Maykel, MD.)

Endoscopy

Whereas direct observation of the perianal area and anoscopy will identify disease such as skin tags,

external fistula openings and fissures, endoscopy is needed to identify the extent and severity of the

disease and perform biopsies to aid in diagnosis.51 In the clinic, flexible or rigid sigmoidoscopy can be

performed as adjuncts to the physical examination to evaluate the mid-to-upper rectum and sigmoid

colon. However, endoscopic evaluation of the entire colon, including the terminal ileum, with

colonoscopy along with appropriate biopsies is required in patients suspected of Crohn disease. Early

changes seen in the mucosa include aphthous ulcerations, erosions, and serpiginous ulcers that occur in a

skip-type pattern. As the full-thickness inflammatory cycle continues, these ulcerated areas become

progressive, enlarge, and coalesce forming the cobblestone-type pattern. The presence of rectal sparing

and terminal ileal disease may help differentiate Crohn disease from ulcerative colitis, although the

latter may demonstrate similar characteristics due to medical therapy and backwash ileitis,

respectively.52 Finally, the presence of strictures or associated masses may indicate the need for surgical

or therapeutic intervention.

Esophagogastroduodenoscopy (EGD) also plays a role for patients with suspected or known proximal

disease and can identify ulcers, fistulas, and strictures that may be responsible for various upper GI

symptoms (Fig. 50-10). In addition, EGD allows for therapeutic intervention such as dilation for those

with gastric outlet obstruction.53 Overall, both upper and lower endoscopies are relatively safe

procedures with complications in IBD patients occurring in <5%,54 and generally consist of bleeding –

though perforation remains a very small risk of every endoscopic procedure. Additionally, endoscopic

evaluation provides an ability to track and quantify disease activity by use of the scoring systems such

as the Crohn disease endoscopic index of severity (CDEIS) or Simple Endoscopic Score for Crohn disease

(SES-CD).55

Figure 50-10. Endoscopic view of pyloric stenosis in a Crohn patient; this high-grade stenosis requires balloon dilation to pass the

scope. (Courtesy of Mark Cumings, MD.)

Pathology

Classically, the presence of noncaseating granulomas on pathologic examination is pathognomonic of

Crohn disease. However, in reality they are only found in 25% to 42% of patients, and may simply be a

marker of more virulent disease.56 In addition, long-standing ulcerative colitis patients may occasionally

show granulomas on biopsy.57 Furthermore, granulomas may be present but are not typically

demonstrated on the specimens that are taken with routine depth endoscopic biopsies, rather only

visible on resected full-thickness specimens. Other histologic evidence of Crohn disease includes

architectural distortion of the crypts (size, shape, and symmetry) (Fig. 50-11), ulcerations, pseudopolyps

(Fig. 50-12), and skip areas – some of which may also be found in ulcerative colitis. Other

discriminating features of Crohn’s include the potential for full-thickness involvement of the bowel wall,

and the presence of “creeping fat,” where the mesenteric fat extends over the serosal surface of the

bowel wall – “creeping” over the normally distinct mesenteric/bowel wall interface. Furthermore, gross

pathologic examination of Crohn specimens may range from acutely inflamed, edematous, hyperemic

bowel to thickened, fibrotic, and “woody.” Finally, the mesentery is classically thickened, with marked

edema, friability and hypervascular in nature.

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Figure 50-11. Active colitis with crypt abscess formation and atypical regenerative features consistent with chronic cryptdestructive colitis. (Courtesy of George Leonard, MD.)

Figure 50-12. Full-thickness involvement of chronic inflammatory infiltrate from mucosa to serosa and pseudopolyp formation.

(Courtesy of George Leonard, MD.)

Laboratory Analysis

No single laboratory examination will provide a definitive diagnosis of Crohn disease; yet, there are

tests available to help discriminate between Crohn’s and other processes. Routine serum profiles such as

perinucelar antineutrophil cytoplasmic antibodies (p-ANCA) and anti-Saccharomyces cerevisiae

antibodies (ASCA) have traditionally been used to help differentiate Crohn disease from ulcerative

colitis. The former is a known marker associated with ulcerative colitis, whereas elevated levels of

ASCA are associated with Crohn disease. Unfortunately, only 30% to 50% of Crohn patients will test

positive for ASCA, and up to 10% of healthy individuals will also have elevated serum levels.58

C-reactive protein is a nonspecific marker for inflammation that has been useful in tracking disease

activity and response to treatment. More recently, fecal biomarkers such as fecal calprotectin,59

lactoferrin, and neopterin60 are used to monitor intestinal inflammation, and have been shown to

reliably correlate with disease activity and mucosal healing as measured endoscopically.61 In addition

they may play a role in helping to make a distinction between inflammatory bowel disease and

functional bowel disorders, with reported sensitivities and specificities of ∼80% to 85%.62 While

nonspecific, persistent elevations in fecal biomarkers have been shown also to correlate with higher

levels of recurrence following surgical resection.63

DIFFERENTIAL DIAGNOSIS

The differential diagnosis in Crohn disease is wide and includes both benign and malignant processes

(Table 50-2). While Crohn disease has certain traits that are more suggestive of its presence (e.g.,

noncontiguous multisite disease, fistulas, creeping fat), a variety of abdominal process may mimic

Crohn’s (Fig. 50-13). It is not an uncommon scenario for ileocolic Crohn’s to be ultimately diagnosed

from a clinical picture that may at first resemble acute appendicitis, right-sided diverticulitis, an

infectious process, or a perforated malignancy. Radiologic studies may demonstrate similar patterns of

bowel inflammation, laboratory examination often shows elevated CRP and/or white blood cell counts

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in each, and the patient demographics are routinely alike. When this occurs intraoperatively, a decision

must then be made regarding whether or not to proceed with resection versus closure and medical

management alone based on clinical findings. If a resection is performed, questions arise regarding the

extent of resection such as whether or not to perform an ileocectomy versus appendectomy alone and

what margins of resection are required for the situation at hand.

Table 50-2 Differential Diagnosis of Crohn Disease

When confronted with this situation in the operating room and Crohn’s is suspected, traditional

teaching recommends performing an appendectomy if the cecum is normal, or to withhold on resection

and undergo medical treatment only. Yet, there are data to support performing an ileocolic resection at

the time of surgery, with one series reporting almost half of patients required no further surgery as a

result of their Crohn disease, compared to 92% of those undergoing appendectomy only (65% within

the next 3 years).64 Hence early ileocolonic resection may be in the patient’s long-term best interests to

avoid recurrent disease and repeated trips to the operating room.

When disease is isolated to the colon, the major differentiation involves distinguishing Crohn colitis

from ulcerative colitis, though other infectious and inflammatory colitides remain in the differential. As

previously noted, many of the same clinical and histopathologic traits are shared in both diseases, and

contribute to the initial diagnostic dilemma, as well as those patients with indeterminate colitis or those

that undergo a change in diagnosis from ulcerative colitis to Crohn’s. Ultimately it is the entire

evaluation to include information taken from laboratory, pathologic, endoscopic, radiologic, and clinical

examinations as outlined above that will help clarify the picture and aid in diagnosis.

Figure 50-13. “Creeping” fat on an ileal specimen.

TREATMENT

Medical Management

While an in-depth look regarding the medical management of Crohn disease is beyond the scope of this

chapter, a few points are worth noting (Table 50-3). First, despite the spectrum of disease presentations,

Crohn’s remains one hallmarked by inflammation (i.e., abdominal pain) and diarrhea. As such,

supportive care to include antidiarrheals and antimotility agents, along with a bland diet, are good firstline approaches to provide symptomatic control. It is important to exclude the concomitant presence of

“super-infections” such as cytomegalovirus or Clostridium difficile infection, as antimotility medications

may result in the onset of toxic megacolon and a rapidly progressive clinical deterioration. Yet, simple

over-the-counter, readily available medications such as loperamide, diphenoxylate, and bismuth, along

with prescription medications such as codeine and tincture of opium often provide tremendous relief to

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abdominal pain, cramping, and loose stools.

Crohn’s has also been traditionally been called a “wasting disease,” though increasing numbers of

obese patients with Crohn’s are observed. Despite this seeming paradox, nutritional support in both

groups remains paramount. Ideally, preservation of oral feeding in any form is crucial for maintenance

of the absorptive and protective mechanisms provided by the GI mucosal lumen villi and microvilli.

However, when this is not possible, parenteral nutrition has become invaluable in preserving nutritional

stores, aiding in maintenance of positive nitrogen balance, preventing weight loss and improving

perioperative outcomes.65 This must be weighed against the potential complications involved with

intravenous routes to include infectious complications and thromboembolic events.

A tiered strategy for medical therapy is often utilized, taking into account the disease activity (flare

vs. chronic), pattern (inflammatory vs. fistulizing vs. fibrotic) and location. Antibiotics and

aminosalicylates are typically used in the induction and maintenance of remission, respectively,

especially for those with mild-to-moderate disease. Antibiotics are also utilized for the treatment of an

acute infection for both the abdominal and perianal locations, with metronidazole and fluoroquinolones

among the most commonly used. In select cases, antibiotics can be given to patients with perianal

disease including fistulas for maintenance of remission as well as decreasing pain. While the exact

mechanism of action of antibiotics in Crohn disease is debated, by decreasing bacterial load and altering

the bacterial milieu of the GI tract, disease activity is lessened.

Aminosalicylates (5-ASA) are traditionally used as first-line maintenance agents, and are generally

well tolerated by patients. Depending on the predominant location of the disease, different moieties can

be formulated to allow maximal drug concentration to be targeted at the appropriate site. 5-ASA

compounds are not aspirin or nonsteroidal derivatives, though they do work to decrease

proinflammatory mediators and function at the mucosal level with reduced systemic absorption. Similar

to antibiotics, the mechanism of action in inflammatory bowel disease remains unclear, though levels of

NF-KB, TNF, and interleukin-1 have all been shown to decrease, as well as inhibiting both B- and T-cell

function.66 Additionally, they can be used in the perioperative period without increasing the risk of

postoperative complications. Overall, this class of medications has been shown to prevent disease flares

and minimize Crohn disease activity index for patients with mild disease, though the results have been

inconsistent with questionable clinical benefit.67 However, at most they have little downside and there

is some data to suggest a decrease in disease recurrence following resection.

Steroids remain a mainstay in the treatment of Crohn disease for both the induction and maintenance

of remission. They are especially useful in the setting of disease flares, where a “burst” followed by a

weaning strategy may allow some of the more well-tolerated medications to be initiated as a

maintenance regimen. Purported advantages to steroids include their low cost, ability to give via the

intravenous, oral and rectal routes, and the relative speed and efficacy that they are able to help achieve

quiescent disease. On the downside, ∼14% to 45% of patients will ultimately have steroid recalcitrant

disease, requiring either an escalation of medical therapy or surgical resection. Additionally, the wide

range of potential complications of steroids ranging from adrenal suppression, insulin resistance, ocular

disease, and osteopenia to psychosis, acne and weight gain, limits durable sustained use considerably.

Budesonide is a synthetic corticosteroid that is taken orally or rectally, and the steroid effect is

predominantly local due to a significant first-pass metabolism in the liver. While pooled analysis

demonstrated inferior effects compared to systemic steroids, it has been shown to maintain rates of

remission higher than placebo and comparable to prednisolone for those with mild disease.68

Table 50-3 Medical Treatment for Crohn Disease

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The immunomodulator class of medications includes 6-mercaptopurine, azathioprine, methotrexate,

tacrolimus, and cyclosporine. They work via different mechanisms of action, yet all serve a common

purpose to alter the immune system in some capacity to blunt the patient’s intrinsic response to what is

considered “foreign” and to decrease inflammation. The first two (thiopurines) act via inhibition of

purine synthesis, and must be monitored, as metabolites can lead to bone marrow suppression and

hepatotoxicity. These drugs are useful for both the induction and maintenance of remission and

particularly helpful in dose reduction and weaning patients off prednisone.69 They also have a longer

onset of action, and may take months until the full effect of the medication is witnessed. Methotrexate

inhibits dihydrofolate reductase, also inhibiting purine and pyrimidine synthesis, and ultimately

cytokine production. Its effects are better demonstrated with intramuscular or subcutaneous injection

compared to oral, where both induction and remission rates are significantly worse.70 Side effects range

from blood dyscrasias and secondary malignancies to pneumonitis and hepatic fibrosis, and serial

monitoring of liver function tests is recommended.

The comparatively new group of medications are the biologic agents such as infliximab, adalimumab,

and certolizumab, which are monoclonal antibodies targeting tumor necrosis factor-α. They are also

administered via subcutaneous or intravenous injection, with dosing intervals dependent on the patient

response. Adalimumab is a fully human monoclonal antibody, and while still possible, provides the

advantage of being less likely to develop drug antibodies than infliximab.71 Together they are extremely

useful in the induction of remission, and more and more are utilized as first-line therapy for moderateto-severe disease (especially those with fistulizing disease), as well as in the maintenance of remission

for medically refractory patients. Several large-scale multicenter randomized trials including CLASSIC I

and II, CHARM, PRECiSE-1, and WELCOME have all demonstrated not only their collective efficacy, but

also the ability to induce and maintain remission in patients who had previously lost response to one of

the others.72 They are not without reported significant side effects, however, including anaphylaxis,

secondary malignancies, and opportunistic infections. Patients should be tested for latent tuberculosis

prior to their administration to avoid resurgence. Additionally there is considerable debate in the

literature as to their impact on perioperative complications and anastomotic leaks, with large center

studies reporting contradictory results, and pooled analysis demonstrating a nonsignificant trend toward

increased total complications (OR 1.72; 95% CI 0.93 to 3.19).73 Despite this controversy, discretion may

warrant consideration for diversion when these medications are used in the setting of higher-risk

anastomoses.

Operative Management

Indications for Surgery

2 One of the basic tenets in the management of Crohn disease is that surgery is typically reserved either

for failure of medical therapy (i.e., intractable disease or steroid dependency) or complications from the

disease. Failure of medical management is still the most common reason for surgery in patients with

Crohn disease, especially in colonic disease. Complications resulting in a potential need for operative

intervention include fistula, abscess, obstruction (stricture), growth retardation, perforation, EID,

bleeding, and malignancy. Of note, hemorrhage in Crohn disease tends to be a more rare event, and is

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