INDETERMINATE

COLITIS
Kwan, Marlisa Yanuarti 1015033
Albert Jonathan 1015116
Paramitha Setiadi 1015171

Indeterminate Colitis
In 2005, Working Party of the World Congress of
Gastroenterology in Montreal:
The term Indeterminate colitis should be used only
when colectomy has been performed and the
pathologists are unable to make a definite diagnosis of
either UC or CD after careful examination of the
surgical specimen
The term IBD-type unclassified or IBDU should be
used in all other IBD cases when no colectomy is
performed and a distinction between UC and CD
cannot be made despite an extensive diagnostic work-
up.
In contrast, the IBD Working Group for the
European Society for Pediatric Gastroenterology,
Hepatology and Nutrition (ESPGHAN) in the Porto
Criteria:
Recommended the use of the term IC for children
and adolescences with IBD, when a full
endoscopic examination including biopsies of the
upper GI, colon and terminal ileum, in addition to
a small bowel follow-through or enteroclysis,
cannot establish a diagnosis of either UC or CD
with certainty.
Recently, an International Organization of
Inflammatory Bowel Diseases (IOIBD) working
party proposed an other classification for IBD
patients with an unclear diagnosis.
They recommended the term IBD-unclassified
(IBDU), as suggested by the Montreal Working
Party, for patients that clearly have IBD colitis but
definitive features of UC or CD are absent and
proposed the term colitis of uncertain type or
etiology for colectomy specimens, thus
abandoning the term IC.
Indeterminate colitis is not currently recognized
as a diagnosis in the International Classification of
Diseases, 9th revision, Clinical Modification (ICD-
9-CM), or in the International Statistical
Classification of Disease and Related Heath
Problem, 10th revision, version of 2006 (ICD-10).
However, the World Health Organization ratified
revisions at a meeting in Tokyo in October 2005,
and the diagnosis, indeterminate colitis K52.3,
added to the ICD-10 in January 2009.
Epidemiology
In adults, an incidence of about 1/100.000/year and a
prevalence of 3-7/100.000 were found in some
European countries (Denmark, Hungary, Spain,
Holland) but a higher unclassified incidence (about
2.5/100 000/year) has been reported in Scandinavia
and Canada.
IC accounts for 3%-6% of all initial IBD diagnoses in
Europe, as well as in Australia, Japan, Lebanon, Saudi
Arabia, and South Africa; slightly lower figures have
been occasionally reported from some south-European
areas, and much higher figures (10%-18%) in a single
study from Canada.
By contrast, the frequency of IC appears to be
higher (up to 29%) among children, especially in
northern Europe. The incidence of IC in children
has been assessed in Sweden, France, and Wales,
ranging from 0.12-0.7/100 000/year.
A meta-analysis study showed that frequency of
IC is higher in children 12.7% than in adults 6%.
From the literature, IC cases show an equal sex
distribution and the mean age at onset is 36-39
years.
Diagnosis
Macroscopically: an extensive severe colitis
which can take two main patterns; either a
severe continuous disease throughout the
colon often with relative rectal sparing or a
discontinuous involvement of the colon with
extensive intermittent ulceration.
More than 50% of the mucosal surface is
affected and the lesions are more severe at
the right and transverse colon.

Microscopically, there is severe and extensive
ulceration with non specific transmural
inflammation, but also intervening mucosal
islands with normal epithelium and a well
preserved population of goblet cells.
The presence of multiple V shaped fissures in
areas of severe inflammation, which are covered
by inflammatory cells and accompanied by loss of
smooth muscle cells (myocytolysis) and vascular
congestion in surrounding tissue is a common
finding.
Some authors have also described knife like
fissures in IC colectomy specimens.
In IC well defined transmural epithelioid
granulomas and transmural lymphoid aggregates
are absent and their presence is strongly
suggestive of CD.
In contrast, mucosal microgranulomas, especially
those adjacent to inflamed and distorted crypts,
and the presence of scattered monocytes in the
muscularis propia can be seen in IC cases.

Figure 1
A total colectomy specimen showing indeterminate colitis.
There is continuous disease more proximally with relative rectal
sparing. The transverse colon is dilated with early toxic
megacolon. The involved areas show widespread ulceration.
Figure 2
A total colectomy specimen showing indeterminate colitis. The
transverse colon is notably dilated and there is extensive ulceration
with the appearance of skip lesions. The depth of the ulceration is
evidenced by the fact that muscularis propria is discernible in the
bed of the more extensive areas of ulceration, especially in the
transverse colon.
Figure 3
A total colectomy specimen showing indeterminate colitis (IC). Perhaps the
features here might seem to favour ulcerative colitis (UC), as there is
continuous distal disease, but there is focal inflammation and ulceration in
the proximal colon, producing skip lesions. There are few stigmata of chronic
UC microscopically and this serves to sustain the designation of IC.
Figure 4
The microscopy of indeterminate colitis. There is extensive
ulceration with typical superficial V -shaped fissures, parallel to
each other. The surviving mucosal islands show modest
stigmata of chronic inflammatory bowel disease
Genetic
In 2001, CD was shown to be associated with variants of the gene
CARD15 NOD2 on chromosome 16, the gene product of which is
involved in controlling the gut inflammatory response to bacteria.
Genomic surveys have identified IL23R and IL12B as susceptibility
loci for inflammatory bowel disease and there is an association of
IL23R and IL12B with IBD in the Spanish population. It had been
found that IL12B SNP rs6887695 modulates the susceptibility and
the phenotype of IBD.
Other study found a highly significant association between Crohns
disease and the IL23R gene on chromosome 1p31, which encodes a
subunit of the receptor for the proinflammatory cytokine
interleukin-23. An uncommon coding variant (rs11209026,
c.1142G>A, p.Arg381Gln) confers strong protection against Crohns
disease.
Serology
Mucosal inflammation is almost always mediated by one of
two pathways: either an excessive Th1 response that is
associated with increased secretion of IL-12, gamma
interferon and TNF or an excessive Th2 response that is
associated with increased secretion of IL-4, IL-5 and IL-13.
Crohn's disease is due to stimulation of Th1 and ulcerative
colitis is due to stimulation of Th2.
Mucosal T cells from indeterminate colitis exhibit an
intrinsic hyperreactivity to IL-2 and grew similarly to those
of CD mucosa.
Other study demonstrated that there is an increase in IL-10
and INF-gamma levels and decrease in TNF-alfa levels in
patients with IC.

Capsule Endoscopy
In more recent years, Capsule Endoscopy (CE)
has been emerging as a promising tool to
identify subtle small bowel abnormalities in
patients with IC, thus allowing a change in
diagnosis to CD or UC.
Patients with longstanding IBDU/IC and
negative serology, CE can detect small-bowel
lesions which lead to a CD diagnosis in a
significant proportion of patients.
Serological Markers
Joosens et al 2002 in a multicenter prospective
study, had found that ASCA + /pANCA- predicts
CD in 80% of patients with IC and ASCA- /pANCA
+ predicts UC in 63.6%. Patients who remain IC do
not show antibodies against ASCA or pANCA.
ASCA develops due to an increased permeability
of yeast antigens in the small bowel which
activates immune cells. In case of pANCAs, they
are directed against antigens in the nuclei, the
granules and the cytosol.
Anti-Saccharomyces cerevisiae antibody (ASCA)
Perinuclear antineutrophil cytoplasmic antibody (pANCA)
Typically, patients who lack these markers
continue to have indeterminate colitis,
whereas patients who have one or both of
these markers will likely manifest with CD or
UC over time.
Treatment
Medical treatment commonly used in UC and CD is also
being used in IC, but up to now no prospective studies
regarding medical therapy in IC have been published.
In a retrospective study which included 20 patients with
severe, active, medically refractory IC who received 1 to 16
infusions of infliximab, 16 patients responded to infliximab
but 8 of them were later on diagnosed as CD.
However, those patients who remained with a diagnosis of
IC had similar long term response as those with a
subsequent diagnosis of CD. Other studies on the use of
infliximab, tacrolimus and 6-thioguanines have either
included a very small number of IC cases or both IC and UC
patients making difficult the determination of the efficacy
in the IC group only.
Patients with indeterminate colitis are often managed
the same as patients who have UC; clinicians usually
use the same drug regimen and surgical approach for
both groups and patients with indeterminate colitis
have more complications following colectomy than
patients with UC, but they do better than patients with
CD.
Others use biologic therapy that neutralize the pro-
inflammatory cytokines and use of anti-inflammatory
cytokines instead of corticosteroid and
immunosuppressive drugs.
Surgical Management
Total proctocolectomy and ileal pouch-anal anastomosis
(IPAA) has become the surgical treatment of choice for a
large number of patients with UC.
It offers complete relief of symptoms in patients not
responding to medical treatment or experiencing serious
side effects and eliminates the danger of carcinogenesis,
while preserving normal sphincter function and defecation.
IPAA is generally not recommended in CD due to high rates
of pouch failure (30-50%), leading to the excision of the
pouch with significant loss of small intestinal length and
serious postoperative complications like pelvic infections
and fistula formation.

The distinction of IC from Crohns colitis is of great
importance, because IC patients can be submitted to
IPAA with success rates similar to UC patients and only
a slightly increased risk of postoperative complications.
In the largest published study by Delaney et al, pouch
failure rates were similar in IC and UC but
complications like pelvic abscesses and fistulas were
increased in IC patients.
Increased serum levels of TNF-alpha in IC patients with
perianal complications after IPAA have been reported
and this finding may support the use of anti-TNF alpha
antibodies(Infliximab in such patients.
References
Annals of Gastroenterology 2008: Indeterminate colitis
- definition, diagnosis, characteristics and management
Division of Gastroenterology and Hepatology, Mayo
Clinic College of Medicine, Rochester, MN, USA 2006:
Indeterminate colitis definition, diagnosis and
management
Journal of Gastroenterology and Hepatology Research
2012: A Review Of Inflammatory Bowel Disease
Unclassified Indeterminate Colitis
http://www.ccfa.org/resources/diagnosing-and-
managing-ibd.html