A Review Of Inflammatory Bowel Disease Unclassified --Indeterminate Colitis

Batool Mutar Mahdi

Batool Mutar Mahdi, Department Of Microbiology, Al-Kindi College Of Medicine, Baghdad University, AL-Nahda Square, Baghdad, Iraq

Correspondence: Batool Mutar Mahdi, Department Of Microbiology, Al-Kindi College Of Medicine, Baghdad University, AL-Nahda Square, Baghdad, Iraq.
Telephone: +096417702553215
Received: June 11, 2012
Revised: July 6, 2012
Accepted: July 8, 2012
Published online: November 21, 2012


The precise diagnosis of colitis cannot always be established with the available diagnostic tools. A diagnosis of Crohn's disease (CD) and ulcerative colitis (UC) is based on a mixture of clinical, histologic, endoscopic, and radiologic results. The difference between UC and CD can be difficult because of the lack of a differentiating single gold standard. Indeterminate colitis (IC) or inflammatory bowel disease unclassified (IBDU) was introduced by pathologists for the diagnosis of surgical colectomy specimens showing an overlap between the features of UC and CD. The term indeterminate colitis is more widely applied to include all cases with endoscopic, radiographic, and histologic evidence of chronic inflammatory bowel disease confined to the colon, but without fulfillment of diagnostic criteria for UC and CD. IC is generally considered to be a temporary diagnosis. Furthermore, serologic markers such as perinuclear antineutrophil cytoplasmic antibody and anti-Saccharomyces cerevisiae, which are strongly linked with UC and CD and other autoantibodies may be of value in the diagnosis. The possibility that IC could be a separate entity must be investigated and the diagnosis of IC or inflammatory bowel disease unclassified was based on macroscopic and microscopic features, serologic, radiologic, endoscopic presentation. The definition of IBDU is valuable in clinical practice for those who had no clear clinical, endoscopic, histological, or other features affording a diagnosis of either UC or CD, IBDU could be used incidentally. The abnormality in the immune system will favor the use of biologic therapy that neutralize the pro-inflammatory cytokines and use of anti-inflammatory cytokines instead of corticosteroid and immunosuppressive drugs.

Key words: Ulcerative colitis; Crohn's disease; Indeterminate colitis; Inflammatory bowel disease unclassified

© 2012 The Author. Published by Thomson research Group Ltd.

Mahdi BM. A Review Of Inflammatory Bowel Disease Unclassified --Indeterminate Colitis. Journal of Gastroenterology and Hepatology Research 2012; 1(10): 241-246 Available from: URL: http://www.ghrnet.org/index./joghr/


Indeterminate colitis (IC) is a vague term that requires qualification to identify the criteria that are applied when it is used as a diagnosis. 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). World Health Organization approved revisions at a meeting in Tokyo in October 2005, and the diagnosis; indeterminate colitis will be added to the ICD-10 2009[1]. The term indeterminate colitis is controversial. Pathologist Price originally used this term in 1978 to describe colectomy specimens in which no specific features for either Crohn’s disease (CD) or ulcerative colitis (UC) were seen[2]. Kent et al 1979[3] used the term indeterminate colitis when evaluation rendered a diagnosis of UC or Crohn’s indefinite. Burakoff supported the basis that IC may be a separate entity in 2004[4]. This term used by clinician in whom a diagnosis of UC or CD cannot be made based on standard clinical testing, including colonoscopy, imaging, laboratory tests, and biopsy. The pathologist Geboes K et al 2009[5] used the term inflammatory bowel disease unclassified and the surgeons used the term indeterminate colitis for the same condition.


Indeterminate colitis remains a mysterious inflammatory bowel disease (IBD) phenotype. A small number of statistics are available on the incidence and prevalence of IC in the general population. Several studies have consistently shown that such a diagnosis could be made in 5%-15% of inflammatory bowel disease cases. This figure has not been changed over the past 30 years, despite the introduction of newer diagnostic modalities[6]. 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 incidence (about 2.5/100 000/year) has been reported in Scandinavia and Canada[7]. Many population-based studies and hospital-based surveys have consistently found that, in adults, 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[8]. 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[7]. A meta-analysis study showed that frequency of IC is higher in children 12.7% than in adults 6%. In both children and adults IC was more frequent in prospective studies compared to retrospective studies[9]. From the literature, IC cases show an equal sex distribution and the mean age at onset is 36-39 years[10,11,12]. IC is diagnosed in between 9% and 20% of colectomy specimens[13]. Thus, we conclude from above that epidemiology of this disease will become more obvious once a diagnostic test will be available to diagnose IC because this disease still in between UC and CD.


The causes of IC remains unknown. Thus, we revise the different aspects of this disease in order to reach some possible causes.

Histopathological Aspect

Inflammatory bowel disease represents a spectrum of disease, both macroscopically and microscopically, with classical UC and classical CD at either end but numerous cases liberally distributed in the spectrum between. Some of these cases, especially those in the middle ground, represent ‘indeterminate colitis’. Pathologists consider macroscopic assessment of colorectal resection specimens is important as microscopic assessment. The characteristic features of UC are a continuous mucosocentric pathology, with the rectum bearing the brunt of the disease and a variable extension of disease proximally. Ulcerative appendicitis (UA), the appendiceal counterpart of ulcerative colitis (UC), is frequently present in colectomy specimens from patients with universal UC and is regarded as part of the continuous inflammatory process that is a hallmark of this disease. On the other hand, CD shows a fibro-stricturing pathology and the other primarily inflammatory and associated with deep fissures and fistulation[14].

It is no surprise that IC cases show overlap of these two disease processes (Table 1)[15].

The affected colorectum in IC demonstrates an extensive colitis, which itself can take two main patterns. The first pattern is that of severe continuous disease throughout the colon, often with relative rectal sparing, more than 50% of the mucosal surface of the colon is involved and the disease process tends to affect the right and transverse colon more severely than the left (Figure 1). While in CD, there is an inflammation involves the full thickness of the wall from the mucosa to the serosa with granuloma formation.

The second is that of extensive intermittent ulceration that can give the false impression of skip lesions (Figures 2 and 3). The mucosa between these ulcers may appear normal, Fissures may also be seen macroscopically. Some of the cases may be diagnosed radiologically as ‘toxic megacolon’ and show dilation accordingly[16,17]. In UC the inflammation involves the superficial mucosal layer with infiltration of lymphocytes, granulocytes and lose of goblet cells. In addition to that presence of ulceration and crypt abcesses.

Microscopically: The picture is dominated by severe and extensive ulceration (Figure 4) (Table 2) seen in in areas of the colon that are maximally dilated very severe cases will show very extensive ulceration almost throughout the colon and rectum. Because of the fulminant disease, IC also shows myocytolysis, telangiectasia and some fissuring.

This Scanty deep penetrating slit-like fissures, described more recently by some authors as ‘knife-like’, spreading into the superficial half of the muscularis propria[18,19].

The quality of the fissuring ulcers is different from that seen in CD. The fissures may take the form of either squat V-shaped clefts or knife-like breaks, both of which may extend into the submucosa and may extend into the superficial muscularis propria (Figures 4 , 5 and 6). The V-shaped clefts of IC tend to be sparsely lined by inflammatory cells the adjacent bowel shows myocytolysis and capillary engorgement[18]. These ulcers are associated with marked chronic inflammation in the adjacent mucosa. They may be relatively deep and extend into the superficial muscularis propria.


This disease results from an aberrant immune response and loss of tolerance to many self-antigens, leading to chronic inflammation of the gut. This idea is supported by the occurrence of antibodies directed to microbial and self antigens and increased levels of various autoantibodies directed against bacterial components and cross-reactive antigens[20]. Peeters et al 2001[21] evaluated patients with IC prospectively to determine if the serological autoantibody tests might be helpful in improving the diagnostic accuracy of categorizing IC. Autoimmune disorders form part of a broad spectrum of diseases which are often associated with impaired Treg production or maintenance[22]. 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[23]. Other study done in 2011 demonstrated that sera of patients suffering from inflammatory bowel disease unclassified contain Auto-antibodies reacting with one or more antigens (pANCA 66.6%, ASCA 58.3%, exocrine part of pancreatic acinar cells 53.3% and intestinal goblet cells 3.33%) and significantly different from others UC and control groups. The Auto-antibodies were of mixed isotypes (IgG, IgM and IgA)[24]. ASCA develops due to an increased permeability of yeast antigens in the small bowel which activates immune cells[25]. In case of pANCAs, they are directed against antigens in the nuclei, the granules and the cytosol[26]. Other Auto-antibodies such as exocrine pancreas which is found in 30% of CD patients[27] is directed against normal pancreatic juice[28]. There is a variations in the development of Auto-antibodies may be due to genetic factors[29], geographical[30], and ethnic factors[31], socioeconomic status[32] and human leukocyte antigen (HLA) typing[33]. These serological markers are important in the diagnosis, management, disease monitoring, severity and prognosis of disease in UC and CD or inflammatory bowel disease unclassified. Other authors found that serology might not be helpful in diagnosis of IC and both of perinuclear antinutrophil cytoplasmic antibodies and anti Saccharomyces cerevisiae antibodies are negative in patients with indeterminate colitis[34,35] while Tremaine 2007[36] demonstrated that diagnosis of inflammatory bowel disease unclassified by exclusion and serological studies would not be diagnostic for indeterminate colitis until (if) there exists at least one test that positively identifies the subgroup. In addition to that, Tremaine 2011[37] reported that the most reliable technique for evaluating patients with indeterminate colitis is serology. The serologic markers that have proven most useful for diagnosing indeterminate colitis are anti-Saccharomyces cerevisiae antibody (ASCA) and perinuclear antineutrophil cytoplasmic antibody (pANCA), also known as nuclear‑specific antigen. Most patients with indeterminate colitis are negative for both of these markers. Thus, testing for these markers can help clinicians predict whether patients will maintain a long-term diagnosis of indeterminate colitis. 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. Other study concluded the auto-immune nature of this disease and there are some antigens originating from gastrointestinal tract or the bile system that may be involved in the initiation of this disease[24].

Genetic study

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[38]. Mutations in this gene are almost always associated with CD. The contribution of the HLA region, which has been widely studied, shows low sensitivity and specificity for CD and UC. Although it is very early days, such genetic analyses have considerable potential so that, in the future, we may have much more rigorous[39]. 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[40]. It had been found that IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD[41]. Other study found a highly significant association between Crohn’s 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 Crohn’s disease[42].

Immunological features in intestinal mucosa

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[43]. Crohn's disease is due to stimulation of Th1 and ulcerative colitis is due to stimulation of Th2[44]. Mucosal T cells from indeterminate colitis exhibit an intrinsic hyperreactivity to IL-2 and grew similarly to those of CD mucosa. This may represent a primary pathogenic abnormality in this condition[45]. 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[46]. The abnormality in the immune system will favor the use of biologic therapy that neutralize the pro-inflammatory cytokines and use of anti-inflammatory cytokines instead of corticosteroid and immunosuppressive drugs.


It is generally believed that in most cases IC merely represents a provisional diagnosis; indeed, follow-up studies have shown that a vast proportion (up to 80%) of patients are eventually reclassified as being affected by either CD or UC, and up to 20% as not affected by IBD. However, a small subset of patients exists in which IC still remains the most accurate diagnosis a long time after disease onset (more than 10 years). It is likely that in such cases IC really represents a separate clinical entity[8]. 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[47]. 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[48]. Thus, authors hope that progress being made in genetic, serological, colonoscopic and radiologic imaging studies leads to more reliable phenotyping and easily diagnosis of indeterminate colitis[49]. The definition of IBDU is valuable in clinical practice for those who had no clear clinical, endoscopic, histological, or other features affording a diagnosis of either UC or CD, IBDU could be used incidentally[50].

Treatment of indeterminate colitis

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[37]. Others use biologic therapy that neutralize the pro-inflammatory cytokines and use of anti-inflammatory cytokines instead of corticosteroid and immunosuppressive drugs[51].


The term indeterminate colitis is more widely applied to include all cases with endoscopic, radiographic, and histologic evidence of chronic inflammatory bowel disease confined to the colon, but without fulfillment of diagnostic criteria for UC and CD. Capsule endoscopy, genetic and serology will be added to confirm the diagnosis. Immunologic abnormalities in patients with IC will favor the use of biologic immune therapy as an alternative tool to treat IC.


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Peer reviewers: Ole Haagen Nielsen, Department of Gastroenterology DM 112, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark; Takayuki Yamamoto, Inflammatory Bowel Disease Center, Yokkaichi Social Insurance Hospital, 10-8 Hazuyamacho, Yokkaichi, Mie 510-0016, Japan; Zhan-ju Liu, department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University, No. 301 Yanchang Road, Shanghai 200072, China.


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