ARTICLE
Auteur(s) : Filiz
Cebeci1, Ayşenur Tanrikut1, Elif
Topcu1, Nahide Onsun1, Neslihan
Kurtulmus2, Ahmet R Uras3
1Dermatology Clinic, Vakıf Gureba Teaching Hospital,
Istanbul, TurkeyFax : (+90) 212 621 75 80
2Endocrinology Clinic Vakıf Gureba Teaching Hospital,
Istanbul , Turkey
3Biochemistry Laboratory, Vakıf Gureba Teaching
Hospital, Istanbul, Turkey
accepté le 15 Février 2006
Chronic idiopathic urticaria (CIU) diagnosis is established when
the pathophysiological mechanism of persistent urticaria is not
clear [1]. Recent advances seen in pathogenesis of CIU have
suggested an autoimmune cause in most cases. Histamine-releasing
autoantibodies to high-affinity IgE reseptor (FcepsilonRI) or, less
commonly, to IgE have been demonstrated in CIU, the former being
present in 20% to 40% of patients with CIU [2, 3]. There is an
increasing body of evidence that there is an association between
urticaria and/or angioedema and thyroid autoimmunity, with a subset
of patients responding to the administration of thyroid hormone
[4-6]. Therefore, when CIU patients are evaluated, thyroid
autoimmunity (anti-thyroperoxidase and anti-thyroglobulin) should
also be investigated [4, 7]. However, this association has most
often been suggested in studies investigating thyroid microsomal
antibodies, which are less sensitive and specific than
anti-thyroperoxidase (TPO) antibodies [8-10].The aim of this study
was to learn the extent of autoimmune thyroid disease in a large
case-control series who presented with CIU.
Materials and methods
We conducted a prospective case-control study for 24 months. From
December 2002 to December 2004; 140 selected adult patients with
CIU and 181 healthy volunteer controls were enrolled in this study.
The study group comprised patients who attended the dermatology
outpatient clinic. The control group was composed of patients who
were age-and sex-matched with CIU patients and control cases did
not have any known autoimmune disease and thyroid disease. The
diagnosis of CIU was established by the presence of urticarial
wheals lasting longer than six weeks, disappearing in less than 24
hours and having no history of drug or food allergy known to cause
urticaria [11]. Patients with urticarial vasculitis, hereditary
angioedema, and physical urticaria were excluded from the study. In
suspicious cases a skin biopsy was taken to confirm the diagnosis.
The group with CIU was selected from the patients not having been
detected with any infection foci and having no history of known
drug or food allergies, being IgE antibody negative directed
against food (egg white, milk, wheat, peanut, soybean) (Food panel
5, DPC, Immunometric assay) and respiratory allergens
(dermatophagoides pteronvssinus, cat ephitelium, dog dander,
mixture of grass, mixture of tree, grass, penicillium notatum,
alternaria tenuis) (Alatop, DPC, Immunometric assay). A thorough
investigation of history, of physical examination and of laboratory
tests was carried out in all patients. Those who were included in
the study were assessed to have normal test results, such as
complete blood counts, erythrocyte sedimentation rate, urinalysis,
stool examination, hepatitis serology negative (ELISA, Pasteur,
France) and whose chest and sinus x ray was normal. In addition,
rheumatoid factor (RF) (Nephelometer, Behring, Germany),
antinuclear antibody (ANA) (ELISA, Genesis Diagnostics, England),
anti-double-stranded DNA antibody (dsDNA) (ELISA, Genesis
Diagnostics, England), anti-extractable nuclear antigens (ENA)
(ELISA), Complement (C) 3 and 4 (Nephelometer, Behring, Germany),
total IgE (Immunometric assay, Immulite 2000, USA) were applied.
In both the patient and control groups, total triiodothyronine
(TT3) (normal, 72-170 ng/dL), total thyroxine
(TT4) (normal, 4.5-12.5 μg/dL), free thyroxine
(FT4) (normal, 0.8-1.9 ng/dL) and thyroid-stimulating
hormone (TSH) were measured by chemiluminescent immunometric assay
(DPC, USA). The normal reference range for TSA was 0.4-4.0 μg/dL.
TPO and TG antibodies were measured by chemiluminescent
immunometric assay (DPC, USA). The presence of TPO and TG
antibodies in titers ≥ to 100 IU/mL, and in addition, thyroid
dysfunction, were considered the criteria to meet the diagnosis of
autoimmune thyroid disease [12]. The diagnosis of hypothyroidism
was made by clinical and laboratory criteria of FT4 <
0.8 ng/dL, TSH > 4.0 μg/dL. Patients were classified as having
subclinical hypothyroidism if they were clinically euthyroid with
normal FT4 levels but had significantly elevated TSH
levels. The diagnosis of hyperthyroidism has been based on the
detection of low-serum TSH values (< 0.4 μg/dL) and
elevated levels of FT4 (> 1.9 ng/dL) in serum.
All patients who had thyroid disease were examined by the
endocrinologist. The Chi square, Student-t and Mann-Whitney U tests
were used for statistical analysis. Differences were mentioned only
when the level of signifigance was < 0.05.
Results
There were 140 patients with CIU with a mean age of 40 years (range
18 to 66 years). Of these, 102 were females (mean age 40 years;
range 20 to 66 years) and 38 were males (mean age 39 years; range
18 to 66 years). The control group was comprised of 143 females
(mean age 40 years; range 18 to 66 years) and 38 males (mean age 44
years; range 23 to 63 years). Because the patients were age-and
sex-matched with control group there was no statistical difference
between the controls and the patients with respect to age and sex.
Angioedema was found in 60 (42.85%) patients with chronic
idiopathic urticaria. The duration of urticaria varied from 2 to 48
months. Total IgE values in cases with CIU were from 6.6 to 1548
mg/dL (mean, 221 ± 252 IU/mL). RF and Anti-ds DNA was found to be
negative in all patients. Fifteen (10.71%) patients were determined
as ANA positive and in one patient with ANA positive euthyroid
autoimmune thyroiditis was established. In patients with ANA
positivity the ENA profile was negative and collagen tissue disease
was not found in any patients. In one (0.71%) patient C3
and in two (1.42%) patients C4 levels were low. TG
antibody in 18 (12.85%) patients, TPO antibody in 14 (10%) and both
TG and TPO antibodies in 9 (6.42%) were higher than the normal
antibody titres. In patients with CIU antiTG titers were ranging
from 108 to 3000 IU/mL and antiTPO antibody titers from 100 to 1000
IU/mL. Autoimmune thyroiditis was seen in 41 cases (29.28%) with
CIU. In the control group, 10 cases (5.52%) were diagnosed as
autoimmune thyroiditis. Compared with the control group, the
frequency of both TPO and TG antibodies was significantly higher in
those with CIU (p < 0.001). table 1( Table
1 ) shows the frequency of thyroid antibodies in the study
group.
Among the patients with autoimmune thyroiditis, 31 (75.6%) were
euthyroid, 7 (17.07%) cases were subclinically hypothyroid and one
(2.43%) was hypothyroid autoimmune thyroiditis. Graves’ disease was
found in two (4.87%) patients. Fifteen patients (twelve euthyroid,
two subclinical autoimmune thyroiditis and one Graves’ disease)
were found to have goiter on USG. Compared with control cases,
TT4 values of patients with CIU were determined to be
significantly low. There was no statistically significant
difference with regard to TT3, FT4, TSH
between patients with CIU and the control group. table 2( Table 2 ) shows thyroid hormone levels and
autoimmune thyroiditis status in the patient and control groups.
Compared with the control group, the frequency of both TPO and TG
antibodies was significantly higher in those with CIU.
Table 1 Frequency of thyroid autoantibodies in the
study group
|
AntiTG
|
AntiTPO
|
AntiTG and AntiTPO
|
Total
|
|
Patients
|
18 (12.85%)
|
14 (10%)
|
9 (6.42%)
|
41 (29.28%)
|
|
Controls
|
2 (1.1%)
|
2 (1.1%)
|
6 (3.31%)
|
10 (5.52%)
|
Table 2 Thyroid hormone levels and autoimmune
thyroiditis status in the patient and control groups
|
Euthyroid
|
Subclinic
|
Hyper-thyroid
|
Hypo-thyroid
|
TT3
|
TT4
|
FT4
|
TSH
|
|
n
|
n
|
n
|
n
|
mean ± SD
|
mean ± SD
|
mean ± SD
|
mean ± SD
|
|
patients
|
31
|
7
|
2
|
1
|
129 ± 54.1
|
8.30 ± 2.05
|
1.23 ± 0.34
|
1.93 ± 2.78
|
|
controls
|
5
|
4
|
1
|
0
|
130 ± 24.8
|
8.97 ± 2.02
|
1.26 ± 0.39
|
1.61 ± .44
|
|
p
|
|
|
|
|
0.922
|
0.003
|
0.514
|
0.452
|
Discussion
The association of chronic urticaria with thyroid autoimmunity has
been known since 1983, but its frequency seems to vary in different
reports. The prevalence in series ranges from 12% to 33% [4, 13].
More recently, some studies have suggested that there may be a link
between chronic urticaria and thyroid autoimmunity [8-10, 13, 14].
However, this association was first assumed in studies
investigating thyroid microsomal antibodies, which are less
sensitive and less specific than anti-TPO antibodies [8-10].
Although some recent studies have used TPO antibodies, they have
not used a control group at the same time [13, 14]. The three
studies more recently published have both used TPO antibodies and
have had control groups, but these studies have not included large
numbers of patients and controls [15-17]. For this reason, using
more specific thyroid antibodies, we carried out a large
case-control study. As a result, our study can be much better
interpreted in that it both has used more specific thyroid
antibodies and has had large numbers of patients and controls. In
the light of literature, using TPO and TG antibodies together seems
to increase the frequency of thyroid antibody accompanying CIU.
table 3( Table 3 ) shows the frequency
of thyroid antibodies in patients with CIU. We detected thyroid
autoantibodies in 29.28% of patients with CIU and this may be
considered to be a relatively high percentage. The frequency of
thyroid antibodies in the control group was 5.52%, when comparing
with the previous studies (0-5.6%) [16]. Our study shows that, in
patients with CIU, the frequency of thyroid autoantibodies (29.28%)
is significantly higher (p < 0.001) than the (5.52%) frequency
in the control group, demonstrating a statistical association
between CIU and antithyroid antibodies.
Thyroid autoimmunity is the original paradigm for autoimmune
diseases in general [7, 18] and, with the striking association of
these two entities, autoimmunity may play a role in the
pathogenesis of CU [7, 9]. The most direct evidence of an
autoimmune process in some patients with CIU is the demonstration
of functional IgG autoantibodies to the alpha subunit of the
high-affinity IgE receptor (FcepsilonRI) or to IgE itself [2-4,
19].
Among patients with autoimmune thyroiditis only 2 were diagnosed
with Graves’ disease and most patients fell in the euthyroid
autoimmune thyroiditis group. Euthyroid patients with positive
thyroid antibody, have an appreciable risk of progression to
hypothyroidism [12, 20]. Our results confirmed previous studies [8,
12, 16] showing that chronic urticaria was more frequently
associated with Hashimoto’s thyroiditis than with Graves’ disease.
While the diagnosis of subclinical hypothyroidism was established
in 7 patients, 31 were euthyroid. Of 41 patients with thyroiditis
only 7 were male. This suggests that between CIU and thyroid
autoimmunity there is a female sex predominance as found in
previous studies [13, 16]. Therefore, it would seem to be more
interesting to test particularly for antithyroid autoimmunity in
women.
The group with urticaria was selected from patients having no
cause in the etiopathogenesis. No collagen tissue disease was
determined in this group using clinical and immunological tests.
And this result seems to be close to that of Verneuil et al. [16].
A decrease of 0.6 % Complement 3 and 1.3 % Complement 4
activities was seen in patients. None of them had a family history
of CIU. The complement components in CIU patients were the same as
those in healthy individuals, as shown by Passeron et al. [21] ANA
positivity was found to be 10 % in our study. Turktas et al.
[10] found ANA positivity in 5% of cases. Ryhal et al. [15] did not
suggest more ANA positivity in controls than that in CIU patients.
Thus, comprehensive immunological tests are unnecessary.
These results suggest the need for systematically including
anti-TG and anti-TPO antibodies in the assessment of CIU. The high
frequency of thyroid autoantibodies in our study can be attributed
to large numbers of patients comprising the CIU group who had no
cause for etiopathogenesis for CIU. Furthermore, using more
specific thyroid antibodies (TG,TPO) could contribute to this high
frequency.
Table 3 Frequency of thyroid antibodies in patients
with chronic idiopathic urticaria
|
Patients
|
Thyroid antibodies, %
|
Thyroid antibodies studied
|
|
Chronic urticaria
|
Healthy controls
|
Chronic urticaria
|
Healthy controls
|
Chronic urticaria
|
Healthy controls
|
|
Leznoff et al., [9]
|
140
|
427
|
12.1
|
5.6
|
TMA
|
TMA
|
|
Leznoff and Susman [8]
|
624
|
|
14
|
|
TMA+TG
|
|
|
Turkas et al., [10]
|
94
|
80
|
11.7
|
3.7
|
TG
|
TG
|
|
Turktas et al., [10]
|
94
|
80
|
9.5
|
3.7
|
TMA
|
TMA
|
|
Gaig et al., [14]
|
170
|
|
14.7
|
|
TG+TPO
|
|
|
Zauli et al., [13]
|
52
|
|
23
|
|
TG+TPO+TSI
|
|
|
Ryhal et al., [15]
|
25
|
75
|
20
|
|
TG+TPO
|
|
|
Verneuil et al, [16]
|
45
|
30
|
26.7
|
3.3
|
TG+TPO+TSI
|
TG+TPO
|
|
Palma-Carlos et al, [17]
|
56
|
56
|
28.5
|
|
TG+TPO
|
TG+TPO
|
|
Present study
|
150
|
181
|
29.3
|
5.5
|
TG+TPO
|
TG+TPO
|
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|
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