Maribel Vera Mendoza
Hospital Universitario Puerta de Hierro-Majadahonda. Madrid
II.1.1.1. Endoscopy in the diagnosis of Crohn’s disease
Crohn’s disease (CD) is a chronic inflammatory bowel diseases that, unlike ulcerative colitis (UC) and indeterminate colitis, can affect any location in the digestive system. More than 90% of patients diagnosed with CD present involvement in any of the following three areas: small intestine, colon or both locations simultaneously. The segment most often involved is the terminal ileum in two-thirds of patients, and distribution of the disease is approximately the following1-9:
• Small intestine + colon: 40–50%.
• Small intestine: 30–40%.
• Colon: 15–25%.
Involvement of the oesophagus, stomach
or duodenum is the most rare and it generally appears associated with impairment of the small intestine or colon. Only 0.2% of patients will have oesophagus involvement, followed by the stomach and duodenum in 1%–4%10,11.
Colonoscopy with ileal exploration is crucial for diagnosing CD.
INITIAL ANALYSIS IN CROHN’S DISEASE. ILEOSCOPY AND GASTROSCOPY?
In the initial analysis of CD, it is important to perform a colonoscopy and ileoscopy to assess the mucosa and take biopsies of the affected mucosa, healthy mucosa and terminal ileum, although there may be no macroscopic involvement. Endoscopic impairment of the terminal ileum is more common in CD (Video 1).
The endoscopic appearance in CD will change based on the duration of the disease, or symptoms, since there are patients who report symptoms several years before diagnosis, as well as the severity of the outbreak.
The rectum is usually respected and the colonic segments that are most regularly affected are the caecum and ascending colon. CD impairment is usually patchy with affected mucosal areas and preserved areas within the same segment (Video 2 and Video 3). In the initial stages of CD, which currently are generally consistent with the diagnosis, we can find aphthous ulcers, characterised by round, superficial, small lesions with a fibrin coating that are surrounded by apparently normal mucosa (Video 4).
These aphthous ulcers are the result of the expansion of submucosal lymphoid follicles with penetration in the mucosa (Fig. 1). When the disease progresses, these superficial ulcers tend to increase in size, becoming more profound or “punched out” (Fig. 2 and Fig. 3) or they combine to form linear, cracked ulcers (Fig. 4). With the disease progression and the appearance of oedema in the submucosa, some nodular lesions may develop with a wide, low implantation base that gives a “cobbled” appearance to the wall, constituting what is known as a “cobblestone” pattern, which is virtually pathognomonic in CD (Fig. 5, Fig. 6 and Fig. 7). In the most advanced phases of the disease, deep, serpiginous, linear ulcerations appear, which are characterised by following the axis of the bowel (Fig. 8) and even appear as areas with denuded mucosa (Fig. 9).
When the impairment of the wall reaches the entire thickness and circumference of the lumen, stenosis may appear (Fig. 10). Although all these lesions can help us to distinguish CD from UC, in patients with severe activity, it can sometimes indistinguishable (Table I).
As in any endoscopic procedure, we need, on one hand, proper colon preparation in order to adequately visualise the mucosa, even more so in initial cases in which one must examine all the details of the mucosa and, on the other hand, we need to be rigorous when describing the lesions by using an ordered, detailed and accurate description and generally accepted terminology. We must also familiarise ourselves with the use of endoscopic indexes such as the Crohn’s Disease Endoscopic Index of Severity (CDEIS), but especially the most simplified indexes such as the Simple Endoscopic Score for Crohn’s Disease (SES-CD), which will be discussed in the next chapter. In a disease that has already been diagnosed, these indexes provide us with the degree of endoscopic inflammatory activity.
Taking biopsies of the affected and healthy areas is essential in any endoscopic procedure in order to collect microscopic information. In this regard, in CD we histologically examine transmural impairment with a predominance of mononuclear inflammatory infiltration, focal distortion of the crypt architecture, the presence of prominent lymphoid follicles and fissures. Granulomas are a typical finding in CD; however, they are only detected in 10–25% of biopsies12 (Fig. 11). These granulomas usually appear in the early stages of the disease and can be diagnosed in the upper gastrointestinal tract in up to 40% of cases, even on healthy mucosa13. This is the reason why it is recommended that a gastroscopy be performed when the distinction between CD and UC is unclear after having analysed the small intestine to assess the extension of the disease.
The diagnostic accuracy of colonoscopy in differentiating between CD and UC is between 85–90% of cases14. We have previously mentioned that visualising the terminal ileum and taking biopsies is
essential, even when the mucosa is normal.
It is important to distinguish between these two diseases given that the therapeutic, surgical and prognostic options can differ amongst themselves (Table I). It is also important to reassess the initial diagnosis as well as to follow-up on indeterminate colitis, which does not meet the clear criteria for either CD or UC, given that it may progress over time. This hypothesis has been studied in two works: Moun et al.15 monitored 527 UC, 228 CD and 36 indeterminate colitis (IC) cases for 2 years. 88% of UC and 91% of CD maintained their initial diagnosis, while 33% and 17% of IC were reclassified as UC and CD respectively. Moreover, Langevin et al.16 monitored 96 initial ulcerative proctitis, of which 14% changed their diagnosis to CD after 29 months of monitoring.
In indistinct cases, among CD or UC colitis, even with ileal biopsies, a gastroscopy must be performed for biopsies of the upper gastrointestinal tract, preferably when the small intestine has been analysed and no signs of differentiation have been found.
In addition to the distinction between colonic CD and UC, other possible diagnoses should be taken into account, which are sometimes difficult, especially in the initial stages of the disease. In this regard, it is important to keep infectious colitis in mind, given that these can be virtually clinically identical, endoscopically and histologically, primarily during the initial stage of the symptoms. Approximately 30% of patients with diarrhoea
with blood, mucus and suspected inflammatory bowel disease (IBD) have an infectious cause17
and the agents can be highly varied (Table II).
A comprehensive medical record, in which data is collected with a epidemiological history related to recent trips to endemic areas, the ingestion of suspicious foods, and epidemic outbreaks in an area of influence, can help us make a distinction. In infectious colitis, usually we endoscopically see multiple small areas of inflammation over an apparently normal mucosa, in the form of petechiae or areas of haemorrhaging, erythema, focal oedema or erosions (Video 5).
Some infectious agents such as Clostridium difficile develop pseudo-membranous colitis due to the characteristic presence of yellowish membranes or plaque on a apparently healthy mucosa, although, when detaching them, they leave a bloody surface (Video 6). From a histological standpoint, we can find acute inflammatory infiltration, constituted by polymorphonuclear infiltratration in the upper half of the mucosa, as opposed to predominant lymphocyte or mixed infiltration in CD. In specific cases, such as Clostridium difficile, the pseudo-membranes will be examined, which can also be seen with E. coli O157:H7, intranuclear inclusions in cases of herpes simplex II and cytomegalovirus (CMV) and intracytoplasmic inclusions with CMV. In some cases, the responsible parasite or agent can be detected in biopsies.
Another pathology in which there is a differential diagnosis is ischemic colitis, which usually appears in elderly people with cardiovascular risk factors, in young patients who consume vasoconstrictor substances such as cocaine or in cases of coagulation disorder. It typically affects the splenic flexure, sigmoid colon and rectosigmoid junction. The lesions vary, depending on their degree of severity. In mild cases, only mucous oedema can be detected and, in more advanced cases, we find friability, petechiae, ulcers, stenosis and even necrosis in the walls. Typically, these lesions tend to improve or disappear in little time if progress is favourable. In case of suspected ischemia, endoscopy must be performed with minimum insufflation to prevent complications such as perforation. Biopsies can assist in distinguishing, with the finding of mucosal and submucosal haemorrhaging areas, inflammatory infiltration rich in oeosinophils in the lamina propria, intravascular platelet thrombosis and necrosis.
Post-radiation colitis is another pathology to consider in endoscopic distinction, especially with UC. It usually appears in the distal sigmoid and proximal rectum, with an oedematous, friable mucosa and typical telangiectatic lesions.
Diverticulitis can also be confused with inflammatory disease. Endoscopic findings include peridiverticular oedema with patchy erythaema, petechiae and friability. The medical record and presence of diverticula suggest this diagnosis. These symptoms are known as segmental colitis syndrome associated with diverticula (SCAD)18.
A Solitary rectal ulcer can also simulate a rectal CD. Generally, when ulcers appear, usually they are situated on the anterior side and are sometimes associated with pseudo-nodular or non-ulcerated polypoidal and erythaematous lesions.
On the other hand, colitis resulting from drugs, not only non-steroidal anti-inflammatory drugs (NSAIDs), but also others such as acetylsalicylic acid, ticlopidine, lansoprazole, ranitidine, sertraline and clozapine, can cause indistinct endoscopic and clinical symptoms, although together they can help with the diagnosis, as well as the detection of fibrosis in the submucosa and lesions (Video 7).
Oeosinophilic colitis is another uncommon disease in which one must make a distinction. It generally affects young patients and is usually associated with atopic diseases related to hypersensitivity reactions and peripheral oeosinophilia. Endoscopically, the onset can be CD and tissue oeosinophila is detected histologically, which can vary, according to the segments, from <10 oeosinophils per field in the rectum to >30 in the caecum. Therefore, it is important to take serial biopsies and properly specify its appropriateness.
Other inflammatory illnesses of the colon that should be considered in the differential diagnosis are disinfectant colitis , generally due to contact with solutions that contain hydrogen peroxide, used in the disinfection of colonoscopes, although they are very rare. In these cases, whitish plaque appears that leads to pseudo-lipomatous colitis.
ANALYSIS OF CROHN’S DISEASE IN THE SMALL INTESTINE FOR DIAGNOSIS. IS IT NECESSARY TO CONDUCT AN EXTENDED ANALYSIS?
Assessment of the extent of CD in diagnosis enables us to not only have “a map” of the disease, but also helps us to propose the adequate treatment and consider the most appropriate surgery when necessary.
There are various diagnostic alternatives for assessing the small intestine in CD. Moreover, CT enterography, and most recently MR enterography, which lacks ionising radiation, have displaced intestinal barium radiological tests that would indirectly provide information regarding the status of the bowel mucosa.
CT enterography or MR enterography enables the assessment of the entire intestinal wall, providing information regarding the presence or absence of inflammation with the administration of contrast, as well as extramural impairment. However, their sensitivity is not high enough to detect mucosal lesions19,20. However, a recent study has compared the Montreal Classification (Table III), which has prognostic value in the progress of these patients, with MR enterography and with the findings of the surgical piece in the same patients, obtained 4 weeks after surgery. In this work, a radiologic-surgical interobserver concordance of 0.937 was detected in over 74 patients, with the best correlation in the fistulae. The highest sensitivity was 97% in the detection of a stenosis or B2 pattern, and the least sensitivity was 81% in the inflammatory masses21.
Push- , and most recently, double-balloon enteroscopy enables the direct visualisation of lesion and biopsies. However, they are painful explorations that require analgesics and sedation, have a long duration and have risks such as perforation. The use of enteroscopy is more therapeutic than diagnostic, especially for stenosis dilation, stent placement in stenosis and disimpaction of the endoscopic capsule. In very specific cases, it can be used to biopsy suspected and inaccessible bowel lesions by other means (clinical case). However, it is not considered an initial procedure for the extended analysis of CD.
The appearance of capsule endoscopy in 2001 enables, by ingesting a capsule slightly larger than a paracetamol pill, visualisation of the entire small intestine. It contains an image-capturing mini-camera, a light source, a battery and a radio-transmitter that enables images to be captured on an external recorder. This exploration has the advantage that it is relatively comfortable to ingest, sedation is not required and it allows the patient to have autonomy during the recording. On the other hand, it has some disadvantages, including possible retention if there is a stenosis in the bowel and the need to spend a long time reviewing the images.
In order to prevent retention in cases of suspected stenosis, there is an alternative that consists of ingesting a soluble capsule called Patency. If the capsule is excreted intact and with no deformities, it confirms that there are no obstacles in the gastrointestinal tract and that it is “permeable” to objects the size of the endoscopic capsule.
The capsule has a diagnostic yield higher than intestinal radiological barium tests, CT enterography, MR enterography and push enteroscopy22. However, its specificity is less that other procedures, although sensitivity is higher23. The capsule can establish new diagnoses, confirm existing ones, assess the extent of the disease and exclude suspected CD in up to 70% of the cases analysed24, with a clinical impact of 74.5%25. However, it has been discovered that up to 17% of healthy volunteers subjected to the capsule have lesions in the intestine26. Moreover, the lesions found by the capsule do not specify any particular pathology. In order to establish the value of the lesions found, an index known as the Lewis Index, was created that initially included 23 variables, then 7 and lastly, 3. The variables assessed include the appearance of the villi (normal or oedematous), the presence or absence of ulcers (single or multiple) and the presence or absence of stenosis (ulcerative or non-ulcerative, permeable or impermeable). With all these variables, the intensity and extent of the lesions are assessed27. We currently have several inflammatory activity indexes for patients with CD, none of which have acquired a preeminent role, based on the clinical symptoms, analytical parameters or endoscopic findings.
Moreover, and in view of the foregoing, the use of capsule endoscopy would be the initial diagnostic test for the extended analysis of CD, as well as to evaluate the small intestine when diagnosing suspected CD. Obviously, it must be avoided in cases in which stenosis is suspected or confirmed in the small intestine, prior to which the Patency capsule can be administered.
INITIAL PREDICTIVE TEST AND PROPOSAL OF A THERAPEUTIC APPROACH
For a patient with symptoms suggesting CD, the initial imaging test is ileocolonoscopy with biopsy of the affected and healthy segments, as we have previously mentioned. If CD is confirmed, an extended analysis should be performed in order to assess the entire digestive tract potentially involved in the disease, and in this way, a “snapshot” can be obtained to properly plan treatment. The capsule would be the procedure of choice in patients recently diagnosed with CD. On the other hand, MR enterography would contribute little, given that in its initial stages the disease mostly presents an inflammatory pattern, in which the sensitivity of the capsule is higher. However, in patients in which a more progressed disease is suspected, based on prior symptoms or progression time of the disease, we could suggest an imaging technique that offers an assessment of the entire wall and potential extramural involvement. Under this circumstance, MR enterography would be an ideal procedure, as previously stated.
With all this data, the patient can be grouped within the classification with prognostic value in this disease, in other words, the patient would be grouped in the Montreal Classification28 (Table III).
The use of serological markers has been proposed that could offer prognostic value for diagnosis and enable the reclassification of these patients. In this regard, markers such as anti-OMPc, anti-I2 and anti-CBir1 flagellin have been identified, which, when combined with others such as ASCA or ANCA, could detect subgroups of patients with a more complicated disease, worsened progression and a higher need for surgery29,30.
Furthermore, genetic markers have also been considered when staging these patients. Thus NOD2/CARD 15 have been the most analysed, with a high association with CD, ileal impairment, worsened progression and a more complicated disease associated with a stenosing and fistulising pattern (Video 8). Also, other markers have been studied, such as multidrug resistance 1 (MDR1), drosophila discs large homologue (DLG5) and toll-like receptor 1,2,4,6 (TLR1,2,4,6), which likewise have been related to the disease with the worst prognosis31.
It has been proposed that the combination of genetic and serologic markers could help detect clinical phenotypes with different progressive courses, which would be very significant in therapeutic and prognostic planning. However, there isn’t enough evidence to involve these markers individually, nor are these tests provided on a routine basis in clinical practice.
Therefore, the choice of initial treatment (maintenance treatment will not be discussed in this chapter) will be basically determined by inflammatory activity, which can be indirectly determined via clinical indexes and directly via endoscopy, location and phenotype. Obviously, we must consider, without a doubt, the Montreal Classification, which will indicate the possible progression.
Thus, adequate medical treatment must be considered following generally-accepted guidelines, taking different scenarios into account32,33 (Fig. 12).
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