INFLAMMATORY BOWEL DISEASE

PREPARED BY; DR. SYED FAHAD HAMID

Major forms
Two major forms;

1) Crohns disease
2) Ulcerative colitis

CROHNS DISEASE
Definition;
Crohns disease is a chronic recurrent disease characterized by patchy transmural inflammation involving any segment of the gastrointestinal tract from mouth to the anus.

ULCERATIVE COLITIS
Definition; Ulcerative colitis is a chronic, recurrent disease characterized by diffuse mucosal inflammation involving only the colon. It invariably involves the rectum and may extend proximally in a continuous fashion to involve part or all of the colon.

Crohns Disease
Incidence
410 per 100 000 per year

Prevalence
27106 per 100 000

September 2004

Ulcerative Colitis

Incidence
615 per 100 000 per year

Prevalence
80150 per 100 000

September 2004

 Jews are more prone than other ethnic

groups. Crohns is slightly more commoner in females. Highest incidence and prevalence rates are from Northern Europe, UK and North America.

Aetiopathogenesis
Three major interactive co-factors.
1) Genetic susceptibility
2) The environment (both local

microenvironment and nutritional

environment
3) Host immune response

Familial
Family history is the largest independent

risk factor.
1 in 5 with crohns and 1 in 6 with UC will

have a first degree relative with the

disease.

Genetic
Increase concordance for the disease in

monozygotic twins than dizygotic twins. Susceptibilty loci have been found on chromosome 16(IBD1), 12, 6, 14, 5, 19, 1, 16(IBD8) and 3, These have been renamed IBD1-9 respectively.

Genetic; contd.
Significant loci also found on chromosome

13q and in jewish families on 1p and 3q. Linkage mutations on Card 15(NOD2), the underlying gene on chromosome 16 (IBD1), and genes underlying IBD5 and IBD3 loci. The Card 15 (NOD2) gene is associated; Crohns disease in whites and stricturing small bowel crohns disease.

Genetic; contd.
Recent SNP (single nucleotide polymorphism)

scans have identified a locus for UC and Crohns disease at ECM1 (extracellular matrix protein 1). Other risk loci; on IL23R, IL12B, NKX2-3 and MST1. The autophagy genes ATG16L1 and IRGM, (along with CARD 15) are specific for Crohns disease.

Genetic; contd.
HLA genes involved: HLA genes on chromosome 6 also appear to have a role in modifying the disease. DRB 0103 allele- linked to aggressive course of Ulcerative colitis and the need for surgery, and with colonic crohns disease. DRB*0103 and MICA*010- perianal disease DRB*0701- ileal Crohns disease

Environmental Factors

Good domestic hygiene has been shown to

be a risk factor for Crohns disease.

Life style
Nutritional factors: Higher sugar and fat intake. Smoking exacerbates Crohns disease. Smoking improves Ulcerative colitis. Nicotine is

effective treatment of Ulcerative colitis.

Adverse life events and psychological factors

increase relapses in patients with quiescent disease

Appendicectomy
Is protective for Ulcerative colitis before 20

years of age.

Increases the risk of Crohns disease.

Intestinal microflora
IBD is characterized by an overaggressive

immune response to luminal bacterial

antigens and other products in the genetically susceptible.

Intestinal microflora;contd.
Alteration in the bacterial flora: Increase in anaerobic bacteria in Crohns disease and aerobic in UC. Bacterial antigens: Exert their pro-inflammatory influence by producing toll like receptor ligands, which interact with the normal intestine with surface toll like receptors (TLRs). The disruption of the surface TLR signalling prevents the mucosa to withstand bacterial insults.

Toll-like Receptors

Medzhitov, R. et al. N Engl J Med 2000;343:338-344 September 2004

Intestinal microflora;contd.
Intestinal mucosal invasion;

The intestinal wall in IBD patients is contaminated by adherent and invading bacteria. e.g. there is increased E.coli adherence to the ileal-epithelial cells in Crohns disease. This occurs via E.colis type 1 pilli to a protein called carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM 6). The latter may become a marker for inflammation.

Intestinal microflora;contd.
Defective chemical barrier or intestinal

defensins
Evidence suggests a decrease in human alpha defensin-1 (HD-1) in both Crohns disease and UC and lack of induction of HD-2 and HD-3, HD-5 in Crohns disease

Intestinal microflora;contd.
Impaired mucosal barrier function;

It explains the presence of unusual and

potentially pathogenic bacteria, e.g. Mycobacterium paratuberculosis (MAP), Listeria and mucosal adherent E.coli.

Intestinal microflora;contd.
Butyrate :
Sulphate producing bacteria increase luminal levels of hydrogen sulphide resulting in reduction of butyrate oxidation in colonic mucosa, producing energy deficient state and leading to mucosal inflammation

Pathogenesis
Defective mucosal immune system producing

an inappropriate response to luminal antigens such as bacteria . Bacterial ligands interact with toll like receptors TLRs expressed on epithelial membranes via co-stimulatory molecules which enable the epithelial cells to act as antigen presenting cells to the myeloid dendritic cells.

Pathogenesis; contd..
Then follows the cascade of stimulation of the

naive Th 0 cells to the effector Th 1, Th2, and Th17 which predominate over the regulatory T cells. Cytokines released from the above cells stimulate the macrophages to secrete TNFalpha, IL-1 & IL-6 in large quantities Macrophages are also stimulated by plasmacytoid dendritic cells via natural killer cells which themselves can cause direct cytotoxic effects on cells and secrete inflammatory cytokines.

 All the above result in leucocytes leaving the

circulation and releasing cytokines (lymphokines, arachidonic acid metabolites, neuropeptides, and free o2 radicals leading to tissue damage and also attract more inflammatory cells like a viscious circle.

Toll-like Receptors

Medzhitov, R. et al. N Engl J Med 2000;343:338-344 September 2004

Pathology; Chrons disease

Any part can be affected.

Increase tendency to involve the terminal

ileum and ascending colon.

Can involve single(e.g. terminal ileum) or

multiple areas(skip lesions)

Can involve whole of the colon (total colitis)

Pathology Ulcerative Colitis

Proctitis ( the rectum alone)

left sided colitis (Sigmoid and descending

colon)
Total colitis
backwash ilietis (inflammation of the

terminal ileum )

Macroscopic changes; Crohns Disease

Small bowel is thickened and narrowed
Deep fissures and ulcers in the mucosa Cobble stone appearance

Colon : fistulae and abscesses

Initially the ulcers are aphthoid but later

larger and deep ulcers appear in patchy distribution.

Aphthae

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September 2004

September 2004

Ileitis

September 2004

Macroscopic changes; Ulcerative Colitis

Mucosa looks redenned, inflammed and

bleeds easily Severe disease -extensive ulceration and the mucosa adjacent to it looks like inflammatory polyps Fulminant disease of either type- loss of most of the mucosa leaving a few islands of oedematous mucosa and toxic dilatation occurs.

Ulcerative Colitis

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September 2004

Microscopy; Crohns disease

Inflammation extends through all three layers

(transmural).
Increase in chronic inflammatory cells and

lymphoid hyperplasia
Non caseating granulomas in 50-60 %

Granuloma

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September 2004

Microscopy; Ulcerative colitis

Superficial inflammation. Chronic inflammatory cell infiltrate in the

lamina propria
Crypt abscesses and goblet cell depletion

Ulcerative Colitis

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September 2004

Differentiation
Sometimes it becomes difficult to diffrentiate

between the two so in those cases, serological testing might help.

Extragastrointestinal manifestations
Occur in both the diseases
Joint complications are the commonest The peripheral arthropathies are classified as

Type 1 (pauci articular) acute self limiting (<10 weeks) and occurs with IBD relapses Type 2 lasts longer (months to years), is independent of IBD activity and usually associated with uveitis

EXTRAGASTROINTESTINAL MANIFESTATIONS
ULCERATIVE COLITS (Percent cases) CROHNS DISEASE (Percent cases) 5 3-10

EYES
Uveitis Episcleritis, Conjunctivitis 2 5-8

JOINTS
Type 1(pauci-articular) Arthropathy Type 2(polyarticular) arthropathy Arthralgia Ankylosing Sponylitis Inflammatory back pain 4
2.5 5 1 3.5

6
4 14 1.2 9

SKIN
Erythema nodosum Pyoderma gangrenosum 1 1 4 2

Association of HLAs
HLA DRB1*0103 with pauci articular large

joint arthritis in Ulcerative Colitis and Chrons

disease
HLA-B44 Small joint symmetrical arthritis HLA-B27 with sacroilietis

Differential Diagnosis
All causes of diarrhoea should be excluded

Ileo colonic tuberculosis

Lymphomas

CROHNS DISEASE

Clinical features:
Major symptoms are diarrhoea, abdominal

pain, and weight loss. Constitutional symptoms include malaise, lethargy, anorexia, nausea, vomitting and low grade fever

Clinical presentation:
15% have no GI symptoms Patients with extensive disease have more

frequent recurrences 30 % present with ilietis 25 % present as anal and perianal disease In 20-40 % enteric fistulae form, i.e. bladder or vagina.

Clinical presentation:
Acute or insidious Clinical features are variable and depend on the region of

the bowel affected The abdominal pain can be colicky suggesting obstruction. 80 percent present with diarrhoea and in colonic involvement, will contain blood. Can present with steatorrea in small bowel disease Can present as an emergency mimicking appendicitis Can be complicated by anal and perianal disease in 25% preceding colonic and small intestinal symptoms by many years.

Examination
Weight loss and general ill health Aphthous ulcers Tenderness in RIF, although mostly

abdominal examination is normal Mass (abscess or matted inflammed bowel loops) Oedematous anal tags, fissures or perianal abscess

 Extragastrointestinal features
Sigmoidoscopy : Rectum may appear normal,

but a biopsy must be taken to find nonspecific inflammatory changes. In extensive colonic disease the rectum may be spared but there still can be patchy involvement with an oedematous hemorrhagic mucosa.

Investigations
Blood tests
Normochromic normocytic anemia of chronic

disease.
Iron or folate deficiency.

Megaloblastic anemia due to B-12 deficiency is

unusual despite terminal ileum involvement.

Hypoalbuminemia(in severe disease)

Blood cultures (if septicemic)

Raised ESR, CRP and TLC.

 Liver biochemistry may be abnormal Serological tests (saccharomyces cerevisiae

antibody) is usually present pANCA is negative

Stools cultures

Should always be performed if diarrhoea is present.

 Radiology and imaging Ba follow through or CT scan with oral contrast, in every patient with crohns disease.
Findings -asymmetrical alteration in mucosal pattern with deep ulceration and areas of narrowing and thickening. Terminal ileum is the most common site.

 Magnetic resonance enteroclysis ( for

imaging of the small bowel) Colonoscopy, if colonic involvement is suspected, except in severe acute disease.
Plain abdominal X-rays, U/S or CT in patients presenting acutely with colonic symptoms, High resolution U/S and CT scan are helpful in

defining the thickness of the bowel wall and mesnetry as well as intraabdominal and para intestinal abscesses.

 Endoanal US and MRI for perianal disease Radionuclide scans with gallium labelled

polymorphs or indium or technetium labelled leucocytes, to identify small intestinal and colonic disease and to localise extraintestinal abscesses

Disease activity
Assessed by using simple parameters such as Hb, white cell count. Inflammatory markers (ESR, CRP, and platlet count) and serum albumin. Calprotectin is a calcium binding protein and accounts for 60 % of cytosolic protein of neutrophils. Faecal calprotectin is cheap noninvasive marker of disease activity in IBD and may be of help in predicting response to and failure of treatment.

Medical management
Aim Inducing remission Maintaining remission

Management of mild symptoms

Mild symptoms- symptomatic treatment Stop smoking Diarrhoea : anti diarrhoeals ( loperamide, codein

phosphate or co-phenotrope Cholestyramine if diarrhoea is due to bile acid malabsorption Anemia depending on the cause should be treated Anemia of chronic disease will improve as the disease improves (erythropoetin can be used) Active (moderate to severe) disease may require hospital admission Moderate to severe chrons colitis are treated as for UC

Remission induction
Glucocorticoids oral or IV (30-60 mg/day) Slow realease formulations such as

budesonide in ileocaecal disease It has a high topical activity and is rapidly eliminated by the liver so less suppression of the cortisol and least adverse effects Remission response rates vary(60-90 %) depending upon the site and extent of the disease.

 Enteral nutrition Can be used in moderate to severe disease Rates of induction of remmision are the same

as steroids if a low fat (1.3% of total calories) and a low linoleic acid content are administered as a sole agent for 28 days. In colonic involvement however the relapse rates are high

 Unresponsive patients- raise the dose of

azathioprine to levels that make patients leucopenic.

Remission maintenance
Flareups occur on tapering steroids or

stopping enteral diets. They can be treated by temporarily increasing steroid doses for inducing remission. Aminosalicylates for treating remission in crohns colitis. Immunosuppressives (azathioprine, 6mercaptopurine, methotrexate and mycophenolate mofetil) are used in all other patients for maintaining remission.

Side effects of immunosuppresives

Hypersensitivity (carefull monitoring is required) Bone marrow depression (3 monthly blood counts should be performed in all patients)

Biological agents
Failure to induce or maintain remission,

biological agents can be used. Infliximab a chimeric anti TNF-alpha monoclonal antibody Is the most widely used biological agent. Most successful at inducing remission in cortocosteroid/immunosuppressive resistant patients and also maintaining it. Efficacy is reduced due to formation of antibodies

Two other TNF-alpha antibodies are now widely used. Adalimumab fully human anti-TNF monoclonal antibodies Used in patients who fail to respond to infliximab as well as those who have not received it.

 Certolizumab pegol is a pegylated Fab

fragment of humanized anti-TNF-alpha monoclonal antibody. Short-term and longer-term efficacy has been demonstrated.

 Other new anti-TNF antibody therapies

include CDP571, etanercept and onercept.

Surgical management
Approximately 80% require an operation at some time in their life during the course of their

disease Nevertheless surgery should be avoided if possible and only minimal resection should be undertaken as recurrence(15%) is almost inevitable. Chances of recurrences can be reduced in patients undergoing their second surgery by treating them with Azathiprine and 6Mercaptopurine.

 Indication for surgery Failure of medical therapy, with acute or chronic symptoms producing ill health. Complications (e.g. toxic dilatation, obstruction, perforation, abscesses and enterocutaneous fistula) Failure to grow in children despite medical treatment

 Surgical approach Stricturoplasty(some strictures) Resection and end to end anastamosis(others) Subtotal colectomy and ileorectal anastamosis when entire colon is involved and rectum is spared. Panproctocolectomy with an ileostomy is the standard procedure for whole colonic and rectal involvement.

ULCERATIVE COLITIS

Ulcerative colitis
Clinical features Major symptoms (diarrhoea with blood and mucous) General features include malaise, lethargy, anorexia and weight loss Aphthous ulceration in mouth

 Can be classified as mild moderate and

severe Runs a course of remissions and exacerbations 10% have persistent chronic symptoms Others have only a single attack In proctitis urgency, tenesmus, are common

 Acute attack of Ulcerative colitis patients

have a bloody diarrhoea, passing upto 10-20 liquid stools per day. Occasionally blood and mucous may be passed alone.

 Toxic megacolon is a serious complication. On plain abdominal a dilated thin walled

colon with a diameter of >6cm will be seen. Serious complication and may result in perforation and high mortality(15-25%). Urgent surgery is required in all patients in whom toxic dilatation has not resolved within 48 hours.

Severe attack of ulcerative colitis

Definition Stool frequency
fever tachycardia ESR Anemia Albumin

>6 stools/day with blood +++

>37.5 C >90 per minute >30 mm per hour < 10g/dl haemoglobin <30g/dl

Severe attack; contd

Management

Admitt to hospital
Assess IV fluids Monitor daily: Stool frequecy Abdominal X ray FBC, CRP albumin

Examination
Generally no specific signs Slight distention and tenderness on palpation Rectal examination: blood will be seen Rigid sigmoidoscopic examination:

inflammed bleeding and friable mucosa. can be normal in cases of rectal sparing.

Investigations
Blood tests

Iron deficiency anemia White cells and platlet counts are raised ESR and CRP are raised Liver biochemistry may be abnormal Hypoalbuminemia occurs in severe disease pANCA may be positive

Stool cultures
Should always be performed to exclude

infective causes of colitis

Imaging Plain abdominal xrays with an abdominal ultrasound: key investigations in moderate to severe attacks The extent of the disease can be assessed by the degree of air distribution in the colon. Thickening of the colonic wall can be detected on ultrasound as can the degree of hyperemia in the colonic wall.

 Radionuclide scans Used to assess colonic inflammation

Colonoscopy Should not be performed in acute attacks because of the risk of perforation. Can be performed in long standing chronic diseases in defining the extent and activity of the disease and excluding the onset of dysplasia and carcinoma in patients with longstanding disease of 10 years duration or more

Medical management
All patients should be treated with an aminosalicylate. The active moiety is 5-aminosalicylic acid(5-ASA). The 5-ASA is absorbed in the small intestine (and may be nephrotoxic) so the design of various aminosalicylate preparation is based on the binding of 5-ASA by an azo bond to sulphapyridine(sulphasalizine), 4 amino benzyl beta alanine(balsalazide), or to 5-ASA itself(olsalazine), coating with a PH sensitive polymer(Asacol), or packaging of 5-ASA in microspheres(pentasa)

Proctitis : Oral amino salicylates +local rectal steroid preparation are the first line treatement. Mesalazine enemas and budesonide enemas can be tried. Resistant cases: oral cortiocosteroids alone or combination with azathioprine can be tried

Left sided proctocolitis: Oral aminosalicylates + local rectal steroid preparation Moderate to severe attacks: oral prednisolone. Unresponsive patient: to be admitted to the hospital

Total colitis(moderate to sever attacks) Admitt to hospital Intially hydrocortisone 100mg IV 6hourly + oral aminosalicylates Full investigation and full supportive therapy (IV fluids, nutritional support) Patients with previpous moderate to severe attacks of total colitis- Azathioprine

 Monitor clinical status(fever, tachycardia,

abdominal signs). Daily FBC, ESR, CRP, electrolytes, urea, LFTS, X-ray erect abdomen and stool weight. Persistent fever, tachycardia, falling Hb, rising TLC, falling potassium, falling Albumin, and persistently raised stool weight(>500gm/day) with loose blood stained stool shows non responsiveness and is an indication for surgery.

 Rescue therapy to avoid colectomy: (for

patients with poor prognostic signs and a CRP more than 45mg/L after 3 days of IV hydrocortisone) Hydrocortisone + IV cyclosporin 2mg/kg/day or TNF- alpha antibody therapy Other agents: visilizumab and leucocytapheresis(selective removal of white cells from blood and reinfusion of RBCs and leucocyte poor plasma)

 Patients responding to i.v. hydrocortisone

treatement, oral prednisolone therapy should be substituted and doses should be tailed off(5-10mg/weekly) Maintenace of remission is with aminosalicylates. In patients in whom it is not possible to reduce the dose without a flareup, azathioprine is used.

Surgical Management
Treatment of Ulcerative colitis is mainly medical, but surgery has a very central role as well. Indications for surgery in Ulcerative colitis are

Fulminant acute attack:

Failure of medical treatment (3 days) Toxic dilatation Haemorrhage perforation

Chronic disease
Incomplete response to medical treatment Excessive steroid requirement Non-compliance with medication

Risk of cancer

Surgical approach Subtotal colectomy with end ileostomy and preservation of the rectum is the operation of choice in acute disease Later a number of options can be tried. These include, proctectomy with a permanent ileostomy or Ileorectal anastomosis if a permanent ileostomy is to be avoided

 Annual biopsies of the rectal mucosa must be

carried out to detect dysplasia. With ileoanal anastomosis, a pouch of the ileum is formed that acts as a reservoir. A third patients will experience pouchitis which is characterized by the pouch mucosa with clinical symptoms of diarrhoea, bleeding, fever and at times exacerbation with extracolonic manifestations

 Pouchitis is twice as high in primary

sclerosing cholangitis. Two thirds will recur as acute relapsing or chronic unremitting forms. Treatment is not always satisfactory and includes topical and oral 5-ASA, corticosteroids, metronidazole and ciprofloxacin.

 Probiotics (four strains of lactobacillus, three strains of bifidobacterium, and one of streptococcus) have been shown to prevent the onset of pouchitis and to maintain remission. Short chain fatty acid enemas and alicaforsen( a selective inhibitor of intercellular adhesion molecule 1, ICAM-1, expression) enemas have shown promise in pouchitis treatment.

Course and Prognosis

Third of the patients with distal inflammatory

proctitis due to Ulcerative colitis will develope more proximal disease, with 5-10% developing total colitis. A third will have a single attack Others will have relapsing course A third will undergo colectomy within 20 years of diagnosis

Cancer and IBD

There is an increased risk Screening strategies Screening colonoscopy with multiple biopsies should be done every 2 years in patients with total UC and crohns colitis of 10 years and every

year after 20 years Left sided UC and those with less than total crohns colitis should have a screening colonoscopy at 15 years and therafter biannually Patients with Ulcerative colitis and primary sclerosing cholangitis are particularly at risk of developing colon cancer and should have yearly screening

Pregnancy and Inflammatory bowel disease

Women with inactive IBD have normal

fertility Fertility however may be decreased in active disease Spotaneous abortions are twice as likely in those with active disease than those with inactive disease. Relapse rates in pregnancy are similar to those of non pregnant patients.

 Flareups in the first trimester enhances the

risk of flareups in puerperial period. There is no risk of flareup in pregnancy for both Crohns disease and ulcerative colitis Relapse if it does occur is however more likely in the first trimester. Amino salicylates, steroids, and azathiprine are safe at the time of conception and during pregnancy

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