There are two forms of idiopathic inflammatory bowel disease (IBD)

Ulcerative colitis: a mucosal inflammatory condition confined tothe rectum and colon

Crohn’s disease: a transmural inflammation of the gastrointestinaltract that can affect any part, from the mouth to the anus.

The etiologies of both conditions are unknown, but they may havesome common pathogenic mechanisms.

EPIDEMIOLOGY

The highest rates of IBD are assumed to be in developed countries,and the lowest are considered to be in developing regions

Colder climate regions and urban areas have a greater rate of IBDthan those of warmer climates and rural areas.

Internationally, the incidence of IBD is approximately 0.524.5cases per 100,000 person annually for ulcerative colitis and 0.116cases per 100,000 person annually for Crohn disease.

Overall, the prevalence for IBD is 396 cases per 100,000 personsannually.

Although the exact etiology of ulcerative colitis and Crohn’s diseaseis unknown, similar factors are believed responsible for bothconditions.

IBD represents theoutcome of three essentialinteractive co-factors:

INFECTIOUS FACTORS

Measles virus, protozoans, mycobacteria, such asMycobacterium paratuberculosis, and other bacteriasuch as Listeria monocytogenes, Chlamydia trachomatis,and Escherichia coli.

Also, certain strains of bacteria produce toxins(necrotoxins, hemolysins, and enterotoxins) that causemucosal damage.

Bacteria elaborate peptides (e.g., formyl-methionyl-leucylphenylalanine) that have chemotactic properties and thatcause an influx of inflammatory cells with subsequent release ofinflammatory mediators and tissue destruction.

Microbes may elaborate superantigens, which are capable ofglobal T-lymphocyte stimulation and subsequent inflammatoryresponse.

As many as 60% of patients with Crohn’s disease have circulatingantibody to Saccharomyces cerevisiae, but this may not representa disease mechanism.

GENETIC FACTORS

A positive family history is the largest independent risk factor forthe disease. Thus up to 1 in 5 patients with CD and 1 in 6 patientswith UC will have a first-degree relative with the disease.

There is increased concordance for the disease (CD more thanUC) in monozygotic twins in comparison with dizygotic twinswho demonstrated familial aggregation.

UC and CD are polygenic diseases.

There is no single locus but susceptibility loci have been identifiedon chromosomes 16 (IBD1), 12, 6, 14, 5, 19,1, 16 (IBD8) and 3,and these have been renamed IBD1–9 respectively.

Linkage mutations have been found on caspase recruitmentdomain-containing protein 15 [Card 15]/ Nucleotide-bindingoligomerization domain-containing protein 2 (NOD 2) , theunderlying gene on chromosome 16 (IBD1), and also genesunderlying the IBD5 and IBD3 loci.

The Card 15 (NOD 2) gene is associated with CD in whitepopulations, and has been associated with stricturing smallbowel CD.

Recent SNP (single nucleotide polymorphism) scans haveidentified a locus for UC and CD at ECM1 (extracellular matrixprotein 1).

NOD2 plays an important role in the immune system. Itrecognizes bacterial molecules (peptidoglycans) and stimulatesan immune reaction.

This gene is a member of the NOD1/Apaf-1 family (also knownas NOD-like receptor family) and encodes a protein withtwo caspase recruitment domains (CARDs) and eleven leucine-rich repeats (LRRs).

The protein is primarily expressed in the peripheralblood leukocytes.

It plays a role in the immune response by recognizing thebacterial molecules which possess the muramyl dipeptide (MDP)moiety and activating the NF-κB protein [nuclear factor kappa-light-chain-enhancer of activated B cells]

Apart from susceptibility, HLA genes on chromosome 6 alsoappear to have a role in modifying the disease.

Thus the DRB*0103 allele, which is uncommon, is linked to aparticularly aggressive course of UC and the need for surgery, aswell as with colonic CD.

DRB*0103 and MICA*010 are associated with perianal diseaseand DRB*0701 with ileal CD.

The HLA complex and the structure of HLA molecules. A, The location of genes in the HLAcomplex. The sizes and distances between genes are not to scale. The class II region alsocontains genes that encode several proteins involved in antigen processing (not shown).B, Schematic diagrams and crystal structures of class I and class II HLA molecules. LT,leukotriene; TNF, tumor necrosis factor.

IMMUNOLOGIC MECHANISMS

The immune system is known to play a critical role in theunderlying pathogenesis of IBD.

In Crohn’s disease, the bowel wall is infiltrated with lymphocytes,plasma cells, mast cells, macrophages, and neutrophils.

Similar infiltration has been observed in the mucosal layer of thecolon in patients with ulcerative colitis.

Inflammation in IBD is maintained by an influx of leukocytes fromthe vascular system into sites of active disease.

This influx is promoted by expression of adhesion molecules (suchas α4-integrins) on the surface of endothelial cells in themicrovasculature in the area of inflammation.

The immune theory of IBD assumes that IBD is caused by aninappropriate reaction of the immune system.

Potential immunologic mechanisms include both autoimmune andnonautoimmune phenomena.

Autoimmunity may be directed against mucosal epithelial cells oragainst neutrophil cytoplasmic elements.

Dysregulation of cytokines is a component of IBD.

Specifically, T-helper type 1 (TH1) cytokine activity (whichenhances cell-mediated immunity and suppresses humoralimmunity) is excessive with Crohn’s disease,

T-helper type 2 (TH2) cytokine activity (which inhibitscellmediated immunity and enhances humoral immunity) isexcessive with ulcerative colitis.

The result is that patients have inappropriate T-cell responses toantigens from their own intestinal microflora.

Expression of interferon γ (a TH1 cytokine) in intestinal mucosaof diseased patients is increased, whereas interleukin-4 (a TH2cytokine) is reduced.

Studies of increased intake of refined sugars or chemical foodadditives and reduced fiber intake have provided conflictingresults regarding risk for Crohn’s disease.

Smoking plays an important but contrasting role in ulcerativecolitis and Crohn’s disease.

Smoking is protective for ulcerative colitis.The risk of developing ulcerative colitis in smokers is

approximately 40% of that in nonsmokers.Clinical relapses are associated with smoking cessation, and

nicotine transdermal administration has been effective inimproving symptoms in patients with ulcerative colitis.

In contrast, smoking is associated with a twofold increasedfrequency of Crohn’s disease.

Crohn’s disease patients who stop smoking have a more benigncourse than patients who continue smoking.

The mechanisms of these differing effects have not been identifiedUse of nonsteroidal antiinflammatory drugs (NSAIDs) can trigger

disease occurrence or lead to disease flares.The effect of NSAIDs to inhibit prostaglandin production through

cyclooxygenase inhibition may impair mucosal barrier protectivemechanisms.

Appendicectomy is ‘protective’ for the development of UC, particularly ifperformed for appendicitis or for mesenteric lymphadenitis before the age of 20.

Signs and symptoms Abdominal cramping Frequent bowel movements, often with

blood in the stool Weight loss Fever and tachycardia in severe disease Blurred vision, eye pain, and

photophobia with ocular involvement Arthritis Raised, red, tender nodules that vary in

size from 1 cm to several centimeters

Physical examination Hemorrhoids, anal fissures, or perirectal abscesses may be

present Iritis, uveitis, episcleritis, and conjunctivitis with ocular

involvement Dermatologic findings with erythema nodosum, pyoderma

gangrenosumLaboratory testsDecreased hematocrit/hemoglobinIncreased erythrocyte sedimentation rateLeukocytosis and hypoalbuminemia with severe disease

Signs and symptomsMalaise and feverAbdominal pain Frequent bowel movementsHematochezia FistulaWeight lossArthritis

Physical examination Abdominal mass and tenderness Perianal fissure or fistula

Laboratory tests Increased white blood cell count and erythrocyte

sedimentation rate

Comparison of the distribution patterns of Crohn’s disease and ulcerative

colitis, and the different conformations of the ulcers and wall thickenings

It is thought that IBD develops because of an abnormal host responseto an environmental trigger in genetically susceptible individuals.This causes inflammation of the intestine and release ofinflammatory mediators, such as TNF, IL-12 and IL-23, which causetissue damage.These mediators are targets for therapeutic intervention.In both diseases the intestinal wall is infiltrated with acute andchronic inflammatory cells.There are important differences in the distribution of disease and inhistological features

(1)Bacterial antigens aretaken up by specialisedM cells, pass betweenleaky epithelial cells orenter the lamina propriathrough ulceratedmucosa.

(2)After processing they arepresented to type 1 T-helper cells by antigen-presenting cells (APC) inthe lamina propria.

(3)T-cell activation and differentiation results in a Th1 T cell-mediated cytokine response

(4) with secretion of cytokines including gamma interferon (IFN-γ).Further amplification of T cells perpetuates the inflammatoryprocess with activation of non-immune cells and release of otherimportant cytokines, e.g. (IL)-12, IL-23, IL-1, IL-6 and tumournecrosis factor (TNF).

These pathways occur in all normal individuals exposed to aninflammatory insult and this is self-limiting in healthy subjects. Ingenetically predisposed persons, dysregulation of innate immunitymay trigger inflammatory bowel disease.

Ulcerative colitis is an ulceroinflammatory disease affecting the colon, which islimited to the mucosa and submucosa, except in the most severe cases.

Ulcerative colitis begins in the rectum and extends proximally in a continuousfashion, sometimes involving the entire colon.

The primary lesion of ulcerative colitis occurs in the crypts of the mucosa in the formof a crypt abscess.

Here, frank necrosis of the epithelium occurs; it is usually visibleonly with microscopy, but may be seen grossly when coalescence ofulcers occurs.

Extension and coalescence ulcers may surround areas of uninvolvedmucosa. These islands of mucosa are called pseudopolyps.

Other typical ulceration patterns include a “collar-button ulcer,”which results from extensive submucosal undermining at the ulceredge.

The extensive mucosal damage seen in ulcerative colitis can result insignificant diarrhea and bleeding, although a small percentage ofpatients experience constipation.

Inflammation invariably involves the rectum (proctitis) but canspread to involve the sigmoid colon (proctosigmoiditis) or thewhole colon (pancolitis).

Inflammation is confluent and is more severe distally. In long-standing pancolitis the bowel can become shortened and

‘pseudopolyps’ develop which are normal or hypertrophiedresidual mucosa within areas of atrophy.

The inflammatory process is limited to the mucosa and spares thedeeper layers of the bowel wall

Hepatic complications

Include fatty liver, pericholangitis, chronic active hepatitis, andcirrhosis. Biliary complications include sclerosing cholangitis,cholangiocarcinoma, and gallstones.

Fatty infiltration of the liver may be a result of malabsorption, protein-losing enteropathy, or concomitant steroid use.

The most common hepatic complication is pericholangitis (acuteinflammation surrounding the intrahepatic portal venules, bile ducts,and lymphatics)

This is associated with progressive fibrosis of intrahepatic andextrahepatic bile ducts, and is referred to as primary sclerosingcholangitis.

Cirrhosis may be a sequela of cholangitis or of chronic active hepatitis.

Joint Complications

The joints most often affected, in decreasing frequency, are theknees, hips, ankles, wrists, and elbows.

Arthritis associated with ulcerative colitis is generally related to theseverity of colonic disease.

It is nondeforming and nondestructive, even after multipleepisodes.

Another potential joint complication is ankylosing spondylitiswhich is often unresponsive to treatment.

The incidence of ankylosing spondylitis in patients with ulcerativecolitis is 30 times that of the general population and occurs mostcommonly in patients with the HLA-B27 phenotype.

Ocular Complications

Ocular complications, including iritis, uveitis, episcleritis, andconjunctivitis, occur in up to 10% of patients with IBD.

The most commonly reported symptoms with iritis and uveitisinclude blurred vision, eye pain, and photophobia.

Episcleritis is associated burning, and increased secretions.

These complications may parallel the severity of intestinal disease,and recurrence after colectomy with ulcerative colitis isuncommon.

Dermatologic and Mucosal Complications

Skin and mucosal lesions associated with IBD include erythema

nodosum, pyoderma gangrenosum, and aphthous ulceration.

Five to 10% of IBD patients experience dermatologic or mucosal

complications.

Examination

In general there are no specific signs in UC. The abdomen may be slightly distended or tender to palpation. The anus is usually normal. Rectal examination will show the presence of blood. Rigid sigmoidoscopy is usually abnormal, showing an inflamed,

bleeding, friable mucosa.

Investigations

Blood tests■ In moderate to severe attacks an iron deficiency anaemia is

commonly present and the white cell and platelet counts areraised.

■ The ESR and CRP are often raised; liver biochemistry may beabnormal, with hypoalbuminaemia occurring in severe disease.

■ pANCA [ Perinuclear Anti-Neutrophil Cytoplasmic Antibodies]may be positive. This is contrary to CD, where pANCA is usuallynegative.

Stool cultures

These should always be performed to exclude infective causes ofcolitis.

Imaging

A plain abdominal X-ray with an abdominal ultrasound are the keyinvestigations in moderate to severe attacks.

The extent of disease can be judged by the air distribution in thecolon and the presence of colonic dilatation can be noted.

Thickening of the colonic wall can be detected on ultrasound as canthe degree of hyperaemia in the colonic wall, present in severedisease.

The presence of free fluid within the abdominal cavity can also beassessed.

Plain abdominal X-ray showing a grossly dilated colon due to severe ulcerative colitis

Plain abdominal X-ray showing toxicdilatation. The arrows indicate mucosal islands.

Colonoscopy

A colonoscopy should not be performed in severe attacks of diseasefor fear of perforation.

In more longstanding and chronic disease it is useful in definingextent and activity of disease, and excluding the onset of dysplasiaand carcinoma in patients with longstanding disease of 10 yearsduration or more.

Radionuclide scans

These can be used to assess colonic inflammation

Crohn’s disease is best characterized as a transmural inflammatoryprocess.

Complications -- Small-bowel stricture and subsequent obstruction is acomplication that may require surgery.

Fistula formation is common and occurs much more frequently thanwith ulcerative colitis.

Fistulae may connect a segment of the GI tract to skin (enterocutaneousfistula), two segments of the GI tract (enteroenteric fistula), or theintestinal tract with the bladder (enterovesicular fistula) or vagina.

Crohn’s disease fistulae or abscesses associated with them frequentlyrequire surgical treatment.

Systemic complications of Crohn’s disease are common, andsimilar to those found with ulcerative colitis.

Arthritis, iritis, skin lesions, and liver disease often accompanyCrohn’s disease.

Examination

Physical signs are few, apart from loss of weight and general ill-health.

Aphthous ulceration of the mouth is often seen. Abdominal examination is often normal although tenderness

and/or a right iliac fossa mass are occasionally found. The mass is due either to inflamed loops of bowel that are matted

together or to an abscess. The anus should always be examined to look for oedematous anal

tags, fissures or perianal abscesses.

Extragastrointestinal features of inflammatory bowel diseaseshould be looked for.

Sigmoidoscopy should always be performed in patients withsuspected CD.

With small bowel involvement the rectum may appear normal, buta biopsy must be taken as nonspecific histological changes cansometimes be found in the mucosa.

Even with extensive colonic CD the rectum may be spared and berelatively normal, but patchy involvement with an oedematoushaemorrhagic mucosa can be present.

Investigations

Blood tests

■ Anaemia is common and is usually the normocytic, normochromicanaemia of chronic disease. Deficiency of iron and/or folate alsooccurs. Despite terminal ileal involvement in CD, megaloblasticanaemia due to B12 deficiency is unusual, although serum B12levels can be below the normal range.

■ 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 cerevisiae antibody is usually

present while pANCA antibody is negative. The reverse is true inUC but the clinical value of these tests is limited.

Stool cultures

These should always be performed on presentation if diarrhoea ispresent.

Radiology and imaging

A barium follow-through examinationor CT scan with oral contrast shouldalways be performed in patientssuspected of having CD.

The findings include an asymmetricalalteration in the mucosal pattern withdeep ulceration, and areas of narrowingor stricturing.

Colonoscopy is performed if colonicinvolvement is suspected

Colonoscopic appearances of (a)aphthoid ulcers typical of Crohn’sdisease, (b) cobblestone appearance.

In patients presenting acutely with colonic symptoms, plainabdominal X-ray, ultrasound or CT is used to outline the colon asfor UC

High-resolution ultrasound and CT scanning are both helpfultechniques in defining thickness of the bowel wall and mesenteryas well as intra-abdominal and para-intestinal abscesses.

Endoanal ultrasound and MRI are used to evaluate perianaldisease.

Radionuclide scans with gallium-labelled polymorphs or indium-or technetium-labelled leucocytes are used in some centres toidentify small intestinal and colonic disease and to localizeextraintestinal abscesses.

In patients presenting acutely with colonic symptoms, plainabdominal X-ray, ultrasound or CT is used to outline the colon asfor UC

High-resolution ultrasound and CT scanning are both helpfultechniques in defining thickness of the bowel wall and mesenteryas well as intra-abdominal and para-intestinal abscesses.

Endoanal ultrasound and MRI are used to evaluate perianaldisease.

Radionuclide scans with gallium-labelled polymorphs or indium-or technetium-labelled leucocytes are used in some centres toidentify small intestinal and colonic disease and to localizeextraintestinal abscesses.

DESIRED OUTCOMETo treat IBD properly, the clinician must have a clear concept of realistictherapeutic goals for each patient.

These goals may relate to Resolution of acute inflammatory processes Resolution of attendant complications (e.g., fistulas and abscesses),

Alleviation of systemic manifestations (e.g., arthritis),Maintenance of remission from acute inflammation, or surgical

palliation or cure. The approach to the therapeutic regimen differs considerably with

varying goals, as well as with the two diseases, ulcerative colitis andCrohn’s disease.

Nutritional Support

Many specific diets have been tried to improve the condition ofpatients with IBD, but none has gained widespread acceptance.

With each individual it is helpful to eliminate specific foods thatexacerbate symptoms.

Some patients with IBD, although not the majority, have lactasedeficiency; consequently, diarrhea may be associated with milkintake.

In such patient avoidance of milk or supplementation with lactasegenerally improves the patient’s symptoms.

Patients with small-bowel strictures as a consequence of Crohn’sdisease should avoid excessive high-residue foods, such as citrusfruits and nuts.

Parenteral nutrition is an important component of the treatment ofsevere Crohn’s disease or ulcerative colitis.

The use of parenteral nutrition allows complete bowel rest inpatients with severe ulcerative colitis, which may alter the need forproctocolectomy.

There is a growing interest in using probiotic approaches for IBD.Oral administration of live bacteria such as nonpathogenic E. coli,bifidobacteria, lactobacilli, or Streptococcus thermophilus.

Surgery

Even with medical therapy 30% to 40% of patients with ulcerativecolitis and 70% to 80% of patients with Crohn’s disease requiresurgical intervention at some point in their life.Proctocolectomy

It is curative for ulcerative colitis, this is not the case for Crohn’sdisease.

Colectomy: surgical resection of any extent of the large intestineComplications of the disease such as colonic perforation, toxic dilation(megacolon), uncontrolled colonic hemorrhage, or colonic strictures.

Surgery with Crohn’s disease are not as well established as forulcerative colitis, and surgery is usually reserved for thecomplications of the disease.

The surgical procedures performed include resections of themajor intestinal areas of involvement.

In some patients with severe rectal or perianal disease,particularly abscesses, diversion of the fecal stream is performedwith a colostomy.

Other indications for surgery include strictures, resection ofcolon cancer or an inflammatory mass, or management ofintestinal perforations or fistulae.

Drug therapy plays an integral part in the overalltreatment of IBD.

None of the drugs used for IBD are curative; at best theyserve to control the disease process.

Therefore a reasonable goal of drug therapy is resolutionof disease symptoms such that the patient can carry onnormal daily functions.

Class / Drugs used in treatment of IBD

Mesalamine Derivatives for Treatment of Inflammatory Bowel Disease

First-line therapy for mild to moderate ulcerative colitis generallyinvolves Mesalamine

Although mesalamine is a salicylate, its therapeutic effect does notappear to be related to cyclooxygenase inhibition; indeed,traditional nonsteroidal antiinflammatory drugs actually mayexacerbate IBD. Sulfasalazine or mesalamine inhibition of theproduction of IL-1 and TNF-α, inhibition of the lipoxygenasepathway, scavenging of free radicals and oxidants, and inhibitionof NF-kB, a transcription factor pivotal to production ofinflammatory mediators.

Specific mechanisms of action of these drugs have not beenidentified.

Adverse Effects

Some are dose-related, headache, nausea, and fatigue. Thesereactions can be minimized by giving the medication with meals orby decreasing the doseAllergic reactions include rash, fever, Stevens-Johnson syndrome,hepatitis, pneumonitis, hemolytic anemia, and bone marrowsuppression.

Infliximab

A chimeric immunoglobulin (25% mouse, 75% human) that binds to and neutralizes TNF-α, represents a new class of therapeutic agents for treating IBD

Although a great many of both pro- andantiinflammatory cytokines are generated in theinflamed gut in IBD, there is some rationale for targetingTNF-a because it is one of the principal cytokinesmediating the TH1 immune response characteristic ofCrohn's disease

Sometimes you may feel helpless when facing inflammatory boweldisease. But changes in your diet and lifestyle may help control yoursymptoms and lengthen the time between flare-ups

Limit dairy productsTry low-fat foodsIf you have Crohn's disease of the small intestine, you may not beable to digest or absorb fat normally. Instead, fat passes throughyour intestine, making your diarrhea worse. Try avoiding butter,margarine, cream sauces and fried foods

Take care with fiberIf you have inflammatory bowel disease, high-fiber foods, such asfresh fruits and vegetables and whole grains, may make yoursymptoms worse, especially if you have narrowing in the bowel. Ifraw fruits and vegetables bother you, try steaming, baking orstewing them.In general, you may have more problems with foods in the cabbagefamily, such as broccoli and cauliflower, nuts, seeds, corn, andpopcorn.Avoid other problem foodsSpicy foods, alcohol and caffeine may make your signs andsymptoms worse.

Eat small mealsYou may find you feel better eating five or six small meals a dayrather than two or three larger ones.Drink plenty of liquidsTry to drink plenty of fluids daily. Water is best. Alcohol andbeverages that contain caffeine stimulate your intestines and canmake diarrhea worse, while carbonated drinks frequently producegas.Consider multivitaminsMultivitamin and mineral supplements are often helpful. Checkwith your doctor before taking any vitamins or supplements.