Inflamatory bowel disease

Dr. Samir Ismail

Inflammatory bowel disease (IBD) is an idiopathic disease, probably involving an immune reaction of the body to its own intestinal tract. The 2 major types of IBD are ulcerative colitis and Crohn disease. ulcerative colitis is limited to the colon wherease Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus.

Anatomic Distribution for UC

37%

46%

17%

Crohns Disease: Anatomic Distribution

Small bowel alone (33%) Ileocolic (45%) Freq of involvement Most Least Colon alone (20%)

Epidemiology
o

In United States, An estimated 1-2 million people in the United States have ulcerative colitis or Crohn disease Before 1960, the incidence of ulcerative colitis was several times higher than that of Crohn disease latest data suggest that the current incidence of Crohn disease is approaching that of ulcerative colitis, although this change may reflect improved recognition and diagnosis of Crohn disease. Internationally, incidence of IBD is assumed to be highest in developed countries and lowest in the developing regions of the world. Persons living in colder climates have a greater rate of IBD than persons living in warmer climates. Persons living in urban areas have a greater rate of IBD than persons living in rural areas.

Con

Mortality/Morbidity: The most frequent cause of death in persons with IBD is the primary disease, followed by malignancy and thromboembolic disease. Race: The incidence of IBD has been reported to be highest in Jewish populations, followed by nonJewish white populations. Sex: The male-to-female ratio is approximately equal for both ulcerative colitis and Crohn disease. Age: Ulcerative colitis and Crohn disease are most commonly diagnosed in young adults (ie, late adolescence to the third decade of life). The age distribution of newly diagnosed IBD cases is bellshaped

Pathophysiology

o o

o o

The common end pathway is inflammation of the mucosal lining of the intestinal tract, causing ulceration, edema, bleeding, and fluid and electrolyte loss. Possible factors related to this event include : pathogenic organism (yet unidentified), immune response to an intraluminal antigen (eg, protein from cow milk), autoimmune process (alteration in barrier function ). potential genes linked to IBD: Early one, NOD2 gene on chromosome 16 (now called CARD15) Strong susceptibility genes on chromosomes 5 (5q31) and 6 (6p21 and 19p) in some studies. One important point, these potential genes appear to be permissive (ie, allow IBD to occur) but not causative (ie, just because the gene is present does not necessarily mean the disease will develop).

Con

First-degree relatives have a 5- to 20-fold increased risk of developing IBD The child of a parent with IBD has a 5% risk of developing IBD. Twin studies show a concordance of approximately 70% in identical twins versus 5-10% in nonidentical twins. For unclear reasons, research suggests that smoking increases the risk of Crohn disease but reduces the likelihood of ulcerative colitis. Appendectomy early in life also reduces the lifetime risk of developing ulcerative colitis. antibodies against inflammatory mediators or methods to block the production or receptors for these mediators hold great promise for potential therapy for IBD.

Aetiology of IBD

Genetic Factors

Genetics: IBD clearly has a familial tendency . First-degree relatives have a 5- to 20-fold increased risk of developing IBD compared to subjects from unaffected families. A parent with IBD has approximately a 5% chance of having a child develop IBD. Monozygous twin studies show a high concordance for Crohn disease but less so for ulcerative colitis . Twin studies show a concordance of approximately 70% in identical twins versus 510% in nonidentical twins.

More than 30 genetic regions that increase susceptibility to both ulcerative colitis (UC) and Crohn's disease (CD). One of the most important genetic discoveries to date was the identification of a genetic variant called NOD2 (CARD15) on chromosome 16 . Three main mutations within CARD15 have been found in association with CD .
CARD15 varients are associated with younger age of onset , Ileal ,Tendency to develop stricture in CD .

A number of interesting new genes were implicated in study, including genes associated with other autoimmune conditions such as celiac disease (TAGAP), type 1 diabetes (IL2RA, TAGAP), ankylosing spondylitis (ERAP1), multiple sclerosis (IL2RA), asthma (DENND1B), and rheumatoid arthritis (TAGAP), suggesting a common shared biological pathway across inflammatory diseases. IBDs are associated with HLA Genes on chromosome 6

Environmental Factors

Crohn's disease is associated with a more sanitary childhood environment preventing the host from developing tolerance to organisms that may present later in life .

Diet

Crohn's disease is common in industrialized nations where the diet is low in fiber and high in processed food. Dietary fiber may act by blocking the interaction between intestinal bacteria and the epithelium . There is no definitive data to support nutrional factors as a cause of either CD or UC .

Smoking

Crohn's disease patients are more likely to be smokers . smokers have higher relapse rates . smokers have more aggressive disease (earlier onset, ileal disease, and penetrating disease) . UC suggests a benefit of smoking to disease course, in that patients with UC are more likely to be ex-smokers .

Appendectomy

Overall having an appendectomy reduced the rate of presenting with UC later. In contrast appendectomy may increase the risk for CD and may result in more sever aggressive disease .

Microbes and Enteric Flora

organisms might be exogenous in our environment or even incorporated into our bowel flora early in life . loss of tolerance to constituent organisms within the normal bowel flora. Mycobacterium avium paratuberculosis (MAP) as a potential etiological agent continues to be controversial. There is an increased prevalence of Helicobacter pylori DNA was found in the UC tissues compared to Crohn's disease or controls . Systemic Infections may Cause IBD Flare-up . Observational studies have noted a significant association between infections (eg, upper respiratory, urinary, or gastrointestinal) and a subsequent flare of IBD.
Systemic Infections may Cause release of inflammatory cytokines or may indirectly affect the trafficking of inflammatory cells to the intestine.

Stress

Stress may Cause IBD Flare-up . Stress hypothalamus-pituitary-adrenal axis and autonomic nervous system axis affect immune and inflammatory functions neuropeptides and proinflammatory mediators increased intestinal mucosal permeability and inflammation . Although the majority of studies evaluating the association of stressful events and flare of IBD suggest a relationship, the definitive answer is yet unknown .

Drugs

oral contraceptives oral contraceptives increase risk of developing UC and CD . Similarly, long-term users of HRT had an increased risk of CD but not UC.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) NSAIDs Cause IBD Flare-ups . NSAIDs inhibition of prostaglandins and mitochondrial oxidative phosphorylation in the mucosal enterocytes ( ATP) increased mucosal permeability and progressive mucosal disruption .

Antibiotics Antibiotics may Cause IBD Flare-ups . Antibiotics cause changes in the indigenous bowel flora overgrowth of potentially injurious organisms (eg, Clostridium difficile) or suppression of protective microbes so IBD Flare-ups

Clinical picture: symptoms

Ulcerative colitis bloody diarrhea occasionally with tenesmus (most typical manifestation ) Pain is uncommon but may occur. Patients are commonly fatigued which is often related to the inflammation and anemia that accompany disease activity.

Cont.
Crohn disease abdominal pain and diarrhea (most typical manifestations ) the classic location is the lower abdomen or right lower quadrant (appendicitis like ).

Patients are commonly fatigued, which is often related to the pain, inflammation, and anemia that accompany disease activity .

Signs:
Ulcerative colitis :

diarrhea with occult or frank blood loss .

Weight loss and anemia .

typically do not develop fistulae or perianal disease, although they may have perianal abscesses.

Cont.
Crohn disease : occult blood loss and low-grade fever .

Growth retardation is seen in children and may be the only presenting sign in young patients .

Fistulae and perianal disease are not uncommon.

Disease Severity at Presentation of uc

Mild Activity:20%
< 4 stools daily No systemic disturbance ESR: Nl (normal )

Moderate Activity: 71%

> 4 stools daily Minimal systemic effects

Cont.
Severe Activity:9%
> 6 stools daily Bloody stools Fever Tachycardia Anemia ESR > 30 mm/hr

Extraintestinal manifestations

Extraintestinal manifestations
Joints . Arthritis
axial (or central ) arthritis e.g ankylosing spondylitis and sacroiliitis . peripheral arthritis ( nondestructive arthritis , asymmetric , mostly affects large weight-bearing joints )

Eye
episcleritis and iritis (uveitis)associated with uc

Cont,
Skin:
erythema nodosum and pyoderma gangrenosum. Infectious skin lesions related to immune suppression may also be seen (eg, herpetic lesions)

Stones:

Calcium oxalate stones are the most common type of renal calculi associated with Crohn disease. Gallstones are common in persons with Crohn disease (occasionally, cholecystectomy is necessary)

Cont.
Blood:
anemia 2 types ,,,iron deficiency anemia, anemia of chronic disease. A hypercoagulable state (occur in one third of patients with IBD ) Strokes, retinal thrombi, and pulmonary emboli

Liver:

Primary sclerosing cholangitis. Fatty liver. Hepatitis. Liver cirrhosis.

Diagnosis

Investigation
1.CBC :
with differential anemia may result from acute or chronic blood loss or malabsorption (iron, folate, vitamin B-12) or may reflect the chronic disease state. Leukocytosis, and thrombocytosis are common. ESR: is typically elevated and has been used to monitor disease activity.

2.Serum chemistry:
-Hypokalemia reflects the severity of the diarrhea. -Abnormal liver function test results may represent pericholangitis or sclerosing cholangitis, which are complications of inflammatory bowel disease . -Hypoalbuminemia, resulting from proteinlosing enteropathy, suggests extensive colitis. -Decreased serum calcium level may reflect reduced serum albumin level

3.Stool studies:
Perform a stool culture (and C difficile toxin assay) on patients before making a definitive diagnosis of idiopathic IBD. Any patient hospitalized with a flare of colitis should, at a minimum, have a C difficile toxin assay performed because, commonly, pseudomembranous colitis is superimposed on ulcerative colitis.

Blood culture:
Cultures may be positive if peritonitis or fulminant colitis is present.

Diagnostic Role and Clinical Association of ASCA and ANCA in Patients with Inflammatory Bowel Disease
The results evidenced that low sensitivity of ASCA and pANCA markers limits their use in IBD screening in the general population; however, their specificity may contribute to differentiation between CD and UC in IBD patients. The sensitivity and specificity of pANCA were 51% and 100%, respectively for UC. ASCA (IgA or IgG isotypes) presented sensitivity of 62% and specificity of 93% for CD.

Imaging Studies
-Upright chest radiography and abdominal series evaluate for an edematous irregular colon with "thumb printing. -Occasionally, pneumatosis coli (air in the colonic wall) may be present. -Also there is free air and especially for evidence of toxic megacolon, depicted in the image, which appears as a long continuous segment of air-filled colon greater than 6 cm in diameter. Associated findings include nephrolithiasis, cholelithiasis, or arthritis of the spine or the sacroiliac joints.

Barium enema In ulcerative colitis, a barium enema (BE) may reveal a shortened colon, with loss of haustrations and destruction of the mucosal pattern (ie, lead pipe colon). CT scanning and ultrasonography: are best for demonstrating intra-abdominal abscesses, mesenteric inflammation, and fistulas. MRI may be of help in detecting fistulas and abscesses.

Flexible sigmoidoscopy:

it can only help diagnose distal ulcerative colitis or proctitis, but not pancolitis. Rarely, Crohn colitis can be diagnosed based on flexible sigmoidoscopy findings; use caution interpreting sigmoid inflammation, particularly in older patients, because Crohn colitis may be confused with diverticulitis or ischemia. Upper endoscopy: Esophagogastroduodenoscopy is used for the evaluation of upper gastrointestinal tract symptoms, particularly in patients with Crohn disease. Aphthous ulceration occurs in the stomach and duodenum in 5-10% of patients with Crohn disease

Small bowel enteroscopy: This is of limited use in patients with Crohn disease and is of almost no value in those with ulcerative colitis
Capsule enteroscopy: Most commonly used for finding obscure sources of gastrointestinal blood loss, the images can find ulcerations associated with Crohn disease if upper endoscopy and colonoscopy are unrevealing

Inflammatory bowel disease. Severe colitis noted during colonoscopy. The mucosa is grossly denuded, with active bleeding noted.

Inflammatory bowel disease. Stricture in the terminal ileum noted during colonoscopy. Narrowed segment visible upon intubation of the terminal ileum with the colonoscope..

Double balloon enteroscopy in Crohn's disease

More recently, a double balloon endoscope has been developed that allows intubation of the entire small bowel. This endoscope contains a working channel that allows for all the interventions possible with standard colonoscopes.

New endoscope for early diagnosis of inflammatory bowel disease

Confocal Laser Endomicroscope (CLE), which has a powerful microscope allowing clinicians to view the bacteria that are believed to causes bowel disease such as Crohn's disease and ulcerative colitis. the new technology will allow the detection of patients at risk or in the early stages of such diseases. It is believed that bacteria within the mucous membrane of the gut plays a role is causing such diseases. The present treatment method prevents observation of the bacteria's exact location and also of the way in which it interacts with the mucous membrane.

Fecal Calprotectin a Sign of Inflammatory Bowel Disease

useful tool for identifying patients who are most likely to need endoscopy for suspected IBD sensitivity of 93% and specificity of 96% of the fecal calprotectin test is remarkable, "considering the diverse and complex antigenic environment of faeces . However, the test cannot be recommended as a diagnostic test for IBD in primary care because the results of the study apply to patients referred to secondary care. In primary care, patient characteristics and populations are "probably different," which would affect the negative and positive predictive value of fecal calprotectin screening.

Faecal Lactoferrin A Novel Test to Differentiate between the Irritable and Inflamed Bowel?
-Lactoferrin (LF) is an iron binding glycoprotein secreted by most mucosal membranes and a major component of secondary granules of polymorphonuclear neutrophils, a component of the inflammatory response. -Elevated LF has been used as a marker of active IBD and for monitoring patients for response to treatment. Some studies report a high sensitivity of LF for active IBD in comparison with IBS. -However, the use of LF for the distinction of inactive IBD and IBS is less clear. -The aim of this study was to investigate the clinical utility of LF as a marker of GI inflammation in patients with active and inactive IBD compared with patients with diarrhoea predominant IBS and healthy controls.

Histologic Findings
-In ulcerative colitis, Biopsy specimens demonstrate neutrophilic infiltrate along with crypt abscesses and crypt distortion. Granulomas do not occur in ulcerative colitis. -in Crohn disease, Biopsy specimens frequently demonstrate granulomas (approximately 50% of the time). The presence of granulomas is often helpful for making the diagnosis but is not necessary. -Because biopsy specimens obtained at colonoscopy are generally superficial mucosal tissue samples, the pathologist often has difficulty making a definitive diagnosis of ulcerative colitis or Crohn disease based on histologic findings alone. However, other causes of inflammation may be suggested based on pathology findings (eg, infectious colitis).

Treatment

Goals of Therapy for IBD

Inducing remission Maintaining remission

Restoring and maintaining nutrition

Maintaining patients quality of life Surgical intervention (selection of optimal time for surgery)

Remission induction

1-liquid enteral feeding 2-aminosalysilic acid 3-corticosteroids 4-metronidazole 5-methotrexate 6-cyclosporine 7-infliximab

Mentainence therapy

1-aminosalysilic acid 2-azathioprine 3- methotrexate 4- infliximab

Severe
Surgery Cyclosporine

Moderate

Infliximab Systemic Corticosteroids

Mild

Oral Steroids

Aminosalicylates

Lines of treatment

Diet Medical therapy Surgical treatment

Diet

Have little or no influence on inflammatory activity in persons with ulcerative colitis. Diet may influence symptoms. Patients are often advised to make a variety of diet modifications, especially the adaptation of a lowresidue diet

Cont..

Evidence does not support a low-residue diet as beneficial in the treatment of ulcerative colitis, although it might decrease the frequency of bowel movements.

Unlike ulcerative colitis, diet can influence inflammatory activity in persons with Crohns disease. Nothing by mouth (status NPO) can hasten the reduction of inflammation

Medical treatment

The medical approach in IBD is symptomatic (flaring) care A step-wise approach may be taken. With this approach, the most benign (or temporary) drugs are used first. As they fail to provide relief, drugs from a higher step are used.

Step I (aminosalicylates)

sulfasalazine, mesalamine, balsalazide, and olsalazine. Enema and suppository formulations are also available. All are useful for treating flares of IBD and for maintaining remission. Sulfasalazine, not mesalamine, may ameliorate arthropathy in ankylosing spondylitis associated with IBD.

Step IA (antibiotics)

The antibiotics metronidazole and ciprofloxacin are the most commonly used antibiotics in persons with IBD. Because ulcerative colitis increases the risk of developing antibiotic-associated pseudomembranous colitis.

UC used in the perioperative setting ,CD most commonly for perianal disease.
Adverse effects, including nausea, anorexia, diarrhea, and monilial (candidal) infections; peripheral neuropathy can be observed in association with metronidazole use and, when present, requires discontinuation of therapy with that drug.

Step II (corticosteroids)

Corticosteroids are rapid-acting anti-inflammatory agents used in the treatment of IBD Used for acute flares of disease only; corticosteroids have no role in the maintenance of remission. Different route of adminstration intravenously (ie, methylprednisolone, hydrocortisone), orally (ie, prednisone, prednisolone, budesonide, dexamethasone), or topically (ie, enema, suppository, or foam preparations) IV corticosteroids are used for patients who are severely ill and hospitalized . Adverse effect ..

Step III (immune modifiers)

The immune modifiers 6-MP and azathioprine are used in patients with IBD in whom remission is difficult to maintain with the aminosalicylates alone. Immune modifiers work by causing a reduction in the lymphocyte count, their onset of action is relatively slow (typically 2-3 mo). Used for steroid-sparing action in persons with refractory disease adverse effects of the immune modifiers include fever, rash, infectious complications, hepatitis, pancreatitis, and bone marrow depression. The most common reason for discontinuing the immune modifiers within the first few weeks is the development of abdominal pain; occasionally, a biochemically pancreatitis occurs..

Cont..

Use of these agents mandates monitoring of blood parameters; they can cause significant neutropenia or pancytopenia Routine CBC counts with differentials and platelet counts are checked monthly for a year, and LFTs can be performed intermittently. The cytopenic effect is typically dose dependent

Cont..

Infliximab is generally administered as infusions of 5 mg/kg for the treatment of moderate-to-severe IBD.
It is administered as 3 separate infusions of 5 mg/kg at weeks 0, 2, and 6, often followed by doses every 8 weeks for maintenance of remission. For Crohn disease, the response rate is 80% and the induction of remission rate is 50% after a single dose; with multiple dosing, higher rates of remission are attained. For ulcerative colitis, the response rates are 50-70%.

Cont..

Infliximab is also indicated for the treatment of fistulizing Crohn disease; for this indication, the fistula responds (closes) in 68% of patients treated with infliximab, although 12% develop an abscess. The response can be maintained by continuing regular dosing (ie, every 8 wk) after the induction dose The adverse effects of infliximab commonly include hypersensitivity and flulike symptoms; the latter can often be avoided by pretreatment with acetaminophen and diphenhydramine. Rare reports of lupuslike reactions and lymphoproliferative malignancies have been reported Infliximab has an excellent response rate for Crohn disease (>80%); its response rate for ulcerative colitis is clearly less (approximately 50%). .

Combination therapy with infliximab and azathioprine have higher rate of clinical remission among patient with moderate to severe CD than monotherapy

Infliximab Treatment of Fistulas

70% 60% 50%

% Patients
40% 30% 20% 10% 0% Placebo 5 mg/kg 10 mg/kg 50% Reduction Complete Response

Healing of Colonic Ulceration with Infliximab

Pretreatment

4 weeks post-treatment

Natalizumab (Antegrin), an agent aimed at preventing the accumulation of lymphocytes in the diseased bowel by blocking the effects of integrin, has been approved but is only available through a restricted distribution program. Natalizumab is an intravenous medication that has shown efficacy in Crohn disease but is not as effective as anti-TNF agents. Natalizumab has been linked to reports of progressive multifocal leukoencephalopathy (a potentially fatal opportunistic viral infection) in 3 patients.

Step IV

Include methotrexate (orally or intramuscularly),

Weekly IM MTX is effective for chronic active CD Do not use in pregnancy Monitor: CBC, LFT

Thalidomide (50-300 mg/d orally), Interleukin 11 (1 mg/wk subcutaneously).

Surgical treatment

The approach to surgical treatment of IBD varies depending on the disease. Most important, ulcerative colitis is a surgically curable disease because the disease is limited to the colon. However, Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus; thus, surgical resection is not curative.

Surgery for ulcerative colitis

The indications for colectomy are (1) inflammation that is difficult to control (2) early changes found during surveillance (highgrade dysplasia, low-grade dysplasia in some instances), (3) strictures, (4) significant adverse medication effects, (5) an unacceptable quality of life referable to the ulcerative colitis

Total proctocolectomy with ileostomy creation is the simplest procedure with the lowest overall complication rate

Surgery in Crohn disease

Surgery in Crohn disease is most commonly performed for complications of the disease (ie, strictures, fistulae, bleeding) rather than for the disease itself. This is a variation on the simple segmental resection. In patients with severe perianal fistulae, a diverting ileostomy or colostomy is a surgical option.

Endoscopic balloon dilation has been shown to be an alternative to surgery in the treatment of Crohn's symptomatic strictures. Infliximab has proven to provide mucosal healing. A consequent therapy with this agent, following a balloon-dilation, might reduce the reappearance of

strictures in Crohn's disease.

Endoscopic balloon dilation is a safe and effective procedure in the management of Crohn's strictures. The success rate of balloon dilation and the need of surgery seem to depend on the type of stricture, primary or anastomotic, its location and its length.

Prevention
1. 2.

3.

No known dietary or lifestyle changes prevent IBD. Dietary manipulation may help symptoms in persons with ulcerative colitis, and it actually may help reduce inflammation in persons with Crohn disease However, no evidence indicates that consuming or avoiding any particular food item causes or avoids flares of IBD. Smoking cessation is the only lifestyle change that may benefit patients with Crohn disease.

Prognosis

Ulcerative colitis

The average patient with ulcerative colitis has a 50% probability of having another flare during the next 2 years. ; some patients may only have one flare over 25 years (as many as 10%), and others may have almost constant flares (much less common). Patients with ulcerative colitis limited to the rectum and sigmoid at the time of diagnosis have a greater than 50% chance of progressing to more extensive disease and a 12% rate of colectomy over 25 years. More than 70% of patients presenting with proctitis alone continue to have disease limited to the rectum over 20 years.

Cont..

Of patients with ulcerative colitis involving the entire colon, 60% eventually require colectomy, whereas very few of those with proctitis require colectomy. Of interest, most surgical interventions are required in the first year of disease; the annual colectomy rate after the first year is 1% for all patients.
Surgical resection for ulcerative colitis is considered curative for that disease, although postoperative pouchitis may occur in some patients. Of note, pouchitis is far more common in patients who have had a colectomy for ulcerative colitis than in those who have had a colectomy for other reasons (eg, familial adenomatous polyposis)

Crohn disease
. A patient in remission has a 42% likelihood of being free of

relapse for 2 years and only a 12% likelihood of being free of relapse for 10 years. Over a 4-year period, approximately one quarter of patients remain in remission, one quarter have frequent flares, and one half have a course that fluctuates between periods of flares and remissions. Surgery for Crohn disease is generally performed for complications (eg, stricture, stenosis, obstruction, fistula, bleeding) rather than for the inflammatory disease itself . After operation, the frequency of recurrence of Crohn disease is high, generally in a pattern mimicking the original disease pattern, often on one or both sides of the surgical anastomosis.

Approximately one third of patients with Crohn disease who require surgery require surgery again within 5 years, and two thirds require surgery again within 15 years. Endoscopic evidence of recurrent inflammation is present in 93% of patients 1 year after surgery for Crohn disease. Surgery is an important treatment option for Crohn disease, but it is not curative and that disease recurrence after surgery is the rule.

complications

Strictures and obstructions are not uncommon in persons with Crohn disease Fistulae and perianal disease are not uncommon in persons with Crohn disease Toxic megacolon is a life-threatening complication of ulcerative colitis Malignancy is the most dreaded long-term intestinal complication of ulcerative colitis The risk of cancer in persons with Crohn disease may equal to that of persons with ulcerative colitis if the entire colon is involved