Review
Differential diagnosis of inflammatory bowel disease: imitations and complications

https://doi.org/10.1016/S2468-1253(18)30159-6Get rights and content

Summary

Inflammatory bowel disease (IBD) is characterised by episodes of relapse and periods of remission. However, the clinical features, such as abdominal pain, diarrhoea, and rectal bleeding, are not specific. Therefore, the differential diagnosis can include a broad spectrum of inflammatory or infectious diseases that mimic IBD, as well as others that might complicate existing IBD. In this Review, we provide an overview of ileocolitis of diverse causes that are relevant in the differential diagnosis of IBD. We highlight the importance of accurate patient profiling and give a practical approach to identifying factors that should trigger the search for a specific cause of intestinal inflammation. Mimics of IBD include not only infectious causes of colitis—and particular attention is required for patients from endemic areas of tuberculosis—but also vascular diseases, diversion colitis, diverticula or radiation-related injuries, drug-induced inflammation, and monogenic diseases in very-early-onset refractory disease. A superinfection with cytomegalovirus or Clostridium difficile can aggravate intestinal inflammation in IBD, especially in patients who are immunocompromised. Special consideration should be made to the differential diagnosis of perianal disease.

Introduction

Ulcerative colitis and Crohn's disease, also known as inflammatory bowel disease (IBD), are characterised by episodes of relapse and periods of remission. The clinical features typically include abdominal pain, diarrhoea, and rectal bleeding. However, many other intestinal or systemic symptoms can occur, such as weight loss, fever, fatigue, nausea or vomiting, or even extra-intestinal disease manifestations.1, 2 Available biomarkers do not have the specificity to differentiate IBD from other causes of ileocolitis.3 Serological tests, such as anti-neutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies, have low diagnostic accuracy and are therefore used as adjunct measures to diagnosis.1 Characteristic endoscopic findings of ulcerative colitis include confluent colonic inflammation commencing from the anal verge, which typically involves the rectum, and a clear demarcation of the inflammation.4 Crohn's disease features patchy inflammation with so-called skip lesions and areas of macroscopically normal mucosa in between. Inflammation in Crohn's disease is represented by aphthous, deep, linear, stellate, or serpiginous ulcers, which can be associated with a cobblestone appearance.4 Two representative biopsies from each of the six segments that are visualised during colonoscopy are recommended to obtain a diagnosis of Crohn's disease.4 Basal plasmacytosis is the earliest histopathological feature with the highest predictive value for diagnosis of ulcerative colitis.5 Mucosal or crypt architectural distortion appear afterwards during progression of the disease. Non-caseous granulomas are detectable in about 50–60% of cases of Crohn's disease, with detection depending on the severity of inflammation and the number and location of biopsies taken.6

Although these characteristic diagnostic findings are well known, none of the individual items is solely specific for IBD. Therefore, diagnosis is always based on the combination of clinical symptoms, serology, imaging and endoscopy appearance, and histopathology.1, 2 The differential diagnosis includes a broad spectrum of inflammatory diseases that mimic IBD or others that can complicate existing IBD.

The purpose of this Review is to provide an overview of various causes of ileocolitis that are relevant for the differential diagnosis of IBD. We highlight the importance of patient profiling and provide a practical approach to identify factors that should trigger the search for a specific cause of intestinal inflammation. Additionally, special consideration is dedicated to the differential diagnosis of perianal disease.

Section snippets

Intestinal tuberculosis

Tuberculosis is a primary differential diagnosis of IBD in patients in endemic areas, in patients migrating or travelling from endemic areas, and in immuno-compromised individuals.7 The pathophysiological mechanisms of intestinal tuberculosis transmission include the ingestion of infected sputum or contaminated beverages, but the disease can also be haematogenous or spread directly from adjacent organs in an individual with tuberculosis.8 The clinical presentation of intestinal tuberculosis can

Ischaemic colitis

Ischaemic colitis arises when blood supply is acutely compromised in a setting of low flow state, such as cardiac insufficiency or dehydration. However, in most cases, no specific cause can be identified.34 Transient ischaemia leads to mucosal damage first at the most vulnerable sites, such as the splenic flexure and the rectosigmoid junction, where the so-called watershed areas of vascular supply are located.35 By contrast with other inflammatory or infectious conditions, symptoms of ischaemic

Non-steroidal anti-inflammatory drugs (NSAIDs)

The upper gastrointestinal damage caused by NSAIDs is well known. However, lower gastrointestinal injury is also common, although frequently subclinical.44 Diaphragm-like strictures are pathognomonic of NSAID injury.45 Multiple lesions can occur and cause obstructive symptoms, which can require balloon dilation—if the area is endoscopically accessible—or surgical resection. Further non-specific findings can include erosions, ulcers, and colitis, all of which should improve after drug

Monogenic diseases that mimic IBD

Children with very early disease onset (ie, aged 6 years or younger) have a particularly high risk of having an IBD-like intestinal inflammation induced by an underlying monogenic disease.55 Although challenging, diagnosis should be sought, because mortality and morbidity is high for these monogenic diseases and treatment options can differ from those for IBD.

Monogenic diseases have been found to alter intestinal immune homoeostasis through several mechanisms; for example, X-linked ectodermal

Segmental colitis associated with diverticulosis (SCAD)

Patients with SCAD usually present with rectal bleeding and, occasionally, with abdominal pain and diarrhoea. The endoscopic appearance of SCAD is typically segmental colitis restricted to the sigmoid colon, in the area of the diverticular disease (figure 3).63 Histological examination can reveal non-specific mucosal inflammation. SCAD has a self-limited course and usually resolves spontaneously without further recurrence.

Diversion colitis

Diversion colitis occurs in segments of the bowel that have been excluded

Clostridium difficile infection

C difficile infection has become increasingly common in patients with IBD and is associated with increased hospital admissions, colectomy rates, and mortality.68 Risk factors are similar to those in people without IBD, including antibiotic use, older age, and immunosuppressive treatment. Additionally, patients with IBD are at increased risk of a recurrent episode of C difficile infection.69 Therefore, screening for C difficile is recommended at every flare in patients with IBD and colonic

Perianal disease

During the course of Crohn's disease, approximately 30% of patients develop at least one fistulising episode.74 Perianal disease is frequently accompanied by luminal activity, but can also be the initial manifestation of Crohn's disease, preceding the onset of luminal disease in about 10% of patients.74 Additionally, non-fistulising perianal manifestations, such as skin tags, fissures, ulcers, and strictures are also associated with Crohn's disease in up to a quarter of patients. However, in

Conclusions

The clinical presentation of IBD is not specific, and diagnosis is based on the combination of symptoms, laboratory findings, imaging and endoscopy, and histopathology. The differential diagnosis includes a broad spectrum of inflammatory diseases that mimic IBD and others that can aggravate inflammation in existing IBD. In this Review, we have highlighted specific patient profiles that should trigger the search for an underlying cause, different from that of IBD. Careful profiling and

Search strategy and selection criteria

We searched PubMed for articles published up to Aug 31, 2017. We used general search terms, such as “[inflammatory bowel diseases OR Crohn OR ulcerative colitis] AND [differential]”, and specific search terms were used to identify further differential diagnoses, including “[colitis OR proctitis OR enteritis] AND [intestinal tuberculosis OR Yersiniases OR Y enterocolitis OR Actinomycosis OR Actinomyces israelii OR chlamydiasis OR Chlamydia trachomatis OR herpes simplex OR syphilis OR Treponema

References (83)

  • W Marlicz et al.

    Nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and gastrointestinal injury: contrasting interactions in the stomach and small intestine

    Mayo Clin Proc

    (2014)
  • MK Selbst et al.

    Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil

    Mod Pathol

    (2009)
  • LE Cheng et al.

    Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome

    Clin Immunol

    (2009)
  • F Meissner et al.

    Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease

    Blood

    (2010)
  • BI Korelitz et al.

    Proctitis after fecal diversion in Crohn's disease and its elimination with reanastomosis: implications for surgical management. Report of four cases

    Gastroenterology

    (1984)
  • S Johnson

    Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes

    J Infect

    (2009)
  • S Ben-Horin et al.

    Prevalence and clinical impact of endoscopic pseudomembranes in patients with inflammatory bowel disease and Clostridium difficile infection

    J Crohns Colitis

    (2010)
  • B Siegmund

    Cytomegalovirus infection associated with inflammatory bowel disease

    Lancet Gastroenterol Hepatol

    (2017)
  • DA Schwartz et al.

    The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota

    Gastroenterology

    (2002)
  • F Gomollon et al.

    3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management

    J Crohns Colitis

    (2017)
  • F Magro et al.

    Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders

    J Crohns Colitis

    (2017)
  • S Vermeire et al.

    Laboratory markers in IBD: useful, magic, or unnecessary toys?

    Gut

    (2006)
  • G Schumacher et al.

    A prospective study of first attacks of inflammatory bowel disease and infectious colitis. Histologic course during the 1st year after presentation

    Scand J Gastroenterol

    (1994)
  • MT Weng et al.

    Seminar report from the 2014 Taiwan Society of Inflammatory Bowel Disease (TSIBD) spring forum (May 24th, 2014): Crohn's disease versus intestinal tuberculosis infection

    Intest Res

    (2015)
  • JB Marshall

    Tuberculosis of the gastrointestinal tract and peritoneum

    Am J Gastroenterol

    (1993)
  • GK Makharia et al.

    Anti-Saccharomyces cerevisiae antibody does not differentiate between Crohn's disease and intestinal tuberculosis

    Dig Dis Sci

    (2007)
  • Z Kurti et al.

    Tuberculin skin test and quantiferon in BCG vaccinated, immunosuppressed patients with moderate-to-severe inflammatory bowel disease

    J Gastrointestin Liver Dis

    (2015)
  • BJ Kim et al.

    Prospective evaluation of the clinical utility of interferon-gamma assay in the differential diagnosis of intestinal tuberculosis and Crohn's disease

    Inflamm Bowel Dis

    (2011)
  • R Mao et al.

    Computed tomographic enterography adds value to colonoscopy in differentiating Crohn's disease from intestinal tuberculosis: a potential diagnostic algorithm

    Endoscopy

    (2015)
  • YJ Lee et al.

    Analysis of colonoscopic findings in the differential diagnosis between intestinal tuberculosis and Crohn's disease

    Endoscopy

    (2006)
  • GK Makharia et al.

    Clinical, endoscopic, and histological differentiations between Crohn's disease and intestinal tuberculosis

    Am J Gastroenterol

    (2010)
  • MA Almadi et al.

    Differentiating intestinal tuberculosis from Crohn's disease: a diagnostic challenge

    Am J Gastroenterol

    (2009)
  • CC Boehme et al.

    Rapid molecular detection of tuberculosis and rifampin resistance

    N Engl J Med

    (2010)
  • D Hillemann et al.

    Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system

    J Clin Microbiol

    (2011)
  • J Limsrivilai et al.

    Meta-analytic bayesian model for differentiating intestinal tuberculosis from Crohn's disease

    Am J Gastroenterol

    (2017)
  • P Nahid et al.

    Executive summary: official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical practice guidelines: treatment of drug-susceptible tuberculosis

    Clin Infect Dis

    (2016)
  • T Dalby et al.

    Development of an LPS-based ELISA for diagnosis of Yersinia enterocolitica O:3 infections in Danish patients: a follow-up study

    BMC Microbiol

    (2017)
  • M Leirisalo-Repo

    Yersinia arthritis. Acute clinical picture and long-term prognosis

    Contrib Microbiol Immunol

    (1987)
  • SM Ostroff et al.

    Clinical features of sporadic Yersinia enterocolitica infections in Norway

    J Infect Dis

    (1992)
  • JR Cintron et al.

    Abdominal actinomycosis

    Dis Colon Rectum

    (1996)
  • VK Wong et al.

    Actinomycosis

    BMJ

    (2011)
  • Cited by (84)

    • Crohn's disease

      2024, The Lancet
    View all citing articles on Scopus
    View full text