A new form of chronic inflammatory bowel disease associated with chronic liver disease

In this issue of SJG, Mousatta et al. report on their findings of an isolated ileitis in three patients with primary sclerosing cholangitis (PSC). The interest here is that the majority of patients with PSC have a colitis, mostly labelled as ulcerative colitis (UC) and very rarely Crohn’s colitis with or without small bowel involvement, but there are very few cases of isolated small bowel involvement of Crohn’s disease.[1,2] The findings of Mousatta et al. are not earth shattering, but timely for those who are involved in the care of these patients and classic inflammatory bowel disease (IBD) as there is a wider issue emerging, which has been somewhat suppressed by the traditionalists (conservative clinicians!).

Gastroenterologists, as in other specialties, can be divided into clinicians and academics; the former (lumpers) like to lump clinical findings into diagnostic categories whereby treatment is simplified by following algorithms and academics (splitters) who enjoy teasing out specific pheno- or genotypes from the pool of patients with a specific diagnosis with the connotation that the aetiology, pathogenesis, prognosis and perhaps treatment of these sub-groups may differ.

Clinical consensus has it that PSC is associated with UC in the vast majority of these patients. This is widely accepted, but not all is well when we look at the facts. These patients differ significantly from patients with classic UC: the clinical course of disease is much milder with infrequent clinical relapses, the prevalence of colorectal cancer is much higher, rectal sparing is the rule rather than the exception, the genetics are completely different and the rate of pouchitis following ileoanal pouch construction is many times greater.[1,3,4] Indeed, the incidence of pouchitis is greater than in patients with Crohn’s disease [5] where these types of operation have largely been abandoned. Yet, the clinicians are content and surgeons continue with their pouches!

PSC has two other closely related liver disease equivalents, namely autoimmune hepatitis (the two are often considered at the opposite spectrum like UC and Crohn’s disease) and what has been termed as an overlap syndrome, namely autoimmune sclerosing cholangitis (ASC).[6,7] The 3 have distinctive common and discriminating clinical and diagnostic features, but all share the UC like colitis, being progressively less common with ASC and autoimmune hepatitis.

ASC was only described as a distinct clinical entity this century and is the least well characterized of these 3 disorders from the gastrointestinal point of view.[6] Nevertheless the colitis associated with ASC does not seem to differ substantially from that of PSC associated UC. A systemic exploratory approach was made to compare the two.[8] Hence colonoscopy marco and microscopy, faecal calprotectin and capsule enteroscopy findings were reviewed or assessed in a group of PSC and ASC patients who had relatively mild clinical disease activity scores. The essential findings were that the colitis in both disorders was practically identical. The microscopy findings confirmed predominantly right sided disease with rectal sparing except when the disease was very active in which case the rectum was inflamed but proportionally less than the right side; hence the term relative rectal sparing. The histology although consistent with UC was usually that of a nonspecific mild colitis and showing somewhat less of the characteristic features of UC, namely only very mild if any goblet cell depletion, crypt abscesses and crypt branching. Nevertheless, intestinal inflammatory activity, assessed as faecal calprotectin, was similar to that of classic IBD (UC and Crohn’s), suggesting a more rapid transfer of neutrophils across the mucosa into the intestinal lumen than in classic IBD (the transit and localization – accumulation of neutrophils depends on the site of neutrophil chemoattractant and activation). However, and this is the main point, one-third of the patients with ASC had small bowel capsule enteroscopy findings of mucosal breaks (erosions and/or ulcers), scattered throughout the small bowel, that are impossible to distinguish from Crohn’s disease (and other similar pathology, such as NSAID-enteropathy), although the clustering of these lesions and confluence of inflammation in the distal terminal ileum was not as apparent as in Crohn’s disease. Patients with PSC however had normal small bowel capsule findings, apart from a few that had very mild changes that were reminiscent of small bowel bacterial overgrowth (patients with PSC and ASC were on identical immunosuppressive drugs).

How do we interpret these findings? The clinicians would have us believe that having a colitis and small bowel disease simply transfers the diagnosis from UC to Crohn’s and the two-thirds of ASC patients without small bowel involvement remain as UC. Furthermore, whatever particular diagnostic label you put on this, they would argue, it does not matter so much as the treatment is identical to classic IBD.

We, the splitters, would argue forcibly and with passion that even before this study the clinical features (detailed above) of PSC associated UC differed significantly and in such a major way from that of classic UC and the two sit uncomfortably under the same diagnostic umbrella.[1,3,5] Similarly there is no real justification in calling the IBD associated with ASC (small bowel pathology with a colitis that is indistinguishable from the PSC-UC) Crohn’s disease as there are no other cardinal features of Crohn’s disease in these patients clinically or on investigation.

Clinicians have sought to incorporate many colitides under the umbrella of classic IBD. Intestinal inflammation due to drugs, including NSAIDS and the contraceptive pill, the inflammation associated with Chronic Granulomatous Disease of Childhood,[9] oro-facial granulomatosis, cystic fibrosis, glycogen storage disease,[10] Ankylosing spondylitis and other spondylo-arhtropathies,[11] but these have largely been found to be distinctively different from classic IBD. Many of these diseases had fewer common features with classic IBD than the colitis of PSC, ASC and autoimmune hepatitis. The time may therefore have come to have a comprehensive reassessment of the colitis associated with these liver diseases, which only superficially resemble classic UC. In a way, the realization that this colitis differs from UC is already evidenced in practice in that these patents have yearly colonoscopy surveillance because of the vastly increased risk of colorectal cancer, not least once they have had a liver transplant. The protocols for maintenance treatment and relapses of the disease may not differ significantly from IBD, but once surgery is contemplated the choice of surgery certainly should differ significantly from that practiced for UC (many colorectal surgeons are not aware of this) and of course it will be important to elucidate and contrast the aetiology and pathogenesis of the colitis and entero-colitis associated with these chronic liver diseases from classic IBD. Perhaps, the best term is chronic IBD in patients with chronic liver disease.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.