Inflammatory Bowel Disease

Question 1

What are the types of inflammatory bowel disease?

Answer 1

Ulcerative colitis and crohn’s disease

Question 2

What are the 6 main characteristics features of ulcerative colitis?

Answer 2

-diffuse inflammation limited to the colonic mucosa. - Disease can be confined to the rectum (proctitis), - extend more proximal into the sigmoid and descending colon (left sided colitis), or involve the entire colon (pancolitis). - The inflammation will almost always involve the rectum, - Inflammation will be continuous to its proximal most extent (i.e. there are no skip lesions), - Does not involve the upper gastrointestinal tract or small bowel.

Question 3

What are the main features of crohn’s disease?

Answer 3

• characterized by transmural inflammation - can affect any part of the gastrointestinal tract - locations of involvement such as the terminal ileum, colon and perianal area are much more common than other areas. - If Crohn’s disease is confined to the colon without small bowel or perianal involvement it can be difficult to distinguish from ulcerative colitis → In this case the term indeterminate colitis is often employed.

Question 4

What are the features of microscopic and collagenous colitis?

Answer 4

• Collagenous colitis and microscopic colitis (also called lymphocytic colitis) are colitides characterized by: = watery, non-bloody diarrhea with inflammation present on the microscopic level but normal appearing mucosa when viewed endoscopically. = Commonly occur in woman age 50 and older.

Question 5

drugs used to treat UC?

Answer 5

1. sulfasalazine - 5-ASA molecule 2. 6-MP - purine synthesis inhibitor 3. Infliximab - anti TNFalpha 3. Colectomy NB: Mesalamine does not work for Crohn’s But first line for UC Immunomodulators –> 6MP, azathioprine and MTX

Question 6

treatment of colorectal cancer

Answer 6

1. excision of the tumor and involved lymph nodes 2. adjunct chemotherapy 5-FU

Question 7

What is the difference in the gross morphology of UC and Crohn’s?

Answer 7

• In Crohn disease = “cobblestone” mucosa, strictures and creeping fat - In ulcerative colitis, there is pseudopolyps

Question 8

What are the differences in barium imaging between Crohn’s and UC?

Answer 8

Crohn’s –> string pipe = narrowing of the lumen UC –> lead pipe appearance = loss of haustra

Question 9

Biologic agents

Answer 9

-Infliximab, Certolizumab and Adalimumab –> injection or IV. Work well. Work against TNF alpha. Keep people from having abscesses, flares and surgeries. - Vedolizumab –> helps with homing. Only interacts with the alpha4B7 which is only in the gut unlike natalizumab which also works in the brain. - Natalizumab –> blocks interaction between integrin/addressin pairs – > problem causes PML (progressive multifocal leukoencephalopathy)

Question 10

Differences in extraintestinal manifestations seen in UC vs. Crohn’s?

Answer 10

Crohn disease is associated with migratory polyarthritis and nephrolithiasis - Ulcerative colitis is associated with primary sclerosing cholangitis (p-ANCA positive) - Both subtypes are associated (to varying degrees) with the following disorders: Pyoderma gangrenosum; Erythema nodosum; Ankylosing spondylitis; Uveitis; Aphthous ulcers

Question 11

Compare effectiveness of biologics and immunomodulators.

Answer 11

-Biologics are better than immunomodulators -Also better in combinaton

Question 12

Risks of biologics?

Answer 12

Serious infection –> clear association of biologic agents with TB

Question 13

What is the difference between Crohn’s and UC in the location of the GI affected?

Answer 13

• Crohn disease begins anywhere from mouth to anus with “skip lesions”; the rectum is very rarely involved. - Ulcerative colitis begins in the rectum and can extend up to the cecum, with continuous involvement (and sparing of the remainder of the GI tract)

Question 14

What is the difference in the pattern of inflammation seen in UC and Crohn’s?

Answer 14

• Crohn’s = transmural inflammation, Th1-mediated process; lymphoid aggregates with noncaseating granulomas. - UC = mucosal inflammation (superficial submucosa may also be affected), Th2-mediated process; crypt abscesses with neutrophils, but no granulomas.

Question 15

Risk = probability X consequence

Answer 15

perceived risk is more important

Question 16

Three ways of presentation of colorectal cancer? (second leading cause of cancer-related deaths in the US)

Answer 16

• Asymptomatic discovered through screening - Suspicious symptoms and signs - Emergency admission for intestinal obstruction, peritonitis, or acute GI bleed

Question 17

How do notable signs and symptoms of colorectal cancer differ based on location along the GI tract?

Answer 17

• Proximal (right-sided) tumors commonly appear as fungating exophytic masses. More commonly produce occult bleeding leading to iron deficiency anemia. - Distal (left-sided) tumors commonly appear annular (sometimes called a “napkin-ring” or “apple core” appearance). - Distal tumors also more commonly produce obstructive symptoms (constipation, decreased stool caliber, bowel obstruction). - Rectal cancer symptoms may include tenesmus (constantly feeling the need to pass stools despite an empty colon), rectal pain, and diminished caliber of stools.

Question 18

What are the two common most important risk factors from IBD?

Answer 18

• Malnutrition due to inflammation which destroys the mucosal cell wall and decreases the intestine’s ability to digest and absorb nutrients. - Adenocarcinoma due to higher turnover of epithelial cells, which increases the risk of cancer. Seen in all chronic inflammatory conditions.

Question 19

How often do immunomodulators cause lymphoma? How often do they cause pancreatitis?

Answer 19

0.04% (4 in 10 000) 3% Absolute risks better than relative risk 5-ASA works well for UC not Crohn’c Combination therapy is most effective for both

Question 20

What can we learn about lymphoma from the transplant literature?

Answer 20

Mostly caused by reactivation of IBD

Question 21

Complications more commonly associated with Crohn’s

Answer 21

Obstruction caused by stricture formation Fistula formation Perianal disease Cholelithiasis

Question 22

Complications more commonly associated with UC

Answer 22

Toxic megacolon Sclerosing cholangitis

Question 23

What are adverse events associated with use of TNF alpha medications?

Answer 23

Infusion or injection site reactions drug related lupus like reaction serious infections*** TB lymphoma*** multiple sclerosis, heart failure, serious liver injury *** –> patients worry about most.

Question 24

Lymphoma due to infliximab

Answer 24

Risk of lymphoma is about 2-4X the risk Absolute is about 6X –> worry about Serious infections vs getting NHL

Question 25

What are some characteristics of IBS?

Answer 25

- chronic abdominal pain in the absence of physiologic cause - common in middle aged women

Question 26

Risk factors for IBS?

Answer 26

- History of childhood sexual abuse - Domestic abuse in women - Presence of stress, depression, or a personality disorder

Question 27

what is primary sclerosing cholangitis?

Answer 27

chronic, progressive inflammation and fibrosis of the intrahepatic and extrahepatic ducts - median age is 40 - more common in men than women and children

Question 28

Most common malignancy of the large intestine?

Answer 28

adenocarcinoma

Question 29

What is familial adenomatous polyposis?

Answer 29

- autosomal dominant condition - characterized by the presence of multiple colorectal adenomatous polyps, typically more than 100. - caused by germline mutations in the tumor suppressor gene, adenomatous polyposis coli (APC) located on chromosome 5.

Question 30

What is lynch syndrome?

Answer 30

hereditary nonpolyposis colorectal cancer (HNPCC) - autosomal dominant disorder, - occurs due to mutations in mismatch repair genes (MSH2 and MLH1)

Question 31

Genetic Pathogenesis of Sporadic colorectal adenocarcinomas

Answer 31

- involve the APC/β-catenin pathway, causing adenomas and eventually carcinomas. - APC is a key tumor suppressor gene and loss of both alleles can lead to activation of KRAS, a proto-oncogene. Other tumor suppressor genes such as SMAD2/4 and p53 can also become mutated leading to dysregulated cell growth. - Also "microsatellite instability" pathway. Mutations in mismatch repair genes (e.g. MLH1 and MSH2) result in the accumulation of mutations in microsatellites = carcinogenesis.

Question 32

Treatment options for Crohn's

Answer 32

Corticosteroids Azathioprine (purine synthesis inhibitor) Infliximab (anti-TNFα antibody) Adalimumab (anti-TNFα antibody) Vedolizumab (anti-α4β7-integrin antibody) - replaced natalizumab due to the risk of PML Antibiotics (ciprofloxacin, metronidazole)

Question 33

Which IBD is associated with primary sclerosing cholangitis?

Answer 33

- Mostly UC - Titers for perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) are often positive in patients with PSC and ulcerative colitis (60-80%). - bile ducts become infiltrated with lymphocytes, which results in chronic inflammation and eventually leads to ductal destruction. This continued destruction leads to fibrosis and results in constriction of bile ducts. - etiology is unknown, but it has a strong association with inflammatory bowel disease, especially ulcerative colitis.

Question 34

Most common areas for carcinomas to metastasize

Answer 34

- metastasizes to the liver through the portal circulation. This is the most common cancer to metastasize to the liver, largely due to the rich portal circulation. In fact, in the US, liver cancer secondary to colorectal carcinoma metastasis is far more common than a primary hepatocellular carcinoma. - The second most common location is the lungs. - peritoneal seeding may lead to ovarian involvement.

Question 35

Prognostic factors and staging of colorectal cancer

Answer 35

- The most important prognostic factors are tumor invasion, lymph node involvement, and metastasis. TNM tumor staging. T0 = Carcinoma confined to mucosa or carcinoma in situ T1 = Invasion of the submucosa T2 = Invasion of the muscularis propria T3 = invasion of the serosa T4 = invasion of other organs or the peritoneum The most common site of metastasis is the liver.

Question 36

Signs and symptoms of primary sclerosing cholangitis

Answer 36

Some may have unremarkable physical exam. Some may have: Fatigue; Pruritis (sometimes extreme), which can lead to excoriations; Jaundice; Hepatosplenomegaly

Question 37

Labs and imaging of primary sclerosing cholangitis

Answer 37

LABS: suggest cholestatic pattern: conjugated bilirubin \>50%, bilirubinuria, absent urobilinogen, increased alkaline phosphatase and gamma-glutamyl transferase (GGT). IMAGING: of the biliary tree via endoscopic retrograde cholangiopancreatography (ERCP) [gold standard procedure for diagnosing PSC] - Narrowing and dilation of bile ducts (beads on a string) - most specific histologic finding is fibrous obliteration of small bile ducts with concentric replacement by connective tissue in an "onion skin" pattern. - PSC is associated with certain HLA antigens and polymorphisms such as HLA-DR52a (100%) and HLA-Cw7 (86%)

Question 38

Diagnosis of IBS?

Answer 38

Diagnosed based on the presence of recurrent abdominal pain or discomfort associated with 2 more of the following: - Pain improves upon defecation - Onset associated with a change in frequency of stool - Onset associated with a change in appearance of stool

Question 39

Non-pharmacological treatment of IBS?

Answer 39

- increased intake in fiber and avoidance of aggravating foods.

Question 40

most common bacterial cause of pseudomembranous colitis and what is this a result of?

Answer 40

- this is an inflammatory colitis characterized by the development of pseudomembranes - associated with amoxicillin, ampicillin, cephalosporins, and fluoroquinolones, though classically it is associated with prolonged clindamycin therapy. The most commonly caused by Clostridium difficile, though Salmonella, C. perfringens and S. aureus possible

Question 41

Risk factors of pseudomembranous colitis

Answer 41

Patients who are hospitalized Patients who are on prolonged antibiotics (particularly clindamycin or a 3rd gen. cephalosporin) Patients who are of advanced age

Question 42

Diagnosis of colorectal cancer

Answer 42

- gold standard = colonoscopy. Study of choice in a patient with fecal occult blood test - histology = dysplastic columnar cells with some varying degree of epithelial differentiation. - Barium enema may show an apple-core lesion due to luminal narrowing. - Patients with colorectal cancer often present with a normal physical exam.

Question 43

Poor prognosis of colorectal cancer

Answer 43

Mucinous differentiation and signet-ring formation is more commonly seen on the right side and carries a poorer prognosis.

Question 44

Staging of colorectal cancer and following progression.

Answer 44

- Carcinogenic embryonic antigen (CEA) can be used to monitor disease progression and recurrence, but is a poor screening test. - CT scans of the chest, abdomen, and pelvis are needed for staging of colorectal cancer.

Question 45

Recommendation for colorectal cancer screening

Answer 45

Colonoscopy recommended every 10 years beginning at age 50 for most patients, and beginning at age 45 for African Americans. Another screening option is flexible sigmoidoscopy plus fecal occult blood testing every 5 years.

Question 46

How would a tubular adenoma look on histology?

Answer 46

Question 47

How would a tubular adenoma look on histology?

Answer 47

Question 48

How would a colorectal cancer look grossly?

Answer 48

Question 49

Appearance of the intestinal wall in UC

Answer 49

Question 50

Appearance of the intestinal wall in Crohn's

Answer 50