BYDr. Nwalozie J.C.
INFLAMMATORY BOWEL DISEASE
OutlineIntroductionClassificationEpidemiologyAetiopathogenesisPathologyClinical presentation -G.I. Complications -Extraintestinal manifestationsDifferential diagnosesInvestigations/Work- upTreatmentPrognosisSummary
INTRODUCTIONInflammatory bowel disease(IBD) is a chronic
idiopathic , immune- mediated gastrointestinal condition that arises from a dysregulated immune response to host intestinal microflora.
There is a genetic predisposition.
They pursue a protracted relapsing and remitting course(usually extending over years) & give rise to extraintestinal manifestations.
Classification2 major types(Typical IBD): Ulcerative
colitis(UC)/Colitis ulcerosa & Crohn’s disease(CD)/ Crohn syndrome/Regional enteritis.
Atypical IBD: Lymphocytic colitis Collagenous colitis Ischaemic colitis Diversion colitis Indeterminate colitis Behcet’s disease
EPIDEMIOLOGYIncidence increasing:0.5-24.5/100,000 person-years(UC). 0.1-16/100,000 person-years(CD).
Overall prevalence:396/100,000 person-years UC:80-150/100,000 person-years CD:25-100/100,000 person-years
The incidence of IBD varies within different geographic areas
Highest incidence occurs in Europe, United Kingdom and North America.
Jewish > non-Jewish white > African American >Hispanic>Asian
• More common in developed countries, colder climates, urban areas, higher socio-economic classes.
• Appendectomy & cigarette smoking are protective in UC but are assoc. with increased risk for CD.
• OCP use assoc. with increased risk of CD.
• The peak age of onset is between 15-30yrs. A second peak occurs between the ages of 60-80yrs M:F for UC is 1:1 and for CD is 1.1-1.8 :1
A retrospective study was done by Nwosu M.N et al between January 2007 and June 2010 at 3 teaching hospitals in Southern Nigeria.
-Diagnosis was made from clinical features, colonoscopic and histopathologic findings.
-12 patients presented with IBD: 8(66.7%) were males and 4(33.3%) were females. Age ranges from 18 to 80yrs with a median of 25.5yrs.
AETIOPATHOGENESISThe aetiology of IBD is unknown.
Genetic susceptibilityA familial disease(5-10%)
Risk is increased(10%) among 1st degree relatives,5% if a parent has IBD & 36% if both parents have it.
Association with genetic syndromes( Turner, Hermansky-Pudlak, WAS,CGD,IPEX etc)
There is increased concordance of the disease in monozygotic twins in comparison to dizygotic twins
163 susceptibility loci(as at 2012)
Genes associated : NOD 2, ATG16LI, IRGM, JAK2, STAT 3(innate immunity & autophagy), XBP1, ORMDL3, OCTN(ER stress & metabolism), IL23R, IL12B, IL10,PTPN 2(adaptive immunity), MST1, CCR6, TNFAIP3( devt. & resolution of inflammation)
Others: ECM 1,IL-26(12q15),1p36. HLA DRB0103,-0701,MICA 010,HLA
B44,HLA B27 have modifying effect.
Presence of gene overlap.
Genetic influences increases the risk of 1 form while decreasing the risk for another.
ENVIRONMENTAL FACTORS
• Nutrition- Many food and food components have been suggested to play a role in the aetiopathogenesis of IBD eg high sugar or fat intake.E3N prospective study: high animal protein
Smoking
Appendectomy
NSAIDS
Psychological factors
Hygiene
The Intestinal microbiotaDysbiosis
Bacterial antigens
Specific bacterial pathogens
Defective chemical barrier/intestinal defensins
Impaired mucosal barrier function
Butyrate
HOST IMMUNE RESPONSENormally the mucosal immune system is unreactive
to luminal content due to oral(mucosal) tolerance
This tolerance is induced by multiple mechanisms – deletion or anergy of antigen reactive T cells, induction of CD4 T cell type that suppress inflammation (those expressing the fox p3 transcription factor)
In IBD, this suppression is altered leading to uncontrolled inflammation
In IBD there is inappropriate innate immune sensing and reactivity to commensal bacteria triggering the inflammation pathway
This pathway entails activation of CD4 T cell that secrete inflammatory cytokines which recruits other inflammatory cells
These cytokines are also normally produced in response to infection but are turned off at appropriate time to limit tissue damage. But in IBD, their activity are not regulated resulting in the disease condition.
PATHOLOGYUlcerative colitis- there are macroscopic and
microscopic featuresMacroscopic FeaturesIt is a mucosal disease that usually involves
the rectum and extends proximally to involve all or part of the colon
There are no skip areas
The mucosa is erythematous and has fine granular surface resembling sandpaper.
In severe disease the mucosa is hemorrhagic, edematous and ulcerated.
In long standing disease, inflammatory polyps as a result of epithelial regeneration.
In remission mucosa may appear normal but in patients with many years of disease it appears atrophic. it can be narrowed and shortened.
Microscopic FeaturesFindings are limited to mucosal and submucosa
The crypt architecture of the colon is distorted. They can be bifid and reduced in number
There can also be cryptitis and cryptal abscess
There is plasma cells and multiple basal lymphoid aggregates
Mucosal vascular congestion with edema and focal hemorrhage
There is inflammatory cell infiltrate of plasma cells, neutrophil, lymphocytes and macrophages
If ileum is involved there is villous atrophy, neutrophil and mononuclear infiltration of lamina propria
Crohn’s diseaseMacroscopic featuresIt can affect any part of the G I tract from mouth to the
anus
30-40%(small bowel disease), 40-55%(terminal ileum and ascending colon), 15-25%(large bowel alone)
Affectation is segmental with skip areas in the midst of diseased intestine
It is a transmural process
In mild disease there is aphthous or superficial ulceration
Perirectal fistulas, fissures, abscess, and anal stenosis
occurs in 1/3rd of patients
Rarely it can involve liver and pancreas.
Cobblestone appearance is characteristic of Crohn's dx and is seen on endoscopy and barium study
Microscopic featuresThere are aphthoid ulcerations and focal crypt
abscesses with loose aggregate of macrophages which form non Caseating granulomas in all layers of the bowel.
There is submucosal or subserosal lymphoid aggregate, occurring away from areas of ulceration with gross and microscopic skip areas
Cobblestoning
CLINICAL PRESENTATIONULCERATIVE COLITISI. Diarrhea (post prandial/nocturnal)II.Rectal bleedingIII.Tenesmus and passage of mucusIV.Cramps abdominal painV.Few constitutional symptoms- fever, malaise,
anorexiaOn examinationAbdomen- slightly distended and tenderDRE-tender anal canal, blood on examining
finger
Disease severity
MILD MODERATE SEVERE
Bowel movement
< 4 per day 4-6 per day > 6 perday
Blood in stool small moderate severe
Fever none < 37.5 *C >37.5*C
Pulse rate normal <90 beats/min >90 beats/min
Anaemia mild > 75% </= 75%
ESR < 30mm1st hr >30mm1st hr
Endoscopy Erythema, decreased vascular pattern, fine granularity
Marked erythema, coarse granularity, absent vascular markings, contact bleed and ulcerations
Spontaneous bleed and ulcerations
CROHN’S DISEASEAbout 15% of patients have constitutional
symtomsSite of the disease determines clinical
featuresILEOCOLITISRight lower abdominal painBloody diarrhoeaWeight lossRight iliac fossa massBowel obstruction`
JejunoilieitisSteatorrhea and malabsorptionNutritional deficienciesDiarrheaColitis and perianal diseaseConstitutional symptomsHaematocheziaDiarrhoeaFecal incontinence, anorectal fistula and
perirectal abscessGastro duodenal diseaseNausea, vomiting, epigastric pain, features of
GOO
G.I.COMPLICATIONSUlcerative colitis- HaemorrhageToxic megacolonPerforationStrictureColonic CaCrohn’s disease- AdhesionsFistula formation- enterocutaneous, colovaginalPerforationIntra abdominal and pelvic abscessIntestinal obstructionColonic Ca
Extra Intestinal Manifestations
Up to one-third of IBD patients have extra intestinal disease manifestation
DERMATOLOGICErythema nodosum- found in 15% of CD
patient and 10% of UC patientDigital clubbingPyoderma gangrenosumPyoderma vegetans Sweet syndrome- neutrophilic dermatosisPsoriasis- shared immunologic basisPerianal skin tags
RheumatologicArthropathyArthralgiaInflammatory back painAnkylosing spondylitisSacroilitisOcularOccurs in 1-10% of patientsConjunctivitisAnterior uveitis/iritisEpiscleritis
HepatobiliaryFatty liver & cirrhosisCholelithiasisPrimary sclerosing cholangitisUrologicCalculi formationUreteral obstructionIleo-vesical fistulaMetabolic bone diseaseOsteopeniaOsteonecrosis
Others includeHypercoagulable states
Vasculitides
Endocarditis
Interstitial lung disease
Amyloidosis
Pancreatitis
Differential DiagnosisInfectious diseasesBacterial- Campylobacter colitis, Salmonellosis,
Shigellosis, Clostridium difficile, E.coli (enterohaemorrhagic,enteroinvasive)
Viral- Cytomegalovirus, Herpes simplex
Protozoal- Isospora belli, Entamoeba histolytica
Parasitic- Trichuris Trichura, Strongyloides
Fungal- Histoplasmosis, Candidiasis
Non infectiousDiverticulitis
Ischaemic bowel disease
Radiation colitis
Appendicitis
Neoplasia- Ca ileum, familial polyposis
Drugs- NSAIDS, OCP, Cocaine
InvestigationsFull blood count: anaemia, leukocytosis
Acute phase reactants: ESR, CRP
Markers of intestinal inflammation- Fecal lactoferrin, Fecal calprotectin
Reduced albumin levels
Stool culture- to exclude superimposed enteric infection
EndoscopySigmoidoscopy- used to view the rectum and
sigmoid colon. Biospies can be taken for histology
Colonoscopy- shows active inflammation with ulcers and pseudopolyps. Complicating carcinoma can also be seen. Biopsies can be taken to determine disease extent. It should not be done in severe attacks for fear of perforation.
Capsule endoscopy
Wireless Capsule
Barium studies
Barium enema- it is used in colonic disease. In ulcerative colitis the colon is shortened,there are pseudopolyps and loss of haustrations. In crohn’s colitis there are strictures and ulcers with skip lesions.
Barium meal and follow through- used to detect ulcers and strictures in the upper gastrointestinal tracts
OTHER IMAGING:Abdominal ultrasound and CT scan- shows
thickened bowel wall and mesentery as well as intra abdominal and paraintestinal abscess
Radionuclide scan- used to localize extraintestinal abscess
Plain abdominal x-ray- shows dilated bowel and multiple air fluid level in intestinal obstruction.
Serological markersCan be used 2 differentiate btw CD and UC
and help in predicting the course of the disease
Perinuclear antineutrophil cytoplasmic antibodies(pANCA) – this is found in 60-70% of UC patients and 5-10% of CD patients, 5-15% of 1st degree relatives of UC patients are pANCA +ve. 2-3% of the general population are pANCA +ve. They are often associated with pancolitis, early surgery, primary sclerosing cholangitis
Anti Saccharomyces cerevisiae antibodies (ASCA)- found 60-70% of CD patients and 10-15% of UC patients.5% of non IBD patients are +ve.
Outer membrane porin C(OMPC)- about 55% of CD patients are +ve. Most are likely to have intestinal obstruction.
pANCA +ve with ASCA –ve results showed 57% sensitivity and 97% specificity for UC
pANCA –ve with ASCA+ve showed 49% sensitivity and 97% specificity for CD
Anti flagellin(anti CBir1)- identified in 55% of CD patients. It is associated with small bowel disease and is usually fibrostenosing type.
TREATMENTThe management of IBD involves the physician,
surgeons, radiologist and dieticians.
Medical Management(Stepwise approach)Aminosalicylates(5ASA)- sulfasalazine, melsalazine,
olsalazine, balsalazide
Used in the treatment of both CD and UC.
Sulfasalazine consist of sulfapyridine linked to 5ASA via an azo bond
Intestinal bacteria breaks the azo bond releasing sulfapyridine which is absorbed and excreted in urine.5ASA stays in the lumen in contact with the mucosa an eventually excreted in feaces.
Mechanism of action: modulates cytokine release from the mucosa thereby regulating inflammation
Side effects: abd. discomfort attributed to salicylate effect on the GI tract, folate deficiency due to folate competition with sulfasalazine for absorption. Others include skin eruptions, bone marrow suppression.
Other 5ASA preparations- much of the side effects are related to the sulfa portion. So some preparations have the sulfa portion replaced.
They include: -Olsalazine(diperitum )- consist of 2 5ASA
moieties joined by an azo bond, requires bacteria degradation in the colon
-Ascol- controlled release tablet form of 5ASA encapsulated by acrylic resin that dissolves at PH higher than 6.0
Pentasa- controlled release formulation of 5ASA encapsulated in ethylcellulose microgranules
Balasalazide- 5ASA preperation containing azo bond. 5ASA moiety is release in the colon by cleavage of azo bond by colonic bacteria.
They induce and maintain remission in UC. They have limited role in inducing remission in CD, but no clear role in maintaining remission.
GlucocorticoidsUsed in moderate to severe disease of UC and CDBoth oral and parenteral formulations are usedUsed in those who are intolerant or unresponsive
to aminosalicylatesOral prednisolone 40-60mg dly,
methylprednisolone 40-60mg daily and hydrocortisone 300mg dly
Budesonide is a controlled ileal release steroid with fewer side effects
Dosage: 9mg dly then taperSide effects: fluid retention, fat redistribution,
hypergylcaemia, osteoporosis, myopathy etc
AntibioticsThose used are metronidazole and ciprofloxacin
Metronidazole is used in active inflammation, fistulous and perianal CD
Dosage is 15-20mg/kg/day in 3 divided doses
Side effects: nausea, metallic taste, disulfiram like reaction, peripheral neuropathy
Ciprofloxacin beneficial in inflammatory, perianal and fistulous CD but has been associated with achilles tendinitis and rupture.
Purine analoguesAzathioprine and 6 mercaptopurine
Used in the management of glucocorticoid dependent IBD and also as post operative prophylaxis of CD
They act by inhibiting immune response
Efficacy is seen by 3-4wks but can take up to 4-6wks
Dosage:Azathioprine(2-3mg/kg/day), 6MP (1-1.5mg/kg/day)
Side effects: Pancreatitis, hepatitis, nausea, fever, rash, bone marrow supression
Methotrexate Inhibits dihydrofolate reductase resulting in
impaired DNA synthesis
There is also anti inflammatory property by reducing IL 1 production
Can be given subcut or IM
Side effects: Leukopenia, hepatic fibrosis ,hypersensitivity pneumonitis
CyclosporinHas inhibitory effects on both cellular and humoral
immunity
Given 2-4mg/kg IV in severe disease that is refractory to glucocorticoids
Side effects: renal toxicity, hypertension, tremors, parasthesias, gingival hyperplasia
Tacrolimus It is a macrolide antibiotic with
immunomodulatory properties
Used in children with refractory IBD and in adults with extensive involvement of the small bowel.
Biologic TherapyThey are reserved for moderate to severe ill
persons who have failed with other therapies
They include:Anti TNF therapy: eg infliximab. It is a chimeric
IgG 1 antibody against TNF-alphaIt is used in patients refractory to glucorticoid, 6
MP, 5 ASAUsed in those with refractory perianal and
enterocutanous fistula
Side effects: Malignancies like lymphoma, leukaemias, melanoma, hepatosplenic T cell lymphoma. Opportunistic infections like disseminated Histoplasmosis, coccidiodomycosis, exacerbate symptoms in patients with AF
Patients losing response to infliximab can change to adalimumab or certolizumab pegol
NatalizumabIt is used for patients who are refractory or
intolerant to anti TNF therapy
It was approved in February 2008
There is an increased risk of progressive multifocal leukoencephalopathy in patients been treated with natalizumab
Therapies in developmentMonoclonal antibodies against IL 12, 23 derived
from intestinal antigen presenting cell
Probiotics and PrebioticsProbiotics are live micro organisms that are used
as drug therapy to help develop healthy innate immunity. Eg lactobacillus, bifidobacterium.
Prebiotics are nutrients that are utilized by the gut microflora and they support the growth of these organisms and help improve the host immune system. Eg lactulose, inulin, oligofructose.
They are currently been investigated in clinical trials as treatment for IBD.
Medical therapy for UC
Medical management of CD
Medical management of fistulizing CD
Maintaining remission(UC)Oral +/- topical 5ASAAzathioprine(frequent relapses)
Maintaining remission(CD)Oral 5ASA(limited role)AzathiopineMethotrexate(intolerant to azathiopine)Infliximab
Nutritional therapyMany nutritional deficiencies are associated with
IBD due to malabsorption.
Iron depletion, hypoproteinemia, deficiencies in water and fat soluble vitamins, trace elements and electrolytes can be corrected using a suitable replacement regimen
Majority of the patients are advised to eat a well balanced diet and to avoid only those food which by experience are poorly tolerated.
Patient with small bowel strictures should avoid nuts, pulses, raw fruit and vegetable which may precipitate intestinal obstruction.
Those with proctitis and constipation will benefit from increase dietary fiber
Patient with active Crohn’s disease respond to bowel rest along with parenteral nutrition
Surgical Management
Ulcerative colitisUp to 60% of patients with extensive UC
eventually require surgery
Surgery involves removal of the entire colon and rectum. It offers the patient cure.
Choice of surgery is either panproctocolectomy with ileostomy or proctocolectomy with ileal anal anastomosis
Indications for surgery(UC)Intractable diseaseFulminant diseaseToxic megacolonColonic perforationMassive colonic hemorrhageExtra colonic diseaseColonic obstructionColon cancer prophylaxisColon dysplasia or cancer.
Crohn’s diseaseOperation are often necessary to deal with
fistulae, abscess, perianal disease and intestinal obstruction.
Up to 80% of patient eventually need some form of surgical intervention but ,unlike UC, it does not offer cure
Recurrence rate is high
Surgical intervention should therefore be conservative to minimize loss of viable intestine and to avoid short bowel syndrome.
Those with extensive colitis require total colectomy but ileal anal pouch formation should be avoided because of risk of disease reoccurrence within the pouch and subsequent fistulae, abscess and pouch failure
Those with perianal disease are managed conservatively by drainage of abscess and avoidance of reconstructive procedures
Indication for surgery(small bowel CD)Stricture and obstruction
Unresponsive to medical therapy
Massive hemorrhage
Refractory fistula
Abscess collectionColon and rectum CD Intractable disease
Fulminant disease
Perianal disease unresponsive to medical therapy
Refractory fistula
Colonic obstruction
Colon dysplasia or cancer
IBD and PregnancyWomen with inactive IBD have normal fertility.
Those who have had surgery secondary to IBD, there fertility rate is reduced to one third of normal due to scarring or occlusion of the fallopian tube secondary to pelvic inflammation
Spontaneous abortion, stillbirths and developmental defects are increased with increase disease activity not medication
Most patients can deliver vaginally but caesarean section may be preferred in patients with anorectal, perirectal abscess and fistula to reduce the likelihood of fistula developing or extending into episiotomy scar
Sulfasalazine and melsalazine are safe for use during pregnancy and nursing but folate supplementation is required.
Glucocorticoids are generally safe during pregnancy and nursing and are indicated with moderate to severe disease activity
Safest antibiotics to use are ampicillin and the cephalosporins
6MP and azathiopine pose minimal or no risk during pregnancy but experience is limited
Little data exist on cyclosporine. In patients treated with IV cyclosporine during pregnancy, 80% were completed.
Methotrexate is contraindicated in pregnancy and nursing.
No increased stillbirth, miscarriages or spontaneous abortion has been seen with infliximab or adalimumab.
Surgery should be performed only for emergency indication
Fetal mortality is high during surgery.
Cancer in IBD
Ulcerative colitisPatients with long standing UC are at increased
risk for developing colonic dysplasia and carcinoma
For patient with pancolitis, the risk of cancer rises 0.5-1%/yr after 8-10 yrs
This has lead to surveillance colonoscopy with biopsies for patient with chronic UC as the standard care
Annual or biennial colonoscopy with multiple biopsies has been advocated for patients with >8-10 yrs pancolitis or 12-15yrs of left sided colitis
Crohn’s diseaseRisk factors for developing colorectal cancer
in CD are a history of colonic(or ileocolic) involvement , long disease duration, family history of colorectal Ca and presence of PSC.
Cancer risk for CD and UC are equivalent for similar extent and duration of disease.
Same endoscopic surveillance strategy used for UC is recommended for patients with chronic Crohn’s colitis
CD patients have a 12-fold increased risk of developing small bowel cancer but this type of carcinoma is extremely rare
Patients with CD may have an increased risk of developing non-Hodgkin’s lymphoma and squamous cell carcinoma of the skin.
ManagementFor flat high grade dysplasia, for UC treatment is
colectomy and for CD is either colectomy or segmental resection.
For flat low grade dysplasia, immediate colectomy is done.
Adenoma in UC and CD patients with chronic colitis are removed endoscopically provided surrounding areas are free of dysplasia.
Prognosis The chance of survival for patients with IBD is generally
good
For both conditions, the overall mortality is currently less than 5%. UC is curable with proctocolectomy and ileostomy.
In CD, intestinal resection and re-anastomosis is followed by reoccurrence in about 20-25%
Extensive involvement has poor prognosis in both conditions while isolated small bowel CD and ulcerative proctitis carry good prognosis
Study done in Sweden on 709 patients with IBD, survival in the 1st year is 94% and 77% after 12yrs
Summary
ULCERATIVE COLITIS
CROHN’S DISEASE
INCIDENCE(NORTH AMERICA)
2.2-14.3:100000 3.1-14.6:100000
MALE TO FEMALE RATIO
1:1 1.1-1.8:1
MONOZYGOTIC TWINS
6% Concordance
58% Concordance
DIZYGOTIC TWINS
0% Concordance
4% Concordance
SMOKING Found more in non smokers
More in smokers
OCP No increased risk
Increased risk
APPENDECTOMY Protective Not protective
ULCERATIVE COLITIS
CROHN’S DISEASE
AREA OF INVOLVEMENT
Rectum +/- colon Entire GI tract
TYPE OF LESION Continuous Skip lesions
LAYERS INVOLVED
Mucosa & submucosa
Transmural
GROSS BLOOD IN STOOL
Yes Occasionally
MUCUS Yes Occasionally
ABDOMINAL PAIN Occasionally Frequently
ABDOMINAL MASS
Rarely Yes
SYSTEMIC SYMPTOMS
Occasionally Frequently
ULCERATIVE COLITIS
CROHN’S DISEASE
PERIANAL DISEASE
No Frequently
FISTULAS No Frequently
SMALL BOWEL OBSTRUCTION
No Frequently
COLONIC OBSTRUCTION
Rarely Frequently
RECTAL SPARING
Rarely Frequently
COBBLESTONING
No Yes
GRANULOMA ON BIOPSY
No Occasionally
ULCERATIVE COLITIS
CROHN’S DISEASE
pANCA-POSITIVE Frequently Rarely
ASCA-POSITIVE Rarely Frequently
USE OF ANTIBIOTICS AND TPN
No Yes
SURGERY Offers cure Does not offer cure
ConclusionIBD is a chronic relapsing immune-mediated GI
condition with extraintestinal manifestations.
UC and CD are the major types and are ,in many respects, similar but there are contrasting features which relate to sites of involvement and other features.
Diagnosis is based on clinical, endoscopic and histopathologic features.
Management is multidisciplinary & should be individualized.
ThankS For listening!