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!