39
Inflammatory Bowel Disease:
Diagnosis and Evaluation
Walter A. Koltun
543
History
In 1932 Crohn, Ginzburg, and Oppenheimer1 described 13 patients with “regional ileitis” included in a total of 52 cases of nonspecific granulomatous inflammation of the intestine.
Before their publication, numerous others had reported various cases of what were in retrospect, probably Crohn’s disease (CD), as early as 1813,2 but it was their published description that established the formal classification of the disease syndrome and association with noncaseating granulomas. The surgeon involved in the care of the majority of the patients, Dr. A.A.
Berg, did not want his name included in the article. Because of the variable clinical and anatomic manifestations of the illness,
“Crohn’s disease” has subsequently become as common a descriptor of this disease entity as the term “regional enteritis.”
The difficulty in distinguishing the colonic form of CD and ulcerative colitis (UC) confused the diagnosis and treatment of these illnesses until their differences were clarified by clas- sic publications by Brooke3in 1959 and Lockhart-Mummery and Morson4in 1960. These authors pointed out both the seg- mental and granulomatous features of the colitis in CD. In addition, Brooke contributed significantly to the treatment of these inflammatory illnesses by pioneering surgical tech- niques in the 1950s that created a more functional ileostomy, which until that time was a miserable and disabling conse- quence of colectomy.5Truelove et al.6in 1959 reported on a double-blind, controlled study demonstrating the value of high-dose cortisone as treatment for severe colitis. Other turning points in the management and treatment of CD include the demonstration of the therapeutic value of metron- idazole,7 6-mercaptopurine,8 and more recently, the tumor necrosis factor (TNF)-αantagonist, infliximab.9
The surgical management of UC has been a continuous evolution starting with colectomy/ileostomy,10,11 supplanted by the continent Kock ileostomy,12and finally the definitive reconstruction procedure known as the ileal pouch–anal anas- tomosis (IPAA), first described by Parks and Nicholls13 in 1978 and subsequently refined by Utsunomiya.14The IPAA is now the standard of care for the surgical correction of UC.
Epidemiology
The causes of UC and CD are unknown, and thus epidemio- logic data have been collected over many years in the hopes of providing some clues to the etiologies of these illnesses.
Much of these data must be viewed with caution, however.
Variations in diagnostic criteria, definitions of disease, and biases resulting from surveys done in tertiary care specialty centers, make universal conclusions difficult. However, some general statements can be made using such data that relate to disease prevalence and associated risk factors (Table 39-1).
The prevalence of inflammatory bowel disease (IBD) varies greatly with region of the world studied. Prevalence is the product of incidence and disease duration. Because IBD symptoms tend to wax and wane in severity, prevalence may be underestimated in some studies. IBD is found most fre- quently in the more temperate climates of North America and Europe. Studies from those regions show prevalence rates much higher than those in Asia, South America, or Africa.
Prevalence rates as high as 300–400 per 100,000 population are found in Minnesota (USA), Manitoba (Canada), and the United Kingdom. Conversely, prevalence rates of approxi- mately 23/100,000 are found in Japan, 10/100,000 in Singapore, and 75–120/100,000 in Israel. The relative inci- dence of Crohn’s versus UC is again, variable, with either being found greater than the other depending on geographic region studied.15–19
It is generally recognized that both CD and UC have been increasing in incidence to a remarkable degree over the past 20–30 years with two- to tenfold increases depending on pop- ulation and region studied.18,20These dramatic increases sug- gest an environmental effect, because a genetic factor would probably not alter disease rates so rapidly.
CD usually occurs in the third decade of life, whereas chronic UC in the fourth decade. There may be a bimodal dis- tribution of disease incidence with a second peak in the sixth or seventh decade, but this is unclear and may simply be attributable to difficulty in differentiating it from other coli- tides such as diverticulitis or ischemic colitis.21
Although originally thought to be relatively rare in blacks, more recent case control studies in the United States suggest a similar incidence to whites, although Africa itself has a very low incidence of IBD.17There is great variability in the inci- dence of IBD in Jews around the world, but nonetheless seems to be consistently higher than that found in the non-Jewish population in most countries studied.22IBD is more common in urban, “indoor” populations of individuals of middle to upper socioeconomic status, suggesting the “hygiene” hypoth- esis that relates the lack of early exposure to environmental antigens to the later development of disease.15,19,23
There is very little evidence that a specific dietary factor causes IBD although increased sugar consumption is associ- ated with CD and alcohol intake is inversely related to chronic UC.24,25 Childhood diarrheal illness, oral contraceptive and nonsteroidal antiinflammatory (NSAIDs) use are measurable risk factors for IBD, with NSAIDs reported as precipitating relapse in patients with inactive disease.26Smoking has been clearly shown to worsen CD, with increased risk of develop- ing the disease de novo and increased risk of recurrence after surgical resection.27,28Conversely, smoking is protective for chronic UC, as is prior appendectomy.27
There is clearly a genetic predisposition to IBD. It is prob- ably stronger in CD than UC. If an individual has IBD, there
is a 10%–20% risk of having another family member with IBD. Twin studies have shown that the concordance rate for identical twins is much higher than that for dizygotic or paternal twins (approximately 50% versus 15%), stressing the role genes have in the disease. However, the fact that identi- cal twins do not have a 100% concordance, reinforces the fact that there must also be a nongenetic component to the illness.
In families who have multiple affected members, the age of onset is probably earlier and some studies suggest that the anatomic pattern, extent and severity of disease may be simi- lar.29–31Genetic techniques of analysis, including linkage and transmission disequilibrium testing using both sporadic and family registries of IBD patients have identified seven areas of the human genome (on chromosomes 1, 5, 6, 12, 14, 16, 19) that are significantly relevant to disease susceptibil- ity,32underscoring the complexity of the genetic predisposi- tion to IBD. It seems that no one gene locus is responsible for disease, but that many gene products have a role in the illness.
The strongest genetic linkage is with CD and mutations in a locus on chromosome 16 which has now been identified as being in the NOD2/CARD15 gene.33,34This gene is involved in innate host defense against enteric bacteria and mutations in this gene are believed to be responsible for approximately 15%–30% of patients with CD. Its discovery represents a breakthrough in the conceptualization of disease pathogenesis in IBD. Overall, both the epidemiology and now the molecu- lar genetic evidence furthers the concept that IBD is the con- sequence of environmental exposure to a causative agent in a genetically susceptible individual.
Signs and Symptoms
Gastrointestinal Symptoms
Crohn’s DiseaseCD can affect any portion of the gastrointestinal (GI) tract from the mouth to the anus. It is usually discontinuous, usu- ally involving several areas of the bowel at once, with sections of normal intestine interposed. The inflammation of CD involves the entire bowel wall, from mucosa to serosa and even into adjacent structures. These features are responsible for its presenting symptomatology.
The most common complaints of any patient with CD are abdominal pain and diarrhea, being found in more than 75%
of patients. Weight loss, fever, and bleeding are present in approximately 40%–60% of patients, whereas anal symptoms of abscess and/or fistula occur in 10%–20% of patients. Many classification systems for CD have been suggested but the anatomic one has direct practical relevance in explaining symptoms. CD is most frequently found in the ileocecal region, making up approximately 40% of patients. Abdominal pain usually correlates with disease in this region.20Colonic disease is found in approximately 30% of patients and most directly correlates with symptoms of diarrhea and bleeding.
TABLE39-1. Epidemiologic and associated risk factors for IBD Epidemiology
Race/ethnicity
Whites and blacks > Hispanic, Native American, Asian Jews > non-Jews
Geography
Northern climates > Southern
Scandinavia, North America, Europe > Asia, Africa, South America, Japan, Spain
Sex CD: F > M UC: M > F
Age at greatest incidence CD: third decade UC: fourth decade Residence
Urban > rural Indoor > outdoor Risk factors
Diet
Sugar consumption, ↑CD ETOH, ↓UC
Margarine, no association Coffee, no association Fiber, no association Food additives, no association Childhood diarrheal illness ↑IBD Higher socioeconomic status ↑IBD Oral contraceptive use ↑IBD Cigarettes ↑CD
↓UC Appendectomy ↓UC NSAIDs ↑symptoms IBD
The remaining 30% of patients have disease confined to the small bowel proximal to the terminal ileum and correlates with abdominal pain, bloating, and a sense of postprandial nausea especially if partial obstruction caused by inflamma- tion or strictures occurs. Anal disease is typically associated with patients having the terminal ileal and colonic distribu- tions of disease.
The more recently developed Vienna classification of CD segregates patients into three categories based on behavior:
inflammatory (B1), stricturing (B2), and fistulizing (B3).35 This classification attempts to characterize disease biology but is imperfect. Patients will frequently change categories as disease progresses, because inflammatory disease usually becomes stricturing or fistulizing disease. Louis et al.,36over a 10-year period, found that in 125 patients with CD, the B2 and B3 categories (stricturing and fistulizing) each increased from approximately 10% to approximately 30%–40% with a compensatory decrease in the inflammatory, B1category.
Thus duration of disease has a critical role in defining the category in this classification system.
Clinical severity of symptoms is widely variable, because CD typically has a waxing and waning course characterized by periods of disease activity interspersed with periods of remission. At any one time, approximately 50% of CD patients will be in clinical remission. The majority of patients (60%–75%) will have alternating years of quiescence and dis- ease activity. Approximately 10%–20% will have either a chronic, unremitting course or repetitive annual flaring of dis- ease. Prolonged quiescence is found in approximately 10%–15% of patients. The only useful predictor of future disease activity is past clinical behavior.
Ulcerative Colitis
The inflammation of UC characteristically starts in the rectum and extends proximally. So-called backwash ileitis is the only possible area of the small bowel that can be affected in UC, or CD should be suspected. Clinical symptoms relate to the extent and location of disease. Thus, rectal disease results in increased stool frequency, hematochezia, and tenesmus.
Diarrhea is a frequent symptom and with tenesmus can result in incontinence, especially at night. Despite severe rectal inflammation, constipation with a sense of incomplete evacu- ation can be a complaint in 20%–25% of patients, but blood and mucous are nearly always present. With more proximal involvement, abdominal complaints increase including left lower quadrant pain and pain associated with peristalsis or stool evacuation. With increasing severity and extent of dis- ease, nausea, vomiting, and weight loss ensue. Weight loss is attributed both to the loss of serum proteins through the dis- eased mucosa and the reluctance of the patient to eat in order to avoid exacerbation of symptoms. The development of systemic signs of illness such as tachycardia, fever, and increasing fluid requirement bespeaks severe disease. High- dose steroids may disguise worsening abdominal complaints,
including peritonitis in such circumstances and should not divert the clinician from recognizing the gravity of the devel- opment of such symptoms and signs. So-called “toxic mega- colon” is a moniker that should be discarded, because severe life-threatening colitis may occur without colonic dilatation and urgent surgical intervention should be based on the triad of toxicity defined by tachycardia, fever, and increased white blood cell count.
Extraintestinal Manifestations
MusculoskeletalThe most common non-GI complaints in IBD patients relate to the musculoskeletal system. Osteopenia and osteoporosis are very common, in part because of therapeutic steroid use, occurring in as many as 50% and 15% of IBD patients, respectively. Such bone density loss is now recognized as leading to significant comorbidity and complications in IBD patients. One study found a 40% increased risk of bone frac- tures in IBD patients.37The arthropathies associated with IBD are found in up to 30% of patients and are divided into two broad categories. Peripheral arthritis usually affects multiple small joints and has little relation to GI disease activity. Axial arthritis (ankylosing spondylitis) is associated with certain human leukocyte antigen subtypes (B27) and is found in approximately 5% of both CD and UC patients. Its severity usually parallels disease activity. Recently, anti-TNF thera- pies have been shown to be effective in both CD and the arthropathy of IBD.38,39
Cutaneous
Pyoderma gangrenosum and erythema nodosum occur in approximately 0.5%–5% of patients with IBD. These, as well as oral lesions such as aphthous stomatitis and pyostomatitis vegetans, are more frequently associated with CD than UC and usually parallel underlying GI disease activity. The new appearance of pyoderma gangrenosum around the ileostomy of an IBD patient after colectomy is unexplained but is a clear clinical phenomenon.40There is a reported increased rate of psoriasis and eczema in IBD patients that does not parallel disease activity. One-third to one-half of patients with pyo- derma gangrenosum have IBD.41
Hepatobiliary
Primary sclerosing cholangitis (PSC) has a reported incidence of approximately 3% in both CD and UC patients. It may present independently of intestinal disease activity, and colec- tomy in UC patients does not affect progression of liver disease. The presence of PSC in the UC patient increases the risk for malignant disease in both the colon and hepato- biliary system.42
Several studies have suggested an increased incidence of gallstones in IBD, especially CD although this is disputed.
The mechanism is presumed to be attributable to an altered enterohepatic biliary circulation caused by ileal disease.43
Ophthalmologic
Iritis, uveitis, and episcleritis can affect 2%–8% of UC and CD patients and are generally unrelated to disease activity.
Iritis and uveitis present as blurred vision, eye pain, and pho- tophobia and require prompt treatment to avoid scarring and even blindness. Episcleritis is typically less threatening and is characterized by scleral injection, burning, and tearing.
Coagulopathy
There is an identified increased risk of deep venous thrombo- sis, mesenteric thrombosis, and pulmonary embolism in IBD patients that is not explained simply by increased hospitaliza- tion and surgery. Decreased protein S and antithrombin III levels attributed to mucosal loss and increased levels of acute phase reactants including factors V and VIII have been impli- cated. The mortality of postoperative mesenteric thrombosis in the IBD patient has been reported to be as high as 50%,44but probably occurs more frequently than previously recognized with an overall lower mortality and morbidity in its milder forms.45,46 Anticoagulation and work-up for coagulation disorders are usually recommended.
Disease Severity Assessment
Crohn’s Disease
The CD activity index (CDAI) is the most frequently used method for quantitating disease severity in CD. It was developed by Best et al.47using multiple regression analysis and includes a total of eight items that are measured, multi- plied by respective weighting factors, and then summated to yield a score (Table 39-2). It is generally accepted that a total score less than 150 points is quiescent disease, whereas more than 450 is severe, active disease. Relapses are defined
as a score increasing to more than 150 or an increase of 100 points over baseline. The CDAI is most frequently used in longitudinal clinical studies to evaluate the results of experimental interventions. It suffers from many deficien- cies including its reliance on subjective complaints and that it is time consuming, requiring the patient to keep a diary for 7-day periods defining symptomatology. Some measured symptoms, such as diarrhea and belly pain, may reflect short gut caused by prior surgery or strictures that do not repre- sent active, inflammatory disease.47Other indices have been developed in an attempt to address these criticisms. The Harvey Bradshaw index (or modified CDAI) and the Van Hees index, which relies entirely on nine objective factors such as erythrocyte sedimentation rate (ESR), albumin, temperature, and stool consistency are two such measure- ment tools, but they are infrequently used, even in protocol settings.48
The Vienna classification, discussed above, is an attempt to classify or categorize subsets of CD patients and is not used as a severity assessment tool.35
Ulcerative Colitis
The benchmark study evaluating the effect of cortisone on UC by Truelove et al.6in 1955 also described the still most often used clinical assessment tool for severity assessment in UC (Table 39-3). The simplicity and clinical relevancy of the fac- tors in this index allow for its daily use as a clinical tool and also for clinical response in study protocols. Variations on its initial format have included the creation of a “moderate” cate- gory for patients displaying features intermediate in value between the mild and severe categories. This index also does not take into account variability in the anatomic extent or observed severity of disease within the colon. Modern clinical studies requiring disease assessment will thus often use a vari- ation on the Truelove and Witts classification which will include additional criteria based on colonoscopic appearance and possibly pathologic severity as well.49,50
TABLE39-2. The CDAI
Item Data collected Calculation Weighing factor
No. of liquid stools 7-day diary Sum of 7 days 2
Abdominal pain 0–3 scale, 7-day diary Sum of score for each day 5
General well-being 0–4 scale, 7-day diary Sum of score for each day 7
Symptoms* At clinic visit Sum (6 total possible) 20
Lomotil use 7-day diary Yes = 1, No = 2 30
Abdominal mass At clinic visit None = 0, questionable = 2, definite = 5 10
Hematocrit (HCT) At clinic visit M (47 subtract patient’s HCT) 6
F (42 subtract patient’s HCT)
Weight At clinic visit % below ideal weight 1
*Symptoms include presence or absence of each of arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/
aphthous stomatitis, anal fissure/fistula/abscess, other fistula, or temperature >100°F.
Evaluation
Radiology
The diagnosis of IBD depends on the triad of clinical presen- tation, radiologic work-up, and histopathology of tissue biopsy. Thus, radiologic studies are critical in the evaluation of the patient with suspected or confirmed IBD.
Plain X-rays
Conventional radiologic studies have a significant role in the work-up and management of IBD. Plain abdominal radi- ographs can show signs of obstruction, perforation (free air), and at times thickening of the bowel or loss of haustral mark- ings. The initial presentation of any patient with belly pain and a known or suspected diagnosis of IBD will incorporate a plain and upright film looking for these signs. On the plain film, air can act as a contrast medium and can allow the iden- tification of the more subtle findings of nodularity of the mucosa suggesting ulceration or pseudopolyp formation.
Chronic colitis may result in an ahaustral, tube-like colon that can be seen with air contrast (see Figure 39-1). Fulminant or rapidly worsening colitis may result in toxic dilatation (“toxic megacolon”) that mandates surgical intervention and the specific avoidance of colonoscopy or contrast enema studies that may result in perforation. Incidental discoveries of
gallstones or renal calculi that occur with increased incidence in patients with IBD may also be made.
Contrast Radiologic Studies
Contrast studies will more frequently be used in the patient with CD than UC because of its predisposition for small bowel involvement. For the colitic patient, whether caused by CD or UC, colonoscopy is usually the preferred study, frequently obviating the need for barium enema. However, a double-contrast barium enema may still be used to discover or delineate extent of disease in the patient with GI symptoms, especially when caused by CD. Colonic contrast studies in the CD patient can show segmental disease, strictures, and fistu- las. Reflux into the terminal ileum occurs in approximately 85% of patients and can reveal ileal disease more effectively than small bowel follow through because of less superposition of intestinal loops. When fistulas or near obstructing strictures are suspected, a water-soluble dye, such as Gastrografin is preferred. This minimizes the complications associated with possible extravasation of the dye if a fistula or intestinal per- foration is present or subsequent impaction of barium if passed proximal to a stricture. Not infrequently in the patient with CD, an unsuspected rectal fistula tracking to a diseased terminal ileum is found on rectal contrast study (see Figure 39-3, below). Such a fistula can be easily missed on colonoscopy because it originates with the diseased terminal ileum and the rectum infrequently has other evidence of CD.
The difficulty of reaching the small bowel using fiberoptic instruments results in the common use of small bowel contrast studies to assess the degree of CD involvement of the small bowel. Small bowel series can effectively show areas of stric- turing and upstream dilatation but may be difficult to perform or interpret because of slow intestinal transit from strictures, overlying loops of bowel, and pain associated with compres- sion spot views (Figure 39-2). Enteroclysis is preferred over simple small bowel follow through, although its need for the placement of a naso-intestinal tube makes patient cooperation and satisfaction with this study much less. High-density bar- ium must be used as the contrast agent, because water-soluble dyes rapidly dilute out in the small bowel, making detailed assessment of the intestinal mucosa difficult. After placement of the nasal tube beyond the pylorus, relatively small boluses of barium are injected that coat the walls of the intestine and then air is insufflated distending the bowel allowing detailed examination of the mucosa. Repetitive infusions of dye and air, with subsequent spot compression films, can result in remarkable detail being revealed but results are clearly dependent on operator expertise and patient cooperation.
GI contrast studies surpass computed tomography (CT) for detecting enteroenteric and enterocolic fistulas.51The discov- ery of an enteric fistula can be made when orally consumed contrast material is seen in a distal portion of bowel without illuminating intervening intestine, such as can occur with ileal disease fistulizing into the rectum. Sometimes the dye will TABLE39-3. Truelove and Witts UC activity index
Mild Severe
Bowel frequency/ 24 hours < 4 > 6
Blood in stool + +++
Fever Absent > 37.5
Pulse < 90 > 90
Hgb > 75% nL < 75% nL
ESR < 30 > 30
FIGURE39-1. Plain radiograph of a patient with worsening symptoms of ulcerative colitis. Note the ahaustral left and transverse colon, signs of small bowel ileus and enlarged (“mega”) transverse colon.
directly illuminate the fistula or involved organ, such as the bladder, as it tracks from the bowel, whether the contrast is given orally or rectally (Figure 39-3).
Sinography or fistula-gram can be used to delineate the path or origin of fistulous disease in CD patients, whether involving the abdominal wall or perineum. Such studies can
also be done via the drainage catheter after percutaneous drainage of an abscess to document intestinal communication and, again, should be done with water-soluble contrast. Such anatomic localization assists in directing subsequent surgical care (especially when fistulous disease involving the urinary tree is found) and assessing response to therapy.
Retrograde studies through a stoma, especially an ileostomy, can provide very good evaluation for disease. The effectively foreshortened intestine allows better delineation of disease with less overlapping bowel loops and better double- contrast definition.
Computed Tomography
Abdominal and pelvic CT is probably the most frequently obtained study in the acute work-up of patients with IBD, especially CD. Such studies should be done with orally ingested low-density barium or iodinated contrast material that has been allowed to traverse the entire GI tract. Because of strictures or slow transit time, rectal administration of con- trast will sometimes be necessary. CT scanning is especially useful for delineating enterovesical or colovesical fistulas and scans should be obtained before administering intravenous contrast, as contrast originating from the bowel will be seen in the bladder defining the fistula. Air within the bladder without prior instrumentation is also a very sensitive sign defining the presence of a fistula.
The great advantage of CT is its ability to look at the entire thickness of the intestine and its adjacent structures. Thus, thickened intestine, phlegmon, abscess, air in extraintestinal structures, and fistula formation are signs of CD that can be found on CT scan (Figure 39-4). Percutaneous drainage of abscess collections done under CT guidance can also be per- formed. Although less frequently performed for UC, CT findings that can be seen include increased perirectal and presacral fat, inhomogeneous areas of colonic thickening, target or “double halo” sign of the colon, and changes consistent with cancer development such as strictures or mass lesions.51
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is playing an increasing role in the evaluation of IBD patients. Intestinal CD can be identified simply by thickened bowel loops on conventional MRI. MRI differs from CT, however, in that the intensity of T2-weighted signals from areas of disease correlate with severity of inflammation, especially after gadolinium admin- istration. Such signal intensity in both the mesentery and bowel decreases with resolution of acute inflammation and may hold promise for monitoring the response of patients to medical therapy.52,53
MRI’s value in defining perineal disease in the CD patient approaches, and may exceed, that achieved with examination under anesthesia.52,53Endorectal coil placement may improve FIGURE39-2. Small bowel follow through contrast study showing
terminal ileal stricturing disease, with displacement of adjacent bowel loops caused by ileal thickening.
FIGURE39-3. Colonic contrast study in CD patient showing complex fistulizing disease. Contrast is present in the proximal, diseased ileum and air and contrast in the bladder because of fistulizing disease.
sensitivity but is infrequently necessary and sometimes impossible in the diseased anus. Intravenous injection of gadolinium highlights the fistula tract, and combined with MRI’s ability to accurately define soft tissue anatomy, can result in remarkable delineation of disease.54,55MRI testing is expensive, however, and is probably unnecessary in the con- ventional perineal CD patient because an examination under anesthesia performed by a competent surgeon is usually as accurate and can also provide simultaneous treatment.56 However, MRI is finding a role in reassessing the failed patient for unrecognized pathology and, more recently, in defining whether medical treatment with infliximab has truly healed a patient’s fistulous disease. Several studies using gadolinium-enhanced MRI have shown that many fistulas that respond to exclusive medical management are, in fact, still present but quiescent.57,58
Ultrasound
The role of ultrasound in IBD is presently very limited.
European centers are more familiar with its use for assessing the GI tract in IBD patients where it is sometimes used to lon- gitudinally follow a patient’s response to therapy. In the hands of an experienced operator, so-called transabdominal bowel sonography (TABS) can look for bowel wall thickening, fistula formation, and can even assess functional effects of strictures by observing bowel peristalsis and distention in the vicinity of such pathology.59This method of noninvasive intestinal evalu- ation has not gained wide popularity in the United States.
Intrarectal ultrasound can be used to document and map perianal fistula formation by injecting a solution of hydrogen peroxide into the external opening. The resulting bubbles are easily seen on ultrasound as they outline the path of the fistula tract. However, such uncomfortable and operator-dependent
techniques of fistula assessment have been largely replaced by MRI scanning (see above).
Nuclear Medicine
The injection of radionuclide-labeled white cells allows subse- quent scintigraphic imaging of the abdominal organs and is increasingly being used as a technique to visualize actively inflamed bowel. Most techniques use indium111 labeling of autologous leucocytes that are harvested from the patient, labeled, and then reinjected. Indium111has the advantage of a long half-life that allows scanning at 6, 12, and 24 hours with any visualized bowel activity as being abnormal. A fixed area of activity suggests an abscess. Newer techniques using tech- netium-99m–hexamethylpropyleneamine oxime (HMPAO) provide for better image quality because of their relatively selective labeling of granulocytes and also result in a lower radiation dose to the patient. Some studies using this tracer have shown very high sensitivity rates, but specificity is less because of its inability to differentiate between IBD and infec- tious causes of disease.60The advantage of such radionuclide scanning techniques relate mostly to their ability to differenti- ate between inflamed versus quiescent disease and their use will probably increase as newer labeling agents are devised.
Endoscopy
Colonoscopy has strongly influenced the diagnosis and eval- uation of the patient with IBD. It is the study of choice for the patient with suspected UC because it can directly visualize the entire extent of the disease process. It is similarly relevant for CD when involving the colon, and can also be used to intubate and evaluate the terminal ileum. Most significantly, colonoscopy provides biopsies, which allows a tissue diagno- sis to be made by the pathologist. There are numerous indica- tions for colonoscopy in the IBD patient (Table 39-4) and it has a significant role in both medical and surgical treatment.
The gross appearance of the colon as seen on colonoscopy can frequently differentiate between CD and UC (Table 39-5).
Its use in the patient with severe disease is controversial.
Although studies exist suggesting it can be safely done in the FIGURE39-4. CT scan of CD patient with severe terminal ileal thick-
ening and early abscess formation under anterior abdominal wall.
TABLE39-4. Indications for colonoscopy in IBD
●Diagnosis: –Gross appearance
–Tissue biopsy
●Disease extent
●Disease complications: –Fistulas –Stricture –Bleeding
●Preoperative “staging”
●Monitor response to therapy
●Stricture management: –Biopsy
–Dilatation
●Cancer surveillance
severely colitic patient, the risk of perforation caused by insufflation, biopsy, or mechanical bending of the scope is generally acknowledged as being high and thus colonoscopy is generally avoided in the acute setting. However, such severely ill patients still need endoscopic evaluation to rule out concurrent diseases such as pseudomembranous or cytomegalovirus-induced colitis. Rigid or flexible procto- scopic evaluation is thus recommended, with biopsies done in the lower rectum below the peritoneal reflection to minimize the risk of free perforation.
The flexible sigmoidoscope is conveniently used for the eval- uation of the unsedated office patient, but is limited by its 65-cm length to visualizing the colon up to approximately the splenic flexure. This can often be adequate, however, and in the case of UC, definitive. In the patient with typical presenting symptoms of bloody diarrhea and tenesmus, a flexible sigmoidoscopy with biopsies and stool culture for pathogens and ova/parasites may complete the work-up and make the diagnosis.
There is an increasing experience with through-the-scope (TTS) pneumatic dilatation of colonic or ileocolonic strictures in CD. The technique incorporates repetitive insufflation of the TTS balloon for 15- to 60-second periods, with the larger balloons (25 mm) being associated with more patient pain and complications than the smaller ones (12 mm). In a prospective study of 55 patients, long-term success (mean follow-up of 34 months) with complete relief of obstructive symptoms was achieved in 62% of patients whereas 19 (38%) required operation and six (11%) suffered a perforation.61
Upper endoscopy or esophagogastroduodenoscopy (EGD) will infrequently be used in the management of CD because gastroduodenal CD occurs in less than 5% of patients. When CD does affect the stomach or duodenum, however, strictures are common and therapeutic dilatation and biopsies to evalu- ate for malignancy via EGD are necessary. More frequently,
EGD is useful in the evaluation of the differential diagnosis of upper abdominal pain or dysphagia in the IBD patient.
Esophageal candidiasis brought on by immunosuppression, duodenal or gastric ulcerative disease caused by steroids or reflux disease from downstream partial obstruction all occur with increased frequency in the IBD patient and is well eval- uated by EGD. So-called push enteroscopy using specially designed flexible scopes has been developed to improve access by the endoscopist to the jejunum, but its use is very limited. The preferred study for evaluation of small bowel CD is still small bowel contrast follow through or enteroclysis.
Wireless Capsule Endoscopy
Wireless capsule endoscopy (WCE) is a recent unique devel- opment for the visualization of the small bowel. An 11 ×26 mm capsule is swallowed that transmits two video images per second to a receiver worn on the belt. Over the 8-hour bat- tery life of the device, more than 50,000 images are transmit- ted and stored which are subsequently evaluated at 25 frames per second by dedicated software and the human eye. Subtle small bowel lesions, usually out of the reach of the colono- scope or upper endoscope, can be appreciated. Its role in CD is still being clarified, but criteria for its use include the rec- ommendation of prior colonoscopy and intubation of the ter- minal ileum. Many studies using WCE have found CD in this most common of regions that can be easily reached by a colonoscope obviating the need for the more expensive WCE.
In addition, a small bowel contrast series is also necessary because the size of the capsule may cause it to impact at a stricture precipitating acute bowel obstruction requiring sur- gery. Other problems include its limited battery life in patients with slow transit, the inability to biopsy, and its imperfect localization of identified lesions. Nonetheless, this technol- ogy provides an added and potentially more sensitive tool in the diagnosis and management of patients with CD.53,62,63
Pathology
Ulcerative Colitis
UC begins in the rectum and extends proximally a variable distance with the worst disease being distal and the least dis- ease being proximal. Disease may be limited to the rectum (ulcerative proctitis), extend to only the left colon, or com- pletely to the cecum (pancolitis). The terminal ileum may be inflamed in continuity with the cecum (backwash ileitis).
Disease is in continuity and segmental or “skip” disease does not occur, although so-called “rectal sparing” or some degree of patchiness can be seen in the actively treated patient, espe- cially when enema therapy has been given. The gross appear- ance of the inflammatory process depends on the severity and duration of the disease (Table 39-5). In early disease, inflam- mation is restricted to the mucosa but in its severest, toxic TABLE39-5. Gross (colonoscopic) features of colitis
UC CD
Early Edema Aphthous ulcers
Confluent erythema Patchy, asymmetric erythema Loss of vascular markings Anal disease:
Waxy skin tags Linear fissures
Intermediate Granularity Linear serpiginous ulcers
Bleeding Pseudopolyps
Micropurulence Anal disease:
Fistulas Abscesses Advanced/late Ulcerations, transmural
disease Confluent ulcers
Pseudopolyp formation Deep “bear claw”
ulcerations
Purulence Strictures
Variable thinning/ Mucosal bridging thickening of colon
Mucosal bridging
form it can become transmural and indistinguishable grossly and histopathologically from CD, with deep ulcerations, pseudopolyp formation, and variable areas of thickened and thinned colonic wall.
The histopathologic features of UC are listed in Table 39-6.
There are no pathognomonic features of UC and in its extreme form it can resemble CD. However, typical UC is associated with inflammation limited to the mucosa or lamina propria including relatively uniform crypt distortion and crypt abscesses. Goblet cell mucin depletion is common and the inflammatory infiltrate is usually neutrophilic, two features that distinguish it from CD where mucin depletion is uncom- mon and the inflammation is usually mononuclear. More severe UC leads to the entire loss of the crypt with deeper submucosal and transmural inflammation and ulceration. In the chronic, more quiescent phase, UC will have mucosal reconstitution but will still have crypt distortion, foreshorten- ing, and branching. Inflammation will be variably reduced, even absent, but when present still relatively uniform in distribution. Dysplasia in longstanding UC is common but can only be interpreted in the setting of noninflamed bowel, because many of its features are common with inflam- mation, namely, crypt distortion, increased mitotic index, and nuclear atypia.
Crohn’s Disease
The gross features of CD include its ability to affect any por- tion of the GI tract, its transmural inflammation, and its propensity to create fistulas and strictures, including in the perianal area. Skip lesions are common, resulting in multiple areas of bowel affected simultaneously with intervening seg- ments of normal intestine. Diseased bowel may fistulize into adjacent bowel that is otherwise unaffected, a type of
bystander injury that only requires surgical removal of the offending segment of intestine with primary repair of the fis- tula in the remaining, healthy bowel. Serositis is common in CD, as is fat wrapping or creeping fat, all nonspecific responses to the transmural inflammation seen. On the mucosal surface, the earliest changes are aphthous ulcers, which are tiny white pinpoint lesions representing mucosal ulcerations in the vicinity of enlarged lymphoid follicles.
These are thought to then enlarge and coalesce into the larger, deeper, longitudinal serpiginous ulcers often found in CD.
These will have a deep, fissuring appearance and will extend ever deeper into the bowel wall, infrequently perforating freely, but instead recruiting an inflammatory response from adjacent organs that tend to wall off the inflamed bowel and that can then lead to fistulization. Healing is associated with granulation tissue and stricture formation, features not usually found in UC.
Microscopically, the inflammatory infiltrate is frequently mononuclear and there is minimal goblet cell dropout in the mucosa. When crypt abscesses occur, they are nonuniform, affecting some crypts and not others. Vasculitis is some- times seen (20%) and neuronal hyperplasia is common, both features that are rarely seen in UC. The classic noncaseating granuloma is found in 20%–60% of patient biopsies and is composed of epithelioid and giant cells of the Langhans type. Granulomas probably wax and wane in their presence and can also be found in adjacent tissues affected in continuity, such as bladder, lymph nodes, ovaries, and perianal squamous epithelial skin tags. Their significance is unclear, with some suggesting they indicate a less- aggressive form of CD.
Indeterminate Colitis
Approximately 10%–15% of colitis patients will have either clinical or pathologic features that do not allow a clear diag- nosis of either CD or UC to be definitively made. This is often attributable to rapidly deteriorating, fulminant colitis, where even UC can have transmural or irregular mucosal involve- ment. Sometimes the gross anatomic appearance is compli- cated by incomplete response to various medications, especially when delivered transanally as enemas, which can lead to relative “rectal sparing” and therefore suggest CD over UC. Frequently, the correct diagnosis involves the judgment of an experienced clinician who considers not only the histopathology, but also the clinical characteristics of the patient, the history of disease progression, and even more sub- tle data such as serum antineutrophil cytoplasmic antibody (ANCA) and ASCA testing (see Serum Tests for IBD). More than half of such indeterminate cases can usually be resolved with such consideration of the entire clinical picture. This is especially important in the patient who is a candidate for pelvic pouch reconstruction, where the results of such surgery are significantly worse in the misdiagnosed Crohn’s diseased patient.64
TABLE39-6. Histology of IBD
UC CD
Early Crypt distortion, branching Patchy crypt distortion Goblet cell mucin depletion Minimal goblet cell mucin Vascular congestion depletion
(without inflammation) Aphthoid ulcers Mucosal inflammation
Intermediate Uniform crypt abscesses Focal crypt abscesses Loss of mucosa with Vasculitis (20%)
retention of crypts
Lamina propria neutrophils Noncaseating granulomas (20%–60%)
Mononuclear cell infiltrate Advanced/late Crypt destruction Transmural inflammation
Neuronal hyperplasia Neuronal hyperplasia
uncommon common
Deeper submucosa Mucosal and submucosal
inflammation thickening
Pseudo polyp, mucosal Fibrosis and strictures bridging
Dysplasia common Dysplasia uncommon
Serum Tests for IBD
Serum tests for IBD can be divided into several categories:
acute phase reactants, nutritional parameters, and inflamma- tory markers. The prototypic acute phase reactant is the ESR, which is frequently used, especially in CD despite its imperfect correlation with disease activity. It is a necessary component to determine the CDAI (see section above). Some have suggested ESR correlates better with colitis, either CD or UC, than small bowel CD. This may be attributable to the fact that ESR may be normal in CD patients with noninflam- matory disease who nonetheless may be very symptomatic because of the presence of “burned-out” fibrotic strictures.65 Conversely, an acute abscess from a longstanding fistula in ano may increase the ESR without any evidence for flaring of intestinal disease. Similar difficulties have been encountered in correlating disease status with other acute phase reactants, such as C-reactive protein (CRP), orosomucoid (α-1-acid gly- coprotein), α-1-antitypsin, and α-2-globulin.66 The fecal excretion of α-1-antitrypsin when measured as a clearance ratio has some correlation to active intestinal disease but dif- ficulty with collection methodology makes this test rarely used. Presently, ESR and CRP are the only two tests fre- quently used in the clinical arena.
Nutritional parameters are often used to assess the conse- quence of acute and subacute disease in IBD. Albumin, preal- bumin, and iron studies (transferrin, serum iron) are reflective of the combined effects of decreased food intake (to minimize symptoms), compromised absorption (from inflammation or surgical shortening of the bowel), and increased losses (from loss of proteins and blood from mucosal ulceration). B12 is often decreased in CD patients with ileal disease or after sur- gical resection. Such nutritional tests are nonspecific, but extremely valuable in clinical decision making from either a surgical or medical perspective. Other relevant serum studies include liver function testing that may reveal subclinical PSC.
Research into the immune regulatory pathways that have a role in the inflammation seen in IBD has resulted in the identi- fication of numerous chemokines that are altered in IBD.48 Many of these, including interleukin (IL)-1, IL-2, IL-6, IL-8, TNF, CD45, soluble IL-2, and interferon-gamma have not been used beyond investigative protocols for a number of reasons.
Frequently, serum levels of these cytokines do not correlate with the abnormal levels found in the tissues affected, thus obviating their use as serum tests. A possible exception may be the solu- ble IL-2 receptor (sIL-2r). Increased serum levels of sIL-2r seem to correlate with mucosal inflammatory activity. Levels decrease with response to therapy in parallel with the CDAI, and high levels have been predictive of clinical relapse.67
Perinuclear ANCA (pANCA) is an autoantibody found in the serum of approximately 50%–70% of UC patients but only 20%–30% of CD patients.68It does not correlate with disease activity, but is thought to indicate a more aggressive disease type, because of its association with patients who are relatively resistant to medical management and also with
patients who frequently suffer pouchitis after ileal pouch anal anastomosis.69,70Another serum antibody, that to a common yeast, Saccharomyces cerevisiae (ASCA), has been shown to be present in 50%–70% of CD patients but only 10%–15% of UC patients. Thus, the measurement of both ANCA and ASCA is increasingly being used to try to differentiate between CD and UC when disease is limited to the colon and confusing features, such as rectal sparing, exist.
Although strictly speaking not a serum test, there has been the recent discovery of certain genetic mutations as being associated with CD. The presence of these mutations can be assayed using the DNA of leukocytes harvested by peripheral blood draw. Three mutations affecting the NOD2/CARD15 gene on the short arm of chromosome 16 have been identified as being associated with CD.33,34 The NOD2/CARD15 gene codes for an intracellular protein that has high binding affinity for bacterial peptidoglycan and may have a role in innate immunoresponsiveness to enteric bacteria. Mutations in this gene are found in approximately10%–30% of CD patients ver- sus 8%–15% of healthy controls. The relative risk of develop- ing CD if mutations are carried in both copies of this gene is 10–40 times that of the general population. The presence of this mutation in a patient with CD is associated with ileal dis- ease, earlier age of onset, and possibly fibrostenosing charac- teristics.29,71Mutations can be easily assayed by polymerase chain reaction techniques, and holds promise for possibly predicting responsiveness to medical or surgical therapies.
Evaluation of the Acute IBD Patient
The clinical and laboratory evaluation of the presenting IBD patient will depend on many factors. Obviously, a good his- tory and physical examination will focus the clinical caregiver in one or another area that will then direct subsequent testing and care. Many of the testing regimens described previously in this chapter apply to a greater or lesser degree based on clinical circumstances. There is no one good test for IBD, so the clinical judgment, experience, and acumen of the physi- cian is key in patient management. Nonetheless, there are some basic and fundamental testing regimens that should be at least considered, if not repetitively performed, whenever IBD is considered the possible diagnosis. A basic outline of evaluation of the acutely presenting IBD patient is found in Table 39-7. It is important to remember that the patient with a known diagnosis of IBD will frequently still require such a basic work-up whenever their disease flares. This is in part attributable to the recognition that these patients are at signif- icant risk for the development of a superimposed secondary diagnosis not infrequently related to iatrogenic causes. These might include pseudomembranous or cytomegalovirus colitis, stress- or steroid-induced gastric ulceration, fungal sepsis, or neutropenia. In addition, a known IBD patient presenting with worsening symptoms may now have progression of disease or the development of a directly related complication, such as an intraabdominal abscess, bowel obstruction, toxic colitis, or
colovesical fistula. Thus, the studies outlined in Table 39-7 should be regularly considered for the acutely presenting IBD patient, tempered by the good clinical judgment of the caring physician.
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Test Purpose
Serum labs CBC r/o anemia, leukocytosis
Electrolytes, renal function r/o electrolyte disturbance 2°diarrhea, dehydration
ESR or CRP ↑in systemic disease
LFTs, albumin r/o PSC, nutritional compromise Stool studies C. diff. r/o infectious causes
O & P r/o infectious causes
Pathogens r/o infectious causes
X-rays Plain abdominal X-rays r/o free air, toxic colitis, stones, obstruction SBFT / enteroclysis For small bowel disease Barium / Gastrografin enema For fistulas, strictures,
distribution of disease
CT scan For abscess, obstruction,
fistulas, adjacent organ involvement
Endoscopy Flexible / rigid scope For biopsy to r/o CMV, granulomas, pseudomembranes Colonoscopy For biopsy, visualize extent
and severity of disease LFTs: liver function tests
O & P: ova and parasites C. Diff: Clostridium difficile toxin SBF T: small bowel follow through CMV: cytomegalovirus
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