Crohn's disease of the Crohn's disease of the small small intestineintestine: : clinical course clinical course variants and problems of variants and problems of differential diagnosticsdifferential diagnosticsLeonid BLeonid B..LazebnikLazebnik, , AsfoldAsfold I.ParfenovI.Parfenov, , EleonoraEleonora SS..SivashSivashCentral Research Institute of Gastroenterology (CRIG)Central Research Institute of Gastroenterology (CRIG),,

MoscowMoscow, , RussiaRussia

Falk Falk simposiumsimposium 154, Moscow, 10.06.2006154, Moscow, 10.06.2006

The dadsThe dads

In 2009 we shall notice 75In 2009 we shall notice 75--year of the first year of the first describing natural history of this disease by B. describing natural history of this disease by B. Crohn, L. Oppenheimer and G. Ginsberg in 1932.Crohn, L. Oppenheimer and G. Ginsberg in 1932.

Crohn'sCrohn's disease (disease (ССD) D) ofof small small intestineintestine ((loclocalalggranulomatous enteritis) ranulomatous enteritis) is one of the most is one of the most difficult one for diagnosticsdifficult one for diagnostics. .

The problems are possible longThe problems are possible long--term nonterm non--signs natural signs natural hystoryhystory, often significances with , often significances with the the extraintestinalextraintestinal manifestations and complexity manifestations and complexity of visualization characteristic of the most part of of visualization characteristic of the most part of the intestine.the intestine.

For For 19911991--20052005 in Department of Small Intestine in Department of Small Intestine Diseases of CRIG Diseases of CRIG ysys ((AsfoldAsfold I.I. Parfenov)120 Parfenov)120 patients with small intestine patients with small intestine CrohnCrohn’’ss disease (disease (66 66 male andmale and 54 54 female with agefemale with age 2323--7777 ysys) were ) were observed.observed.It was 1.2% of whole other patients with It was 1.2% of whole other patients with diseases of bowel.diseases of bowel.The first symptoms, that could be associated with The first symptoms, that could be associated with CD at 53% of them where fixed with age of CD at 53% of them where fixed with age of 2020--30.30.WithWith 8282..5% 5% of them the CDof them the CD was diagnosed within was diagnosed within 22--7 years after the appearance of the first clinical 7 years after the appearance of the first clinical symptoms.symptoms.

Affecting factors of the clinical pictureAffecting factors of the clinical picture::

localization of injurylocalization of injury, , acuteness of the disease developmentacuteness of the disease development, , severity and extension of local severity and extension of local inflammationinflammation, , complications,complications,extraintestinal manifestationsextraintestinal manifestations..

Localization of inflammationLocalization of inflammation

With 77 pts (61.7%) process was With 77 pts (61.7%) process was localized in the terminal part of the ileum localized in the terminal part of the ileum (terminal (terminal ileitisileitis), in 32 pts in the ), in 32 pts in the caecumcaecum, , in 8 pts in the in 8 pts in the ascending ascending coloncolon, and in 3 , and in 3 pts into the duodenum.pts into the duodenum.So, 97.5% of pts suffering from CD of the small intestine had an affected distal part of the ileum, and 33.3% had a concominant inflammation of the colon (mostly caecum)

Clinical forms of the small intestine Clinical forms of the small intestine CrohnCrohn’’ss disease (of the incoming for disease (of the incoming for

CRIG)CRIG)

Acute startAcute start

ChronicalChronical recurrentrecurrent

StenosiStenosingng of intestineof intestine

Acute startAcute start((n=n=3636, 30.0%) , 30.0%) --

Were hospitalized into the Surgery Were hospitalized into the Surgery Department of CRIG because of Department of CRIG because of haevyhaevy pain at pain at right right hypogastriumhypogastrium,,Were operated on due to emergency Were operated on due to emergency indications,indications,Terminal part of the ileum was Terminal part of the ileum was resectedresected with with 17,17,Terminal part of the ileum plus segment of the Terminal part of the ileum plus segment of the small intestine was small intestine was resectedresected with 9,with 9,Resection of the ileum plus Resection of the ileum plus right right hemicolectomyhemicolectomy was made with 4.was made with 4.

ChronicalChronical recurrent (n=38, 31,6%)recurrent (n=38, 31,6%)

In the half of them inflammation restricted In the half of them inflammation restricted mainly to the submucous layer of the intestine.mainly to the submucous layer of the intestine.The initial clinical manifestations were fever, The initial clinical manifestations were fever, accelerated ESR, accelerated ESR, hyperleukocytosishyperleukocytosis and other and other signs of inflammation.signs of inflammation.A few months or years later the signs of a A few months or years later the signs of a transmural lesion of intestinal wall and lumen transmural lesion of intestinal wall and lumen constriction (constriction (chronicalchronical diarrhea, bleeding a. diarrhea, bleeding a. cramping pain) were appeared. cramping pain) were appeared. So symptoms of So symptoms of malabsormalabsorbbtiontion (anemia, loss of (anemia, loss of proteinproteins, s, oedemasoedemas and less of body weight) were and less of body weight) were accrued.accrued.

StenosisStenosis of intestineof intestine (n=46, 38,4%)(n=46, 38,4%)

ChronicalChronical abdominal pain and extraintestinal abdominal pain and extraintestinal manifestations for a long time (episodes of manifestations for a long time (episodes of unmotivated fever, pains in the joints, erythema unmotivated fever, pains in the joints, erythema nodosum, etc.).nodosum, etc.).The disease can remain undiagnosed for many The disease can remain undiagnosed for many years. If it breaks out in the childhood, the years. If it breaks out in the childhood, the patient can become physically disabled.patient can become physically disabled.Sometimes it is possible to reveal an infiltrate in Sometimes it is possible to reveal an infiltrate in the the abdomabdomeenn with thewith the palppalpititationation. Symptoms of . Symptoms of intestinal obstructionintestinal obstruction can accrue later: cramping can accrue later: cramping pains mostly in the right iliac region accompanied pains mostly in the right iliac region accompanied by vomiting, by vomiting, abdominal swellingabdominal swelling, loud , loud borborygmusborborygmus, and , and stool stool and flatus and flatus retentionretention..Visible Visible peristalperistalttiiccss with with occasionaloccasional rising swells rising swells appears.appears.The diagnosis is confirmed by an XThe diagnosis is confirmed by an X--ray ray examination or examination or laparotomylaparotomy..

The mucous coat had an uneven relief. Cicatricial The mucous coat had an uneven relief. Cicatricial alterations of the wall resulted in the constriction alterations of the wall resulted in the constriction of the intestinal lumen and development of partial of the intestinal lumen and development of partial and even complete intestinal occlusion.and even complete intestinal occlusion.The inflammation extended to the serous coat The inflammation extended to the serous coat and adjacent tissues and organs, which was and adjacent tissues and organs, which was confirmed by revealed fistulas and commissures confirmed by revealed fistulas and commissures as well as typical alterations of vessels.as well as typical alterations of vessels.

Sample of Sample of stenosingstenosing form of CDform of CD

Signs of the transmural lesion of the intestinal Signs of the transmural lesion of the intestinal wall at CDwall at CD

The inflammation extended The inflammation extended to the serous coat and and to the serous coat and and adjacent tissues and adjacent tissues and organs, which was organs, which was confirmed by revealed confirmed by revealed fistulas and commissures as fistulas and commissures as well as typical alterations well as typical alterations of vessels.of vessels.Arterioles thickened and Arterioles thickened and were surrounded with were surrounded with conjunctive and tissue conjunctive and tissue ““couplerscouplers”” constricting the constricting the lumen.lumen.

Extraintestinal manifestations of CrohnExtraintestinal manifestations of Crohn’’s s disease in observed 120 patients (CRIG)disease in observed 120 patients (CRIG)

27 27 (22(22..5%)5%)

Total Total

5 5 (4(4..1%)1%)

EyesEyes (iridocyclitis, (iridocyclitis, keratoconjunctivitis)keratoconjunctivitis)

8 8 (6(6..77%%))

Skin and Skin and mucousamucousa ((erythema erythema nodosumnodosum, stomatitis), stomatitis)

14 14 (11(11..7%)7%)

MyoMyoartarthrhricularicular ((arthritis, arthritis, spondylitis, sacroileitisspondylitis, sacroileitis))

nn (%)(%)Localization Localization

ExtraintestinalExtraintestinal manifestations of Crohnmanifestations of Crohn’’s disease s disease (collected literature database)(collected literature database)

NNeuropathyeuropathy. . EpilepsyEpilepsy, , depressiondepressionNervous, Nervous,

AAmyloidosismyloidosisKidneysKidneys

GGranulomatous hepatitis, sclerosing ranulomatous hepatitis, sclerosing cholangitis. cholangitis.

LiverLiver

GGranulomatous tracheobronchitis, sarcoidosisranulomatous tracheobronchitis, sarcoidosisLungsLungs

AAortitisortitis, Takayasu's disease, Sch, Takayasu's disease, Schöönleinnlein--Henoch vasculitisHenoch vasculitis

VesselsVessels

Orbital Orbital myositis myositis EyesEyes

MMyopathyyopathyMusclesMuscles

GGranulomatous cheilitis, ranulomatous cheilitis, saliva saliva glandulitisglandulitis,,stomatitisstomatitis

Mucous coatsMucous coats

Sweet syndrome (Sweet syndrome (acute acute dermatosisdermatosis, , pyoderma). pyoderma). VesiculoVesiculo--ulcerousulcerous andandgranulomatousgranulomatous lesionslesions

SkinSkin

CharacteristicsCharacteristicsLocalizationLocalization

Diagnostics Diagnostics

In CRIGIn CRIG

the diagnosis of acute form of the diagnosis of acute form of CrohnCrohn’’ss disease was disease was confirmed within confirmed within laparoscopylaparoscopy or or laparotomylaparotomy..

MorphologyMorphology

AA BBSarcoidSarcoid granulomas with Pirogovgranulomas with Pirogov--Langhans cells Langhans cells located in the submucous layer and marked located in the submucous layer and marked infiltration of the intestinal wall with lymphoid infiltration of the intestinal wall with lymphoid cells (A) and ulcers extending to the serous coat cells (A) and ulcers extending to the serous coat (B) were revealed in the surgery material in the (B) were revealed in the surgery material in the intestinal walls in 40% of patients.intestinal walls in 40% of patients.

Clinical diagnostics of the primary Clinical diagnostics of the primary chronicalchronical and stenosing forms of CDand stenosing forms of CD

The diagnosis for the stenosing in primary chronic The diagnosis for the stenosing in primary chronic forms of CD was usually made 3forms of CD was usually made 3--5 years after the 5 years after the appearance of clinical symptoms.appearance of clinical symptoms.A loss of body weight.A loss of body weight.An asymmetry of the stomach in some patients An asymmetry of the stomach in some patients due to the due to the infiltrates.infiltrates.FeFe-- a.a.\\or or ВВ1212--deficiency anemia in some patients.deficiency anemia in some patients.Stable Stable hypoproteinemiahypoproteinemia..

VVideoimageideoimage endoscopyendoscopy(small intestine of patient 45 (small intestine of patient 45 ysys with severe myopathy with severe myopathy

of uncertain genesis (CRIG). of uncertain genesis (CRIG).

Multiple erosions of the small intestine.Multiple erosions of the small intestine.The The intestinoscopyintestinoscopy in the middle parts of the small intestine in the middle parts of the small intestine revealed signs of revealed signs of granulomatous inflammationgranulomatous inflammationcharacteristic of CD.characteristic of CD.The treatment with Metypred and Pentasa arrested pains in The treatment with Metypred and Pentasa arrested pains in the muscles and resulted in the morphological remission of the muscles and resulted in the morphological remission of CD.CD.

IleoscopyIleoscopy of terminal part of the of terminal part of the ileumileum

OedemaOedema, uneven hyperemia, aphthosis (initial , uneven hyperemia, aphthosis (initial morphological alterations)morphological alterations)Ulcers Ulcers

According to the classification suggested by HAccording to the classification suggested by H.. HerlingtrHerlingtr andand DD..MedlinteMedlinte and based on Xand based on X--ray morphological alterations, three stages ray morphological alterations, three stages

of CD are of CD are distinguishdistinguisheded

Stage Stage II –– early alterations (early alterations (7.5%)7.5%). . Typical characteristicsTypical characteristics: : thickening and straightening of folds, presence of multiple supethickening and straightening of folds, presence of multiple superficial rficial ulcers being 0.1ulcers being 0.1--0.2 cm in the diameter. The intestinal wall is still 0.2 cm in the diameter. The intestinal wall is still elastic. elastic. Stage Stage II II –– intermediate alterations (intermediate alterations (22.5%)22.5%). . Nodular relief, Nodular relief, ulcerations, rigidity of the mesenteric edge and bulging of the ulcerations, rigidity of the mesenteric edge and bulging of the opposite edge in the form of pseudodiverticulums. The intestinalopposite edge in the form of pseudodiverticulums. The intestinal wall wall is thickened, and the width of the intestinal lumen is within this thickened, and the width of the intestinal lumen is within the limits e limits of the norm. of the norm. Stage Stage III III –– marked alterations (marked alterations (70%70%)). . Ulcerative and nodular Ulcerative and nodular relief (the relief (the ““cobblestone pavementcobblestone pavement”” symptom), presence of deep slotsymptom), presence of deep slot--like ulcerations and formed constriction of the lumen in the forlike ulcerations and formed constriction of the lumen in the form of a m of a cord. The distance between the loops is enlarged, and the walls cord. The distance between the loops is enlarged, and the walls are are thickened and rigid. thickened and rigid.

XX--ray film of the ileum CD stage Iray film of the ileum CD stage I

((EleonoraEleonora S.SivashS.Sivash) ) The folds are The folds are

enlarged, there are enlarged, there are multiple filling defects multiple filling defects in the relief, in the relief, d ~ 0.2 d ~ 0.2 cm with a point depot cm with a point depot in the center in the center ––aphthous ulcers.aphthous ulcers.

XX--ray films of CD stage IIIray films of CD stage III((EleonoraEleonora S.SivashS.Sivash) )

1 21 21.1. An enlargement XAn enlargement X--ray film of the terminal part of the ileum ray film of the terminal part of the ileum

–– constriction of the terminal loop in the form of a constriction of the terminal loop in the form of a ““cordcord””for a great length. Two blind ducts, one of them being for a great length. Two blind ducts, one of them being ~ ~ 2.52.5 cm long cm long –– fistulas.fistulas.

2.2. A fragment of the XA fragment of the X--ray film of the ileum. Shortening of the ray film of the ileum. Shortening of the mesenteric edge of the ileum with the bulging of the mesenteric edge of the ileum with the bulging of the opposite edge and formation of pseudodiverticulums.opposite edge and formation of pseudodiverticulums.

UUltrasonographyltrasonography

1 2 1 2 UUltrasonography ltrasonography makes it possible to record makes it possible to record the thickening of the intestinal wall (1) and the thickening of the intestinal wall (1) and infiltrate infiltrate iofiof small intestine (2).small intestine (2).

Differential diagnosticsDifferential diagnostics

DISEASESDISEASESAAcutecute appendicitisappendicitisYersiniYersiniousous ileitisileitisFFollicularollicular ileitisileitisChronic ulcerous Chronic ulcerous nonnon--granulomatousgranulomatous ileitis ileitis ((jejunoileitisjejunoileitis))EEosinophilicosinophilic enteritis enteritis

AAcute appendicitiscute appendicitis

In contrast for acute In contrast for acute appendicitis, CD has a appendicitis, CD has a longer anamnesis with longer anamnesis with preceding exacerbations.preceding exacerbations.VVideoimageideoimage endoscopyendoscopyand laparoscopy and laparoscopy facilitates the differential facilitates the differential diagnostics greatly (a. diagnostics greatly (a. sudden morphology sudden morphology exam!) exam!)

YersiniYersiniousous ileitisileitis

Clinical and morphological Clinical and morphological manifestations of Ymanifestations of Yersiniersiniousousileitisileitis and CD can be very and CD can be very similar.similar.SSerologicerological and bacteriological al and bacteriological markers (antibody) of the markers (antibody) of the Yersinia infection are positive.Yersinia infection are positive.Opposite to CrohnOpposite to Crohn’’s disease, the s disease, the clinical and morphological clinical and morphological remissions of remissions of YersiniousYersinious ileitis ileitis begin under of the begin under of the antibacterialantibacterialtherapy (diagnosis ex therapy (diagnosis ex juvantibusjuvantibus).).

FFollicularollicular ileitisileitis

A typical A typical endoscopyendoscopy symptomsymptom: : nodularnodular lymphoid hyperplasia lymphoid hyperplasia forming an uneven relief of the mucous forming an uneven relief of the mucous coat in the distal part of the ileumcoat in the distal part of the ileum..Acute follicular ileitisAcute follicular ileitis develops in develops in childhood childhood simultantlysimultantly measles or other measles or other infections. Its clinical picture looks at infections. Its clinical picture looks at acute appendicitis. Laparotomy reveals acute appendicitis. Laparotomy reveals hyperemia a. edema of terminal part hyperemia a. edema of terminal part of ileum and even NLH 10of ileum and even NLH 10--20 cm 20 cm longinitylonginity, infiltration and enlargement , infiltration and enlargement of of mesenterialmesenterial lymphoid nodes.lymphoid nodes.

FFollicularollicular ileitisileitis

Subacute follicular ileitis Subacute follicular ileitis develops within several develops within several weeks and is characterized by pains, diarrhea, nausea, weeks and is characterized by pains, diarrhea, nausea, vomiting and high temperature. An infiltrate can form in vomiting and high temperature. An infiltrate can form in the right iliac region. Reasons: tuberculosis, yersiniosis, the right iliac region. Reasons: tuberculosis, yersiniosis, viral or some other infection.viral or some other infection.ChronicalChronical follicular ileitisfollicular ileitis is characterized by is characterized by moderate pains in the right iliac region. Marked NLH moderate pains in the right iliac region. Marked NLH forms a relief resembling that at CD. Difference: absence forms a relief resembling that at CD. Difference: absence of sclerosis of the intestinal wall.of sclerosis of the intestinal wall.NonNon--sclerosing ileitissclerosing ileitis. . EEtiology is unknown, yet in tiology is unknown, yet in some cases it can be chronic Yersinia ileitis.some cases it can be chronic Yersinia ileitis.

Chronic ulcerous Chronic ulcerous nonnon--granulomatousgranulomatous ileitis ileitis ((jejunoileitisjejunoileitis))

A rare disease of unknown A rare disease of unknown ethiologyethiology. Symptoms: chronic . Symptoms: chronic diarrhea, enteropathy with a diarrhea, enteropathy with a hypoproteinemiahypoproteinemia, , emaciation, pains in the stomach, fever, anemia, emaciation, pains in the stomach, fever, anemia, leukocytosisleukocytosis,.,.A histologic study of biopsy: A histologic study of biopsy: atrophyatrophy of the intestinal of the intestinal mucousamucousa with ulcerations and mostly with ulcerations and mostly lympholymphoplasmocyticplasmocyticinfiltration of the plate in the mucous coat of the small infiltration of the plate in the mucous coat of the small intestine.intestine.The treatment with an The treatment with an agluten dietagluten diet has no effect. has no effect. Corticosteroids promote the remission.Corticosteroids promote the remission.The prognosis is uncertain, and spontaneous remissions The prognosis is uncertain, and spontaneous remissions are possible.are possible.

EEosinophilicosinophilic enteritis enteritis

Its clinical and macroscopic Its clinical and macroscopic morphological picture morphological picture resembles that of CD very resembles that of CD very much.much.Differential and diagnostic Differential and diagnostic criteria are infiltration of criteria are infiltration of the mucous coat with the mucous coat with eosinophileosinophils and absence of s and absence of sarcoidsarcoid granulomagranulomas.s.

ConclusionConclusion

Successful early diagnostics of CrohnSuccessful early diagnostics of Crohn’’s s disease of small intestine is stipulated by disease of small intestine is stipulated by the knowledge of clinical manifestations of the knowledge of clinical manifestations of the disease and wellthe disease and well--directed search for directed search for jointly brain storming with jointly brain storming with gastroenterologist, gastroenterologist, abdomenalabdomenal surgeon, surgeon, roentgenologistroentgenologist, , endoscopistendoscopist a. a. morphologist.morphologist.