This study investigates the natural history of CCD and provides both new results and confirmation of results already reported in the literature.
Although the complications of CD tend to develop just after the diagnosis of CD in most cases, these complications can also arise even after many years (Figure 1). This confirms the well-known importance of maintaining a regular clinical follow up in all coeliac patients, especially those diagnosed in adulthood. Very interestingly, we demonstrated that on the basis of the initial response to a GFD it is possible to identify two different clinical forms of CCD and that these present substantial differences in terms of survival (Figure 3). In patients who develop a complication after remission of the symptoms that led to the initial diagnosis of CD (type B cases), the prognosis is better than in patients in whom the complication of CD developed without the initial symptoms ever going into remission (type A cases). To explain this finding, we noted that EATL, UJI and SBC are more frequent among cases type A than cases type B. On the other hand, RCD1 is more frequent among cases type B. Thus, we could hypothesise that, in those coeliac patients who developed complications very rapidly without GFD being able to induce any remission of the symptoms, a malignant complication had already been triggered when CD was diagnosed. The course of the disease was therefore much more aggressive. Finally, since nowadays there is no efficient treatment for these complications , this finding is unlikely to have an immediate, strong clinical impact. Nevertheless, it certainly helps in better understanding the clinical course of these conditions and in figuring out their prognoses.
As regards the different histopathological subtypes, we showed that RCD, UJI, and EATL, the complications well-known to share a common pathogenetic link , are definitely the most common complications (64/87, 73.5%), SBC and ABL occur in 18% and 7% of the cases respectively, and CS seems to be exceptionally rare. Having found that almost 75% of the cases share a common pathogenetic link and that the others are affected by abdominal malignancies certainly supports are choice of considering all the cases as affected by CCD. According to our data, survival in each of these subtypes does not appear to be significantly different. However, since the literature reports very different survival rates for each of these subtypes of complication [8–12], we believe that our result is due to the relatively limited size of our sample rather than to a really similar mortality.
Patients with RCD2 have already been found to be significantly more anaemic and hypoalbuminemic than patients with RCD1 . Here we show that, already at the time of diagnosis of CD, not only haemoglobin and albumin but also electrolytes and cholesterol are significantly reduced in coeliac patients who will later develop complications compared to coeliac patients who will respond to a GFD. The reason why these nutritional parameters are lower in the first ones is likely to be linked to the fact that they are almost always affected by a classic/major form of CD (Table 1). On the other hand, the increased levels of ESR and CRP we found in some cases suggest that an increased systemic inflammatory response, likely to be linked to the onset of the complication, was already present at the time of diagnosis of CD.
Our study made it possible to confirm a series of results already present in the literature, and this is an obvious demonstration of the validity of all our results. In particular, we confirm that the complications of CD are burdened by a high rate of mortality and that death occurs soon after the diagnosis of the complication (Figure 2). We also confirmed that coeliac patients who do not adhere to a strict GFD, with symptoms of classic CD at the onset and with a diagnosis late in life are at greater risk of developing these complications .
This study also presents some problems, linked fundamentally to its retrospective and multicentre nature. The study is based on 87 cases who had been attending 11 different Italian centres over the last 15 years; 37 of them were already dead when the data were collected. Moreover, the diagnoses of the CCD subtypes were those made by the individual centres and it was not possible to bring them into line. While this is probably not a problem as regards the diagnosis of lymphoma and cancer of the small intestine, it is inevitable that it influenced the differential diagnosis between RCD1 and RCD2, a diagnosis that has only been possible for a few years and certainly not in all centres. This type of problem is, on the other hand, well known and already reported in the literature . Moreover, in seven of our cases of RCD the available data did not make it possible to distinguish between type 1 and 2. Evaluation of the strictness of a GFD was also necessarily based on the clinical judgement of each centre, without it being possible to even out this evaluation. Finally, our median follow up was rather short (2,9 years). However, this was due to the rapid onset of most complications and to their severe prognosis.
These organisational problems could be resolved with a prospective study. This is, however, very difficult to organise. Since CCD develops in less than 1% of patients [4–6, 8], then to enrol at least 100 patients with CCD we would have to diagnose at least 10000 new adult patients with CD, follow them for several years before identifying those that will develop a complication and then study their clinical evolution and survival.