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2005 Report From: WSAVA Gastrointestinal Standardization
Group
Report From: WSAVA Gastrointestinal Standardization Group
Robert J. Washabau, VMD, PhD, Dipl. ACVIM
Professor of Medicine and Department Chair
Department of Veterinary Clinical Sciences
College of Veterinary Medicine, 1352 Boyd Avenue
University of Minnesota, St. Paul, Minnesota 55108
(612) 625-5273 Office/(612) 624-0751 FAX
E-Mail:[email protected]
Background
The WSAVA Gastrointestinal Standardization Group was initially developed to obtain a world-wide
standard for the histological evaluation of gastrointestinal tract disease of cats and dogs. At the
present time, a number of histological grading schemes have been proposed but none are
universally accepted. Consequently, an intestinal biopsy sent to four different pathologists may
result in four different biopsy reports. This is true of many gastrointestinal disorders (e.g.,
malignancy, toxicity, infection, lymphatic dilation, inflammation, villus atrophy), but it is particularly
true of inflammatory bowel disease. The situation is further complicated by different nomenclatures
for the same disease or disease severity in different parts of the world. With the support of the
WSAVA, the Gastrointestinal Standardization Group has proposed to develop a standardized
histologic evaluation system that will be applied to all companion animal gastroenterologic
disorders. Standardization will yield several obvious benefits including uniform diagnosis of disease,
staging of disease, and the subsequent development of controlled clinical trials for the treatment of
canine and feline gastrointestinal disorders.
Membership of the Group
Study Group Participants: Name/Country + Affiliation/Discipline/E-Mail
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Bilzer, Thomas/Germany, University of Dusseldorf/Pathology [email protected]
Day, Michael/UK, University of Bristol/Pathology [email protected]
Guilford, Grant/New Zealand, Massey University/Internal Medicine
[email protected]
Hall, Edward/UK, University of Bristol/Internal Medicine [email protected]
Jergens, Albert/USA,Iowa State University/Internal Medicine [email protected]
Mansell, Joanne/USA, Texas A & M University/Pathology [email protected]
Minami, Takeo/Japan, Pet-Vet, Yokahoma/Pathology [email protected]
Washabau, Robert/USA, University of Minnesota/Internal Medicine [email protected]
Wilcock, Brian/Canada, Univ. of Guelph-HistoVet/Pathology [email protected]
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Willard, Michael/USA, Texas A & M University/Internal Medicine [email protected]
WSAVA Officers
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Brovida, Claudio/Italy, WSAVA/Nephrology [email protected]
Varga, Gabriel/Slovak Republic, WSAVA/Medicine [email protected]
Goals of the Group
Gastrointestinal diagnosis in small animals (dogs and cats) has been fraught with many difficulties,
particularly in the histologic interpretation of intestinal biopsies. What constitutes normal intestinal
morphology is only now being determined, and the recognition of subtle abnormalities is quite
challenging. Although a number of criteria can be applied in the examination of biopsy specimens,
the interpretation by the histopathologist is often quite subjective. Discrepancies in biopsy reports
between different pathologists is surprisingly common. Consequently, several groups (including the
Comparative Gastroenterology Society, the European Society for Comparative Gastroenterology, and
the American College of Veterinary Internal Medicine) have called for national and international
efforts to standardize the histologic evaluation of the gastrointestinal tract of cats and dogs. The
recent work of the WSAVA Liver Standardization Group has provided additional impetus and urgency
to the need for standardization of the primary disorders of the gastrointestinal tract.
Specific Aims
(1) An international group of scholars was organized from the specialties of Veterinary Pathology
and Internal Medicine to review gastrointestinal tract diseases of dogs and cats. Clinicians and
pathologists have been reviewing major and minor diseases of the gastrointestinal tract with the aim
of standardizing language and nomenclature that are applied to the histologic characterization and
diagnosis of gastrointestinal disease. To accomplish these goals, the group will hold four or five
meetings over a two- to three-year period. Histology slides are distributed among the pathologists
for their interpretation three to four months in advance of each meeting, and the pathologists and
clinicians review, discuss, revise, and re-classify gastrointestinal diseases during 1-2 day meetings
over a multi-headed microscope.
(2) Members of the International Working Group were recruited from the ACVIM, ECVIM, and other
international Specialty Colleges and universities.
(3) Meetings of the International Working Group are held at annual meetings of the ACVIM, ECVIM,
and WSAVA for the purposes of elevating the visibility and stature of the Working Group in the eyes
of the relevant International Specialty Colleges. (Many members of the Working Group are also likely
to attend their own professional meeting, e.g., ACVIM Forum and ECVIM Congress.)
(4) The Group will report findings to Gastroenterology specialists in attendance at the annual
meetings of the ACVIM and ECVIM during the two-year timeframe of the Working Group.
(5) After final consultation with other Gastroenterology specialists at the ACVIM and ECVIM annual
meetings, the Group will develop and publish one or more Consensus Statements and other
manuscripts in the pathology and internal medicine journals.
First Meeting of the Group
The Group held its first meeting on June 8 & 9, 2004 in St. Paul, Minnesota on the occasion of the
2004 ACVIM Forum in Minneapolis. The agenda for that meeting included problems in the
interpretation of G.I. biopsies; gastric, intestinal, and colonic histopathology and immunopathology;
problems and pitfalls in the diagnosis of IBD; gastrointestinal disease distribution; and, endoscopic
standards and biopsy techniques.
The Need for Standardization �V Following that meeting, the Group concluded that there is a great
need for three types of standardization: histologic descriptions of gastrointestinal disease, the
functional disorders (i.e., those disorders for which there are prominent gastrointestinal clinical signs
but for which is there minimal to no histologic change), and each of the steps of a medical
investigation. The latter standardization could include history taking, physical examination,
laboratory tests including intermediate endpoint biomarkers, imaging procedures and reports,
endoscopic procedures and reports, biopsy procedure, histopathology and biopsy reports,
immunohistochemistry, treatment trials, and patient response/outcome.
Initial Working Groups (chair in bold)
Inflammatory Bowel Disease:
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Al Jergens
Ed Hall
Michael Day
Joanne Mansell
Thomas Bilzer
Endoscopic Examination:
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Mike Willard
Grant Guilford
Al Jergens
Joanne Mansell
Ed Hall
Food Sensitivity Reactions
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Grant Guilford
Robert Washabau
Mike Willard
Michael Day
Brian Wilcock
Gastrointestinal Neoplasia
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Brain Wilcock
Takeo Minami
Joanne Mansell
Thomas Bilzer
Robert Washabau
Second Meeting of the Group
The Standardization Group will hold its second meeting in Baltimore on May 31, 2005 on the
occasion of the 2005 ACVIM Forum. The agenda for this meeting will include reviewing the progress
of the subgroups working on endoscopic standardization, food sensitivity reactions, and
gastrointestinal neoplasia; re-visiting plans for inflammatory bowel disease; and, entertaining a new
proposal for validation of diagnostic tests.
New agendae �V The Group is considering a specific proposal to derive guidelines for the validation
of specialized gastrointestinal assays available to veterinary practices and veterinary laboratories.
The Group would hope to establish criteria to define whether tests are certainly valid, probably
valid, or if there is insufficient evidence to support their validity. Details of reference standards
would be published for various analytes used in gastrointestinal diagnosis. Reference laboratories
and assay companies would be able to cite the guidelines as standards to which they adhere.
Area of Interest - Canine Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) may be defined using clinical, histologic, immunologic,
pathophysiologic, and genetic criteria.
Clinical Criteria
IBD has been defined clinically as a spectrum of gastrointestinal disorders associated with chronic
inflammation of the stomach, intestine and/or colon of unknown etiology.1 A clinical diagnosis of
IBD is considered only if affected animals have: (1) persistent (>3 weeks in duration) gastrointestinal
signs (anorexia, vomiting, weight loss, diarrhea, hematochezia, mucousy feces), (2) failure to
respond to symptomatic therapies (parasiticides, antibiotics, gastrointestinal protectants) alone, (3)
failure to document other causes of gastroenterocolitis by thorough diagnostic evaluation, and (4)
histologic diagnosis of benign intestinal inflammation.2 Small bowel and large bowel forms of IBD
have been reported in both dogs and cats, although large bowel IBD appears to be more prevalent in
the dog.
Histologic Criteria
IBD has been defined histologically by the type of inflammatory infiltrate (neutrophilic, eosinophilic,
lymphocytic, plasmacytic, granulomatous), associated mucosal pathology (villus atrophy, fusion,
crypt collapse), distribution of the lesion (focal or generalized, superficial or deep), severity (mild,
moderate, severe), mucosal thickness (mild, moderate, severe), and topography (gastric fundus,
gastric antrum, duodenum, jejunum, ileum, cecum, ascending colon, descending colon).3 As with
small intestinal IBD, subjective interpretation of large intestinal IBD lesions has made it difficult to
compare tissue findings between pathologists. Subjectivity in histologic assessments has led to the
development of several IBD grading systems.3-10
Immunologic Criteria
IBD has been defined immunologically by the innate and adaptive response of the mucosa to
gastrointestinal antigens. Although the precise immunologic events of canine and feline IBD remain
to be determined, a prevailing hypothesis for the development of IBD is the loss of immunologic
tolerance to the normal bacterial flora or food antigens, leading to abnormal T cell immune
reactivity in the gut microenvironment.11 Genetically engineered animal models (e.g., IL-2, IL-10,
and T cell receptor knockouts) that develop IBD involve alterations in T cell development and/or
function suggesting that T cell populations are responsible for the homeostatic regulation of mucosal
immune responses.12 Immunohistochemical studies of canine IBD have demonstrated an increase in
the T cell population of the lamina propria, including CD3+ cells and CD4+ cells, as well as
macrophages, neutrophils, and IgA-containing plasma cells. Many of the immunologic features of
canine IBD can be explained as an indirect consequence of mucosal T cell activation. Enterocytes are
also likely involved in the immunopathogenesis of IBD. Enterocytes are capable of behaving as
antigen-presenting cells, and interleukins (e.g., IL-7 and IL-15) produced by enterocytes during acute
inflammation activate mucosal lymphocytes. Up-regulation of Toll-like receptor 4 (TLR4) and Toll-like
receptor 2 (TLR2) expression contribute to the innate immune response of the colon.13 Thus, the
pathogenesis and pathophysiology of IBD appears to involve the activation of a subset of CD4+ T
cells within the intestinal epithelium that overproduce inflammatory cytokines with concomitant
loss of a subset of CD4+ T cells, and their associated cytokines, which normally regulate the
inflammatory response and protect the gut from injury. Enterocytes, behaving as antigen-presenting
cells, contribute to the pathogenesis of this disease.14
Pathophysiologic Criteria
IBD may be defined pathophysiologically in terms of changes in transport, blood flow, and motility.
The clinical signs of IBD, whether small or large bowel, have long been attributed to the
pathophysiology of malabsorption and hypersecretion, but experimental models of canine IBD have
instead related clinical signs to the emergence of abnormality motility patterns.
The pathophysiology of IBD is explained by at least two interdependent mechanisms: the mucosal
immune response, and accompanying changes in motility.
Immune Responses - A generic inflammatory response involving cellular elements (B and T
lymphocytes, plasma cells, macrophages, and dendritic cells), secretomotor neurons (e.g., VIP,
substance P, and cholinergic neurons), cytokines and interleukins, and inflammatory mediators (e.g.,
leukotrienes, prostanoids, reactive oxygen metabolites, nitric oxide, 5-HT, IFN-�^, TNF-�, and
platelet-activating factor) is typical of canine and feline inflammatory bowel disease.15,16 There are
many similarities between the inflammatory response of the small and large intestine, but recent
immunologic studies suggest that IBD of the canine small intestine is a mixed Th1/Th2
response1,17,18 whereas IBD of the canine colon may be more of a Th1 type response with
elaboration of IL-2, IL-12, INF-�^, and TNF-alpha.19 Other studies of canine colonic IBD have
demonstrated increased numbers of mucosal IgA- and IgG-containing cells,4,20-22 nitrate,21 CD3+ T
cells, nitric oxide (NO),23 and inducible nitric oxide synthase (iNOS)23 in the inflamed colonic
mucosa. Increases in the CD3+ positive T cell population of the inflamed colon are consistent with
changes reported in the inflamed canine intestine. Thus, there are important similarities and
differences between small and large bowel IBD.
Motility Changes - Experimental studies of canine large intestinal IBD have shown that many of the
clinical signs (diarrhea, passage of mucus and blood, abdominal pain, tenesmus, and urgency of
defecation) are related to motor abnormalities of the colon. Ethanol and acetic acid perfusion of the
canine colon induces a large bowel form of IBD syndrome indistinguishable from the natural
condition.24,25 Inflammation in this model suppresses the normal phasic contractions of the colon,
including the migrating motility complex, and triggers the emergence of giant migrating contractions
(GMCs). The appearance of these GMCs in association with inflammation is a major factor in
producing diarrhea, abdominal cramping, and urgency of defecation. GMCs are powerful lumenoccluding contractions that rapidly propel pancreatic, biliary, and intestinal secretions in the fasting
state, and undigested food in the fed state, to the colon to increase its osmotic load.26-28
Malabsorption results from direct injury to the epithelial cells and from ultrarapid propulsion of
intestinal contents by giant migrating contractions (GMCs) so that sufficient mucosal contact time is
not allowed for digestion and absorption to take place.
Inflammation impairs the regulation of the colonic motility patterns at several levels, i.e., enteric
neurons, interstitial cells of Cajal, and circular smooth muscle cells. Inflammation suppresses the
generation of tone and phasic contractions in the circular smooth muscle cells through multiple
molecular mechanisms. Inflammation shifts muscarinic receptor expression in circular smooth
muscles from the M3 to the M2 subtype.29 This shift has the effect of reducing the overall
contractility of the smooth muscle cell. Inflammation also impairs calcium influx30 and downregulates the expression of the L-type calcium channel31, which may be important in suppressing
phasic contractions and tone while concurrently stimulating GMCs in the inflamed colon. Changes in
the open-state probability of the large conductance calcium-activated potassium channels (KCa)
partially attenuate this effect.32 Inflammation also modifies the signal transduction pathways of
circular smooth muscle cells. Phospholipase A2 and protein kinase C (PKC) expression and activation
are significantly altered by colonic inflammation33,34 and this may partially account for the
suppression of tone and phasic contractions. PKC ��, �], and �� isoenzyme expression is downregulated, PKC �� and �� isoenzyme expression is up-regulated, and the cytosol-to-membrane
translocation of PKC is impaired.34 The L-type calcium channel, already reduced in its expression, is
one of the molecular targets of PKC. Inflammation also activates the transcription factor NF-��B
which further suppresses cell contractility.35
Genetic Criteria
IBD may be defined by genetic criteria in several animal species. Crohn��s disease and ulcerative
colitis are more common in certain human genotypes, and a mutation in the NOD2 gene (nucleotidebinding oligomerization domain2) has been found in a sub-group of patients with Crohn��s
disease.14 Genetic influences have not yet been identified in canine or feline IBD, but certain breeds
(e.g., German shepherds, Boxers) appear to be at increased risk for the disease.
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