Indeterminate Colitis: A Distinctive Clinical Pattern of Inflammatory Bowel

Disease in Children
Claudio Romano, Annalisa Famiani, Romina Gallizzi, Donatella Comito, Valeria
Ferrau' and Paolo Rossi
Pediatrics 2008;122;e1278-e1281
DOI: 10.1542/peds.2008-2306

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
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SPECIAL ARTICLE

Indeterminate Colitis: A Distinctive Clinical Pattern

of Inflammatory Bowel Disease in Children
Claudio Romano, MD, Annalisa Famiani, MD, Romina Gallizzi, MD, Donatella Comito, MD, Valeria Ferrau’, MD, Paolo Rossi, MD

Department of Pediatrics, University of Messina, Messina, Italy

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT
Inflammatory bowel diseases such as Crohn disease and ulcerative colitis are fre-
quently clinical conditions in children. Another clinical entity, indeterminate colitis,
is considered a subgroup of pediatric inflammatory bowel disease. It is generally www.pediatrics.org/cgi/doi/10.1542/
peds.2008-2306
characterized by early onset in the first years of life, and clinical behavior is rapidly
progressive to pancolitis. The definition of indeterminate colitis has changed over the doi:10.1542/peds.2008-2306
years, but it is usually used to identify severe colitis with overlapping features of Key Words
indeterminate colitis, IC, Crohn disease, CD,
ulcerative colitis and Crohn disease. Ileal pouch-anal anastomosis is the surgical ulcerative colitis, UC
treatment of choice for patients with ulcerative colitis, but increased rates of com-
Abbreviations
plications have been found in indeterminate colitis. Therefore, it is better to be IBD—inflammatory bowel disease
cautious in patients with indeterminate colitis who present with severe attacks and CD—Crohn disease
require surgery. Pediatrics 2008;122:e1278–e1281 UC— ulcerative colitis
IC—indeterminate colitis
ASCA—anti–Saccharomyces cerevisiae
antibody

C OLITIS, WHATEVER ITS origin, may be considered an inflammatory disease of the

colon. Several forms of colitis have been identified, some with a well-known
etiology and others with unknown origin. Clinical presentation characterized by
p-ANCA—p-antineutrophil cytoplasmic
antibody
ASCA—anti–Saccharomyces cerevisiae
antibody
acute or chronic diarrhea, with or without blood, recurrent abdominal pain, and
Accepted for publication Aug 18, 2008
tenesmus is often not sufficient to allow a physician to distinguish between acute
Address correspondence to Claudio Romano,
colitis and chronic relapse. A clinical approach may be distinguished by first-level MD, University of Messina, Pediatric
testing (parasitological and bacteriologic tests on the feces) or second-level testing Department, Viale Gazzi, 98122 Messina, Italy.
E-mail: [email protected]
(radiographs and endoscopy). A histologic assessment is the gold-standard procedure
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
for diagnosing and defining the type of inflammation and the presence of architec- Online, 1098-4275). Copyright © 2008 by the
tural disorders. Diagnoses range from infectious colitis with a well-known bacterial American Academy of Pediatrics
or parasitical etiology to those with unknown etiology, such as acute self-limited
colitis, microscopic colitis, ischemic colitis, drug-induced colitis, and chronic inflammatory bowel disease (IBD).
Two clinical entities are classified within IBD: Crohn disease (CD) (Table 1) and ulcerative colitis (UC) (Table 2).
Although histopathologically, clinically, and pathogenetically different, CD and UC do share some features such as
the inflammatory nature of lesions, unknown etiology, and a chronic relapsing clinical trend. A definite diagnosis is
necessary for proper clinical follow-up, to define a suitable therapy, and to assess predictive risk of surgery. In some
patients with suspected IBD at onset, some endoscopic and histologic features are common to both CD and UC,
making a definite diagnosis impossible. The definition used for these forms of colitis was that of “indeterminate
colitis” (IC) (Table 3). Such definition has often been a subject for controversy and discussion.

HISTORICAL BACKGROUND
The term IC has been widely used in the last few decades. It was first adopted in 1978 by Price,1 who identified 30
cases of IC (10% of colectomies for IBD) on the basis of clearly overlapping histologic features between CD and UC
after surgery had been performed. During follow-up, Wells et al2 reclassified these patients as being affected by
“potential CD colitis” or “potential UC.” In later studies,3,4 patients with severe or fulminating onset of colitis, who
underwent colectomy, were termed as patients with IC. In 2003, a Japanese study5 observed 725 patients, 23 of
whom were classified as having IC; during follow-up, 13 patients were then reclassified as having CD (8 patients) or
UC (5 patients). On this occasion, it was hypothesized that IC may be considered a “temporary” diagnosis to be made
before reaching a definite diagnosis. Finally, in 2006, the International Organization for the Study of Inflammatory
Bowel Disease suggested adopting the term IC only for patients with suspected IBD, diagnosed after resection, and
for “unclassified” IBD for patients diagnosed after a biopsy result that did not suggest CD or UC.6

EPIDEMIOLOGY
In an epidemiologic study conducted in Wales in 2000, Hassan et al7 reported an annual IC incidence in the pediatric
population of 0.48 in 100 000. This rate is lower than that reported by Moum et al8 in 1997 (2.4 in 100 000). In
children, the percentage of cases diagnosed as IC ranges from 4% to 23%, with no marked geographical difference.9–13

e1278 ROMANO et al
Downloaded from www.pediatrics.org by on April 5, 2010
 TABLE 1 Major Diagnostic Criteria for CD tected by a full colonoscopy with ileoscopy; (3) radio-
1. Abdominal pain, diarrhea, and weight loss logic evidence of stenosis in the small intestine, fistulas,
2. Macroscopic features of endoscopy such as aphthous erosions, skip lesions, or segmental colitis; and (4) histologic evidence of trans-
and cobblestone appearance mural inflammation or presence of giant-cell epithelioid
3. Radiologic evidence of intestinal stenosis, fistulae, and segmental colitis granuloma. With regard to IC, Meucci et al18 also tried to
4. Histologic evidence of transmural flogosis or presence of giant-cell define the macroscopic features of IC, generally charac-
epithelioid granuloma terized by a spared rectum and segmentary lesions. In
2007, Martland and Shepherd22 defined some macro-
scopic and microscopic aspects from biopsies that were
TABLE 2 Major Diagnostic Criteria for UC suggestive of IC. Macroscopic elements include extended
1. Diarrhea with a without blood and/or mucus in the feces ulcers, an involvement of the right colon but with the
2. Chronic flogosis of the colon, starting from the rectum distal colon showing a more severe clinical picture, mu-
3. Histologic features typical of UC cosal inflammation extended to ⬎50% of the mucous
membrane, widespread disease (even with spared rec-
tum), and possible colon dilatation associated with toxic
megacolon (radiologically diagnosed). Microscopic ele-
TABLE 3 Major Diagnostic Criteria for IC
ments include severe and extended ulcers (above all in
1. Abdominal pain, bleeding diarrhea, and weight loss
the most dilated regions in the colon), transmural flogo-
2. Endoscopic macroscopic features of erosions and ulcers of the colon
sis23 with no aggregate lymphoids (typical of CD), no
3. Pancolitis with “rectal sparing”
4. Early onset epithelioid granuloma distant from the crypts, and mul-
5. Diffuse, transmucosal lamina propria cell increase and patchy inflammation tiple ulcers and knife-like fissures extended on the upper
portion of the muscularis mucosa.24,25

DIAGNOSTIC TESTS
There is no difference between male and female patients, Other tests that might prove useful for making a diag-
either.14–16 There is, instead, a higher incidence of IC at a nosis include those for serologic markers, genetic tests,
younger age (children ⬍2 years of age). These data are high-definition radiologic tests (entero-MRI), esophago-
distinguished on the percentages of CD (36%) and UC gastroduodenoscopy, and capsule endoscopy. Among se-
(31%) diagnoses; between 3 and 5 years of age, UC is rologic tests, positivity for p-antineutrophil cytoplasmic
diagnosed more frequently. The higher the age (13–17 antibodies (p-ANCAs) and anti–Saccharomyces cerevisiae
years), the lower the incidence of IC (9%).17 antibodies (ASCAs) has been studied in patients with IC.
Joossens et al26 showed that 50% of patients with an
CLINICAL ASPECTS initial diagnosis of IC and positive serologic test results
Data on the clinical presentation of IC were reported in were reclassified as having CD or UC. In particular, 80%
an article by Meucci et al,18 who, after observing 50 adult of the patients with ASCA⫹/pANCA⫺ IC developed CD,
patients with IC, reported that the great majority (95%) and 63.6% of pANCA⫹/ASCA⫺ patients developed UC.
of them had diarrhea at onset, 72% had bleeding diar- Finally, those patients whose initial diagnosis of IC was
rhea, and 74% complained of abdominal pain; a lower confirmed (48%) showed negative results in both
percentage presented with weight loss (44%) and fever pANCA and ASCA tests. Thus, seronegativity may be a
(26%). In 2000, Lindberg et al19 suggested that for pe- feature of IC, but for the time being, such serologic
diatric patients with IC, if compared with patients with markers are not specific enough to make a definite di-
UC or CD, there is a worse prognosis with a higher agnosis. Immunogenetic markers may contribute to a
number of relapses as a result of the more aggressive better knowledge of IBD subgroups, but few data are still
character of these IC forms compared with the onset of available on patients with unclassified IBD or IC.
CD and UC. These reports confirm the hypothesis that IC Among instrumental tests, the use of entero-MRI
may be considered a “chronic colitis,” classifiable as IBD, with gadolinium has been suggested. This technique
but with some peculiar clinical, laboratory, endoscopic, allows a deeper observation of the intestinal loops and
and histologic aspects according to some international an indirect evaluation of ulcers in the mucous mem-
criteria.20 IBD, in 5% to 15% of the cases, may be clas- brane or alterations in the walls of the large and small
sified as IC at onset.21 With regard to differential diag- intestines. It is widely used for diagnosing IBD. It is
nosis, sufficient criteria for UC diagnosis may be the 100% specific, with 31% sensitivity compared with the
presence of at least 3 of the following: (1) diarrhea with present gold-standard technique (colonoscopy).27 In a
or without blood and/or mucus in the feces; (2) chronic recent study conducted by Darbari et al,28 entero-MRI
inflammation of the colon, starting from the rectum; (3) with gadolinium was adopted for patients with sus-
histologic features typical of UC; and (4) exclusion of pected IBD, and the results were compared with those
lesions in the small intestine by means of radiologic, obtained by routine histologic tests. Of 58 patients,
endoscopic, and histologic tests, which thus would lead only 6 were not classified by gadolinium-MRI, com-
to a diagnosis of CD. On the other hand, CD is diagnosed pared with 17 of 58 in the latter group. In the same
in the presence of at least 3 of the following elements: study, 2 patients previously classified as having IC on
(1) typical clinical features such as abdominal pain, di- the basis of macroscopic and microscopic criteria were
arrhea, and weight loss; (2) macroscopic features de- diagnosed as UC after using gadolinium-MRI.29

PEDIATRICS Volume 122, Number 6, December 2008 e1279

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CLINICAL COURSE patients with UC, the severity of symptoms at the mo-
An extended study on the natural history of IC was ment of diagnosis is an unfavorable prognostic factor in
conducted in 1991 by Wells et al,2 who reviewed the terms of progression of the disease and response to treat-
results obtained from the clinical and histologic fol- ment.
low-up of the patients observed in the Price1 study who
had a received colectomy. Data regarding 675 patients
CONCLUSIONS
who had received a colectomy for IBD from 1960 to
The term IC has been endowed with different meanings
1983 were reviewed. On a long-term basis, 46 cases of IC
over the years. Price’s original hypothesis referred to
were followed for a minimum period of 2.5 years. After
biopsies, from patients who had received a colectomy for
reexamining the initial diagnosis of IC on the basis of
severe or fulminating forms of colitis, that did not show
further clinical, radiologic, and histopathologic informa-
any definite histologic characteristics, neither for CD nor
tion, 19 patients were considered as affected by probable
UC. The term was later extended to those cases of sus-
CD, 11 patients were considered to have probable UC,
pected IBD with clinical, endoscopic, and histologic (but
and the initial diagnosis of IC was confirmed for 16
not diagnostic) features similar to those of CD and UC.
patients. At the end of the follow-up period, 3 of the said
The latter has made the distinction between various
16 patients were reclassified as having UC, and 1 patient
forms of IBD and non-IBD colitis even more confusing.
was classified as having CD. This article showed that
Studies conducted on a pediatric population in the last
histologic evaluation alone gives sufficient data for a
few years have shown a high incidence of patients hav-
definite diagnosis, which is often not the case when such
ing a form of “severe colitis” at onset, which is difficult to
evaluation is conducted only clinically and instrumen-
define as either UC or CD. There was an increased risk
tally. A Norwegian article12 published in 1995 reported
for colectomy and increased rates for pouch failure after
on IBD patients who were followed up for 1 to 5 years.
ileal pouch-anal anastomosis. For such patients, subtotal
Initially, 518 patients with UC were included, 221 with
colectomy and ileostomy with preservation of the rec-
CD, 64 with “uncertain colitis,” and 40 with IC.30 After
tum should be considered to obtain, from the whole
the first year of follow-up, the characteristics of the
specimen, a definitive diagnosis.32 Finally, observational
patients affected by IC (gender; age at onset; C-reac-
studies would suggest that IC in pediatric patients is an
tive protein, hemoglobin, platelet, and albumin levels;
aggressive and rapidly progressive disease phenotype
blood in feces; weight loss) were very similar to those
and can be considered a distinctive clinical entity of IBD.
of patients with UC. After 1 year, the initial number of
patients with IC and uncertain colitis decreased: 30
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 Indeterminate Colitis: A Distinctive Clinical Pattern of Inflammatory Bowel
Disease in Children
Claudio Romano, Annalisa Famiani, Romina Gallizzi, Donatella Comito, Valeria
Ferrau' and Paolo Rossi
Pediatrics 2008;122;e1278-e1281
DOI: 10.1542/peds.2008-2306
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