IN PATIENTS WITH classical symptoms of hypothyroidism

Transcription

1 X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(1): Printed in U.S.A. Copyright 2006 by The Endocrine Society doi: /jc Neuropsychological Function and Symptoms in Subjects with Subclinical Hypothyroidism and the Effect of Thyroxine Treatment Rolf Jorde, Knut Waterloo, Hilde Storhaug, Audhild Nyrnes, Johan Sundsfjord, and Trond Geir Jenssen Institute of Clinical Medicine (R.J., K.W.), University of Tromsø, 9037 Tromsø, Norway; Departments of Internal Medicine (H.S., A.N.) and Clinical Chemistry (J.S.), University Hospital of North Norway, 9038 Tromsø, Norway; and Department of Nephrology (T.G.J.), National Hospital, 0027 Oslo, Norway Objective: Our objective was to examine the relation between neuropsychological function and subclinical hypothyroidism (SHT), defined as serum TSH of and normal serum free T 4 and free T 3 levels, and to study the effect of T 4 supplementation. Subjects: A total of 89 subjects (45 males) with SHT and 154 control subjects (72 males) were recruited from a general health survey (the fifth Tromsø study). Sixty-nine of those with SHT were included in a placebo-controlled, double-blind intervention study with T 4 medication for 1 yr. Main Outcome Measures: We used fourteen tests of cognitive function, Beck Depression Inventory, General Health Questionnaire, and a questionnaire on hypothyroid symptoms. IN PATIENTS WITH classical symptoms of hypothyroidism and with elevated level of serum TSH combined with a low serum free T 4, the decision to start treatment with T 4 is usually easy. However, whether to treat subjects with subclinical hypothyroidism (SHT), defined as an elevated serum TSH level free T 4 and free T 3 levels within the normal range and no overt symptoms of hypothyroidism, is controversial (1 4) and has been the topic of several recent review articles (5 8). The effect of T 4 supplementation in SHT has been most thoroughly studied regarding the lipid profile, and there appears to be a slight effect on serum total and low-density lipoprotein cholesterol levels (9). However, studies regarding effects of T 4 supplementation on clinical symptoms and neuropsychological dysfunction in SHT are less conclusive with reports showing a clear positive effect (10, 11), a moderate or no effect (12), and even an adverse effect (13). By definition, subjects with SHT should not have overt symptoms of hypothyroidism. However, because the disease usually develops gradually, the symptoms may go unrecognized by the patients and their families. Symptoms compatible with hypothyroidism are also seen in subjects with First Published Online November 1, 2005 Abbreviations: BDI, Beck Depression Inventory; BMI, body mass index; CalCAP, California Computerized Assessment Package; GHQ, General Health Questionnaire; SHT, subclinical hypothyroidism; WAIS, Wechsler Adult Intelligence Scale. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community. 145 Results: The mean SD serum TSH in the SHT and control were and , respectively. There were no significant differences in cognitive function and hypothyroid symptoms between the two s, but those with SHT scored significantly better than the controls on the GHQ-30. At the end of the intervention study, serum TSH in the T 4 (n 36) and the placebo (n 33) were and , respectively. T 4 substitution had no effect on any of the parameters measured. Conclusion: In subjects with SHT where the serum TSH level is in the range, there is no neuropsychological dysfunction, and compared with healthy controls, there is no difference in symptoms related to hypothyroidism. (J Clin Endocrinol Metab 91: , 2006) normal thyroid function (14), and accordingly, the presence of such symptoms in subjects with SHT may have causes other than thyroid dysfunction. Many patients are therefore diagnosed with SHT because thyroid function tests are often performed in subjects with nonspecific symptoms such as fatigue and depression. Therefore, to assess the true association between reduced thyroid function and symptoms, which may be of importance in the discussion on treatment with T 4, one should not include subjects recruited from clinical practice. In addition, the subjects should not be aware of their thyroid status before testing. We recently had the opportunity to study such a. Thus, the Tromsø study, which is an epidemiological health survey, was performed for the fifth time in 2001, and serum TSH was measured in 7954 subjects. From this cohort, subjects with SHT and normal controls were recruited and examined with a broad range of neuropsychological tests and symptom scores. To study a of subjects where the thyroid function was only moderately reduced, we included subjects TSH in the range of Subjects and Methods The fifth Tromsø study was performed as a general health survey in 2001 in a manner similar to the previous ones (15). All men and women older than 29 yr, living in the municipality of Tromsø and that participated in the second phase of the fourth Tromsø study (16) or became 30, 40, 45, 60, or 75 yr old during 2001, were invited to participate. All subjects filled out a health questionnaire, and they were also asked whether they would prefer not to be invited to additional studies based on results from the present one. Nonfasting blood samples were drawn and analyzed for serum TSH.

2 146 J Clin Endocrinol Metab, January 2006, 91(1): Jorde et al. Neuropsychological Function and TSH Subjects TSH level between 3.5 and 10.0 were invited to a follow-up examination at the Clinical Research Unit at the University Hospital of Tromsø. Those who reported a history of coronary infarction, angina pectoris, or stroke in the questionnaire, those participating in other follow-up studies, those using thyroid medication, and those above the age of 80 were not invited. The hospital records were also reviewed to exclude subjects with serious diseases not reported in the questionnaire. For each subject TSH between 3.5 and 10.0, a randomly selected age- and sex-matched control subject from the fifth Tromsø study TSH in the range was also invited. The invitation letter informed about the purpose of the study but did not disclose the subject s TSH status. At the follow-up visit, blood was drawn in the nonfasting state and serum samples analyzed for TSH, free T 4, and free T 3. A clinical examination was performed, height and weight were measured in light clothing wearing no shoes, and body mass index (BMI) was calculated as weight (kg) divided by squared height (m 2 ). A questionnaire focusing on hypothyroid symptoms was administered. Those who still had serum TSH between 3.5 and 10.0 and with free T 4 and free T 3 within the reference range, and without obvious clinical symptoms of hypothyroidism, were considered to have SHT. They were informed that their thyroid status was similar to that at the Tromsø study and invited to additional examinations. The control subjects who at the follow-up visit still had serum TSH within the range and with normal serum free T 4 and free T 3 were similarly informed that their thyroid status was unchanged and invited to additional examinations. Those consenting were, on a separate day, in the nonfasting state, examined with neuropsychological tests for cognitive and emotional function. The tests were administered in two sessions on the same day, each lasting 1 or 2 h and separated by a coffee break. The examiners, who were nurses extensively trained and certified by a clinical neuropsychologist (K.W.) and an experienced technician, carried out the tests in a standardized fashion and in the same order. The examiners were blinded to the TSH status of the participants. The subjects were then informed about their thyroid status. Those with SHT were invited to a 12-month intervention study. Those willing were randomized to placebo or T 4. The T 4 tablets were in 25-, 50-, and 100- g doses, and the corresponding placebo tablets were identical looking. Each subject was to take three tablets every day, and by combining T 4 and placebo tablets, daily doses of T 4 could be 25, 50, 75, 100, 125, 150, or 175 g. During the first 6 wk, all subjects in the T 4 were given 50 g daily, and for the following 6 wk 100 g daily. Thereafter, the T 4 dose was given according to the TSH levels, aiming at a level between 0.5 and 1.5 using the following algorithm: serum TSH less than 0.50 and free T 4 more than 29 pmol/liter, reduce T 4 dose by 50 g; serum TSH less than 0.50 and free T 4 less than 30 pmol/liter: reduce T 4 dose by 25 g; serum TSH , unchanged T 4 dose; serum TSH , increase T 4 dose by 25 g; serum TSH more than 4.00, increase T 4 dose by 50 g (if good compliance). Nonfasting blood samples for serum TSH, free T 4, and free T 3 were drawn after 3, 6, 9, and 12 months. On the blood sampling days, the T 4 or placebo tablets were taken after the blood sampling. The TSH results were available after 1 or 2 d, and T 4 (or placebo) tablets for the next 3-month period were sent by mail. The subjects continued their previous dose until they received the new tablets. At each visit, unused tablets from the previous period were counted. The compliance rate was calculated as number of tablets not returned divided by the corresponding number of days. After 12 months, a questionnaire focusing on change in symptoms since the first visit was administered and the neuropsychological tests repeated. Tests of cognitive function For attention, sustained attention, and working memory, we used the Digit Span forward and backward test (subtests from Wechsler Memory Scale-Revised) (17) and the Seashore Rhythm test from the Halstead- Reitan test battery (18). For psychomotor/cognitive speed, we used the Trail Making test, part A (18); the Stroop Color-Word test, parts 1 and 2 (reading speed) (scores for 1 and 2 added together) (19), modified version (20); and the Digit Symbol test (21). For memory, we used the verbal and visual paired associates immediate and 30-min delayed recall (from Wechsler Memory Scale-Revised) (17) and verbal recall test and a word list consisting of 12 words, a subtest from California Verbal Learning Test (22). For language/word fluency, we used the led Oral Word Association test with words beginning with the letters F, A, and S (23). For cognitive flexibility/executive function, we used the Trail Making test, part B (18), and the Stroop Color-Word test, part 3 (color-word interference effect) (19, 20). For speed of information processing, we used the California Computerized Assessment Package (CalCAP) (24). For intelligence, we used the subtest Vocabulary from the Wechsler Adult Intelligence Scale (WAIS) (21). A composite score for cognitive function was made by adding together the Z-scores for the following seven tests: Digit Span forward, Digit Span backward, Stroop test parts 1 and 2 (scores added together), Digit Symbol test, verbal recall, visual recall, and Stroop test part 3. If a negative score was favorable, the Z-score was multiplied by 1. Tests of emotional function Depressed mood was measured with the Beck Depression Inventory (BDI), which is a self-completed questionnaire of 21 items in multiplechoice format (25). The items constituting the BDI have been divided into two subscales. The first, Cognitive-Affective, assesses the mental aspect of depression (items 1 13). The second, Somatic-Vegetative, measures vegetative and somatic symptoms (items 14 21). For the BDI, the total score and the subscale scores were obtained for each patient. Mental health status (or psychological distress) was assessed by the General Health Questionnaire (GHQ), which is a generic health instrument and may thus be applied across different diseases or conditions (26). The GHQ comes in several versions, and we applied the GHQ-30 version. On each of the 30 items, subjects are asked to compare their perceived state of health with four standard answers in the questionnaire. If scored according to the GHQ-scoring method ( ), it may be used as a screening instrument identifying cases with nonpsychotic psychiatric disturbances or as a measure of psychiatric disturbance in the population. Because the objective of this study was not to identify cases but to obtain quantitative measures of well-being and mental health, we applied the Likert-scoring method ( ), which also allows factor-scoring within the five subscales of GHQ-30. These factors are identified as factor A (anxiety), factor B (feelings of incompetence), factor C (depression, hopelessness), factor D (difficulty in coping), and factor E (social dysfunction) (27). Symptom score A questionnaire containing 19 questions related to hypothyroid symptoms was administered at inclusion. A total symptom score was created by adding together the number of present symptoms (28). At the end of the study, a similar questionnaire with 10 questions on change of symptoms was administered, and a change score was calculated, giving 1 point if the change was in the better (more euthyroid) direction, 1 point if the change was in the hypothyroid direction, and 0 point if there was no change. Laboratory analyses Serum TSH levels from the fifth Tromsø study and the study on the SHT and control s were analyzed with the Modular E instrument (Hoffmann-La Roche, Basel, Switzerland) with reference range Accordingly, the values from this assay were used when including the subjects. At the start of the intervention study, our Department of Clinical Chemistry changed to the AxSYM (Abbott, IL) instrument with inherent reagents. Because we knew about this change in advance, serum samples from the SHT/control study were stored and later analyzed with the new assay. All serum TSH, free T 4, and free T 3 values presented therefore represent analysis on the AxSYM instrument with reference values , 9 22 pmol/liter, and pmol/liter, respectively. Statistical analyses Normal distribution was evaluated with determination of skewness and kurtosis and visual inspection of histograms. The scores for tests of

3 Jorde et al. Neuropsychological Function and TSH J Clin Endocrinol Metab, January 2006, 91(1): cognitive function were considered normally distributed except for Seashore Rhythm test, Trail Making B, Stroop Color-Word test parts 1 and 2, and the Stroop Color-Word test part 3. After logarithmic transformation, these latter variables assumed normal distribution and were applied as such when used as dependent variables. To test for interactions, factor analyses with scores for cognitive function as dependent variables; TSH (SHT or control), gender, smoking status (current smoker/nonsmoker) as factors; and age and BMI as covariables were performed. This revealed significant effects of smoking status as well as interactions between smoking status and TSH regarding several of the tests for cognitive function, and additional analyses regarding cognitive function were therefore done in nonsmokers only because there were too few smokers to allow significant relations to be found in that. None of the tests for emotional function were normally distributed, nor did they assume normal distribution after logarithmic transformation. When compared with the Mann-Whitney U test in the control and the s separately, smokers and nonsmokers did not differ significantly on any of the tests for emotional function [P 0.07 for GHQ-E (social dysfunction) in the ; all other P values 0.33]. Similarly, the symptom scores were not normally distributed, and there were no significant effects of smoking status when tested as above. Smokers and nonsmokers were therefore evaluated together regarding emotional function and symptom scores, but the results are also given for the nonsmokers separately. Cognitive function was compared between the two s with Student s t test and also with a general linear model with the parameter in question as dependent variable and with TSH (SHT or control) and gender as factors and age and BMI as independent variables. A multiple linear regression model was used to assess independent predictors of the test scores for cognitive function. Because of the high correlation between free T 4 and free T 3, two models were used, with gender, age, BMI, serum TSH, and serum free T 4 (or serum free T 3 )as covariables. For emotional function and the symptom scores, the and the controls, and the males and the females, were compared with the Mann-Whitney U test. The Kruskal-Wallis test was used to evaluate other predictors of emotional function and symptom scores. For this purpose, the subjects were divided into age, BMI, TSH, free T 4, and free T 3 quartiles. The Mann-Whitney U test was used as post hoc test between the lowest and the highest quartiles. The main analyses were done comparing the with TSH range with the controls, but in addition, those in the TSH in the range were also compared separately with the control. In the intervention study, comparisons between the T 4 and placebo s at the start and end of the intervention were done similarly as between the and the controls. In addition, values (value at end of intervention minus value at inclusion) were compared between the two s with similar statistics. Correlations were evaluated with the Pearson correlation coefficient. Unless otherwise stated, all data are expressed as mean sd. All tests were done two-sided, and P 0.05 was considered statistically significant. Corrections for multiple comparisons were not performed. Statistical analyses were performed with SPSS version 11.0 (SPSS Inc., Chicago, IL). Ethics The Regional Ethics Committee approved the study, and all participants gave their written informed consent. Results Among the 7954 subjects TSH measurements in the fifth Tromsø study, 1253 were excluded because of the health questionnaire (heart disease, stroke, or diabetes) and an additional 576 subjects had answered no to the question on willingness to participate in follow-up studies. Among the remaining 6125 subjects, 363 had serum TSH in the range After review of hospital journals, 114 were excluded because of T 4 use, illness, or participation in other studies. The remaining 249 subjects were invited to the follow-up study; 167 attended, and 89 fulfilled the criteria for SHT. Among these, 38 subjects had serum TSH in the range. Also, 249 age- and sex-matched controls who in the fifth Tromsø study had serum TSH in the range were invited; 162 attended, and 154 had normal serum free T 4 and free T 3 and serum TSH in the same range as in the fifth Tromsø study at the reexamination. The characteristics of the SHT and control subjects are given in Table 1. Tests of cognitive function There were no significant differences between the SHT and the controls on any of the individual tests or on the composite score for cognitive function (Table 2). In the multiple linear regression model, age was the most important (and negative) predictor of cognitive performance. The serum TSH level was significantly and negatively associated with performance on the Trail Making test A; the serum free T 4 level was significantly and positively associated with performance on the Stroop test parts 1 and 2 and the word association test; whereas the serum free T 3 level was significantly and negatively associated with performance at the visual recall test (Table 3). There was no significant association between serum TSH, free T 4, or free T 3 and the composite score for cognitive function (Table 3). Tests of emotional function Those with SHT had a significantly more favorable score than the controls on the GHQ-30 test (P 0.006, Mann- Whitney U test) (Table 4). There was an almost significant TABLE 1. Characteristics of the subjects in the SHT and control s and those in the intervention study All subjects Nonsmokers Intervention study Males/females 45/44 26/12 a 72/82 39/39 21/9 a 48/61 19/17 18/15 Age (yr) BMI (kg/m 2 ) a Smokers/nonsmokers 11/78 b 8/38 45/109 6/30 3/30 Serum TSH () b b b b Serum free T 4 (pmol/liter) b b b b Serum free T 3 (pmol/liter) a P 0.05; b P 0.01, SHT vs. control (Student s t test or 2 test). T 4 Placebo

4 148 J Clin Endocrinol Metab, January 2006, 91(1): Jorde et al. Neuropsychological Function and TSH TABLE 2. Score on cognitive function tests in SHT and control s (nonsmokers) and at baseline and after 12 months in the intervention study Intervention study T 4 at baseline Placebo at baseline T 4 at 12 months Placebo at 12 months Result a n Score n Score n Score n Score n Score n Score n Score Attention and working memory Digit Span forward Digit Span backward Seashore Rhythm test Psychomotor/cognitive speed Trail Making test A Stroop test, parts 1 and Digit Symbol test Memory Verbal recall b Visual recall b Word list test Language led word association test Cognitive flexibility/executive function Stroop test, part Trail Making test B Speed of information processing CalCAP Intelligence Vocabulary (WAIS) Composite cognitive score a Arrow indicates favorable (1) or unfavorable (2) result. b Immediate and delayed recall.

5 Jorde et al. Neuropsychological Function and TSH J Clin Endocrinol Metab, January 2006, 91(1): TABLE 3. Standardized -coefficients and t values from the linear regression models in the 177 nonsmoking subjects who completed all cognitive function tests Independent variables Dependent variables Result a Gender b c Age BMI TSH Free T 4 Free T 3 difference between males and females on the GHQ-30 test ( and , respectively, P 0.07, Mann- Whitney U test). Therefore, the GHQ-30 scores in the SHT and control were compared in males and females separately [ vs (P 0.03) in males and vs in females (P 0.06), respectively, Mann-Whitney U test]. When the cohort was divided into serum TSH quartiles, there was a significant association t t t t t t Attention and working memory Digit Span forward Digit Span backward Seashore Rhythm test Psychomotor/cognitive speed Trail Making test A Stroop test, parts 1 and Digit Symbol test Memory Verbal recall d Visual recall d Word list test Language Word association test Cognitive flexibility/executive function Stroop test, part Trail Making test B Speed of information processing CalCAP Intelligence Vocabulary (WAIS) Composite cognitive score R 2 values are based on the model with gender, age, BMI, serum TSH, and free T 4 as independent variables. Values of t 1.96, t 2.58, and t 3.29 correspond to P 0.05, P 0.01, and P 0.001, respectively. a Arrow indicates favorable (1) or unfavorable (2) result. b Male 1; female 2. c When free T 3 was used in the model, the other covariables were gender, age, BMI, and serum TSH. d Immediate and delayed recall. TABLE 4. Score on emotional function tests in SHT and control s Result a All subjects between serum TSH and the GHQ-30 score (P 0.03, Kruskal-Wallis test). The GHQ-30 score in the lowest and highest serum TSH quartiles were and , respectively (P 0.05, Mann-Whitney U test). Also, when evaluating nonsmokers separately, there was a significant difference between the SHT and control regarding the GHQ-30 test (Table 4). On the BDI, those with SHT had more favorable results Nonsmokers n Score n Score n Score n Score n Score n Score Depressed mood BDI (1 13) BDI (14 21) BDI total score Mental health status GHQ b b Likert score GHQ factor scores A (anxiety) B (feeling of incompetence) C (depression, hopelessness) D (difficulty in coping) E (social dysfunction) a Arrow indicates favorable (1) or unfavorable (2) result. b P 0.01, SHT vs. control (Mann-Whitney U test). R 2

6 150 J Clin Endocrinol Metab, January 2006, 91(1): Jorde et al. Neuropsychological Function and TSH than the controls, but the differences were not significant. Contrary to that seen for cognitive function, there was no association between age and emotional function. Questionnaire on hypothyroid symptoms Except for a single question ( Are you more tired than before? ) where those in the TSH in the range scored significantly more favorably than the controls, the and the controls did not differ significantly on any of the questions on hypothyroid symptoms or on the total symptom score (Table 5). Examining the nonsmokers separately did not add additional information. There was no significant relation between quartiles of serum TSH, free T 4, or free T 3 and the total symptom score when evaluated with the Kruskal-Wallis test. Intervention study Thirty-six subjects were included in the T 4 and 34 subjects in the placebo. One subject in the placebo dropped out after 6 months because of serious disease unrelated to thyroid function and was excluded from analyses in the intervention study. Characteristics of the subjects are given in Table 1. In the T 4, one subject had serum TSH less than 0.05, nine subjects had , nine subjects had , nine subjects had , four subjects had , and four subjects had at the end of the study. The compliance rate in the T 4 and the placebo for the entire study was in both s. There was a significant and negative correlation between compliance rate the first 3 months and serum TSH at the 3-month visit (r 0.40; P 0.017) but not at later intervals. The thyroid status, T 4 use, and compliance during the intervention study are given in Table 6. There were no significant differences in any parameter on cognitive function (Table 2), emotional function (Table 7), or hypothyroid symptoms (Table 8) between the T 4 and the placebo, either at the start of the intervention or at the end of the study. The symptom score at the end of the study (10 questions on change of symptom) were and in the T 4 and placebo s, respectively. Furthermore, when evaluating values (scores at the end of study minus scores at the start), there were no significant differences regarding cognitive or emotional function, whereas on one of the individual questions regarding change in hypothyroid symptoms ( Are your clothes looser/no change/tighter than one year before? ), those given T 4 scored significantly more in the positive direction (clothes looser) than the placebo (Table 8). There was no relation between these values and serum TSH, free T 4, and free T 3, either when looking at all 69 subjects in the intervention study together or when analyzing those given T 4 and those given placebo separately. At the end of the study, most of the subjects felt no general improvement in health, and most subjects in both s thought they had been given placebo or answered do not know (Table 8). Discussion In the present study, we have found no significant differences in cognitive function or hypothyroid symptoms between the SHT and the control, whereas for emotional function, those with SHT scored more favorably than the controls on the GHQ-30. In the, we included subjects TSH TABLE 5. Percentage of subjects who answered yes to questions related to hypothyroidism in the SHT and control s and the total symptom score in the SHT and control s with TSH (n 89) All subjects with TSH (n 38) (n 154) with TSH (n 78) Nonsmokers with TSH (n 30) (n 109) Have you gained weight in the last year? Do you feel colder than other people? Is your skin more dry now than 1 yr ago? Are your clothes tighter than 1 yr ago? Is your hair drier than 1 yr ago? Are your hands puffier than before? Are your muscles weaker than before? Are your nails more brittle than before? Do you feel pins and needles in your hands or feet? Do you fatigue easier than 1 yr ago? Do you need to dress more warmly than others? Do you have muscle cramps? Are you more short of breath than 1 yr ago? Do your feet swell? Is your voice coarser than before? Is your skin colder than before? Do you have numbness in hands or feet? Are you more constipated than 1 yr ago? Are you more tired than before? a a 42.2 Total symptom score [median (range)] 4 (0 14) 3 (0 13) 4 (0 18) 4 (0 14) 3 (0 13) 4 (0 14) a P 0.01, SHT vs. control (Mann-Whitney U test).

7 Jorde et al. Neuropsychological Function and TSH J Clin Endocrinol Metab, January 2006, 91(1): TABLE 6. T 4 dose and compliance rate in those given T 4, and serum TSH, free T 4, and free T 3 in the T 4 and placebo s at inclusion and at 3-month intervals during the intervention study T 4 dose ( g/d) Compliance rate T 4 (n 36) Placebo (n 33) TSH () Free T 4 (pmol/liter) Free T 3 (pmol/liter) TSH () Free T 4 (pmol/liter) Free T 3 (pmol/liter) Inclusion 50/ months months months months , which is a lower range than what has been used in most other studies. However, the upper normal TSH level is a matter of definition and depends on whether subjects with presence of thyroid autoantibodies and other risk factors for hypothyroidism are included or not. Thus, in the study by Bjøro et al. (29) the upper normal serum TSH level was approximately 3.5 if excluding those with thyroid autoantibodies, and in the NHANES III study (30) the TSH 97.5 percentile was reduced from 5.80 in the total population to 4.12 if excluding those with thyroid autoantibodies and other risk factors. Cognitive symptoms such as slow mentation, reduced memory function, and inability to concentrate are frequently reported in subjects with overt hypothyroidism (31, 32) and also in some studies on SHT. Thus, impaired memory function in SHT was found by Baldini et al. (33), del Ser Quijano et al. (34), and Monzani et al. (10). In the latter study, 14 subjects with SHT were compared with 50 control subjects. There was a significant impairment in memory in the SHT and a significant improvement after treatment with T 4. However, their of SHT subjects had a mean serum TSH of 8.8, which was considerably higher than in our study. Similarly, Jaeschke et al. (12) found T 4 treatment to significantly improve a composite psychometric memory score in SHT, but their mean serum TSH level was 12.1, which in this context is rather high. In our study, we applied a broad range of tests of cognitive function. On 11 of the 14 tests, the control subjects scored slightly better than the, and they also had a better composite cognitive function score. However, none of the differences were statistically significant. Furthermore, in the multiple linear regression model, the direction of the association between serum TSH and cognitive function was in favor of a low serum TSH in only six of the 14 tests, and on only one of these six tests (the Trail Making A test) was the association statistically significant. Because we did not do a Bonferroni or other correction for multiple testing, this significance could well be the result of chance. Accordingly, cognitive function was not markedly affected in our SHT, probably because their serum TSH levels were not raised above 10. Similar to cognitive function, there is an association between overt hypothyroidism and depression (35). Depressive features are also reported more frequently in SHT with slight improvement after T 4 treatment (10, 36). However, in a large epidemiological study by Pop et al. (37), depression was only weakly and nonsignificantly associated with SHT, and in our study the subjects with SHT actually had a better score on the BDI than the controls. Furthermore, in our study those with SHT had a significantly better score than the controls on the GHQ-30. When evaluated with the Likertscoring method, this trend was also seen for each of the five subfactors anxiety, feeling of incompetence, depression, difficulty in coping, and social dysfunction. The classical signs of hypothyroidism are well known, and symptom scores have been developed that clearly discriminates between euthyroid and hypothyroid subjects (38, 39). The number of symptoms correlate with degree of hypothyroidism (38, 39), which was also demonstrated in the large epidemiological Colorado Thyroid Disease Prevalence Study (40) that included 25,862 subjects voluntarily attending a health fair. Among the 2336 subjects classified as SHT (in- TABLE 7. Score on emotional function tests at baseline and after 12 months in those given T 4 and placebo in the intervention study Placebo at baseline T 4 at 12 months Placebo at 12 months T 4 at baseline Result a n Score n Score n Score n Score Depressed mood BDI (1 13) BDI (14 21) BDI total score Mental health status GHQ Likert score GHQ factor scores A (anxiety) B (feeling of incompetence) C (depression, hopelessness) D (difficulty in coping) E (social dysfunction) a Arrow indicates favorable (1) or unfavorable (2) result.

8 152 J Clin Endocrinol Metab, January 2006, 91(1): Jorde et al. Neuropsychological Function and TSH TABLE 8. Change in symptoms at end of the intervention study and belief concerning drug given in the T 4 and placebo s cluding 269 subjects taking T 4 ), the percentage of subjects reporting symptoms associated with hypothyroidism was slightly but significantly higher than in the euthyroid (13.7 vs. 12.1%) (40). Furthermore, in a study of 63 patients with SHT treated with T 4 or placebo by Meier et al. (11), those given T 4 had a significant improvement in symptom score as compared with baseline values. However, the change in symptoms over the 48-wk treatment period between the placebo and the T 4 did not differ significantly, and the improvement in symptom score was seen in those that had serum TSH higher than 12 before the start of T 4 treatment. In accordance with this, because we included only subjects in the that had serum TSH between 3.5 and 10.0, there was no difference between the SHT and control regarding symptoms in our study. In addition to the comparison between the SHT and control, we also performed a double-blind placebo-controlled intervention study with T 4 for 1 yr. Because we did not find any significant differences between the and the controls (except for GHQ-30), it was no surprise that intervention with T 4 had no effect on cognitive function or depression and that most of the subjects thought they had received placebo. Furthermore, there was no negative effect on the GHQ-30 score by T 4 substitution, which does bring into question the importance of our finding of a difference between the SHT and control regarding this score. We tried to tailor the T 4 dose in steps of 25 g to achieve a serum TSH between 0.5 and 1.5. However, despite acceptable compliance and strict adherence to a dosage algorithm designed to reach this target, and serum TSH measurement and dose adjustment every third month, the treatment goal was reached only in nine of the 36 subjects. This illustrates that a target range of probably is too narrow and that T 4 doses may need to be titrated in smaller steps than 25 g per day. However, there was no relation between change in serum TSH in the intervention and any of the parameters measured, and because the average serum TSH was 1.52 at the end of the intervention, we feel it is unlikely that a slightly higher average T 4 dose would have significantly affected the neuropsychological test scores. Our study has several weaknesses. We cannot rule out that we would have found significant differences between the SHT and the control had we included more subjects. T 4 Placebo If comparing with 1 yr ago, do you feel warmer/no change/colder? 6/27/3 4/26/3 is your skin less dry/no change/more dry? 4/25/7 1/27/5 are your clothes looser/no change/tighter? 10/24/2 a 4/22/7 is your hair less dry/no change/more dry? 3/25/8 1/28/4 are your muscles stronger/no change/weaker? 0/32/4 2/26/5 are your nails less brittle/no change/more brittle? 3/29/4 1/26/5 are you less short of breath/no change/more short of breath? 2/31/3 2/25/6 is your voice less coarse/no change/more coarse? 1/30/5 1/25/6 is your skin warmer/no change/colder? 3/32/1 3/28/2 do you feel less constipated/no change/more constipated? 6/26/4 2/30/1 do you feel better/no change/worse? 4/29/3 3/25/5 Do you believe you were given T 4 /placebo/do not know? 3/15/18 4/10/18 a P 0.05, T 4 vs. placebo (Mann-Whitney U test). However, to include 89 subjects with SHT, we had to screen almost 8000 subjects, and a larger would be hard to find. Furthermore, including subjects from an epidemiological survey would exclude those whose hypothyroid symptoms had made them seek medical help leading to T 4 treatment. Accordingly, the true prevalence of symptoms and dysfunction related to serum TSH in the range miu/ liter and with free T 4 and free T 3 within the reference range, is probably higher than that found by us. Furthermore, our SHT patients had a mean TSH level of 5.5, and our results do not necessarily apply to those with higher serum TSH levels. However, when looking separately at those with serum TSH in the range , there was no trend toward a difference between these SHT subjects and the controls. The subjects were not informed about their thyroid status when they were invited, but they knew that the focus of the study was thyroid dysfunction. Because only 66% of those invited to the follow-up examination attended, we cannot rule out a selection basis favoring those with symptoms compatible with thyroid disease. In addition, we excluded a considerable number of subjects because of concomitant diseases, and our results do therefore mostly apply to a fairly healthy population. The SHT and control s were well matched regarding age and gender. However, there were significantly more smokers in the control than in the. This could possibly be explained by the TSH-lowering effect of smoking (41), which would reduce the number of smokers with TSH values slightly above our 3.5 limit. Because of this difference in number of smokers, and the interactions between smoking and TSH status regarding cognitive function, subanalyses in nonsmokers were done on all tests. However, the number of smokers was too small to analyze these subjects separately, and we cannot exclude an effect of SHT on neuropsychological function in these subjects. In the intervention study, the mean serum TSH after 1 yr in those given T 4 was 1.52, which was approximately 0.5 above the target level. However, this is lower than in most other studies on the effects of T 4 on neuropsychological function and symptoms (11 13), and we find it unlikely that a higher dose of T 4 would have disclosed differences between those treated and those not. On the other hand, our study has considerable strength. We applied a broad range of tests and used strict selection

9 Jorde et al. Neuropsychological Function and TSH J Clin Endocrinol Metab, January 2006, 91(1): criteria for both SHT and control subjects. Those included were recruited from an epidemiological survey and not from clinical practice, which would have favored inclusion of subjects with symptoms unrelated to thyroid diseases. Our subjects also had a stable thyroid function because the serum TSH level was elevated (or normal) on at least two occasions before inclusion in the study. These points on inclusion criteria for SHT subjects in clinical trials have recently been emphasized in a commentary by Biondi et al. (42). Furthermore, we had a serum TSH level of 10.0 as the upper limit for inclusion in the. Patients with higher TSH levels may well have subclinical disease, but most of these patients will be started on treatment regardless of symptoms. Finally, although it could be considered a weakness that our patients had SHT TSH in the narrow range , this is also a strength of the study and shows that, at least with regard to cognitive and emotional function, there is no need to start treatment because of a slightly elevated serum TSH level. In conclusion, in subjects whose serum TSH levels are not raised above 10, as in our study, there are hardly any symptoms or neuropsychological dysfunctions. Acknowledgments The assistance by the staff at the Clinical Research Unit, University Hospital of North Norway, and by test technician Kari Bjerkaas, Neuropsychological Laboratory, Department of Neurology, University Hospital of North Norway, is gratefully acknowledged. The T 4 and placebo tablets were generously supplied by NycoMed Pharma. Received August 8, Accepted October 25, Address all correspondence and requests for reprints to: Rolf Jorde, Medical Department B, University Hospital of North Norway, 9038 Tromsø, Norway. rolf.jorde@unn.no. This work was supported by a grant from the Norwegian Research Council and The Northern Norway Regional Health Authority. References 1. McDermott MT, Ridgway EC 2001 Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab 86: Chu JW, Crapo LM 2001 The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab 86: Owen PJ, Lazarus JH 2003 Subclinical hypothyroidism: the case for treatment. Trends Endocrinol Metab 14: Vanderpump M 2003 Subclinical hypothyroidism: the case against treatment. Trends Endocrinol Metab 14: Ayala AR, Danese MD, Ladenson PW 2000 When to treat mild hypothyroidism. Endocrinol Metab Clin North Am 29: Fatourechi V 2001 Subclinical thyroid disease. Mayo Clin Proc 76: Cooper DS 2001 Subclinical hypothyroidism. N Engl J Med 345: Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ 2004 Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291: Danese MD, Ladenson PW, Meinert CL, Powe NR 2000 Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab 85: Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, Baschieri L 1993 Subclinical hypothyroidism: neurobehavioral features and beneficial effect of l-thyroxine treatment. Clin Investig 71: Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog R, Müller B 2001 TSH-controlled l-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel thyroid study). J Clin Endocrinol Metab 86: Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, Harper S, Griffith L, Carbotte R 1996 Does treatment with l-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med 11: Kong WM, Sheikh MH, Lumb PJ, Freedman DB, Crook M, Doré CJ, Finer N 2002 A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med 112: Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJG, McMahon AD, McLaren EH 2001 Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ 323: Bønaa KH, Arnesen E 1992 Association between heart rate and atherogenic blood lipid fractions in a population. The Tromsø Study. Circulation 86: Jorde R, Bønaa KH, Sundsfjord J 1999 Population based study on serum ionised calcium, serum parathyroid hormone, and blood pressure. The Tromsø study. Eur J Endocrinol 141: Wechsler D 1987 Wechsler Memory Scale-Revised. Manual. New York: The Psychological Corp. 18. Reitan RM, Wolfson D 1993 The Halstead-Reitan Neuropsychological Test Battery. 2nd ed. Tucson, AZ: Neuropsychology Press 19. Golden CJ 1978 Stroop color and word test. Chicago: Stoelting 20. Lund-Johansen M, Hugdahl K, Wester K 1996 Cognitive function in patients with Parkinson s disease undergoing stereotaxic thalamotomy. J Neurol Neurosurg Psychiatry 60: Wechsler D 1955 Wechsler Adult Intelligence Scale. New York: The Psychological Corp. 22. Delis DC, Kramer JH, Kaplan E, Ober BA 1987 California Verbal Learning Test: Adult Version. San Antonio, TX: The Psychological Corp. 23. Spreen O, Strauss E 1998 A compendium of neuropsychological tests. 2nd ed. New York: Oxford University Press 24. Miller EN 1990 California Computerized Assessment Package. Los Angeles: Norland Software 25. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J 1961 An inventory for measuring depression. Arch Gen Psychiatry 4: Goldberg D, Williams P 1988 A user s guide to the General Health Questionnaire. Windsor, UK: NFER-Nelson 27. Huppert FA, Walters DE, Day NE, Elliott BJ 1989 The factor structure of the General Health Questionnaire (GHQ-30). Br J Psychiatry 155: Jaeschke R, Guyatt G, Cook D, Harper S, Gerstein HC 1994 Spectrum of quality of life impairment in hypothyroidism. Qual Life Res 3: Bjøro T, Holmen J, Kruger O, Midthjell K, Hunstad K, Schreiner T, Sandnes L, Brochmann H 2000 Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The health study of Nord-Trøndelag (HUNT). Eur J Endocrinol 143: Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE 2002 Serum TSH, T 4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87: Kudrajavcev T 1978 Neurologic complications of thyroid dysfunction. Adv Neurol 19: Leentjens AFG, Kappers EJ 1995 Persistent cognitive defects after corrected hypothyroidism. Psychopathology 28: Baldini IM, Vita A, Mauri MC, Amodei V, Carrisi M, Bravin S, Cantalamessa L 1997 Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry 21: del Ser Quijano T, Delgado C, Martinez Espinosa S, Vazquez C 2000 Cognitive deficiency in mild hypothyroidism. Neurologia 15: Kirkegaard C, Faber J 1998 The role of thyroid hormones in depression. Eur J Endocrinol 138: Bono G, Fancellu R, Blandini F, Santoro G, Mauri M 2004 Cognitive and affective status in mild hypothyroidism and interactions with l-thyroxine treatment. Acta Neurol Scand 110: Pop VJ, Maartens LH, Leusink G, van Son MJ, Knottnerus AA, Ward AM, Metcalfe R, Weetman AP 1998 Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab 83: Zulewski H, Müller B, Exer P, Miserez AR, Staub JJ 1997 Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 82: Canaris GJ, Steiner JF, Ridgway EC 1997 Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med 12: Canaris GJ, Manowitz NR, Mayor G, Ridgway EC 2000 The Colorado thyroid disease prevalence study. Arch Intern Med 160: Kapoor D, Jones TH 2005 Smoking and hormones in health and endocrine disorders. Eur J Endocrinol 152: Biondi B, Palmieri EA, Lombardi G, Fazio S 2003 The importance of using strict inclusion criteria in subclinical hypothyroid studies. Am J Med 114:76 JCEM is published monthly by The Endocrine Society ( the foremost professional society serving the endocrine community.