http://orcid.org/0000-0003-4690-573X
Abstract
Objectives: Onset of microscopic colitis (MC) in patients with ulcerative colitis (UC) or Crohn’s disease (CD), or vice versa, has been reported occasionally but the subject is not well described. We therefore report a retrospective observational study of such patients and review the literature.
Methods: Forty-six Swedish gastroenterology clinics were contacted about patients with diagnoses of both inflammatory bowel disease (IBD) and MC. Publications were searched on PubMed.
Results: We identified 31 patients with onset of MC after a median (range) of 20 (2–52) years after diagnosis of IBD, or vice versa; 21 UC patients developed collagenous colitis (CC) (n = 16) or lymphocytic colitis (LC) (n = 5); nine CD patients developed CC (n = 5) or LC (n = 4); one CC patient developed CD. Of the 21 UC patients, 18 had extensive disease, whereas no consistent phenotype occurred in CD. Literature review revealed 27 comprehensive case reports of patients with diagnoses of both IBD and MC. Thirteen MC patients developed IBD, of which four required colectomy. Fourteen IBD patients later developed MC. There were incomplete clinical data in 115 additional reported patients.
Conclusions: Altogether 173 patients with occurrence of both IBD and MC were found. The most common finding in our patients was onset of CC in a patient with UC. Although these are likely random associations of two different disorders, MC should be considered in the patient with UC or CD if there is onset of chronic watery diarrhoea without endoscopic relapse of IBD.
Introduction
Ulcerative colitis (UC) and Crohn’s disease (CD), the two major forms of inflammatory bowel disease (IBD), have been known for a long time [Citation1]. Collagenous colitis (CC) and lymphocytic colitis (LC), together constituting microscopic colitis (MC), are in this respect fairly new conditions, described in 1976 and 1989, respectively [Citation2,Citation3]. UC, CD and MC differ regarding epidemiology, clinical presentations, endoscopic and histopathologic features. Ulcerative colitis and CD generally have an onset early in life at 20–40 years of age [Citation4], whereas onset of CC and LC is generally later in life, with a peak incidence rate around 60–70 years of age [Citation5]. The typical clinical presentation of UC and CD is diarrhoea, rectal bleeding, abdominal pain or fever, whereas watery, non-bloody diarrhoea is characteristic for CC and LC. The endoscopic appearance of UC and CD displays macroscopic signs of inflammation and ulcerations, whereas the colonic mucosa in MC is generally normal. Furthermore, histopathologic findings are different.
The relationship between UC, CD and MC is unclear. Case reports have been published about patients with UC or CD who later in life develop CC or LC, or vice versa [Citation6–26]. Furthermore, there are a few reports about simultaneous occurrence of UC or CD and MC [Citation10,Citation12,Citation16,Citation26–28]. These may be chance associations of two fairly common disorders [Citation29], but underlying common pathogenetic factors cannot be ruled out. There are currently no data on how often this occurs.
The aim of this study is to describe clinical characteristics of patients with UC or CD who later develop MC, or vice versa, and to review the literature on this topic.
Materials and methods
Patients
This retrospective study was conducted among members of the Swedish Organization for the study of IBD (SOIBD). Forty-six Swedish gastroenterology clinics were contacted by letter about patients with diagnoses of both UC or CD and collagenous or lymphocytic colitis. Inclusion criteria were patients with an established diagnosis of either UC or CD, who later in life developed CC or LC, or vice versa.
Patients’ files were reviewed (AW) with respect to clinical data and endoscopic findings. Diagnostic biopsies, available at diagnosis and follow-up both of IBD and of MC, were reviewed by an expert gastro pathologist (ÅÖ). The diagnoses of UC and CD relied on a combination of generally accepted criteria: clinical history, endoscopy, histopathology and in some cases radiology [Citation30–32]. The diagnoses of CC and LC were based on a combination of clinical and histopathological criteria consistent with definitions earlier used in our studies [Citation33,Citation34]. The phenotype of UC and CD was assessed according to Montreal classification [Citation35], and the clinical course of MC was defined as asymptomatic, single attack (SA), chronic intermittent course (CIC) or chronic continuous course (CCC). Asymptomatic diagnosis and course of MC referred to an IBD patient in clinical remission who underwent a surveillance colonoscopy after long-standing disease where biopsies yielded a histopathologic diagnosis of MC without any clinical symptoms.
Literature search
Publications for this review were identified by searching PubMed using the following MeSH terms: microscopic colitis, collagenous colitis, lymphocytic colitis, ulcerative colitis and Crohn’s disease. Additional reports were found by searching the reference lists of pertinent articles.
Statistics
Age, time span between the two diagnoses, and follow-up time are presented in years as median (range).
Ethical statement
The study was approved by the Ethical Committee of Uppsala (Ref no. 2005:341).
Results
Current study
Patients
We reviewed patient files of 55 potential cases reported by 18 of 46 clinics. Twenty-four patients were excluded due to not fulfilling inclusion criteria of having two diagnoses (n = 13), insufficient medical data (n = 8), and synchronous findings of UC/CC (n = 2) and UC/LC (n = 1) in biopsies from the same colonoscopy.
The remaining 31 patients were included in the study (). In all cases except one, IBD was the first diagnosis and MC was diagnosed at a later stage. The age of all patients at first diagnosis was 37 (13–73) years, at second diagnosis 56 (31–81) years and the time period from first to second diagnosis was 20 (2–52) years. The follow-up time after second diagnosis was 2 (0–27) years.
Table 1. Clinical data on 31 patients with inflammatory bowel disease (IBD) and microscopic colitis (MC) in current study.
Patients with ulcerative colitis who developed microscopic colitis
Sixteen patients (nine female) with a diagnosis of UC later in life developed CC. The age at diagnosis of UC was 43 (21–73) years, at diagnosis of CC 59 (51–75) years and the time period from first to second diagnosis was 19 (2–52) years. Fourteen patients had extensive UC (E3). Twelve patients had symptomatic onset of CC, i.e., they had first flares with bloody diarrhoea and macroscopically inflamed colonic mucosa typical for UC, and later the clinical presentation changed to watery, non-bloody diarrhoea with a macroscopically normal or almost normal colonic mucosa consistent with CC. The follow-up time after CC diagnosis was 3 (0–12) years. Interestingly, six patients had flares of UC 3.5 (1–10) years after diagnosis of CC.
Five patients (two female) with a first diagnosis of UC subsequently developed LC. The age at diagnosis of UC was 35 (13–45) years, at diagnosis of LC 56 (31–66) years and the time from first to second diagnosis was 29 (11–30) years. Four patients had extensive UC (E3) and one had left-sided disease (E2). Four patients had symptomatic onset of LC with characteristic symptoms. The follow-up time after LC diagnosis was 5 (0–10) years. One patient had a flare of UC one year after symptomatic onset of LC.
Patients with Crohn’s disease who developed microscopic colitis
Nine patients (all female) with a diagnosis of CD later developed MC; CC in five and LC in four patients. All five patients who developed CC had characteristic clinical symptoms. The age at diagnosis of CD was 33 (23–40) years, at diagnosis of CC 53 (39–79) years, and the time from first to second diagnosis was 22 (4–47) years. The maximal location of CD was ileal (L1) (n = 4) and colonic (L2) (n = 1), and behaviour was non-stricturing, non-penetrating (B1) in all cases but one with unknown behaviour. The follow-up time after CC diagnosis was 2 (1–27) years. Three patients had earlier undergone an ileocecal resection and developed CC 4, 25 and 47 years later, respectively. One of these patients had a relapse of CD eight years after diagnosis of CC.
Four patients with ileocolic CD (L3) developed LC. The age at diagnosis of CD was 32 (28–45) years, at diagnosis of LC 60 (44–81), and the time from first to second diagnosis was 29 (12–35) years. Non-stricturing, non-penetrating disease behaviour (B1) was seen in two patients, stricturing behaviour (B2) in one, and penetrating disease behaviour (B3) in one. The follow-up time after LC diagnosis was 1 (0–5) year.
Patient with microscopic colitis who developed Crohn’s disease
A woman with a diagnosis of CC at 42 years of age developed duodenal CD six years later. She was examined due to abdominal pain, anaemia and weight loss. Upper and lower endoscopic procedures revealed inflammation and aphthous ulcers in the duodenum, and histopathological examination showed inflammation typical of CD with findings of cryptitis and epithelioid cell granulomas. The terminal ileum and colon were macroscopically normal. A microscopic discontinuous inflammation without granulomas was seen in the terminal ileum and in the colon but no findings of CC at the time of diagnosis of CD. The patient was treated with azathioprine, had two courses of budesonide due to flares of CD, and was in clinical but not endoscopic remission two years after diagnosis of CD.
Review of literature
Twenty-seven patients (21 female) were found with comprehensive reports of IBD and subsequent MC or vice versa (). The age at first diagnosis was 51 (16–75) years and the time from first to second diagnosis was 7 (0.5–39) years.
Table 2. Clinical data on 27 reported cases in the literature with inflammatory bowel disease (IBD) and microscopic colitis (MC).
Fourteen patients had IBD first and later developed MC; 10 patients with UC developed CC (n = 6) or LC (n = 4). Of the four patients with LC, two were asymptomatic and were diagnosed due to surveillance colonoscopies because of longstanding UC. Four patients with CD developed CC (n = 3) or LC (n = 1). Thirteen patients with a first diagnosis of MC later developed IBD; 11 CC patients were diagnosed with UC (n = 7) or CD (n = 4), and two patients with LC developed UC (n = 1) or CD (n = 1), respectively. All eight patients who developed UC or IBD-U (unclassified IBD) had extensive colitis (E3) and four patients underwent acute colectomy due to severe colitis 0.5–4 years after an initial MC diagnosis [Citation7,Citation9,Citation15,Citation21].
Furthermore, 115 more cases with both IBD and MC were briefly described in a few sentences or in a table without any clinical data or details of the clinical course [Citation11,Citation13,Citation17,Citation26,Citation36–40].
Discussion
The first report of CC and subsequent CD was published in 1987 [Citation8], and was followed by additional case reports and small case series [Citation6,Citation7,Citation9–28,Citation37,Citation38]. Herein, we report a large series of patients with an established diagnosis of IBD who later develop MC, or vice versa. Thirty patients diagnosed with UC or CD developed CC or LC 20 (2–52) years later, and one patient diagnosed with CC developed duodenal CD six years later.
The common denominator was a long history of UC or CD. Due to change of clinical symptoms with onset of chronic watery diarrhoea, patients had a colonoscopy showing no endoscopic signs of active IBD, but biopsies revealed findings consistent with MC. Thus, in the majority of patients the histopathologic changes of MC were accompanied by a change of clinical presentation and symptoms, emphasizing their clinical relevance. Interestingly, eight patients had clinical recurrence of IBD 3 (1–10) years after onset of MC. Similarly, Zhang et al [Citation40] reported a case, where a patient first had LC, later developed UC and subsequently had onset of CC, and Li et al. [Citation26] reported a case where MC and UC were transformed back and forth in the later course of disease over 13 years.
In six cases, the diagnosis of MC was asymptomatic and found due to surveillance colonoscopy because of long-standing IBD. It can be questioned whether such histopathologic findings in patients with UC or CD are clinically relevant or only remnants of past mucosal inflammation [Citation12]. However, careful assessment of the biopsies at the time of diagnosis of MC revealed no features of UC or CD, but characteristic findings of MC. Diagnosis of MC based only on histopathologic criteria have been used earlier and therefore such cases were included herein [Citation41–44]. We excluded 12 cases in the literature with synchronous diagnoses of either UC or CD and CC or LC [Citation10,Citation12,Citation16,Citation26–28], and three such cases in our study. Most of these patients had clinical symptoms consistent with UC or CD, endoscopic features of IBD, histopathologic findings of IBD in inflamed areas, but findings of MC in unaffected areas. The relevance of these findings is unknown and focal LC or CC has been suggested to represent patterns of Crohn’s colitis [Citation12].
The occurrence of a previous diagnosis of UC or CD among patients with MC is unknown. Hence, we calculated the frequency in our epidemiological cohort from the Örebro University hospital catchment area [Citation34], and six out of 229 (2.6%) MC patients had a history of UC or CD. We have no such data in other participating clinics, as number of MC patients at risk was not known. In the Canadian study by Li et al. [Citation26], 44 (1.9%) of 2324 MC patients had a history of both IBD and MC, thus fairly similar to our result.
The cause of onset of MC was unknown in most patients with IBD. Drug exposure is a well-known risk factor for MC [Citation45,Citation46]. Treatment with proton pump inhibitors, mirtazapine, carbamazepine or statins in 5/31 patients may possibly have been a precipitating factor for development of MC. In one of the cases found in the literature, the development of CC in a patient with UC was suspected to be triggered by faecal microbiota transplantation due to recurrent Clostridium difficile enteritis [Citation24], and in yet another case, the onset of CC in a patient with UC occurred after treatment with high-dose chemotherapy and autologous stem-cell transplantation due to primary AL amyloidosis [Citation14].
Likely, our observations represent random occurrence of two different bowel disorders in one and same individual. The long period of 20 years elapsed between the two different diagnoses may support this view. Alternatively, it may be hypothesized that IBD and MC may share common pathophysiologic pathways and the type of inflammation depends on which luminal agent(s) triggers inflammation. However, there are virtually no immunology or pathophysiology data on patients with occurrence of both IBD and MC. In an immunohistochemistry study, Li et al. compared 20 patients with MC who evolved into IBD with 22 MC patients whose MC resolved. They concluded that increased Th1/Tc1 and TNFα-producing cells, and likely a subset of Th2/Tc2 cells, may be involved in MC-to-IBD transformation [Citation26]. An altered gut microbiome plays a role in both IBD and MC. Two controlled studies of microbiota have shown low levels of Veruccomicrobia (Akkermansia spp) in MC patients [Citation47] and of Ruminococcaceae in patients with CC [Citation48], respectively. The latter finding has been observed in patients with IBD [Citation49,Citation50] and may possibly point to common mechanisms in the pathogenesis of these diseases.
Our patients differed from the cases found in the medical literature. Almost all of our patients, 30/31 (97%), had IBD first and later were diagnosed with MC, whereas 13/27 (48%) of literature cases had MC first and later developed IBD. It is well established that age at diagnosis of IBD peaks in younger age groups, whereas MC is mainly seen in older age groups. One would, therefore, expect the development from IBD to MC to be more common, as seen in our cases, than the findings in the literature survey suggest. Of clinical interest is that all eight MC patients found in the literature search who later developed UC or IBD-U had extensive colitis (E3), and four of them underwent acute colectomy due to severe colitis 0.5–4 years after an initial MC diagnosis [Citation7,Citation9,Citation15,Citation21]. A possible reason for the differences between the cases in our study and the case reports found in the literature is publication bias, as more spectacular cases will more likely be published. There may, furthermore, be diagnostic bias, since the diagnosis of MC was not well established in the 1980s and early 1990s, and the risk of overlooking such a diagnosis in a patient who later was diagnosed with IBD will be substantial. Another possible bias is that the MC diagnosis in patients with IBD may be overlooked and misinterpreted as irritable bowel syndrome (IBS).
The key message herein is relevant in daily clinical practice. In the patient with UC or CD, who develops chronic, non-bloody diarrhoea without endoscopic relapse of mucosal inflammation, mucosal biopsies should be obtained to rule out MC. Some cases in the present study were erroneously considered at first to have diarrhoea-predominant irritable bowel syndrome (IBS-D) before biopsies were obtained and analysed. It is well established that IBS-like symptoms may occur in up to 30–50% of patients with inactive IBD [Citation51,Citation52] and there is furthermore a symptomatic overlap of MC and functional bowel disorders [Citation53–55]. Hence, a correct diagnosis of MC is important in those patients, as the therapy of choice in active MC is budesonide and different from the treatment of IBS-D [Citation33,Citation54,Citation56].
In conclusion, we found 31 patients with UC or CD who developed CC or LC or vice versa. The most common feature was IBD in younger age and onset of MC in older age and most patients had an initial diagnosis of UC and later developed CC. By adding all 142 cases identified in the literature search, a total of 173 patients were found, supporting the assertion that this issue needs attention in daily clinical practice.
| Abbreviations | ||
| MC | = | microscopic colitis |
| CC | = | collagenous colitis |
| LC | = | lymphocytic colitis |
| IBD | = | inflammatory bowel disease |
| IBD-U | = | unclassified inflammatory bowel disease |
| UC | = | ulcerative colitis |
| CD | = | Crohn’s disease |
| IBS | = | irritable bowel syndrome |
| IBS-D | = | diarrhoea-predominant irritable bowel syndrome |
Acknowledgements
We are grateful to Drs Robert Stig, Cecilia Benoni, Kenneth Lång, Olle Broström, Kristina Zachrisson, Bengt Ödman, Jonas Halfvarson, Pierre Ahlqvist, Einar Thorhallsson, Maria Wikander, Jörgen Nielsen, René Tour, Bengt Sundbaum, Anders Lindgren, Anders Lundberg, and Claes-Henrik Florén, who contributed with inclusion of patients.
Disclosure statement
Johan Bohr has served as speaker for Dr Falk Pharma, Tillotts Pharma. Andreas Münch has served as a speaker for Dr Falk Pharma, Tillotts, Abbvie and Ferring. Curt Tysk has served as a speaker for Dr Falk Pharma, Tillotts Pharma, Ferring, MSD and AstraZeneca. Lina Vigren has served as speaker for Dr Falk Pharma, Takeda, Otsuka, Abbvie and been involved in the board of two clinical trials for MSD and Abbvie. The other authors report no competing interest.
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