Small Bowel Imaging in Celiac Disease

Small Bowel Imaging in CeliacDisease

Christina A. Tennyson, MDa, Carol E. Semrad, MDb,*

KEYWORDS

� Enteroscopy � Small intestine � Enterography � Imaging � Celiac disease

KEY POINTS

� Recent advances in small bowel imaging technologies have improved the care of patientswith small bowel diseases. Small bowel endoscopic and radiologic technologies arecomplementary and are often used in conjunction.

� In patients with celiac disease and gastrointestinal symptoms, radiologic imaging may bediagnostic of celiac disease.

� It is critical that radiologists and gastroenterologists are familiar with findings suggestive ofceliac disease with new imaging modalities.

� Video capsule endoscopy, enterography, and device-assisted enteroscopy are usuallyreserved for those with alarm symptoms, refractory celiac disease, or suspicion of smallbowel lymphoma/adenocarcioma.

INTRODUCTION

The small intestine is the longest organ of the gastrointestinal tract, which is fanned onthe mesenteric stalk in the abdominal cavity. The multiple folds of small bowel loopsin the abdominal cavity and peristalsis make it difficult to examine using standardendoscopic and radiologic imaging techniques. As a result, the small intestine haslong been considered the black hole of the gastrointestinal tract. Upper endoscopy,push enteroscopy, and colonoscopy allow examination of only a small portion ofthe jejunum and distal ileum. Radiologic imaging by small bowel barium study andtraditional abdominal computed tomography (CT) show luminal findings suggestiveof celiac disease but provide poor examination of the small bowel wall. In addition,small bowel series is a time-consuming, operator-dependent study that has fallenout of favor for CT imaging. Recent advances in endoscopic imaging technologies(capsule and device-assisted eneroscopy) have enabled detailed visualization of the

a Department of Medicine, Columbia University College of Physicians and Surgeons, 180 FortWashington Avenue, Room 936, New York, NY 10032, USA; b Department of Medicine, TheUniversity of Chicago Medicine, 5841 South Maryland Avenue, MC 4080, Chicago, IL 60637, USA* Corresponding author.E-mail address: [email protected]

Gastrointest Endoscopy Clin N Am 22 (2012) 735–746http://dx.doi.org/10.1016/j.giec.2012.07.013 giendo.theclinics.com1052-5157/12/$ – see front matter � 2012 Elsevier Inc. All rights reserved.

mailto:[email protected]

http://dx.doi.org/10.1016/j.giec.2012.07.013

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Tennyson & Semrad736

entire small bowel mucosa. Radiologic advances (CT enterography [CTE] andmagnetic resonance enterography [MRE]) have markedly improved examination ofthe small bowel wall and surrounding structures. Intraoperative enteroscopy, consid-ered the gold standard of complete enteroscopy, has largely been replaced. Newimaging technologies provide less-invasive methods, with excellent reader agree-ment, for examining the small bowel. These technologies have improved the diagnosisand management of patients with small bowel diseases, such as small bowelbleeding, Crohn, disease, and celiac disease.Celiac disease is a common inflammatory disease of the small bowel that affects

1% of the white population.1 It is triggered, in genetically predisposed individuals,by the ingestion of gluten, a protein component of wheat, rye, and barley.2 Most indi-viduals are diagnosed with celiac disease in adult life. Celiac disease may present withclassic (diarrhea-predominant) symptoms or atypical symptoms or may be asymp-tomatic and detected via screening.3 Atypical presentations of celiac disease includenonspecific abdominal pain/dyspepsia, constipation, bloating, reflux, infertility,anemia, osteoporosis, dental enamel defects, short stature, vitamin deficiencies,fatigue, or neurologic problems, such as neuropathy or ataxia.4 The rash of dermatitisherpetiformis is virtually always associated with celiac disease whereas intestinalbiopsy may be normal with gluten ataxia. Serology for the antibodies directed againsttissue transglutaminase (tTG IgA) is the best screening test for celiac disease.5 Thegold standard for diagnosis is upper endoscopy with small bowel biopsy. Patientswith positive serology should have an upper endoscopy performed with 4 to 6 biopsiesof the small intestine with samples from both the bulb and the second portion of theduodenum to maximize yield.6,7 If the suspicion for celiac disease is high, endoscopywith biopsy should be performed despite negative serology results. Endoscopic find-ings of celiac disease include loss of folds and scalloping, a mosaic pattern, andfissuring of mucosa (Fig. 1).8,9 Endoscopic abnormalities are not present in all casesand biopsies should be obtained even if the duodenum appears normal. Marsh10 andOberhuber and colleagues11 described the histologic changes of celiac disease asincreased intraepithelial lymphocytes, crypt hyperplasia, and villous atrophy. Thesefindings largely account for abnormalities detected on radiologic imaging studies.Endoscopic biopsies of the duodenum may be normal if the disease is patchy. Jejunalbiopsies may improve diagnostic yield in such patients.The only current available treatment of celiac disease is a gluten-free diet. Up to

30% of celiac patients experience continued symptoms on a gluten-free diet orincomplete histologic recovery and are considered nonresponsive.12,13 Other causesof ongoing symptoms include continued gluten exposure, microscopic colitis, smallintestinal bacterial overgrowth, lactose or fructose intolerance, pancreatic exocrineinsufficiency, and refractory celiac disease (RCD).14 RCD is defined as persistent diar-rhea with villous atrophy, crypt hyperplasia, and inflammation, despite adherence toa strict gluten-free diet for 6 to 12 months.15,16 Its prevalence is unknown. RCD is clas-sified into type 1 and type 2 depending on intraepithelial lymphocyte expression.17 InRCD type 1, intraepithelial lymphocytes have normal surface expression of both CD3and CD8 with a polyclonal T-cell receptor. In RCD type 2, however, an abnormallymphocyte population is present with a loss of surface CD3 and CD8 expression,retention of intracellular CD3, and a monoclonal T-cell receptor rearrangement. Ina study of 57 patients with RCD, the 5-year survival rate was 93% in patients withRCD type 1 and 44% with RCD type 2.18 Enteropathy-associated T-cell lymphoma(EATL) occurs in more than 50% of patients with RCD type 2 and is a significant causeof mortality.17–20 Evaluation of poorly responsive and refractory celiac patientsincludes consultation with a skilled dietician, endoscopy with biopsy, stool studies,

Fig. 1. Endoscopic findings in the duodenum in celiac disease. (A) Normal. (B) Scalloping. (C)Fissuring. (D) Mosaic pattern.

Small Bowel Imaging in Celiac Disease 737

hydrogen breath testing, and, in cases of alarm symptoms and refractory disease,video capsule endoscopy, enterography, and deep enteroscopy if a suspicious lesionis identified. This review focuses on the role of standard radiologic imaging, enterog-raphy, and device-assisted enteroscopy in celiac disease.

DEVICE-ASSISTED ENTEROSCOPY

Device-assisted enteroscopy allows for diagnosis, tissue sampling, and therapy. Theprocedure can be performed using balloons or a spiral element attached to the endo-scope. Therapeutic options can be performed during enteroscopy, such as hemo-stasis, lesion marking, and stricture dilation/stenting. The majority of publishedliterature has involved double-balloon enteroscopy (DBE) because it has been avail-able for the longest period of time.

Balloon-Assisted Enteroscopy

DBE, or push-and-pull enteroscopy, was introduced in 2003 and allows completeexamination of the small bowel via the oral (antegrade) or rectal (retrograde) approachor both approaches.21,22 The DBE system (Fujinon, Wayne, New Jersey) consists ofa 140-cm polyurethane overtube back-loaded on a 200-cm enteroscope with 2 latexballoons attached at the tips of the overtube and enteroscope. Single-balloon entero-scopy (SBE) (Olympus Optical, Tokyo, Japan) uses a stiffer enteroscope and single,latex-free, balloon on the end of the overtube. A series of push-and-pull maneuvers


are performed with serial inflation and deflation of the balloons. These maneuvers holdthe bowel in place, prevent looping, and allow advancement deep into the small bowelby pleating the small bowel onto the overtube. The exact depth of insertion is difficultto measure. The procedure is time consuming and the average procedure time of DBEin initial experience ranged from 70 to 110 minutes.23–26 The retrograde approach isparticularly challenging due to retroflexion of the thin flexible endoscope in the cecumon advancement into the ileocecal valve with unstable intubation of the terminal ileum.In several initial studies, the overall diagnostic yield of DBE ranged from 43% to 80%and total enteroscopy varied from 5% to 86%.23–26 Success of total enterosocpy isinfluenced by endoscopist experience, procedure time, patient body habitus, andprior abdominal surgery. Complication rates for DBE in an international multicenterstudy were 0.8% and 4.3% for diagnostic and therapeutic procedures, respectively.27

Reported complications of DBE are pancreatitis, bleeding, and perforation. Perfora-tion was highest in the setting of ulcerating disease and altered small bowelanatomy.27,28 The absolute contraindications to balloon-assisted enteroscopy is smallbowel obstruction, and in the case of DBE, latex allergy with relative contraindicationsbeing coagulopathy, pancreatitis, and large esophageal varices.29 When comparedwith push enteroscopy, DBE had higher diagnostic yield (63% vs 44%) and greaterdepth of insertion (230 cm vs 80 cm).30 In 1 study, carbon dioxide insufflation ratherthan air, increased the depth of insertion and reduced patient discomfort.31

In small studies comparing the DBE and SBE techniques, diagnostic yields weresimilar, but total enteroscopy rate was higher with DBE.32,33 In a prospective, multi-center trial, the DBE system had a significantly higher diagnostic yield and total entero-scopy rate when 2 balloons were used compared with a single balloon used at the tipof the overtube.34 This study did not use the actual SBE system, which containsa stiffer enteroscope. It is unclear if using the SBE system would have changed theseresults.The literature on the use of enteroscopy in celiac disease is limited. A small series

using DBE for the evaluation of malabsorption suggests DBE was useful in excludingcomplications of celiac disease (Figs. 2 and 3).35 Because balloon-assisted entero-scopy is time consuming and invasive, it best complements video capsule endoscopyand enterography when suspicious lesions are identified. In a series of 21 patients withRCD, DBE was useful in detecting or excluding complications, such as EATL orulcerative jejunitis.36 In this study, low-risk lesions were defined as a reduction

Fig. 2. Endoscopic findings in RCD using device-assisted enteroscopy. Ulcerative jejunitiswith stensosis. (Courtesy of Suzanne Lewis, Columbia University, New York.)

Fig. 3. Endoscopic findings of small bowel lymphoma using device-assisted enteroscopy. (A)White nodules. (B) Ulcerated lesion.


(<3 per endoscopic field of view) or loss of folds, scalloping, nodularity, and presenceof visible vessels after air insufflations. High-risk lesions were defined as stenosis andulcerations more than 5 mm in diameter. Hadithi and colleagues36 detected EATL in 5of 21 patients (24%) that appeared as circumferential, discrete, or confluent ulcera-tions whereas 2 of 21 patients (9%) were diagnosed with ulcerative jejunitis in theabsence of EATL. DBE helped to exclude EATL in 4 patients with CT findings sugges-tive of malignancy due to small bowel wall thickening. A recent small case seriesexamined the role of DBE using virtual chromoendoscopy (Fujinon intelligent colorenhancement [FICE]). There was no improvement in the detection of features of celiacdisease using FICE.37

Spiral Enteroscopy

Spiral enteroscopy (SE) is a method of device-assisted enteroscopy that uses rota-tional energy to pleat the small bowel. The Endo-Ease Discovery SB (OlympusOptical), a 118-cm polyvinyl chloride overtube with a 21-cm spiral element at thetip, can be back-loaded and locked onto an enteroscope. Using clockwise rotation,the device pleats the small bowel on to the overtube until the device can no longerbe advanced. The enteroscope is subsequently unlocked and advanced throughthe overtube with a subsequent series of hook-and-suction maneuvers to further pleatsmall bowel. Advantages of SE include reduced procedure times and stability for ther-apeutics deep in the small intestine, because the enteroscope can be removed andreinserted through the overtube. In the initial experience, mean procedure time was36.5 minutes and diagnostic yield 33%.38 In a subsequent prospective multicenterstudy of SE, the diagnostic yield was 65% and average procedure time 45 minutes.39

In a small, prospective, crossover, single-center study comparing SE and DBE, SEhad a reduced examination time (43 minutes vs 65 minutes) but decreased insertiondepth compared with DBE (250 cm vs 310 cm).40 Although there are no publishedstudies of SE in celiac disease, the device has been used in celiac patients withoutcomplications (personal experience).

RADIOLOGIC SMALL BOWEL IMAGING

Abnormal findings on radiologic imaging have been described in celiac disease since1934.41,42 These findings are not specific for celiac disease but reflect changes thatoccur with small bowel inflammation, fluid secretion, and altered motility. Radiologicexaminations of the small bowel are frequently obtained in individuals with abdominal


pain and diarrhea and, therefore, it is important to be familiar with radiologic findingsthat are suggestive of celiac disease. Although video capsule endoscopy providesa noninvasive means to visualize the small bowel mucosa, the miss rate for isolatedmass lesions is up to 20%.43 Ongoing advancement of enterography technologymakes detection of ever-smaller bowel wall lesions possible. CTE and MRE areboth useful in the examination of the bowel wall and extraluminal structures.

Small Bowel Barium Study

Several radiologic findings have been described in celiac disease using barium.44

Jejunal dilation, fold thickening, hypomotility, and intussusceptions are nonspecificfindings that can be found with other diseases, such as tropical sprue, scleroderma,and hypoalbuminemia. Small bowel intussusceptions are usually transient and maybe multiple without a lead point (Fig. 4).45,46 They may be related to laxity of the bowelwall. Specific barium findings for celiac disease include decreased jejunal fold patternand increased ileal fold pattern (jejunization of ileum), so-called reversal of fold pattern(see Fig. 4). In a small study of celiac patients with active disease, 3 or fewer folds perinch of proximal jejunumwere found in 73% of patients47 and not in other inflammatoryconditions or control subjects (greater than 5 folds per inch). The cause of decreasedor absent jejunal fold pattern is unclear but may be associated with bowel dilation andbarium retention in the segment. An increase of ileal fold thickness greater than 1 mmwas found in 78% of patients with celiac disease. It likely reflects the high capacity forileal adaptation in the setting of decreased jejunal nutrient absorption48 and is usuallyfound with long-standing disease. Celiac individuals with milder inflammation may notshow these findings. Reversal of fold pattern can be found on cross-sectional abdom-inal imaging as well.The use of small bowel barium studies remains relevant as in 1 study of 280 adults

diagnosed with celiac disease49; 49 patients had barium studies before their diagnosisof celiac disease due to diarrhea, weight loss, or abdominal pain. Almost all studiesshowed findings suggestive of celiac disease that aided in the diagnosis. Severeceliac disease with bowel wall edema may mimic small bowel ischemia on bariumstudy (see Fig. 4).

Abdominal CT Scan

With advancement in imaging technology, abdominal CT scan has surpassed bariumstudy in the evaluation of abdominal symptoms and has the advantage of luminal andextraluminal examination. In a recent large study of CT findings in adults with celiacdisease, a pattern of findings was identified suggestive of celiac disease.50 Most ofthese findings stem from bowel inflammation and fluid secretion in the intestinallumen. The pattern of CT findings suggestive of celiac disease included (1) dilated,fluid-filled loops of small bowel, (2) flocculation (flecks of precipitated barium in dilatedloops), (3) telescoping/intussusception of bowel loops, (4) prominence of uppermesenteric lymph nodes, (5) large colon volume with gas and cecal plume of fluid,(6) small bowel wall thickening, (7) duodenal and jejunal wall fat, (8) hypervascularmesentery, (9) hyposplenism, and (10) mesenteric cavitary lymph node. The reversalof fold pattern is difficult to define on cross-sectional CT imaging due to poor localiza-tion of jejunal and ileal folds. This problem has been overcome by the use of CT enter-ography (CTE), a powerful tool in the evaluation of small bowel disease. Reversal ofjejunoileal fold pattern in celiac disease has been identified using negative contrastand coronal reformatted images that demonstrated loss of valvulae conniventes injejunum and thickened folds in ileum.51 CT enteroclysis in adults with active celiacdisease also identified reversal of jejunoileal fold pattern.52

Fig. 4. Small bowel barium findings in celiac disease. (A) Small bowel intussusception(coiled-spring appearance). (B) Reversal of jejunal and ileal fold patterns. (C) Severe smallbowel wall edema. (Courtesy of Arunas Gasparaitis, The University of Chicago, Illinois.)


CT enterographyImprovements in technology have allowedmultidetector rowCT scans to rapidly acquirehigh-resolution images and create multiplanar reconstructions. In CTE, a large volume(1350–2000mL)ofneutral ornegativeoralcontrast is rapidly ingested todistend theentiresmall intestinal lumen and intravenous dye is administered while thin-slice (1–3 mm)images are acquired using a helical CT scanner.53 Enteroclysis refers to contrast admin-istration via a nasojejunal catheter. Although this achieves uniform filling of the bowellumen, it is uncomfortable and invasive. CT enteroclysis andCTE have similar diagnosticaccuraciesof88%and80%.54CTEprovidesdetailedvisualizationof thesmall bowelwallas well as the mesentery, lymph nodes, and external structures in a short time. Con-traindications to CTE include pregnancy, renal insufficiency, or contrast allergy.


CTE is useful to examine celiac patients for signs of severe disease, such as dilatedsmall bowel, hyposplenism, and mesenteric (sometimes cavitary) adenopathy, as wellas ulceration with stricture and lymphoma (Fig. 5). CTE performs well in the detectionof small bowel tumors. In a study comparing endoscopy, enteroscopy, video capsuleendoscopy, CT enteroclysis, and clinical follow-up, enteroclysis detected tumors assmall as 5 mmwith a reported sensitivity and specificity of 95% and 100%.55 Mucosalenhancement, mural thickening, fatty proliferation, and dilated vasa recta are imagingparameters of active inflammation, although these have been studied primarily inpatients with Crohn disease, not celiac disease.53 CT enteroclysis findings of reversedjejunoileal fold pattern, ileal fold thickening, vascular engorgement, and splenicatrophy strongly correlated with active celiac disease.52 Other CT findings in celiacdisease include small bowel intussusception, dilation, increased splanchnic circula-tion, and mesenteric and retroperitoneal lymphadenopathy.56,57

Magnetic resonance enterographyMRI has the advantage of high-quality imaging without radiation exposure andprovides more detailed imaging of soft tissue structures when compared with CT.Disadvantages of MRE include higher cost, motion artifact, and increased length ofthe examination. Magnetic resonance (MR) enteroclysis is also possible using a naso-jejunal catheter. The technique for MRE requires an overnight fast, the rapid ingestionof a large volume of contrast (1350–2000 mL), and use of an antispasmodic agent insome protocols to decrease bowel peristalsis.58,59 MRI has the benefit of safety inpregnancy and renal disease58 when contrast agent is contraindicated. There isa limited literature comparing CTE and MRE; sensitivities are comparable (95.2%and 90.5%, respectively) for detecting small bowel inflammation.60 In this study,CTE had higher-quality images when compared with MRE, possibly from more rapidimage acquisition.MRE and MR enteroclysis have been used to examine for features of the celiac

disease and complications, including malignancy. MRI is often more commonly per-formed in European centers. An MR enteroclysis score has been validated to helpdifferentiate RCD type 2 patients using parameters of mesenteric fat infiltration, bowelwall thickening, and loss of jejunal folds.61 A positive score was defined as 2 or more ofthe following features associated with RCD type 2: fewer than 10 folds per 5 cmjejunum, mesenteric fat infiltration, and bowel wall thickening. The score was positivein 13 of 15 patients with RCD type 2 (sensitivity 0.87) and negative in 24 of 25 patientswithout RCD type 2 (specificity 0.96). In those patients with a positive score, the 5-yearsurvival rate was 56% versus 95% in patients with a negative score (P<.0001). MR

Fig. 5. Abdominal CT findings in celiac disease. (A) Increased size of mesenteric lymphnodes. (B) Lymphoma. (Courtesy of Aytekin Oto, The University of Chicago, Illinois.)


enteroclysis also helped identify 7 of 8 malignancies. MRE has also been used to eval-uate morphologic traits in a small series of 10 patients with non-Hodgkin lymphoma.Lymphoma can be seen as a smooth, single, long (>10 cm) continuous bowel segmentwith aneurysmal dilation in the absence of a distinct mesenteric or antimesentericdistribution.62 Luminal stricturing was present in cases of low-grade lymphomawhereas mesenteric fat infiltration was found in high-grade lymphoma. A recent smallstudy performed by 2 radiologists blinded to clinical history reported an association ofintestinal fold pattern on MRE with clinical presentation in celiac patients.63 Patientswith a normal intestinal fold pattern were more likely to have silent celiac diseasewhereas those with reversal of jejunoileal fold pattern had typical celiac disease.

UltrasoundAlthough abdominal ultrasound is a noninvasive, safe, inexpensive, and portablemodality that can provide high-quality images, it is rarely used in the United Statesto visualize the small intestine.64 During abdominal ultrasound, the small intestine isexamined for wall thickening, stenosis, dilatation, and motility as well as dupleximaging of the celiac and superior mesenteric arteries. Limitations include impaireddepth of penetration in obese patients and limited view when luminal gas is present.Ultrasound in celiac disease is not well studied, but features include fluid-filled dis-tended intestinal loops, increased peristalsis, and enlarged mesenteric lymphnodes.65

SUMMARY

Recent advances in small bowel imaging technologies have improved the care ofpatients with small bowel diseases. Small bowel endoscopic and radiologic technol-ogies are complementary and are often used in conjunction. In patients with celiacdisease and gastrointestinal symptoms, radiologic imaging may be diagnostic ofceliac disease. It is critical that radiologists and gastroenterologists are familiar withfindings suggestive of celiac disease with new imaging modalities. Video capsuleendoscopy, enterography, and device-assisted enteroscopy are usually reserved forthose with alarm symptoms, refractory celiac disease, or suspicion of small bowellymphoma/adenocarcioma.

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Small Bowel Imaging in Celiac Disease