

85

Lipocalin

remove lipids to starve bacteria

86

indoleamine 2,3-dioxygenase

Tryptophan removal to starve bacteria

87

anti-inflammatory mediators

IL-10, IL-1ra

88

pro-inflammatory mediators

IFN-gamma, TNF-alpha, IL-12

89

TH1 Lymphocytes

Acute Inflammation
pro-inflamatory in inflammatory bowel disease

90

IFN-γ

Acute Inflammation

91

M-1 Macrophage

Acute Inflammation

92

IgG

Acute Inflammation

93

sIgA

Acute Inflammation

94

CTL cells

Acute Inflammation

95

NK cells

Acute Inflammation

96

TH2

Chronic Inflammation

97

TH17 Lymphocytes

Chronic Inflammation

98

IL-4

Chronic Inflammation

99

IL-17

Chronic Inflammation

100

M-2 Macrophage

Chronic Inflammation

101

IgE

Chronic Inflammation

102

Eosinophils

Chronic Inflammation

103

Basophils

Chronic Inflammation

104

INFLAMMATORY BOWEL DISEASE

Chronic inflammatory condition resulting from inappropriate mucosal immune activation.

Consists of two diseases, chronic ulcerative colitis (also known simply as ulcerative colitis, UC) and Crohn’s disease (CD).

Etiology is not completely understood, but IBD appears to be caused by an aberrant mucosal immune response, associated with intestinal micro-organisms and intestinal epithelial dysfunction, in genetically susceptible individuals.

IBD often presents between the ages of 15-30, with a second smaller peak between 50 and 80 years (although it can occur at any age). IBD is more common in developed countries such as North America, northern Europe, and Australia, although the incidence is rising in other areas of the world (hygiene hypothesis with changes in gut microbiota). In the USA, 1.4 million have IBD.

Clinical manifestations of UC:
Typically bouts of bloody diarrhea with mucus discharge, along with lower abdominal pain and cramps. Patients may experience tenesmus (feelings of urgency and incomplete evacuation) secondary to proctitis (rectal inflammation).

105

Ulcerative colitis (UC)

Inflammatory changes involve the mucosa and at most the superficial submucosa (no transmural involvement); disease is limited to the colon and rectum in a continuous fashion (rectum is always involved, so this is a “left sided disease of the colon” which involves the rectum and can involve the whole colon). If only the rectum is involved by UC, it is called ulcerative proctitis.

pANCA positive

Chronic, relapsing disease
Hematochezia, tenesmus, pain
Rectum with confluent proximal extension.
Colectomy rate: 30% over 30 years
Colon cancer: 18% over 30 years
Primary Sclerosing Cholangitis 4%
joint problems
erythema nodosum, pyoderma gangrenous (unexplained bruising, important)
gallstones

106

Crohn’s disease


Clinical manifestations of Crohn’s disease:
Quite variable, typically beginning with bouts of mild diarrhea, fever, and abdominal pain. Approximately 20% of patients can present with marked acute abdominal pain, with symptoms related to either bowel obstruction and/or fistulas. In some patients, cigarette smoking can trigger Crohn’s disease.

Approximately 10-20% of patients with Crohn’s disease or ulcerative colitis can have extra-intestinal disease, some of which include primary sclerosing colangitis (UC > CD), erythema nodosum, pyoderma gangrenosum, iritis/uveitis (CD > UC), and HLA B27 positive sacroiliitis/arthritis.

ASCA positive

A pan-enteric transmural inflammatory disease
Mouth to anus, usually spares rectum

70% involve the terminal ileum

Skip lesions

Perianal involvement

Transmural complications – Fistulae, abscess, strictures

Pain diarrhea, anemia, infrequent bleeding

80% require surgery by 15 years

107


Indeterminate colitis

Pathologic and clinical overlap exists between UC and CD, and in 10% of patients presenting with IBD it may not be possible to distinguish between the two entities. These patients present with colonic disease only and have features that do not permit a definitive subtyping of their inflammatory bowel disease between UC or CD, and the findings are called indeterminate colitis. Serologic studies may be helpful in distinguishing between UC and CD in these cases.

108

Diversion colitis

Colitis developing in a blind distal segment of the colon which is excluded from the fecal stream, following surgery with formation of a temporary or permanent diverting ostomy.

Cause of diversion colitis is thought to be a deficiency of short-chain fatty acids, which are normally produced from fermentation of dietary starches by normal colonic bacterial flora. These dietary starches are absent in the diverted segment, due to changes in the luminal microbiota and diversion of the normal fecal stream. If the fecal stream is re-established, the colitis regresses.

Typical pathologic changes include mucosal erythema, friability, and nodularity (due to mucosal lymphoid hyperplasia) with aphthous uclers. In some cases, the changes can mimic IBD such as UC or CD, and if the pathologist is not aware that the biopsy is taken in a diverted segment, an erroneous diagnosis of IBD could be rendered.

Treatment is re-anastomosis with return of the normal fecal stream. Enemas containing short-chain fatty acids have also been used.

109

Microscopic colitis

Consists of two related entities, lymphocytic colitis and collagenous colitis.

Patients present with chronic watery diarrhea and a normal colonoscopic exam.

In lymphocytic colitis, the biopsy shows increased lamina propria chronic inflammation (especially increased plasma cells) along with increased intra-epithelial lymphocytes and surface epithelial damage. In collagenous colitis, a band of subepithelial collagen is seen in addition to the above inflammatory changes. In both types of conditions, crypt architecture is intact (as opposed to distorted crypts in IBD).

Pathogenesis in both conditions is thought to be an autoimmune mechanism, and both conditions can be associated with celiac disease as well as other autoimmune diseases. It is also believed that certain medications can trigger the disease (e.g. NSAIDs in collagenous colitis).

Microscopic colitis can be treated with glucocorticoids.

110

Radiation enterocolitis

Occurs when the GI tract is irradiated.

Epithelial damage occurs acutely; chronic injury is often ischemic, resulting from vascular injury with occlusion of blood vessels. Patients can develop ulcers, strictures, fistulas, and serosal adhesions.

Mucosal changes are characterized by patchy erythema, secondary to mucosal telangiectasias. Blood vessels show hyalinization and thickening of the walls, with reduced luminal diameter. Atypical pleomorphic “radiation fibroblasts” can be seen.

111

Neonatal necrotizing enterocolitis

Can develop in the first week of life in premature infants. Both the small and large bowel exhibit necrosis which can become transmural. Bacterial overgrowth can produce gas in the wall of the intestine, seen as air bubbles (pneumatosis intestinalis). Etiology is probably multifactorial, resulting in mucosal injury in premature infants that can have impaired GI defenses to mucosal injury.

112

Drug induced enterocolitis

NSAID enteropathy/colitis: use of NSAIDs can result in gastric and proximal duodenal erosions/ulcerations as discussed previously. However, NSIADs can also cause erosions/ulcerations in the jejunum, ileum, and colon. In some cases, the pathologic findings can create confusion with Crohn’s disease (e.g. aphthous ulcers).

Chemotherapeutic agents can cause ulcerative lesions of the entire GI tract.

Antibiotics can cause pseudomembranous colitis due to C. difficile.

113

Graft vs. host disease

Can occur following allogeneic bone marrow transplantation.

Typically involves small bowel and colon.

Key pathologic finding is apoptotic epithelial cell death in crypts without inflammation.

114

Irritable bowel syndrome (IBS)

Irritable bowel syndrome is characterized by chronic, relapsing, abdominal pain or discomfort, bloating, and changes in bowel habits (diarrhea or constipation), in the absence of any known causative agent that could explain the symptoms.

Endoscopic and colonoscopic examination reveals no abnormalities, and no abnormalities are seen on microscopic exam.

Diagnostic criteria have been developed to define this clinical syndrome, which requires excluding organic causes of the symptoms (next slide). Prevalence of IBS is estimated at 5-10%. IBS is a very common disorder!

IBS has been classified into different subtypes, based on stool consistency (e.g. constipation-predominant IBS, diarrhea-predominant IBS, mixed-subtype IBS, and unsubtyped IBS). Thus IBS is a syndrome, and consists of many different disorders.

115

Ischemic bowel disease

Ischemic damage ranges from mucosal infarction, to mural infarction of mucosa and submucosa, to transmural infarction of all three layers.

Many causes, including:

Acute arterial obstruction/thrombosis: atherosclerosis, aortic aneurysm, hypercoagulable states, and thromboembolism. This typically results in transmural infarction (e.g. superior mesenteric artery (SMA) thromboembolism or thrombosis).

Mesenteric venous thrombosis: hypercoagulable states, portal hypertension due to cirrhosis, trauma, invasive neoplasms, abdominal masses that compress portal drainage.

Hypoperfusion: cardiac failure, shock, dehydration, vasoconstrictive drugs, vasculitis. Systemic hypoperfusion can cause ischemic damage in the watershed zones (see below).

Intestinal segments located at the end of an arterial supply are susceptible to ischemic damage. Such areas include the splenic flexure (SMA and IMA watershed zone) and the sigmoid colon and rectum (IMA, pudendal artery, iliac artery watershed zone).

Ischemic bowel disease pathology: mucosal ischemic injury results in atrophy/loss of surface epithelium, a hemorrhagic and hyalinized lamina propria, and crypt atrophy. Severe ischemic injury results in coagulative necrosis of the bowel layers (complete necrosis of all three layers in transmural infarcts).

Complications of ischemic bowel necrosis include sepsis due to break down of the mucosal barrier, with septic shock and death. These complications can occur suddenly, within hours of presentation.

Acute mesenteric ischemia with transmural necrosis can present with the sudden onset of abdominal pain, loss of bowel sounds, nausea, vomiting, bloody diarrhea, and melanotic (more correctly, melenic) dark “tarry” stool. Diagnosis requires high level of suspicion, and demonstration of vascular obstruction (angiography is the gold standard test).

Chronic mesenteric ischemia can present with abdominal pain following eating (mesenteric angina). Bouts of bloody diarrhea may occur, and the symptoms can mimic inflammatory bowel disease.

Ischemic bowel disease tends to occur in older individuals with coexisting cardiac or vascular disease.

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Angiodysplasia

Lesion consists of malformed submucosal and mucosal blood vessels.

Typically occurs in the cecum and right colon in older adults. Etiology is uncertain, but may be acquired and incidence increases with age (cecal wall stress from stretching).

Prevalence is only 1%, but angiodysplasia accounts for 20% of cases with lower GI bleeding. The bleeding may be acute and massive (hematochezia, bright red blood in the stool) or chronic and intermittent.

Diagnosis is with colonoscopy, and angiography if necessary.

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Sigmoid diverticulitis

Diverticular disease or diverticulosis refers to a condition characterized by the formation of multiple diverticulae, usually located in the sigmoid colon. If these diverticulae become inflamed, the condition is known as diverticulitis.

In Western countries, the incidence of diverticulosis in individuals over the age of 60 is 50%. Colonic diverticulae are rare in individuals under the age of 30.

Pathogenesis is related to elevated intra-luminal pressure in the sigmoid colon. In the colon, where nerves and arteries penetrate the muscular layer, focal discontinuities of the inner muscular coat exist. This can lead to outpouchings of mucosa and the formation of diverticulae. It is believed that exaggerated peristaltic contractions with spasmodic sequestration of bowel segments, enhanced by diets low in fiber, lead to increased intraluminal pressure and the formation of diverticulae.

Most individuals with sigmoid diverticulosis are asymptomatic. However, sigmoid colon diverticulosis can lead to lower GI bleed and sigmoid diverticulitis.

Symptoms of diverticulitis include lower abdominal discomfort and pain, intermittent cramping, abdominal tenderness, fever, and change in bowel habits

Uncomplicated acute sigmoid diverticulitis is often treated with clear liquid diet (bowel rest) and antibiotics, followed by a high fiber diet. Complicated diverticulitis may require surgery.

Some patients with sigmoid diverticulosis can develop an inflammatory colitis in the affected sigmoid

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Solitary rectal ulcer syndrome


Disorder thought to be caused by malfunction of the puborectalis muscle, leading to excessive straining on defecation. The straining may lead to rectal mucosal prolapse that can ulcerate and form polypoid masses (inflammatory polyp), typically on the anterior rectal wall, 4-10 cm from the anal verge.

Most patients are relatively young, healthy adults who complain of blood in their stools, pain or discomfort with defecation, and alternating constipation and diarrhea.

Grossly, the lesion can mimic adenocarcinoma, or the ulcers seen in Crohn’s disease. Microscopically, one sees fibromuscular hyperplasia of the lamina propria, along with inflammation and ulceration, including reactive crypt hyperplasia.

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Inflammatory polyps

Present as a result of an inflammatory, non-neoplastic process in the GI tract.

Associated with conditions such as solitary rectal ulcer syndrome, ulcerative colitis, and Crohn’s disease.

Can occur anywhere in the GI tract.

In UC and CD the inflammatory polyps are often called “inflammatory pseudopolyps” as they represent inflamed and regenerating mucosa that projects above the level of the surrounding mucosa, which is frequently ulcerated.

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Juvenile polyps (retention polyps)


Hamartomatous polyp that can occur sporadically or as the result of a polyposis syndrome. This polyp is the most common type of polyp to occur in young children, but this polyp can also occur in adults.

Sporadic juvenile or retention polyps occur in the colon (usually rectum) and are typically solitary; however, multiple juvenile polyps can occur throughout the stomach, small bowel, and colon when associated with the juvenile polyposis syndrome.

Sporadic juvenile or retention polyps have no increased risk of malignancy. However, patients with juvenile polyposis syndrome are at increased risk for GI tract adenocarcinomas and can have mutations of genes that regulate cell growth such as mutations of SMAD4 (encodes a cytoplasmic intermediate of the TGF-Beta signaling pathway) or BMPRIA (a kinase). As these mutations are seen on only 50% of patients, other mutations must be present in this syndrome.

These polyps, if symptomatic, can result in rectal bleeding. Many patients with juvenile polyposis syndrome are discovered in childhood, and 30%-50% of these patients can develop colonic adenocarcinoma by age 45.

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Peutz-Jeghers polyps

Hamartomatous polyp that occurs as a result of the Peutz-Jeghers syndrome.

Patients with the Peutz-Jeghers syndrome (PJS) present with multiple Peutz-Jeghers polyps and mucocutaneous hyperpigmentation. The polyps are most common in the small bowel, followed by the colon and stomach.

Patients with PJS can have loss of function mutations of STK11 which is a tumor suppressor gene. As a result, patients are at risk for the development of GI tract adenocarcinomas, as well as malignancies of other organs (breast, lung, pancreas, gonads, uterus). GI tract adenocarcinomas can arise independently of the hamartomatous polyps.

The Peutz-Jeghers polyps have a characteristic arborizing smooth muscle pattern and are frequently pedunculated. Patients can present in childhood with GI bleeding and intussusception. Because of increased risk of malignancy, patients undergo routine cancer surveillance.

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Cowden syndrome

associated with mutations of PTEN, a tumor suppressor gene. These patients typically develop mucocutaneous lesions that include trichilemmomas, acral keratoses, and oral papillomas. There is also an association with breast lesions (fibroadenomas, cancer), thyroid lesions, macrocephaly, and increased risk for endometrial and renal cell carcinoma. Patients have hamartomatous polyps of the stomach, small bowel, and colon that resemble juvenile polyps. An increased risk for GI tract malignancy has not been observed.

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Cronkhite-Canada syndrome

this is a rare, non-hereditary hamartomatous polyposis syndrome of unknown etiology. Patients develop multiple juvenile type polyps in the stomach, small bowel, and colon. Significant GI tract inflammation is also present, and the patients experience diarrhea, weight loss, abdominal pain, and weakness. Other symptoms include alopecia, cutaneous hyperpigmentation, and nail atrophy and splitting. Typically presenting in adults, this is a severe illness and as many as 50% of patients die of malnutrition, GI bleeding, or infection.

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Hyperplastic polyps

Occurring in the colon, typically in adults, this is the most common type of adult colonic polyp.

The majority of hyperplastic polyps are small (less than 0.5 cm in size) and are found in the left colon, especially the rectum. Polyps may be single or multiple.

Most investigators believe that the traditional hyperplastic polyp is a proliferative polyp without significant malignant potential. Hyperplastic polyps need to be distinquished from sessile serrated polyps and serrated adenomas, which are neoplastic polyps associated with an increased malignant potential.

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Adenoma (adenomatous polyp, colonic or small bowel adenoma)

Neoplastic polyp characterized by dysplastic glandular proliferation.

Can consist largely of a tubular proliferation of glands (tubular adenoma), or more villous proliferation (villous adenoma). Adenomas with mixed features are called tubulovillous adenomas.

In the colon, adenomas can occur anywhere. In the small bowel, adenomas are more rare than in the colon, but when they occur they often involve the duodenum, especially the ampulla.

Adenomas, which are benign, can be precursors to adenocarcinoma, although most adenomas do not become malignant. Increasing size, presence of villous features, and presence of high grade dysplasia increase the chance that an adenoma will become malignant.

When an adenoma is discovered, it needs to be completely removed (usually accomplished endoscopically). This is the basis for using colonoscopy as a modality for preventing colorectal cancer, by discovering adenomas and removing them before they become malignant.

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Sessile serrated polyp

These are sessile polyps, resembling hyperplastic polyps, that can be precusors to adenocarcinoma. These polyps lack the adenomatous epithelium of the conventional adenoma described previously. They are often found in the right colon.

Adenomatous type epithelial changes can occur in sessile serrated polyps, and when that occurs, the polyp is said to have low grade dysplasia. High grade dysplasia can also occur, and is designated as such.

The natural history of these polyps is under intense investigation, but it is apparent that this type of polyp can be a precursor to adenocarcinoma. As a result, complete endoscopic polypectomy is recommended, as with conventional adenoma.

Another type of serrated polyp has also been described as the serrated adenoma (aka traditional serrated adenoma) which exhibits serration along with uniform, eosinophilic dysplastic epithelium. As theses lesions can also be precursors to adenocarcinoma, complete polypectomy is advised, as with conventional adenoma

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Familial adenomatosis polyposis (FAP)

Autosomal dominant inheritance, caused by mutations in the APC tumor suppressor gene. Patients inherit a single APC mutation, and then acquire a second APC mutation, resulting in adenomas. Approximately 75% of cases are inherited, with the remaining cases the result of de novo mutation.

Patients develop large numbers of adenomatous polyps in the colon and rectum during late childhood, adolescence, and early adulthood. There is a 100% risk of colorectal adenocarcinoma (mean age of carcinoma 35-40 years, but can occur in the teenage years).

Morphology of the adenomas is similar to that seen in sporadic adenomas. Approximately 1% of colon cancers are due to FAP.

Diagnosis of classic FAP is established by clinical presentation (>100 polyps) and detection of germline mutations of the APC gene. About 70-80% of FAP patients have congenital hypertrophy of the pigmented retinal epithelium, which can be seen on ophthalmic exam.

Treatment is screening in adolescence followed by postadolescent prophylactic colectomy.

Patients also have adenomatous polyps in the stomach and small bowel, especially the duodenum, and are at greatly increased risk for upper GI tract adenocarcinoma, especially at the ampulla.

For the diagnosis of classic FAP, at least 100 adenomatous polyps must be present. Attenuated forms of FAP exist, in which the patient has fewer than 100 polyps. These patients have an 80% lifetime risk of colon cancer, as well as the delayed appearance of colon cancer, to ages 50 and above. Some patients with attenuated FAP syndrome have mutations of MUTYH, which encodes a DNA repair enzyme, as opposed to APC mutations.

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Gardner’s syndrome

in addition to FAP (with the APC mutation), patients develop desmoid tumors, osteomas, epidermal cysts, dental abnormalities, and thyroid tumors.

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Turcot syndrome

defined as coexistence of a hereditary colon cancer syndrome along with CNS tumors. Some patients have FAP (with the APC mutation) and develop medulloblastoma. Other patients have mutations associated with HNPCC (DNA mismatch repair gene mutation) and are prone to develop glioblastoma multiforme.

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Hereditary Non-polyposis Colorectal Cancer (HNPCC, Lynch syndrome)

HNPCC is caused by mutations in the genes that encode enzymatic mismatch repair proteins responsible for the detection, excision, and repair of errors that occur during DNA replication.

Patients with HNPCC inherit one defective allele and one normal allele. When the second allele is lost through an acquired mutation or epigenetic silencing (second hit), the defect in these mismatch repair enzymes (MLH1, MSH2, MSH6, and PMS2) leads to the accumulation of mutations, mostly in the regions containing short repeating DNA sequences known as microsatellite DNA. The accumulation of microsatellite mutations can be assessed and measured as microsatellite instability.

Mismatch repair enzyme defects also lead to the accumulation of mutations in genes that regulate cell growth. With regard to the colon, HNPCC patients do not develop an increased number of adenomas. However, when adenomas occur, they have a greatly increased risk of malignant transformation, and the risk for colon cancer is 80-90%. Approximately 3% of all colorectal carcinomas are due to HNPCC. Risk for small bowel carcinoma is also increased.

Patients with HNPCC can present with colon cancer before the age of 50, and sometimes with multiple primary colon cancers. These patients can also present with extra-colonic tumors, such as sebaceous tumors of the skin (Muir-Torre syndrome), endometrial cancer (most common), or cancers of the stomach, small bowel, liver, biliary tract, pancreas, ovary, ureters, renal pelvis, and brain (Turcot syndrome).

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Colorectal adenocarcinoma

Most common malignancy of the GI tract. There are approximately 140,000 new cases every year in USA, with about 50,000 deaths.

Most cases occur in the elderly, with peak ages 60-70. Approximately 10% occur before the age of 50.

Multiple risk factors, including:

Diet low in vegetable fiber and high in refined carbohydrates and fat (high fat diet enhances hepatic synthesis of cholesterol and bile acids which can be converted into carcinogens by intestinal bacteria; it is also thought that a low fiber diet alters the composition of the intestinal microbiota, as well as reducing transit time, resulting in greater exposure to toxic oxidative by-products of bacterial metabolism). Cigarette smoking, obesity, heavy alcohol intake, inactivity are also risk factors.

Personal or family history of colon cancer or polyps (genetic or shared environmental exposure).

Inflammatory bowel disease (dysplasia-carcinoma sequence, UC > CD).

Use of aspirin and NSAIDs protect against the development of colon cancer, due to inhibition of cyclooxygenase-2 (COX-2), which is expressed in colorectal carcinomas (90%) and many adenomas. COX-2 is necessary for production of prostaglandin E2, which promotes epithelial proliferation.

The majority of colorectal adenocarcinomas arise from adenomatous polyps
Two main genetic pathways for the development of colorectal adenocarcinoma have been described:

APC/Beta-catenin pathway
Microsatellite instability pathway (MSI)

Tumors can occur anywhere in the colon.

Can present with variable gross morphology, such as a large fungating, exophytic mass, as a deeply penetrating, ulcerated tumor, or as an obstructive annular lesion. Right sided tumors are rarely obstructive, as opposed to left sided tumors which can form “napkin ring” lesions that produce narrowing and obstruction.

Tumors associated with microsatellite instability are more often right sided. They may have mucinous or medullary differentiation.

Tumors can metastasize to the regional lymph nodes (nodal metastases), as well as to the liver and lung (hematogenous metastases).

Symptoms may develop insidiously over a long period of time.

Patients with left sided tumors may present with cramping, left lower quadrant discomfort, changes in bowel habits (constipation, diarrhea), and occult bleeding.

Patients with cecal and right sided tumors may present with fatigue and weakness due to iron deficiency anemia as a result of the occult bleeding (please remember that iron deficiency is a symptom and not a diagnosis, and the clinical maxim, that the underlying cause of iron deficiency anemia in an older man or postmenopausal woman is GI tract cancer until proven otherwise).

Diagnosis is established by colonoscopy with tissue biopsy. Primary treatment is surgical resection of the bowel segment, including regional lymph nodes.

Key factors that affect prognosis are depth of invasion, and presence or absence of lymph node and hematogenous metastases. Some histologic types (poorly differentiated, mucinous, signet ring cell) are also associated with a poorer prognosis.

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cancer genes

Morphologic and molecular changes in the adenoma-carcinoma sequence (APC/Beta-catenin pathway). This pathway is the most common pathway activated in sporadic colon cancer (70-80% of all sporadic cases). This pathway is also activated in Familial Adenomatosis Polyposis (FAP). Loss of one normal copy of the tumor suppressor gene APC occurs early. Individuals born with one mutant allele (as in FAP) are therefore at increased risk of developing colon cancer. Alternatively, inactivation of APC in colonic epithelium may occur later in life (sporadic cases). This is the “first hit” according to the Knudson hypothesis (Chapter 7). The loss of the intact second copy of APC follows (“second hit”). Other changes, including mutation of KRAS, losses at 18q21 involving SMAD2 and SMAD4, and inactivation of the tumor suppressor gene TP53, lead to the emergence of carcinoma, in which further mutations occur. Although there seems to be a temporal sequence of changes, the accumulation of mutations, rather than their occurrence in a specific order, is most critical. 

Morphologic and molecular changes in the mismatch repair pathway of colon carcinogenesis. Defects in mismatch repair genes result in microsatellite instability and permit accumulation of mutations in numerous genes. If these mutations affect genes involved in cell survival and proliferation, cancer may develop. This pathway is activated in HNPCC, in which the individual inherits a mutation of a mismatch repair gene. This pathway can also be activated in sporadic colon cancer, in which there is an acquired loss of MMR gene function, either through acquired mutation of MMR genes or epigenetic silencing (typically hypermethylation of the promotor region of MLH1). Approximately 10-20% of all sporadic cases of colon cancer are due to activation of this pathway. These pathways are common in sessile serrated polyps and the cancers arising from these polyps.

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Small bowel adenocarcinoma

Much less common than colorectal adenocarcinoma.

Approximately 50% occur in the duodenum, especially at the ampulla of Vater.

Many of these arise from sporadic adenomas, via the adenoma-carcinoma pathway as with CRC.

Known risk factors include FAP, Crohn’s disease (arising from dysplasia, often in the ileum), and celiac disease.

Patients can present with symptoms of bowel obstruction, bleeding, intussusception, or perforation. Patients with tumors at the ampulla can present with bile duct obstruction, pancreatitis, and jaundice.

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Small and large bowel neuroendocrine (carcinoid) tumors

Small bowel is the most common location for neuroendocrine tumors of the GI tract. Most occur in the ileum, and are multiple in 30% of cases. Duodenal tumors can be functional, and some will secrete gastrin and are associated with the Zollinger-Ellison syndrome.

Clinical presentation of non-functioning tumors is usually vague, with crampy abdominal pain, nausea, vomiting, and weight loss as the most common complaints. Unfortunately, those arising in the ileum and jejunum often present with size greater than 2 cm and show transmural invasion with metastases at the time of diagnosis. Thus, patients may present with the carcinoid syndrome.

Colonic neuroendocrine tumors are rare, and often present as bulky, right sided high grade neuroendocrine carcinomas, with morphology similar to small cell carcinoma of the lung.

Rectal neuroendocrine tumors are more common than colonic tumors, and typically present as polyps, and are usually less than 1 cm and have a favorable prognosis.

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Gastrointestinal stromal tumors of the small and large bowel (GIST)

Discussed in the gastric lecture. Determination of biologic behavior is based on site specific criteria, which typically involves size and mitotic count.

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Small and large bowel lymphomas

small bowel is more frequently involved by lymphoma than the large bowel. Almost all types of lymphomas can occur, either as part of a systemic lymphoma or as a primary GI tract lymphoma. Most are of B-cell type. A few notable examples are listed below (select list, not all entities discussed):

Enteropathy-associated T-cell lymphoma (association with celiac sprue).

Immunoproliferative small intestinal disease (IPSID): prevalent in the Mediterranean region and Middle East (known as Mediterranean lymphoma or Middle East lymphoma).

Mantle cell lymphoma (multiple lymphomatous polyposis).

Burkitt lymphoma (children).

Diffuse large B-cell lymphoma.

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Acute appendicitis


Defined as acute inflammation involving at least the muscularis propria. In advanced cases, suppurative inflammation with gangrenous necrosis occurs, which can lead to perforation and suppurative peritonitis. Etiology is thought to be related to increased intraluminal pressure that compromises venous outflow. Ischemic injury and stasis of luminal contents, which lead to bacterial overgrowth, trigger an acute inflammatory response with edema and neutrophilic infiltration. These sequences of events can be initiated by obstruction, either by a fecalith, which is a stone-like mass of hard stool, or by lymphoid hyperplasia (following viral infection in children).

Lifetime risk of developing acute appendicitis is 7% (one of the most common causes of acute abdominal pain). Acute appendicitis can occur at any age, but is more common in adolescents and young adults.

Classic clinical presentation is periumbilical pain that ultimately localizes in the right lower quadrant, with abdominal tenderness on examination over “McBurney’s Point” (located two thirds of the distance from the umbilicus to the right anterior superior iliac spine). Nausea and vomiting follows the development of abdominal pain. Elevated white count with neutrophilia is seen in 80% of patients.

Very young and elderly can have an atypical presentation. Imaging studies (US and CT scan) can be used to assist in diagnosis. Treatment is with appendectomy.

Complications include perforation with periappendiceal abscess, pyelophlebitis, portal venous thrombosis, liver abscess, bacteremia, sepsis, and death.

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Appendiceal neuroendocrine tumor

The most common tumor of the appendix. Can occur at any age and is usually found incidentally following appendectomy.

Typically a small non-functioning tumor, measuring less than 1 cm, often located in the tip of the appendix. When measuring 1 cm or less and confined to the appendix without invasion into the mesoappendix, these tumors are considered to be benign and simple appendectomy is almost always curative.

Tumors larger than 2 cm typically invade into the mesoappendiceal soft tissues and are considered low grade malignant neuroendocrine tumors. These tumors are best treated with right hemicolectomy, as they have the capability to metastasize to regional lymph nodes and liver, which may result in the carcinoid syndrome clinically.

Rarely, appendiceal neuroendocrine tumors can show mucinous differentiation (goblet cell carcinoid tumor). This type of tumor is usually considered to be a low grade malignant tumor, and depending on size, mitotic rate, and invasiveness, a right hemicolectomy may be recommended.

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Appendiceal mucinous tumors

spectrum of differentiation and behavior exist, ranging from mucinous adenomas (confined to appendix, no high grade cytologic atypia or architectural complexity, and no invasion, and since often cystic, called mucinous cystadenomas), to low grade mucinous neoplasms (invasive, low grade cytology), to mucinous adenocarcinomas (invasive, high grade cytology). As all appendiceal mucinous tumors have the capability for invasion thru the appendiceal wall and can cause pseudomyxoma peritonei, some investigators consider all mucinous neoplasms of the appendix with low grade cytology as low grade appendiceal mucinous neoplasms and lesions with high grade cytology (which typically show invasion) as mucinous adenocarcinomas.

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Pseudomyxoma peritonei

gross descriptive term for the presence of abundant mucinous material on the peritoneal surfaces. Almost all cases are due to appendiceal mucinous tumors. Pathologically, the pools of mucin can be virtually acellular or of very low, non-atypical cellularity (low grade mucinous adenocarcinoma) or mucin pools with high cellularity or high grade cytology (high grade mucinous adenocarcinoma).

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signet ring adenocarcinoma


Rarely, signet ring adenocarcinoma (as in the stomach) can occur in the appendix. These are very aggressive tumors. Adenocarcinomas with an appearance similar to typical colonic adenocarcinoma can also be rarely encountered, but most appendiceal adenocarcinomas of the appendix are mucinous tumors

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Hemorrhoids

result from ectasia of the hemorrhoidal (rectal) venous plexus, due to persistently elevated venous pressure. External hemorrhoids are located below the pectinate line and are due to dilation of the inferior rectal vessels. Internal hemorrhoids are located above the pectinate line and are due to dilation of the superior rectal vessels. Some common causes include straining at stool because of constipation and the venous stasis of pregnancy. Internal hemorrhoids can prolapse out of the rectum. Hemorrhoids often present with pain and rectal bleeding, particularly bright red blood seen on toilet paper. Treatments include sclerotherapy, rubber band ligation, and in severe cases, hemorrhoidectomy.

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Anal fissure

linear separation of the tissues of the anal canal extending through the mucosa. Most (90%) are posteriorly located, typically caused by firm bowel movements.

Internal sphincter spasm
Impairs healing: decreases perfusion, widens fissure
Pain and bright blood with stool passage
Comorbidities: constipation, diabetes, Crohn’s
Treatment:
Stool softening and bulking (fiber)
Topical nitrates, calcium channel blocker (NTG, diltiazem, nifedipine)
Botulinum toxin
Lateral sphincterotomy – risk of incontinence
Sphicter dilation – mixed efficacy

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Anal fistula

fistula tract may lead to the skin, or end blindly in perianal soft tissue. Most cases are due to an intersphincteric abscess arising in an anal duct. Can be caused by trauma, Crohn’s disease, or ulcerative colitis.

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Condyloma accuminatum

polypoid wart, HPV associated.

146

Anal intraepithelial neoplasia

Describes various degrees of premalignant squamous dysplasia of the anal canal, and similar to cervical intraepithelial neoplasia, lesions are graded based on the microscopic and cytologic atypia present (so just as there is CIN I, CIN II, and CIN III, there is AIN I, AIN II, and AIN III). These grades correspond to mild squamous dysplasia, moderate squamous dysplasia, and severe squamous dysplasia/carcinoma in situ.

AIN lesions are associated with HPV infection, and like the cervix, AIN is a sexually transmitted disease. In immunocompromised individuals (e.g. HIV), AIN can progress to invasive cancer; rate of disease progression in immunocompetent individuals is uncertain.

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Anal carcinoma

Relatively rare carcinoma, comprises 2-3% of all GI tract carcinomas.

Most common type is squamous cell carcinoma (either keratinizing, non-keratinizing, or basaloid type). Most of the squamous cell carcinomas are associated with HPV, particularly HPV type 16 or 18.

Tumors most commonly arise at the pectinate line, and can extend superiorly into the rectum or radially into the perianal tissues. Because of the dual lymphatic supply at the pectinate line, lymph node metastases can be to the rectal lymph nodes or to the inguinal lymph nodes.

Patients can present with bleeding, pain, mass lesion, and pruritis. Approximately 25% of patients are asymptomatic.

Many patients with advanced anal cancers are treated with radiation and chemotherapy; patients that do not respond to this regimen may have either local excision or abdominoperineal resection of the residual tumor.

Other types of malignancies can occur in the anal canal, including adenocarcinoma (many are actually overgrowths of rectal adenocarcinomas), Paget’s disease (malignant glandular neoplasm having a predominant or exclusive intraepithelial location), and malignant melanoma.

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Ulcerative Colitis vs Crohn's symptoms

UC: Bloody diarrhea and tenesmus
Crohns: Nonbloody, abdominal pain, wight loss anorexia.
surgery cures UC

149

Ulcerative Colitis vs Crohn's complications

UC:
Toxic megacolon*
Hemorrhage
Stricture
Hypercoagulability
Colon cancer
PSC*

Crohn’s:
Abscess
Perforation
Obstruction, SBO
Hypercoagulability
Colon cancer
Hemorrhage

Ileal disease or
resection (> 100cm)
Bile salt diarrhea
Gallstones
Vit B12 deficiency
Oxylate stones

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Inflammatory Bowel Disease Colorectal cancer risks

Increased risk with:
Disease proximal to splenic flexure
> 8 years duration; young age at diagnosis
Primary sclerosing cholangitis
Family history of CRC
Pseudopolyps at colonoscopy

5-ASA treatment is protective

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Acute Colonic Diverticulitis

Diverticulosis affects 5-10% > age 40 and 80% > age 85.

Symptoms of diverticulitis or hemorrhage occur in about 20%.

Symptoms:
Pain, diarrhea, fever & abdominal tenderness
Hemorrhage is rare

Complications: abscess, rupture or fistulize to adjacent organs

Diagnosis is made by CT, not endoscopy or barium enema

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Treatment of Diverticulitis

Mild diverticulitis without peritoneal signs:
oral hydration, liquid diet, 10 days of oral antibiotics (metronidazole and ciprofloxacin)(Amox/Clavulanate)

Severe pain; elderly, comorbidities, no PO intake:
hospitalize, IV antibiotics, NPO, CT scan

Peritonitis; sepsis; perforation
surgical intervention

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Acute Diverticular Hemorrhage

Accounts for 50% of acute lower GI bleeding

Massive bleeding occurs in 5% of patients with diverticulosis

Hemorrhage is self-limited in 80%

Bleeding recurs in 1/3

Risk of rebleeding after a 2nd bleed is > 50%

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Inflammatory Bowel Disease Treatment

5-ASA for induction, much better for UC than Crohns
Surgery will cure UC, not Crohns

steroids are not maintenance therapies
NOT MTX during pregnancy

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Ischemic Colitis

Diagnosis
History
CT: Thickened colon wall
Colonoscopy: confluent, mucosal ulceration friability, usually splenic flexure.
Biopsy

Management: Improve perfusion (volume)
Correct underlying cause.
If self-limited, early colonoscopy not indicated (high risk)
Elective colonoscopy in 6-8 weeks – rule out other cause, stricture
If peritonitis, sepsis - Surgery

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Neoplasm

Location-dependent symptoms
Right colon – anemia Left colon – obstruction
Occult, slow bleeding or anemia
Rarely hematochezia
Cause in 50

Treatment: surgical resection

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Enterobius vermicularis

Pinworm infection
Worldwide distribution, most common helminth infection in US
Prevalence can reach 50% in children, caregivers of infected children, and institutionalized individuals.
Symptom: perianal pruritis
May also present with insomnia, abdominal pain, anorexia, irritability
Rarely, peritoneal granulomas and vulvovaginitis
Acquired by ingestion of pinworm eggs
Eggs can remain viable on surfaces for 2-3 weeks
Eggs will likely NOT be found in stool sample!

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Necator americanu

Pruritic Papular Erythematous Rash
Cause hookworm and strongyloidiasis

Stool sample for diagnosis:
Necator eggs or Strongolides larvae
Skin penetration
Hookworms are bloodsuckers…
Major symptom is iron-deficiency anemia

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Ancylostoma duodenale

Pruritic Papular Erythematous Rash
Cause hookworm and strongyloidiasis

Stool sample for diagnosis:
Necator eggs or Strongolides larvae
Hookworms are bloodsuckers…
Major symptom is iron-deficiency anemia

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Strongolides stercoralis

Stomach and GI complaints
Respiratory
dry cough
throat irritation
Skin
an itchy, red rash that occurs where the worm entered the skin
recurrent raised red rash typically along the thighs and buttocks.
What makes it different:
Autoinfection possible, especially with Immunosuppressed individuals

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Trichuris trichiura

Whipworm or Trichuriasis
Diagnosis:
Eggs in feces have a characteristic barrel-shaped appearance
Finger clubbing best indicator of
severity of infestation
Bloody diarrhea = iron
deficiency anemia
Heavy cases:
Frequent, painful stools with mucus, water and blood, tenesmus
Rectal prolapse
Finger clubbing

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Ascaris lumbricoides

ascariasis
About half of the populations in tropical and subtropical areas are infected with this parasite
Disease: IF symptoms are experienced, abdominal discomfort
If a severe case, intestinal blockages
Ultrasonography and radiology to determine
Has a lung stage of life cycle, may cause cough
Chest radiograph of newly-infected individual may reveal infiltrate
Charcot-Leyden crystals


Diagnosis: eggs w/thick shells

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parasite vaccines

there are none

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Albendazole

Broad-spectrum benzimidazole drugs
Roundworms and tapeworms
Distribution: Limited oral absorption, albendazole is better absorbed if targeting tissue-migrating larvae is important
Mechanism: Binds to parasite β-tubulin and inhibits the formation of microtubules
Death can take several days, for some helminths more than one dose may be necessary
Specificity: differences in tubulin
Toxicity:
Systemic toxic affects on liver/bone marrow rare
Abdominal pain, nausea, dizziness, headache
Embryotoxic and teratogenic in pregnant rats
Evidence suggests safe for use in children when warranted

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Mebendazole

Broad-spectrum benzimidazole drugs
Roundworms and tapeworms
Distribution: Limited oral absorption, albendazole is better absorbed if targeting tissue-migrating larvae is important
Mechanism: Binds to parasite β-tubulin and inhibits the formation of microtubules
Death can take several days, for some helminths more than one dose may be necessary
Specificity: differences in tubulin
Toxicity:
Systemic toxic affects on liver/bone marrow rare
Abdominal pain, nausea, dizziness, headache
Embryotoxic and teratogenic in pregnant rats
Evidence suggests safe for use in children when warranted

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Pyrantel pamoate

The cholinergic antihelmintics
Mechanism:
Levamisole selectively opens a restricted subgroup of nematode acetylcholine receptor (AChR) ion channels in nematode nerve and muscle. depolarization entry of calcium through the opened channels, and an increase in sarcoplasmic calcium, producing spastic muscle contraction the parasite is then unable to maintain its location (often in the intestine) and is then swept away, effecting the cure.
Toxicity: Causes nausea, vomiting, diarrhea
Distribution: Poorly absorbed

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Levamisole

The cholinergic antihelmintics
Mechanism:
Levamisole selectively opens a restricted subgroup of nematode acetylcholine receptor (AChR) ion channels in nematode nerve and muscle. depolarization entry of calcium through the opened channels, and an increase in sarcoplasmic calcium, producing spastic muscle contraction the parasite is then unable to maintain its location (often in the intestine) and is then swept away, effecting the cure.
Toxicity: Causes nausea, vomiting, diarrhea
Distribution: Poorly absorbed

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Ivermectin

A macrocyclic lactone
Mechanism: Binds to glutamate-gated chloride channels in invertebrate nerve and muscle cells, causing deactivation of channel: worm paralysis and death by starvation
Resistance: efflux transporters
Toxicity:
Generally well-tolerated
Itching, swollen lymph glands and rarely dizziness
Inflammatory reaction due to death of adult worms
Specificity: This type of channel restricted to phyla Nematoda and Arthropoda. in humans are only in the CNS , Doesn’t cross blood-brain barrier
Spectrum: Nematodes- Ascaris, Strongyloides and Onchocerca

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Diphyllobothrium

Fish tapeworm

Life cycle:
Acquired by eating the musculature of fish where larvae have migrated
Adheres to mucosa of small intestine

Diagnosis:
The standard intestinal “problems”
Anemia due to competition for B12 in intestine*
Stool contains eggs and/or proglottids

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Taenia

Beef or pork tapeworm
Diagnosis:
The standard intestinal “problems”
Stool contains eggs and/or proglottids
Cysticercosis possible if cysticerci migrate to muscle, brain, or other tissue

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Echinococcus

eggs in feces to Oncosphere hatches, penetrates intestinal lining to Slow growing cysts in organs
Diagnosis
Not really a GI illness at all
Pain or discomfort in the upper abdominal region or chest
Sheep farming + uncontrolled living with canines; trappers

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Praziquantel

Mechanism: increased permeability of the parasite to divalent cations leading to contraction of the worm’s musculature
Toxicity: Generally well-tolerated, but dizziness and nausea are side effects
Spectrum: Cestodes (tapeworms) and trematodes (flukes)

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Schistosoma mansoni

Causes the disease schistosomiasis
“In terms of impact this disease is second only to malaria as the most devastating parasitic disease.”-CDC
Two major forms of schistosomiasis – intestinal and urogenital – disease incidence numbers lump both together
Urogenital caused by the species Schistosoma haematobium

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S. japonicum

Causes the disease schistosomiasis
“In terms of impact this disease is second only to malaria as the most devastating parasitic disease.”-CDC
Two major forms of schistosomiasis – intestinal and urogenital – disease incidence numbers lump both together
Urogenital caused by the species Schistosoma haematobium

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Schistosomiasis


After skin penetration, schistosomulae find capillaries and migrate first to lungs, second to heart, and third to LIVER
Average lifespan is 5 years, but adult worms can live up to 20 years.

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Schistosomiasis Mechanism

Symptoms are caused by immune response to egg stage of Schistosoma
Eggs shed by the adult worms become lodged in the intestine or bladder, causing inflammation, scarring.
After years, this damages the liver, intestine, spleen, lungs, and bladder
Repeatedly-infected children can develop anemia, malnutrition, and learning difficulties

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Schistosomiasis Symptoms

Within days of infection: rash or itchy skin
1-2 months of infection: fever, chills, cough, and muscle aches
Chronic: abdominal pain, enlarged liver, blood in the stool or urine, and problems passing urine.
Chronic infection can also lead to increased risk of bladder cancer.

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Schistosomiasis Diagnosis

Stool or urine samples can be examined microscopically for parasite eggs
Eggs are passed in small amounts intermittently, it may be necessary to perform a blood (serologic) test.

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Schistosomiasis Treatment


Antiparasitic: praziquantel
Low efficacy against immature worms, so may need to give a second dose if eggs still present in stool or urine 2-3 months later
In acute cases, treatment with praziquantel is usually delayed until three months after infection as this is when it is most effective
Steroid medication (corticosteroids) may be used to relieve the symptoms of acute schistosomiasis, as they help control the allergic reaction to the eggs responsible for the symptoms.

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Schistosomiasis Prevention

Superior sanitation
Do not swim in freshwater that may be contaminated
Mass Drug Administration (MDA) of Praziquantel in endemic areas has reduced disease burden and eliminated Schistosomiasis in some disease foci

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What's crucial for a colon cancer diagnosis?

Biopsy

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Colon cancer treatment algorithm
T4 and/or

if yes: high risk and treat with folfox: 5-FU/LV or
Capecitabine
if no, check dMMR

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Colon cancer treatment algorithm
dMMR

if yes, low risk: no therapy
if no, medium risk: oncotype it

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Recommended Follow Up for Colon cancer

Physical exam every 3 months for 2 years, then every 6 months for 3 years.
CEA every 3 months for 2 years, then every 6 months for 3 years for T2, T3, T4 tumors.
Colonoscopy in 1 year
Repeat in 1 year if abnormal polyps noted
Repeat every 3-5 years if negative
Repeat in 3-6 months after diagnosis if 1st colonoscopy with “unprepped” bowel.

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Metastatic colon cancer

Incurable
Treatment goals to improve survival and quality of life
Standard of care is FOLFOX or FOLFIRI with bevacizumab
Second-line options include use of cetuximab or panitumumab
-MUST be k-ras wild-type to use either drug
Regorafenib
-Recent FDA-approved multi-kinase inhibitor
-Inhibits both VEGFR2 and TIE2

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Chemoprevention of colon cancer

COX-2 inhibitors used to prevent in adenomas in FAP patients
Aspirin to prevent adenomas in patients with prior colon cancer or family history of colon cancer.

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Is colon cancer curable?

Yes, yes, yes!

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colorectal cancer metastasis

local site of CRC metastasis are the mesenteric lymph nodes
distant site is most often the liver, next lung, often present as numerous undetectable micrometastases

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CIMP

CpG island methylator phenotype (CIMP) is reported in ~ 20% of Colorectal cancers, mostly linked to MSI CRCs

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APC/CIN

complete disruption of APC and/or its pathway (WNT/beta catenin)
chromosomal instability (CIN)
mostly left side
often loss of p53
 RAS activity
hereditary syndrome: FAP (thousands of tumors)
~ 85% of all CRC
poor prognosis (30% survival)

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MMR/MIN

complete loss of mismatch repair (MMR) (mostly MLH1 or MSH2)
microsatellite instability (MIN)
mostly right side
methylator phenotype common
hereditary syndrome: Lynch (a sub-type of HNPCC, 1 or several tumors)
~ 15% of all CRC
better prognosis (90% survival)

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APC

APC loss is rate-limiting in adenomagenesis
APC is a classic tumor suppressor gene (Knudson’s two-hit hypothesis), thus expression of both copies must be lost in tumorigenesis

APC is also involved in cell adhesion, migration, cytoskeletal integrity and chromosomal fidelity

APC controls WNT signaling via regulating cytoplasmic levels of B-catenin

loss of APC leads to buildup of B-catenin, induction of growth stimulatory genes, cell proliferation and cancer

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K-Ras

currently the most effective clinically predictive biomarker

K-Ras is a key cell signaling molecule that acts downstream of receptor tyrosine kinases such as EGFR; activating K-Ras mutations occur in ~ 40% of CRC and K-Ras mutations are associated with poor prognosis and poor survival
two anti-EGFR monoclonal antibody drugs, cetuximab and panitumumab, are ineffective in patients with activating K-Ras mutations

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familial adenomatous polyposis

transmitted in an autosomal dominant fashion as a heterozygous mutation in APC that is recessive at the cellular level; 80% inherited from a parent, 20% new mutations, FAP has 100% penetrance
classic FAP characterized by thousands of polyps in left colon that manifest by age 15, with cancer by mid-30’s, colectomy is only effective treatment but NSAIDs can prevent some polyps
FAP cancers are very similar (genetics, morphology) to sporadic APC/CIN, only earlier and far more in number
FAP patients at higher risk for several other cancers and syndromes
FAP phenotype depends on site of germline APC mutation - most severe is truncation mutation between codons 1250 and 1464 with hotspot at 1309, with extracolonic diseases also site dependent

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AFAP

characterized by relatively low polyp number (1-100), later age for presentation (polyps ~ 44, cancer ~ 52 years)
caused by mutations in APC gene that occur at either extreme amino terminus (