INFLAMMATORY BOWEL DISEASE

References: II. EPIDEMIOLOGY

 Harrison’s
th
 Robbins pathology, 10 ed
 Sitaraman and friedman’ss essntias of gastroenterology (2018)
 Internet (Armando H , - youtube, medscape)

OUTLINE:
I. INTRODUCTION
II. EPIDEMIOLOGY
III. ETIOLOGY
a.) Genetic Consideration
b.) Diseases and genetic factor shared with IBD
c.) Genetic Loci associated with CD and/or UC
d.) Defective immune regulation in IBD
e.) The inflammatory cascade in IBD
IV. PATHOLOGY of UC and CD
V. CLINICAL MANIFESTATION
VI. DIAGNOSIS
A.) Differential Dx
III. ETIOLOGY
VII. MANAGEMENT
 GENETIC FACTOR
I. INTRODUCTION  Exogenous Factor (Composition of normal intestinal
IBD microbiota
 Chronic inflammatory bowel disease which pursue a  Endogenous Factor (Intestinal Epithelial cell barrier
protracted relapsing and remitting course. function, innate and adaptive immune function)
 An immune-mediated chronic intestinal condition  regulatory cells - very powerful regulatory
pathways that function within the immune system in which
 2 major types: Ulcerative colitis and Crohn’s Disease
the gut is restrained from full immunologic responses to
the commensal microbiota and dietary antigens 0P-

 ENVIRONMENTAL FACTOR
 Enteropathogen
 Diet
 Stess
 Smoking
 Antibiotics

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Genetic consideration  adaptive immunity-regulate the balance between

 IBD is a polygenic disorder that gives rise to multiple inflammatory and regulatory cytokines
clinical subgroups  inflammation -ultimately leukocyte recruitment and
 Genetic approaches: candidate gene studies, linkage inflammatory mediator production
analysis and genome-wide association studies  focus
DEFFECTIVE IMMUNE REGULATION IN IBD
on the identification of disease associated, single-
 When soluble antigens are administered orally: antigen-
nucleotide polymorphisms (SNP) within the human specific non responsiveness is induced.
genome have identified Approximately 100 disease-  Mechanism involved in induction of oral tolerance:
associated loci on many different chromosomes  deletion or anergy of antigen-reactive T cells

Diseases and genetic factors shared with IBD:  Why we need this oral tolerance?
- Because it is responsible for the lack of immune
 Rheumatoid arthritis (TNFAIP3)
responsiveness to dietary antigens and the commensal
 psoriasis (IL23R, IL12B)
microbiota in the intestinal lumen (which we need)
 ankylosing spondylitis (IL23R)
 In IBD this suppression of inflammation is altered, leading
 type 1 diabetes mellitus (IL10, PTPN2)
to uncontrolled inflammation
 asthma (ORMDL3)
 (TH) cells- associated with colitis
 systemic lupuserythematosus (TNFAIP3, IL10)
 TH1 cells [secrete interferon (IFN)
- induce transmural granulomatous
inflammation that resembles CD
- initiated by IL-12 (a key cytokine in
the pathogenesis of experimental models of
mucosal inflammation)

 TH2 cells (secrete IL-4, IL-5, IL-13)

and related natural killer T cells (that
secrete IL-13) –induce superficial mucosal
inflammation resembling UC
- induced by IL-4

 TH17 cells (secrete IL-17, IL-21)-

neutrophilic recruitment
- Induced by IL-23, together with IL-
6 and TGF-

 Activated macrophages secrete

tumor necrosis factor (TNF and IL-6)

The inflammatory cascade in IBD

 abnormal innate immune sensing
of bacteria (by parenchymal cells and
hematopoietic cells)  T-cell activation IL-1, IL-6, and
TNF (promote fibrogenesis, collagen production,
Genetic Loci associated with CD and/or UC:
activation of tissue metalloproteinases, coagulation
cascade in local blood vessels) (usually turned off or
 innate immunity and autophagy- function in innate immune
inhibited at the appropriate time to limit tissue damage)
cells (both parenchymal and hematopoietic).
 In IBD their activity is not regulated = imbalance
- respond to and clear bacteria, mycobacteria and viruses
between the proinflammatory and anti-inflammatory
 endoplasmic reticulum (ER) and metabolic stress- regulate
mediators
the secretory activity of cells.
- involved in responses to the commensal microbiota (Paneth
and goblet cells)

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 segmental with skip areas in the midst of diseased intestine

Exogenous Factors  Perirectal fistulas, fissures, abscesses, and anal stenosis –
 Salmonella, Shigella, Campylobacter, Clostridium present in 1/3 of the patient
difficile spp  transmural process
 Anaerobic organisms: Bacteroides and Clostridia species  Endoscopic findings:
 aerobic species: Escherichia  Mild: aphthous or small superficial ulcerations
 probiotics: Faecalibacterium prausnitzii, Lactobacillus,  Active: stellate ulcerations fuse longitudinally and
Bifidobacterium, Taenia suis, and Saccharomyces boulardii transversely to demarcate islands of mucosa
spp (may inhibit inflammation in animal models and  “cobblestone” appearance
humans.)  Can form pseudopolyps
 Psychological factor: divorce or separation, interpersonal  Active CD characteristics: focal inflammation and formation
conflict of fistula tracts (resolve by fibrosis and stricturing of the
bowel), bowel wall thickness, narrowed and fibrotic,
IV.PATHOLOGY (Macroscopic and microscopic features) Projections of thickened mesentery encase the bowel,
serosal and mesenteric inflammation promotes adhesions
ULCERATIVE COLITIS and fistula formation.
-usually involves the rectum and extends proximally to involve  Earliest lesions : aphthoid ulcerations and focal crypt
all or part of the colon abscesses with loose aggregations of macrophages 
 40–50% of patient- rectum and rectosigmoid noncaseating granulomas (can be seen in lymph nodes,
 30–40%- beyond the sigmoid but not involving the whole colon mesentery, peritoneum, liver, and pancreas)
 20%- total colitis (2–3 cm into the terminal ileum in 10–20% of  other histologic features:
patients)  submucosal or
 backwash ileitis- superficial and mild can be seen in  subserosal lymphoid aggregates
endoscope  gross and microscopic skip areas
 Mild inflammation: Mucosa: erythematous and fine has  transmural inflammation that is accompanied by fissures
granular surface that resembles sandpaper that penetrate deeply into the bowel wall (sometimes form
 Severe inflammation: Mucosa: hemorrhagic, edematous, fistulous tracts or local abscesses)
and ulcerated
 long-standing disease: has inflammatory polyps
(pseudopolyps) due to epithelial regeneration

two major histologic features:

1. the crypts (may be bifid and reduced in number)
architecture of the colon is distorted
2. some patients have basal plasma cells and multiple basal
lymphoid aggregates

 Mucosal vascular congestion, with edema and focal

hemorrhage, and an inflammatory cell infiltrate of
neutrophils, lymphocytes, plasma cells, and macrophages
may be present.
 neutrophils  invade epithelium in crypts  cryptitis 
crypt abscess
 Ileal changes in patients with backwash ileitis:
 villous atrophy
 crypt regeneration

CROHN’S DISEASE
-mouth to the anus
 30–40%: smallbowel disease alone (90% involves terminal
ileum)
 40–55%: both the small and large intestines
 15–25%: colitis alone.

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V. CLINICAL MANIFESTATION  Enterovesical fistulas: dysuria or recurrent bladder

infections or less common pneumaturia or fecaluria
ULCERATIVE COLITIS  Enterocutaneous fistulas: follow tissue planes of
Major symptoms: least resistance, usually draining through abdominal
 Diarrhea (intermittent) (nocturnal and/or postprandial) surgical scars
 Rectal bleeding (intermittent)
 Enterovaginal fistulas: dyspareunia, feculent or foul-
 Tenesmus (urgency with a feeling of incomplete
evacuation) smelling, painful vaginal discharge
 Passage of mucus 2.) Jejunoileitis
 Crampy abdominal pain (rare)  Malabsorption and steatorrhea( due to loss of
digestive and absorptive surface
 Fresh blood or blood-stained mucus (pt. With proctitis)  poor intake and enteric losses of protein and
 liquid stool containing blood, pus, and fecal matter (if nutrients
severe)  Anemia, hypoalbuminemia, hypocalcemia,
 others with moderate to severe: anorexia, nausea, hypomagnesemia, coagulopathy, and hyperoxaluria
vomiting, fever, and weight loss with nephrolithiasis ( due to Intestinal malabsorption)
 signs of proctitis: tender anal canal and blood on rectal
 vertebral fractures ( due to vitamin D deficiency,
examination
 toxic colitis: severe pain and bleeding hypocalcemia, and prolonged glucocorticoid use)
 megacolon: hepatic tympany  Pellagra (niacin deficiency in extensive small
bowel disease)
 Diarrhea, cause:
(1) bacterial overgrowth in
obstructive stasis or fistulisation
(2) bile-acid malabsorption due
to a diseased or resected terminal
ileum
(3) Intestinal inflammation with
decreased water absorption and
increased secretion of electrolytes
3.) Colitis and perianal disease
CROHN’S DISEASE  low-grade fevers, malaise, diarrhea, crampy
 inflammatory process evolves toward 2 pattern: abdominal pain, and sometimes hematochezia
 fibrostenotic obstructing  pain (caused by passage of fecal material through
 penetrating fistulous narrowed and inflamed segments of the large bowel)
 The site of disease influences the clinical  Decreased rectal compliance (causes diarrhea)
manifestations:  rectovaginal fistula (10% of women)
1.) Ileocolitis  incontinence, large hemorrhoidal tags, anal strictures,
 chronic history of right lower quadrant pain anorectal fistulae, and perirectal abscesses (one third
 diarrhea of patients)
 sometimes, mimic appendicitis: right lower quadrant 4.) Gastroduodenal disease
pain, a palpable mass, fever, and leukocytosis  nausea, vomiting, and epigastric pain (Symptoms and
 pain (colicky) signs of upper GI tract disease)
 precedes and is relieved by defecation  The second portion of the duodenum is more
 low-grade fever commonly involved than the bulb
 High-spiking fever suggests intraabdominal abscess
formation
 Fistulas involving the stomach or duodenum arise
from the small or large bowel and do not necessarily
 Weight loss (10–20% of body weight) consequence of
signify the presence of upper GI tract involvement
diarrhea, anorexia, and fear of eating.
 Patients with advanced gastroduodenal CD may
 Palplable inflammatory mass in RLQ (composed of
develop a chronic gastric outlet obstruction
inflamed bowel, adherent and indurated mesentery,
and enlarged abdominal lymph nodes
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V. DIAGNOSIS Serologic tests lack sensitivity to diagnose IBD and are not
recommended for routine use. There does not seem to be
 The diagnosis of UC or CD is based on the combination of the any correlation between pANCA or ASCA titers and disease
clinical presentation and results of laboratory, imaging, and activity, duration of illness, extent of disease, extraintestinal
endoscopic studies. No single test is considered diagnostic of manifestations, or need for surgical or medical treatment in
CD or UC.- Sitaraman and friedman’ss essntias of patients with IBD
gastroenterology (2018)
Imaging studies
Testing
 Upright chest and abdominal radiography
 Complete blood count (leukocytosis, anemia, thrombocytosis)  Barium double-contrast enema radiographic studies
 Nutritional evaluation: vitamin b12 evaluation, iron studies, red  Abdominal ultrasonography
blood cell folate, nutritional markers  Abdominal/pelvi computed tomography scanning/magnetic
 Markers of inflammation: resonance imaging
 Erythrocyte sedimentation rate and C-reactive protein levels  Computed tomography enterography
neither sensitive nor specific for IBD, but may be useful to  Useful in the detection of extraluminal disease and
assess disease activity in individual patients complications of CD such as perforation and abscess
Elevations predict relapsing disease  The sensitivity is 80–88% for the diagnosis of suspected CD
Elevations may identify patients likely to progress to  Magnetic resonance imaging (MRI) and MR enterography:
colectomy for severe UC  MRI and MR enterography are used to assess
 Fecal calprotectin level inflammatory processes in the bowel wall, submucosal
>250 μg g–1: correlates with the presence of large inflammation and fibrosis, as well as complications such as
ulcerations in CD (sensitivity 60%, specificity 80%) abscess and fistula
≤250 μg g–1: correlates with mucosal healing in CD  MR enterography is highly sensitive and specific for the
(sensitivity 94%, specificity 62%) diagnosis of small‐bowel ulceration, strictures, and fistulas
>203 μg g–1: predicts postoperative recurrence of CD with a specificity approaching 100% and sensitivity of 80–
>1900 μg g–1: predicts 87% colectomy rate at one year in 100%.
UC  Consider MR enterography for women of childbearing age
 Serologic studies: Perinuclear anti neutrophil cytoplasmic instead of CT
antibodies (ANCA), anti-Saccharomyces cerevisiae antibodies  enterography, small‐bowel follow‐through, or small‐bowel
(ASCA) enteroclysis (slow‐infusion small‐bowel follow‐through)
 Stool studies: Stool culture, ova and paraite studies, bacterial  Endoscopy:
pathogens culture, and evaluation for clostridium difficlie  Colonoscopy, with biopsies of tissue/lesions
infection considered an integral part of the initial evaluation in
 Serologic markers: order to diagnose IBD, assess the severity, and institute
 perinuclear antineutrophil cytoplasmic antibodies (pANCA), appropriate medical therapy
anti‐Saccharomyces cerevisiae antibodies (ASCA), anti‐CBir1, Microscopic examination of the mucosa typically show
anti‐I2, and anti‐outer membrane porin from E. coli (OmpC) crypt abscess, crypt distortion, and increased cellularity
antibodies is available to help diagnose IBD in the lamina propria. These finding do not distinguish
 ‘Atypical’ ANCA yielding a perinuclear staining pattern IBD from infectious diseases of the colon
(pANCA) with alcohol-fixed neutrophils are found in 60–65%  Flexible sigmodoscopy
of patients with UC; pANCA are also detectable in 20–25% of  Upper gastrointestinal endoscopy
patients with CD.  Capsule enteroscopy/ doubleballoon enteroscopy
 ASCA, anti‐Bir, and anti‐OmpC are detected primarily in Wireless capsule endoscopy (WCE): 30% of patients
patients with CD; ASCA are detectable in 46–70% of patients with CD have small‐bowel disease alone, and WCE has a
with CD, and in 5% of those with UC. higher diagnostic yield for small‐bowel CD compared
 Anti‐CBir1 expression is associated independently with with radiologic studies. In some cases, intestinal
small‐bowel penetrating, and fibrostenosing CD obstruction can be excluded by enteroclysis

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small‐bowel follow‐through, or with a self‐dissolving,  Behcet’s disease

radiopaque patency capsule prior to WCE delivery to  Diverticulitis
avoid acute obstruction  Drugs and toxins (e.g., chemotherapy, gold,
penicillamine)
Differential Diagnosis  Ischemic colitis
INFECTIOUS DISEASE:  Microscopic colitis (collagenous colitis and lymphocytic
colitis)
 Neutropenic colitis
 NSAIDs
 Radiation colitis

VII. MANAGEMENT

 The choice of medical therapy depends on the extent,

location, and severity of the disease and the presence or
absence of fistulas
 Certain drugs are used for the induction of remission (IOR),
and others for the maintenance of remission (MOR). Some
agents may be used for both IOR and MOR.
 Surgery is generally reserved for patients who are refractory
to medical therapy or who have fulminant disease (such as
toxic megacolon), a complication (such as perforation),
NONINFECTIOUS DISEASE dysplasia, or malignancy.

(*Medscape):
SYMPTOMATIC THERAPY
AVOID:
 Antidiarrheal agents (loperamide or
diphenoxylate/atropine) – because it can precipitate toxic
megacolon
 Other agent that may have anticholinergic effects

OVERVIEW OF THERAPY
1st step: Aminosalicylates (mild IBD)
2nd step: Corticosteroid
3rd step: immune-modifying agents
-Anti TNF monoclonal antbody therapy

AMINOSALICYLATES
 More effective in ulcerative colitis than I crohn’s disease
 Probiotic agents :
-supplementation of the high-potency probiotic mixtures
have been shown in some reports to reduce ulcerative colitis
diseaseactivity index scores in patients with mild to moderate
relapsing ulcerative colitis who are being treated with 5-ASA.

THE ATYPICAL COLITIDES ANTIBIOTICS

 collagenous colitis - increased subepithelial collagen  Metronidazole and ciprofloxacin
deposition and colitis with increased intraepithelial  Are used only sparingly in ulcerative colitis due to limited
lymphocytes efficacy and increased risk of developing antibiotic-asocaited
 Lymphocytic colitis- almost same as collagenous pseudomembraneous colitis. It can also increase the risk of
clostridium difficile colitis
colitis, however, intraepithelial lymphocytes are
increased
 Other Ddx:
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CORTICOSTEROID
 Indicated for acute flares of disease only and have no role in
the maintenance of remission
 They should be tapered once remissio has been induced

IMMUNOMODULATORS
 Have a slower onset of action and, consequently, are not
used for induction of remssion
 Have shown effectiveness for their steroid-sparing action in
persons with refractory disease
 Also use for primary trearment for fistulas and maintenance
of remission in patients intolerant of or not responsive to
aaminosalicylates

SURGICAL INTERVENTION

ULCERATIVE COLITIS
 Consier if medical therapy fails
 2 common choices: Proctocolectomy with eleostomy and
total protocolectomy with ileal pouch/anal anastomosis
(IPAA)
 Most commonoperation: IPAA- a diverting ileostomy is
performed and an ileal pouch is created and anastomosed
directly to the anus, with complete removal of the rectal
mucosa. After the ileoanal anastomosis is healed, the
ileostomy is taken down, adn flow through the anus is re-
established

CROHN’S DISEASE
 Usuallyy performed in pts with complications of the disease
(strictures, fistulas)

DIET,LIFESTYLE MODIFICATIONS, AND ACTIVITY

 Low residue diet- decrease the frequency of bowel
movements
 Multivitamin supplementation (vit b12, vit D deficiency is
common in pt.)
 Physical activity is limited only by the extent of fatigue and
the abdominal pain or diarrhea the patient is experiencing
 Moderate to vigorous physical activity for as long as 12
weeks has been shown to improve symptom scores and
many specific quality of life dimensions, including energy,
sleep, emotion and physical functioning

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