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Original Studies |
Departments of Endocrinology and Metabolism (R.K.M., N.T., N.G., N.K.) and Pathology (A.K.K., K.V.), All India Institute of Medical Sciences, New Delhi, India
Address all correspondence and requests for reprints to: Prof. N. Kochupillai, Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.
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Abstract |
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1:1600) and TGA (1:160) in 52
(7.2%) and 4 (0.55%) girls, respectively. Only 29 (67.4%) girls with
Hashimoto’s thyroiditis were TMA positive. In patients with FNAC-proven JAT, overt clinical and biochemical hypothyroidism was seen in three (6.5%) and subclinical hypothyroidism in seven (15%). Subclinical hyperthyroidism was detected in 5.1% cases of JAT, and none had overt hyperthyroidism. No definite correlation was seen between urinary iodine excretion and thyroid autoimmunity.
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Introduction |
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It has been argued in the literature that introduction of iodine in a previously iodine-deficient population may precipitate the emergence of thyroid autoimmunity (7, 8, 9). This made it relevant to study in detail, using internationally accepted criteria, the prevalence and spectrum of autoimmune thyroid disease in postsalt iodization phase in India.
Autoimmune thyroiditis can manifest either as a goitrous or atrophic variant. Goitrous autoimmune thyroiditis could either present as focal or diffuse lymphocytic thyroiditis. The latter, when associated with eosinophilic changes and follicular destruction, is called Hashimoto’s thyroiditis (HT) (8). The role of iodine in triggering and/or causing autoimmune thyroiditis has long been debated. Iodine supplementation in iodine-deficient areas increases the prevalence of lymphocytic infiltration of the thyroid 3-fold (7). Also, the prevalence of thyroid autoantibody positivity in such areas rises to over 40% within 5 yr of initiating supplementation (10). In view of these observations, we studied the prevalence of goiter and thyroid autoimmunity in cohorts of apparently healthy, school-going girls from Delhi and other States of India, using fine-needle aspiration cytology (FNAC) and serological techniques.
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Materials and Methods |
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Among these patients, 2464 were students of private schools (representing higher socioeconomic strata) and 3819 studied in state-aided schools (representing lower socioeconomic strata); there were 3727 from Delhi and 2556 from other states. To get a countrywide cross-section of schoolgirls for the study, attendees of the National Integration Camps of the National Cadet Corps were included.
Goiter was graded as per recommendations of WHO/UNICEF/ICCIDD consultation on iodine deficiency disorders indicators (11). The consensus view of two trained endocrinologists was taken in case of any discrepancy in individual assessment. Those found to have goiter were subjected to blood tests for total T4, TSH, thyroid microsomal antibody (TMA), and thyroglobulin antibody (TGA), as well as urinary iodine estimation in spot samples. The study was initiated after institutional approval. The clinical examination and all investigations were performed after taking informed consent for each component of the study. FNAC was advised for all goitrous girls and performed in those who gave informed consent. Every 10th nongoitrous girl was selected to serve as control, until 100 individuals from different age groups had been recruited. They were then subjected to all the above investigations, except FNAC. FNAC of the thyroid was performed in 947 girls (52.3% of goitrous girls), who gave their consent, by a cytopathologist (A.K.K.) under field conditions. FNAC was satisfactory in 764 (80.6%) girls. The stained slides were reported blindly by two cytopathologists (K.V. and A.K.K.) independently, who had no access to clinical and serological data. The criteria adopted for the diagnosis of juvenile lymphocytic thyroiditis were (12, 13): the presence of lymphocytic infiltrate, diminished colloid and minimal to moderate follicular destruction, with or without Hürthle cell change. The presence of mild focal lymphocytic infiltration in the absence of follicular destruction was used to diagnose focal lymphocytic thyroiditis (FLT).
Definition
Juvenile autoimmune thyroiditis (JAT) was diagnosed if the cytopathological features were consistent with either FLT or HT (12) or if TMA titers were 1:1600 or greater (14). Of 764 satisfactory FNACs, complete information on thyroid hormones (T4 and TSH) and thyroid antibodies (TMA and TGA) and UIE status was available in 722 goitrous subjects (58 with JAT and 664 without thyroiditis). Total T4 estimation was carried out by an in-house RIA (15, 16), and TSH was assayed by an immunoradiometric assay technique (Immunocorp., Montreal, Canada). The normal range of values for total T4, as standardized in our laboratory, was 51–154 nmol/L, whereas the normal range for TSH provided by the manufacturers of the kit was 0.3–4. µIU/mL. In clinically euthyroid individuals, subclinical hypothyroidism was diagnosed if serum T4 levels were normal and serum TSH was elevated (>5 µIU/mL), whereas subclinical hyperthyroidism was diagnosed if low TSH (<0.1 µIU/mL) levels were detected in the presence of normal T4 concentration. Overt hypothyroidism was diagnosed with low T4 (<51 nmol/L) and high TSH (>5 µIU/mL) and overt hyperthyroidism by high T4 levels (>154 nmol/L) and low TSH levels (<0.1 µIU/mL). The cutoff values of TSH for diagnosis of hypothyroidism and hyperthyroidism are based on normative data generated in our laboratory.
Hemagglutination kits (Thymune-M and Thymune-T; Murex Diagnostics) were used for detection of thyroid microsomal and thyroglobulin antibodies in goitrous and control subjects. Titers 1:100 or greater and 1:1600 were considered as positive and significantly positive, respectively, for TMA and 1:10 or greater and 1:160 for TGA.
Urinary iodine content was quantitated by the wet ashing methodology using the Perchloric acid-Vanadate system, which was originally used by Zak and Baginski (17) for serum protein-bound iodine, modified and adopted in our laboratory for urine iodine estimations.
Statistical analysis
Data were entered using Microsoft Corp. Excel, and statistical analysis was done using test of proportion, Pearson’s correlation coefficient, and Spearman’s rank correlation.
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Results |
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15 yr; 3469
girls >15 yr) from different states of India were examined clinically.
Diffuse goiter was detected in 1803 individuals (28.7%), whereas
solitary nodule was palpable in 7 subjects (0.1%). Thyroid enlargement
of grades 1 and 2 were seen in 1381 (76.2%) and 429 (23.7%) students,
respectively. Among the girls 15 yr of age or younger, 30.8% were
goitrous (81% grade 1, 19% grade 2), whereas in girls more than 15 yr
of age 27% had a goiter (72% grade 1, 28% grade 2). Those from a
poor socioeconomic background had a significantly higher prevalence
rate (31.9%) compared with girls from a higher socioeconomic status
(23.8%). A significant difference was observed in the goiter
prevalence between Delhi (26.3%) and other states of the country
(32.3%; P < 0.0001). This difference persisted on
further subcategorization to the 15-yr or less and more than 15-yr age
groups (P = 0.0213 and P < 0.0001,
respectively). Detailed results of clinical examination are summarized
in Table 1
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). From the available data, there is a
trend of higher prevalence of HT in older girls more than 15 yr (6.6%)
than in younger ones (4.2%) and in girls from state-aided schools
(6.4%) than those from private schools (3.3%). However, the
difference did not reach statistical significance.
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A total of 43 cases were diagnosed to have HT on the basis of FNAC
(Table 3). Goiter was grade 1 in 21
(49%) and grade 2 in 22 (51%) girls, firm on palpation in 26 (60.4%)
cases and soft in 17 (39.6%) cases of HT. Overt hypothyroidism was
detected in one (2.3%) and subclinical hypothyroidism in eight
(18.6%) girls with HT. On the contrary, among goitrous patients
without thyroiditis, overt hypothyroidism was present in 2 (0.3%) and
subclinical hypothyroidism in 20 (3.01%) subjects, respectively, which
was significantly less (P < 0.05 and P
< 0.0001, respectively) than in patients with thyroiditis (Table 4). None of the patients with HT had
either overt (including clinical features of Graves’ disease) or
subclinical hyperthyroidism. None of the controls had either hypo- or
hyperthyroidism. T4 values, when compared between
HT and other goitrous individuals, showed no difference, whereas TSH
was significantly higher in HT group (P < 0.0004).
Also, no significant difference was found in UIE in the above groups.
Furthermore, there was no difference in the prevalence of HT on
subdividing goitrous subjects into groups based on UIE (0.79
µmol/L, 0.79–1.57 µmol/L, and 1.57 µmol/L).
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1:1600) and TGA (1:160) were detected in only 19
(44%) and 1 (2.3%) cases, respectively (Table 5). However, in goitrous girls without
thyroiditis, TMA was positive in 58 (8.7%) and TGA in 49 (7.3%), but
significant titers of TMA and TGA were present in only 28 (4.2%) and 3
(0.45%).
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1:1600), was significantly higher in HT than in goitrous patients
without thyroiditis (P < 0.0001) and controls
(P = 0.001). However, TGA positivity and the prevalence
of significant TGA titers, were no different between these groups. FLT
FLT was diagnosed on FNAC in 15 (1.9%) goitrous girls, and the
hormonal and antibody status was estimated in all of these subjects
(Table 3
). Goiter was firm on palpation in eight (53.3%) and soft in
seven (46.7%) cases. No significant differences were seen in FLT
prevalence among girls 15 yr of age or less and more than 15 yr and in
grade 1 and grade 2 goiters. However, a significant difference was
noticed between private (0%) and state-aided (2.7%) schools, being
much higher in girls from a poorer socioeconomic status
(P < 0.05).
Overt hypothyroidism was detected in two (13.3%) girls with FLT, and
no individual had subclinical hypothyroidism. Among patients with FLT,
three (20%) had evidence of subclinical hyperthyroidism (Table 4).
Individually, TMA and TGA were positive in five (33.3%) cases of FLT,
respectively, and together in four (28.5%) cases. However, high titers
of TMA and TGA were present in only four (28.5%) and zero subjects
(Table 5).
Among the 722 goitrous subjects for whom both cytological and
serological data are available, 51 (7.1%) had significantly positive
titers of TMA (Table 3). These included 24 patients with
cytomorphological evidence of JAT, whereas the remaining 27 subjects
had colloid goiter. In the group of significantly seropositive
individuals, subclinical hypothyroidism was observed in eight subjects
(15.7%), whereas three subjects (5.9%) had overt hypothyroidism. In
contrast, in the subgroup of 637 subjects, with neither cytological nor
serological evidence of thyroiditis, none had overt hypothyroidism,
whereas only 2% had subclinical hypothyroidism. Subclinical
hyperthyroidism was observed in 5.88% of individuals with significant
seropositivity, as compared with only 1.3% of subjects with either
absent or weak titers of TMA (P < 0.05). No
significant difference was found in UIE of the group with significant
seropositivity and that without either cytological or serological
positivity. Furthermore, there was no difference in the prevalence of
significant serological positivity on subdividing goitrous subjects
into groups based on UIE (0.79, 0.79–1.57, and 1.57 µmol/L).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Comparison of our results with studies available in the literature is difficult due to differences in study design. In few studies FNAC was done only in serologically positive subjects (18, 19, 20). To the best of our knowledge, the current study and a related preliminary report are the only ones that used both serological and cytomorphological criteria to assess the prevalence of JAT (21).
The overall prevalence of serologically diagnosed JAT in 2801 schoolgirls surveyed by Jaksic et al. (18) was 0.6%, whereas the goiter-specific prevalence was 12.4%. All the 19 girls with positive serology had FNAC features of autoimmune thyroiditis. Also, in two studies from Japan (19, 20) where FNAC was done in seropositive subjects, the prevalence of JAT varied between 0.31% and 0.8%. If we had followed the same protocol, the prevalence of JAT in our study population would have been nearly halved, to 0.9%, which is similar to that reported in the above-mentioned studies.
In many studies, prevalence of JAT was based on positivity of circulating TMAs. In our study, among goitrous subjects, 7.2% were strongly positive for TMA, whereas none of the nongoitrous controls were strongly positive for TMA. TMA positivity in goitrous subjects was significantly different from nongoitrous controls in terms of titers and prevalence (P < 0.05).
The reported overall prevalence of JAT in girls, using TMA positivity as criteria, varies from 0.6–1.6% (18, 23, 24, 25) and from 10:8–12.5% among goitrous girls. In a study from Epirus, an area under salt iodization for 3 decades, overall prevalence of JAT was 3.3% and the goiter-specific prevalence was 16.5% (26). This scenario resembles what we currently see in India. In our study, using serological criteria, the overall prevalence of JAT was 2.0%, and the goiter-specific prevalence was 7.1%. In both the studies, due to absence of preiodization data, no conclusions can made on the role of iodization in causing thyroid autoimmunity.
In the present study, among patients with HT on FNAC, TMA was positive in 67.4% and strongly positive in 44.2%. The discrepancy between cytological and antibody-based criteria is well recognized, in children and young adults, in the early stage of the disease (12). Another cause for this discrepancy may be antibody production confined to intrathyroidal lymphocytes, as shown by Baker et al. (27). These facts strongly support the superiority of cytomorphological studies to diagnose JAT. Such results are corroborated by Roth et al. (22), Poropatich et al. (28), and Droese et al. (29). Finally, it is recognized that antibody titers might change but cytomorphological features persist during the clinical course of HT (30). Our data, along with the above studies, indicate the need to combine cytological and serological evaluation to diagnose JAT.
In our study, 53.9% of subjects with significant titers of TMA turned out to have colloid goiter on FNAC. Focal thyroiditis in the "missed hit" could be one possible cause. Moreover, patients with colloid goiter are known to become TMA positive on iodine repletion (31).
The fact that roughly 55% of patients with JAT are missed by either of the two diagnostic approaches justifies the need to apply both to diagnose this entity. Reanalyzing our data using dual criteria show a goiter-specific prevalence of 11.8% and an overall prevalence of 3.4% of JAT in the whole cohort. This is a 60% increase over the prevalence based on FNAC and is among the highest in literature. Differences in the prevalence of autoimmune thyroiditis in different races have been well described (32, 33) and could, in part, be due to different immunogenetic predisposition (34). The absence of preiodization prevalence data does not permit the conclusion that the high prevalence of JAT in the present study is due to salt iodization.
Among the goitrous girls studied, 0.5% were already known to be hypothyroid and were receiving 1-thyroxin supplementation. In addition, 0.7% and 3.7% of goitrous girls were freshly diagnosed to have overt and subclinical hypothyroidism, respectively. Studies, conducted in children with JAT from various ethnic populations, have reported a prevalence of hypothyroidism that vary from 0–22% and of subclinical hypothyroidism from 0–68.8% (18, 22, 23, 25, 26). In comparison, in the current study, 5.2% and 13.8% of girls with FNAC-proven JAT had overt and subclinical hypothyroidism, respectively. Similarly, in our set of patients, who are diagnosed to have JAT on purely serological criteria, prevalence of overt hypothyroidism was 5.9% and subclinical hypothyroidism was 15.7%.
Iodine-induced thyroiditis has been well documented in animal strains (35), whereas in humans the prevalence of autoimmune thyroiditis is correlated with high iodine intake (8). Increase in prevalence of positive serum antithyroid antibodies and lymphocytic infiltration in thyroidectomy specimens have been reported after introduction of iodine prophylaxis (7, 9, 10, 31).
In our study, the median UIE was no different between patients with JAT
(diagnosed by cytology or serology), colloid goiter, or controls.
Furthermore, there was no significant difference in the prevalence of
JAT between goitrous girls (UIE 0.79, 0:79–1.57, and 1.57
µmol/L). Similarly, UIE did not correlate with prevalence of
antithyroid antibodies or the presence of significant titers of these
antibodies. Hence, unlike other workers (26, 31), we did
not find any relationship between UIE and thyroid autoimmunity from the
point of view of histology and serology.
In conclusion, we found the prevalence of JAT, as diagnosed by cytological criteria, is the same as that reported for iodine-sufficient regions.
Individuals with JAT had a significantly higher prevalence of thyroid dysfunction as compared with goitrous subjects without thyroiditis. It is important to emphasize that for diagnosis of JAT it is imperative to conduct both cytological and serological assessment. Finally, the study that has comprehensively evaluated the clinical, biochemical, serological, and cytological parameters in goitrous schoolgirls from various parts of India will serve as a baseline for any future comparison.
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Acknowledgments |
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Footnotes |
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Received March 13, 2000.
Revised June 23, 2000.
Accepted July 3, 2000.
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References |
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