Discussion
In this large cohort of celiac disease patients who had undergone a follow-up biopsy after 1 year on diet, the most prominent factor predicting incomplete small-bowel recovery was the presence at diagnosis of more severe disease in terms of histology and serology and signs of malabsorption. Further, while mucosal recovery was still ongoing, most of the clinical parameters measured had improved and were already at the same level in the Atrophy and Recovery groups, and the groups also showed no difference in long-term outcomes. Although the patients with incomplete recovery represented one-third of the subjects here, we have shown that in a highly adherent population at least 96% of patients achieve complete recovery on long-term treatment and only 0.3% develop refractory celiac disease. In accord with this, only 2.3% of all patients here still showed no signs of histological improvement after 1 year, and only one presented with complications and type I refractory disease. These findings indicate that follow-up biopsy after 1 year correlates poorly with clinical outcome and long-term prognosis, and represents only a 'snapshot' rather than the end point of ongoing mucosal healing.
Altogether, 68% of the subjects evinced morphological mucosal recovery after 1 year on diet, which is in fact a relatively high percentage compared with previous reports. Nevertheless, it is in line with our previous studies and very likely reflects the generally high dietary adherence in Finland. The good availability and strict labeling of gluten-free products and financial subsidization by the government are all likely to reduce inadvertent gluten intake. This was seen in the present study, as both the histologically recovered and non-recovered patients showed, in global perspective, excellent dietary adherence. It is thus evident that, in contrast to many previous reports, dietary lapses explained only a small minority of non-responsive cases in this study.
The most conspicuous difference here was in the presence of more severe mucosal damage in the Atrophy group at diagnosis. In accord, Rubio-Tapia et al. discovered an association between the severity of the baseline damage and slow histological recovery. Another recent study showed that patients with less severe atrophy were also more likely to respond to the diet. However, this was the first time a quantitative approach has been used to assess the actual speed (ΔVh/CrD) of villous recovery and it was observed to be lower in the Atrophy group. This slower recovery combined with severe atrophy at diagnosis explains why these patients had not regained normal mucosa during 1 year despite a strict diet. Some studies have indirectly investigated whether the speed of histological recovery is associated with the severity of the baseline damage, but results have been controversial. This might be explained by differences in dietary adherence and by the use of inexact grouped classifications (e.g., Marsh) in histology.
Another indicator of the presence of more severe disease in the Atrophy group at diagnosis was their higher levels of TG2ab, even if these antibodies are poor predictors of the severity of histological and clinical findings in individual patients. TG2ab also remained at a higher level in the incompletely recovered patients after 1 year, with the difference, however, being small and the median values in both groups falling within normal limits. Further, most of the patients in the Atrophy group also became seronegative, indicating that the disappearance of the antibodies occurs faster than the healing of the mucosa.
Of clinical presentations, the presence of malabsorption was associated with histological non-recovery. This was most evident in the lower levels of iron as well as hemoglobin in the Atrophy group. These results, together with the lower BMD T-scores also observed, probably reflect insufficient absorption of nutrients in patients with severe villous atrophy. Previous studies have likewise found a correlation between the presence of anemia at diagnosis and more severe histological and clinical presentation. Despite the differences in mucosal healing, after 1 year all laboratory values, excluding a minor difference in hemoglobin, were comparable in both groups. This demonstrates that, as with serology, on treatment laboratory values improve faster than the mucosa. In contrast, BMD, although improved, still remained lower in the Atrophy group after 1 year on diet. Obviously, normalization of BMD takes more than 1 year to complete.
Similar to most of the other clinical parameters, we found no association between self-perceived symptoms and quality of life and mucosal recovery at follow-up. In fact, there was no significant difference between the groups even at diagnosis, this probably reflecting the high individual variation in these respects. On the contrary, there was a trend toward poorer GSRS and PGWB values at baseline in the Atrophy group, whereas after 1 year the results were practically identical. These findings further indicate that histological healing lags behind clinical recovery.
The poor correlation between histological recovery and other outcomes indicates that a follow-up biopsy taken after 1 year is not an optimal approach in monitoring celiac disease. Our long-term follow-up results support this view, as there were no differences between the groups in mortality and other complications or in gastrointestinal symptoms and quality of life. Then again, although their prevalence remains unclear, the risk of severe complications in the long run has been associated with incomplete mucosal recovery and warrants careful follow-up. Unfortunately, there are currently no sensitive surrogate markers for ongoing mucosal damage, and endoscopic investigations are still needed. Nevertheless, here only 1 out of 87 subjects evincing incomplete recovery after 1 year presented with complications, suggesting that in almost all cases it is merely a question of slow mucosal healing. Our results support the need to individualize the current procedures, taking into account both the baseline severity of the disease and the dietary response. Whether a routine follow-up biopsy is mandatory for all patients who have uncomplicated celiac disease with good clinical response is a subject for future studies.
Major strengths of this study are the large number of patients and the diversity of outcomes measured, and the use of validated questionnaires. Further, the fact that follow-up biopsies were taken systematically after 1 year and were analyzed by quantitative Vh/CrD reduces the risk of misclassification bias. We were also able to collect a substantial body of long-term follow-up data regarding mortality and other complications. The high dietary adherence in our cohort enabled us to evaluate other causes behind non-recovery than the usually dominating poor compliance; however, the results may not be directly applicable to countries where dietary lapses are common. A limitation is that we were not able to compare subjects consenting to follow-up biopsy and those who refused (~15% of subjects in our center). This may cause bias as non-compliant patients may be more prone to refuse, and lack of follow-up biopsy has also been associated with increased mortality. Also, no systematic follow-up was undertaken for those with incomplete recovery, as in our settings patients with uncomplicated disease are assigned to primary health care for further follow-up. Nevertheless, according to our clinical practice patients with persistent atrophy would have been referred to us for further investigations. Finally, as the study was initiated before routine biopsies from the duodenal bulb were recommended, they were not systemically taken, and thus some cases with lesion only in the bulb might have been missed.
In conclusion, we showed that only the presence of more severe disease in terms of histology and serology were associated with incomplete histological recovery at the follow-up biopsy. Moreover, differences in the speed of mucosal healing were not reflected in the short- or long-term clinical outcomes. Based on these findings a more personalized approach should be adopted when deciding the optimal timing of the histological follow-up. One year is often too short a time for the mucosa to recover, and postponing the biopsy, e.g., for another year, would presumably result in lower number of cases with ongoing atrophy.