CROHN’S DISEASE

Gastroenterology unit

OUTLINE

• Introduction• Aetiopathogenesis• Pathology• Clinical features• Differential diagnosis• complications• Investigations• Management • Prognosis

Introduction

• IBD encompasses two distinct chronic,idiopathic inflammatory diseases of the GI tract:Crohn’s disease which can affect any part of the GI tract and Ulcerative colitis which affect only the large bowel

• There is overlap bwn these two conditions in their clinical features,histological and radiological abnormalities

• In 10% of cases of colitis a definitive diag of either CD or UC is nt possible

CROHN’S DISEASE

• The incidence of CD varies from country to country but is apprx 4-10/100,000 annually

• Prevalence of 27-106/100,000• World-wide distribution but commonly found in

the west• Incidence lower in non whites races• Jews more prone than non-jews and Ashkenazi

jews have higher risk than sephardic jews

• Slightly commoner in females(M:F=1:1.2)• Occurs at younger age than UC(mean age

26yrs)• In nigeria the incidence and prevalence is not

known but there are some case reports from Zaria,Enugu etc.The writers suspect lack of awareness of the disease,lack of adequate diagnostic facilities to the suspected low incidence in this part of the world

Aetiopathogenesis

• The etiology of CD is unknown• Represents the interaction of 3 essential co-

factors:Genetic susceptibility,environment and host immune response

• The environment represents both local microenvironment (enteric microflora) and also the nutritional environment

Familial

• FH is the largest independent risk factor for the disease

• Upto 1 in 5 patients with CD and 1 in 6 patients with UC will have a first degree relative with d disease

Genetic

• Increase concordance of the disease among monozygotic twins compared to dizygotic twins who show familial aggregation

• Both CD and UC are polygenic diseases-no single locus identified

• Susceptibility loci identified on chromosomes 16(IBD1),12,6,14,5,19,1,16(IBD8) and 3 and these have been renamed IBD1-9

• Linkage mutations have found on CARD15(NOD2), the underlying gene on chromosome 16(IBD1)

• The CARD15 gene is ass with CD in white populations and has also been ass with stricturing small bowel disease

• The autophagy genes ATG16L1 and IRGM,which control intrcellular degradation process(along wt CARD15),are specific for CD

• Modifying HLA genes on chromosome 6• HLA DRB*0103 is linked to an aggrasive course

of UC and need for surgery and colonic disease in CD

• DRB*0103 and MICA*010 are ass wt perianal disease and DRB*0701 wt ilial CD

Environmental factors

• Good domestic hygiene has been shown to be a risk factor for CD

• H pylori seroprevalence is reduced in CD• A clean environment may not expose the

immune system to pathogenic or non pathogenic micro-organisms particularly helminthic parasites and therefore be untrained to confront minor infections

lifestyle

• Breastfeeding may provide protection against IBD in the offspring

• Nutritional:high sugar and fat intake have been suggested to play a role in the pathogenesis of IBD

• Smoking:pts wt CD are more likely to be smokers and smoking has been shown to exacerbate CD

• Appendicectomy though protective against UC may result in icrease risk of dev CD and more aggressive dx

Intestinal microflora

• There is an alteration in bacterial microflora,wt an increase in anaerobic bacteria in CD and aerobic bacteria in UC

• Bacteria may exert their pro-inflammatory influence by producing toll-like receptor ligands such as PG-PS,LPS

• These interact wt intestinal surface toll-like receptors

• The disruption in TLR signalling could prevent mucosa withstanding bacterial insult

Pathogenesis

• IBD results from defective mucosal immune system producing an inappropriate response to luminal antigens such as bacteria

• Bacterial ligands interact wt toll-like receptors the epithelial cell membrane which act as antigen presenting cells to myeloid dendritic cells

• There then follows a stimulation of naïve Th 0 cells into effector T cells(Th1(IL12,INFδ),Th2(IL-5)and Th17(IL-17),wc predominate over regulatory T cells(T reg)

• The pro-inflammatory cytokines released by these activated T cells stimulate macrophages to secrete TNFα,IL-1 and IL-6 in large quantities

• These mechanisms all results in leucocytes leaving the circulation to enter the tissue and release chemokines wc lead to tissue damage and also atract more inflammatory cells like a vicious circle

Pathology

• CD is a chronic inflammatory dx that may affect any part of the GI system from mouth to anus bt has a particular tendency to affect the terminal ilium and ascending colon(iliocolonic disease)

• The disease may affect one small part of the gut such as the terminal ilium or multiple areas wt relatively normal bowel in between(skip lesions)

• May involve the whole colon(total colitis) sometimes without small bowel involvement

Macroscopic changes

• In CD the involved small bowel is usually thickened and narrowed

• There are deep ulcers and fissures in the mucosa producing a cobblestone appearance

• Fistulae and absceses maybe seen in the colon• An early feature is aphthoid ulceration,usually seen

at colonoscopy• Later larger n deeper ulcers appear in a patchy

distribution,again producing a cobblestone appearance

Microscopic changes

• In CD the inflammation extends through all layers(transmural) of the bowel.

• There is increase in chronic inflammatory cells and lymphoid hyperplasia

• In 50-60% of pts granulomas are seen• These granulomas are non-caseating

epithelioid cell aggregates wt langhans giant cells

Extragastrointestinal manifestations

• Eyes:uveitis,episcleritis,conjunctivitis• Joints:Type 1 (pauci articular) arthropathy-ass wt

HLA DRB1 0103• Type 2 (poly articular) arthropathy-HLA B44 ass wt

small joint symmetrical arthritis• Arthralgia,ankylosing spondylitis and inflammatory

back pain• Skin:Erythema nodosum and pyoderma

gangrenosum, Liver and biliary tree:sclerosing cholangitis,fatty liver,gall stones etc

Clinical features

• The major symptoms are diarrhoea,abdominal pain and wt loss

• Constitutional symptoms of lethargy,anorexia,nausea,vomitting and low-grade fever may be present and in 15% of these pts there are no GI symptoms

• Other clinical manifestations include bleeding,perianal disease,internal fistulae

• CD may present as an emergency wt right iliac fossa pain mimicking appendicitis

• If laparotomy is perfomed an oedematous,reddened terminal ilium is found

Differential diagnosis

• Ileocecal small bowel disease: infectious-acute appendicitis,cecal diverticulitis,PID,ileocecal tuberculosis,yersinia enterocolitica infection

• Non infectious:celiac disease,ectopic pregnancy,lymphoma,radiation enteritis

• Colonic disease: infectious-acute bacterial colitis(salmonella,shigella,campylobacter),amoebic colitis

• Non-infectious:ulcerative colitis,radiation colitis,ischaemic colitis

Complications

• Perforating disease:some group of pts have penetrating transmural disease that may lead to abscess or fistula formation

• Strictures:formation of recurrent strictures is the hallmark of the fibrostenotic variant of CD and a common complication of CD

• Perirectal disease: this may result in fistulas and abscesses

• Cancer:there is clearly an increased risk of small bowel adenocarcinoma in pts wt CD

Investigations

• FBC: normocytic,normochromic anaemia of chronic disease,deficiency of iron/folate also occurs

• Raised ESR and CRP and a raised white cell count

• Hypoalbuminaemia is present in severe disease

• Liver biochemistry may be abnormal

• Blood cultures are required if septicaemia is suspected

• Serological tests: saccharomyces ceravisiae antibody is usually present while p-ANCA is negative.The reverse is true in UC

• Stool cultures should be performed on presentation if diarrhoea is present

Radiology and imaging

• Barium follow-through: the findings include an assymetrical alteration in the mucosal pattern wt deep ulceration,and areas of narrowing or stricturing

• Although commonly confined to the terminal ilium,other areas of small bowel can be involved and skip lesions can also be seen btwn affected sites

• Colonoscopy: is performed if colonic involvement is suspected except in pts presenting wt severe acute disease

• High-resolution ultrasound and spiral CT scanning are both helpful techniques in defining thickness of the bowel wall and mesentry as well as intra-abdominal and paraintestinal abscesses

• Rectal uss and MRI are used to evaluate perianal disease

Disease activity

• This can be assesed using simple parameters such as HB,white cell count,inflammatory markers(raised ESR,CRP and platelet count) and serum albumin

• Fecal calprotectin has the potential as a cheap,simple non invasive marker of disease activity in IBD and may be of value in predicting response to and failure of treatment

Medical management

• The aim of management is to induce and maintain remission

• Pts with mild symptoms may require only symptomatic treatment

• Cigarette should be stopped,diarrhoea can be controlled with loperamide,codeine sulphate or co-phenotrope

• Diarrhoea in long standing disease may be due to bile acid malabsorbtion and should be treated wt cholestyramine

• Anaemia if due to vit B12,folic acid or iron def should be treated wt appropriate hematinics

• Anaemia of chronic disease will usually improve as the pt gets better

• Pts wt active moderate/severe attack may have to be admitted

Remission induction

• Glucocorticoids are commonly used to induce remission in moderate and severe attack of CD

• Oral prednisolone 30-60mg/day• In pts wt ileocaecal,but not colonic CD,slow release

formulations of budesonide are as efficatious as prednisolone

• Enteral nutrition: is an underutilised means of inducing remission in moderate/severe attacks of CD and efficacy is independent of nutritional status

• Enteral diets wt a low fat(1.3% of total calories) and a low linoleic acid content are administered as the sole source of nutrition for 28 days,rates of induction of remission are similar to those obtained wt steroids

• Relapse rates are high particularly in those wt colonic involvement

• In unresponsive pts remission is sometimes and maintained by raising the dose of azathioprine to levels that make pts leucopaenic

Maintainance of remission

• Remission can be maintained in crohn’s colitis but not in those wt small bowel involvement with aminosalicylates

• Remission in other pts can be maintained wt azathioprine(AZT,2.5mg/kg/day),6-mercaptopurine(6MP,1.5mg/kg/day),methotrexate(25mg i.m/week) and mycophenolate mofetil(1g/day)

• These drugs have steroid sparing properties

Biologic agents

• In pts in whom remission could not be induced or maintained wt corticosteroid/immunosupressive therapy,treatment with a biologic agent will be indicated

• Infliximab: a chimeric anti TNF-α monoclonal antibody,is the most widely used biologic agent

• Succesful at inducing remission in corticosteroid/immunosuppressive resistant patients,remission can be maintained(5mg/kg iv.weeks 0,2,6 and 8-weekly until week 46)

• Further courses of treatment can be given to reinduce and maintain remission

• Two other anti TNF-α antibodies inhibitors are now widely used:Adalimumab and certolizumab pegol

• New anti TNF-α antibody therapies include CDP571,etanercept and onercept

Surgical management

• Apprx 80% of pts will require surgery during the course of their illness

• Nevertheless surgery should be avoided if possible or minimal resections undertaken as recurrence(15%/year) is almost inevitable

• Indications for surgery include:failure of medical therapy with acute or chronic symptoms producing ill-health,complications( eg toxic dilatation,obstruction,perforation etc),failure to grow in children despite medical therapy

Prognosis

• The course of CD is highly variable.majority of pts lead a productive ,satisfying life punctuated by intermittent episodes of disease relapse

• Over the course of their disease 80% will require surgery and another 50% will subsequent surgery at some point

• Currently mortality rates appear to be only slightly higher than in age marched controls,this maybe due to cancer ass wt CD