Iodine deficiency disorders (IDD) encompass a broad spectrum

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1 2 JAPI april 22 VOL. 6 Original Article Status of Thyroid Function in Indian Adults: Two Decades After Universal Salt Iodization Raman Kumar Marwaha, Nikhil Tandon #, Mohd Ashraf Ganie **, Ratnesh Kanwar, Aparna Sastry ***, MK Garg *, Kuntal Bhadra ****, Satveer Singh ***** Abstract Objectives: The aim was to find impact of two decades of universal salt iodization on the prevalence of goiter, thyroid autoimmunity and thyroid dysfunction in Indian adults. Methods: This was a cross sectional study from Delhi, India. The subject population included 449 adult members of resident welfare associations of 5 residential colonies, from -9 years of age, who participated in general health check-up camps. The subjects underwent a detailed evaluation including history, anthropometry, goiter grading, USG thyroid, thyroid auto-antibodies and thyroid function tests. All these subjects were regularly consuming iodized salt. Results: Overall, 9.6 % of subjects had clinical goiter (.% women and.% in men). Prevalence of nodules on palpation was found to be in.6% which was lower in men. The nodule prevalence increased to 4.6% in men and 5.6 % in women on ultrasonography. Thyroid hypoechogenicity was seen in.6% of subjects with severe hypoechogenicity higher in women (5.7% men and 5.5 % women). TPO antibody was positive in.% adults and it showed a positive correlation with age, female sex and hypothyroidism. Subclinical hypothyroidism was the commonest abnormality encountered and affected 9. % subjects (5.9% men; 2.4% women). Thyroid dysfunction showed a rising trend with age in both genders. Conclusions: Normal UIE and low goiter prevalence, especially in males, suggest success of the universal salt iodization program in the region under review. High prevalence of subclinical hypothyroidism was not correlated with either thyroid autoimmunity or iodine intake, as reflected in urinary iodine excretion. Introduction Iodine deficiency disorders (IDD) encompass a broad spectrum including goiter, reduced cognitive function and work efficiency, delay in physical and mental milestones in childhood, and in the extreme, cretinism. Though supplementation of iodine is associated with large scale benefits, concerns have been raised regarding side effects related to varying levels of iodine intake. 2, Evidence from literature indicates that iodine intake up to mg/day is tolerated by normal adults. 4 However, reports suggest that continued exposure to iodine may result in clinical conditions like goiter, thyroid dysfunction (both hypoand hyper-thyroidism), and thyroid autoimmunity. -5 In India, Universal Salt Iodization (USI) has been in force since 94. The impact of this programme on thyroid status has been reported by us and other Indian workers in school age children.,5,6 However, there are limited data evaluating the impact of salt iodization on thyroid function in Indian adults. In view of this, the present study was undertaken to evaluate thyroid functional status of adults after more than two decades of salt iodization. Additional Director and Head, # Professor, ** Associate Professor, Scientist D, *** Scientist C, * Adviser Medicine, **** Senior Technical Assistant (B), ***** Technical Officer (B), Department of Endocrinology and Thyroid Research Centre, Institute of Nuclear Medicine and Allied Sciences, Timarpur, * Army Referral and Research Hospital, #Department of Endocrinology and Metabolism, All India Institute of Medical Sciences New Delhi 54, INDIA and Department of ** Endocrinology Sher-i-Kashmir Institute of Medical Sciences Srinagar, Jammu and Kashmir. Received:..2; Revised: 2..2; Re-revised: ; Accepted: Subjects and Methods Study participants This cross sectional study was conducted between Dec 27- Jan 2 in -9 year old men and women recruited from various regions of Delhi. The subject population was taken from general health camps established in residential colonies (one each from 5 different geographical zones of Delhi). These camps were conducted in association with the Residential Welfare Associations of these colonies. All adults residing in these colonies were invited to participate. All subjects were asked to sign an informed consent and the study was approved by the Institutional Ethics committee of the Army Referral and Research Hospital, New Delhi. Methods All adults (n=449) were evaluated by taking a detailed clinical history and general physical examination, including anthropometry. After excluding 7 adults with history of receiving thyroid medication, the study population comprised of 42 subjects (6 males; 272 females). Thyroid palpation was carried out independently by two endocrinologists with experience in thyroid epidemiology. The concordance of grading was recorded and in case there was disagreement between the observers, a higher grade was chosen. Goiter was graded according to WHO/UNICEF/ICCIDD recommendations and any evidence of nodularity and characteristics of consistency was also recorded. 6 Body weight was measured to the nearest. kg using a beam balance-weighing scale. The adults were weighed wearing the light clothing but without shoes, belts or any other items found on them. Height was measured to the nearest. cm using the height scale. Body mass index (BMI) was calculated as weight in kgs /(height in meters) 2. Family history of known thyroid dysfunction in first degree relatives of study subjects was noted.

2 JAPI april 22 VOL. 6 Thyroid ultrasonography USG thyroid gland was performed with subjects in supine position with neck hyper-extended by a single sonologist who was blinded to the results of thyroid palpation, using a portable ultrasound machine (Sonosite Titan, Germany) with a 7.5 MHz transducer. The gain settings of the ultrasound scanner were adjusted so that the lumina of the carotid artery and internal jugular vein were free of echoes. Hypoechogenicity was diagnosed if echogenecity of the thyroid was uniformly less than that of the connective tissue and similar to or less than that of the neck muscles. Mild hypoechogenicity was defined when the echogenecity was less than that of connective tissue but more than that of strap muscles of the neck. This USG reduction in Table : Description of clinical parameters in the study population Parameter Overall n=42 (Range 44.56±.6 Age (years) (-9) 6.74±.79 Height (cm) (-94) 65.4± 2.5 Weight (Kg) (2.4-.6) 25.5±4.7 BMI Kg/m 2 (.-5.54) *FT pmol /L (2.-7.) *FT4 pmol /L (2.-22.) *TSH µiu/l ( ) *Anti-TPO antibody (<4 units) Urinary Iodine excretion µg/l 4.5±..2 (.75-.) 5.2±.56 (.-4.9).2±.74 (.--) 42.42±2.2 (5-6) 2.4±. (5-66) Men n=6 (Range) 5.7±.4 (-9) 6.4±6.94 ( ) 7.29±.7 (2.4-26) 24.7±.9 (.-4.7) 4.75±.7 (.-.) 5.2±.4 (.-2.9).6±.22 (.-).6±2. (5-6) 229.2±4.7 (5-664) Women n=272 (Range) 4.26±7.6 (-9) 56.6±6.2 (-79) 62.47±2.57 (2-.6) 25.69±5.4 (.7-5.5) 4.7±. (.65-.9) 5.2±.47 (.2-4.9).9±.66 (.-) 49.6±2.9 (5-6) 2.5±.75 (5-664) P<.5 general linear model; Values are represented as Mean ± SEM (standard error of Mean) thyroid echogenecity was considered suggestive of autoimmune thyroid disease as described in literature. 7 The presence and size of any nodules was noted. Assays All adults were subjected to blood sampling for estimation of thyroid function status (free T4, free T and TSH), and thyroid peroxidase autoantibody (TPO Ab). FT, FT4 and TSH were analysed by electrochemiluminescence assay (Cobas-Roche Elecys analyzer). Normal range for FT4, FT and TSH were pmol/l, pmol /L and miu/l respectively, with intra assay and inter assay coefficient of variation (CV) being less than 7 % for all three parameters. The presence of either subclinical or overt, hypo- or hyperthyroidism was used to define thyroid dysfunction. The definition of subclinical hypothyroidism/ hyperthyroidism was defined as normal FT, FT4 and elevated TSH (between 4.2 to. miu/l) /suppressed TSH ((less than.2 miu/l) respectively. TPO Ab were analyzed by electrochemiluminescence assay (Cobas-Roche Elecys analyser) with an analytical sensitivity of <5 IU/mL and range of measurement, 5-6 IU/mL. Values between 4 IU/mL and 2 IU/mL were arbitrarily considered as mild TPO Ab positive and those >2 IU/mL as strongly TPO Ab positive. The intra assay CV for TPO Ab was <4.2% while the inter-assay CV was <7.2 %. Iodine excretion was evaluated through casual urine samples in random manner in alternate subject analyzed for iodine concentration with a Sandell Kolthoff reaction using unique microplate reader. The inter assay and intra assay CV were (<6%) within the kit prescribed limits (Bioclone Australia Pty Limited, NSW, Australia)Urinary iodine excretion (UIE) of < µg/l was considered as iodine deficiency and > µg/l as iodine excess. Statistical analysis SPSS.5 version (Chicago, IL, USA) was used to analyze the data. The quantitative variables have been described as mean ± SD. In addition to descriptive statistics, the percentages of subjects positive or negative on a particular test modality from each sex were compared by ANOVA. Spearman correlation was used to assess correlation between the TPO Ab, UIE, hypoechogenicity and thyroid dysfunction, since the data was of non- normal distribution. Table 2 : Age-wise goiter prevalence and thyroid dysfunction in men and women Total Goiter Subclinical Hypothyroidism Overt Hypothyroidism Subclinical Overt Men N N % N % N % N % N % > Total Women > Total

3 4 JAPI april 22 VOL. 6 Table : Association of thyroid dysfunction with thyroid autoimmunity, as represented by TPO Ab positivity and ultrasound hypoechogenecity TPO Ab Positivity Normal TPO Ab negative subjects (<4) Mild TPO Ab positivity (4-2) Strong TPO Ab (>2) Euthyroid Sub Clinical Hypothyroidism Overt Hypothyroidism Overt Subclinical Men Women Men Women Men Women Men Women Men Women N(%) N(%) N(%) N(%) N(%) N(%) N(%) N(%) N(%) N(%) 7 (9.) 45 (.5) 6 (4.7) Thyroid echogenecity on ultrasound Normal echogenecity Mild Hypoechogenicity Moderate Hypoechogenicity 7 (.9) 79 (.7) 5 (4.4) 767 (.4) 6 (4.) 47 (7.4) 64 (67.) 9 (9.5) 274 (.5) 2 (4.2) (5.) 27 (.7) 72 (67.7) 59 (2.2) 2 (9.) 42 (74.) 9 (6.) 9 (9.) 22 (55.7) 42 (24.6) 4 (9.7) 6 (64.) 9 (6.) (4.) 5 (2.) (4.) 24 (4.) (6.) 2 (46.) 22 (44.) (6.) 2 (4.) 5 (.) (6.7) 6 (.) (66.7) (.) (25.) 6 (5.) (25.) (25.) (6.) (2.) (2.) 4 (.) (2.) 4 (5.) 2 (7.7) (.5) (42.) 7 (26.9) (.) Logistic regression was used in the analysis of the influence of urinary iodine excretion and TPO Ab levels on thyroid nodules and thyroid enlargement. A p value of <.5 was taken as significant. Results Among a total of 42 subjects studied, 6 (7.9%) were males and 272 (62. %) were females. The sex-wise descriptive analysis of these subjects is compared in Table. Goiter prevalence Overall, 9.6 % of subjects had goiter, which was more common in women (.%) than men (.%). The goiter prevalence decreased as age advanced e.g. it was 5. % in rd decade as compared to 2.% in 7 th decade in men while it was.5 % in rd decade as compared to. % in 7 th decade in women (Table 2). Family history of thyroid dysfunction was noted in 76 (4.%) of subjects and it was similar in men (4%) and women (4.%). Thyroid nodularity and echogenecity On palpation, thyroid nodules were found in 6 (.6%) subjects, (.9% in men; 2.% in women). On ultrasonography, the prevalence of thyroid nodules increased to 4.6% in men and 5.6 % in women. The nodule prevalence decreased with advancing age in both men and women. Hypoechoic pattern on ultrasound was noted in 5 (.6%) subjects, of which mild and severe hypoechogenicity was observed in 5 (.7%) and 5 (.9 %) subjects respectively. Sex-wise segregation indicated that 5.7% men had severe hypoechogenicity as compared to 5.5% women (p=<.5). Thyroid hypoechogenecity was positively correlated with TPO Ab (r=.5; p=.), but did not show any significant correlation with goiter, thyroid dysfunction or urinary iodine excretion. Thyroid autoimmunity TPO Ab was positive in 574 (.%) subjects. TPO Ab positivity and its severity were noted more in women than men. Mild elevation (defined as 4-2 IU) of TPO Ab was noted in.62 % men and 4.7% women, while 6.% men and.% women were strongly TPO Ab positive (defined as >2). TPO Ab positivity showed positive correlation with age, female sex and hypothyroidism (r=.7, p=.;r=.74, p=. and r=.6, p=. respectively). Serum TSH levels and TPO Ab were positively correlated. Urinary iodine excretion Mean urinary iodine excretion was 2± µg/l ( µg/l in men and 2 ± 7 µg/l in women). Urinary iodine showed no significant correlation with TPO Ab (r=., p=.6), serum TSH (r=., p=.9), thyroid gland echogenecity (r=.2, p=.57), and thyroid dysfunction (r =.24, p=.25). Iodine deficiency, as defined by a UIE < µg/l was observed in 2.7% subjects while 2.5% subjects had iodine excess defined as UIE > µg/l. There was no significant difference in TPO, echogenecity and thyroid function status between the subjects with UIE more than µg/l or those below this. Thyroid dysfunction The prevalence of thyroid dysfunction was high and was commoner in women than men (24.7% % vs..2%). Subclinical hypothyroidism (SCH) was the commonest abnormality encountered and affected 9.% subjects (5.9% men, 2.4% women). The prevalence of SCH in men and women with TPO Ab was 5.% and 25.9% respectively. Overt hypothyroidism was the second commonest abnormality and affected a total of subjects (4.2%), which included 75 (.7%) subjects with newly diagnosed disease and 6 subjects with previously diagnosed hypothyroidism on therapy., both overt and sub-clinical was found in 49 (.%) subjects and affected.7 % men and.4 % women. Thyroid dysfunction showed a rising trend with age in both sexes, although this was more prominent in women (Table 2). Table describes the association of various risk factors on the prevalence of thyroid dysfunction. Discussion Consequent to the USI program, India is making a transition from being an iodine-deficient to an iodine-replete nation. The present study was conducted exclusively in Delhi, which is iodine replete for at least the last one decade. 5 In view of changes in thyroid function anticipated in response to USI, we evaluated this in an adult population. Since conventionally, goiter prevalence in school age children

4 JAPI april 22 VOL. 6 5 is estimated to assess response to iodine supplementation, there are limited data on adult goiter prevalence from community based studies. 6 We report an overall goiter prevalence of 9.6% in adults (.% males;.% females), which suggests persistence of mild endemicity of goiter despite two decades of successful USI. A small study from coastal Kerala of India, reported similar goiter prevalence in adults (2.2%), in a region where median UIE was consistent with iodine sufficiency (), while as in contrast a study performed in rural North India, in a population with persistent iodine deficiency (UIE < µg/l in 47.% subjects) reported a much higher goiter prevalence in adults 6.7% in men; and.6% in women. 9 There are several reports of adult goiter prevalence after iodine supplementation programs from across the world. While some suggest an impressive decline in goiter prevalence to as low as.-5.6%,, others report a post iodization goiter prevalence similar to that in the present study. - In contrast, two studies conducted at least 5 years post salt iodization, from Iran and Taiwan, continue to show significantly higher goiter prevalence rates ranging from 9-25%. 4,5 Prevalence of clinical nodules reported in the present study (.6% subjects;.9 % men; 2.% women) was lower than that observed in other recent studies, though most of these were in iodine deficient regions. 6,7 The prevalence of thyroid nodules by USG in our study was 4.6% in men and 5.6 % in women. Reports from regions which have recently become iodine sufficient demonstrate nodule prevalence from a low of.-.6% 5,7 to a high of between -%. 7, The precise reason for such a wide range of ultrasound diagnosed nodules could include the duration and severity of iodine deficiency, age of population studied (younger ages showing lower prevalence), pre-supplementation prevalence of nodules, and efficacy of supplementation program. Further, different studies have used ultrasound transducers which vary from the commonly used 7.5 MHz transducer, as used by us, to highly sensitive transducers ranging from - MHz. The impact of different transducers on estimation of nodules becomes apparent from a nation-wide study from an area of borderline iodine deficiency in Germany, where nodule prevalence rose from % (7.5MHz transducer) to 6% ( MHz transducer). 9,2 Even iodine sufficient regions show varying prevalence of nodules, with studies from China and Hungary 2 reporting a prevalence of 2.4-.%, while that from HongKong demonstrating 2.% nodule prevalence. 2 Reduced thyroid echogenecity on USG is considered to be characteristic of autoimmune thyroiditis. 22 The degree of hypoechogenicity has not only been shown to correlate with the levels of circulating thyroid antibodies and thyroid dysfunction but also to predict the evolution towards hypothyroidism in euthyroid subjects The present study also confirmed the positive correlation between thyroid hypoechogenicity and TPO Ab positivity reported by other investigators and by us in children Thyroid TPO Ab was mildly positive (>4 but < 2 IU/mL) in.% adults and strongly positive (i.e. >2 IU/mL) in 6.% men and.% women. The only other Indian study describing adults with long term iodine sufficiency (Median UIE 22 micro gm/l) in the South Indian state of Kerala showed a prevalence of 6.7%. While some reports suggest a lower TPO Ab positivity in iodine deficient regions (4.-9.5%), 25 studies from iodine deficient areas of Brazil and Denmark report high TPO Ab positivity prevalence (-6.9%). 26,27 The prevalence of TPO Ab positivity was higher than that in the present study, in several reports from areas either in transition from iodine deficient to replete states (9-7. %),2 or with long-term iodine sufficiency (. %-.5%).,2 Higher prevalence of TPO Ab positivity in these populations can be explained by unmasking of underlying autoimmunity or cytopathic effect of supra-physiological doses of iodine. However, the prevalence of the positive antibodies reported by different groups is difficult to compare given the variability in assay methods, lack of international standards, varying cut off values and use of one or both antibodies in different studies. In an Italian adult population with similar iodine status as ours 2.% men and.2% women had TPO Ab positivity as was shown in another Italian study from three regions (4.% in men and % in women). 29 Our observation of a high prevalence of thyroid dysfunction, in women more than men, especially sub-clinical hypothyroidism, is consistent with earlier reports from iodine sufficient regions., The prevalence of SCH in the present study is 9.%, but a cross-sectional population survey from Kerala, India, showed a relatively lower prevalence (9.4%) of SCH. This study was conducted in a coastal region, where due to consumption of sea-food the population has always been iodine sufficient (median UIE 22 micro gm/l). The studies from areas with borderline to moderate iodine deficiency, including a report from the Indian state of Gujarat, show a lower prevalence of SCH ranging from.% to 7%.,,2 The prevalence of sub-clinical hypothyroidism from areas transitioning to an iodine sufficient state, have been shown to vary between 4.9 and.4%. 2,27,, The data from populations with iodine sufficiency show variable prevalence of subclinical hypothyroidism, e.g 2.7% in Denmark, 2.4% 27 Zhangwu region of China, 4.% in NHANES data on US population, 2 5. % from Isfahan, Iran, 4 and 9.5% from the Colorado health fair study. Overt hypothyroidism was the second commonest abnormality (.6% men and.9 % of women) which was comparable to some of the data published worldwide from iodine sufficient areas,4 but higher than that reported by Menon et al from Kerala, India. However, studies from iodine rich areas of Japan show a higher prevalence of overt hypothyroidism than in the present study. 4, both overt and subclinical was found in.7 % of men and.4 % of women. These values are not significantly different from other population based studies reported in literature,,4 except for a study from Germany which reported a significantly lower prevalence (.2%). 5 The mean urinary iodine excretion (UIE) was adequate 2.4±. µg/l (5-664; median 22) suggesting iodine sufficiency, similar to that reported from Kerala. No correlation was seen between UIE and thyroid autoimmunity and thyroid dysfunction. Similar observation was seen earlier by our group in studies conducted in children. 5 The mean UIE (SE) was 2 µg/l and 2 (7) µg/ L for euthyroid and hypothyroid individuals respectively, in the Isfahan study. 4 Conclusion In conclusion, after two decades of USI, this is the first Indian study on adults assessing their thyroid functional status. The normal UIE and low goiter prevalence in adults, especially in males, indicates the success of the program. The high prevalence of subclinical hypothyroidism did not correlate with TPO Ab positivity or UIE. These results may represent the pattern of thyroid dysfunction during the transition period of iodine deficiency to sufficiency.

5 6 JAPI april 22 VOL. 6 Acknowledgments We solicit the help of Mr Tariq Wani, for assistance in statistical analysis and those of Madan Prasad, Amit Panwar, MI Beg, and Abhishek Kaushik for their assistance in conducting the general health check camps. References. Larsen PR, Davies TF, Schlumberger MJ, et al Thyroid Physiology and diagnostic evaluation of patients with thyroid disorders. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS (eds) Williams Textbook of endocrinology, th edition. Philadelphia, Saunders; 22:P Stanbury JB, Ermans AE, Bordoux P,et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 99;:-.. Gopalakrishan S, Singh SP, Prasad WR, et al. Prevalence of goitre and autoimmune thyroiditis in schoolchildren in Delhi, India, after two decades of salt iodisation. 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