Inflammatory bowel disease

Mahdi Alemrajabi MD.Colorectal surgeon

Faculty member of Iran university of medical sciencesFiroozghar general hospital

www.alemrajabi.irMahdialemrajabi@gmail.com

HISTORICAL ASPECT

The history of Crohn’s disease

•

Medical historians suggest that Crohn’s disease was first described as early as the 9th century A.D. Alfred the Great (849–899 A.D.) suffered from a painful illness for much of his life. Records described his illness as abdominal pain, discomfort, diarrhea, and rectal problems beginning at the age of 20. Now we know that this was probably Crohn’s disease. In 1913, Sir Kennedy Dalziel published an article in the British Medical Journal describing patients having transmural inflammation of the small and large intestines, a characteristic finding of Crohn’s disease.

In 1932, Dr. Burrill Bernard Crohn and his two colleagues Dr. Leon Ginzburg and Dr. Gordon Oppenheimer published an important paper describing similar conditions in 14 patients; they called it “terminal ileitis.” This paper was presented to a large medical audience in New York and, as a result, was given a large amount of recognition and publicity. Because Crohn was the first author on the paper, the disease was subsequently called Crohn’s disease.

The history of colitis

Ulcerative colitis is even older than Crohn’s disease. I call it the “big brother” of Crohn’s. The first description of ulcerative colitis dates back to Ancient Greece. Many physicians from this period, including Hippocrates (ca. 460–377 B.C.), described a condition of chronic diarrhea associated with blood and ulceration of the large intestines. In the late 1600s, Thomas Sydenham (1624–1689) coined the term bloody flux to describe this type of diarrheal disease. Historians have speculated that Bonnie Prince Charles, The Young Pretender (1766–1788), suffered from ulcerative colitis and cured himself by adopting a milk-free diet in 1745. Sir Samuel Wilks (1824–1911) described “ulcerative colitis” as a specific disease for the first time in 1859 and recognized it as distinct from the then more common infectious diarrhea. In 1909, around 300 cases of ulcerative colitis were collected from various London hospitals and presented at a symposium of the Royal Society of Medicine.

CROHN”S DX

• Crohn's disease is a chronic, idiopathic transmural inflammatory disease with a propensity to affect the distal ileum, although any part of the alimentary tract can be involved.• Estimates of the incidence of Crohn's disease in the United States

have ranged from 3.6 to 8.8 per 100,000, with recent studies suggesting a prevalence of about 200 cases per 100,000.• A dramatic increase in incidence in the United States was observed to

occur from the mid-1950s though the early 1970s. Incidence rates have been stable since the 1980s.

bimodal distribution

• 1-The mean age at which patients are diagnosed with Crohn's disease falls in the third decade of life years• 2-A second smaller peak in the sixth decade of life.

The age at diagnosis can, however, range from early childhood through the entire life span.

• Substantial regional and ethnic variations in incidence have been observed,

Peoples of northern latitudes.

Eastern European Ashkenazi Jewish population.

Higher socioeconomic status

more prevalent in females than in males

• Most studies have found breastfeeding to be protective against the development of Crohn's disease.

• Crohn's disease is more prevalent among smokers. Furthermore, smoking is associated with the increased risk for both the need for surgery and the risk of relapse after surgery for Crohn's disease.

• Both genetic and environmental factors appear to influence the risk for developing Crohn's disease. • The relative risk among first-degree relatives of patients with Crohn's

disease is 14 to 15 times higher than that of the general population. Approximately one in five patients with Crohn's disease will report having at least one affected relative.• The concordance rate among monozygotic twins is as high as 67%;

however, Crohn's disease is not associated with simple mendelian inheritance patterns. Although there is a tendency within families for either ulcerative colitis or Crohn's disease to be present exclusively, mixed kindreds also occur, suggesting the presence of some shared genetic traits as a basis for both diseases.

PATHOPHYSIOLOGY

Specific genetic defects associated with Crohn's disease in human patients are beginning to be defined.• For example, the presence of a locus on chromosome 16 (the so-called IBD1

locus) has been linked to Crohn's disease. The IBD1 locus has been identified as the NOD2 gene. Persons with allelic variants on both chromosomes have a 40-fold relative risk of Crohn's disease compared to those without variant NOD2 genes. The relevance of this gene to the pathogenesis of Crohn's disease is biologically plausible, as the protein product of the NOD2 gene mediates the innate immune response to microbial pathogens.

• Other putative IBD loci have been identified on other chromosomes (IBD2 on chromosome 12q, and IBD3 on chromosome 6), and are under investigation.

PATHOPHYSIOLOGY

• Crohn's disease is characterized by sustained inflammation. 1-appropriate response to a yet unrecognized pathogen 2-inappropriate response to a normally innocuous stimulus

• Many infectious agents :

chlamydia, Listeria monocytogenes, Pseudomonas species, reovirus ,

Mycobacterium paratuberculosis,

PATHOPHYSIOLOGY

• Crohn's disease is characterized by sustained inflammation . 1-appropriate response to a yet unrecognized pathogen 2- inappropriate response to a normally innocuous stimulus

in a genetically susceptible host, nonpathogenic, commensal enteric flora are sufficient to induce a chronic inflammatory response resembling that associated with Crohn's disease. In these models,

• Poor barrier function is hypothesized to permit inappropriate exposure of lamina propria lymphocytes to antigenic stimuli derived from the intestinal lumen.

• In addition, a variety of defects in immune regulatory mechanisms, (e.g., over-responsiveness of mucosal T cells to enteric flora-derived antigens) can lead to defective immune tolerance and sustained inflammation.

PATHOLOGY• pathologic hallmark of Crohn's disease is focal, transmural inflammation of the

intestine, • The earliest lesion characteristic of Crohn's disease is the aphthous ulcer. These superficial ulcers

are up to 3 mm in diameter and are surrounded by a halo of erythema. In the small intestine, aphthous ulcers typically arise over lymphoid aggregates.

PATHOLOGY

• As disease progresses, aphthae coalesce into larger, stellate-shaped ulcers. Linear or serpiginous ulcers may form when multiple ulcers fuse in a direction parallel to the longitudinal axis of the intestine.

• With transverse coalescence of ulcers, a cobblestoned appearance of the mucosa may arise.

PATHOLOGY

• Granulomas are highly characteristic of Crohn's disease and are reported to be present in up to 70% of intestinal specimens obtained during surgical resection. These granulomas are noncaseating and can be found in both areas of active disease and apparently normal intestine, in any layer of the bowel wall, and in mesenteric lymph nodes.

• With advanced disease, inflammation can be transmural. Serosal involvement results in adhesion of the inflamed bowel to other loops of bowel or other adjacent organs.

• Transmural inflammation also can result in fibrosis with stricture formation, intra-abdominal abscesses, fistulas, and, rarely, free perforation. Inflammation in Crohn's disease can affect discontinuous portions of intestine: so-called skip lesions that are separated by intervening normal appearing intestine.

• A feature of Crohn's disease that is grossly evident and helpful in identifying affected segments of intestine during surgery is the presence of fat wrapping, which represents encroachment of mesenteric fat onto the serosal surface of the bowel .

• This finding is virtually pathognomonic of Crohn's disease. The presence of fat wrapping correlates well with the presence of underlying acute and chronic inflammation.

CLINICAL PRESENTATION

The most common symptoms of Crohn's disease are• abdominal pain• diarrhea• weight loss.

• Constitutional symptoms, particularly weight loss and fever, or growth retardation in children, may also be prominent and are occasionally the sole presenting features of Crohn's disease.

• Patients with Crohn's disease can be classified by their predominant clinical manifestation as having primarily

(a) fibrostenotic disease (b) fistulizing disease (c) aggressive inflammatory disease

• The disease affects the small bowel in 80% of cases, and colon alone in 20%.• In those with small bowel disease, the majority have ileocecal

disease. The small bowel alone is affected in 15 to 30% of patients.• Isolated perineal and anorectal disease occurs in 5 to 10% of affected

patients. • Uncommon sites of involvement include the esophagus, stomach, and

duodenum.

• Features that allow for differentiation between Crohn's disease of the colon and ulcerative colitis include the layers of the bowel wall affected (inflammation in ulcerative colitis is limited to the mucosa and submucosa but may involve the full thickness of the bowel wall in Crohn's disease) and the longitudinal extent of inflammation (inflammation is continuous and characteristically affects the rectum in ulcerative colitis but may be discontinuous and spare the rectum in Crohn's disease).• In the absence of full expression of features of advanced disease, Crohn's

colitis can sometimes be difficult to distinguish from ulcerative colitis. It is also important to remember that, although ulcerative colitis is a disease of the colon, it can be associated with inflammatory changes in the distal ileum (backwash ileitis).

An estimated one fourth of all patients with Crohn's disease will have an extraintestinal manifestation of their disease.

One fourth of those affected will have more than one manifestation.

• Many of these complications are common to both Crohn's disease and ulcerative colitis, although as a whole, they are more prevalent among patients with Crohn's disease than those with ulcerative colitis.

• The clinical severity of some of these manifestations, such as erythema nodosum and peripheral arthritis, is correlated with the severity of intestinal inflammation.

Extraintestinal Manifestations of Crohn's Disease

Dermatologic

Erythema nodosum

Pyoderma gangrenosum

Rheumatologic

Peripheral arthritis

Ankylosing spondylitis

Sacroiliitis

Ocular

Conjunctivitis

Uveitis/iritis

Episcleritis

Hepatobiliary

Hepatic steatosis

Cholelithiasis

Primary sclerosing cholangitis

Pericholangitis

Urologic

Nephrolithiasis

Ureteral obstruction

Miscellaneous

Thromboembolic disease

Vasculitis

Osteoporosis

Endocarditis, myocarditis, pleuropericarditis

Interstitial lung disease

Amyloidosis

Pancreatitis

DIAGNOSIS• DX is established with endoscopic findings in a patient with a compatible clinical history. ulcerative colitis functional bowel disorders such as irritable bowel syndrome mesenteric ischemia collagen vascular diseases carcinoma and lymphoma diverticular disease, • infectious enteritides Acute ileitis caused by Campylobacter and Yersinia species Typhoid enteritis caused by Salmonella typhosa. Mycobacterium tuberculosis . CMV can cause intestinal ulcers, bleeding, and perforation.

• No single symptom, sign, or diagnostic test establishes the diagnosis of Crohn's disease.

complete assessment of the clinical presentation radiographic endoscopic pathologic tests.

• Several antibodies also have been identified in patients. perinuclear antineutrophil cytoplasmic antibody (pANCA)

anti–Saccharomyces cerevisiae antibody (ASCA).

ASCA+/pANCA, is associated with a diagnosis of Crohn's disease, while ASCA–/pANCA+ is correlated with ulcerative colitis.

THERAPY

• Because no curative therapies are available for Crohn's disease, the goal of treatment is to palliate symptoms rather than to achieve cure. Medical therapy is used to induce and maintain disease remission.• Surgery is reserved for specific indications described below in the

Surgical Therapy section.• In addition, nutritional support in the form of aggressive enteral

regimens or, if necessary, parenteral nutrition, is used to manage the malnutrition that is common in patient's with Crohn's disease.

MEDICAL THERAPY

Pharmacologic agents used to treat Crohn's disease include

• Antibiotics• aminosalicylates• Corticosteroids• immunomodulators..

• Most studies have shown oral 5-aminosalicylic acid (5-ASA) drugs (e.g., mesalamine) to be superior to placebo in inducing disease remission. Its efficacy in the maintenance of remission is less clear. Aminosalicylates are associated with minimal toxicity and are available in a variety of formulations that allow for their delivery to specific regions of the alimentary tract. In Crohn's disease, sulfasalazine, the parent compound of 5-ASA and widely used in ulcerative colitis, has been shown to be less effective than 5-ASA.

• Orally administered glucocorticoids are used to treat patients with mildly to moderately severe disease that does not respond to aminosalicylates. Patients with severe active disease usually require IV administration of glucocorticoids. Although glucocorticoids are effective in inducing remission, they are ineffective in preventing relapse and their adverse side-effect profile makes long-term use hazardous. Therefore, they should be tapered once remission is achieved. Some patients are unable to undergo glucocorticoid tapering without suffering recurrence of symptoms. Such patients are said to have steroid dependence. For these patients, along with those who do not respond to steroids at all (steroid resistant), use of immune modulators should be considered

• The thiopurine antimetabolites azathioprine and its active metabolite, 6-mercaptopurine, have demonstrated efficacy in inducing remission, in maintaining remission, and in allowing for glucocorticoid tapering in glucocorticoid-dependent patients. A response to the medications is usually observed in 3 to 6 months. There is also some evidence that they decrease the risk of relapse after intestinal resection for Crohn's disease. These agents are relatively safe but can induce bone marrow suppression and promote infectious complications. For patients who do not respond to the thiopurines, methotrexate is an alternative that usually is given intramuscularly before switching to oral form after achieving symptomatic control. There is little role for cyclosporine in Crohn's disease; its efficacy/toxicity profile in this disease is poor.

• Infliximab is a chimeric monoclonal anti–tumor necrosis factor alpha antibody that has been shown to have efficacy in inducing remission and in promoting closure of enterocutaneous fistulas.35 It generally is used for patients resistant to standard therapy to help taper steroid dosage. Infliximab generally is well tolerated but should not be used in patients with ongoing septic processes, such as undrained intra-abdominal abscesses.

• For patients with perianal disease, antibiotic therapy with metronidazole or ciprofloxacin is the primary step. Two to 4 weeks of therapy is needed before improvements are seen, and often long-term therapy is required to prevent relapse. In cases of relapse, azathioprine can be considered. In patients with fistulas, infliximab and azathioprine are drugs of choice.

SURGICAL THERAPY Indications for Surgical Intervention in Crohn's Disease

Acute onset of severe disease

Crohn's colitis ± toxic megacolon (rare)

Failure of medical therapy

Persistent symptoms despite long-term steroid use

Recurrence of symptoms when high-dose steroids are tapered

Drug induced complications (Cushing's disease, hypertension)

Development of disease complications

Obstruction

Perforation

Complicated fistulas

Hemorrhage

Malignancy risk

• Fifty to 70% of patients with Crohn's disease will ultimately require at least one surgical intervention for their disease.

For disease is unresponsive to aggressive medical therapy

or who develop complications of their disease specifically corticosteroid-related complications, such as cushingoid features, cataracts, glaucoma, systemic hypertension, compression fractures, or aseptic necrosis of the femoral head.

Growth retardation constitutes an indication for surgery in 30% of children with Crohn's disease.

Stricturoplasty

A- >12cm B- <25cm

contraindicated inabccessfistulaone stricture close to resectable bowel

• Intestinal bypass

• Since the 1990s, laparoscopic surgical techniques have been applied to patients with Crohn's disease.

ANAL AND PERIANAL CROHNS DISEASE• Anal and perianal manifestations of Crohn's disease are very common. Anal or perianal

disease occurs in 35% of all patients with Crohn's disease. • Isolated anal Crohn's disease is uncommon, affecting only 3 to 4% of patients. Detection of

anal Crohn's disease, therefore, should prompt evaluation of the remainder of the GI tract.• The most common perianal lesions in Crohn's disease are skin tags that are minimally

symptomatic. Fissures also are common. Typically, a fissure from Crohn's disease is particularly deep or broad and perhaps better described as an anal ulcer. They often are multiple and located in a lateral position rather than anterior or posterior midline as seen in an idiopathic fissure in ano. A classic appearing fissure in ano located laterally should raise the suspicion of Crohn's disease. Perianal abscess and fistulas are common and can be particularly challenging. Fistulas tend to be complex and often have multiple tracts Hemorrhoids are not more common in patients with Crohn's disease than in the general population, although many patients tend to attribute any anal or perianal symptom to "hemorrhoids."

OUTCOME

• Overall complication rates following surgery for Crohn's disease range from 15 to 30%. Wound infections, postoperative intra-abdominal abscesses, and anastomotic leaks account for most of these complications.• Most patients whose disease is resected eventually develop recurrence. If

recurrence is defined endoscopically, 70% recur within 1 year of a bowel resection and 85% by 3 years.42 Clinical recurrence, defined as the return of symptoms confirmed as being due to Crohn's disease, affects 60% of patients by 5 years and 94% by 15 years after intestinal resection.• Reoperation becomes necessary in approximately one third of patients by

5 years after the initial operation, with a median time to reoperation of 7 to 10 years

NUTRITION

• Patients with inflammatory bowel disease often are malnourished. Abdominal pain and obstructive symptoms may decrease oral intake. Diarrhea can cause significant protein loss. Ongoing inflammation produces a catabolic physiologic state. Parenteral nutrition should be strongly considered early in the course of therapy for either Crohn's disease or ulcerative colitis. • The nutritional status of the patient also should be considered when

planning operative intervention and nutritional parameters such as serum albumin, prealbumin, and transferrin should be assessed.• In extremely malnourished patients, especially those who also are being

treated with corticosteroids, creation of a stoma often is safer than a primary anastomosis.

ULCERATIVE COLITIS

• Ulcerative colitis is a dynamic disease characterized by remissions and exacerbations.• The clinical spectrum ranges from an inactive or quiescent phase to

low-grade active disease to fulminant disease.• The onset of ulcerative colitis may be insidious, with minimal bloody

stools, or the onset can be abrupt, with severe diarrhea and bleeding, tenesmus, abdominal pain, and fever. • . Although anemia is common, massive hemorrhage is rare. Physical

findings often are nonspecific.

• Diagnosis of ulcerative colitis almost always is made endoscopically. proctoscopy may be adequate to establish the diagnosis.

• The earliest manifestation is mucosal edema, which results in a loss of the normal vascular pattern. In more advanced disease, characteristic findings include mucosal friability and ulceration. Pus and mucus also may be present. Although mucosal biopsy often is diagnostic in the chronic phase of ulcerative colitis, biopsy in the acute phase often will reveal only nonspecific inflammation

• . A complete evaluation with colonoscopy or barium enema during an acute flare is contraindicated because of the risk of perforation.

• Barium enema has been used to diagnose ulcerative colitis and to determine the extent of disease. However, this modality is less sensitive than colonoscopy and may not detect early disease. In long-standing ulcerative colitis, the colon is foreshortened and lacks haustral markings ("lead pipe" colon). Because the inflammation in ulcerative colitis is purely mucosal, strictures are highly uncommon. Any stricture diagnosed in a patient with ulcerative colitis must be presumed to be malignant until proven otherwise.

INDICATION OF SURGERY

• Indications for surgery in ulcerative colitis may be emergent or elective.

• Emergency surgery is required for patients with massive life-threatening hemorrhage, toxic megacolon, or fulminant colitis who fail to respond rapidly to medical therapy.

• Patients with signs and symptoms of fulminant colitis should be treated aggressively with bowel rest, hydration, broad-spectrum antibiotics, and parenteral corticosteroids.• Colonoscopy and barium enema are contraindicated, and

antidiarrheal agents should be avoided. Deterioration in clinical condition or failure to improve within 24 to 48 hours mandates surgery.

Indications for elective surgery include• intractability despite maximal medical therapy • high-risk development of major complications of medical therapy• patients at significant risk of developing colorectal carcinoma.

Risk of malignancy increases with pancolonic disease and the duration of symptoms is approximately 2% after 10 years, 8% after 20 years, and 18% after 30 years.

INDETERMINATE COLITIS

• Approximately 15% of patients with inflammatory bowel disease manifest clinical and pathologic characteristics of both ulcerative colitis and Crohn's disease. Endoscopy, barium enema, and biopsy may be unable to differentiate ulcerative colitis from Crohn's colitis in this setting.• The indications for surgery are the same as those for ulcerative

colitis: intractability, complications of medical therapy, and risk of or development of malignancy .

• Surveillance is recommended annually • after 8 years in patients with pancolitis• after 15 years in patients with left-sided colitis• After 7 years in patients with crohns disease

• any patient with dysplasia should be advised to undergo proctocolectomy.

• prophylactic proctocolectomy

www.alemrajabi.irmahdialemrajabi@gmail.com