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Abstract. – OBJECTIVE: The aim of ourstudy was to compare the apparent diffusioncoefficient (ADC) values of pathological bowelloops wall (pADC) with the ADC values of nor-mal appearing ones (naADC) and to determinea discriminating threshold.

PATIENTS AND METHODS: 60 patients werestudied at our Institution through a MR-enterog-raphy that included free-breathing axial Diffu-sion Weighted Imaging (DWI) with two b (0 and800 s/mm2) after histological diagnosis of ac-tive Crohn’s disease (CD). The one (whenunique) or the best analyzable (when multiple)pathological bowel loop was identified in eachpatient, on the basis of the MRI features: wallthickness, presence of mural oedema and wallcontrast enhancement after contrast mediumadministration. A normal appearing bowel loopwas used for comparison. ADC values weremeasured in consensus by two radiologists,and they were compared with t-test. The ADCthreshold value for the differentiation betweenpathological and normal appearing bowel loopswas determined.

RESULTS: The pADC values were significantlylower than the naADC values (1.48 ± 0.058 x 10-3mm2/s versus 3.525 ± 0.07 x 10-3 mm2/s; p <0.05). A threshold of 2.416 x 10-3 mm2/s showed100% sensitivity and 100% specificity for thediscrimination between normal and pathologi-cal bowel loops.

CONCLUSIONS: In patients with active CDthe ADC values of the pathological bowel wallare significantly lower than those of normal ap-pearing bowel loops. A threshold of ADC valueof 2.416 10-3 mm2/s could discriminate normalfrom pathological bowel loops.

MR-enterography with diffusion weightedimaging: ADC values in normal andpathological bowel loops, a possible thresholdADC value to differentiate active frominactive Crohn’s disease

V. NINIVAGGI1, M. MISSERE2, G. RESTAINO2, E. GANGEMI1, M. DI MATTEO1,A. PIERRO2, G. SALLUSTIO2, L. BONOMO1

Corresponding Author: Valeria Ninivaggi, MD; e-mail: ninivaggi.valeria@hotmail.it

Introduction

Crohn’s disease (CD) is a chronic inflammato-ry condition of the gastrointestinal tract of un-known origin that can involve the entire length ofthe digestive tract.This relapsing and destructing disorder affects

both children and adults and can confer signifi-cant increased morbidity and mortality in affect-ed patients. Its incidence and prevalence are in-creasing worldwide and it is a condition of socialrelevance.Currently, colonoscopy is considered as the

gold standard for colonic inflammatory activityassessment, but in most of the cases, it is inade-quate for small bowel investigation and gives onlyinformation about superficial mucosal layers1,2.The small bowel can be investigated by both

magnetic resonance imaging (MRI) and comput-ed tomography (CT); in recent studies, they haveshown similar accuracy and sensitivity for the de-tection of active inflammation1.Nevertheless, these patients need serial exami-

nations because of the natural history of the dis-ease, so MRI should be preferred to the CT, ow-ing to its non-ionizing characteristics3. In addi-tion, MRI has the potential advantage of provid-ing both functional and quantitative informationregarding the bowel wall such as diffusion, perfu-sion and motility that cannot be obtained by CT4.The correlation between MRI and indices of

clinical severity of disease has been evaluated.

2016; 20: 4540-4546

1Department of Radiological Sciences, Institute of Radiology, Catholic University of the SacredHeart, School of Medicine, Rome, Italy2Department of Radiological Sciences, Institute of Radiology, “John Paul II” Research andHealth-Care Foundation, Catholic University of the Sacred Heart, Campobasso, Italy

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obtained at the time of the procedure. Specific re-quirement for informed consent for the study waswaived. This was a retrospective, single-centrestudy including 60 patients who underwent toMR enterography with DWI at our Institution af-ter histological diagnosis of active CD from Sep-tember 2012 to September 2013.

MRI techniqueMRI was performed using a 1.5 Tesla (T) MR

scanner (GE Healthcare, Milwaukee, WI, USA)and a 12 channels surface phased-array bodycoil. The standard imaging protocol includedfree-breathing axial DWI (b=800 and 0 s/mm2).No oral or rectal preparation was performed

the days before the exam. Patients fasted 6 h be-fore the examination and 1500 ml of polyethyl-ene glycol electrolyte (PEG) solution (Isocolan,Giuliani S.P.A., Milan, Italy) was orally given toall patients 30-45 minutes before the MRI. Ex-aminations were performed in the prone position.The details of the MRI protocol are described inTable I. Images were acquired during a time ofbreath holding and 0.5 mg of intravenousGlucagon (GlucaGen, Novo Nordisk A/s,Bagsvaerd, Denmark) was administrated beforepre-contrast T1-w 3D-LAVA (3 DimensionalLiver acquisition with Volume Acceleration).

MRI data and Image AnalysisVisual assessment was performed by two

trained radiologists, blinded of patients informa-tion in consensus, under the direction of an expertradiologist. All the images were reviewed on apicture archiving and communication system(PACS). One (when unique) or the best analyz-able (when multiple) affected bowel loop was

MRI has been validated in comparison to alterna-tive imaging modalities and correlated with his-tology5. Several authors reported the usefulness ofT1-weighted (T1-w) after gadolinium MRI in theassessment of disease activity and recent studiessupport the role of Diffusion-weighted imaging(DWI) to differentiate active from inactive CD1,6.DWI sequence is a functional imaging tech-

nique that reflects molecular diffusion, which isthe thermally induced Brownian motion of watermolecules, without the administration of a con-trast medium. Changes in proton diffusivity arean early indicator of alterations in cellular home-ostasis in acute ischemic stroke and may alsohelp in detecting inflammatory foci1. Restrictedwater motion on tissue is hyperintense on DWIsequence and this provides a very helpful instru-ment for the qualitative assessment of daily prac-tice. From DWI acquisition an ADC value mapcan be generated; this adds quantitative informa-tion to the evaluation7.The aim of our study has been to compare the

ADC values of pathological bowel loops wall(pADC) with those of normal appearing bowelloops wall (naADC) in patients with the previoushistologically proven CD, in order to demon-strate the capability of this coefficient to discrim-inate these two conditions.

Patients and Methods

Study Population and DesignAll procedures performed in this study involv-

ing human participants were in accordance withthe ethical standards of the institutional ReviewBoard. Informed consent for the examination was

Sequences FOV Slice thickness Matrix NEX

Coronal CINE-FIESTA 46 8 200x320 1glucagone 5 mg injectionCoronal 3D-LAVA no contrast 48 3 245x182 0.78Coronal 3D-LAVA after gadolinium injection 48 3 245x182 0.78Axial 3D-LAVA 42 3 256x256 0.78Axial SE/EPI (Diffusion) b:0, 800 40 8 9x128 6Axial FIESTA 42 4 200x288 1Axial T2-w SSFSE 42 4 200x288 1Axial T2-w SSFSE with fat-saturation 42 4 200x288 1Coronal SSFSE 48 4 252x244 0.57

Table I. MR-enterography basic protocol. CINE-FIESTA: Fast Imaging Employing Steady State Free Acquisition (balancedSteady State Free Procession sequence). 3D-LAVA: Liver acquisition with Volume Acceleration (3-Dimensional Fast Spoiledgradient echo sequence). SE/EPI: Spin Echo, Echo Planar Imaging. SSFSE: Single Shot Fast Spin Echo.

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V. Ninivaggi, M. Missere, G. Restaino, E. Gangemi, M. Di Matteo, A. Pierro, et al.

identified in each patient, according to the MRI-derived features: wall thickening, presence ofmural edema detected as hyperintensity on fat-suppressed T2-weighted (T2-w) images relativeto psoas muscle and parietal enhancement aftercontrast medium administration. A normal ap-pearing and well-distended bowel loop was usedas internal control for comparison, defined as asegment with a normal parietal thickness, absenceof edema on T2-w sequences or of relevant rela-

tive contrast enhancement at visual assessment,and necessarily not adjacent to pathological loopbut in its same bowel’s segment (Figure 1). ThepADC and the naADC values were measured sep-arately by the two radiologists, using an Advan-tage Workstation with Functool2 software (GEHealthcare, Milwaukee, WI, USA), drawing with-in the bowel wall a circular region of interest(ROI), whose area measured between 29 and 39mm2 (Figure 1). In cases where the difference be-

FFiigguurree 11.. The figure shows the visual assessment and thefollowing measurement of ADC of normal appearing (arrow-head) and pathological bowel loops (arrow). T1-w pre-con-trast (A), T1-w post-contrast (B) MRI images on coronalplanes and T2-weighted image with fat saturation (C) on axi-al plane show inflammatory wall lesions involving the termi-nal ileum with increased bowel thickness, mural oedema andwall contrast enhancement after contrast agent administrationof the pathological bowel tract. The DWI sequence (b=800s/mm2) (D) depict hyperintense bowel wall of pathologicalbowel loop where the ROI 1 has been placed. ROI 2 has beenplaced on the wall of the normal appearing bowel loop. TheADC map (E) shows the different ADC values of intestinewall measured with the ROI.

A B

E

C D

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MR-enterography with diffusion weighted imaging

tween measurements was ≤5%, ADC values wereaveraged between the two observers, while in cas-es where the differences were greater than 5% an-other series of measurements were performed.

Statistical Analysis The pADC and naADC values were compared

with t-test. The calculation was done with SAS(Statistical Analysis System, SAS Institute Inc.,Cary, NC, USA). A p-value <0.05 was consid-ered to be statistically significant.Normal (or Gaussian) function was used to

show the distribution of ADC values, in both nor-mal and pathological bowel loops. The ADCthreshold value (TADC) for the differentiation be-tween pathological bowel loops and normal ap-pearing bowel loops was determined, using the fol-lowing formula: TADC=(SnaMp+SpMna)/Sna+Sp (Snaand Mna are the standard deviation and the averageADC value of normal appearing bowel loops; Spand Mp are the standard deviation and the averageADC value of pathological bowel loops)8.

Results

A total of 60 patients were evaluated (33male, 27 female; mean age 43.4 years, range 17-76 years). 60 pathological intestinal segmentswere evaluated (18 distal ileum segments, 42 ter-minal ileum segments). The mean value of wallthickness was 7.35 mm (range 4-11 mm). 60normal appearing intestinal segments were alsoevaluated as internal controls.The pADC values were significantly lower

than the naADC values (1.481±0.0517 × 10-3

mm2/s versus 3.525 ± 0.072 × 10-3 mm2/s;p<0.05) (Table II).Gaussian function showed that the distribution

of ADC values in normal appearing and patho-logical bowel loops is different, without overlap-ping (Figure 2).The ADC threshold value of 2.416 x10-3

mm2/s showed a sensitivity and a specificity of100% for discriminating normal from pathologi-cal bowel loops.

Pathological Normal appearing bowel loops bowel loops

Mean ADC value (x10-3 mm2/s) 1.481983 3.525Variance 0.051719 0.072123086Observations 60 60Pearson’s correlation -0.0115

Table II. Statistical analysis.

Figure 2. Normal distribution of ADC values measured on pathological and normal appearing bowel walls.

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Discussion

Our results demonstrate that the wall of bowelsegments affected by CD have significantly low-er ADC value than the normal appearing ones.The explanation for this phenomenon is not clearand is still controversial. Restricted diffusion has been reported in in-

flammatory processes of brain and abdomen, as inviral hepatitis in pyelonephritis and renal abscess-es9,10. DWI qualitative evaluation has been investi-gated as a possible imaging biomarker for the as-sessment of intestinal bowel diseases activity.The restricted diffusion could be related to an

increased cell density and viscosity, typical of in-flammation and other pathological changes ob-served in CD4. In early acute CD, lamina propriaand submucosa are infiltrated by inflammatorycells and early lesions of active CD, such as aph-thoid ulcers, are strongly associated with lym-phoid aggregates that have restricted diffusionbecause of the increased cell density6,11. The as-sociation of other pathological changes such asincreased number of inflammatory cells, dilatedlymphatic channels, hypertrophied neuronal tis-sue, and the development of granulomas withinthe bowel wall can narrow the extracellular spaceand therefore can reduce the motion of watermolecules. Changes of epithelial and inflamma-tory cells may also have an effect on the reduceddiffusion6. Fibrosis of the bowel wall may befound in the fibrostenosing variant of the diseaseand it is also associated to the restriction of diffu-sion, as previously demonstrated in the liver byTaouli et al9. Tielbeek et al12 in a study of 25 pa-tients recently reported a significant correlationbetween low ADC values and extent of parietalfibrosis; no significant correlation was observedbetween ADC values and histopatological scoresof inflammation but a trend was reported withhigh inflammation scores12. Moreover, inflamma-tion and fibrosis can coexist in the same affectedbowel loop, as demonstrated recently13,14.Quantitative evaluation of the ADC maps with

measurement of ADC values could add preciousinformation. It could complete the qualitativeevaluation improving the diagnostic performanceof MR-enterography. The mean pADC value, ob-served in our large series, is 1.481 ± 0.0517 10-3

mm2/s and appears similar to the values recentlydescribed by other scholars1,4,15. Kiryu et al1 stud-ied 31 patients and reported ADC values of 1.61± 0.44 × 10-3 mm2/s and 2.56 ± 0.58 × 10-3 mm2/sof active and inactive segments respectively, us-

ing b values1 of 0, 50 and 800s/mm2. Oto et al4 ina group of 18 patients reported slightly higherpADC value (1.91 × 10-3 mm2/s) and a similarnaADC value (3.11 × 10-3 mm2/s, b values 0, 600s/mm2) compared to our results4. Hordonneau etal15 found on a larger group of 130 patients ADCvalues of 1.45 ± 0.39 × 10-3 mm2/s of bowelwalls of active disease segments and 2.62 ± 0.46× 10-3 mm2/s of bowel walls of inactive diseasesegments (b values: 0, 800s/mm2)15.The ADC value threshold between CD patho-

logical and normal bowel segments we found inour study (2.416 × 10-3 mm2/s) shows high sensi-tivity and specificity; it is similar to the value of2.47 × 10-3 mm2/s previously described by Oto etal4 (b values 0, 600 s/mm2) in a smaller sample. In our study, no oral or rectal preparation

was performed the days before the exam, andthis, as previously demonstrated1, reduces thepatients burden.Before pre-contrast LAVA, we used an intra-

venous injection of glucagon to minimize motionartifact as reported in the literature and this iswell tolerated by patients16,17.A high b-value (b=800 s/mm2) was preferred

because it improves the detection of inflamedbowel through the suppression of the backgroundsignal arising from body fluids and non-inflamedtissue surrounding the area, as confirmed in liter-ature18.Our study has some limitations due to the ret-

rospective design; no correlation was performedwith histopathology after surgery or with clinicalactivity index. The identification of the bowelsegments to be analyzed may have introducedsome selection bias.In spite of this, the study sample is one of

largest in the literature and it is quite homoge-neous because all patients have a previous histo-logical diagnosis of CD, without previous surgi-cal or medical treatment. Furthermore, the high accurate threshold was

found and it can be used to distinguish pathologi-cal from normal findings, even in order to avoidcontrast agent i.v. injection19. Gadolinium injec-tion is considered invasive and sometimes is nottolerated by patients, can induce nephrogenicsystemic fibrosis and is contraindicated in case ofsevere renal failure. A high occurrence of renalinsufficiency was found in patients sufferingfrom intestinal bowel diseases (16%)20. More-over, a MRI examination including DWI andwithout contrast medium administration wouldbe shorter than a conventional contrast-enhanced

V. Ninivaggi, M. Missere, G. Restaino, E. Gangemi, M. Di Matteo, A. Pierro, et al.

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MR-enterography with diffusion weighted imaging

MRI, as long as DWI sequence requires a shorttime to be performed3. In a very recent studycomparing DWI and post-contrast T1-weighedimages the possibility of replacing post-contrastsequences with DWI is controversial, especiallyfor the evaluation of penetrating complications21. In our work, we focused on finding a possible

threshold ADC value to differentiate active frominactive CD rather than a diagnosis of bowel inflam-

mation or evaluation of penetrating complica-tions. In our opinion, DWI could represent an al-ternative to post-contrast study in patients inwhich contrast medium administration is con-traindicated.Concerning these aims and in order to better

understand the pathophysiology of restricted dif-fusion in CD of the small bowel further research-es are needed, mostly to better correlate DWIfindings to stages of bowel inflammation.

Conclusions

DWI is a very promising tool for the assess-ment of bowel inflammation and may improveMR-enterography diagnostic performance in pa-tients affected by CD.ADC values of the wall of affected bowel

loops are found to be significantly lower thanthose of the normal bowel loops in patients withCrohn’s disease. The ADC threshold value of2.416X10-3 mm2/s could be used to discriminatenormal appearing from pathological bowel loops.

–––––––––––––––––-––––Conflict of InterestThe Authors declare that they have no conflict of interests.

References

1) KIRYU S, DODANUKI K, TAKAO H, WATANABE M, INOUEY, TAKAZOE M SAHARA R, UNUMA K, OHTOMO K. Free-breathing diffusion-weighted imaging for the as-sessment of inflammatory activity in Crohn's dis-ease. J Magn Reson Imaging 2009; 29: 880-886.

2) AL-HAWARY M, ZIMMERMANN EM. A new look atCrohn's disease: novel imaging techniques. CurrOpin Gastroenterol 2012; 28: 334-340.

3) BUISSON A, JOUBERT A, MONTORIOL PF, DA INES D,HORDONNEAU C, PEREIRA B, GARCIER JM, BOMMELAERG, PETITCOLIN V. Diffusion-weighted magnetic reso-nance imaging for detecting and assessing ileal

inflammation in Crohn's disease. Aliment Phar-macol Ther 2013; 37: 537-545.

4) OTO A, KAYHAN A, WILLIAMS JT, FAN X, YUN L, ARKANIS, RUBIN DT. Active Crohn's disease in the smallbowel: evaluation by diffusion weighted imagingand quantitative dynamic contrast enhanced MRimaging. J Magn Reson Imaging 2011; 33: 615-624

5) NEUBAUER H, PABST T, DICK A, MACHANN W, EVANGE-LISTA L, WIRTH C, KÖSTLER H, HAHN D, BEER M. Small-bowel MRI in children and young adults withCrohn disease: retrospective head-to-head com-parison of contrast-enhanced and diffusion-weighted MRI. Pediatr Radiol 2013; 43: 103-114.

6) OTO A, ZHU F, KULKARNI K, KARCZMAR GS, TURNER JR,RUBIN D. Evaluation of diffusion-weighted MRimaging for detection of bowel inflammation in pa-tients with Crohn's disease. Acad Radiol 2009; 16:597-603.

7) QAYYUM A. Diffusion-weighted imaging in the ab-domen and pelvis: concepts and applications. Ra-diographics 2009; 29: 1797-1810.

8) CHIORRI C Teoria e tecnica psicometrica. Costruireun test psicologico. The McGraw-Hill CompaniesS.r.l., Publishing Group Italia, 2001.

9) TAOULI B, TOLIA AJ, LOSADA M, BABB JS, CHAN ES,BANNAN MA, TOBIAS H. Diffusion-weighted MRI forquantification of liver fibrosis: preliminary experi-ence. AJR Am J Roentgenol 2007; 189: 799-806.

10) VERSWIJVEL G, VANDECAVEYE V, GELIN G, VANDEVENNEJ, GRIETEN M, HORVATH M, OYEN R, PALMERS Y. Diffu-sion-weighted MR imaging in the evaluation of re-nal infection: preliminary results. JBR-BTR 2002;85: 100-103.

11) RIDDELL RH. Pathology of idiopathic inflammatorybowel disease. In: Kirsner JB (ed) Inflammatorybowel disease, 3rd edn. Philadelphia, USA; WBSaunders, 2000; pp. 427-452.

12) TIELBEEK JA, ZIECH ML, LI Z, LAVINI C, BIPAT S, BEMEL-MAN WA, ROELOFS JJ, PONSIOEN CY, VOS FM, STOKERJ. Evaluation of conventional, dynamic contrastenhanced and diffusion weighted MRI for quanti-tative Crohn's disease assessment withhistopathology of surgical specimens. Eur Radiol2014; 24: 619-629.

13) ZAPPA M, STEFANESCU C, CAZAL–HATEM D BRETAGNOL F,DESCHAMPS L, ATTAR A, LARROQUE B, TRÉTON X, PANISY, VILGRAIN V, BOUHNIK Y. Which magnetic reso-nance imaging findings accurately evaluate in-flammation in small bowel Crohn’s disease? Aretrospective comparison with surgical pathologicanalysis. Inflamm Bowel Dis 2011; 17: 984-993.

14) ADLER J, PUNTIGLIA DR, DILLMAN JR, POLYDORIDES AD,DAVE M, AL-HAWARY MM, PLATT JF, MCKENNA BJ, ZIM-MERMANN EM. Computed tomography enterogra-phy findings correlate with tissue inflammation,not fibrosis in resected small bowel Crohn’s dis-ease. Inflamm Bowel Dis 2012; 18: 849-856.

15) HORDONNEAU C, BUISSON A, SCANZI J, GOUTORBE F,PEREIRA B, BORDERON C, DA INES D, MONTORIOL PF, GARCI-ER JM, BOYER L, BOMMELAER G, PETITCOLIN V. Diffusion-

4546

V. Ninivaggi, M. Missere, G. Restaino, E. Gangemi, M. Di Matteo, A. Pierro, et al.

weighted magnetic resonance imaging in ileocolonicCrohn's disease: validation of quantitative index ofactivity. Am J Gastroenterol 2014; 109: 89-98.

16) FROEHLICH JM, DAENZER M, VON WEYMARN C, ERTURKSM, ZOLLIKOFER CL, PATAK MA. Aperistaltic effect ofhyoscine N-butylbromide versus glucagon on thesmall bowel assessed by magnetic resonanceimaging. Eur Radiol 2009; 19: 1387-1393.

17) GUTZEIT A, BINKERT CA, KOH DM, HERGAN K, VONWEYMARN C, GRAF N, PATAK MA, ROOS JE,HORSTMANN M, KOS S, HUNGERBÜHLER S, FROEHLICHJM. Evaluation of the anti-peristaltic effect ofglucagon and hyoscine on the small bowel: com-parison of intravenous and intramuscular drug ad-ministration. Eur Radiol 2012; 22: 1186-1194.

18) QI F, JUN S, QI QY, CHEN PJ, CHUAN GX, JIONG Z,RONG XJ. Utility of the diffusion-weighted imaging

for activity evaluation in Crohn's disease patientsunderwent magnetic resonance enterography.BMC Gastroenterol 2015; 15:12.

19) PANÉS J, RICART E, RIMOLA J. New MRI modalities forassessment of inflammatory bowel disease. Gut2010; 59: 1308-1309.

20) LEWIS B, MUKEWAR S, LOPEZ R, BRZEZINSKI A, HALL P,SHEN B. Frequency and risk factors of renal insuffi-ciency in inflammatory bowel disease inpatients.Inflamm Bowel Dis 2013; 19: 1846-1851.

21) SEO N, PARK SH, KIM KJ, KANG BK, LEE Y, YANG SK, YEBD, PARK SH, KIM SY, BAEK S, HAN K, HA HK. MREnterography for the Evaluation of Small-BowelInflammation in Crohn Disease by Using Diffu-sion-weighted Imaging without Intravenous Con-trast Material: A Prospective Noninferiority Study.Radiology 2016; 278: 762-772.