Delay in diagnosis in patients with severe presentation is associated with increased mortality, primarily because of malignancy.
A major question is the ultimate outcome of undiagnosed, presumed silent CD? It has been suggested that there is a significantly increased risk of mortality in patients with undiagnosed CD. However, the association with increased mortality is not universal nor is the association with increased malignancy[ 10 - 12 ]. Early diagnosis and treatment of CD has the potential to decrease risks of lymphoma, gastrointestinal cancer, bone disease, endocrine abnormalities, infertility and other autoimmune diseases[ 13 ]. As a consequence of an intensified screening policy, individuals with positive antibodies but without diagnostic small-bowel mucosal villous atrophy frequently are found.
The condition often is considered false-positive, but there also is evidence to suggest that such a finding is indicative of early stage CD.
Randomized clinical trials on the natural history and treatment of CD patients with mild mucosal changes and positive antibodies are lacking, and there is no consensus whether these patients should be treated at all with a gluten-free diet before villous atrophy has developed[ 2 , 10 , 13 - 15 ].
Despite recent advances in endoscopic imaging and serological tests, the accurate diagnosis of CD remains challenging. The site and number of biopsies to diagnose CD correctly have been the focus of recent research. Newly introduced technologies may carry a high yield but availability may limit their widespread use. The gold standard of diagnosis relies on duodenal biopsy[ 16 ]; however, the reliability of duodenal biopsy is not straightforward. Patients come to biopsy because of the result of positive serological tests, a high index of suspicion for a mucosal disease process, or because of routine duodenal biopsy at endoscopy[ 17 ].
Human Physiology/The gastrointestinal system - Wikibooks, open books for an open world
Biopsies from different sites of the duodenum in patients with positive celiac serology undergoing biopsy showed that none of the biopsies were considered normal. An interesting observation is that total villous atrophy significantly increased in a distal direction. Although more severe degrees of villous atrophy have been found distally, the diagnosis has mostly been confirmed in any location in the duodenum or jejunum[ 2 , 9 , 10 , 15 ]. CD involves the proximal small intestine including duodenum and upper jejunum and extends distally for a variable length into the ileum.
Damaged small bowel mucosa heals in a distal to proximal direction. Mucosal atrophy is continuous in most patients as a diffuse proximal enteropathy, which can be seen by any means of endoscopy. Autopsy studies on CD patients have also confirmed the involvement of the duodenum and jejunum in most cases and occasional extension into the ileum.
However, distribution and extent of the CD are variable[ 13 , 18 ]. Dickey et al[ 19 ] have evaluated terminal ileal biopsies of 30 patients with CD and control patients and found that IEL counts were significantly higher in the CD group. They concluded that increased IELs in the terminal ileum correlated with duodenal atrophy, and that this finding should alert physicians to consider CD. Although evaluation of the extent of the bowel involvement is not possible by conventional methods, capsule endoscopy CE can give an estimation about whether the whole of the small bowel is affected.
It has been reported that According to Murray et al[ 21 ], in the majority of patients, the abnormal findings seen in the CE started in the proximal duodenum and extended into the jejunum. Findings of atrophy were seen in a continuous pattern in the duodenum, but features of atrophy were seen less obviously and were patchy in the jejunum. Mucosal specimens can be obtained using radiographically guided suction capsule Crosby capsule biopsy, which has disadvantages such as long procedure time, high failure rate, discomfort and radiation exposure during the procedure, although it is possible to take large biopsy specimens.
Perforation, intramural hematoma of the small bowel and pancreatitis are reported complications[ 22 ]. Nowadays, Crosby capsule biopsy is not performed due to comparable efficacy of the duodenal biopsy to detect villous atrophy. Another important fact to take into account is the patchy nature of CD, which necessitates multiple biopsy approach to minimize sampling errors[ 23 ].
There are no clear-cut recommendations for the exact number of biopsy specimens to confirm or exclude diagnosis of CD, although the American Gastroenterological Association technical review recommends biopsies[ 24 ]. Unfortunately, there is a gap between evidence-based data and real-life practice. Site of the biopsy is another object of the debate.
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Pais et al[ 26 ] have found that duodenal biopsy specimens show some variability in terms of histological changes, and a minority of patients may have a discrepancy of more than two Marsh grades between biopsy sites. Ravelli et al[ 15 ] have found no cases of normal histology and coexisting villous atrophy in the same patient. This observation was supported by another study by Thijs et al[ 22 ] in which no discrepancy between jejunal and duodenal biopsies was found.
Biopsies from the duodenum have been demonstrated to be useful for the diagnosis of CD and almost replaced the need for the jejunal biopsy. Unfortunately, biopsy specimens from the duodenum harbor some problems and may not be a good place for the diagnosis of CD, given the nature of the disease and necessity of a strict diet. Not only is there more natural irregularity of the proximal duodenal mucosa, but specifically, the influence of nutrients mixed with gastric acid from the stomach and digestive fluids released into the duodenum in reaction to a meal may induce a chronic mild inflammatory response[ 27 , 28 ].
This may alter the appearance of mucosal inflammation and villous architectural changes, and therefore, disqualify duodenal biopsies for diagnostic use, especially when minor architectural changes and intraepithelial lymphocytosis must be considered[ 29 ]. All of the current endoscopic imaging techniques rely on the morphological changes of the mucosa associated with CD, which may direct the endoscopist for sampling.
The value of endoscopy in the diagnosis of CD is limited to villous atrophy Marsh grade 3. Celiac patients with villous atrophy are easily diagnosed, and most of them have positive serology, thus making this group of patients non-challenging. Histological changes in this group are so characteristic that they cannot be mistaken for other diseases.
In contrast, patients with milder enteropathy, which is the most prevalent form of the disease at present, may show increased IELs that cannot be identified under white light or even with narrow band imaging or magnification endoscopy. Diagnostic accuracy of biopsy specimens can be improved with advanced endoscopic technologies. Magnification endoscopy with narrow band imaging is a useful tool for obtaining biopsies at diseased sites[ 30 ].
These white light or blue-green light endoscopies are not capable of detecting increased IELs, which in turn limits us to the advanced stage of the disease with apparent atrophy and changes, but the problem is to detect the patients with subtle changes i. Confocal endomicroscopy CEM may aid in diagnosis in theory. However, fact is a little different from theory; CEM is good at detecting atrophy, although it cannot differentiate subgrades, and increased IELs, but falls short at detecting crypt hyperplasia, topical acriflavine use is helpful for quantification of IELs but fluorescein is not helpful.
Very limited availability and safety issues on acriflavine use are the major drawbacks of CEM, and some imaging improvements should be done before its prime time use in CD[ 31 ]. The opportunity to make a correct diagnosis of CD might, therefore, also depend on the endoscopic appearance of the small bowel mucosa. Several endoscopic markers related but not specific to CD have been identified. These endoscopic markers are useful to determine whether duodenal biopsies are indicated and possibly to target from where biopsies should be taken.
Endoscopic markers of CD are as follows: a reduction or absence of duodenal folds; scalloping, which is a notched appearance of the duodenal folds; visible submucosal vasculature; a mosaic pattern, which is the micronodular or cobblestone appearance of the mucosal surface; and mucosal fissures, crevices or grooves[ 17 ] Figure 1. These indirect signs of villous atrophy have been helpful for predicting the presence or absence of duodenal villi and for targeting duodenal biopsies during upper endoscopy for diagnosing CD.
Nevertheless, the sensitivity of these signs has been demonstrated to be variable in the different studies, and therefore, multiple endoscopic biopsies from descending duodenum and bulbar mucosa are recommended to ameliorate the diagnostic accuracy and to avoid underdiagnosis of patchy forms of CD[ 32 , 33 ]. Contradictory results concerning the value of these endoscopic markers of villous atrophy have been reported.
Several possible explanations exist for the absence of endoscopic markers in patients with CD. For example, such markers might actually be absent for degrees of enteropathy milder than subtotal or total villous atrophy e. Scalloping is not specific for CD but rather a predictor of mucosal disease as evidenced by villous atrophy, widening, and edema[ 35 ]. It is possible to augment the villous changes by a simple procedure of underwater examination of the mucosa, which is called the water-immersion technique WIT , which consists of the instillation of water into the duodenum after removal of air and adds only a few seconds to the examination time.
WIT-assisted duodenoscopy has been demonstrated as reliable in distinguishing accurately the presence or absence of villi in the duodenal bulb and the descending duodenum[ 32 , 33 ]. However, no study has specifically addressed the value of WIT during enteroscopy. We usually perform WIT to assess the villi structure in the jejunum during the enteroscopy examination of patients with diarrhea and malabsorption and find it useful for diagnosis of CD. CD is a gluten-dependent enteropathy characterized by chronic small intestinal inflammation and villous atrophy.
However, CD is not the only cause of an inflammatory cell infiltrate with or without villous atrophy in duodenal mucosa. It has been proposed that the anatomical location of the bulb makes it more vulnerable than the more distal duodenum to injury by gluten.
Gastrointestinal system anatomy
However, similar reasoning applies also to potential injury of the bulbar mucosa by aforementioned causes and gastric acid. On biopsy, lymphoid aggregates are also commonly found in the duodenal bulb of younger children. That is why some findings in the bulb may be a part of life rather than disease. Biopsy samples from the duodenal bulb may be difficult to interpret, in fact, the duodenal bulb is not considered a useful site for the diagnosis of CD, even though this site has rarely been reported to be the only one showing reliable histological changes in adults and children with CD.
The Small and Large Intestines
Taking biopsy samples more distally may decrease the likelihood of confusing histological findings[ 34 ]. CD has many atypical manifestations, and endoscopic findings alone are not considered sensitive or specific for the diagnosis of CD. Pais et al[ 26 ] examined patients to determine how many duodenal biopsy specimens were needed to diagnose CD. Comparison of biopsy specimens from the second, third, and fourth parts of the duodenum, the ligament of Treitz, and the proximal jejunum has shown that each site is suitable for diagnosing CD[ 7 ].
Mucosal specimens taken from the distal duodenal or jejunal mucosa are strongly correlated, therefore, biopsy samples from the second or third part of the duodenum are considered adequate to obtain material for histological interpretation[ 29 ]. Thus, biopsy of the other parts of the small intestine may be needed for precise diagnosis of CD, which is an indication for enteroscopy.
We have long been aware that complete examination of the small bowel is crucial for evaluation of refractory disease or its complications. However, conventional endoscopy has limited value for evaluation of complications like ulcerative jejunoileitis and lymphoma that may be located deep in the small bowel, which necessitates deep enteroscopy techniques such as push enteroscopy PE , balloon-assisted enteroscopy BAE and CE. There are specialized goblet cells that secrete mucus throughout the GI tract located within the mucosa.
On the mucosa layer there are Villi and Micro Villi. Submucosa : The submucosa is relatively thick, highly vascular, and serves the mucosa. The absorbed elements that pass through the mucosa are picked up from the blood vessels of the submucosa. The submucosa also has glands and nerve plexuses. Muscularis : The muscularis is responsible for segmental contractions and peristaltic movement in the GI tract. The muscularis is composed of two layers of muscle: an inner circular and outer longitudinal layer of smooth muscle.
These muscles cause food to move and churn with digestive enzymes down the GI tract. Serosa : The last layer is a protective layer.
Related Ultrastructure of the Small Intestinal Mucosa: Normal and Disease-Related Appearances
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