[résumé]
Paper reprints may be obtained from: Dr. Ernest G. Seidman, Division of GastroenterologyNutrition, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine, Montreal QC H3T 1C5; fax 514 345-4999
As in other chronic pediatric disorders such as diabetes mellitus and inflammatory bowel disease, compliance with therapy often declines dramatically during adolescence.[5] Interestingly, many adolescent patients seem to tolerate occasional or even regular amounts of gluten ingestion. Nevertheless, it is well established that in most such asymptomatic patients with celiac disease who are eating a normal diet there is histologic evidence of gluten sensitivity.[48] More recently, serologic testing for antibodies to gliadin, reticulin or endomysium has been proposed as a less invasive substitute for follow-up and post-challenge biopsy.[3] Although they may help predict the timing of histologic relapse in some patients,[6,9] such tests have not been shown to be useful in detecting the adverse consequences of prolonged ingestion of small amounts of gluten.[5,8] Histologic evidence of a relapse thus remains the gold standard for diagnosis of cases in which a challenge is deemed worthwhile.[3]
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Explanations for lack of relapse
It was previously thought that the absence of a relapse, defined on the basis of mucosal changes within 2 years of eating a normal diet, ruled out celiac disease and that patients who did not suffer a relapse probably had transient gluten intolerance. In fact, there is increasing evidence that the mucosa may deteriorate only after many years on a diet containing gluten and that this 2-year rule can be abandoned.[710] The observation that patients do not uniformly show mucosal relapse after a gluten challenge of 2 years' duration may be explained in two ways: (1) these patients may be late relapsers who do not follow the "2-year rule" or (2) celiac disease may disappear or become latent during certain periods of life, particularly adolescence. The most controversial suggestion has been that some patients with biopsy-proven celiac disease appear to recover, having a normal or "nearly normal" mucosa after long-term ingestion of a diet containing gluten.[11,12] If the abnormal reactivity of intestinal lymphocytes to gliadin can be overcome, the permanency of the sensitivity of the intestinal mucosa to gluten, from early childhood through to adulthood, is in doubt. The conclusion that a strict gluten-free diet should be maintained for life would thus be challenged.[1113] However, as we will detail, no randomized controlled study has ever supported the possibility that celiac disease is not lifelong.
Latent celiac disease
Celiac disease certainly has a highly variable clinical presentation at the time of diagnosis as well as during follow-up. Although most often diagnosed during childhood, celiac disease may first appear during adolescence or even late in adulthood.[14,15] Periods of clinical and, in some cases, histologic remission may occur, mainly during adolescence and young adulthood.[4,6,12,13] Gluten challenge in adolescents diagnosed during infancy has revealed that a relatively small percentage (11%) do not have a relapse within 2 years of the reintroduction of gluten.[6] Since normal results of biopsies have been reported after the patients had eaten normal diets containing gluten for 3 and 6 years, with subsequent histologic relapse after 9 years,[7,8,10] the 2-year rule recommended by the ESPGAN is clearly outdated. Thus, the small percentage of teenagers who have a clinical tolerance to gluten and normal or "nearly normal" results of histologic tests likely represent a subgroup of patients with "latent" celiac disease who will eventually have a relapse after years or even decades.[7,8] Declaring that such patients no longer have gluten-sensitive enteropathy is unjustified, since long-term follow-up will likely show an eventual histologic relapse upon serial biopsy. Furthermore, prolonged ingestion of gluten by patients who eventually have a subclinical relapse may be accompanied by serious complications, as we will discuss. Indeed, we and others[15] have encountered patients with celiac disease diagnosed in adulthood who had clearly suffered from malabsorption during childhood. One plausible explanation for such cases could be a transient histologic recuperation during adolescence and early adulthood. Nevertheless, this possibility does not contradict the long-lasting nature of the sensitivity to gluten, since these patients experience clinical and histologic relapses in adulthood, with potentially serious complications.[8]
The ESPGAN recommended a challenge in children with a diagnosis of celiac disease after they had eaten a gluten-free diet for some years to verify the accuracy of the original diagnosis and, hence, the permanence of the disease.[1,3] Obviously, if celiac disease is not permanent, a gluten-free diet, which is very restrictive and quite different from contemporary eating habits, is not indicated. On the other hand, by subjecting patients to a gluten challenge, one is disrupting the eating habits to which patients have generally adapted. Patients often encounter difficulties in returning to their gluten-free diet after a positive result of a challenge.[4] During a challenge, patients and their parents understandably develop hope and expectations. Since most patients have a relapse, they should be told that they must probably return to the gluten-free diet after the challenge. Nevertheless, it is important to explain that celiac disease often "disappears" during adolescence, at least in terms of clinical symptoms. We believe that patients who no longer adhere to a strict, gluten-free diet must therefore be followed throughout life with the use of serial serologic tests or biopsy to confirm any relapse as soon as possible. Only such a lifelong follow-up approach, conducted in the form of a well-controlled study, will permit us to know more about the long-term natural history of this disease in patients who eat gluten.
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Is recovery possible?
The possibility that the mucosa of patients with celiac disease may recover despite a normal diet containing gluten was first mentioned by Schmitz, Jos and Rey.[11] Three adolescents who ate a normal diet were reported as having a "nearly normal" mucosa after previously having a biopsy-proven, positive result of gluten challenge. In fact, two of these patients had eaten relatively small amounts of gluten. Moreover, it is well established that celiac disease, like other disorders of the immune system (such as inflammatory bowel disease and autoimmune hepatitis), is frequently associated with temporary, unexplained periods of remission. Similar observations involving a larger group of patients were subsequently reported by the same group in abstract form.[12] Once again, these observations were not part of a randomized study with proper control groups. A more recent study involved 21 patients who "tolerated" a normal diet over a long period.[16] Nine of these were reported to have recovered a normal or "nearly normal" mucosa. However, these adolescent patients with "tolerance" to gluten did not have entirely normal results of biopsy.[16] Such patients will be probably be late, eventual relapsers, as shown by others.[7,8,10,14] In patients eating a normal diet containing gluten, villous atrophy is taken as suggestive of active celiac disease, whereas a normal result of a biopsy indicates that celiac disease is ruled out. In fact, a normal result of a biopsy while the patient is eating gluten does not exclude celiac disease for life.
Even if a partial recovery of villi may occur in certain patients due to variation in the sensitivity of the intestinal mucosa to gluten, a reported marked increase in the gamma delta T cell receptor-positive intraepithelial lymphocytes (gamma delta+ IELs) in patients' mucosa provides evidence that celiac disease is present in a latent form.16 Patients who had a "normal" small-bowel mucosa while eating gluten but also had a marked increase in gamma delta+ IELs developed the lesions typical of celiac disease some years later.[14,17] Such cases, as well as reports of delayed mucosal relapse after years or decades of eating a normal diet, illustrate that we still do not know what exogenous triggering agent, in addition to the consumption of gluten in a genetically predisposed host, causes the onset of the disease or influences the tolerance to gluten. These possible triggering agents could include external physiologic or psychologic stressors such as a surgical intervention, pregnancy or even an acute viral infection. Randomized studies with proper control groups and a much longer follow-up are required before we accept the concept that patients with properly diagnosed celiac disease who do not have a relapse within a certain time frame while undergoing a gluten challenge no longer have celiac disease. Furthermore, specimens obtained by biopsy should be analysed not only by routine light microscopy but also by morphometric techniques and by immunofluorescence for IELs. The follow-up of such patients also requires serial bone-density measurements and anthropometric, biochemical and micronutrient analyses over a long follow-up period into adulthood. Until such properly conducted trials are published in peer-reviewed journals, we must conclude that a gluten-free diet is needed for life. The controversy seems to involve adolescent patients, since temporary histologic remissions have not been reported in patients in whom celiac disease has been diagnosed during adulthood.
Necessity of a gluten-free diet
To challenge the permanence of the disease is to challenge the necessity of adhering to a strict gluten-free diet. The strongest point in favour of strict adherence to a gluten-free diet is that patients eating a normal diet or even a diet containing only moderate amounts of gluten can experience complications, despite the absence of symptoms. Aside from the eventual risk of cancer, which largely accounts for a twofold higher death rate in adult patients with celiac disease than in the general population,[18] the long-term follow-up of patients who adopt a diet containing gluten has revealed other serious, late complications: permanent short stature, epilepsy with cerebral calcifications and osteoporosis.[8,19,20] Anemia, malnutrition and fetal growth retardation are other complications that have affected some patients who do not adhere to a gluten-free diet.[8] The ingestion of a strict gluten-free diet for 5 or more years has been associated with a significant decrease in the excess morbidity due to cancer.[21] Interestingly, it has been reported that celiac disease diagnosed in childhood does not carry an increased risk of cancer.[18] In this regard, it is notable that children in whom the disease was diagnosed according to the original ESPGAN criteria showed the best long-term compliance with a gluten-free diet.[5,8] Also, putatively asymptomatic adolescents and adults who consume gluten have been reported to "discover an unexpected feeling of well-being" upon resumption of a gluten-free diet, decades after the initial diagnosis of celiac disease.[22]
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Conclusions
The overwhelming evidence suggests that celiac disease, once properly diagnosed during childhood, adolescence or adulthood, must be considered a permanent condition. This lifelong nature of the disease certainly does not exclude temporary, unexplained periods of remission. It is well established that the presence or absence of symptoms bears no correlation with the histologic activity of the disease. Older children, adolescents and young adults often clinically "tolerate" the consumption of small or even normal amounts of gluten. With very few exceptions, however, patients in whom in celiac disease was diagnosed during childhood eventually have a relapse, proven histologically, although many years may elapse before such a relapse. Mucosal recovery observed in some patients eating a normal diet is partial in most cases and probably transient in all. Indeed, a persistent mucosal response to gluten persists in "gluten-tolerant" patients, as demonstrated by the expression of increased levels of gamma delta+ IELs, in comparison with the levels in control patients, in the mucosa.[16] The evidence supporting a permanent natural recovery linked to a decreased sensitivity of the intestinal mucosa to gluten is anecdotal at best. Most importantly, serious long-term complications may ensue despite even a relatively modest gluten intake. Therefore, recommending the long-term consumption of any gluten for either children or adults with celiac disease is not currently justified. Long-term randomized studies, involving morphometric and ultrastructural measurements that demonstrate villous integrity, the absence of abnormal inflammation and the lack of excessive long-term complications among patients eating gluten are needed before the current "zero-gluten" approach is altered. The individual variation in the disease's extent and time course does not contradict the evidence that celiac disease, once properly diagnosed, lasts throughout life, either actively, silently or latently.[23]
Acknowledgements
The publication of this article was supported in part by a grant and a Chercheurboursier clinicien Research Scholarship (E.S.) from the Fonds de la recherche en santé du Québec. We would like to thank the Canadian Celiac Association for its sponsorship of the invited speakers' program.
References