Ulcerative Colitis: only a mucosal disease?

Ulcerative Colitis has traditionally been regarded as a mucosal inflammatory disorder with at most superficial submucosal ulceration and no tendency to fibrosis, in contrast to Crohn’s Disease. Yet in very early histological descriptions of UC resection specimens, a sequence of events was proposed in which acute-phase submucosal congestion and oedema evolve over time into repair by fibrosis and possibly fat infiltration, with concomitant thickening of the muscularis mucosae and perhaps the muscularis propria. In long-standing disease, the colonic lumen may become extremely narrow, and an atrophic mucosa combines with shortening of the colon and bowel wall thickening to produce the so-called lead-pipe colon. There may be persisting symptoms even in the absence of active inflammation. Localised fixed stenotic areas of various lengths (2–30 cm), called strictures, may arise in 5%–10% of patients and must be investigated carefully for malignancy, which is present in about 25% of cases. Long disease duration (> 20 years), right-sided location of the stricture and clinical presentation with obstructive symptoms raise suspicion for malignancy [1, 2].

In spite of these findings and their potential clinical relevance, there has long been practically no histological research into the mesenchymal changes in the bowel wall in Ulcerative Colitis. A few early studies focused on benign strictures and described localised marked hypertrophy of the muscularis mucosae, which in a state of forceful contraction would both narrow the lumen and shorten the colon [3]. Also, significantly higher numbers of fibroblast growth factor-producing inflammatory cells and proliferating alpha-smooth muscle actin-positive myofibroblasts have been found in ulcers in stenotic areas than in the non-stenotic segments. This perhaps points to a phenotypic switch of fibroblasts or progenitor cells to myofibroblasts, initiated and maintained by ongoing active chronic inflammation and leading to superficial submucosal fibrosis [4]. The exact contribution of the two components, muscular hypertrophy and fibrosis, to the establishment of a particular stricture may be variable from case to case.

More general descriptions of non-strictured colectomy specimens focused initially on morphological alterations of the myenteric plexus, which shows cell damage, neuronal and glial cell loss, limited plexitis and a rarefaction and disruption of the network of interstitial cells of Cajal. These alterations may be related to an increased mast cell density and may have a pathophysiological impact on colon motility [5]. Also, the CD34+ telocyte network, which is normally present throughout the bowel wall, is severely reduced or completely absent in the muscularis mucosae and submucosa already from an early stage of fibrosis. This may remove a brake to the transdifferentiation of fibroblasts to myofibroblasts [6].

The fibrosing process itself has only recently been studied in more detail by histopathological evaluation of colectomy specimens. The results are variable and depend on disease duration and location in the bowel wall. The following findings have been described for the various bowel wall layers [7, 8]:

• Mucosal lamina propria fibrosis with deposition of collagen I and fibronectin
• Early deposition of collagen III and subsequently collagen I in a thickened muscularis mucosae and in the muscularis propria
• An initial intense congestion and microvessel proliferation in all layers of the bowel wall, followed in late Ulcerative Colitis by increasing collagen deposition and a concomitant decrease in elastic fibres, which may contribute to decreasing stretchability and ultimately stiffening of the colon

Lastly, established submucosal fibrosis has been studied in detail in multiple, transmural, well-oriented biopsies along the colon in numerous colectomy specimens, both in adults and in the paediatric patient population [9, 10]. In general, submucosal fibrosis and thickening or splitting of the muscularis mucosae have been found to be present almost exclusively in involved colon segments (increasing from proximal to distal). They are related to chronic and active chronic inflammation but may be present even in patients with a short disease duration. Most of the bowel wall thickening in long-standing disease seems to be due to thickening of the inner bowel wall layers, with no remarkable changes in the muscularis propria. Clinically refractory disease has been related to fibrosis burden. In adults, previous use of biologics has been associated with a reduced muscularis mucosae thickness while in children the opposite has been observed (perhaps because colectomy is postponed as long as possible in children).

In conclusion, transmural mesenchymal changes such as fibrosis and muscular hypertrophy can also be present in Ulcerative Colitis, although they are not as severe and extensive as in Crohn’s Disease. They are virtually absent in the non-involved colon and increase from a proximal to a distal location. They develop early on in the disease course and seem to be initiated by active ulcerating inflammation. The extent and composition of the inflammatory cell infiltrate, locally produced growth factors, loss of normal cell populations and phenotypic switches between mesenchymal cell types may all be related to the early phase of the fibrosing process. With chronic non-resolving inflammation, fibrosis becomes established and may extend from an initial superficial submucosal location to the deeper bowel wall layers. Progressive fibrosis may be accompanied by a loss of the elastic fibre network and by damage to the myenteric plexus, both of which would contribute to dysmotility. Ultimately, extensive mucosal fibrosis and muscularis mucosae thickening may cause a decrease in colonic diameter and a shortening of the colon, which will perpetuate functional symptoms such as abdominal pain, diarrhoea, urgency and incontinence even if no active inflammation remains.

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