Figure 50-1. Terminal ileum with forceps pointing to intraloop chronic abscess cavity.
The distribution of disease will in large part dictate the clinical presentation. The terminal ileum (along with the cecum) is the most commonly affected site, in addition to isolated more proximal small bowel disease. Patients with disease in this location will classically present with abdominal pain, fever, fatigue, nausea, and vomiting. The weight loss seen is a byproduct of both decreased oral intake as well as the malabsorptive process associated with Crohn’s. When the disease is in the terminal ileum and ileocecal region, patients may present with a slow onset of right lower quadrant pain following meals, an abdominal mass, and (when the psoas is involved) pain with hip extension. Obstructive symptoms may also occur in patients with either fibrostenotic or acute inflammation (Fig. 50-2). Diarrhea tends to be nonbloody, though heme-positive stools may occur, and rarely gross blood is a manifestation from a small bowel source.
Colonic involvement may occur in isolation in approximately one in four patients, though it is most often seen concomitantly in those with perianal (left-sided) or terminal ileal (cecal and ascending colon) disease.26 Within the colon the distribution is somewhat variable, with approximately one-third of patients having total colonic involvement, 40% showing segmental disease, and left-sided only in up to 30%.27 Regardless of the exact location within the large intestine, patients with colonic involvement may experience abdominal pain, and in some cases, malnutrition. Diarrhea is often of smaller volume and may be from several sources – malabsorptive (e.g., salt/water and bile acid malabsorption), infectious (e.g., CMV super-infection), or as a result from an entero-colonic fistula.28,29 Unlike ulcerative colitis, rectal bleeding is not routine, and bowel movements are often nonbloody, except in those with moderate-to-severe Crohn colitis. In addition, similar to disease in the small bowel, patients can experience hip pain from fistulas, cramping and obstructive symptoms. Patients with chronic disease may also demonstrate pseudopolyps on endoscopic examination (Fig. 50-3).
Bissel30 was the first to describe the anorectal component of Crohn, almost two years after the original description of the disease. Despite advances in the understanding of many features of Crohn disease, perianal complaints have been recognized as one of its most challenging aspects. Isolated perianal disease is the presenting symptom in ∼5% to 15% of Crohn patients; though over the course of their lifetime, it is seen in 25% to 80%. The perianal area in Crohn patients has classically been felt to be a “window” into the abdomen, and perianal involvement is clearly more common in those with concomitant rectal or colonic disease.31,32 In addition, active disease in the perineum is felt to act as a harbinger of an overall more virulent course.33 The traditional anorectal complaints witnessed in non-Crohn patients are similar to those with the disease, including “standard” hemorrhoids, fissures, abscesses and fistulae. However, Crohn patients may also manifest edematous (elephant ear) skin tags (Fig. 50-4), blue discoloration of the anus, and abscesses and fistulas that are often recurrent, multiple, and located well away from the anal verge. While fissures due to hypertonicity may be identified, more often Crohn fissures present as deep-seated, burrowing fissures – more like ulcers – and may be multiple, off the midline, extending in the muscle and associated with large skin tags. Finally, patients with long-standing Crohn’s may develop anal stenosis or an anal stricture at the verge secondary to repeated bouts of chronic inflammation.
Figure 50-2. Endoscopic view of a terminal ileum stricture and active Crohn disease.
Figure 50-3. Endoscopic view of colonic pseudopolyps.
Figure 50-4. Anorectal Crohn disease. Large “elephant ear” skin tag.
Clinical evidence of perianal Crohn, as manifested by many of these features, is often deemed a hallmark of disease diagnosis, although occasionally a biopsy may be necessary. Due to local sepsis and perianal tenderness, patients may need to undergo an examination under anesthesia to fully identify the extent of the disease. Patients presenting with perianal findings consistent with Crohn disease should undergo a full alimentary tract evaluation, as previously stated, with endoscopic and radiologic evaluation. In addition, a thorough physical examination to identify any extraintestinal manifestations should be performed.
Upper Gastrointestinal Disease
Upper GI Crohn encompasses disease from the mouth through the jejunum. The incidence of upper tract involvement varies widely, with most studies reporting overall rates of <5%. In patients with ileocolic disease, concomitant upper GI manifestations occur in 0.5% to 13%, yet up to 40% of patients will demonstrate early subclinical evidence of Crohn disease on radiologic and endoscopic evaluation.34 Importantly, when patients have upper GI Crohn disease, they almost uniformly have concomitant disease of lower tract and should be evaluated to determine the extent of involvement. Upper tract disease is hallmarked by both obstructive symptoms and fistulas.35 Patients typically present with abdominal pain, cramping, nausea, vomiting, or intolerance of oral intake leading to weight loss. While fistulas may be virtually to any site, the majority involving the proximal tract are gastrocolic or ileogastric in nature. Patients may be asymptomatic or present with diarrhea from high-output and colonic involvement. Crohn disease of the esophagus is exceedingly rare, involving <0.5% of patients. Most patients will have inflammation or ulcers, though strictures and fistula have also been reported. As with other upper tract Crohn disease, extra-esophageal disease is nearly always present.36
Similar to ulcerative colitis, patients with Crohn disease may have manifestations from the disease process that extend outside of the GI tract (Table 50-1). Extra-intestinal disease (EID) has been reported in ∼6% to 47% of patients with inflammatory bowel disease, and has an increased concordance among siblings and first-degree relatives – suggesting a genetic component that has been linked to the major histocompatibility complex (MHC) on chromosome 6.37,38 EID occurs secondary to the systemic inflammatory process associated with the underlying disease and affect a wide range of organ systems. While the GI tract may be the primary source, the dysfunction in immune regulation incites a pathologic response that may occur in nearly every location in the body simultaneous with, preceding, or following GI manifestations.39 Overall, rheumatologic/joint problems (e.g., peripheral or sacroiliac arthritis, arthralgias) are the most common, occurring in up to one-third of patients. Other more frequent sites of involvement include the skin (Fig. 50-5), eyes, and hepatobiliary system; while the renal, pulmonary, nervous, and coagulation systems are typically involved to a lesser extent. It is important to distinguish between manifestations that parallel bowel disease activity (episcleritis, peripheral arthritis, and erythema nodosum) from those that do not (ankylosing spondylitis, pyoderma gangrenosum, and primary sclerosing cholangitis). Surgical intervention directed at the bowel may occasionally be required for recalcitrant EID that may appropriately go into remission following bowel resection.40
Table 50-1 Classification of Extra-intestinal Manifestations of Crohn Disease
Figure 50-5. Peristomal pyoderma gangrenosum. (Courtesy of W. Brian Sweeney, MD.)
Radiologic work-up for Crohn patients is an invaluable part of the diagnostic evaluation. In addition to providing information on the acute process (i.e., abscess, phlegmon, fistula, stricture), diagnostic imaging is used to determine the extent of disease. Historically, contrast studies such as a barium enema have helped diagnose Crohn disease by identifying longitudinal and transverse linear ulcerations that create cobblestone and nodular patterns, skip lesions, fistulas, and strictures.41 A small bowel follow-through has also been a long-standing modality utilized to evaluate for strictures, active disease (highlighted by ulceration, mucosal granularity, and loss of villous morphology), and fistulas (Fig. 50-6).
In many centers, computed tomography (CT) has now largely replaced the barium enema and small bowel follow-through, with the added ability to identify the extent of the disease and involvement of surrounding structures, manifested by segmental bowel thickening (Fig. 50-7), mesenteric fat stranding, and intra-abdominal fluid.42 Additionally, CT is useful to identify secondarily involved organs or provide information that may be pertinent to preoperative planning, such as bladder or vaginal air indicating presence of a fistula, an adjacent psoas abscess in ileocecal disease, or ureteral obstruction that may require stenting. CT and magnetic resonance (MR) enterography provide improved detail of the mucosal surface and are especially useful in depicting fistulas and strictures, along with the added benefit of lower levels of radiation exposure. The latter is especially relevant considering the generally younger patient population, body habitus, and potential need for life-long repeat imaging associated with Crohn’s.
Figure 50-6. Small bowel follow-through demonstrating a tight stricture with proximal dilation.
Figure 50-7. Coronal cut of a CT demonstrating a jejunal stricture.
Magnetic Resonance Imaging
MR enterography in particular has been shown to be over 85% accurate in predicting stenosis (Fig. 50-8), abscess and fistula in preoperative planning, as well as changing the surgical strategy/approach in up to 10% of Crohn patients.43 Furthermore, its sensitivity (85% to 90%), specificity (100%), and negative predictive value (77%) have made it ideal for detecting recurrent disease after surgery.44,45
MRI has also particularly been useful in the evaluation of complex perianal fistulas seen in Crohn patients, identifying secondary “hidden” tracts and occult abscesses that lend to higher failure rates if not addressed.46 More recently, diffusion-weighted imaging and magnetization transfer imaging sequences have allowed bowel resolution previously not achievable to help identify disease, depict disease activity, and target interventions.47
Another modality typically not associated with inflammatory bowel disease, 18F-FDG positron emission tomography (PET) has been used for Crohn disease largely in academic and research centers to date.48 While cost seems to be somewhat prohibitive, this emerging indication has the potential to (a) determine disease activity in a noninvasive manner, (b) provide information regarding subclinical disease, (c) deliver a qualitative measure of response to treatment, and (d) indicate disease activity that would otherwise be unobtainable by traditional methods.
Video Capsule Endoscopy
Finally, video capsule endoscopy uses wireless technology to capture continuous images of the upper GI tract mucosa. As up to 30% of patients will have disease limited to the small bowel, capsule endoscopy plays a unique role to determine disease presence and activity that are outside the reach of endoscopy and the limitations of traditional small bowel imaging. While the diagnostic yield may not be as high, it has been shown to be comparable to ileocolonoscopy and better than small bowel follow-through for the detection of small bowel inflammation.49 Furthermore, negative predictive values range from 96% to 100%, essentially ruling out the diagnosis of Crohn’s when the results are normal.50 Of note, it is imperative to exclude the presence of moderate–severe strictures prior to its use, as their presence can result in bowel obstruction from the capsule becoming lodged at the point of stenosis (Fig. 50-9).
Figure 50-8. MR enterography demonstrating a small bowel stricture.
Figure 50-9. Video capsule endoscopy “pill” lodged in a Crohn stricture causing a bowel obstruction. (Courtesy of Justin A. Maykel, MD.)
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.)
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.
Figure 50-11. Active colitis with crypt abscess formation and atypical regenerative features consistent with chronic crypt-destructive 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.)
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
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 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.
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 first-line 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 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
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 moderate-to-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.
Indications for Surgery
Intra-abdominal fistulas may arise from either the small or large bowel and affect nearly every adjacent structure. Similar to any fistula, it is important to determine the site of origin of the fistula, as this section of bowel will typically require a formal resection when symptomatic (Fig. 50-14). On the other hand, a section of bowel may simply be involved in the process secondarily as a “bystander,” and the preferred treatment is to take the fistula down and primarily repair the site. It is important to ensure there is no significant active disease at the closure site, as this may predispose to healing problems and a subsequent leak. In this case, the preferred strategy would be to perform a segmental resection.79 Transmural bowel inflammation and communication can also occur more commonly with the skin, bladder, or vagina. Once again, the bowel is the offending organ and should be resected, while ligation of the fistula and closure of the secondarily involved organ is adequate treatment. In certain cases, the inflammatory process is so intense, or there is a concern for concomitant malignancy, that the entire process should be resected en bloc. When an abscess is present, it is often preferable to percutaneously drain the abscess and ensure adequate medical therapy (that often includes biologics), prior to embarking on abdominal exploration.80 Finally, asymptomatic entero-enteric or entero-colonic fistulas are often best left alone and treated medically, especially with the relative success of anti-TNF agents.81
Figure 50-14. Entero-enteric-colonic fistula.