A P Delitala and others Prevalence of undiagnosed 171:1 143–149 Clinical Study thyroid disease Prevalence of unknown thyroid disorders in a Sardinian cohort Alessandro P Delitala, Maria Grazia Pilia1, Liana Ferreli1, Francesco Loi1, Nicolo` Curreli1, Lenuta Balaci1, David Schlessinger2 and Francesco Cucca1,2,3 Correspondence Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy, should be addressed 1Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di to A P Delitala Monserrato, Cagliari, Italy, 2Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA and Email 3Department of Biochemical Science, University of Sassari, Sassari, Italy [email protected] Abstract Objective: To assess thyroid function, the presence of thyroid antibodies, as well as the presence of goiter and/or nodules in subjects without a prior diagnosis of thyroid disorders, in a region with mild to moderate iodine deficiency. Design and methods: This cross-sectional study is based on data obtained from first and third visits of participants in the Sardinian survey. We performed two different analyses. In one, we assessed the prevalence of unknown thyroid dysfunctions among 6252 subjects who had a medical examination and blood collection for assays of thyrotropin, free thyroxine, and antibodies against thyroperoxidase (AbTPO) and against thyroglobulin (AbTG). In a second analysis, we evaluated the frequency of undiagnosed goiter and nodules among 3377 subjects who had a thyroid ultrasound scan. Subjects were excluded if they had a previous history of thyroid disorders or presence of goiter and/or nodules, or thyroid surgery, or if they were taking drugs that could impair thyroid function. Results: We found a low prevalence of overt thyroid dysfunction (hyperthyroidism 0.4% and hypothyroidism 0.7%). The rates of subclinical hypothyroidism and hyperthyroidism were 4.7 and 2.4% respectively. Almost 16% of participants were positive for at least one antibody and 5.2% for both AbTG and AbTPO. Nodules were detected in 17.4% of subjects and the prevalence of goiter was 22.1%. Conclusions: Undiagnosed biochemical thyroid dysfunctions, unknown nodules, and goiter were common in subjects European Journal of Endocrinology living in a mild to moderate iodine-deficient area. In this community, thyroid disorders often go undetected and screening could be reasonable in subjects at a higher risk. European Journal of Endocrinology (2014) 171, 143–149 Introduction Thyroid disorders are one of the most frequent pathologies Moreover, overt hypothyroidism contributes to elevated found in the general population, but identifying thyroid serum LDL cholesterol levels and is a risk factor for coronary disease can be clinically challenging because subclinical heart disease, heart failure, and atherosclerosis (5, 6). Some thyroid dysfunction and autoimmune thyroiditis are studies also suggest that this may also be true in patients often asymptomatic and usually diagnosed biochemically. with subclinical hypothyroidism (7). Most epidemiological Abnormal thyroid function has important public health surveys have reported the biochemical aspects of thyroid consequences. Suppressed thyroid stimulating hormone disorders, although with different results. The difficulties (TSH) levels have been associated with an increased risk of for determinations and their comparison arise from the atrial fibrillation, premature atrial beats, and stroke, and all variable definitions of disease state, the heterogeneity cause mortality (1,2,3). In addition, suppressed TSH levels of the populations studied, the range of normality of have been associated with a decreased bone density (4). biochemical parameters, and the sensitivity of thyroid www.eje-online.org Ñ 2014 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-14-0182 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 09:29:05AM via free access Clinical Study A P Delitala and others Prevalence of undiagnosed 171:1 144 thyroid disease function tests used. For example, the introduction of assays on urinary iodine excretion of subjects living in this area for serum TSH sensitive enough to distinguish between was obtained from a study by Martino et al. (15), showing normal and low concentrations allowed the identification a mild to moderate iodine deficiency. of subjects with subclinical hyperthyroidism. Additional variables include genetic (8, 9) and environmental factors, Biochemical and hormone assays such as iodine intake (10, 11). Indeed, almost one-third of the world’s population lives in areas of iodine deficiency Blood venous samples were drawn between 0700 and 0800 h (12), and the prevalence of goiter can be as high as 80%. after an overnight fast. Serum samples were assayed for TSH, The introduction of ultrasonography in epidemiological free thyroxine (FT4), and antibodies against thyroperoxidase studies has increased the diagnostic power to assess the (AbTPO) and against thyroglobulin (AbTG) using an auto- presence of goiter and/or nodules in comparison with mated chemiluminescence assay system (Immulite 2000, studies in which goiter was assessed by physical exami- Erlangen, Germany). The method is a two-site, solid-phase nation (13). In this study, a large cohort provided a unique chemiluminescent immunometric assay. Normal values are opportunity to conduct a cross-sectional study of abnormal as follows: TSH, 0.4–4.0 mIU/ml; FT4, 0.89–1.76 ng/dl; thyroid function and morphology. We assess both the AbTPO, !35 IU/ml; and AbTG, !40 IU/ml. prevalence of abnormal biochemical thyroid disease and Overt hypothyroidism was defined as a serum TSH the frequency of nodules and goiter in subjects without level above the upper limit of the reference range and known thyroid abnormalities. serum FT4 level below the lower limit of the reference range. Overt hyperthyroidism was defined as serum TSH Materials and methods levels below the lower limit of the reference range and serum FT4 level above the upper limit of the reference The SardiNIA study investigates more than 300 genotypic range. We defined subclinical thyroid dysfunction as and phenotypic aging-related traits in a longitudinal serum FT4 levels in the normal reference range together survey. The main features of this project have been with high serum TSH (subclinical hypothyroidism) or low described in more detail previously (14). All residents serum TSH (subclinical hyperthyroidism) level. from four towns (Lanusei, Arzana, Ilbono, and Elini) in a valley in Sardinia (Italy) were invited to participate. Since November 2001, participants had visited and their blood Thyroid ultrasound samples analyzed about every 3 years, generating three Conventional thyroid ultrasound was performed with a real- European Journal of Endocrinology complete surveys, and some new subjects were pro- time instrument (ATL 3500 HDI machine with a linear gressively enrolled to complete family units. transducer 5–12 MHz). Subjects were supine, with neck We performed two analyses. In one, we analyzed the hyperextended. A nodule was defined as the presence of frequency of biochemical thyroid disorders, including all any distinct lesion within the thyroid gland detected by subjects who had a medical examination at the first time ultrasound, regardless of the echoic pattern. Subjects with in the first or third visit waves. (We did not include nodules were divided into two categories: ‘solitary nodule’ participants from the second survey because TSH was the if only one nodule was detected, and ‘two or more nodules’ only parameter checked at that visit.) We excluded all (otherwise defined ‘multiple’), if the ultrasound scan revealed subjects with self-reported thyroid disease (i.e. Hashimo- the presence of at least two nodules. Thyroid volume was to’s thyroiditis, hyperthyroidism, or hypothyroidism) and calculated according to the ellipsoid model (16).Goiterwas those taking drugs impairing thyroid function (levo- thyroxine, thyrostatics, amiodarone, and carbolithium). Table 1 Characteristics of subjects in the analyses. Data are The final cohort included 6252 participants (female, expressed as median (interquartile range). 54.8%) aged 14–102 years. A second analysis was performed to observe the prevalence of undiagnosed Biochemical analysis Ultrasound analysis thyroid nodules and goiter. We assessed all subjects in Subjects (n) 6252 3377 whom thyroid ultrasound was carried out during the third Sex (M/F) 2826/3426 1608/1769 visit wave. Subjects who reported thyroid nodules, goiter, Age (year) 41.7 (28.8–57) 45.8 (34.4–59.4) TSH (mIU/ml) 1.61 (1.05–2.32) 2.37 (1.12–2.37) or thyroid surgery were excluded, yielding a final sample FT4 (ng/dl) 1.27 (1.14–1.4) 1.39 (1.12–1.39) of 3377 participants (female, 52.4%). The iodine status at the time of evaluation was not assessed. However, the data n, absolute number; TSH, thyrotropin; FT4, free thyroxine. www.eje-online.org Downloaded from Bioscientifica.com at 09/29/2021 09:29:05AM via free access Clinical Study A P Delitala and others Prevalence of undiagnosed 171:1 145 thyroid disease Table 2 Distribution of thyroid status across different age groups. Data are presented as n (%). Age (years) Thyroid status !40 40–49 50–59 60–69 70–79 R80 Overt hypothyroidism 10 (0.3) 11 (1.0) 9 (1.0) 7 (0.9) 4 (0.9) 1 (0.9) Subclinical hypothyroidism 161 (5.5) 51 (4.6) 30 (3.3) 26 (3.5) 16 (3.8) 9 (7.8) Euthyroidism 2721 (92.9) 1027 (92.2) 845 (91.9) 671 (89.6) 379 (89.0) 99 (86.1) Subclinical hyperthyroidism 27 (0.9) 22 (2.0) 33 (3.6) 41 (5.5) 24 (5.6) 5 (4.3) Overt hyperthyroidism 9 (0.3) 3 (0.3) 3 (0.3) 4 (0.5) 3 (0.7) 1 (0.9) Total 2928 (100) 1114 (100) 920 (100) 749 (100) 426 (100) 115 (100) Any dysfunctiona 207 (7.0) 87 (7.9) 75 (8.2) 78 (10.4) 47 (11.0) 16 (13.9) aPresence of any biochemical thyroid dysfunction (subclinical and overt).