Histological Recovery and Gluten-free Diet Adherence

Discussion

This study shows that complete histological recovery is obtained in 66% of patients after 1 year of adequate GFD. It has previously been observed that GFD adherence is highly variable, depending on the population considered; indeed, strict adherence was observed over a range from 36% to 93%.^{[16,21,22,25–30]} In previous studies, interviews performed by dedicated dieticians or using unvalidated questionnaires represented the most common methods of assessing GFD adherence. In our study, we observed that 81.5% of patients had an adequate adherence to the diet, a higher percentage than that observed in previous studies. Most likely, each patient's awareness of his or her study participation represents a valid explanation for the observed high adherence to GFD; such a phenomenon was also reported by the recent BSG guidelines.^[15] The use of a validated dietary questionnaire,^[23] also validated in a multicentre setting,^[24] at the 1-year follow-up point is a simple and practical method of discriminating those patients with adequate adherence to the diet from those with inadequate adherence.

Concerning mucosal healing, previous studies showed that the percentages of histological recovery after starting GFD are extremely broad, ranging from 8% to 96%, with a median of 46%. However, these results were mostly obtained regardless of the patient's adherence to GFD.^{[11,16–21,25–27,31]} Although the majority of these studies delegate dietary assessment to dieticians, differences in the methods used and the lack of a validated tool for dietary assessment may explain the observed results' variability. It has been well established that coeliac patients with inadequate adherence to diet do not completely recover from the histological mucosal damage.^[4,8] Our results show that none of the patients with inadequate GFD adherence completely recovered from histological damage; 58.3% showed only partial histological recovery, whereas 41.7% did not achieve any histological recovery. This finding suggests that a validated dietary assessment may be used as a tool to identify those patients who do not follow an adequate GFD to avoid useless gastroscopic control.

Another innovative aspect of this study is represented by the histological criteria used for complete mucosal recovery. The latter status is defined as the absence of villous atrophy and crypt hyperplasia in presence of normal lymphocytic infiltrate (≤30/100 IELs, Marsh 0). Previous studies have considered the disappearance of villous atrophy alone to signal histological healing after GFD, thereby considering non-atrophic damages, such as Marsh 1 and Marsh 2 as histological healing. Most authors have considered both lymphocytic infiltration and crypt hyperplasia as lacking specificity.^{[11,17,20,23,26,31–35]} However, the data on the outcomes of non-atrophic lesions in patients with CD have been poor and conflicting,^[10,20] particularly because there are insufficient studies on coeliac patients after GFD.^[35] For this reason, we believe that the absence of villous atrophy and crypt hyperplasia in presence of normal lymphocytic infiltrate is truly representative of histological healing, according to the standardised classification (Marsh modified by Oberhuber).^[1,3]

Another peculiar aspect of our study is that we enrolled only adult CD patients. Many studies have considered both adults and children.^{[10,17,19,20,32]} However, intestinal histological healing in children after GFD has been shown to occur earlier and to a greater extent than in adults, with a complete histological recovery of 95%.^{[11,19,20,25]} We believe that the enrolment of both children and adults in the same study may be misleading, ultimately resulting in an overestimation of the complete histological recovery.

Coeliac antibody positivity has been described as both linked^[22,25] and not linked^[12,27,28] to GFD adherence. In our study, serum antibodies (Ab tTG IgA and/or EMA) were positive after 1 year in patients with adequate and inadequate adherence to GFD, with overlapping percentages (29.7% and 30%). This result suggests that evaluating serum antibodies during GFD does not clearly distinguish patients with adequate GFD adherence from those with inadequate adherence.

Several studies have shown that antibody positivity after the start of GFD is more frequently associated with intestinal damage;^[17,25,27] moreover, antibody negativity is not necessarily related to histological recovery and may in fact be associated with false-negative results.^{[7,10,11,19,22,25,27]} In our study, antibody seroconversion after 1 year of GFD did not always indicate a complete resolution of the histological damages because seroconversion was evident in 64.7% of patients with partial histological recovery. In addition, the antibodies were still positive in 24.1% of patients with complete recovery of histological damage; this percentage was not different from that of patients with partial histological recovery (24.1% vs. 35.3%, P = 0.309). This finding confirms the possibility of antibody positivity in patients with complete mucosal recovery, as previously reported.^[6,10,27] Thus, the determination of antibodies as a surrogate marker of histological healing and GFD adherence should be used with caution.

Symptom evaluation after 1 year of adequate adherence to GFD shows that well-being is obtained in a higher percentage of patients with complete histological recovery (91.5%) than in patients with partial histological recovery (76.5%), although these values are not significantly different. This result suggests that symptom resolution after 1 year of adequate adherence to GFD is not strictly associated with complete histological recovery. This finding is consistent with those of other studies reporting that, despite clinical improvements during GFD, histological damage may persist because clinical well-being is observed after a few months of GFD, though complete histological recovery takes more time.^[6,13,14,26]

A lack of adequate adherence to GFD has been described as the most common cause of persistent symptoms in CD.^[25,36] In fact, this study shows a highly significant persistence of clinical symptoms among patients whit inadequate adherence to the diet compared with those with adequate adherence (P = 0.0001). Our study confirms that persistence of symptoms may be indicative of an inadequate adherence to GFD.

Our results show that after 1 year of GFD, the BMD and biochemical/nutritional parameters were not significantly different between patients with partial and complete histological recoveries. Previous studies assessing the effect of GFD on BMD and biochemical/nutritional parameters have shown that after the beginning of GFD, there is a gradual improvement in these parameters that may not align with the histological recovery.^[37,38] These data suggest that even nutritional parameters may not be reliable markers to assess recovery from histological damage.

The factors that influence histological healing in coeliac patients on GFD include age at diagnosis,^{[16,19–21,32]} severity of histological damage,^{[16,20,21,26]} gender,^[16,32] duration^[21,26,32] and adherence to GFD.^[16,32] In our study, we used a logistic regression model to evaluate the reported risk factors for a lack of complete histological recovery. A higher degree of histological damage at diagnosis (Marsh 3C) emerged as the only significant influence. According to our results, patients with more severe histological damage at diagnosis will have a longer histological recovery time suggesting that in adult coeliac patients, despite a strict adherence to GFD, severe damage may require longer than 1 year for complete recovery. Consequently, the repetition of the gastroscopic and histological assessment should be delayed to 18–24 months.

Considering the significant association between persistent histological damage and the risk of lymphoproliferative malignancies,^[26,39] an important conceptual question should be asked of our study. How should we consider patients with a partial histological recovery after 1 year of adequate GFD? For instance, such patients could be considered 'slow responders',^{[10,13,26,31,32,39]} exhibiting a gradual healing process without risks of malignant complications, or 'histologically refractory',^[10,13] reflecting the persistence of histological damage and consequent risk for malignant complications. Although, the present study is not able to settle this question because it was designed to obtain data on the first year of follow-up, it should be kept in mind that no agreement exists regarding the best timing for repeated gastroscopic/histological testing in coeliac patients. This lack of agreement is even less clear in patients who do not achieve complete histological recovery after beginning GFD. Therefore, the present results suggest further research into establishing an optimal timing for repeated gastroscopic/histological assessments in coeliac patients.

In conclusion, this prospective study shows that after 1 year of GFD adherence among adult patients completing a validated dietary questionnaire, complete histological recovery was obtained in two-thirds of the subjects. Furthermore, patients with more severe histological damage (Marsh 3C) at diagnosis are at greater risk for incomplete histological recovery at the 1 year.

Aliment Pharmacol Ther. 2014;40(6):639-647. © 2014  Blackwell Publishing