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The Journal of Clinical Endocrinology & Metabolism 89(8):3879 3884 Copyright 2004 by The Endocrine Society doi: 10.1210/jc.2003-032089

The Thyroid Epidemiology, Audit, and Research Study: Thyroid Dysfunction in the General Population
R. W. V. FLYNN, T. M. MACDONALD, A. D. MORRIS, R. T. JUNG,
AND

G. P. LEESE

Medicines Monitoring Unit (R.W.V.F., T.M.M), Diabetes Centre (A.D.M., R.T.J.), and Wards 1 and 2 (G.P.L.), Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom
The objective of this study was to define the level of treated thyroid dysfunction in a complete and representative population base in an area of sufficient dietary iodine intake. We used record-linkage technology to retrospectively identify subjects treated for hyperthyroidism or hypothyroidism in the general population of Tayside, Scotland from 1 January 1993 to 30 April 1997. Thyroid status was ascertained by record linkage of patient-level datasets containing details of treatments for hyperthyroidism and hypothyroidism. We identified 620 incident cases of hyperthyroidism, an incidence rate of 0.77/1000yr [95% confidence interval (CI), 0.70 0.84] in females and 0.14/1000yr (95% CI, 0.12 0.18) in males. There were 3,486 incident cases of diagnosed primary hypothyroidism, an incidence rate of 4.98/1000yr (95% CI, 4.815.17) in females and 0.88/1000yr (95% CI, 0.80 0.96) in males. For both hyperthyroidism and hypothyroidism, the incidence increased with age, and females were affected two to eight times more than males across the age range. The midyear point prevalence of all-cause hypothyroidism rose from 2.2% in 1993 to 3.0% in 1996. The level of thyroid dysfunction in Tayside, Scotland is higher than previously reported, and it increased from 1993 to 1996. (J Clin Endocrinol Metab 89: 3879 3884, 2004)

HYROID DYSFUNCTION IS a common disorder previously thought to affect 12% of the United Kingdom adult population (1). T4 is also the sixth most commonly dispensed drug in Scotland (2); and with the inclusion of monitoring thyroid dysfunction as a part of the new general practitioners contract in the United Kingdom, its importance for public health is confirmed. Despite this, the epidemiology of thyroid disease and thyroid dysfunction remains unclear, especially when compared with other endocrine disorders. Previous studies have tended to use selected populations that are unrepresentative of the general population (3, 4). In particular, there is a paucity of studies investigating hypothyroid disease as a result of it being routinely managed in community care, thus making area-wide follow-up difficult. Robust data are available from only one region of sufficient iodine intake (Whickham, UK), but the relatively small numbers of subjects studied resulted in unclear findings for males in particular (1, 5). In addition, the incidence of thyroid dysfunction has increased with time and varies between localities [a feature associated with the level of dietary iodine (6, 7)]. There is a requirement for multiple studies from different locations. The present study used record-linkage technology to identify incident and prevalent cases of treated thyroid dysfunction in the population of Tayside, Scotland between 1993 and 1997. The aim of the study was to define the amount of treated thyroid disease in a complete and representative population base.
Abbreviations: CHN, Community health number; CI, confidence interval; MEMO, Medicines Monitoring Unit; RAI, radioactive iodine; SMR1, Scottish morbidity record 1. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

Subjects and Methods

We used databases available at the Medicines Monitoring Unit (MEMO) based at the University of Dundee. MEMO uses record-linkage technology to conduct epidemiological and pharmacoepidemiological studies and has been described in detail elsewhere (8, 9). In brief, we used record linkage of a number of routinely collated population-based datasets. The data linkage was facilitated by the presence of a unique 10-digit patient identifier, the community health number (CHN). Every person in Scotland registered with a general practitioner is assigned a CHN; and in Tayside, this is used as a patient identifier for all contacts with healthcare activity.

Study population
A fixed population comprising all subjects continuously registered with a general practitioner during the study period from 1 January 1993 to 30 April 1997 was used. This population included those who died during the intervening period and those who were born after 1 January 1993.

Definition of hyperthyroid and hypothyroid cases

Six principle databases were used to identify patients with thyroid dysfunction in the population. CHN master patient index. This index provided data on registered Tayside general practitioner, dates registered with general practitioner, date of birth and date of death. It was used to define the study population from which cases were identified. MEMO dispensed prescription database. This database contained validated subject specific data on all prescriptions dispensed from all community pharmacies in Tayside, including drug name, formulation, dosage, frequency, and duration (8). Details of any thyroid replacement or antithyroid medication received from January 1993 to April 1997 were extracted (Table 1). Scottish morbidity record 1 (SMR1). These data are routinely validated and collated by the Information and Statistics Division of the National Health Service in Scotland and were available for Tayside from 1 January 1980 to 30 April 1997. Diagnostic and procedural codes relating to all hospital inpatient episodes of care using the International Classification of Diseases ninth and 10th revisions and the Office of the Population and

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TABLE 1. Data codes used in identifying thyroid dysfunction Thyroid replacement medication found on MEMO prescription database Antithyroid medication found on MEMO prescription database ICD codes Hyperthyroidism ICD9: 242 and ICD10: E05 Thyroid cancer ICD9: 193, 234.8 and ICD10: C73 OPCS codes for surgical procedures on thyroid OPCS3: 070, 071, 072, 075 OPCS4: B08, B12 T4 (Eltroxine) Liothyronine (Tertroxine, Triiodothyronine) Carbimazole (Neomercazole) Propylthiourcil Iodine and iodide

Census Surveys classification of surgical Operations and Procedures were available. These data were used to identify thyroid-related surgical, diagnostic, and therapeutic procedures. Radioactive iodine (RAI) database. This database is a computerized database of all RAI treatments administered in Tayside since 1955. Details included patient, dose, date of administration, and name of prescribing consultant. Tayside thyroid register. This register is a community-based database derived from the Scottish Automated Follow-Up Register (10). This system automatically follows up patients on thyroid replacement therapy, including those with primary hypothyroidism and those previously treated for hyperthyroidism or other thyroid conditions. Since 1991, it has captured GP as well as consultant referrals for thyroid dysfunction. This provided data on diagnosis and date of registration. Biochemistry data. TSH results were used. Electronic data were not complete for all areas for the early part of the study, so they were used only in conjunction with other data to confirm diagnoses.

tronic diagnosis was appropriately assigned and whether incident cases were correctly designated.

Statistical methods
The prevalence was calculated as the number of existing cases of disease divided by the number of live persons from the fixed population on 30 June each year. Confidence intervals (CIs) were calculated for proportions (11). Incidence was expressed as the person-time incidence rate and calculated as the number of new cases divided by the number of person-years at risk during follow-up with units of cases per 1000 persons per year (/1000 per yr). CI limits were calculated assuming a Poisson distribution (12). For the validation exercise, positive predictive values were calculated as the number of correctly identified patients divided by the total number of electronically identified patients in the cohort.

Ethical approval
The databases used by MEMO are anonymized and registered under the Data Protection Act for purposes of research and audit. At all times, confidentiality of individual patients and individual general practice data was maintained, and all statistical analyses were performed on anonymized datasets. This study was approved by the Tayside Research and Ethics Committee, and permission for the case record validation audit was obtained from Tayside Caldicott Guardians (13).

Patient identification
Hyperthyroid patients. Patients were selected if they had been treated for hyperthyroidism by surgery, RAI, or medication or they had a history of hyperthyroidism on the thyroid register. Patients were classified as surgically treated hyperthyroid if there were SMR1 codes for both the diagnosis and procedure fields (Table 1) or if they had a suppressed TSH results (0.04 mU/liter) in the 12 months before the date of thyroid surgery. Patients treated with RAI at a dose with the range 220-1110 MBq were classified as hyperthyroid. Subjects who received more than one prescription for antithyroid medication were classified as medically treated (Table 1). Patients prescribed RAI by an oncologist at a dose of over 1500 Bq, those with appropriate SMR1 codes for thyroid cancer, or those with cancer of the thyroid register were excluded. Prevalent cases were those who had a history of overactive thyroid, regardless of their current thyroid status. Incident cases were newly treated cases arising from 1 July 1993 to 30 April 1997 (this allowed a 6-month screening period to identify the new cases). Hypothyroid patients. Hypothyroid patients were those on continuous long-term thyroid replacement therapy because of an underactive thyroid (Table 1), and with the requirement that the subject should still be receiving it in the 6 months before the end of the study or in the 6 months before death. To establish prevalent cases of hypothyroidism, those with any form of thyroid cancer or those treated with T4 for euthyroid goiter were excluded. Existing cases were all those treated for hypothyroidism from 1 January 1993 to 30 June 1993. Incident cases were all new cases arising from 1 July 1993 to 31 October 1996. In defining primary hypothyroidism, those that were hypothyroid secondary to treatment for other thyroid disorders were excluded.

Results

Case records were retrieved and validated in general practice for 450 subjects (363 hypothyroid, 87 hyperthyroid). The electronic database performed well, with positive predictive values of 0.98 for treated hyperthyroidism and 0.96 for treated hypothyroidism. Errors occurred where case notes showed no evidence of thyroid dysfunction. Of the apparent hypothyroid subjects validated, 2.8% (n 10; 95% CI, 1.5 5.0%) were actually euthyroid goiters being treated by longterm T4. In addition, six cases of prevalent hypothyroidism were misclassified as incident cases.
Hyperthyroidism

Validation of electronically derived cohorts

A manual validation exercise was performed by an experienced research nurse to determine the predictive power of the electronic data linkage. The primary care case records of all thyroid patients identified at four geographically representative general practices in Tayside region were inspected. The validation process considered whether the elec-

The fixed population for Tayside for the period 1 January 1993 to 30 April 1997 was 369,885. During this time, there were 167,781 TSH tests carried out on 78,714 subjects in the population. Of these, 47,975 (28.6%) tests were outside the reference range of 0.4 4.0 mU/liter. We identified 1,910 existing and 620 incident cases of treated hyperthyroidism (Fig. 1). The midyear point prevalence of hyperthyroidism for the years 1993 to 1996 is shown in Table 2. The increasing yearon-year trend in prevalence was found to be highly significant (2trend 43.6; df 1; P 0.0001). Table 3 shows the

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number of cases and incident rates of hyperthyroidism by age and sex.

Hypothyroidism

The fixed population for the period 1 January 1993 to 31 October 1996 was 367,639. Overall we classified 11,745 subjects as receiving long-term thyroid replacement treatment (Fig. 2). The midyear point prevalence of all-cause hypothyroidism for the years 1993 to 1996 is shown in Table 4. The increasing trend in prevalence was found to be highly significant (2trend 503.2; df 1; P 0.0001). There were 3469 cases of incident primary hypothyroidism. Table 5 shows the number of cases and incident rates of treated primary hypothyroidism by age and gender.
Discussion

This study has used record-linkage technology to identify incident and prevalent cases of treated thyroid dysfunction in Tayside from 1993 to 1997. A case-record validation exercise has shown the methodology to have strong positive predictive value in diagnosing thyroid disease and was reassuring in finding only a low level of treatment for conditions other than thyroid dysfunction, such as T4 use for treatment of euthyroid goiter. Although the incidence of both hyperthyroidism and hypothyroidism was found to increase with age, the trend was more pronounced among the hypothyroid subjects, with the highest incidence found in the

80 age category. We have established the incidence of thyroid dysfunction in males, something that has not been possible in previous studies in iodine-replete areas. Thyroid dysfunction is often quoted as affecting 10- to 20-times as many females as males; however, we have found this to vary from a 2-fold increase in the 80 age group to an 8-fold increase in younger age groups (a relationship true for both hyper- and hypothyroidism). Additionally we found a yearon-year increase in the prevalence of both hyper- and hypothyroidism from 1993 to 1996. The cases were drawn from a large fixed population with a long follow-up time. Recent census findings have shown Tayside to have an age-sex distribution that is broadly representative of the Scottish population and to be composed of approximately 2% nonwhite ethnic groups (14). The area has a low subject migration of 2.7%/yr (15). In line with other studies, we have considered any prior cases of hyperthyroidism as being prevalent cases, regardless of the state of the illness at the time (1, 5). Subjects having suffered from thyroid cancer were excluded from the analysis. One feature of our study is that we defined incidence and prevalence rates of diagnosed disease and cannot comment on the amount of subclinical disease. The study could not detect undiagnosed or untreated thyroid dysfunction or cases treated outside Tayside.
TABLE 3. Incidence of hyperthyroidism in Tayside between 1993 and 1997
Incident cases Person-years of follow-up Incidence rate (per 1000 per year) (95% CI)

FIG. 1. Identification of cases of hyperthyroidism in Tayside from 1 January 1993 to 30 April 1997

Females 9 10 19 20 29 30 39 40 49 50 59 60 69 70 79 80 All females Males 9 10 19 20 29 30 39 40 49 50 59 60 69 70 79 80 All males All cases

0 10 60 81 85 73 90 83 44 526 0 2 5 13 20 14 19 13 8 94 620

77,913 72,677 76,743 95,146 94,295 80,596 80,242 64,282 42,050 683,944 81,799 79,937 85,953 98,250 96,782 78,725 70,443 45,528 17,975 655,392 1,339,336

0.00 (0.00 0.05) 0.14 (0.07 0.25) 0.78 (0.60 1.01) 0.85 (0.68 1.06) 0.90 (0.721.14) 0.91 (0.711.14) 1.12 (0.90 1.38) 1.29 (1.031.60) 1.05 (0.76 1.40) 0.77 (0.70 0.84) 0.00 (0.00 0.05) 0.03 (0.00 0.09) 0.06 (0.02 0.14) 0.13 (0.07 0.23) 0.21 (0.13 0.32) 0.18 (0.10 0.30) 0.27 (0.16 0.42) 0.29 (0.15 0.49) 0.45 (0.19 0.88) 0.14 (0.12 0.18) 0.46 (0.43 0.50)

TABLE 2. Prevalent and incident cases of hyperthyroidism from 19931996 measured on 30 June each year
Year 1993 1994 1995 1996

Population Prevalent cases Point prevalence (95% CI for point prevalence) Incident cases previous 12 months Incidence rate (per 1000) (95% CI for incidence rate)

350,136 1,791 0.51% (0.49 0.54%)

349,884 1,933 0.55% (0.53 0.58%) 188 0.54 (0.46 0.62)

349,626 2,040 0.58% (0.56 0.61%) 157 0.45 (0.38 0.53)

349,369 2,188 0.63% (0.60 0.65%) 207 0.59 (0.51 0.68)

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FIG. 2. Identification of cases of hypothyroidism in Tayside from 1 January 1993 to 31 October 1996.

TABLE 4. Prevalent and incident cases of all cause hypothyroidism from 1993 to 1996 measured on 30 June each year
Year 1993 1994 1995 1996

Population Prevalent cases Point prevalence (95% CI for point prevalence) Incident cases previous 12 months Incidence rate (per 1000) (95% CI for incidence rate)

350,136 7,627 2.18% (2.132.23%)

349,884 8,466 2.42% (2.372.47%) 1,113 3.18 (2.99 3.37)

349,626 9,471 2.71% (2.66 2.77%) 1,286 3.68 (3.48 3.88)

349,369 10,408 2.98% (2.923.04%) 1,233 3.53 (3.333.73)

TABLE 5. Incidence of primary hypothyroidism in Tayside between 1993 and 1996

Incident cases Person-years of follow-up Incidence rate (per 1000 per year) (95% CI)

Females 9 10 19 20 29 30 39 40 49 50 59 60 69 70 79 80 All females Males 9 10 19 20 29 30 39 40 49 50 59 60 69 70 79 80 All males All cases

9 22 124 280 498 547 635 496 358 2969 11 6 18 37 54 82 109 107 76 500 3,469

67,205 62,901 67,614 82,485 82,089 70,311 70,099 56,135 36,827 595,666 70,673 69,378 75,281 85,553 83,991 68,778 61,373 39,840 15,683 570,550 1,166,216

0.13 (0.06 0.25) 0.35 (0.22 0.53) 1.83 (1.532.19) 3.39 (3.013.82) 6.07 (5.55 6.62) 7.78 (7.14 8.46) 9.06 (8.379.79) 8.84 (8.08 9.65) 9.72 (8.74 10.87) 4.98 (4.815.17) 0.16 (0.08 0.28) 0.09 (0.03 0.19) 0.24 (0.14 0.38) 0.43 (0.30 0.60) 0.64 (0.48 0.84) 1.19 (0.951.48) 1.78 (1.46 2.14) 2.69 (2.20 3.25) 4.85 (3.82 6.07) 0.88 (0.80 0.96) 2.97 (2.88 3.08)

males to be 0.8/1000yr, with negligible results among males (5). Other studies from the 1970s and early 1980s reported incidences of hyperthyroidism of 0.23 0.28/ 1000yr (16 19), whereas subsequent studies put the figure at 0.43 0.52/1000yr (20, 21). Recently, two areas of Denmark have reported incidences of hyperthyroidism of 0.93/1000yr and 0.65/1000yr (7). The Tayside result of 0.46/1000yr was lower than that of Denmark. The Whickham survey found an incidence of hyperthyroidism of 0.8/1000 in females, a finding similar to Tayside; however, the Whickham population was over 18 yr of age, whereas ours was inclusive of all ages. Recalculating the incidence for Tayside by excluding those under the age of 18 gave a figure of 0.96/1000yr, higher than Whickhams. We also found a year-on-year increase in the prevalence of hyperthyroidism from 1993 to 1996. As with previous studies, we used a cumulative measure of hyperthyroidism, including all patients who have ever been hyperthyroid (1). Using a cumulative measure will cause the year-on-year prevalence to increase; however, this will not reflect the number of cases of active disease.
Hypothyroidism

Hyperthyroidism

The Whickham survey, which followed a cohort over 18 yr of age, found the incidence of hyperthyroidism in fe-

Few studies have attempted to establish the incidence of hypothyroidism in the general population. The Whickham survey found an incidence of 3.5/1000yr in females and 0.6/1000yr in males, whereas the recent Danish findings showed incidences of 0.27/1000yr and 0.40/1000yr, respec-

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tively. Our result of 2.97/1000yr in a combined male/female population is higher than the Whickham follow-up and substantially higher than the Danish findings. Additionally, we have found a year-on-year increase in the prevalence of hypothyroidism from the years 1993 to 1996. The higher than previously recorded incidence and increasing prevalence of hypothyroidism may reflect a temporal increase in autoimmune diseases. Thyroid disease in the United Kingdom is generally of autoimmune etiology; and levels of other autoimmune disease, such as type-1 diabetes, are increasing (22). It has been suggested that recent years have seen a rise in the level of autoimmune disease and of immune mediated disorders in general, and this has been put forward as a possible reason for the perceived increase in thyroid disorders (23). It is also possible that there has been an increase in the diagnosis or ascertainment of thyroid disease due to improved practice and increased availability of diagnostic tests. Another possibility is that there is an increasing older female population due to increasing longevity of life (24). Thus, there is a greater opportunity for the diagnosing of hypothyroidism. There are a number of other possible reasons for the differences found between the results presented here and those found elsewhere. The difference may reflect the methodologies employed: some have used population screening and follow-up of survivors in a cohort over 18 years of age, whereas others have highlighted incident cases from abnormal biochemistry results or hospital admissions (7, 20). The population dynamics of the different locations will also have an impact on the levels of thyroid dysfunction, because incidence was higher among females and the elderly. Another possibility is that there is a geographic variation in the risk of thyroid dysfunction between regions (7, 19), which could reflect a variety of environmental and/or genetic factors. One such factor could be the role of dietary iodine in determining thyroid function. It has been hypothesized that higher levels of dietary iodine decrease the incidence of hyperthyroidism at the expense of increased incidence of hypothyroidism (6, 7). The overall incidence of hyperthyroidism observed in Tayside was lower, and the incidence of hypothyroidism was higher, than that reported from Denmark, with mild or moderate iodine deficiency. The British diet is acknowledged as being sufficient in iodine, with a mean urinary iodine excretion in the United Kingdom of 141 g/liter (25). Similar results have been reported in nonpregnant females from Tayside (26), so our finding of a lower incidence of hyperthyroidism and higher incidence of hypothyroidism is in accordance with the theory. These findings further support the theory that populations with sufficient dietary iodine will have a lower incidence of hyperthyroidism and higher incidence of hypothyroidism than populations that are iodine deficient. In conclusion, this study has established the incidence and prevalence of treated thyroid dysfunction in a populationbased study in a population that is representative of Scotland. The prevalence of hypothyroidism was higher than has been found previously and was found to be increasing from 1993 to 1996.

Acknowledgments
We thank those members of the MEMO team who made this study possible, notably Philip Thompson and Gill Reekie. We also thank those general practices that allowed us access to their case records: Muirhead Medical Centre, Muirhead; Princes Street Surgery, Dundee; Mauve Practice, Drumhar Health Centre, Perth; and Lour Road Group Practice, Forfar. Received December 4, 2003. Accepted May 10. 2004. Address all correspondence and requests for reprints to: G. Leese, Ward 1, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom. E-mail: graham.leese@tuht.scot.nhs.uk. This work was funded by the Chest, Heart and Stroke, Scotland.

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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.

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