Download Pathophysiology

Inflammatory
Bowel
Disease
Inflammatory Bowel Disease
(IBD)
• Immune-mediated chronic intestinal
condition
• “Inflammation of the intestines”
Source:
p.1886
Types of IBD
IBD
Ulcerative
Colitis (UC)
Crohn’s
disease (CD)
Source:
p.1886
Ulcerative Colitis (UC)
• Mucosal disease
• Involves the rectum
and extends
proximally to involve
all parts of the colon
• Produces mucosal
friability and areas of
ulceration
Source:
p.570
Source:
p.1887
Crohn’s disease (CD)
• Chronic inflammatory
disorder that produces
ulceration, fibrosis, and
malabsorption
• Can affect any part of the GI
tract from the mouth to the
anus
– Terminal ileum and colon are
the more common sites
Source:
p.569
Source:
p.1888
Pathophysiology
Possible factors
a pathogenic organism (as yet
unidentified)
an immune response to an intraluminal
antigen (eg, protein from cow milk)
or an autoimmune process whereby an
appropriate immune response to an
intraluminal antigen and an inappropriate
response to a similar antigen is present on
intestinal epithelial cells.
Predisposing factors
genetic predisposition [NOD2 gene (now
called CARD15), chromosomes 5 (5q31)
and 6 (6p21 and 19p)]
abnormal immune reactivity
smoking, diet, drugs, geography and
social status, the enteric flora, altered
intestinal permeability, and appendectomy
Pathophysiology of IBD - pt. 2
Pathophysiology of IBD - Summary
EPIDEMIOLOGY
Ulcerative Colitis
Crohn’s Disease
Age of onset
15-30 & 60-80
15-30 & 60-80
Ethnicity
Jewish>non-Jewish>Caucasian>African
American>Hispanic> Asian
Male-female ratio
1:1
1.1-1.8:1
May prevent disease
May cause disease
No increased risk
Odds ratio 1.4
Protective
Not protective
Monozygotic twins
6% concordance
58% concordance
Dizygotic twins
0% concordance
4% concordance
Smoking
OCP
Appendectomy
CLINICAL FEATURES
Ulcerative Colitis
Crohn’s Disease
Gross blood in stool
Yes
Occasionally
Mucus
Yes
Occasionally
Systemic symptoms
Occasionally
Frequently
Pain
Occasionally
Frequently
Rarely
Yes
Significant perineal
disease
No
Frequently
Fistulas
No
Yes
Abdominal mass
CLINICAL FEATURES
Ulcerative Colitis
Crohn’s Disease
No
Frequently
Rarely
Frequently
Response to antibiotics
No
Yes
Recurrence after
surgery
No
Yes
ANCA-positive
Frequently
Rarely
ASCA-positive
Rarely
Frequently
Small-intestinal
obstruction
Colonic obstruction
ENDOSCOPIC FEATURES
Ulcerative Colitis
Crohn’s Disease
Rarely
Frequently
Continuous disease
Yes
Occasionally
“Cobblestoning”
No
Yes
Granuloma on biopsy
No
Occasionally
Rectal sparing
RADIOGRAPHIC FEATURES
Ulcerative Colitis
Crohn’s Disease
Small bowel significantly
abnormal
No
Yes
Abnormal terminal ileum
Occasionally
Yes
Segmental colitis
No
Yes
Asymmetric colitis
No
Yes
Occasionally
Frequently
Stricture
TREATMENT
Treatment Goals
Relieve symptoms by suppressing the
chronic inflammation of the intestines
– Induce remission
periods of time that are symptom-free
– Maintain remission
prevent flare-ups of disease
– Improve the patient's quality of life
a
Treatment Options
• Pharmacologic
– 5-ASA
– Glucocorticoids
– Antibiotics
– Azathiprine and 6-MP
– Methotrexate
– Cyclosporine
– Tacrolimus
– Anti-TNF Antibody
Treatment Options
Non-Pharmacologic
– Nutritional Therapy
Bowel Rest and TPN
– Surgery
Resection
Strictureplasty
Pharmacologic: 5-ASA
5-aminosalicylate acid
Mainstay of therapy
For mild to moderate UC and CD
Effective at inducing remission in both UC
and CD
Maintains remission in UC
Pharmacologic: 5-ASA
Example: Sulfasalazine
Combined sulfapyridine and 5-ASA
MOA: anti-inflammatory
Side effects: allergic and hypersensitivity
reactions, headache, nausea and
vomiting, anorexia
Pharmacologic: 5-ASA
• Example: Mesalamine
• Sulfa-free 5-ASA
• Similar MOA to Sulfasalazine, less side
effects
– Olsalazine
– Asacol, an enteric coated mesalamine
liberates 5-ASA in pH>7.0
– Balsalazide
– Claversal
– Pentasa uses an ethylcellulose coating to
allow water absorption
Pharmacologic: Glucocorticoids
For moderate to severe UC and CD
unresponsive to 5-ASA
Induces remission but has no role in
maintenance therapy
Should be tapered once clinical remission
has been induced
Pharmacologic: Glucocorticoid
• Oral Glucocorticoid
– Prednisone 40-60mg/day
• Parenteral
– Hydrocortisone 300mg/day
– Methylprednisone 40-60 mg/day
– ACTH – for glucocorticoid naïve patients
• Side effects
– Fluid retention, hyperglycemia, osteonecrosis,
withdrawal symtoms
Pharmacologic: Antibiotics
• Indicated for post-colectomy and IPAA
complication (pouchitis) in UC patients
• Metronidazole
– 15-20mg/kg/day in 3 divided doses for several
months
– SE: metallic taste, nausea, disulfiram-like reaction
• Ciprofloxacin
– 500mg id
– 2nd DOA for active CD after 5-ASA
– 1st DOA in perianal and fistulous CD
Pharmacologic: Azathioprine and
6-MP
Purine analogs employed in the
management of gluocorticoid-dependent
IBD
MOA:
– is metabolized into thionosinic acid which
inhibits the purine ribonucleotide synthesis
and cell proliferation
– Glucocorticoid-sparing agents
Effective for post-operative prophylaxis of
CD
Pharmacologic: Azathioprine and
6-MP
Azathioprine
– 2-3 mg/kg/day
6-MP
– 1-1.5 mg/kg/day
Side effects
– Pancreatitis (reversible), nausea, fever, rash
and hepatitis, dose-related leukopenia
Pharmacologic: Azathioprine and
6-MP
Patients should be monitored (CBCs and
liver function) since they are at a four-fold
increased risk of developing a lymphoma
Pharmacologic: Methotrexate
(MTX)
MOA: inhibits dihydrofolate reductase
leading to impaired DNA synthesis
IM or SC route
Effective in inducing remission and
reducing glucocorticoid dosage, and in
maintaining remission in active CD
SE: leukopenia, hepatic fibrosis, HPS
pneumonitis
Pharmacologic: Cyclosporine
(CSA)
For severe UC patients refractory to
glucocorticoids
MOA: inhibits calcineurin →blocks
production of IL-2 and function of B-cells→
blocks helper T-cells→ inhibits both the
cellular and humoral immune system by
Pharmacologic: Cyclosporine
(CSA)
Best given IV 2-4 mg/kg/day
Oral 7.5 mg/kg/day only effective with 6MP/azathioprine
AE: HPN, gingival hyperplasia, etc
Monitor renal function (Creatinine
cleaance)
Pharmacologic: Tacrolimus
Macrolide antibioitc with
immunomodulatory properties similar to
CSA
100x as potent as CSA, has good oral
absorption
For children with refractory IBD and adults
with extensive small bowel involvement,
steroid dependent or refractory UC or CD
Pharmacologic: Anti-TNF Ab
MOA: Blocks TNF→ blocks inflammatory
cytokine → blocks intestinal inflammation
Examples:
– Infliximab
– Thalidomide
– Adalimumab
– Certolizumab Pegol
SE: increased risk of infections, serum
sickness
Non-Pharmacologic: Nutritional
Therapies
Bowel rest and TPN/EN
Induces remission
Use of peptide-based preparations
– Dietary intervention helpful in CD but not in
UC
a
Non-Pharmacologic: Srugery
Ulcerative Colitis
Crohn’s Disease
Intractable disease
Fulminant disease
Toxic megacolon
Colonic perforation
Massive colonic
hemorrhage
Extracolonic disease
Colonic obstruction
Colon cancer prophylaxis
Colon dysplasia or cancer
Small intestine
Stricture and obstruction unresponsive to
medication
Massive hemorrhage
Refractory fistula
Abscess
Large inestine
Intractable disease
Fulminant disease
Refractory fistula
Colonic obstruction
Cancer prohylaxis
Colon dysplasia/
cancer
Perianal disease unresponsive to medication
Non-Pharmacologic: Surgery
Ulcerative Colitis
Crohn’s Disease
Resection
Small intestine:
Resection and strictureplasty
Colorectal:
Temporary loop ileostomy
Diverting colostomy
Proctocolectomy
Resection
Non-Pharmacologic
Reduce stress
Stop smoking
Do not take NSAIDs if not indicated to
prevent ulcerations