Celiac disease is a lifelong disorder
That celiac disease is a lifelong disorder was suggested by clinical
case records and was considered to have been demonstrated through
the widespread use of intestinal biopsies by the end of the 1950s.
It was clear that the mucosal lesions observed in children and
adults were identical and responded similarly to gluten withdrawal.
In fact, in 1970 the European Society for Paediatric Gastroenterology
and Nutrition instituted the practice of a challenge after diagnosis.
A relapse of clinical symptoms and of the intestinal lesions after
gluten was reintroduced into the diet demonstrated the "permanent"
nature of sensitivity to gluten in children with celiac disease.
Twenty-five years later, the permanence of the sensitivity of
the intestinal mucosa to gluten is again a matter of debate. Several
lines of evidence, gathered during recent years, show that celiac
disease is not always a lifelong condition. First, the long-term
follow-up of children with proven celiac disease shows that 10%
to 20% of them become "tolerant" (defined on clinical,
biological and histologic grounds) to gluten during adolescence.
Second, it has also been shown, in individual cases, that the
mucosal lesions typical of the disease may appear during adulthood.
Our increasing knowledge of the long-term evolution of the disease
suggests that celiac disease develops and, in some cases, fades
in a predisposed group of people with intestinal sensitivity to
gluten, which is probably a common condition. The factors leading
to the appearance or disappearance of the disease, however, are
still unknown.
La perception du caractère permanent de la maladie coeliaque
provient d'observations cliniques et de sa démonstration
par l'emploi répandu des biopsies intestinales à
la fin des années 50. Il n'y avait pas de doute que les
lésions muqueuses étaient identiques tant chez l'enfant
que chez l'adulte et qu'elles répondaient bien au retrait
du gluten. En 1970, la Société européenne
de gastroentérologie pédiatrique et de nutrition
recommanda une épreuve de réintroduction du gluten
après le diagnostic. Ainsi, une récidive des symptômes
cliniques et des lésions intestinales après réintroduction
du gluten dans la diète démontrait le caractère
«permanent» de la sensibilité au gluten chez
les enfants atteints de maladie coeliaque. Vingt-cinq ans plus
tard, la permanence de la sensibilité de la muqueuse intestinale
au gluten fait à nouveau l'objet d'une controverse. Plusieurs
éléments nouveaux démontrent que la maladie
coeliaque n'est pas toujours permanente. Le suivi à long
terme d'enfants avec maladie coeliaque démontre qu'une
tolérance (définie par un des critères cliniques,
biologiques et histologiques) survient chez 10 % à 20 %
d'entre eux à l'adolescence. De plus, l'apparition de lésions
muqueuses caractéristiques de la maladie a été
démontrée chez certains adultes. Les connaissances
nouvelles quant à l'évolution à long terme
suggèrent que la maladie coeliaque survient ou même
disparait chez les sujets avec une sensibilité intestinale
au gluten, celle-ci étant vraisemblablement un problème
fréquent. Les facteurs conduisant à l'apparition
ou à la résolution de la maladie demeurent inconnus.
[Table of contents]
The permanence of celiac disease has recently become a matter
of debate once again. By the end of the 1950s, the lifelong nature
of the condition appeared to have been established. In 1970, the
European Society for Paediatric Gastroenterology and Nutrition
(ESPGAN) instituted a challenge to differentiate celiac disease
from transient, food-induced gastrointestinal disease.[1] This
challenge involved withdrawing gluten from the diet of people
in whom celiac disease was suspected and then reintroducing gluten.
A relapse of clinical symptoms and intestinal lesions after this
reintroduction was considered confirmation of the diagnosis and
a demonstration of the "permanent" nature of gluten
sensitivity in children with celiac disease. However, several
lines of evidence that have arisen in recent years put this assumption
in doubt.
[Table of contents]
Fading of celiac disease during adolescence
It is well established that, on the whole, tolerance to gluten
increases among children with celiac disease as they grow older.
This lesson was first drawn from the widespread use of gluten
challenge. Whereas the clinical picture of active celiac disease
in toddlers is generally the same, the features of the relapse
induced by a gluten challenge in children with celiac disease
3 to 12 years of age is already variable. Furthermore, in only
a small proportion of these children (20% to 40%)[24] do
clinical symptoms, such loss of appetite, decreased activity,
abdominal pain, bloating, diarrhea, weight loss or, sometimes,
only reduced speed of growth, recur. These symptoms are more severe
the earlier in life they occur. In these children with recurring
symptoms, signs of malabsorption, i.e., steatorrhea, sideropenic
anemia and low blood folate levels, also recur. In some children,
there is only biological malabsorption, but it does not cause
any symptoms. In most patients, however, gluten reintroduction
has neither clinical nor biological consequences (except, in some
instances, for low plasma folate levels). In this group, which
constitutes some 50% to 70% of all patients with a relapse, the
relapse is only histologic, characterized by the reappearance
of mucosal damage. Assessment of this damage is based on intestinal
biopsy performed after 1 or 2 years of a gluten-containing diet.
In most of such patients (85% in our experience), the damage is
severe, and in some it is moderate.[24] Later, during adolescence,
many of these patients tolerate a normal diet well, according
to several follow-up studies.[5,6] All 102 teenaged patients in
a cohort followed in England were well and had biochemical levels
and height within normal limits, although only 56% of the patients
had followed a strict, gluten-free diet and although 17 out of
the 44 patients who agreed to have a jejunal biopsy had grossly
abnormal villi (height less than 200 mm).[5] Of the 17 patients
in whom a biopsy was performed, 5 followed a gluten-free diet
strictly, 7 less strictly and 5 not at all. A similar experience
was recently reported in Italy.[6] Among a large group of 47 young
adults who did not adhere to a gluten-free diet, 42 had severe
histologic abnormalities and 34 had biochemical abnormalities
(including IgA antibody to gliadin), yet only 25 had symptoms.[6]
Finally, we prospectively followed a cohort of children with celiac
disease since the late 1960s. Our experience confirms that these
children tend to have a greater tolerance to gluten as times passes.
We used the following protocol for these children. The diagnosis
was made according to early ESPGAN criteria; the children then
adhered to a gluten-free diet for 2 to 4 years, and then underwent
a gluten challenge at between 4 and 6 years of age. In the children
who experienced a clinical or biological relapse, the exclusion
diet was resumed; in the ones who had only a histologic relapse
(half of the children, in our experience) a normal diet was allowed.
The prolonged observation (for up to 25 years) of this cohort
shows that, in the subgroup of children in whom relapse was purely
histologic, gluten was only slightly deleterious or not deleterious
at all.[7,8] Although, in these children, puberty may have been
delayed for less than 1 year, the final height they attained was
at least that which could be predicted from their parents' height.
In 21 young, postpubertal adults still followed in our outpatient
clinic, who attained their adult height and had eaten a normal
diet for 6 to 19 (median 15) years, their final height was greater
(164 ± 7 cm in 16 girls and 175.5 ± 3 cm in 5 boys)
than that predicted (160 ± 5, p < 0.01, Wilcoxon
test) according to a standard formula.[9] Indeed, in series of
patients seen as young adults by gastroenterologists, most (more
than 90%) had a normal height.[5,10,11]
Moreover, in the same cohort of patients who continued to eat
a diet containing gluten, the degree of mucosal damage varied
widely over time. In a survey conducted in 1989, out of 50 such
children followed from 5 to more than 20 years, in whom more than
one biopsy was performed,[35] (70%) continued to have a flat mucosa.
In 15 (30%), however, intestinal lesions improved: mucosal architecture
returned to normal in 4 (8%); mucosal atrophy became moderate,
with a villus-to-crypt ratio above 2, in 6 (12%), or partial,
with a villus-to-crypt ratio of 1, in 5 (10%). In the latter cases,
improvement or normalization of intestinal lesions may indicate
either "transient celiac disease"[12] or the development
of complete or partial tolerance to gluten.
Similar findings have been made by others. In a group of 91 patients
who underwent a planned challenge or a spontaneous diet interruption
of up to 15 years, full relapse with a flat mucosa was observed
in 71; intermediate lesions were found in 11 subjects, who did
not present with any clinical or biological signs of malabsorption;
and a normal mucosa was seen in 6 patients who had eaten a normal
diet for more than 2 years and in 3 who had eaten a normal diet
for less than 2 years. Thus, in 20% of the patients (17 out of
88) there was either a partial relapse or no relapse at all after
more than 2 years.[13] Interestingly, the latter two groups of
patients were older at the time of challenge (median age 14.8
for those with a partial relapse and 10 years for those with no
relapse) than those who had a full relapse (median age 5.8 years),[13]
suggesting that some degree of tolerance had developed with time.
However, only 16 patients had had an initial challenge many years
before the study was performed; therefore, it was impossible to
know whether the patients who did not have a relapse had either
transient gluten intolerance[14] or "transient celiac disease."[12]
In another study conducted in Finland, 38 adolescents underwent
a late gluten challenge (for many of them, the second challenge)
after undergoing a biopsy.[14] In nine (24%), an altered mucosa
(from slight villous changes to a flat mucosa) indicated poor
adherence to a gluten-free diet. Out of the remaining 29, 24 had
a relapse after a mean challenge of 7 months; in an additional
patient there was a dubious relapse (slight alteration in villous
height). In these 25 patients the mucosa was flat on 18 occasions
or showed severe (on 2 occasions) or moderate (on 5 occasions)
architectural disturbances. In the remaining four patients, the
intestinal mucosa remained normal after more than 2 years' exposure
to gluten. Twenty of these patients, including 4 with a normal
mucosa, had an earlier positive result of a challenge. Thus, 11
out of 38 patients (29%) showed improvement or complete normalization
of their mucosal architecture;[15] these data are very similar
to ours.[8,16]
A more recent study involving 123 Italian teenagers with celiac
disease, grouped according to their degree of compliance with
a gluten-free diet, showed that, although symptoms occurred more
frequently in patients eating a diet containing gluten, symptom
rates were far from constant.[17] Indeed, 34% of those following
a normal diet were symptom free. Symptoms were no more frequent
among adolescents eating a semi-strict diet (0.06 to 2.00 g of
gluten per day) than among those eating a strict (no-gluten) diet.
In 36 patients who underwent a jejunal biopsy (6 of whom were
on the gluten-free diet, 14 on the semi-strict diet and 13 on
the normal diet), morphometric analysis of the mucosa showed a
normal mucosa in, respectively, 3 out of the 6, 3 out of the 14,
and 1 out of the 13, as well as considerable villous shortening
in, respectively, 3 out of 6, 7 out of 14, and 2 out of 13 and
a flat mucosa in 0 out of the 6, 4 out of the 14, and 10 out of
the 13. Once again, it appears that in a sizeable proportion of
adolescents not following the gluten-free diet not only clinical
symptoms but also severe histologic lesions are inconstant.
The evolution of the intestinal mucosa of children with proven
celiac disease is thus rather variable from the time of the diagnostic
challenge to adolescence and adulthood, with a general trend toward
greater tolerance of gluten. This developing tolerance is first
revealed by less frequent clinical symptoms as time passes. This
decrease in clinical severity may be related to a reduction in
the length of intestine affected by the immunologic conflict,[18]
although this relation has never been demonstrated in children,
in whom intestinal biopsies are never taken more distally than
the duodenojejunal flexure. In adolescence, an even greater tolerance
seems to develop in a subgroup of patients whose mucosa is no
longer, or only moderately, sensitive to gluten.
The hypothesis that tolerance to gluten may develop in a proportion
of children with celiac disease was strengthened by immunohistochemical
results obtained for our cohort of patients eating a normal diet.
Although a significant increase in the number of T cell receptor
(TcR) gd+ intraepithelial lymphocytes (IELs) was observed in their
gut epithelium, and this increase was not correlated with the
presence of gluten in the diet or the grade of villous atrophy,
the number of intestinal TcR ab+ IELs varied with the stage of
the disease. The number of TcR ab+ IELs was high in the epithelium
of patients with a flat mucosa but significantly lower in patients
whose mucosa had returned to normal or nearly normal in spite
of a normal diet. Furthermore, immunohistochemical markers of
intestinal mononuclear cell activation (the appearance of CD25+
mononuclear cells and the increased expression of HLA-DR antigens
by enterocytes) were either weakly positive or absent in the patients
with a normal or nearly normal mucosa.[16] These observations
suggest that TcR ab+ but not TcR gd+ IELs are sensitized to gluten
in celiac disease and that immunologic tolerance to gluten may
be acquired in a subgroup of patients, although for an unknown
period. Additional evidence that such a subgroup exists has been
brought by the recent immunohistochemical observation that patients
in the latter subgroup (those with "abortive celiac disease")
have significantly more large granular lymphocytes and natural
killer cells (11.93 ± 6.2 cells/mm2, a number
in the normal range) than those with permanent celiac disease
(0.41 ± 0.61 cells/mm2).[19]
[Table of contents]
On the other side of the coin, it has recently been shown that
the mucosal lesions typical of the disease can appear in people
who eat a normal diet and have had a normal intestinal mucosa
on a biopsy performed several years earlier. Such sequences have
been observed twice in monozygotic twins. In both cases, celiac
disease was diagnosed in one twin, and a biopsy was performed
in the other. Seven years after the first biopsy, which had normal
results, a second biopsy revealed an intestinal mucosa with typical
villous atrophy and crypt hyperplasia.[20,21] A normal mucosa
has been observed on biopsy years before an initial diagnosis
of celiac disease in several cases in children and adults; in
these cases, the first biopsy was performed 2 to 9 years before
the diagnosis of celiac disease was made because of suspected
malabsorption, a family history[22] or insulin-dependent diabetes
mellitus.[23] In one such adult case, there was a high number
of TcR gd+ IELs in the apparently normal mucosa obtained by the
first biopsy.[24] These patients have been classified as having
latent celiac disease.[22,25]
[Table of contents]
Both of these lines of observation provide strong evidence against
the received wisdom that, in celiac disease, the sensitivity of
the intestinal mucosa to gluten continues throughout life. Instead,
our increasing experience with the long-term evolution of the
disease suggests that silent or clinically apparent celiac disease
develops and, in some cases, fades in a predisposed group of people
with intestinal sensitivity to gluten (latent celiac disease),
a condition that may be more common than previously thought. However,
the factors leading to the appearance or disappearance of the
disease remain unknown. It has been proposed that genetic factors
could determine the patient's age at the onset of the disease[26]
or the severity of the disease.[27] It is difficult, however,
to understand how the same factors could explain the development
of tolerance as well as of sensitization in a given patient who
continues to eat the same diet. This variability also implies
that gluten cannot be the sole factor that induces villous effacement.[25,28]
[Table of contents]
The publication of this article was supported in part by a grant
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.
[Table of contents]
- Weijers HA, Lindquist B, Anderson CM, et al. Round table discussion.
Diagnostic criteria in celiac disease. Acta Paediatr Scand
1970; 59: 461-3.
- Shmerling DH. An analysis of controlled relapses in gluten-induced
celiac disease [abstract]. Acta Paediatr Scand 1969; 58:
311.
- Visakorpi JK, Kuitunen P, Savilahti E. Frequency and nature
of relapses in children suffering from the malabsorption syndrome
with gluten intolerance. Acta Paediatr Scand 1970; 59:
481-6.
- Bresson JL, Schmitz J, Rey J. Characteristics of the relapse
in celiac disease [abstract]. Acta Paediatr Belg 1980;
33: 270.
- Kumar PJ, Walker-Smith J, Milla P, Harris G, Colyer J, Halliday
R. The teenage coeliac: follow up study of 102 patients. Arch
Dis Child 1988; 63: 916-20.
- Bardella MT, Molteni N, Prampolini L, Giunta AM, Baldassarri
AR, Morganti D, et al. Need for follow up in coeliac disease.
Arch Dis Child 1994; 70: 211-3.
- Schmitz J, Jos J, Rey J. La maladie coeliaque. In: Ribet A,
Frexinos J, editors. Actualités en hépato-gastroentérologie.
Paris: Masson, 1979: 95-109.
- Schmitz J, Arnaud-Battandier F, Jos J, Rey J. Long term follow-up
of childhood coeliac disease (CD): Is there a "natural recovery"?
[abstract]. Pediatr Res 1984; 18: 1052.
- Sizonenko P, Griscelli C. Précis de pédiatrie.
Lausanne, Switzerland: Payot, 1996: 1646.
- Mortimer PE, Stewart JS, Norman AP, Booth CC. Follow-up study
of coeliac disease. BMJ 1968; 2: 7-9.
- Sheldon W. Prognosis in early adult life of coeliac children
treated with a gluten-free diet. BMJ 1969; 2: 401-4.
- Schmitz J, Jos J, Rey J. Transient mucosal atrophy in confirmed
coeliac disease. In: McNicholl B, McCarthy CF, Fottrell PF, editors.
Perspectives in Coeliac Disease. Lancaster: MTP Press,
1978: 259-66.
- Shmerling DH, Franckx J. Childhood coeliac disease: a long-term
analysis of relapses in 91 patients. J Pediatr Gastroenterol
Nutr 1986; 5: 565-9.
- Walker-Smith JA. Transient gluten intolerance. Arch Dis
Child 1970; 45: 523-6.
- Maki M, Lahdeaho ML, Hallstrom O, Viander M, Visakorpi JK.
Postpubertal gluten challenge in coeliac disease. Arch Dis
Child 1989; 64: 1604-7.
- Kutlu T, Brousse N, Rambaud C, Le Deist F, Schmitz J, Cerf-Bensussan
N. Numbers of T cell receptor (TCR) ab+ but not of TcR gd+ intraepithelial
lymphocytes correlate with the grade of villous atrophy in coeliac
patients on a long term normal diet. Gut 1993; 34: 208-14.
- Mayer M, Greco L, Troncone R, Auricchio S, Marsh MN. Compliance
of adolescents with coeliac disease with a gluten free diet. Gut
1991; 32: 881-5.
- Stewart JS, Pollock DJ, Hoffbrand AV, Mollin DL, Booth CC.
A study of proximal and distal intestinal structure and absorptive
function in idiopathic steatorrhoea. Q J Med 1967; 36:
425-44.
- Hadziselimovic F, Emmons LR, Schaub U, Signer E, Burgin-Wolff
AM, Krstic R. Occurrence of large granular lymphocytes and natural
killer cells in the epithelium of the gut distinguishes two different
c0eliac diseases. Gut 1992; 33: 767-72.
- Kamath KR, Dorney SFA. Is discordance for celiac disease in
monozygotic twins permanent? [abstract]. Pediatr Res 1983;
17: 422.
- Salazar de Sousa J, Ramos de Almeida JM, Monteiro MV, Magalhaes
Ramalho P. Late onset coeliac disease in the monozygotic twin
of a coeliac child. Acta Paediatr Scand 1987; 76: 172-4.
- Maki M, Holm K, Koskimies S, Hallstrom O, Visakorpi JK. Normal
small bowel biopsy followed by coeliac disease. Arch Dis Child
1990; 65: 1137-41.
- Catassi C, Natalini G, Ratsch IM, Gabrielli O, Coppa GV, Giorgi
PL. Documented latent coeliac disease in a child with insulin-dependent
diabetes mellitus. Eur J Pediatr 1991; 150: 832-4.
- Mäki M, Holm K, Collin P, Savilahti E. Increase in g/d
T cell receptor bearing lymphocytes in normal small bowel mucosa
in latent coeliac disease. Gut 1991; 32: 1412-4.
- Ferguson A, Arranz E, O'Mahony S. Clinical and pathological
spectrum of coeliac disease-active, silent, latent, potential.
Gut 1993; 34: 150-1.
- Ellis A, Taylor CJ, Dillon-Remmy M, Woodrow JC, McConnell
RB. HLA-DR typing in coeliac disease: evidence for genetic heterogeneity.
BMJ (Clin Res Ed) 1984; 289: 1571-3.
- Demarchi M, Carbonara A, Ansaldi N, Santini B, Barbera C,
Borelli P, et al. HLA-DR3 and DR7 in coeliac disease: immunogenetic
and clinical aspects. Gut 1983; 24: 706-12.
- Polanco I, Mearin ML, Larrauri J, Biemond I, Wipkink-Bakker
A, Pena AS. Effect of gluten supplementation in healthy siblings
of children with coeliac disease. Gastroenterology 1987;
92: 678-81.
[Table of contents]
| CIM: October 1996 / MCE: octobre 1996
|
CMA Webspinners / >
