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Prevalence of thyroid disorders in untreated adult celiac disease patients and effect of gluten withdrawal: An Italian multicenter study

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Many afflictions have been associated with celiac disease, but chance associations may exists. The aim of this study was to establish, by means of a multicenter prospective study, the prevalence of thyroid impairment among adult patients with newly diagnosed celiac disease and to evaluate the effect of a 1-yr gluten withdrawal on thyroid function. A total of 241 consecutive untreated patients and 212 controls were enrolled. In 128 subjects a thorough assessment, including intestinal biopsy, was repeated within 1 yr of dietary treatment. Thyroid function was assayed by measuring the levels of TSH, free T3, free T4, thyroperoxidase, and thyroid microsome antibodies. Thyroid disease was 3-fold higher in patients than in controls (p < 0.0005). Hypothyroidism, diagnosed in 31 patients (12.9%) and nine controls (4.2%), was subclinical in 29 patients and of nonautoimmune origin in 21. There was no difference regarding hyperthyroidism, whereas autoimmune thyroid disease with euthyroidism was present in 39 patients (16.2%) and eight controls (3.8%). In most patients who strictly followed a 1-yr gluten withdrawal (as confirmed by intestinal mucosa recovery), there was a normalization of subclinical hypothyroidism. Twenty-five percent of patients with euthyroid autoimmune disease shifted toward either a subclinical hyperthyroidism or subclinical hypothyroidism; in these subjects, dietary compliance was poor. In addition, 5.5% of patients whose thyroid function was normal while untreated developed some degree of thyroid dysfunction 1 yr later. The greater frequency of thyroid disease among celiac disease patients justifies a thyroid functional assessment. In distinct cases, gluten withdrawal may single-handedly reverse the abnormality.
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Prevalence of Thyroid Disorders in Untreated Adult
Celiac Disease Patients and Effect of Gluten
Withdrawal: An Italian Multicenter Study
C. Sategna-Guidetti, M.D., Ph.D., U. Volta, M.D., C. Ciacci, M.D., P. Usai, A. Carlino,
L. De Franceschi, M.D., A. Camera, M.D., A. Pelli, M.D., Ph.D., and C. Brossa, Ph.D.
University of Torino, Torino; University of Bologna, Bologna; University of Napoli, Napoli; University of
Cagliari, Cagliari; and University of Perugia, Perugia, Italy
OBJECTIVES: Many afflictions have been associated with
celiac disease, but chance associations may exists. The aim
of this study was to establish, by means of a multicenter
prospective study, the prevalence of thyroid impairment
among adult patients with newly diagnosed celiac disease
and to evaluate the effect of a 1-yr gluten withdrawal on
thyroid function.
METHODS: A total of 241 consecutive untreated patients and
212 controls were enrolled. In 128 subjects a thorough
assessment, including intestinal biopsy, was repeated within
1 yr of dietary treatment. Thyroid function was assayed by
measuring the levels of TSH, free T3, free T4, thyroperoxi-
dase, and thyroid microsome antibodies.
RESULTS: Thyroid disease was 3-fold higher in patients than
in controls (p0.0005). Hypothyroidism, diagnosed in 31
patients (12.9%) and nine controls (4.2%), was subclinical
in 29 patients and of nonautoimmune origin in 21. There
was no difference regarding hyperthyroidism, whereas au-
toimmune thyroid disease with euthyroidism was present in
39 patients (16.2%) and eight controls (3.8%). In most
patients who strictly followed a 1-yr gluten withdrawal (as
confirmed by intestinal mucosa recovery), there was a nor-
malization of subclinical hypothyroidism. Twenty-five per-
cent of patients with euthyroid autoimmune disease shifted
toward either a subclinical hyperthyroidism or subclinical
hypothyroidism; in these subjects, dietary compliance was
poor. In addition, 5.5% of patients whose thyroid function
was normal while untreated developed some degree of thy-
roid dysfunction 1 yr later.
CONCLUSIONS: The greater frequency of thyroid disease
among celiac disease patients justifies a thyroid functional
assessment. In distinct cases, gluten withdrawal may single-
handedly reverse the abnormality. (Am J Gastroenterol 2001;
96:751–757. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION
Many afflictions have been associated with celiac disease
(CD) (1); however, because the high prevalence of this
disease (2), chance associations may exist. Recent studies
have shown an increased incidence of thyroid diseases (TD)
among patients with CD (3, 4) but, thus far, data on the
prevalence and clinical significance of this association are
lacking.
This article describes a multicenter study, carried out
under the auspices of the Italian “Club del Tenue,” that
aimed to establish the prevalence of thyroid involvement
among adult patients newly diagnosed with CD and to
evaluate the effect of a 1-yr gluten withdrawal on thyroid
function.
MATERIALS AND METHODS
Five adult study centers from various regions of Italy (Fig.
1) took part in this prospective study.
Patients
Between January 1996 and July 1998, 241 consecutive adult
patients who were newly diagnosed with CD were enrolled.
The study population included 64 men (median age 29 yr,
range 1882 yr) and 177 women (median age 31 yr, range
1985 yr).
The diagnosis of CD was made according to the accepted
criteria (5), i.e., clinical history and typical histological
appearance of the small intestinal mucosa. In 224 of 241
subjects (93%), CD-related serology, i.e., antiendomysium
antibodies (IgA-EmA), was also positive. Persistence of
symptoms before diagnosis ranged from 6 to 120 months in
161 patients (66.8%), whereas symptoms had been present
in 41 patients (17%) since childhood. The clinical pattern
was typical in 40%, atypical in 44%, and silent in 16% of
patients, respectively (6); in the silent disease group, diag-
nosis was reached because of a screening program in a
family study.
Control Subjects
Because an Italian survey to appraise the prevalence of TD
(both subclinical or overt) in the general population had not
yet, to our knowledge, been performed, sera from 212 con-
trol subjects matched for sex, ethnic origin, and age (3 yr)
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 3, 2001
© 2001 by Am. Coll. of Gastroenterology ISSN 0002-9270/01/$20.00
Published by Elsevier Science Inc. PII S0002-9270(00)02410-2
were screened for TD as well. Controls (64 men and 148
women) were healthy volunteers recruited among medical
and nursing staff, blood donors, or patients affected by
chronic obstructive pulmonary disease (COPD), peptic ul-
cer, or nonulcer dyspepsia (NUD) attending for upper en-
doscopy; none had a past or present history of thyroid
function impairment. Exclusion criteria included age 19 yr
and the presence of disease that may affect thyroid function
(i.e., chronic liver or renal disease, malignancy, malnutri-
tion) or the use of medication known to influence serum
TSH or fT4 (i.e., dopamine, glucocorticoids, heparin, furo-
semide). In all participants, CD was excluded by means of
clinical findings and an IgA-EmA test or by duodenal biopsy
performed during endoscopy.
Study Design
At the time of entry into the study, all patients were un-
treated. Initial data collection included clinical history (6)
and findings, associated diseases, clinical and biochemical
nutritional assessment, intestinal biopsy, and thyroid func-
tion appraisal: thereafter, patients were instructed to follow
a gluten-free-diet (GFD) and were considered as treated.
Patients with overt hypo- or hyperthyroidism were started
on an appropriate medical treatment. A thorough assess-
ment, including intestinal biopsy, was repeated within 12
1 months.
The study was performed according to the principles of
the Declaration of Helsinki, and informed consent was ob-
tained from each patient. The research was approved by the
Scientific Committee of the “Club del Tenue.”
Nutritional Assessment
Nutritional status was evaluated by calculating the body
mass index (BMI; kg/m
2
, reference range: men 20,
women 19). Biochemical assessment, performed by stan-
dard methods, included the following: Hb (reference range
14–18 g/dl (for men) and 12–16 g/dl for women); serum
albumin (Alb, reference range 3.6–5.0 g/dl); serum iron (Fe,
reference range 59–158
g/dl for men and 37–145
g/dl for
women).
Thyroid Function Assessment
Serum fT3 and fT4 were estimated by radioimmunoassay
(Ortho-Clinical Diagnostic, Amersham, UK). The sensitiv-
ities of the assays were 0.768 pmol/L for fT3 and 0.769
pmol/L for fT4, respectively, with intra-assay percentage
coefficients of variation (CV) of 4% and 3.8%, and inter-
assay CV of 6.4% and 6.2%.
Serum TSH levels were evaluated by immunoradiometric
assay (Biocode, Lie`ge, Belgium) on solid phase. The min-
imum measurable concentration was at 0.05
IU/ml. The
interassay CVs were 5% and 5.5%, respectively.
Serum thyroid microsome antibodies (TM-Ab) were ap-
praised by immunoradiometric assay (Biocode). The detec-
tion limit has been evaluated at 2.5 IU/ml. The intra-assay
and interassay CVs were 8.1% and 7.9%, respectively. Se-
rum levels of thyroperoxidase antibodies (TPO-Ab) were
detected by radioimmunoassay (Biocode). The sensitivity
has been evaluated at 7 IU/ml. The intra and interassay CVs
were 8.9% and 9.4%, respectively.
We considered as normal the following serum levels:
TSH 0.3–3.0
IU/ml, fT3 2.2–4.7 ng/L, fT4 8–20 ng/L,
TM-Ab 50IU/ml, and TPO-Ab 50 IU/ml.
Thyroid disease was classified, according to the American
Thyroid Association guidelines, as follows (7): overt hyper-
thyroidism: TSH 0.3
IU/ml and fT4 20 ng/ml; sub-
clinical hyperthyroidism: TSH 0.3
IU/ml and fT4 in the
normal range; overt hypothyroidism: TSH 3
IU/ml and
fT4 8 ng/ml; subclinical hypothyroidism: TSH 3
IU/ml and a normal fT4; subclinical autoimmune (AI)
hypothyroidism: TSH 3
IU/ml and a normal fT4 and
100 IU/ml serum levels of TPO-Ab or TM-Ab or both;
subclinical nonautoimmune hypothyroidism (NAI): TSH
3
IU/ml and a normal fT4, without autoantibody serum
level increase; and autoimmune thyroid disease with euthy-
roidism (ATDE): TSH and fT4 in the normal ranges and
100 IU/ml serum levels of TPO-Ab or TM-Ab or both. All
reference limits were provided by the manufacturers, and all
biochemical values were compared with those for the indi-
vidual analyte reference range established in the laboratory.
Intestinal Morphology
All patients underwent intestinal biopsy from the second
part of the duodenum during upper endoscopy. Mucosal
tissue was graded according to the Marsh criteria (8).
Figure 1. Centers participating in the study.
752 Sategna-Guidetti et al. AJG – Vol. 96, No. 3, 2001
Statistical Analysis
Statistical data were generated using the MedCalc software
for Windows (Mariakerke, Belgium). To ascertain whether
possible differences in TD between patients and controls
may be clinically meaningful and worthwhile to detecting,
we previously estimated the required sample size by calcu-
lating the probabilities
and
of a type I and type II error,
respectively.We calculated that 184 patients and 184 con-
trols should be enrolled by assuming that the expected
prevalence of TD among the general population (4) (and
therefore among our controls) is 5%, that the relative risk for
TD in CD is 3-fold higher and by accepting an
error (type
I error) of 5% and a power (1-
)90%.
Data were analyzed using the
2
test (or Fisher’s exact
test, where indicated) for differences in frequencies, the t
test (paired or unpaired, as appropriate) for comparison of
means, and the r correlation coefficient. For all statistical
analysis, a two-tailed pvalue 0.05 was considered sig-
nificant.
RESULTS
Thyroid Function and Clinical Findings
at Diagnosis (Untreated Subjects)
As shown in Table 1, overall TD was found in 73 (61
women and 12 men) of 241 (30.3%) patients with CD, and
in 24 (19 women and five men) of 212 controls (11.3%)
(
2
23.004, p0.0005). However, the differences were
statistically significant only for women (
2
19.165, p
0.0005).
Overall hypothyroidism, which had been diagnosed in 31
patients and nine controls (p0.003), was subclinical in 29
patients and eight controls and was overt in the remainder;
however, the differences were statistically significant only
for women (
2
8.284, p0.0045). In 21 patients and four
controls, a NAI hypothyroidism was found, whereas in 10
patients and five controls an AI hypothyroidism was present.
NAI hypothyroidism was significantly higher (
2
11.821,
p0.0006) than AI.
Table 1. Prevalence of Thyroid Function Impairment Among Newly Diagnosed Celiac Disease Patients and Controls
Thyroid Function
Untreated
Celiac Disease
Patients Controls
Hypothyroidism
Number (%) 31/241 (12.9%) 9/212 (4.2%)
2
9.362, p0.003
Sex 26F,5M 7F,2M
Hyperthyroidism
Number (%) 3/241 (1.2%) 7/212 (3.3%) NS
Sex 2F,1M 7F,0M
Autoimmune thyroid disease
with euthyroidism
Number (%) 39/241 (16.2%) 8/212 (3.8%)
2
17.366, p0.0005
Sex 33F,6M 5F,3M
Total
Number (%) 73/241 (30.3%) 24/212 (11.3%)
2
23.004, p0.0005
Sex 61 F, 12 M 19 F, 5 M
Table 2. Nutritional Assessment in Untreated Patients With Celiac Disease With and Without Associated Thyroid Function
Impairment
Characteristic
Celiac Disease
Without
Thyroid
Disease Celiac Disease and
Thyroid Disease pValue*
BMI kg/m
2
M 20.6, F 20.4 M 22.3, F 19.7
M20 kg/m
2
21/52 (40.4%) 1/12 (8.33%) 0.0448 (Fischer’s),
F19 kg/m
2
37/116 (31.9%) 22/61 (36%) NS
Hb g/dl M 12.8, F 11.4 M 12.1, F 11.6
M14 g/dl 19/52 (36.5%) 8/12 (66.7%) NS
F12 g/dl 58/119 (50%) 26/61 (42.6%) NS
Serum albumin g/dl 4.7 4.4
3.5 g/dl 18/168 (10.7%) 5/73 (6.8%) NS
Serum iron
g/dl M 80, F 48 M 63, F 51
M59
g/dl 11/52 (21.1%) 6/12 (50%) NS
F37
g/dl 45/116 (38.8%) 16/61 (26.2%) NS
Data are median values and number of patients with values below the lower limit. BMI body mass index; F female; M male.
*pValues determined by
2
test unless stated otherwise.
753AJG – March, 2001 Thyroid Disorders in Untreated Adult Celiac Disease
Hyperthyroidism was diagnosed in three patients and
seven controls, and was subclinical in two patients and in
five controls.
ATDE was present in 39 patients and eight controls; but,
again, the difference was statistically significant only in
women (
2
16.744, p0.0005).
The presence of TD was not influenced by geographic
factors. The age of patients and controls with associated TD
did not differ from that of patients and controls with a
normal thyroid function (median age 33 and 32.5 yr, and 29
and 30.5 yr, respectively). There was no variation in TD
prevalence in age groups. The clinical pattern of CD (clas-
sic, atypical, silent) (6), presenting symptoms (diarrhea,
anaemia, weight loss, dyspepsia, bloating, fatigue, weak-
ness, osteoporosis), associated diseases (dermatitis herpeti-
formis, insulin-dependent diabetes mellitus, arthritis, viti-
ligo, aphthous stomatitis), and histological scores (8) were
comparable in patients with and without TD. In three of 73
patients (0.96%) with thyroid function impairment, TD di-
agnosis preceded CD recognition.
Nutritional Assessment
At diagnosis, median BMI values and Hb, serum iron, and
albumin levels were similar in patients with and without TD.
In each group, a number of subjects showed abnormal values
that did not reach a statistical significance, with the exception
of BMI among men (Table 2). No significant correlation was
found among nutritional indices and TSH or fT3 values.
Table 3. Thyroid Function Outcome in 128 Celiac Disease Patients Within 1 Yr of Gluten Withdrawal
Thyroid Function Assessment
at Diagnosis Number of Patients Reassessed Outcome Within 1 Yr
1 overt 3drug therapy 31 subclinical AI hypothyrodism
Autoimmune (AI) 6
33 ATDE
5 subclinical
32 unchanged
Hypothyroidism
310/14 recovery (71.4%)
Nonautoimmune (NAI) 14 subclinical 33 no change
31 subclinical AI
Hyperthyroidism 1 overt 3drug therapy 31 subclinical hyperthyroidism
33 normalization
Autoimmune thyroid disease with 39 unchanged
euthyroidism (ATDE) 16
33 subclinical AI hypothyroidism
31 subclinical hyperthyroidism
32 NAI hypothyroidism
Normal 91 31 subclinical hyperthyroidism
32 ATDE
Subclinical hypothyroidism normalized in 10 of 14 patients with NAI, seven of whom had adhered strictly to the diet. In subjects without thyroid function improvement,
compliance with diet was generally poor. In five patients with a normal thyroid function at diagnosis, there was a shift toward some impairment; only one of these did not strictly
comply with the diet.
AI/NAI autoimmune/nonautoimmune thyroid disease; ATDE autoimmune thyroid disease with euthyroidism.
4/16 (25%)
5/91 (5.5%)
754 Sategna-Guidetti et al. AJG – Vol. 96, No. 3, 2001
Effect of a 1-Yr Gluten-Free Diet:
Thyroid Function and Clinical Findings
A total of 128 patients (53.1%) underwent a complete re-
assessment within 12 1 months after the beginning of
gluten withdrawal, 91 with a normal thyroid function and 37
with an impaired function at diagnosis. An exhaustive re-
view of diet to assess compliance did not show a significant
difference between the two groups. Intestinal biopsy re-
peated in 75 of 128 (58.6%) subjects showed a mucosal
recovery in 43 (57.3%) and persisting partial or total atrophy
in the remaining 32 (42.7%).
The outcome of the 128 patients’ thyroid function is
shown in Table 3. Three points must be stressed. First,
subclinical hypothyroidism normalized in 10 of 14 (71.4%)
patients with NAI disease, seven of whom had presumably
adhered strictly to the GFD; in three of five (60%) patients
with AI disease (two of whom were compliant with the
diet), there was a shift to ATDE. In four of five subjects with
no improvement in thyroid function, compliance with the
diet was poor, as demonstrated by the incomplete recovery
of the intestinal mucosa at duodenal biopsy. Second, out of
four of 16 (25%) patients with ATDE, one patient developed
a subclinical hyperthyroidism, whereas three had AI subclini-
cal hypothyroidism; three of these subjects did not strictly
comply with the diet. Third, 1 yr later, out of five of 91 (5.5%)
patients with a normal thyroid function at diagnosis, one patient
had developed subclinical hyperthyroidism, two ATDE, and
two NAI subclinical hypothyroidism; only one of these patients
did not strictly comply with the diet.
Nutritional Assessment
A 1-yr gluten withdrawal led to a significant improvement
of nutritional indices (Table 4), which was comparable in
patients with and without TD, as shown in Figure 2. In most
patients with persistent mucosal impairment, nutritional in-
dices continued to be abnormal.
DISCUSSION
Our study confirms that patients with celiac disease are at
risk for developing thyroid disease, with an overall 3-fold
higher frequency than in controls. In both populations,
women were significantly more affected than men; preva-
lence of TD did not differ between age groups. These data
should be representative of the Italian population overall, as
a large number of subjects, evenly distributed across the
country, were examined.
In seven patients, diagnosis of TD preceded recognition
of CD (i.e., the disorder developed in a condition of unrec-
ognized and untreated CD).
Clinical presentation, age at diagnosis and incidence of
associated diseases were comparable in patients with and
without TD: our data do not seem to support, at least as far
as thyroid function involvement is concerned, the theory of
Ventura et al. (9) that age at diagnosis, which indirectly
mirrors the duration of gluten exposure, may increase the
risk of developing autoimmune disorders. The discrepancy
could be due to a bias caused by the age of our patients, i.e.,
adults, versus adolescents in the study by Ventura et al.
Our findings confirm the infrequent impairment of nutri-
tional status in untreated CD both with and without TD,
although approximately one-half had anemia and one-third
had iron deficiency. Notwithstanding a sufficient nutritional
status, it is probable that in 21 of 31 patients hypothyroidism
was not of autoimmune origin but rather was attributable to
a decreased thyroid hormone synthesis, induced either by an
iodine organification defect or by a functional hypothalam-
ic–pituitary disturbance consequent to isolated malnutrition
(10, 11). This hypothesis may be supported both by the
relationship between normalization of thyroid function, by
means of gluten withdrawal alone, and by the histological
recovery of duodenal mucosa, or, conversely, by the ab-
sence of thyroid function improvement in subjects with
persistent villous atrophy. This strengthens the view that
gluten withdrawal by itself is able to eliminate the main
etiological factor of NAI hypothyroidism.
The prevalence of thyroid antibody positivity in euthyroid
subjects was 4-fold higher in CD than in controls. It has
been postulated that thyroid autoimmunity is enhanced in
iodine-depleted geographical areas, where an increased
prevalence of goiter and hyperthyroidism of nonautoim-
Table 4. Nutritional Outcome in Celiac Disease Patients
Characteristic Untreated Treated pValue
BMI kg/m
2
M 21.15 3.2, F 22.6 3.3 M 20.8 3.68, F 23 3.44 0.043 (M)*, NS (F)*
M20 kg/m
2
22/64 (34.4%) 7/31 (22.6%) NS
F19 kg/m
2
59/177 (33.33%) 13/97 (13.4%) 0.0006
Hb g/dl 12.74 6.39 13.6 1.64 NS*
M14 g/dl 27/64 (42.2%) 4/31 (12.9%) 0.0091
F12 g/dl 84/177 (47.5%) 10/97 (10.3%) 0.0005
Serum albumin g/dl 4.9 0.503 5.13 0.57 0.0001*
3.5 g/dl 23/241 (9.54%) 5/128 (3.9%) NS
Serum iron
g/dl 63 38.13 92 33.7 0.0001*
M59
g/dl 17/64 (26.6%) 0.31 (0%) 0.0044
F36
g/dl 61/177 (34.4%) 2/97 (2.04%) 0.0005
Data given as mean SD and number of patients with values below the lower limit in each group. BMI body mass index; F female; M male.
* Statistical analysis by paired Student ttest; other statistical analysis by unpaired student tand
2
test.
755AJG – March, 2001 Thyroid Disorders in Untreated Adult Celiac Disease
mune origin are more frequent (12). Although thyroid ul-
trasonography was not performed because of a possible
operator-dependent bias (as this was a multicenter study),
this statement does not apply to our patients; the rate of
antibody positivity was similar in regions with variable
iodine supplies (Napoli and Cagliari are located by the sea),
and both patients and controls had a low overall hyperthy-
roidism rate. Although the clinical significance of these
antibodies in CD is still unclear, there is probably a higher
propensity for thyroid autoimmunity; proposed mechanisms
of autoimmune endocrine disease involve a sequence of
immune, inflammatory events in a genetically susceptible
individual. In most cases, the immune response to the target
cell progressively destroys the endocrine gland, and hypo-
function is the main clinical manifestation (13). This mech-
anism seems to be sustained by the fact that, 1 yr later, three
out of 16 (19%) patients with ATDE developed AI subclin-
ical hypothyroidism and one (6%) a subclinical hyperthy-
roidism. Thus, a longitudinal follow-up would seem neces-
sary in patients who have a positive AI thyroid serology but
who are currently euthyroid; this course would help to
evaluate whether these findings should be considered only
as an epiphenomenon or should be of prognostic help. This
circumstance could change the attitude toward the cost-
effectiveness of screening, as it could be very useful to have
some advance knowledge about subjects who may become
clinically hypothyroid (or, less likely, hyperthyroid).
The importance of gluten withdrawal was further under-
lined, 1 yr later, by the normalization of antithyroid anti-
bodies in three of these 16 ATDE patients (19%), who were
strictly diet compliant, although there exists the possibility
of a spontaneous fluctuation of antibodies.
Reprint requests and correspondence: Prof. Carla Sategna-
Guidetti, Cattedra di Gastroenterologia, Dipartimento di Medicina
Interna, Corso AM Dogliotti, 14. 10126 Torino, Italy.
Received May 9, 2000; accepted Sep. 14, 2000.
REFERENCES
1. Cooke WT, Holmes GKT. Coeliac disease, and associated
disorders. In: Coeliac disease. Cooke WT, Holmes GKT, eds.
London: Churchill Livingstone, 1984:225–48.
2. Catassi C. Screening of coeliac disease. In: Maki M, Collin P,
Visakorpi JK, eds. Coeliac disease. Proceedings of the 7th
International Symposium on coeliac disease. Tampere,
Finland: Coeliac Disease Study Group, 1997:23–34.
3. Counsell CE, Taha A, Ruddell WSJ. Coeliac disease, and
autoimmune thyroid disease. Gut 1994;35:8446.
4. Sategna-Guidetti C, Bruno M, Mazza E, et al. Autoimmune
thyroid disease, and coeliac disease. Eur J Gastroenterol Hepa-
tol 1998;10:927–31.
5. Walker Smith JA, Guandalini S, Schmitz J, et al. Revised
criteria for diagnosis of coeliac disease. Arch Dis Child 1990;
65:909–11.
6. Ferguson A, Arranz E, O’Mahony S. Clinical, and patholog-
ical spectrum of coeliac disease—Active, silent, latent, poten-
tial. Gut 1993;34:150–1.
7. Surks MI, Chopra U, Mariash CN, et al. American Thyroid
Association guideline for use of laboratory tests in thyroid
disorders. JAMA 1990;263:1529–32.
Figure 2. Percentage of abnormal results, as compared to initial values (untreated) most of nutritional indices showed a significant
improvement (
2
test, on actual numbers) after a 1-yr gluten withdrawal (treated). No statistical difference was found between patients
with and without associated thyroid disease. BMI body mass index; s-albumin serum albumin; s-iron serum iron.
756 Sategna-Guidetti et al. AJG – Vol. 96, No. 3, 2001
8. Marsh MN. Morphology, and immunopathology of the jejunal
lesion in gluten-sensitivity. Eur J Gastroenterol Hepatol 1991;
3:108–14.
9. Ventura A, Magazzu G, Greco L, for the SIGEP Study Group
for Autoimmune Disorders in Celiac Disease. Duration of expo-
sure to gluten, and risk for autoimmune disorders in patients with
celiac disease. Gastroenterology 1999;117:297–303.
10. Carter JN, Eastman CJ, Corcoran JM, et al. Effect of severe,
chronic illness on thyroid function. Lancet 1974;ii:971–4.
11. Farthing MJG, Rees LR, Edwards CRW, et al. Thyroid hor-
mones and the regulation of thyroid function in men with
coeliac disease. Clin Endocrinol 1982;16:525–35.
12. Szabolcs I, Podoba J, Feldkamp J, et al. Comparative screen-
ing for thyroid disorders in old age in areas of iodine defi-
ciency, long term iodine prophylaxis, and abundant iodine
intake. Clin Endocrinol 1997;47:87–92.
13. Baker JR Jr. Autoimmune endocrine disease. JAMA 1997;
278:1931–7.
757AJG – March, 2001 Thyroid Disorders in Untreated Adult Celiac Disease
... The pervasiveness of hypothyroidism is demonstrated in various studies to be 3 to 4 times higher risk in CD patients compared to the controls [7,10]. A large recent study of 14,021 patients with CD found that the risk of hypothyroidism and hyperthyroidism and thyroiditis increased by 2.9 to 4.4 times compared to the general population or controls [8]. ...
... A large recent study of 14,021 patients with CD found that the risk of hypothyroidism and hyperthyroidism and thyroiditis increased by 2.9 to 4.4 times compared to the general population or controls [8]. The effect of a gluten-free diet in correcting ongoing thyroid dysfunction has not yet been determined because several studies have shown conflicting results, with one study stating that firm adherence to a gluten-free diet may correct normalized subclinical hypothyroidism [10], but with other studies failing to prove so [11]. ...
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The prevalence of celiac disease (CD) in patients with chronic autoimmune thyroiditis (CAIT) is estimated to be between 2 and 7.8%. A gluten-free diet (GFD) in patients with CD is suggested to have a beneficial effect on CAIT. Thus, the present systematic review was undertaken to achieve more robust evidence about the change in thyroid stimulating hormone (TSH) and thyroid-specific antibodies (T-Ab) levels obtained in CD patients following a GFD. A specific search strategy was planned. The last search was performed on March 2022. The following data were mainly searched for in order to be extracted: sample size, mean and/or median with standard deviation (SD), and error (SE), individually, of thyroid hormones and T-Ab at baseline and after GFD, and the duration of the study. The initial search retrieved 297 records and 6 articles met the inclusion criteria. In total, 50 patients with both CD and CAIT and 45 controls were reported. The effects of a GFD on the thyroid hormonal and immunological profile could be extracted only in a part of the studies. Two studies were case reports. A low risk of bias was observed. These findings advise further studies, ideally randomized, in order to better investigate the potential relationship between GFD and thyroid homeostasis. The level of evidence is not still sufficient to recommend GFD to patients with CAIT.
... It is not known whether treating celiac disease reduces the likelihood of developing autoimmune disorders or alters their natural course. Sategna-Guidetti et al. (2001) showed that a gluten-free diet can reverse abnormalities in people with subclinical hypothyroidism, although, like Viljamaa et al. (2004), they found no correlation between the duration of gluten exposure in adults with celiac disease and the risk of the development of autoimmune thyroid disease. Ventura et al. (2000) found that diabetes and thyroid-related antibodies tended to disappear following a gluten-free diet (11.1% at diagnosis, 5.6% after 6 months, and no diabetes-related antibodies after 12 or 24 months). ...
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Infertility is a social problem today. The causes of infertility can be both on the side of the woman and on the side of the man. One of the most common causes of infertility in women is polycystic ovary syndrome (PCOS). It has been proven that it often coexists with autoimmune thyroiditis (AIT), i.e. with Hashimoto's disease. In many patients with PCOS and AIT, endometriosis and celiac disease are also found. It seems that these disorders: PCOS, AIT, endometriosis and celiac disease may have a common autoimmune basis. More and more patients with infertility or recurrent miscarriages have autoimmune problems. Probably a genetic predisposition is necessary to reveal the disease.
... Recent studies reported the close association of CD with autoimmune endocrine disorders, especially autoimmune hypothyroidism (19). According to these reports, the prevalence of occult autoimmune hypothyroidism in CD patients is higher; therefore, it seems logical to perform routine tests for checking the thyroid function among all CD patients (20)(21)(22). On the other hand, some other studies evaluated the prevalence of occult CD in autoimmune thyroid diseases, namely autoimmune hypothyroidism (23). ...
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Background: The association of celiac disease (CD) with refractory hypothyroidism is a known but less common condition. Objectives: This study aimed to evaluate the prevalence of CD among patients with refractory hypothyroidism and compare the accuracy of different diagnostic procedures of CD in these patients. Methods: During a six-month period, 25 patients with refractory hypothyroidism were included from the endocrinology outpatient clinics of Ahvaz Jundishapur University of Medical Sciences, Khuzestan, Iran. For all the participants, the serological profile of CD, including anti-tissue transglutaminase (anti-tTG), anti-endomysial antibody (anti-EMA), and total immunoglobulin A, was determined, and then they were referred to undergo upper endoscopy and random biopsies from the first and second parts of the duodenum. Results: The average duration of hypothyroidism among the participants was 7 months. In addition, 75% of the patients (n = 19) were female. The mean age values of male and female subjects were 31.3 ± 17 and 34.3 ± 8.5 years, respectively (age range: 17 - 53 years). The average daily dosage of levothyroxine was 285.1 ± 89.9 mg. The most common comorbidities were anemia (72%) and diarrhea (24%). The most frequent serologic findings in these patients were positive anti-tTG (28%) and anti-EMA (16%). The most common results of upper endoscopy were normal mucosa (48%), gastritis (28%), duodenal fissuring (8%), duodenal atrophy (8%), and duodenal erythema (8%). Based on the results of the pathology report, 20% of the patients (n = 5) were diagnosed with CD (mostly marsh 1 and 0 stages). The sensitivity and specificity of tTG were 33 and 87.5%, respectively. The sensitivity and specificity of EMA were 11.1 and 87.5%, respectively. Conclusions: Based on the results of this pilot study, the prevalence of CD among cases with refractory hypothyroidism is higher than that of global reports. Furthermore, routine screening of CD in these patients is highly recommended even with negative serology. The endoscopic view is not adequate for the diagnosis of CD among patients with refractory hypothyroidism. In addition, it is necessary to focus on pathology reports and antibody titer.
... In another perspective, a previous review by Virili et al. indicated that the occurrence of malabsorption syndromes can significantly impact the levels of T4, which can cause secondary hypothyroidism [31]. Eventually, it is recommended that adequate screening for both modalities should be offered whenever the diagnosis of either of them was suspected [32][33]. ...
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The prevalence of thyroid diseases is high in the general population and causes serious abnormalities and disorders that can affect the quality of life. Many complications can result from poor or inappropriate management of the disease, leading to serious cardiovascular and metabolic complications. In the present review study, we aim to discuss the effect of thyroid diseases on metabolic and electrolyte abnormalities and the potential correlation with some common disorders. Evidence from previous studies has demonstrated that thyroid dysfunctions hugely affect the metabolism of glucose in the bodies of the affected patients, which can lead to the development of both type 1 and 2 diabetes mellitus (DM). Hyperthyroidism can lead to the development of impaired glucose tolerance and secondary diabetes mellitus. These include an increased glycogenolysis and gluconeogenesis process, increased intestinal absorption of glucose, and secondary ketogenesis and lipolysis, which will subsequently affect the functions of the insulin-secreting cells of the pancreas. Evidence showed that thyroid diseases are associated with the development of obesity and metabolic syndrome, and the management for these modalities should involve prior management of underlying thyroid diseases. Efforts should be made to adequately manage these cases with concomitant approaches to achieve the best clinical outcomes.
Chapter
Adhering to a gluten-free diet (GFD) is becoming a popular health trend. In this chapter we summarize the current clinical evidence on a potential role for gluten in multiple sclerosis (MS), psoriasis, autoimmune thyroid diseases (ATD), and type 1 diabetes (T1D). Patients with celiac disease have increased risk of ATD, T1D, psoriasis and vice versa, however this is not the case for MS. One clinical trial has found protective effects of a GFD among patients with MS. A few studies suggest that a subgroup of patients with psoriasis presenting gliadin antibodies can benefit from a GFD. No studies have investigated the effects of a GFD in nonceliac patients with ATD, however, some publications suggest that thyroid-related antibodies may respond to a GFD in patients with confirmed CD or tissue transglutaminase antibodies. Lastly, results on the effects of a GFD among patients with T1D are inconsistent, however, it seems likely that a GFD may contribute to normalizing metabolic control possibly by preserving the function of the remaining beta-cells. Altogether, the above results have to be replicated in properly controlled intervention trials of adequate power before we can recommend a GFD to subgroups of patients with autoimmune disorders.
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Background Prevalence of Celiac disease (CD) increased worldwide in recent decades. Approximately 53% of the 33.4 million Saudi population are genetically susceptible and 1.5% develop CD. This underscores the importance of identification of factors associated with CD and the diagnostic accuracy of CD screening tests. Methods In this case-control study records of patients managed between January 2016 and July 2019 at Gastroenterology Department, King Abdul-Aziz Medical City, Riyadh, Saudi Arabia were reviewed. CD cases with confirmed intestinal biopsy were matched (1:1) by age with biopsy negative controls free of CD. Area under the curve (AUC) for anti-tissue transglutaminase IgA (TTG-IgA) and IgG (TTG-IgG) CD diagnostic tests were calculated and compared. Results The study included 270 cases and 270 controls. Sex distribution was similar in both groups. In a stepwise conditional logistic regression analysis, factors significantly associated with CD were family history (odds ratio (OR)=7.76, 95% confidence interval (CI): 2.26-26.63, P=0.001), Helicobacter pylori infection (OR=1.72, 95% CI: 1.10-2.71, P=0.018), diabetes mellitus (OR=3.37, 95% CI: 1.68-6.74, P=0.001), hypothyroidism (OR=2.46, 95% CI: 1.15-5.28, P=0.02) and respiratory infections (OR=4.89,95% CI 2.26-10.56, P<0.001). AUC for TTG-IgA test was 0.934 and for TTG-IgG was 0.787, P<0.001. The optimal cut-off for TTG-IgA was >=12.7 U/ml, with 89% sensitivity and 86% specificity, and for TTG-IgG was >=3.5 U/ml, with 70% sensitivity and 77% specificity. Conclusion The findings of this study can inform strategies for CD screening and prevention. Public awareness campaigns for CD are urgently needed, particularly, for high-risk groups.
Article
Background: The general practice is to screen patients with autoimmune thyroid disease for celiac disease (CD); however, optimal timing for CD screening for patients with Graves’Disease (GD) has not been identified yet. The aim of the study was to show whether positive celiac antibodies persist after euthyroidism is achieved. Materials and Methods: Serum samples were collected from 35 patients with GD (23 female and 12 male) who applied to the endocrine outpatient clinic. Patients and healthy controls were screened for CD with IgG and IgA antigliadin antibodies (IgG – AGA and IgA – AGA), IgA endomysial antibody (IgA-EMA) and IgA tissue transglutaminase antibody (IgA anti-tTG). These antibodies were reevaluated when patients were euthyroid under antithyroid therapy. Small intestine biopsy was offered to the patients who remained antibody positive after being euthyroid. Results: Screening 35 patients with GD revealed positive results for IgA-AGA (n = 6/35, 17%), IgG-AGA (n = 9/35, 26%), IgA-EmA (n = 2/35, 6%) and IgA-tTG (n = 2/35, 6%). No patient had multiple antibodies positive. Selective IgA deficiency was not detected in patients and controls. When patients were euthyroid, baseline positive IgA-AGA, IgG-AGA, and IgA-EmA became negative, while positive anti-tTG persisted in two patients. Endoscopic duodenal biopsy showed a normal villi/crypts ratio in these patients. None of the controls had positive antibodies. Conclusion: Due to possibility of false seropositivity of celiac antibodies in patients with Graves’ thyrotoxicosis, one should defer testing for CD until euthyroidism has been achieved.
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Context: A gluten-free diet (GFD) is the recommended treatment for gluten-dependent disease. In addition, gluten withdrawal is popular and occasionally is suggested as a treatment for other autoimmune diseases (ADs). Objective: The current systematic review summarizes those entities and discusses the logic behind using a GFD in classical non-gluten-dependentADs. Data sources: A search for medical articles in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo published between 1960 and 2020 was conducted, using the key words for various ADs and GFDs. Data exxtraction: Eight-three articles were included in the systematic review (using PRISMA guidelines). Data analysis: Reduction in symptoms of ADs after observance of a GFD was observed in 911 out of 1408 patients (64.7%) and in 66 out of the 83 selected studies (79.5%). The age of the patients ranged from 9 months to 69 years. The duration of the GFD varied from 1 month to 9 years. A GFD can suppress several harmful intraluminal intestinal events. Potential mechanisms and pathways for the action of GFD in the gut - remote organs' axis have been suggested. Conclusion: A GFD might represent a novel nutritional therapeutic strategy for classical non-gluten-dependent autoimmune conditions.
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Selection of appropriate laboratory determinations will enable the clinician to diagnose thyroid dysfunction readily in the majority of patients. At the present time, estimation of free thyroxine and a "sensitive" thyrotropin assay are recommended as the principal laboratory tests for thyroid disease. A decrease in serum free thyroxine estimate and a raised level of serum thyrotropin confirm the diagnosis of hypothyroidism caused by thyroid gland failure. An increase in free thyroxine estimate combined with a serum sensitive thyrotropin level suppressed to less than 0.1 mU/L establishes the diagnosis of thyrotoxicosis. In sick patients, a normal or raised serum free thyroxine estimate together with a normal level of serum thyrotropin suggests that the patient has neither hypothyroidism nor thyrotoxicosis. Patients with severe illnesses, generally in the intensive care unit, and those treated with certain drugs, as well as individuals with unusual thyroid disorders, may present with confusing laboratory findings. An understanding of the regulation of the thyroid hormone system and/or judicious consultation with an endocrinologist should enable the clinician to diagnose thyroid disease, if present, in such patients.(JAMA. 1990;263:1529-1532)
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The relationship between celiac disease and many autoimmune disorders has been explained by the sharing of a common genetic factor. In a multicenter national study, we examined the relationship between the prevalence of autoimmune disorders in celiac disease and the duration of exposure to gluten. Over a 6-month period, 909 patients with celiac disease (group A; mean age, 16.1 +/- 3.8 years; grouped according to age at diagnosis into three subgroups [group A1, <2 years; group A2, 2-10 years; and group A3, >10 years]), 1268 healthy controls (group B; mean age, 20.8 +/- 4.5 years), and 163 patients with Crohn's disease (group C; mean age, 28.8 +/- 10 years) were evaluated for the presence of autoimmune disorders. Prevalence of autoimmune disorders in group A was significantly higher than in group B (14% vs. 2.8%; P < 0.000001) but not higher than in group C (12.9%). Prevalence of autoimmune disorders in celiac disease increased with increasing age at diagnosis: 5.1% in group A1, 17% in group A2, and 23.6% in group A3 (P = 0.000001). In group A3, the prevalence of autoimmune disorders was significantly higher than in group C. In a logistic regression model, age at diagnosis was the only significant predictor variable of the odds of developing an autoimmune disorder (r = 0.3; P < 0.000001). Our data show for the first time that the prevalence of autoimmune disorders in celiac disease is related to the duration of exposure to gluten.
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Selection of appropriate laboratory determinations will enable the clinician to diagnose thyroid dysfunction readily in the majority of patients. At the present time, estimation of free thyroxine and a "sensitive" thyrotropin assay are recommended as the principal laboratory tests for thyroid disease. A decrease in serum free thyroxine estimate and a raised level of serum thyrotropin confirm the diagnosis of hypothyroidism caused by thyroid gland failure. An increase in free thyroxine estimate combined with a serum sensitive thyrotropin level suppressed to less than 0.1 mU/L establishes the diagnosis of thyrotoxicosis. In sick patients, a normal or raised serum free thyroxine estimate together with a normal level of serum thyrotropin suggests that the patient has neither hypothyroidism nor thyrotoxicosis. Patients with severe illnesses, generally in the intensive care unit, and those treated with certain drugs, as well as individuals with unusual thyroid disorders, may present with confusing laboratory findings. An understanding of the regulation of the thyroid hormone system and/or judicious consultation with an endocrinologist should enable the clinician to diagnose thyroid disease, if present, in such patients.
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Most clinically euthyroid patients with severe, chronic, non-thyroidal illnesses (i.e., " sick euthyroid " patients) have abnormal thyroid-function tests, and consequently assessment of their thyroidal status may be very difficult. The most striking abnormality detected in 75 sick euthyroid patients was a highly significant reduction in the mean total serum-triiodothyronine (T3) levels, with most patients having total T3 levels in the hypothyroid range. The severity of the illness correlated well with the reduction in total serum-T3 levels. The mean absolute free serum-T3 concentration was significantly lower than in the control patients. The mean total serum-thyroxine (T4) levels were also significantly reduced, although, unlike the total serum-T3 levels, they remained within the normal range. The total serum-T4/T3 ratios were generally higher in the sick euthyroid patients compared with the controls. The absolute free serum-T4 concentrations (as measured by the effective-thyroxine-ratio test) were normal, and serum-T.S.H. was not increased in any patient. The mean effective binding capacity of thyroid binding proteins in 11 sick euthyroid patients and the control patients was not significantly different. 3 patients had normal T.S.H. and T3 responses to oral thyrotrophin-releasing hormone (T.R.H.) and 2 other patients had normal T3 responses to intramuscular T.S.H. The major cause of the low total and absolute free serum-T3 concentrations in the sick euthyroid patients seemed to be inhibition of extrathyroidal conversion of T4 to T3. Decreased concentrations of binding proteins are unlikely to contribute greatly to the abnormalities of thyroid-function tests in the patients studied. Depressed production of T.R.H., secondary to stress or undernutrition consequent upon chronic illness, may also contribute by reducing thyroidal hormone output.
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SUMMARYA specific pattern of thyroid hormone abnormalities was observed in twenty-seven men with coeliac disease which differed from that observed in patients with non-thyroidal illness (NTI). Serum free thyroxine (FT4) was reduced, but increased after gluten was withdrawn from the diet and jejunal morphology improved. Total T4 (TT4), total triodothyronine (TT3), free triiodothyronine (FT3) and reverse T3 (rT3) levels were unchanged, unlike the findings in nineteen men with Crohn's disease when TT3 fell, rT3 tended to rise but TT4, FT4 and FT3 levels were normal, except FT4 was significantly higher in a subgroup of patients who were more severely ill. The thyroid hormone changes in Crohn's disease are those expected in NTI. Basal serum thyrotrophin (TSH) was normal in all but one of the patients with coeliac disease but 45% of untreated coeliacs had exaggerated responses of TSH to thyrotrophin releasing hormone, an observation which cannot be explained as a feature of NTI. These changes in thyroid hormones in coeliac disease could not be attributed to abnormalities of thyroxine-binding globulin or thyroxine-binding prealbumin, and thyroid autoantibodies were not detected in these patients. Hence, different patterns of thyroid hormone abnormalities can occur in different diseases of the same organ in patients of equivalent nutritional status. Circulating gluten peptides may be involved in the hypothalamic-pituitary disturbance of coeliac disease.
Article
A well defined cohort of coeliac patients was studied prospectively to assess the prevalence of coexisting thyroid disease and positive thyroid autoantibodies. Comparison with epidemiological data on the prevalence of coeliac disease in a neighbouring area suggested that few adult coeliac patients had been missed. Overall, 14% of the coeliac patients had thyroid disease: 10.3% were hypothyroid and 3.7% hyperthyroid, both significantly more than expected. There were significantly more coeliac disease patients with thyroid autoantibodies than expected--11% had thyroglobulin antibodies and 15% had thyroid microsomal antibodies. This association is clinically important. Three patients are described in whom the coexistence of coeliac disease and hypothyroidism led to diagnostic difficulties and delay of treatment.