Initial evaluation of thyroid dysfunction - Are simultaneous TSH and fT4 tests necessary?

OBJECTIVE: Guidelines for thyroid function evaluation recommend testing TSH first, then assessing fT4 only if TSH is out of the reference range (two-step), but many clinicians initially request both TSH and fT4 (one-step). Given limitations of previous studies, we aimed to compare the two-step with the one-step approach in an unselected community-dwelling study population, and develop a prediction score based on clinical parameters that could identify at-risk patients for thyroid dysfunction. DESIGN: Cross-sectional analysis of the population-based Busselton Health Study. METHODS: We compared the two-step with the one-step approach, focusing on cases that would be missed by the two-step approach, i.e. those with normal TSH, but out-of-range fT4. We used likelihood ratio tests to identify demographic and clinical parameters associated with thyroid dysfunction and developed a clinical prediction score by using a beta-coefficient based scoring method. RESULTS: Following the two-step approach, 93.0% of all 4471 participants had normal TSH and would not need further testing. The two-step approach would have missed 3.8% of all participants (169 of 4471) with a normal TSH, but a fT4 outside the reference range. In 85% (144 of 169) of these cases, fT4 fell within 2 pmol/l of fT4 reference range limits, consistent with healthy outliers. The clinical prediction score that performed best excluded only 22.5% of participants from TSH testing. CONCLUSION: The two-step approach may avoid measuring fT4 in as many as 93% of individuals with a very small risk of missing thyroid dysfunction. Our findings do not support the simultaneous initial measurement of both TSH and fT4.

The log TSH-free T4 relationship in a community-based cohort is nonlinear and is influenced by age, smoking and thyroid peroxidase antibody status.

BACKGROUND: The TSH-T4 relationship was thought to be inverse log-linear, but recent cross-sectional studies of selected populations report a complex, nonlinear relationship. The TSH-T4 relationship has not been evaluated in an unselected, community-based cohort, and there are limited data regarding clinical factors which affect it. OBJECTIVE: To analyse the TSH-free T4 relationship in a community-based cohort. DESIGN, PARTICIPANTS AND METHODS: In a cross-sectional, retrospective study, we analysed serum TSH and free T4 concentrations from 4427 participants (55% female) in the 1994 Busselton Health Study who were not taking thyroxine. Simple linear, segmented-linear and nonlinear regression models of log10 TSH on free T4 were compared for goodness of fit. RESULTS: All 5 log TSH-free T4 models tested (separate lines, segmented conterminal line, quartic, error function, double-sigmoid curve) fitted significantly better than a simple linear model (each P < 0·01 by Vuong test). Ranking by Akaike information criterion indicated that the segmented conterminal line and double-sigmoid models provided best fit, followed by the error function, quartic and separate lines models. From multiple regression analysis, age tertile, current smoking and TPOAb status each significantly influenced the TSH-free T4 relationship, whereas BMI category and diabetes did not. A sex difference in the TSH-free T4 relationship was apparent only in the lower part of the free T4 reference range. CONCLUSION: In a community-based setting, the relationship between log TSH and free T4 is complex, nonlinear and influenced by age, smoking and TPOAb status.

Age-related changes in thyroid function: a longitudinal study of a community-based cohort.

CONTEXT: In cross-sectional studies, serum TSH concentrations increase with age. This has not been examined longitudinally, and it is uncertain whether the TSH increase reflects healthy aging or occult thyroid failure. METHODS: We measured serum TSH, free T(4), thyroid peroxidase, and thyroglobulin antibodies in 1100 participants in the 1981 and 1994 Busselton Health Surveys and derived a reference group of 908 individuals without thyroid disease or thyroid antibodies. We examined changes in thyroid function longitudinally and, in 781 participants, explored associations with the CAPZB polymorphism rs10917469. RESULTS: At 13 yr follow-up, mean serum TSH increased from 1.49 to 1.81 mU/liter, a change in mean TSH (ΔTSH) of 0.32 mU/liter [95% confidence interval (CI) 0.27, 0.38, P < 0.001], whereas mean free T(4) concentration was unchanged (16.6 vs. 16.6 pmol/liter, P = 0.7). The TSH increase was most marked in the elderly, such that gender-adjusted ΔTSH increased by 0.08 mU/liter (95% CI 0.04, 0.11) for each decade of baseline age. People with higher baseline TSH values had proportionally smaller increases in TSH, with each additional 1.0 mU/liter of baseline TSH associated with a 0.13 mU/liter decrease (age and gender adjusted) in ΔTSH (95% CI 0.09, 0.16). The ΔTSH did not differ significantly by CAPZB genotype. CONCLUSIONS: Aging is associated with increased serum TSH concentrations, with no change in free T(4) concentrations. The largest TSH increase is in people with the lowest TSH at baseline. This suggests that the TSH increase arises from age-related alteration in the TSH set point or reduced TSH bioactivity rather than occult thyroid disease.

Significant association between thyroid hormones and erythrocyte indices in euthyroid subjects.

OBJECTIVE: Hypothyroidism and hyperthyroidism are each associated with anaemia, but relationships between thyroid function and erythrocyte indices in euthyroid subjects have not been examined. The aim of this study was to examine these relationships in a community-based cohort. DESIGN, SUBJECTS AND MEASUREMENTS: Linear regression models with free T4, free T3 and TSH as predictors of erythrocyte indices and serum iron parameters were fitted to data from a cohort of 1179 participants in the 1994 Busselton health study and a subset of 1011 euthyroid participants. All models were adjusted for age, age(2), sex and an age-sex interaction. RESULTS: In the full cohort and euthyroid subset, there were significant, positive linear relationships between free T4 and each of haemoglobin, haematocrit and erythrocyte count (P < 0·01 for each), such that in euthyroid participants, each 1·0 pM increase in free T4 was associated with an increase in haemoglobin of 0·39 g/l. There were significant relationships between free T3 and each of haemoglobin, haematocrit and erythrocyte count (P < 0·001 for each), with the best model fits obtained using free T3(2), indicating curved relationships. TSH had a significant (P < 0·05) inverse relationship with serum iron and transferrin saturation in the full cohort and the euthyroid subset. Serum iron concentrations were lower in participants with subclinical hypothyroidism (n = 87) than euthyroid subjects [mean (SD) 15·9 (4·7) vs 18·4 (6·0) µM, P = 0·001]. CONCLUSION: In euthyroid subjects, small differences in thyroid function are associated with significant differences in erythrocyte indices.

Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques.

CONTEXT: Longitudinal studies of risk factors for hypothyroidism are required to inform debate regarding the TSH reference range. There are limited longitudinal data on the predictive value of thyroid antibodies measured by automated immunoassay (as opposed to semiquantitative methods). METHODS: We measured TSH, free T(4), thyroid peroxidase antibodies (TPOAbs), and thyroglobulin antibodies (TgAbs) using the Immulite platform on sera from 1184 participants in the 1981 and 1994 Busselton Health Surveys. Outcome measures at follow-up were hypothyroidism, defined as TSH greater than 4.0 mU/liter or on thyroxine treatment; and overt hypothyroidism, defined as TSH above 10.0 mU/liter or on thyroxine treatment. Receiver-operator characteristic analysis was used to determine optimal cutoffs for baseline TSH, TPOAbs, and TgAbs as predictors of hypothyroidism. RESULTS: At 13 yr follow-up, 110 subjects (84 women) had hypothyroidism, of whom 42 (38 women) had overt hypothyroidism. Optimal cutoffs for predicting hypothyroidism were baseline TSH above 2.5 mU/liter, TPOAbs above 29 kIU/liter, and TgAbs above 22 kIU/liter, compared with reference range upper limits of 4.0 mU/liter, 35 kIU/liter, and 55 kIU/liter, respectively. In women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of hypothyroidism at follow-up (with 95% confidence intervals) was 12.0% (3.0-21.0%) when baseline TSH was 2.5 mU/liter or less, 55.2% (37.1-73.3%) for TSH between 2.5 and 4.0 mU/liter, and 85.7% (74.1-97.3%) for TSH above 4.0 mU/liter. CONCLUSIONS: The use of TSH cutoffs of 2.5 and 4.0 mU/liter, combined with thyroid antibodies, provides a clinically useful estimate of the long-term risk of hypothyroidism.

Significant inverse relationship between serum free T4 concentration and body mass index in euthyroid subjects: differences between smokers and nonsmokers.

OBJECTIVE: There are conflicting data regarding the relationship between thyroid function and body mass index (BMI) in euthyroid subjects, and it is uncertain whether tobacco smoking modifies this relationship. The objective of this study was to examine the relationships between thyroid function, BMI and smoking in euthyroid subjects. DESIGN: Linear regression models were used to examine the relationships between serum free T4, serum TSH, BMI and smoking in a cross-sectional, community-based sample of 1853 euthyroid subjects in Busselton, Western Australia. RESULTS: There was a significant negative relationship between free T4 and BMI: after adjustment for age and sex, each 1 pmol/l increase in free T4 was associated with a decrease in BMI of 0.12 kg/m(2) (95% CI 0.06, 0.18; P < 0.001). The mean BMI +/- SD of subjects in the highest quintile of free T4 concentration was 24.4 +/- 3.5 kg/m(2), compared with 26.1 +/- 3.8 kg/m(2) for the lowest quintile. The relationship between free T4 and BMI was statistically significant (adjusted for age and sex) in subjects who had never smoked (P = 0.001) and former smokers (P = 0.011), but not in current smokers (P = 0.77). There was no significant relationship between TSH and BMI: after adjustment for age and sex, each 1 mU/l increase in TSH was associated with an increase in BMI of 0.08 kg/m(2) (95% CI -0.16, 0.32; P = 0.53). CONCLUSIONS: In euthyroid subjects, small differences in free T4 are associated with differences in BMI. This relationship is not present in current smokers. We speculate that this may be relevant to weight changes associated with smoking cessation.

Subclinical thyroid dysfunction and blood pressure: a community-based study.

OBJECTIVE: Overt hypothyroidism and hyperthyroidism are associated with hypertension, but it is uncertain whether the same is true of subclinical hypothyroidism and hyperthyroidism. DESIGN, SUBJECTS AND MEASUREMENTS: Cross-sectional study of 2033 participants (aged 17-89 years) in the Busselton Thyroid Study who did not have a history of thyroid disease. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and the prevalence of hypertension (defined as SBP >or=140 mmHg, DBP >or=90 mmHg or on treatment for hypertension) in subjects with thyroid dysfunction and euthyroid subjects were compared using linear regression models. Subjects with treated hypertension (N = 299) were excluded from analyses of SBP and DBP but included in analyses of hypertension prevalence. RESULTS: Mean SBP, DBP and the prevalence of hypertension did not differ significantly between subjects with subclinical hypothyroidism (N = 105) and euthyroid subjects (N = 1859), nor did they differ between subjects with serum TSH concentrations in the upper reference range (2.0-4.0 mU/l; N = 418) and those with TSH concentrations in the lower reference range (0.4-2.0 mU/l; N = 1441). The prevalence of hypertension was higher in subjects with subclinical hyperthyroidism than euthyroid subjects (prevalence odds ratio 2.8, 95% confidence interval 1.3-6.0 adjusted for age, age(2) and sex), but this was based on a small number of subjects with subclinical hyperthyroidism (N = 35). CONCLUSIONS: Subclinical hypothyroidism is not associated with hypertension. The observed association between subclinical hyperthyroidism and hypertension requires confirmation in a larger sample.

Investigations of thyroid hormones and antibodies based on a community health survey: the Busselton thyroid study.

OBJECTIVE: Overt or subclinical thyroid dysfunction is common within the community, yet the significance of subtle anomalies in thyroid function tests remains contentious. The aims of this study were to: (a) establish reference intervals for serum-free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid antibodies (antithyroperoxidase, TPOAb and antithyroglobulin, TgAb) in the Busselton community of south-western Western Australia; and (b) determine the prevalence of thyroid hormone anomalies in this community. SUBJECTS AND DESIGN: In 1981, 2115 adults residing in Busselton participated in a cross-sectional health survey that involved blood collection and a questionnaire on lifestyle and general health history. MEASUREMENTS: Serum samples were analysed for FT4, TSH, TPOAb and TgAb by immunochemiluminescent assays. RESULTS: Based on standard statistical approaches and using guidelines recommended by the National Academy of Clinical Biochemistry (NACB), reference intervals were derived for each analyte: 9-23 pmol/l for FT4, 0.4-4.0 mIU/l (TSH), < 35 KIU/l (TPOAb) and < 55 KIU/l (TgAb). The prevalence of elevated thyroid antibodies was 12.4% among subjects without a history of thyroid disease and is more common in women than in men. Elevated thyroid antibody levels were observed at both extremes of TSH abnormality, but were more commonly increased when TSH levels were above 4.0 mIU/l (63% subjects) than for those with TSH levels 0.4-4.0 mIU/l (7.8% subjects). CONCLUSIONS: This study establishes the prevalence of antibodies to thyroperoxidase and thyroglobulin in a community-based sample and reference intervals for free T4 and TSH. When the NACB decision limits are applied to older men or women, there is a markedly increased number with 'elevated' autoantibody levels compared to sex- and age-specific reference intervals.

Thyroid dysfunction and serum lipids: a community-based study.

OBJECTIVE: It is uncertain whether subclinical hypothyroidism (SCH) is associated with hypercholesterolaemia, particularly in subjects with SCH and serum TSH < or = 10 mU/l. DESIGN, PATIENTS AND MEASUREMENTS: Cross-sectional study of 2108 participants in a 1981 community health survey in Busselton, Western Australia. Serum total cholesterol and triglycerides were measured in all subjects and high density lipoprotein cholesterol (HDL-C) measured (and low density lipoprotein cholesterol (LDL-C) calculated) in a subgroup of 631 subjects at the time of the survey. In 2001, TSH and free T4 concentrations were measured on archived sera stored at -70 degrees C. Serum lipid concentrations in subjects with thyroid dysfunction and euthyroid subjects were compared using linear regression models. RESULTS: In the group as a whole, serum total cholesterol was higher in subjects with SCH (N = 119) than in euthyroid subjects (N = 1906) (mean +/- SD 6.3 +/- 1.3 mmol/l vs. 5.8 +/- 1.2 mmol/l, P < 0.001 unadjusted, P = 0.061 adjusted for age, age(2) and sex). Serum total cholesterol was similarly elevated in subjects with SCH and TSH < or = 10 mU/l (N = 89) (6.3 +/- 1.3 mmol/l, P < 0.001 unadjusted, P = 0.055 adjusted for age, age(2) and sex). In the subgroup analysis, LDL-C was higher in subjects with SCH (N = 30) than in euthyroid subjects (N = 580) (4.1 +/- 1.2 mmol/l vs. 3.5 +/- 1.0 mmol/l, P < 0.01 unadjusted, P = 0.024 adjusted for age, age(2) and sex). LDL-C was significantly increased in subjects with SCH and TSH < or = 10 mU/l (N = 23) (4.3 +/- 1.3 mmol/l, P < 0.001 unadjusted, P = 0.002 adjusted for age, age(2) and sex). CONCLUSION: SCH is associated with increased serum LDL-C concentrations, which is significant after adjustment for age, age(2) and sex.

Subclinical thyroid dysfunction as a risk factor for cardiovascular disease.

BACKGROUND: There have been few large epidemiological studies examining the association between thyroid dysfunction and cardiovascular disease. In particular, it is uncertain if subclinical hypothyroidism is a risk factor for cardiovascular disease. METHODS: Serum thyrotropin and free thyroxine concentrations were measured in 2108 archived serum samples from a 1981 community health survey in Busselton, Western Australia (Busselton Health Study). In a cross-sectional study, we examined the prevalence of coronary heart disease in subjects with and without subclinical thyroid dysfunction. In a longitudinal study, we examined the risk of cardiovascular mortality and coronary heart disease events (fatal and nonfatal combined) to the end of 2001 (excluding subjects who had coronary heart disease at baseline). RESULTS: In the cross-sectional analysis, subjects with subclinical hypothyroidism (n = 119) had a significantly higher prevalence of coronary heart disease than euthyroid subjects (n = 1906) (age- and sex-adjusted prevalence odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). In the longitudinal analysis of subjects with subclinical hypothyroidism (n = 101), there were 21 cardiovascular deaths observed compared with 9.5 expected (age- and sex-adjusted hazard ratio, 1.5; 95% confidence interval, 1.0-2.4; P = .08) and 33 coronary heart disease events observed compared with 14.7 expected (age- and sex-adjusted hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P < .01). The increased risk of coronary heart disease events remained significant after further adjustment for standard cardiovascular risk factors. Subjects with subclinical hyperthyroidism (n = 39) had no adverse outcomes. CONCLUSION: Subclinical hypothyroidism may be an independent risk factor for coronary heart disease.

Parity and the risk of autoimmune thyroid disease: a community-based study.

CONTEXT: Recent studies have suggested that fetal microchimerism (transplacental passage of fetal cells followed by engraftment into maternal tissues) may play a role in the pathogenesis of autoimmune thyroid disease. If that is true, then parity should be a risk factor for autoimmune thyroid disease. OBJECTIVE: The objective of this study was to examine parity as a risk factor for autoimmune thyroid disease. DESIGN, SETTING, AND PARTICIPANTS: TSH, thyroid peroxidase antibody, and thyroglobulin antibody concentrations were measured on archived sera from 1045 female participants in a 1981 community health survey in Busselton, Western Australia. OUTCOME MEASURES: Odds ratios (ORs) for positive thyroid antibodies (increased concentration of either antibody) or thyroid dysfunction (abnormal serum TSH) were used. RESULTS: After adjustment for age, women who had previously been pregnant did not have a significantly increased risk of positive thyroid antibodies [OR, 1.20; 95% confidence interval (CI), 0.74-1.97; P = 0.46], raised TSH (OR, 0.93; 95% CI, 0.46-1.87; P = 0.84), or reduced TSH (OR, 0.87; 95% CI, 0.33-2.30; P = 0.79) compared with women who had never been pregnant. For each additional pregnancy, the OR was 1.02 (95% CI, 0.94-1.11; P = 0.57) for positive antibodies, 1.02 (95% CI, 0.91-1.14; P = 0.67) for raised TSH, and 1.03 (95% CI, 0.87-1.22; P = 0.73) for reduced TSH. Analysis using number of live births gave similar results. The results were similar in younger and older women. CONCLUSIONS: Parity is not a risk factor for thyroid autoimmunity or thyroid dysfunction. These data do not support a key pathogenic role for fetal microchimerism in chronic autoimmune thyroid disease.