Lymphedema and Crohn's Disease

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Lymphedema and Crohn's Disease

Postby patoco » Sat Jun 10, 2006 2:52 am

Lymphedema and Crohn's Disease

Our Home Page: Lymphedema People

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Lymphedema and Crohn's Disease

An email I received yesterday ask me if there was a tie in between lymphedema and Crohn's Disease. On the face of it, you would think not, however a closer examination of the two conditions reveals a distinct tie in.

I include a quote from renown British lymphedema expert Dr. Peter Mortimer in an article for Lymphovenous Canada:

"It is my belief that many of the types of edema that we see associated with treatment of cancer and other conditions such as Crohn's disease and some arthritic conditions, are in fact related to an underlying genetic weakness in lymph drainage which already exist. If you take Crohn's disease, for example, the pathology of Crohn's disease is effectively lymphedema of the gut. Gastroentologists don't call it that, but that is what it is."

There are two clinical features specifically of Crohn's that can lead to and are associated with lymhpedema.

First is granulomatous lymphangitis. Secondly is hyperplaysia of the lymphatics similar to that in lymphangiectasia. Both of these affet the lymphatics and subsequent have lymphedema presenting as an accompanying complication.

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CROHN'S DISEASE

Background
This is one half of inflammatory bowel disease, its partner is ulcerative colitis. The presenting symptoms are varied including fever, mild diarrhea, and abdominal pain. The attacks may be episodic lasting weeks to months. Bleeding, especially in patients with colon involvement, may occur. Crohn's disease differs from ulcerative colitis in being able to involve the entire gastrointestinal tract from mouth to anus. In addition, a number of organ systems may be involved (see clinical presentations).

EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION

SYNONYMS Terminal ileitis, Regional enteritis, Granulomatous colitis, Crohn's colitis, inflammatory bowel disease

INCIDENCE 3/100,000 in USA

Clinical features of Crohn's disease: a clinical study of one hundred patients found in an unselected population.

Kangas E, Matikainen M, Auvinen O, Harju E, Inkovaara J, Maki M.
Int Surg 1986 Oct-Dec;71(4):256-9 Abstract quote

One hundred patients (mean age 34 years, range from 12 to 70 years) were treated at Tampere University Hospital during the thirteen year period, 1972-1984. Our hospital takes responsibility for the treatment of patients with Crohn's disease found in an unselected population of 400,000 inhabitants.

In 73% of cases Crohn's disease was diagnosed before the age of forty. The mean interval between the first clinical signs and the diagnosis was 3.3 years. In 57% of the patients the diagnosis was reached within one year. In nine patients the primary diagnosis was colitis ulcerosa. Most patient were anemic and were in the state of inflammation and/or catabolism suggested by low blood hemoglobin concentration and high ESR and CRP values on admission. Three percent of the patients had macroscopic Crohn's disease in all parts of the gastrointestinal tract, whereas 22% had it only in the small intestine and 18% only in the colon. Fifty of the hundred patients had lesions in the terminal ileum and 20% in the anus. The specific finding for the present series was a high frequency of rectal lesions, in 29% of the patients.

Histologically the condition was more often (P less than 0.001) revealed by the laparatomy specimen than the endoscopic biopsy, which gave a positive histology more often (P less than 0.001) in the lower than in the upper gastrointestinal tract. No gastrointestinal malignancies were found.

AGE-RANGE AND MEDIAN Peak 2-3rd decades
Minor peak in 6-7th decades

not allowed (MALE:FEMALE) Females slightly more common

GEOGRAPHIC DISTRIBUTION Whites:Nonwhites 2-5:1
Smoking
Jewish et

DISEASE ASSOCIATIONS CHARACTERIZATION

CALCIPHYLAXIS

Calciphylaxis in a patient with Crohn's disease in the absence of end-stage renal disease.

Barri YM, Graves GS, Knochel JP.

Department of Medicine, Presbyterian Hospital of Dallas, TX 75231, USA

Am J Kidney Dis 1997 May;29(5):773-6 Abstract quote

Calciphylaxis is a rare and life-threatening condition of progressive cutaneous necrosis secondary to small and medium-sized vessel calcification previously described in patients with end-stage renal disease and hyperparathyroidism. Early diagnosis may be important in improving the poor outcome in these patients since early intervention may forestall the development of life-threatening complications.

We describe a patient with Crohn's disease complicated by short-bowel syndrome and modest renal insufficiency (not requiring renal replacement therapy) who developed calciphylaxis. It appears that longstanding Crohn's disease and the short-bowel syndrome accelerated the development of calciphylaxis as the chronic renal disease was not end stage. Considering the possibility of calciphylaxis in this setting may avoid delaying the diagnosis and its consequences.

LUPUS ERYTHEMATOSUS

Fatal evolution of systemic lupus erythematosus associated with Crohn's disease.

Chebli JM, Gaburri PD, de Souza AF, Dias KV, Cimino KO, de Carvalho-Filho RJ, Lucca FA.

Division of Gastroenterology, Department of Medicine, Juiz de Fora University, School of Medicine, Juiz de Fora, MG, Brazil

Arq Gastroenterol 2000 Oct-Dec;37(4):224-6 Abstract quote

The authors describe the case of a young Brazilian woman who was treated of ileocolonic Crohn's disease sparing rectum, as confirmed by colonoscopy and histopathological examination.

After a 4-year course of sulfasalazine treatment, she presented with skin facial lesions in vespertilio, fever, arthralgias and high titers of anti-ANA and LE cells. A sulfasalazine-induced lupus syndrome was diagnosed, because after sulfasalazine withdrawal and a short course of prednisone, the clinical symptoms disappeared and the laboratory tests returned to normal. Mesalazine 3 g/day was started and the patient remained well for the next 3 years, when she was again admitted with fever, weakness, arthralgias, diplopy, strabismus and hypoaesthesia in both hands and feet, microhematuria, haematic casts, hypocomplementemia and high titers of autoimmune antibodies.

A diagnosis of associated systemic lupus erythematosus was made. Although a pulsotherapy with methylprednisolone was started, no improvement was noticed. A cyclophosphamide trial was tried and again no positive results occurred. The patient evolved to severe clinical manifestations of general vasculitis affecting the central and peripheral nervous system and lungs, having a fatal evolution after 2 weeks.

Although uncommon, the association of both disease may occur, and the authors call attention to this possibility, making a brief review of literature

PSORIASIS

Connections between psoriasis and Crohn's disease.

Najarian DJ, Gottlieb AB.

University of Virginia School of Medicine, and the Clinical Research Center, University of Medicine and Dentistry of New Jersey-The Robert Wood Johnson Medical School.

J Am Acad Dermatol. 2003 Jun;48(6):805-21. Abstract quote
The prevalence of psoriasis in patients with Crohn's disease (CD) is higher than chance would allow if they were mutually exclusive diseases. A close examination reveals genetic and pathologic connections between these diseases. An appreciation for the role of tumor necrosis factor-alpha in both diseases has proven very important.

Increased levels of this inflammatory cytokine have been measured in CD lesions, and in 1997 a clinical trial demonstrated the response of this disease to infliximab, a monoclonal antibody specific for tumor necrosis factor-alpha. A subsequent clinical trial evaluated infliximab in a patient with CD and psoriasis, another disease in which increased levels of tumor necrosis factor-alpha are seen in lesions.

Scientists noticed the marked skin improvement of this patient and later demonstrated the efficacy of infliximab for psoriasis in a randomized, double-blind, placebo-controlled trial. Thus, an appreciation for connections between psoriasis and CD can suggest novel therapeutic strategies with ensuing benefits to patients.

This article reviews epidemiologic, genetic, and pathologic connections between psoriasis and CD and discusses pharmaceuticals targeting inflammatory mediators common to each disease. (J Am Acad Dermatol 2003;48:805-21.) Learning objective: At the completion of this learning activity, participants should understand how psoriasis and Crohn's disease are related at epidemiologic, genetic, and pathological levels and should appreciate how to use this knowledge to treat these diseases.

PATHOGENESIS CHARACTERIZATION

GENERAL

Molecular Discoveries Alter Our View of Inflammatory Bowel Disease
A Review From Scientific, Clinical, and Laboratory Perspectives

Eric B. Staros, MD

Am J Clin Pathol 2003;;119:524-539 Abstract quote
Within the past decade, knowledge of the molecular basis of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis, has advanced owing to the explosive growth of research involving the human genome.

Furthermore, a shared interest between molecular biologists and clinical researchers has contributed to an emerging understanding of IBD. Nucleotide-binding oligomerization domain 2 (NOD2) belongs to an apoptotic regulatory family of genes and has been linked to CD. In addition, research into nuclear factor kappa B (NF–kappa B), the proteasome, interleukins, and tumor necrosis factor alpha has improved our understanding of IBD. Our understanding of these molecules and other scientific discoveries offers hope for new diagnostic tests and therapeutic agents.

In the future, genetic markers will predict disease susceptibility, therapeutic responsiveness, and long-term sequelae of modern therapeutics. Also on the horizon, molecular markers promise to define disease heterogeneity, thereby providing a rational basis for patient-specific therapies. The molecular discoveries that are changing our views of IBD will affect the clinician, the laboratory professional, and the patient.

BACTERIAL 16S rRNA

Cutaneous manifestations of Crohn's disease, its spectrum, and its pathogenesis: intracellular consensus bacterial 16S rRNA is associated with the gastrointestinal but not the cutaneous manifestations of Crohn's disease.

Crowson AN, Nuovo GJ, Mihm MC Jr, Magro C.

Central Medical Laboratories, Winnipeg, Manitoba, Canada

Hum Pathol. 2003 Nov;34(11):1185-92 Abstract quote.

The classic pathology of skin disease discontinuous from the inflamed gastrointestinal (GI) tract in patients with Crohn's disease (CD) includes pyoderma gangrenosum (PG), erythema nodosum (EN), and so-called metastatic Crohn's disease. The purpose of this study was two-fold: First, we explored the full spectrum of cutaneous lesions associated with Crohn's disease, and second, we sought to explore a potential molecular basis of the skin lesions in patients with CD.

In this regard, we analyzed skin and GI tract biopsies from affected patients for the consensus bacterial SrRNA to determine whether direct bacterial infection was associated with either condition. Formalin-fixed, paraffin-embedded sections were studied and correlated to clinical presentation and histories from 33 patients with CD. Consensus bacterial RNA sequences were analyzed using an RT in situ PCR assay on both skin biopsy and GI biopsy material. The GI tract material included biopsies from 3 patients who had skin lesions and from 7 patients in whom there were no known skin manifestations. There were 8 cases of neutrophilic dominant dermal infiltrates, including pyoderma gangrenosum, 6 cases of granuloma annulare/necrobiosis lipoidica-like lesions, 5 cases of sterile neutrophilic folliculitis, 5 cases of panniculitis, 4 cases of vasculitis, 2 cases of psoriasis, 2 cases of lichenoid and granulomatous inflammation, and 1 case of classic metastatic CD. Intracellular bacterial 16S rRNA was detected in 8 of 10 tissues of active CD in the GI tract, of which 3 of the cases tested were from patients who also developed skin lesions at some point in their clinical course; in contrast, none of the skin biopsies had detectable bacterial RNA.

The dermatopathological manifestations of CD discontiguous from the involved GI tract mucosa have in common a vascular injury syndrome, typically with a prominent extravascular neutrophilic and/or histiocytic dermal infiltrate. In addition, this study, the first to document in situ intracellular consensus bacterial SrRNA in the GI tract in CD, suggests that hematogenous dissemination of viable microbes is not associated with the cutaneous manifestations of this disease. Bacteria do, however, appear to play a role in bowel lesions of patients with CD.
CYTOKINES

Role of cytokines in the pathogenesis of inflammatory bowel disease.

Papadakis KA, Targan SR.

Division of Gastroenterology, Cedars-Sinai Medical Center, University of California, Los Angeles 90048, USA.

Annu Rev Med 2000;51:289-98 Abstract quote

Recent advances in the drug treatment of inflammatory bowel disease (IBD) have paralleled our understanding of the pathophysiology of ulcerative colitis and Crohn's disease.

Several proinflammatory and immune-regulatory cytokines are upregulated in the mucosa of patients with IBD, and differences and similarities in the cytokine profiles of ulcerative colitis and Crohn's disease have been elucidated. Several clinical trials involving a chimeric anti-TNF-alpha (tumor necrosis factor-alpha) antibody have shown marked clinical benefit in the majority of patients with Crohn's disease, verifying the importance of TNF-alpha in the pathogenesis of Crohn's disease.

In preliminary studies, treatment with recombinant human interleukin-10 has been beneficial in Crohn's disease but not in ulcerative colitis.

Future treatment of IBD may include combination or sequential cytokine and anticytokine administration in defined groups of patients based on their mucosal cytokine profiles.

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Comparative Studies of the Colonic In Situ Expression of Intercellular Adhesion Molecules (ICAM-1, -2, and -3), 2 Integrins (LFA-1, Mac-1, and p150,95), and PECAM-1 in Ulcerative Colitis and Crohn's Disease

Ben Vainer, M.D.; Ole Haagen Nielsen, M.D., D.M.Sc.; Thomas Horn, M.D., D.M.Sc.

From the Department of Medicine M (B.V., O.H.N.), Division of Gastroenterology, Glostrup Hospital; and the Department of Pathology (T.H.), Herlev Hospital, University of Copenhagen, Denmark.

Am J Surg Pathol 2000;24:1115-1124 Abstract quote

A dysregulated local immune defense with a constant influx of leukocytes provides a basis for continuous intestinal inflammation in ulcerative colitis (UC) and Crohn's disease (CD). Cell adhesion molecules are pivotal for the migration of leukocytes from the circulation toward the colonic epithelium.

A study quantifying the cells expressing intercellular adhesion molecules (ICAMs), 2 integrins, and platelet–endothelial cell adhesion molecule-1 (PECAM-1) in the colon was performed to illustrate the leukocyte migration pathway in inflammatory bowel disease.

Serial colonic sections (10 UC, 10 CD, and 10 controls) were stained immunohistochemically for ICAM-1, ICAM-2, ICAM-3, CD11a, CD11b, CD18, and PECAM-1. Cell adhesion molecule expression was evaluated quantitatively with reference to topographic localization. In UC, polymorphonuclear leukocytes (PMNs) in contact with the crypt epithelium and in crypt abscesses expressed CD11b. CD tissue was characterized by CD11a-, CD11c-, and ICAM-1-expressing cells. ICAM-1 was detected on endothelial cells, leukocytes, and apical parts of epithelial membranes, whereas ICAM-2 was expressed on basal epithelial membranes. Most infiltrating leukocytes expressed ICAM-3, whereas perivascular mononuclear cells expressed PECAM-1. Interestingly, the epithelial basement membrane in UC stained for CD18.

In conclusion, CD11b, CD18, and ICAM-2 seem to be important for PMN transepithelial migration in UC, whereas CD11a, CD11c, ICAM-1, and ICAM-3 seem central in leukocyte locomotion and aggregation in CD. Differentiated upregulation of cell adhesion molecules is suggested to be essential for the diversities between UC and CD.

MYCOBACTERIUM

Absence of Mycobacterium avium subsp. paratuberculosis in the microdissected granulomas of Crohn's disease.

Baksh FK, Finkelstein SD, Ariyanayagam-Baksh SM, Swalsky PA, Klein EC, Dunn JC.

1Department of Pathology, Lancaster General Hospital, Lancaster, PA, USA

Mod Pathol. 2004 Oct;17(10):1289-94. Abstract quote

The etiology of Crohn's disease remains unknown with inflammatory, infectious, and/or genetic causes suspected. Granulomatous inflammation is a characteristic feature of the disorder, resembling the tissue response to mycobacterium. Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent in Johne's disease, a chronic ulcerative intestinal condition in cattle, and has been implicated as a likely candidate.

We carefully microdissected the granulomas from the paraffin-embedded resection specimens of 18 patients with well-established Crohn's disease. The DNA obtained was PCR amplified for the IS900 and IS1311 repeat elements of MAP, PCR product size maintained at 101 and 124 base pairs, respectively. Archival tissue from bovine Johne's disease was used as a positive control. MAP-specific DNA, confirmed by sequencing and comparison with prototype strain sequence, was appropriately amplified from the positive control.

None of the Crohn's disease cases yielded a positive amplification product, failing to support a role for the organism in the pathogenesis of this illness.

NOD2 GENE

The Nod2 gene in Crohn's disease: implications for future research into the genetics and immunology of Crohn's disease.

Cho JH.

Department of Medicine (GI), University of Chicago Hospitals, Illinois 60637, USA.

Inflamm Bowel Dis 2001 Aug;7(3):271-5 Abstract quote

The association of the Nod2 gene on chromosome 16 with increased susceptibility to Crohn's disease holds the promise of catalyzing fundamental genetic and therapeutic advances.

Coding region variants in the leucine-rich repeat region of Nod2 may affect host interactions with bacterial lipopolysaccharide. Genetic differences in pattern-recognition proteins (such as Nod2) of the innate immune system represent an increasingly important paradigm for understanding host-environment interactions. The central problem for complex disease gene identification through genome-wide searches has been that of locus heterogeneity; it is hoped that this heterogeneity will recede with the identification of Nod2, as the first pieces of a puzzle accelerate placement of subsequent pieces.

The potential for genetic approaches to positively impact the treatment of Crohn's disease and ulcerative colitis is unparalleled among complex, multigenic disorders

YERSINIA

Pathogenic yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn's disease.

Lamps LW, Madhusudhan KT, Havens JM, Greenson JK, Bronner MP, Chiles MC, Dean PJ, Scott MA.

Am J Surg Pathol 2003 Feb;27(2):220-7 Abstract quote
Previously, we detected pathogenic (invasive) DNA in the appendices of two patients who later developed Crohn's disease (CD).

This subsequent investigation is the first to evaluate a series of specimens from CD patients for the presence of pathogenic DNA. A total of 54 intestinal resection specimens from 52 patients with confirmed CD were evaluated.

Lesional tissue was tested by polymerase chain reaction analysis for the presence of genes occurring only in pathogenic Primer pairs are specific for each species, with no known cross reactions with other bacteria. Forty normal bowel specimens, 30 cases of acute appendicitis, and 50 cases of various active colitides served as disease controls. Medical records were reviewed following polymerase chain reaction and histologic evaluation. A total of 17 of 54 resections (31%) contained DNA by polymerase chain reaction. Mesenteric lymph nodes were also positive in eight of these cases.

All controls were negative. -positive patients had carried the diagnosis of CD for a median of 10 years before resection (range 1 month to 40 years).

We report the first documentation of DNA in a series of CD cases. Further studies are needed, including serial study, over time, of -positive CD patients, as well as prospective studies of newly diagnosed CD patients for evidence of infection. Like previous studies associating infectious organisms with CD, much work remains to elucidate whether the presence of DNA is an epiphenomenon or actually a factor in the pathogenesis of CD.

LABORATORY/ RADIOLOGIC/ OTHER TESTS CHARACTERIZATION

Barium enema-radiology

String sign-characteristic narrowing of the small bowel lumen

Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup.

Vasiliauskas EA, Plevy SE, Landers CJ, Binder SW, Ferguson DM, Yang H, Rotter JI, Vidrich A, Targan SR.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Gastroenterology 1996 Jun;110(6):1810-9 Abstract quote

BACKGROUND & AIMS: Antineutrophil cytoplasmic antibodies (ANCA) have been consistently detected in a subgroup of patients with Crohn's disease (CD). This study was designed to determine whether serum ANCA expression in patients with CD characterizes an identifiable clinical subgroup.

METHODS: The study population consisted of 69 consecutive patients with an established diagnosis of CD as determined by a combination of characteristic clinical, radiographic, endoscopic, and histopathologic criteria. Sera from the patients were analyzed for the presence of ANCAs using the fixed neutrophil enzyme-linked immunosorbent assay (ELISA) assay. Perinuclear ANCA (pANCA)-positive and cytoplasmic ANCA (cANCA)-positive results by ELISA were confirmed by indirect immunofluorescence staining. Clinical profiles of the ANCA-positive patients with CD were compared with those of patients with CD not expressing ANCA (ANCA-negative).

RESULTS: pANCA-positive patients with CD have endoscopically and/or histopathologically documented left-sided colitis and symptoms of left-sided colonic inflammation, clinically reflected by rectal bleeding and mucus discharge, urgency, and treatment with topical agents. One hundred percent of patients with CD expressing pANCA had "UC-like" features.

CONCLUSIONS: In patients with CD, serum pANCA expression characterizes a UC-like clinical phenotype. Stratification of CD by serum pANCA provides evidence of heterogeneity within CD and suggests a common intestinal mucosal inflammatory process among a definable subgroup of patients with CD and UC expressing this marker.

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Tumor necrosis factor-alpha in serum of patients with inflammatory bowel disease as measured by a highly sensitive immuno-PCR.

Komatsu M, Kobayashi D, Saito K, Furuya D, Yagihashi A, Araake H, Tsuji N, Sakamaki S, Niitsu Y, Watanabe N.

Division of Laboratory Diagnosis, Department of Clinical Laboratory Medicine, Sapporo Medical University, School of Medicine, South-I, West-16, Chuo-ku, Sapporo 060-8543, Japan.

Clin Chem 2001;47(7):1297-301 Abstract quote

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION The significance of serum concentrations of tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of inflammatory bowel disease (IBD) is uncertain. We measured TNF-alpha in serum from IBD patients by immuno-PCR to analyze the relationship between TNF-alpha and pathophysiologic state in IBD.

METHODS: Serum samples were collected from 54 healthy blood donors, 29 patients with ulcerative colitis (UC; 46 samples), and 7 patients with Crohn disease (CD; 8 samples). DNA label was generated by PCR amplification using biotinylated primer and was bound with streptavidin to biotinylated third antibody. TNF-alpha sandwiched by antibodies was detected by PCR amplification of the DNA label.

RESULTS: TNF-alpha could be measured in all samples. The median serum concentration in IBD patients overall was approximately 390-fold higher than in healthy donors (median increase, 380-fold for UC, 640-fold for CD). The median serum TNF-alpha concentration was 1.7-fold higher in the active stage of UC than in the inactive stage (P <0.05), and this difference could be detected in individual patients.

CONCLUSIONS: Sensitive measurement of serum TNF-alpha could provide an important pathophysiologic marker for the presence and activity of IBD.

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

Site of involvement

Small intestine alone 40%
Small and large intestine 30%
Colon alone 30%

GASTROINTESTINAL TRACT

Characteristic skip lesions with diseased segments of bowel interspersed with normal segments, leading to cobblestone mucosa

Mesenteric fat wraps around bowel forming creeping fat

Intestinal wall is thickened and rubbery with narrowing of the lumen

Aphthous ulcers, focal mucosal ulcers, in early disease, leading to linear ulcers

Numerous fissures and sinus tract formation

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Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn's disease.

Ruuska T, Vaajalahti P, Arajarvi P, Maki M.

Department of Clinical Medicine, University of Tampere, Finland.

J Pediatr Gastroenterol Nutr 1994 Aug;19(2):181-6 Abstract quote
Eighty-eight consecutive children with inflammatory bowel disease were studied, and upper gastrointestinal endoscopy was performed in 80 of them as one of the initial investigations before commencing medical or nutritional treatment.

Forty-one children were found to have Crohn's disease and 47, ulcerative colitis. Upper gastrointestinal endoscopy revealed pathology in 32 (80%) cases of Crohn's disease, esophagitis in 16, and esophageal ulcer in two, nonspecific gastritis in 22, duodenitis or duodenal ulcer in 18, and Helicobacter pylori infection in two cases. Granulomas were detected in 10 patients in the upper gastrointestinal tract: one esophageal, eight gastric, and three duodenal. Of the ulcerative colitis patients, seven had esophagitis, one had esophageal ulcer, 17 had nonspecific gastritis, two had gastric ulcers, two had duodenal ulcers, and five had H. pylori infection; altogether 30 (75%) yielded pathological findings. Radiological studies using barium meal revealed pathology in only eight of all inflammatory bowel disease cases. Symptoms at admission were not conclusive for definite diagnosis because 63% of patients with Crohn's disease had signs of colitis (such as diarrhea, bloody diarrhea) compared to 94% of ulcerative colitis patients.

Upper gastrointestinal endoscopy may be used to achieve a specific diagnosis, thus being helpful when planning treatment. Also a considerable incidence of nonspecific gastritis, duodenitis, and esophagitis with or without concomitant H. pylori infection may be anticipated in children suffering from both ulcerative colitis and Crohn's disease.

EXTRAGASTROINTESTINAL

EYE
Uveitis

JOINTS
Migratory polyarthritis
Sacroiliitis
Ankylosing spondylitis

LIVER
Hepatic sclerosing cholangitis

Noninfectious lung pathology in patients with Crohn's disease.

Casey MB, Tazelaar HD, Myers JL, Hunninghake GW, Kakar S, Kalra SX, Ashton R, Colby TV.

Am J Surg Pathol 2003 Feb;27(2):213-9 Abstract quote
Lung involvement in Crohn's disease is not well characterized. We reviewed our experience with 11 lung biopsies (seven wedge and four transbronchial) from patients with Crohn's disease to study this association further. Negative cultures, special stains for organisms Gomori-methenamine-silver [GMS], acid fast), and polymerase chain reaction for (four cases) were required for inclusion. The group included five women and six men with a mean age of 47 years (range 13-84 years).

A diagnosis of Crohn's disease preceded the lung disease in nine patients. In two patients the diagnosis of Crohn's disease followed the diagnosis of their pulmonary disease 1 and 15 months later. Radiologically, eight patients had diffuse infiltrates, two had bilateral nodular infiltrates, and one had a mass. Chronic bronchiolitis with nonnecrotizing granulomatous inflammation was present in four patients, one of whom was taking mesalamine. Two patients had an acute bronchiolitis associated with a neutrophil-rich bronchopneumonia with suppuration and vague granulomatous features. One patient on mesalamine had cellular interstitial pneumonia with rare giant cells. Four patients demonstrated organizing pneumonia with focal granulomatous features, two of whom were taking mesalamine, and one of these two responded to infliximab (anti-tumor necrosis factor) monoclonal antibody therapy.

Noninfectious pulmonary disease in patients with Crohn's disease has variable histologic appearances, including granulomatous inflammation and airway-centered disease resembling that seen in patients with ulcerative colitis. Drugs may contribute to pulmonary disease in some patients.

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION
Site of involvement Small intestine alone 40%
Small and large intestine 30%
Colon alone 30%
GASTROINTESTINAL TRACT Characteristic skip lesions with diseased segments of bowel interspersed with normal segments, leading to cobblestone mucosa

Mesenteric fat wraps around bowel forming creeping fat

Intestinal wall is thickened and rubbery with narrowing of the lumen

Aphthous ulcers, focal mucosal ulcers, in early disease, leading to linear ulcers

Numerous fissures and sinus tract formation

Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn's disease.

Ruuska T, Vaajalahti P, Arajarvi P, Maki M.

Department of Clinical Medicine, University of Tampere, Finland.

J Pediatr Gastroenterol Nutr 1994 Aug;19(2):181-6 Abstract quote
Eighty-eight consecutive children with inflammatory bowel disease were studied, and upper gastrointestinal endoscopy was performed in 80 of them as one of the initial investigations before commencing medical or nutritional treatment.

Forty-one children were found to have Crohn's disease and 47, ulcerative colitis. Upper gastrointestinal endoscopy revealed pathology in 32 (80%) cases of Crohn's disease, esophagitis in 16, and esophageal ulcer in two, nonspecific gastritis in 22, duodenitis or duodenal ulcer in 18, and Helicobacter pylori infection in two cases. Granulomas were detected in 10 patients in the upper gastrointestinal tract: one esophageal, eight gastric, and three duodenal. Of the ulcerative colitis patients, seven had esophagitis, one had esophageal ulcer, 17 had nonspecific gastritis, two had gastric ulcers, two had duodenal ulcers, and five had H. pylori infection; altogether 30 (75%) yielded pathological findings. Radiological studies using barium meal revealed pathology in only eight of all inflammatory bowel disease cases. Symptoms at admission were not conclusive for definite diagnosis because 63% of patients with Crohn's disease had signs of colitis (such as diarrhea, bloody diarrhea) compared to 94% of ulcerative colitis patients.

Upper gastrointestinal endoscopy may be used to achieve a specific diagnosis, thus being helpful when planning treatment. Also a considerable incidence of nonspecific gastritis, duodenitis, and esophagitis with or without concomitant H. pylori infection may be anticipated in children suffering from both ulcerative colitis and Crohn's disease.

EXTRAGASTROINTESTINAL
EYE
Uveitis
JOINTS
Migratory polyarthritis
Sacroiliitis
Ankylosing spondylitis
LIVER
Hepatic sclerosing cholangitis
LUNGS

Noninfectious lung pathology in patients with Crohn's disease.

Casey MB, Tazelaar HD, Myers JL, Hunninghake GW, Kakar S, Kalra SX, Ashton R, Colby TV.


Am J Surg Pathol 2003 Feb;27(2):213-9 Abstract quote
Lung involvement in Crohn's disease is not well characterized. We reviewed our experience with 11 lung biopsies (seven wedge and four transbronchial) from patients with Crohn's disease to study this association further. Negative cultures, special stains for organisms Gomori-methenamine-silver [GMS], acid fast), and polymerase chain reaction for (four cases) were required for inclusion. The group included five women and six men with a mean age of 47 years (range 13-84 years).

A diagnosis of Crohn's disease preceded the lung disease in nine patients. In two patients the diagnosis of Crohn's disease followed the diagnosis of their pulmonary disease 1 and 15 months later. Radiologically, eight patients had diffuse infiltrates, two had bilateral nodular infiltrates, and one had a mass. Chronic bronchiolitis with nonnecrotizing granulomatous inflammation was present in four patients, one of whom was taking mesalamine. Two patients had an acute bronchiolitis associated with a neutrophil-rich bronchopneumonia with suppuration and vague granulomatous features. One patient on mesalamine had cellular interstitial pneumonia with rare giant cells. Four patients demonstrated organizing pneumonia with focal granulomatous features, two of whom were taking mesalamine, and one of these two responded to infliximab (anti-tumor necrosis factor) monoclonal antibody therapy.

Noninfectious pulmonary disease in patients with Crohn's disease has variable histologic appearances, including granulomatous inflammation and airway-centered disease resembling that seen in patients with ulcerative colitis. Drugs may contribute to pulmonary disease in some patients.

SKIN

J Am Acad Dermatol 1992;26(part 2):371-383
Usually affects lower legs
Trunk
Groin
Axilla
Face, rarely

Genital-cutaneous

Am J Dermatopathol 2000;22:443-446
Two patients with active Crohn's disease, one presented with erythematous nontender swelling of the scrotum and the other presenting with erythematous nontender swelling of the penis

Biopsy showed mixed chronic inflammation with characteristic sarcoidal granulomas but also areas of cystic cavities within the collagen, unassociated with inflammation

Genital cutaneous Crohn's may be the most common presentation in younger persons

Erythema nodosum

Clubbing of the fingertips

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Granulomatous lymphangitis of the scrotum and penis Report of a case and review of the literature of genital swelling with sarcoidal granulomatous inflammation

Michael J. Murphy1, Barry Kogan2 and J. Andrew Carlson3 1

Department of Dermatology, University of Connecticut Health Center, Farmington, Connecticut, USA,2 Division of Urology, Albany Medical College, Albany, New York, USA,3 Divisions of Dermatology and Dermatopathology, Albany Medical College, Albany, New York, USA

Journal of Cutaneous Pathology 2001;28 (8), 419-424 Abstract quote

Background: Acquired lymphedema of the genitalia is a rare childhood presentation and is more common in elderly individuals secondary to pelvic/abdomenal malignancy or its therapy or worldwide due to filariasis.

Objective: Herein, we report a case of a healthy 11-year-old boy who presented with a 1-year history of chronic, asymptomatic scrotal and penile swelling.

Biopsy revealed edema, lymphangiectases and peri- and intralymphatic sarcoidal type granulomas. This histologic pattern of granulomatous lymphangitis is most commonly associated with orofacial granulomatosis (granulomatous cheilitis and Melkersson-Rosenthal syndrome) and Crohn’s disease. Treatment with topical steroids and physical support has resulted in marked improvement. No systemic disease (Crohn’s disease) is evident 1 year later. Literature review revealed 44 cases of genital lymphedema with non-infectious granulomas. The majority of these young patients had Crohn’s disease, frequently with anal involvement and a minority, both with and without Crohn’s disease, had orofacial granulomatosis.

Conclusions: Granulomatous lymphangitis should be considered in the differential diagnosis of chronic idiopathic swelling of the genitalia, particularly in younger individuals. Further clinical examination, additional laboratory studies and close follow-up for co-existing or subsequent development of Crohn’s disease should be performed. The overlap between granulomatous lymphangitis of the genitalia, Crohn’s disease and orofacial granulomatosis suggest that granulomatous lymphangitis of the genitalia may represent a forme fruste of Crohn’s disease.

HISTOLOGICAL TYPES

CHARACTERIZATION

GASTROINTESTINAL TRACT

Transmural involvement with non-caseating granulomas in about 50% of cases and patchy skip lesions, lymphoid aggregates throughout bowel wall

Mucosa may show scattered crypt abscesses

Architectural distortion with progressive atrophy, pyloric metaplasia, and Paneth cell metaplasia

Ulceration

VARIANTS

DYSPLASIA

Hyperplastic-like mucosal change in Crohn's disease: an unusual form of dysplasia?

Kilgore SP, Sigel JE, Goldblum JR.

Department of Anatomic Pathology, Cleveland Clinic Foundation, Ohio 44195, USA

Mod Pathol 2000 Jul;13(7):797-801 Abstract quote

Patients with Crohn's disease are at increased risk of developing intestinal adenocarcinoma. Dysplasia is both a marker and a precursor of adenocarcinoma in this setting. In a review of our cases of Crohn's-related adenocarcinoma, we noted a peculiar hyperplastic-like mucosal change (HPC) in mucosa both adjacent to and distant from the adenocarcinoma in some cases. However, the significance of this change is unknown.

We evaluated 30 cases of Crohn's-related adenocarcinoma and 30 age- and site-matched resection specimens with Crohn's disease without adenocarcinoma to determine the prevalence of this mucosal alteration in these groups. HPC was recognized by a diffuse expanse of flat mucosa with an architecture resembling that seen in colorectal hyperplastic polyps and composed of cells with cytologically bland basal nuclei and apical cytoplasmic mucin distention. The relationship of the HPC to the adenocarcinoma was noted in the Crohn's-related adenocarcinoma cases.

An immunohistochemical stain for p53 (antibody DO7) was performed on all cases with HPC in both groups. HPC was identified in 10 of 30 (33%) cases of Crohn's-related adenocarcinoma compared with 3 of 30 (10%) cases in the control group (P = .03). In the 10 cases of Crohn's-related adenocarcinoma with HPC, this alteration was found adjacent to the adenocarcinoma in 3 cases, distant to the adenocarcinoma in 5 cases, and both adjacent to and distal from the adenocarcinoma in 2 cases. In two specimens, HPC was seen immediately adjacent to adenocarcinoma in the absence of adjacent dysplasia. p53 immunoreactivity was noted in HPC in 5 of 10 (50%) Crohn's-related adenocarcinomas.In contrast, p53 immunoreactivity was not seen in HPC in the three control cases with this mucosal alteration.

In conclusion, HPC is found significantly more commonly in mucosa both adjacent to and distant from Crohn's-related adenocarcinoma when compared with age- and site-matched controls. In addition, p53 immunoreactivity is more commonly seen in HPC in cases of Crohn's-related adenocarcinoma compared with controls. These data suggest that this mucosal alteration may, in some cases, represent an unusual

FOCALLY ENHANCED GASTRITIS

The Clinical Significance of Focally Enhanced Gastritis.

Xin W, Greenson JK.

Department of Pathology, University of Michigan Health System, Ann Arbor, MI. Am J Surg Pathol. 2004 Oct;28(10):1347-1351 Abstract quote

Focally enhanced gastritis (FEG) is typified by small collections of lymphocytes and histiocytes surrounding a small group of foveolae or gastric glands, often with infiltrates of neutrophils. Several studies have found that FEG is commonly seen in Crohn’s disease patients with a positive predictive value of 94%. Additional studies have found that FEG is present in up to 20% of pediatric ulcerative colitis patients, suggesting that FEG is a marker for inflammatory bowel disease (IBD) in general.

We reviewed all gastric biopsies from a single calendar year (1999) to study the incidence of FEG and its relationship to IBD. A total of 34 cases of FEG were found among 971 gastric biopsies from 927 patients. Only 4 FEG patients were found to have IBD (2 Crohn’s, 1 ulcerative colitis and 1 chronic colitis, type indeterminate, 11.8%, positive predictive value of 5.9%). Five FEG patients were status post bone marrow transplantation (14.7%). There were no other clinical correlations and gastric histopathology did not predict which patients with FEG had IBD.

We conclude that FEG is not a common histologic finding in our patient population and that the positive predictive value of this finding is much too low to be thought of as a specific marker for IBD. An isolated biopsy diagnosis of FEG should not be interpreted as being suggestive of Crohn’s disease.

DIFFERENTIAL DIAGNOSIS

CHARACTERIZATION

GENERAL

Biopsy diagnosis of colitis: possibilities and pitfalls.

Tsang P, Rotterdam H.

Department of Pathology, Cornell University Medical College, New York, New York, USA

Am J Surg Pathol 1999 Apr;23(4):423-30 Abstract quote
The histopathologic diagnosis of inflammation is common in colorectal biopsies but is of limited value, if not further specified.

We reviewed 280 endoscopic colorectal biopsy specimens for nonneoplastic disease from 100 consecutive patients in order to assess (a) the frequency of inflammation in excess of the physiologic infiltrate, (b) the frequency with which the cause of the inflammation could be specified, and (c) the interobserver variability in diagnosing inflammation.

Based on the reviewers' impression, each case was classified into one of three categories: (I) normal or nonspecific change, (II) nonspecific inflammation, and (III) inflammation suggestive or diagnostic of specific cause. Inflammation was diagnosed in 68% of cases.

The majority of these cases (75%) showed features typically associated with specific types of colitis, including Crohn's disease (n = 16), ulcerative colitis (n = 13), inflammatory bowel disease not otherwise specified (n = 5), infectious colitis (n = 6), ischemic colitis (n = 4), solitary rectal ulcer syndrome (n = 3), radiation colitis (n = 2), and lymphocytic colitis (n = 2). Interobserver variability was greatest in biopsy specimens interpreted by the reviewers as normal or showing nonspecific changes, most of which had been diagnosed as mild inflammation by the original pathologists. Etiologic classification of colitis was lacking in 59% of the cases interpreted by the reviewers as suggestive or diagnostic of a specific cause.

We conclude that (a) the majority of colorectal biopsy specimens from patients with nonneoplastic disease in this series show inflammation, (b) the majority of such cases allow a specific cause of colitis to be suggested or firmly diagnosed, and (c) pathologists tend to overdiagnose the physiologic inflammatory infiltrate as evidence of colitis and underdiagnose specific etiologic types of colitis.

APPENDICITIS

Histopathology of interval (delayed) appendectomy specimens: strong association with granulomatous and xanthogranulomatous appendicitis.

Guo G, Greenson JK.

Am J Surg Pathol. 2003 Aug;27(8):1147-51. Abstract quote
Patients who present with a ruptured acute appendicitis are often treated with antibiotic therapy and drainage followed by a delayed or interval appendectomy. We noticed interval appendectomy specimens with granulomatous inflammation and postulated that interval appendectomy may lead to granulomatous appendicitis.

To test this hypothesis, we reviewed the histopathology of all interval appendectomy specimens within a 4-year period and compared them with a control group of patients who had acute appendicitis and underwent routine acute appendectomy. All slides were randomized and reviewed blindly to assess the inflammatory patterns, with special attention given to the presence of granulomas and other Crohn-like features.

Twenty-two cases of interval appendectomy were found. The interval between symptom onset and appendectomy ranged from 30 to 95 days with a mean of 58 days, whereas all 44 control patients had surgery within 72 hours of symptoms onset. Thirteen (59.1%) of the 22 interval appendectomy cases contained granulomas compared with only 3 of 44 controls (P < 0.0001). Eight (36.4%) of the interval appendectomy cases had xanthogranulomatous inflammation compared with none in the acute appendicitis group (P < 0.0001). A Crohn-like appearance was seen in 11 (50.0%) of the interval appendectomy cases and 1 of the controls (P < 0.0001). Follow-up data were available in 8 of 11 cases with Crohn-like features; none developed Crohn disease during an average follow-up period of 23 months.

Delayed or interval appendectomy specimens often have a characteristic inflammatory pattern that includes granulomas, xanthogranulomatous inflammation, mural fibrosis/thickening, and transmural chronic inflammation. Without the appropriate clinical history, these changes may be misinterpreted as Crohn disease.

DIVERTICULITIS

Crohn's Colitis-Like Changes in Sigmoid Diverticulitis Specimens Is Usually an Idiosyncratic Inflammatory Response to the Diverticulosis Rather Than Crohn's Colitis

Neal S. Goldstein, M.D.; Carmen Leon-Armin, B.S. (Pathology Assistant); Anju Mani, M.D.

From the Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI, U.S.A.

Am J Surg Pathol 2000;24:668-675 Abstract quote

The clinical outcome and optimum classification of patients who have sigmoid resection specimens that show the histologic features of Crohn's disease (CD) and diverticulitis is not well defined. Historically, these patients were considered to have coexistent diseases, but recent studies have suggested that the CD-like changes are part of the inflammatory reaction of the diverticulitis. Sorting out these issues has been complicated by the lack of distinction between patients with and without CD in other regions of the bowel, short clinical follow-up periods, and small numbers of patients.

We report on the clinical outcome and histology of 29 patients who had sigmoid resection specimens with diverticulitis and CD-like changes. Of the 25 patients who had no prior or concurrent CD at the time of surgery, 23 remained free of CD during the follow-up period (median, 6.0 yrs) and two developed CD in other regions of the bowel. All four patients with CD prior to their sigmoid resection continued to have active CD postoperatively. There were no histologic features of the sigmoid resection specimens that could be associated with the outcome of the patient.

These results suggest that CD-like changes within the sigmoid resection specimen are an idiosyncratic inflammatory response to the diverticulosis rather than coexistent CD in the overwhelming majority of patients who do not have prior or concurrent CD at the time of sigmoid resection. Pathologists should be wary about making the diagnosis of sigmoid CD in the context of diverticulitis unless there is CD in other parts of the bowel.

FOCAL ACUTE COLITIS

The clinical significance of focal active colitis in pediatric patients.

Xin W, Brown PI, Greenson JK.

Am J Surg Pathol. 2003 Aug;27(8):1134-8. Abstract quote
The clinical significance of focal neutrophilic infiltrates in crypt epithelium in colorectal biopsies or focal active colitis has been studied in adult populations, but little is known about this entity in children. The incidence of Crohn's disease in adult patients presenting with focal active colitis has varied between 0% and 13% in previous studies, whereas the incidence of infectious-type colitis has been reported to be nearly 50%.

We reviewed 31 cases of focal active colitis diagnosed in pediatric patients without a history of inflammatory bowel disease between 1989 and 2000. Pathologic variables studied included number and location of inflamed crypts and distribution and character of lamina propria inflammation. Clinical follow-up was obtained from patient charts. Two patients were lost to follow-up. Follow-up on the remaining 29 patients ranged from 4 months to 7 years with a mean of 4.2 years. Eight patients (27.6%) developed Crohn's disease. Nine patients (31%) appeared to have acute infectious-type colitis, one with C. difficile. Eight patients (27.6%) had focal active colitis, which did not correlate with their symptoms or ultimate clinical diagnosis. These were termed idiopathic focal active colitis. Two patients were found to have allergic colitis, one had ulcerative colitis, and one had Hirschsprung's disease.

Pediatric patients with focal active colitis have a much higher incidence of Crohn's disease than adults with same entity. Hence, it is important to document the presence of focal active colitis in pediatric patients.

LYMPHOCYTIC AND COLLAGENOUS COLITIS

Focal lymphocytic colitis and collagenous colitis: patterns of Crohn's colitis?

Goldstein NS, Gyorfi T.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.

Am J Surg Pathol 1999 Sep;23(9):1075-81 Abstract quote

The morphologic findings in mildly active colonic Crohn's disease (CD) include crypt disarray, patchy edema, and small lymphoid aggregates with neutrophils, sometimes associated with aphthous ulcers.

We describe four patients with CD whose colonic biopsies focally showed a lymphocytic colitis morphology, and one patient with CD whose biopsies showed a collagenous colitis morphology.

The lymphocytic and collagenous colitis patterns of injury preceded the eventual clinical pathologic diagnosis of CD in four patients. Colonoscopic abnormalities were found in four patients. The lymphocytic colitis pattern was focal, involving some biopsy fragments, whereas other biopsy fragments were normal or had minimal nonspecific inflammation. In one patient, moderate numbers of neutrophils were admixed with the lymphoplasmacytic infiltrates. The presence of colonoscopic abnormalities, focal changes, and moderate admixed neutrophils could assist in the distinction from lymphocytic or collagenous colitis, both of which are colonoscopically normal, usually diffuse, and devoid of, or contain only a sparse number of, neutrophils.

A limited number of biopsy fragments may be incorrectly interpreted as lymphocytic or collagenous colitis. The temporal relationships suggest that these morphologic patterns precede typical active CD.

FOCALLY ENHANCED GASTRITIS

The Clinical Significance of Focally Enhanced Gastritis.

Xin W, Greenson JK.

Department of Pathology, University of Michigan Health System, Ann Arbor, MI. Am J Surg Pathol. 2004 Oct;28(10):1347-1351 Abstract quote

Focally enhanced gastritis (FEG) is typified by small collections of lymphocytes and histiocytes surrounding a small group of foveolae or gastric glands, often with infiltrates of neutrophils. Several studies have found that FEG is commonly seen in Crohn’s disease patients with a positive predictive value of 94%. Additional studies have found that FEG is present in up to 20% of pediatric ulcerative colitis patients, suggesting that FEG is a marker for inflammatory bowel disease (IBD) in general.

We reviewed all gastric biopsies from a single calendar year (1999) to study the incidence of FEG and its relationship to IBD. A total of 34 cases of FEG were found among 971 gastric biopsies from 927 patients. Only 4 FEG patients were found to have IBD (2 Crohn’s, 1 ulcerative colitis and 1 chronic colitis, type indeterminate, 11.8%, positive predictive value of 5.9%). Five FEG patients were status post bone marrow transplantation (14.7%). There were no other clinical correlations and gastric histopathology did not predict which patients with FEG had IBD.

We conclude that FEG is not a common histologic finding in our patient population and that the positive predictive value of this finding is much too low to be thought of as a specific marker for IBD. An isolated biopsy diagnosis of FEG should not be interpreted as being suggestive of Crohn’s disease.

DIFFERENTIAL DIAGNOSIS

CHARACTERIZATION

GENERAL

Biopsy diagnosis of colitis: possibilities and pitfalls.

Tsang P, Rotterdam H.

Department of Pathology, Cornell University Medical College, New York, New York, USA

Am J Surg Pathol 1999 Apr;23(4):423-30 Abstract quote
The histopathologic diagnosis of inflammation is common in colorectal biopsies but is of limited value, if not further specified.

We reviewed 280 endoscopic colorectal biopsy specimens for nonneoplastic disease from 100 consecutive patients in order to assess (a) the frequency of inflammation in excess of the physiologic infiltrate, (b) the frequency with which the cause of the inflammation could be specified, and (c) the interobserver variability in diagnosing inflammation.

Based on the reviewers' impression, each case was classified into one of three categories: (I) normal or nonspecific change, (II) nonspecific inflammation, and (III) inflammation suggestive or diagnostic of specific cause. Inflammation was diagnosed in 68% of cases.

The majority of these cases (75%) showed features typically associated with specific types of colitis, including Crohn's disease (n = 16), ulcerative colitis (n = 13), inflammatory bowel disease not otherwise specified (n = 5), infectious colitis (n = 6), ischemic colitis (n = 4), solitary rectal ulcer syndrome (n = 3), radiation colitis (n = 2), and lymphocytic colitis (n = 2). Interobserver variability was greatest in biopsy specimens interpreted by the reviewers as normal or showing nonspecific changes, most of which had been diagnosed as mild inflammation by the original pathologists. Etiologic classification of colitis was lacking in 59% of the cases interpreted by the reviewers as suggestive or diagnostic of a specific cause.

We conclude that (a) the majority of colorectal biopsy specimens from patients with nonneoplastic disease in this series show inflammation, (b) the majority of such cases allow a specific cause of colitis to be suggested or firmly diagnosed, and (c) pathologists tend to overdiagnose the physiologic inflammatory infiltrate as evidence of colitis and underdiagnose specific etiologic types of colitis.

APPENDICITIS

Histopathology of interval (delayed) appendectomy specimens: strong association with granulomatous and xanthogranulomatous appendicitis.

Guo G, Greenson JK.

Am J Surg Pathol. 2003 Aug;27(8):1147-51. Abstract quote
Patients who present with a ruptured acute appendicitis are often treated with antibiotic therapy and drainage followed by a delayed or interval appendectomy. We noticed interval appendectomy specimens with granulomatous inflammation and postulated that interval appendectomy may lead to granulomatous appendicitis.

To test this hypothesis, we reviewed the histopathology of all interval appendectomy specimens within a 4-year period and compared them with a control group of patients who had acute appendicitis and underwent routine acute appendectomy. All slides were randomized and reviewed blindly to assess the inflammatory patterns, with special attention given to the presence of granulomas and other Crohn-like features.

Twenty-two cases of interval appendectomy were found. The interval between symptom onset and appendectomy ranged from 30 to 95 days with a mean of 58 days, whereas all 44 control patients had surgery within 72 hours of symptoms onset. Thirteen (59.1%) of the 22 interval appendectomy cases contained granulomas compared with only 3 of 44 controls (P < 0.0001). Eight (36.4%) of the interval appendectomy cases had xanthogranulomatous inflammation compared with none in the acute appendicitis group (P < 0.0001). A Crohn-like appearance was seen in 11 (50.0%) of the interval appendectomy cases and 1 of the controls (P < 0.0001). Follow-up data were available in 8 of 11 cases with Crohn-like features; none developed Crohn disease during an average follow-up period of 23 months.

Delayed or interval appendectomy specimens often have a characteristic inflammatory pattern that includes granulomas, xanthogranulomatous inflammation, mural fibrosis/thickening, and transmural chronic inflammation. Without the appropriate clinical history, these changes may be misinterpreted as Crohn disease.

DIVERTICULITIS

Crohn's Colitis-Like Changes in Sigmoid Diverticulitis Specimens Is Usually an Idiosyncratic Inflammatory Response to the Diverticulosis Rather Than Crohn's Colitis

Neal S. Goldstein, M.D.; Carmen Leon-Armin, B.S. (Pathology Assistant); Anju Mani, M.D.

From the Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI, U.S.A.

Am J Surg Pathol 2000;24:668-675 Abstract quote

The clinical outcome and optimum classification of patients who have sigmoid resection specimens that show the histologic features of Crohn's disease (CD) and diverticulitis is not well defined. Historically, these patients were considered to have coexistent diseases, but recent studies have suggested that the CD-like changes are part of the inflammatory reaction of the diverticulitis. Sorting out these issues has been complicated by the lack of distinction between patients with and without CD in other regions of the bowel, short clinical follow-up periods, and small numbers of patients.

We report on the clinical outcome and histology of 29 patients who had sigmoid resection specimens with diverticulitis and CD-like changes. Of the 25 patients who had no prior or concurrent CD at the time of surgery, 23 remained free of CD during the follow-up period (median, 6.0 yrs) and two developed CD in other regions of the bowel. All four patients with CD prior to their sigmoid resection continued to have active CD postoperatively. There were no histologic features of the sigmoid resection specimens that could be associated with the outcome of the patient.

These results suggest that CD-like changes within the sigmoid resection specimen are an idiosyncratic inflammatory response to the diverticulosis rather than coexistent CD in the overwhelming majority of patients who do not have prior or concurrent CD at the time of sigmoid resection. Pathologists should be wary about making the diagnosis of sigmoid CD in the context of diverticulitis unless there is CD in other parts of the bowel.

FOCAL ACUTE COLITIS

The clinical significance of focal active colitis in pediatric patients.

Xin W, Brown PI, Greenson JK.

Am J Surg Pathol. 2003 Aug;27(8):1134-8. Abstract quote
The clinical significance of focal neutrophilic infiltrates in crypt epithelium in colorectal biopsies or focal active colitis has been studied in adult populations, but little is known about this entity in children. The incidence of Crohn's disease in adult patients presenting with focal active colitis has varied between 0% and 13% in previous studies, whereas the incidence of infectious-type colitis has been reported to be nearly 50%.

We reviewed 31 cases of focal active colitis diagnosed in pediatric patients without a history of inflammatory bowel disease between 1989 and 2000. Pathologic variables studied included number and location of inflamed crypts and distribution and character of lamina propria inflammation. Clinical follow-up was obtained from patient charts. Two patients were lost to follow-up. Follow-up on the remaining 29 patients ranged from 4 months to 7 years with a mean of 4.2 years. Eight patients (27.6%) developed Crohn's disease. Nine patients (31%) appeared to have acute infectious-type colitis, one with C. difficile. Eight patients (27.6%) had focal active colitis, which did not correlate with their symptoms or ultimate clinical diagnosis. These were termed idiopathic focal active colitis. Two patients were found to have allergic colitis, one had ulcerative colitis, and one had Hirschsprung's disease.

Pediatric patients with focal active colitis have a much higher incidence of Crohn's disease than adults with same entity. Hence, it is important to document the presence of focal active colitis in pediatric patients.

LYMPHOCYTIC AND COLLAGENOUS COLITIS

Focal lymphocytic colitis and collagenous colitis: patterns of Crohn's colitis?

Goldstein NS, Gyorfi T.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.

Am J Surg Pathol 1999 Sep;23(9):1075-81 Abstract quote

The morphologic findings in mildly active colonic Crohn's disease (CD) include crypt disarray, patchy edema, and small lymphoid aggregates with neutrophils, sometimes associated with aphthous ulcers.

We describe four patients with CD whose colonic biopsies focally showed a lymphocytic colitis morphology, and one patient with CD whose biopsies showed a collagenous colitis morphology.

The lymphocytic and collagenous colitis patterns of injury preceded the eventual clinical pathologic diagnosis of CD in four patients. Colonoscopic abnormalities were found in four patients. The lymphocytic colitis pattern was focal, involving some biopsy fragments, whereas other biopsy fragments were normal or had minimal nonspecific inflammation. In one patient, moderate numbers of neutrophils were admixed with the lymphoplasmacytic infiltrates. The presence of colonoscopic abnormalities, focal changes, and moderate admixed neutrophils could assist in the distinction from lymphocytic or collagenous colitis, both of which are colonoscopically normal, usually diffuse, and devoid of, or contain only a sparse number of, neutrophils.

A limited number of biopsy fragments may be incorrectly interpreted as lymphocytic or collagenous colitis. The temporal relationships suggest that these morphologic patterns precede typical active CD.

--------------------------

Crohn's Disease

Crohn's disease causes inflammation in the small intestine. Crohn's disease usually occurs in the lower part of the small intestine, called the ileum, but it can affect any part of the digestive tract, from the mouth to the anus. The inflammation extends deep into the lining of the affected organ. The inflammation can cause pain and can make the intestines empty frequently, resulting in diarrhea.

Crohn's disease is an inflammatory bowel disease (IBD), the general name for diseases that cause inflammation in the intestines. Crohn's disease can be difficult to diagnose because its symptoms are similar to other intestinal disorders such as irritable bowel syndrome and to another type of IBD called ulcerative colitis. Ulcerative colitis causes inflammation and ulcers in the top layer of the lining of the large intestine.

Crohn's disease affects men and women equally and seems to run in some families. About 20 percent of people with Crohn's disease have a blood relative with some form of IBD, most often a brother or sister and sometimes a parent or child.

Crohn's disease may also be called ileitis or enteritis.

What causes Crohn's disease?

Theories about what causes Crohn's disease abound, but none has been proven. The most popular theory is that the body's immune system reacts to a virus or a bacterium by causing ongoing inflammation in the intestine.

People with Crohn's disease tend to have abnormalities of the immune system, but doctors do not know whether these abnormalities are a cause or result of the
patoco
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Clarithromycin therapy with Crohn's disease

Postby patoco » Fri Jul 06, 2007 11:58 pm

Open label trial of clarithromycin therapy in Japanese patients with Crohn's disease.

J Gastroenterol Hepatol. 2007 Jul

Inoue S, Nakase H, Matsuura M, Ueno S, Uza N, Kitamura H, Mikami S, Tamaki H, Kasahara K, Chiba T.
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background and Aim: The pathogenesis of Crohn's disease is unclear, but many studies suggest that luminal bacteria play an important role in chronic intestinal inflammation in patients with this condition.

Clarithromycin is a macrolide antibiotic with immunomodulatory activity.

The aim of this study was to evaluate the effect of clarithromycin therapy in Japanese patients with Crohn's disease.

Methods: Fourteen patients with active Crohn's disease (12 with ileocolonic, one with colonic, one with small bowel type) were treated with oral clarithromycin 200 mg twice daily for 4 weeks. Patients who showed a clinical response within 4 weeks continued the therapy for up to 24 weeks.

Four patients also received azathioprine. Clinical activity was assessed with the Crohn's Disease Activity Index (CDAI) at entry and at 4, 12, and 24 weeks after starting clarithromycin.

Results: The mean CDAI score at entry was 343.5. Within 4 weeks, eight (57.1%) of the 14 patients showed clinical improvement, and five (35.7%) of the eight patients achieved remission. All of those eight patients continued clarithromycin therapy after 4 weeks, and six (42.9%) were in clinical remission at 12 weeks. Of the 14 total patients, four (28.6%) continued clarithromycin for more than 24 weeks, and have remained in remission.

Patients who received azathioprine concomitantly had a better response to clarithromycin therapy. No severe side-effects were observed during the study period.

Conclusions: This open label study showed encouraging results of clarithromycin therapy in Japanese patients with active Crohn's disease.

http://www.blackwell-synergy.com/doi/ab ... 06.04533.x
patoco
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Oral interleukin-12/23 inhibitor for Crohn's disease

Postby patoco » Fri Jul 06, 2007 11:59 pm

A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease.

Inflamm Bowel Dis. 2006 Jul;

Burakoff R, Barish CF, Riff D, Pruitt R, Chey WY, Farraye FA, Shafran I, Katz S, Krone CL, Vander Vliet M, Stevens C, Sherman ML, Jacobson E, Bleday R.
Brigham & Women's Hospital, Boston, Massachusetts, USA.

BACKGROUND: Intestinal inflammation associated with Crohn's disease is characterized by a type 1 helper T cell response and elevated levels of interleukin (IL)-12. We report our clinical experience with a novel oral IL-12/IL-23 inhibitor (STA 5326) for the treatment of active Crohn's disease.

MATERIALS AND METHODS: We conducted an open-label, dose-escalating trial of the orally delivered small molecule immunomodulator STA 5326 in 73 patients with active Crohn's disease (Crohn's disease activity index [CDAI] 220-450, inclusive). Five cohorts of patients were treated for up to 4 weeks with 14 mg twice a day (bid), 35 mg daily (qd), 28 mg bid, 35 mg bid, or 70 mg qd. The endpoints of the study included safety and improvement in clinical activity measured by the CDAI and the Crohn's disease endoscopic index of severity.

RESULTS: STA 5326 was well tolerated. Reported adverse events were similar across dose cohorts. The most common (>15%) drug-related adverse events observed were dizziness, nausea, headache, and fatigue. Clinical activity at day 28/29 was observed at qd doses of 28 mg and above for the clinical endpoints of response and remission: 70 points or greater decrease in CDAI (range 42%-82% of patients); 100 points or greater decrease in CDAI (range 38%-64% of patients), and CDAI <150 (range 15%-36%).

CONCLUSIONS: Oral qd dosing of STA 5326 for 4 weeks was well tolerated in doses up to 70 mg qd in patients with active moderate to severe Crohn's disease. Clinical activity was observed at qd doses of 28 mg and above.

PMID: 16804392 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/sites/entre ... stractPlus
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Perianal Crohn's disease.

Postby patoco » Sat Jul 07, 2007 12:01 am

Perianal Crohn's disease.

Semin Pediatr Surg. 2007 Aug

Strong SA.
Departments of Colorectal Surgery and Pathobiology, Cleveland Clinic, Cleveland, Ohio.

Keywords: Perianal Crohn’s disease, Anal stenosis, Anal fissure, Anal fistula, Fistulotomy, Rectal mucosal advancement flap

Perianal Crohn's disease in children is a potentially debilitating condition that can precede or follow the intestinal disease component. The perianal abnormalities are varied and can include lesions of the perianal skin or anal canal, abscesses or fistulas, and malignancies. The appropriate management of these problems is predicated on a thorough evaluation of the perineum and anus as well as the remainder of the alimentary tract.

Therapy usually includes a combination of antibiotics, immunomodulators, and biologic agents as well as conservative operative procedures. The surgical options are intended to safely ameliorate disease-related symptoms without compromising function or continence.

http://www.sempedsurg.org/article/PIIS1 ... 1/abstract
patoco
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Perianal fistulas in Crohn's disease

Postby patoco » Sat Jul 07, 2007 12:09 am

Perianal Crohn's disease.

Semin Pediatr Surg. 2007 Aug

Strong SA.
Departments of Colorectal Surgery and Pathobiology, Cleveland Clinic, Cleveland, Ohio.

Keywords: Perianal Crohn’s disease, Anal stenosis, Anal fissure, Anal fistula, Fistulotomy, Rectal mucosal advancement flap

Perianal Crohn's disease in children is a potentially debilitating condition that can precede or follow the intestinal disease component. The perianal abnormalities are varied and can include lesions of the perianal skin or anal canal, abscesses or fistulas, and malignancies. The appropriate management of these problems is predicated on a thorough evaluation of the perineum and anus as well as the remainder of the alimentary tract. Therapy usually includes a combination of antibiotics, immunomodulators, and biologic agents as well as conservative operative procedures. The surgical options are intended to safely ameliorate disease-related symptoms without compromising function or continence.

http://www.sempedsurg.org/article/PIIS1 ... 1/abstract

........

Perianal fistulas in Crohn's disease: MRI diagnosis and surgical planning : MRI in fistulazing perianal Crohn's disease.

Abdom Imaging. 2007 Mar

Szurowska E, Wypych J, Izycka-Swieszewska E.
Department of Radiology Medical, University of Gdansk, Debinki St 7, 80-211, Gdansk, Poland, eszurowska@amg.gda.pl.

Crohn's disease is a chronic, transmural inflammatory process of the gastrointestinal tract. It often affects the colon with the perianal area. The most common intestinal manifestations include external and/or internal fistulas and abscesses.

Assessment of the activity of perianal fistulas in the course of Crohn's disease seems to be an important factor influencing therapeutic approach. Fistula's activity is evaluated by such methods as magnetic resonance imaging, anal ultrasound and examination under anaesthesia. Usefulness of imaging methods in the diagnosis of fistulas still remains to be defined.MRI is used to present a wide spectrum of perianal fistulazing Crohn's disease. Additionally, it is an important instrument revealing location, extent and severity of inflammation. It is also very helpful to detect clinically silent sepsis related to small, local inflammation.

The most common method used in MR imaging to assess topography of a fistula's track, is Parks' classification.Clinical indications to MRI may include follow-up studies of a diagnosed disease, classification of fistulas' subtypes in the course of Crohn's disease, determination of the extent of fistulas' tracts and spread of an inflammatory process what can guide surgical procedures.

http://www.springerlink.com/content/0173p84up4736225/

........

Treatment of Perianal Fistula and Abscess: Crohn's and Non-Crohn's.

Curr Treat Options Gastroenterol. 2007 Jun

Mardini HE, Schwartz DA.
David A. Schwartz, MD Director, Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, 1501 TVC, Nashville, TN 37232, USA. david.a.schwartz@Vanderbilt.edu.

The management of perianal abscesses and fistulas is relatively straightforward in most cases and based on a sound knowledge of the anatomy of the anorectum and adherence to established medical and surgical principles. Asymptomatic fistulas should not be treated, whereas abscesses require surgical drainage under general anesthesia. Fistula treatment includes drainage of any associated sepsis and eradication of the fistula track to prevent recurrence while preserving sphincter integrity. A small percentage of anal abscesses and fistulas are complex and very challenging to manage, particularly in conditions such as rectovaginal fistulas and abscesses and/or fistulas complicating Crohn's disease. Treatment strategies in these situations rely on an accurate clinical assessment of the degree of rectal inflammation and perianal pathology. Treatment should combine aggressive medical therapy (antibiotics, immunomodulators, and anti-tumor necrosis factor antibody treatment) and minimal surgical interventions. Patients with proctitis have a significantly lower healing rate and a significantly higher complication rate with aggressive surgical interventions.

http://www.treatment-options.com/cr_lin ... 0&page=211

........

Treatment of perianal fistulas in Crohn's disease by local injection of antibody to TNF-alpha accounts for a favourable clinical response in selected cases: a pilot study.

Scand J Gastroenterol. 2006 Sep

Asteria CR, Ficari F, Bagnoli S, Milla M, Tonelli F.
Department of Clinical Physiopathology, Surgery Unit, University of Florence, Italy. corrado.asteria@libero.it

OBJECTIVE: Intravenously administered infliximab, a monoclonal antibody directed against tumor necrosis factor-alpha, has been proven to be efficacious in the treatment of fistulas in patients with Crohn's disease. It has recently been suggested that local injections of infliximab might be beneficial as well. The aim of this study was to assess whether infliximab could play an effective role in the local treatment of perianal fistulas in Crohn's disease.

MATERIAL AND METHODS: Local infliximab injections were administered to 11 patients suffering from Crohn's disease complicated by perianal disease. Eligible subjects included Crohn's disease patients with single or multiple draining fistulas, regardless of status of luminal disease at baseline. Patients, however, were excluded from the study if they had perianal or rectal complications, such as abscesses or proctitis or if they had previously been treated with infliximab. Twenty-milligram doses of infliximab were injected along the fistula tract and around both orifices at baseline and then every 4 weeks for up to 16 weeks or until complete cessation of drainage. No further doses were administered to patients who did not respond after three injections. Efficacy was measured in terms of response (a reduction in fistula drainage of 50% or more) and remission (complete cessation of fistula drainage for at least 4 weeks). Time to loss of response and health-related quality of life were also evaluated.

RESULTS: Overall, 8/11 patients (72.7%) responded to the therapy and 4/11 (36.4%) reached remission, whereas 3/11 patients (27.2%) showed no response. Response or remission was very much dependent on the location of the fistulas, and time to loss of response was generally longer for patients who reached remission compared to patients in response. Changes in health-related quality of life, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), also reflected response or remission, with more marked improvements associated with remission. After a mean 10.5 months' follow-up (range 7-18 months), 6/11 patients (54.5%) are in response and 4/11 patients (36.4%) are in remission. No adverse events have been observed in this cohort of patients.

CONCLUSIONS: Local injections of infliximab along the fistula tract seem to be an effective and safe treatment of perianal fistulas in Crohn's disease. However, further controlled clinical investigations are warranted.

http://www.informaworld.com/smpp/conten ... 0600609941
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Surgical management of Crohn's colitis.

Postby patoco » Sat Jul 07, 2007 12:17 am

Surgical management of Crohn's colitis.

Semin Pediatr Surg. 2007 Aug

Moir CR.
Division of Pediatric Surgery, Mayo Clinic, Rochester, Minnesota.

Keywords: Crohn’s colitis, Segmental colectomy, Total colectomy, Ileorectal anastomosis, Ileal pouch anal anastomosis, Proctocolectomy

Crohn's disease in childhood is changing. The incidence is increasing, colonic disease is becoming more prevalent in younger children, and colon reconstruction is more acceptable. Genetic phenotypes are influencing decisions for surgery, and targeted immunotherapy has renewed hope for more durable remissions following less extensive resections. The tasks facing the surgeon evaluating a child with Crohn's colitis include confirming the specific diagnostic subtype and selecting the correct procedure. This chapter will review the unique aspects of pediatric Crohn's colitis and the increased complexity of surgical choice for this most challenging presentation. Recent success with less extensive surgery offers renewed hope for children with intractable colonic disease.

http://www.sempedsurg.org/article/PIIS1 ... X/abstract

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Surgical management of upper gastrointestinal and small bowel Crohn's disease.

Semin Pediatr Surg. 2007 Aug

Dolgin SE.
Department of Pediatric Surgery, Schneider Children’s Hospital, NS-LIJ Health System, New Hyde Park, New York.

Keywords: Pediatric Crohn’s disease, Surgery, Foregut, Duodenum

Burill Crohn's convincing description of the disease that now carries his name conceived of the illness as arising exclusively from the terminal ileum, involving other sites only secondarily. As a result, he took the condition to be curable by an adequate operative resection. The current concept is that Crohn's disease may affect any segment of the gastrointestinal tract.

The practical implication of this change in thinking is the need to conserve bowel when weighing medical and surgical options for each child. Operations should be used to treat complications of the disease. Absolute indications for the surgery are uncommon and include perforation, bleeding, and refractory obstruction. The margins of resection need only include a short amount of grossly normal intestine. Strictureplasty to relieve obstruction without resection should be done when applicable.

Maintenance medication after an operation to limit recurrence or recrudescence is frequently advocated.

http://www.sempedsurg.org/article/PIIS1 ... 8/abstract

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Long-term clinical results of ileocecal resection for Crohn's disease.

Inflamm Bowel Dis. 2007 Jun

Cullen G, O'toole A, Keegan D, Sheahan K, Hyland JM, O'donoghue DP.
Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland.

Keywords: Crohn's • surgery • ileocecal • biologics

Background: The efficacy of biologic agents in Crohn's disease (CD) has led to proposals that they be introduced early in the disease (top-down treatment) with the aim of reducing corticosteroid dependency and surgical resection. However, the long-term use of biologic agents in limited CD may be difficult to justify. The aims were to assess outcomes for ileocecal resection in CD and evaluate its role in the current era.

Methods: The study included 139 CD patients who underwent ileocecal resection between 1980 and 2000. Data were retrieved from a prospectively maintained database. Disease recurrence was defined as symptoms in addition to endoscopic or radiological evidence of disease activity. Severe disease recurrence was defined as a need for repeat resection surgery.Results: Seventy-two (52%) patients developed disease recurrence. Median (interquartile range) time to recurrence was 7.1 (5-10.6) years. Forty-nine (35%) patients required repeat resection surgery. Median (IQ range) time to repeat surgery was 7.2 (4.9-10.8) years. The presence of granulomas was associated with disease recurrence (P = 0.03) and repeat resection surgery (P = 0.01).

Conclusions: Long-term outcomes for ileocecal resection in CD are excellent with 48% of patients remaining symptom-free and only 35% requiring repeat resection surgery at 10 years. This should be borne in mind when considering biologic therapy.(Inflamm Bowel Dis 2007).

http://www3.interscience.wiley.com/cgi- ... 1&SRETRY=0

..........
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Thiopurine treatment with Crohn's disease

Postby patoco » Sat Jul 07, 2007 12:21 am

Adherence to thiopurine treatment in out-patients with Crohn's disease.

Aliment Pharmacol Ther. 2007 Jul

Bokemeyer B, Teml A, Roggel C, Hartmann P, Fischer C, Schaeffeler E, Schwab M.
Gastroenterology Practice Minden, Minden, Germany.

Background: High frequency of incomplete or non-response to azathioprine (AZA) and/or mercaptopurine (MP) limit their use in Crohn's disease (CD). Non-adherence is considered to be of relevance for ineffectiveness.

Aim: To assess adherence to thiopurines in CD out-patients treated in a single gastroenterology practice.

Methods: Patients were eligible for inclusion if they received AZA/MP for at least 3 months. After follow-up of 3 months, adherence to AZA/MP was assessed by quantitation of relevant thiopurine metabolite levels in red blood cells as well as by patients' self-report using standardized questionnaire.

Results: Sixty-five patients were prospectively included. Six patients (9.2%) had metabolite profiles indicative of non-adherence. Self-assessed questionnaire revealed non-adherence in four of 56 patients (7.1%). Therapeutic drug monitoring (TDM) and self-assessment as two independent methods had a concordance rate of 75%. Metabolite levels and self-assessed adherence were not significantly different between patients in remission compared with those with active disease.

Conclusions: Out-patients with CD treated in a single gastroenterology practice had a satisfactory adherence (>90%) to thiopurine therapy. Different measures of adherence (TDM and self-report) applied to the same patient suggest comparable levels. TDM appears to be a reliable tool to assess adherence to thiopurines in clinical practice.

http://www.blackwell-synergy.com/doi/ab ... 07.03365.x

..........

Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing.

Clin Pharmacokinet. 2007

Teml A, Schaeffeler E, Herrlinger KR, Klotz U, Schwab M.
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

This review summarises clinical pharmacological aspects of thiopurines in the treatment of chronic inflammatory bowel disease (IBD). Current knowledge of pharmacogenetically guided dosing is discussed for individualisation of thiopurine therapy, particularly to avoid severe adverse effects. Both azathioprine and mercaptopurine are pro-drugs that undergo extensive metabolism. The catabolic enzyme thiopurine S-methyltransferase (TPMT) is polymorphically expressed, and currently 23 genetic variants have been described. On the basis of an excellent phenotype-genotype correlation for TPMT, genotyping has become a safe and reliable tool for determination of a patient's individual phenotype. Thiopurine-related adverse drug reactions are frequent, ranging from 5% up to 40%, in both a dose-dependent and -independent manner. IBD patients with low TPMT activity are at high risk of developing severe haematotoxicity if pharmacogenetically guided dosing is not performed. Based on several cost-benefit analyses, assessment of TPMT activity is recommended prior to thiopurine therapy in patients with IBD. The underlying mechanisms of azathioprine/mercaptopurine-related hepatotoxicity, pancreatitis and azathioprine intolerance are still unknown. Although the therapeutic response appears to be related to 6-thioguanine nucleotide (6-TGN) concentrations above a threshold of 230-260 pmol per 8 x 10(8) red blood cells, at present therapeutic drug monitoring of 6-TGN can be recommended only to estimate patients' compliance.Drug-drug interactions between azathioprine/mercaptopurine and aminosalicylates, diuretics, NSAIDs, warfarin and infliximab are discussed. The concomitant use of allopurinol without dosage adjustment of azathioprine/mercaptopurine leads to clinically relevant severe haematotoxicity due to elevated thiopurine levels. Several studies indicate that thiopurine therapy in IBD during pregnancy is safe. Thus, azathioprine/mercaptopurine should not be withdrawn in strictly indicated cases of pregnant IBD patients. However, breastfeeding is contraindicated during azathioprine/mercaptopurine therapy. Use of azathioprine/mercaptopurine for induction and maintenance of remission in corticosteroid-dependent or corticosteroid-refractory IBD, particularly Crohn's disease, is evidence based. To improve response rates in thiopurine therapy of IBD, comprehensive analyses including metabolic patterns and genome-wide profiling in patients with azathioprine/mercaptopurine treatment are required to identify novel candidate genes.

PMID: 17328579 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/sites/entre ... stractPlus
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Crohn's disease different in boys than in girls

Postby patoco » Fri Dec 21, 2007 7:03 am

Crohn's disease different in boys than in girls

Reuters Health

Monday, December 17, 2007


NEW YORK (Reuters Health) - Crohn's disease tends to be more severe in girls than in boys, but boys with the disorder are more prone to stunted growth, new research suggests.

Crohn's disease, along with ulcerative colitis, is a serious inflammatory bowel disease (IBD). The inflammation can occur anywhere in the digestive system from the mouth to the anus, although it is most often found in the small and large intestines. The disease, which can cause abdominal pain, bloating, and diarrhea, is treated with various medications or when an intestinal blockage occurs, with surgery.

"Gender differences in the course of Crohn's disease are unclear," Dr. Melvin B. Heyman at the University of California, San Francisco, and colleagues state in the journal Pediatrics. Identifying how the disease is expressed differently according to gender can improve our understanding of the cause, underlying disease process, and the natural history of Crohn's disease.

Using the Pediatric IBD Consortium Registry, Heyman's team compared 566 boys and 423 girls diagnosed with Crohn's disease before they were 17 years old. The patients were followed for 3.6 years, on average.

Girls had a higher rate of mouth sores and lower blood levels of a protein called albumin, suggesting the presence of malabsorption syndrome. In addition, girls also were at greater risk for common skin rashes seen with the disease and usually required intestinal surgery before boys.

Cyclosporine, a common immune-suppressing drug, was used more often among girls, most likely reflecting more severe disease that doesn't respond to first-line drugs, the authors suggest.

As noted, boys were more likely than girls to develop growth failure: 12.6 versus 4.0 percent, respectively.

Heyman and his team call for further studies to examine gender differences in Crohn's disease.

SOURCE: Pediatrics, December 2007.

http://www.nlm.nih.gov/medlineplus/news ... 58992.html
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Crohn's disease: Genetic, environmental, socioeconomic corre

Postby patoco » Fri Dec 21, 2007 7:05 am

New global map of Crohn's disease: Genetic, environmental, and socioeconomic correlations.

Inflamm Bowel Dis. 2007 Dec 19

Economou M, Pappas G.
Institute of Continuing Medical Education of Ioannina, Greece.

Seventy-five years after the initial characterization of Crohn's disease (CD), much remains obscure about its etiology. The authors sought to evaluate the incidence trends of the last 25 years worldwide, and the existence of potential correlations with genetic, environmental, and socioeconomic factors that could be etiologically implicated in the pathogenesis of CD. Relevant medical literature for individual countries on the incidence of CD, on the incidence of associated genetic mutations, and on the incidence of suggested etiologic infectious agents such as Mycobacterium avium paratuberculosis were retrieved from published medical literature, reports from relevant international congresses, and through official reports from national health authorities. Increasing trends have been observed almost worldwide, with a broad north-south gradient still prevailing in Europe. Distinct regions of New Zealand, Canada, Scotland, France, the Netherlands, and Scandinavia represent the highest incidence areas. Industrialized status and affluence are the common denominators between endemic areas, but are too broad as terms to strongly indicate any particular etiological role. The increasing trends observed in Asia still account for a low prevalence of the disease and may represent increased detection and diagnostic ability of local health systems. Genetic associations are variably reproduced worldwide, in a manner inconsistent with a strong etiologic relationship. Data on paratuberculosis incidence are scarce, and the existing ones are ambivalent regarding an even indirect correlation between CD and an infectious trigger.(Inflamm Bowel Dis 2007).

PMID: 18095316 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum
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The forgotten role of lymphangitis in Crohn's disease.

Postby patoco » Fri Dec 21, 2007 7:06 am

The forgotten role of lymphangitis in Crohn's disease.

Gut. 2008 Jan

Van Kruiningen HJ, Colombel JF.
Department of Pathobiology and Veterinary Science, University of Connecticut, U-3089, 61 North Eagleville Road, Storrs, CT 06269-3089, USA. Herbert.vankruiningen@uconn.edu

Research into Crohn's disease has recently been focused on the genetics of the patient, the gastrointestinal flora, the gut epithelium and mucosal immune responses. For over 60 years pathologists have reported that the fundamental alteration in Crohn's disease occurs in regional lymphatics of the intestine--the disease is a lymphocytic and granulomatous lymphangitis. At an earlier time, experimental sclerosis of regional intestinal lymphatics of the pig produced a chronic segmental enteritis with many features of Crohn's disease, including lymphocytic and granulomatous lymphangitis of the bowel wall and enteroenteric and enterocutaneous fistulas. In Crohn's disease, differences in the anatomic distribution of vasa recta appear to explain long-segment disease of the ileum and short-segment disease of the more proximal intestine. A variety of bacteria and viruses cause lymphangitis, suggesting that microorganisms may be at the centre of the basic changes in Crohn's disease. Dietary antigens and lipids are worthy of consideration as well. Now that antibodies to label lymphatics are available, attention should be directed at defining the initial damage to lymphatic endothelium and agents that might be responsible.

PMID: 18094195 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum
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Dietary patterns and risk for Crohn's disease in children.

Postby patoco » Fri Dec 21, 2007 7:08 am

Dietary patterns and risk for Crohn's disease in children.

Inflamm Bowel Dis. 2007 Dec 18

D'Souza S, Levy E, Mack D, Israel D, Lambrette P, Ghadirian P, Deslandres C, Morgan K, Seidman EG, Amre DK.
Department of Nutrition, University of Montreal, Montreal, Canada.

Background: Some dietary foods are considered protective (vegetables and fruits), whereas others (fatty foods) are thought to enhance the risk for Crohn's disease (CD). The evidence, however, is inconsistent.Methods: We postulated that specific dietary patterns may influence the risk for CD. A case-control study was carried out. Newly diagnosed CD cases with population and/or hospital-based controls </=20 years were selected from 3 tertiary hospitals across Canada. Predisease diet was assessed using a validated food frequency questionnaire (FFQ) administered within 1 month of diagnosis. Factor analyses and unconditional logistic regression (adjusted) was used to determine gender-specific dietary patterns and assess associated risks for CD. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were estimated.Results: A total of 149 cases and 251 controls were included. The mean age (range) of the cases was 13.3 (2.6-20 years). There were more boys (61.1%). Four dietary patterns each were observed among both boys and girls. Pattern 1 in girls, characterized by meats, fatty foods, and desserts, was positively associated with CD (OR 4.7, 95% CI 1.6-14.2). Pattern 2, common to both boys and girls, was characterized by vegetables, fruits, olive oil, fish, grains, and nuts and was inversely associated with CD in both genders (girls: OR 0.3, 95% CI 0.1-0.9; boys: OR 0.2, 95% CI 0.1-0.5).Conclusions: Our results suggest that specific dietary patterns could be associated with higher or lower risks for CD in children. Larger prospective studies are required to confirm these findings.(Inflamm Bowel Dis 2007).

PMID: 18092347 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum
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Re: Lymphedema and Crohn's Disease

Postby patoco » Wed Nov 23, 2011 10:51 am

Role of the lymphatic system in the pathogenesis of Crohn's disease

Current Opinion in Gastroenterology:
July 2011 - Volume 27 - Issue 4 - p 335–341
doi: 10.1097/MOG.0b013e3283476e8f
Inflammatory bowel disease: Edited by Claudio Fiocchi

Abstract
Purpose of review: Intestinal lymph containing interstitial fluid, proteins, immune cells, and digested lipids is actively transported back to the blood stream thanks to rhythmical contractions of the mesenteric lymphatic vessels. During this process, lymph flows through several lymph nodes, allowing antigens to be sampled by the immune system. Abnormalities in lymphatic drainage have been noted in the original descriptions of Crohn's disease, but essentially ignored since. The lymphatic system is re-emerging as a critical player in inflammatory and immune processes and the purpose of this review is to present and discuss new concepts related to the involvement of the lymphatic system in the development of inflammatory bowel diseases (IBDs) and more specifically Crohn's disease.

Recent findings: Recent studies reporting lymphangitis, lymphangiogenesis, bacterial infiltration and lymph node infection, immune cell trafficking, and fat-wrapping in Crohn's disease suggest altered lymph drainage and lymphatic pumping, implicating the lymphatic system as a likely player in inflammatory disorders and IBDs.

Summary: Improved knowledge and appreciation of the roles that the lymphatic system plays in immune cell trafficking, infection, fat transport, distribution and metabolism and, of course, edema resolution is necessary to better understand the pathogenesis of chronic inflammatory conditions such as Crohn's disease and may provide the basis for new therapeutic strategies.

http://journals.lww.com/co-gastroentero ... e=abstract
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Re: Lymphedema and Crohn's Disease

Postby patoco » Wed Nov 23, 2011 11:05 am

Natural history of ileo-caecal Crohn's disease after surgical resection. A long term study.

Dec 2011

Margagnoni G, Aratari A, Mangone M, Moretti A, Spagnolo A, Fascì Spurio F, Luchetti R, Papi C.

Source
Gastroenterology and Hepatology Unit, S. Filippo Neri Hospital, Rome, Italy - c.papi@fastwebnet.it.

http://www.ncbi.nlm.nih.gov/pubmed/22105722

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MRI in Crohn's disease-current and future clinical applications.

Nov 2011

Fiorino G, Bonifacio C, Malesci A, Balzarini L, Danese S.

Source
Division of Gastroenterology and Digestive Endoscopy, Istituto Clinico Humanitas, Via Manzoni 56, Rozzano, Milan 20089, Italy.

http://www.ncbi.nlm.nih.gov/pubmed/22105109

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Smokers with active Crohn's disease have a clinically relevant dysbiosis of the gastrointestinal microbiota.

Aug 2011

Benjamin JL, Hedin CR, Koutsoumpas A, Ng SC, McCarthy NE, Prescott NJ, Pessoa-Lopes P, Mathew CG, Sanderson J, Hart AL, Kamm MA, Knight SC, Forbes A, Stagg AJ, Lindsay JO, Whelan K.

Source
King's College London, School of Medicine, Diabetes and Nutritional Sciences Division, London, UK.

http://onlinelibrary.wiley.com/doi/10.1 ... 87C.d02t02

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Expression profile of genes involved in pathogenesis of paediatric Crohn's disease.

Nov 2011

Sim WH, Wagner J, Cameron DJ, Catto-Smith AG, Bishop RF, Kirkwood CD.
Source
Enteric Virus Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia. Department of Gastroenterology, Royal Childrens Hospital, Parkville, Victoria, Australia.

http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract

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Massive per rectal bleeding following blunt abdominal trauma: First presentation of Crohn's disease.

2011

Majeed MU, Jameel M, Williams DT.

Source
Ysbyty Gwynedd, Penrhosgarnedd, Bangor, Gwynedd LL57 2PW, United Kingdom.

http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed

----------------------

Durability of Infliximab Dose Intensification in Crohn's Disease.

Nov 2011

Lin KK, Velayos F, Fisher E, Terdiman JP.

Source
Division of Gastroenterology, Department of Internal Medicine, University of California at San Francisco, San Francisco, CA, USA, kirk.lin@ucsf.edu.

http://www.springerlink.com/content/vh166v5l40852466/

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Crohn disease in rats induced by different concentrations of trinitrobenzenesulfonic acid and ethanol.

Nov 2011

Yang S, Wang XY, Jing S, Yang X, Sheng YH, Yan X.

Source
Department of Digestive Diseases, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China; E-mail: wxy6687@sina.com.

http://www.ncbi.nlm.nih.gov/pubmed/22088591

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Protein Characterization of a Candidate Mechanism SNP for Crohn's Disease: The Macrophage Stimulating Protein R689C Substitution.

Natalia Gorlatova,1 Kinlin Chao,1 Lipika R. Pal,1 Rawan Hanna Araj,1 Andrey Galkin,1 Illarion Turko,1,2 John Moult,1,3* and Osnat Herzberg1,4*
1Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland, United States of America
2National Institute for Standards and Technology, Gaithersburg, Maryland, United States of America
3Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America
4Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, United States of America
Andreas Hofmann, Editor
Griffith University, Australia
* E-mail: jmoult@umd.edu (JM); Email: osnat@umd.edu (OH)
Conceived and designed the experiments: JM OH. Performed the experiments: NG KC LRP AG IT. Analyzed the data: NG LRP IT JM OH. Contributed reagents/materials/analysis tools: NG KC RHA. Wrote the paper: JM OH.
Received September 19, 2011; Accepted October 13, 2011.

http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed

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Scheduled infliximab monotherapy to prevent recurrence of Crohn's disease following ileocolic or ileal resection: A 3-year prospective randomized open trial.

Nov 2011

Yoshida K, Fukunaga K, Ikeuchi H, Kamikozuru K, Hida N, Ohda Y, Yokoyama Y, Iimuro M, Takeda N, Kato K, Kikuyama R, Nagase K, Hori K, Nakamura S, Miwa H, Matsumoto T.

Source
Department of Lower Gastroenterology, Hyogo College of Medicine, Nishinomiya, Japan.

http://onlinelibrary.wiley.com/doi/10.1 ... 8/abstract

----------------------

Crohn's disease of the mouth: report of a case

Sept 2011

Litsas G.
Source
Tufts University, School of Dental Medicine, MA, USA, Private practice in Orthodontics, Kozani, Greece.

http://www.ncbi.nlm.nih.gov/pubmed/22077691

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Cerebral thrombosis complicating Crohn's disease: two cases.

Nov 2011

Benjilali L, Aidi S, El Mansouri H, Benabdejlil M, Jiddane M, El Alaoui Faris M.

Source
Neurology "A" and Neuropsychology Department, Specialities Hospital, Rabat, Morocco.

http://www.strokejournal.org/article/S1052-3057(10)00090-X/abstract
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