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Department of Endocrinology (J.J.D.), Hospital La Paz, 28046 Madrid, Spain; and Hospital General (P.I.), 40002 Segovia, Spain
Address all correspondence and requests for reprints to: Juan J. Díez, Travesía Téllez 8, 4R, 28007 Madrid, Spain. E-mail: mibarsd{at}infomed.es.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The significance of slightly elevated TSH values is uncertain. Some observational studies have shown that subclinical hypothyroidism is associated with abnormalities in lipid profile (10, 11), endothelial dysfunction (12), and aortic atherosclerosis and myocardial infarction (13). There is a growing debate on the appropriate management of patients with subclinical hypothyroidism, and disparate opinions have been raised with emphasis by different authors (1, 14, 15). However, limited information is presently available on the natural course of this hormonal alteration (9, 16, 17, 18, 19, 20), and no study has focused on the evolution of spontaneous subclinical hypothyroidism in the elderly.
The identification of elderly patients with a high risk of progression to overt hypothyroidism is important to start replacement therapy without delay. Likewise, it is advisable to detect patients with a low probability to develop overt hypofunction because many of them might be managed by periodic follow-ups without medication. Accordingly, we performed this study with the objective to assess the natural course of subclinical hypothyroidism in patients older than 55 yr with no previous thyroid disease. We aimed to quantify the incidence rate of overt hypothyroidism and evaluate the putative risk factors for the development of definitive thyroid failure in our cohort of patients.
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Subjects and Methods |
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One hundred seven patients (93 women and 14 men) with spontaneous subclinical hypothyroidism were studied. All patients were older than 55 yr at the start of the study (mean age, 62.2 ± 7.6 yr; range, 55–83 yr), and there were no significant differences between women and men in age (61.9 ± 7.4 vs. 64.4 ± 8.3 yr, respectively), body mass index (27.4 ± 4.3 vs. 26.6 ± 3.0 kg/m2, respectively), and serum concentrations of TSH (median, 8.40; interquartile range, 6.69–12.53 mU/liter vs. median, 8.15; interquartile range, 6.55–11.36 mU/liter) and free T4 (FT4; 1.04 ± 0.20 vs. 1.00 ± 0.17 ng/dl; 13.4 ± 2.6 vs. 12.9 ± 2.2 pmol/liter). All patients were ambulatory and were studied as outpatients during visits to an endocrinology clinic. Our aim was to evaluate a cohort of patients that was representative of a usual population who is referred to an endocrinology specialist from diverse medical specialties and general practitioners. Forty-nine patients (45.8%) were referred to the endocrine clinic from the community by their general practitioners because of the incidental finding of an elevated TSH concentration in an analytical checking. The rest of the patients were referred by different hospital specialists, mainly from the Departments of Neurology (10 patients), Cardiology (10 patients), Pneumology (eight patients), Gastroenterology (eight patients), Rheumatology (seven patients), and others (15 patients); these patients were also referred because of the finding of elevated TSH in an analytical survey. The follow-up period was performed through periodic visits as ambulatory patients in such a way that was not different from the follow-up of usual patients in our endocrine clinic. Before giving verbal informed consent to be included in this study, all patients understood the nature of their subclinical thyroid hypofunction and the necessity of periodic follow-up visits to monitor thyroid function tests and to decide whether L-T4 therapy was or was not needed. The study was performed in a non-iodine-deficient area, with a median urinary iodine concentration of 110 µg/liter (21).
Eleven patients had diabetes mellitus, 28 patients were hypertensive, 28 had hyperlipidemia, four had ischemic heart disease, and four had been diagnosed with cardiac arrhythmias. Drug therapy in this population was as follows: hypolipidemic agents (14 patients), diuretics (12 patients), angiotensin converting enzyme inhibitors (11 patients), calcium channel blockers (10 patients), salicylates (four patients), antiplatelet agents (four patients), ß-adrenergic antagonists (three patients), antidiabetic oral agents (two patients), insulin (two patients), nonsteroidal antiinflammatory drugs (two patients), 
-adrenergic antagonists (two patients), oral anticoagulants (two patients), and digitalis (two patients). There were no patients taking iodinated drugs, lithium salts, glucocorticoids, androgens, estrogens, or antiepileptic agents. Patients were in good clinical status, and drug therapy remained stable throughout the study period. No patients had undergone neck radiation therapy.
Thyroid autoimmunity, estimated by thyroid peroxidase antibodies (TPOAb) concentration, was positive in 81 patients (75.7%) and negative in 26 patients (24.3%). Therefore, the etiology of subclinical hypothyroidism was autoimmune thyroiditis in most of our population. Nine patients (8.4%) exhibited palpable goiter, six patients in the autoimmune thyroiditis group and three in the nonautoimmune hypothyroidism group. Clinical manifestations of hypothyroidism were qualitatively evaluated according to the more common symptoms and signs of thyroid hypofunction (22, 23). Sixty patients (56.1%) exhibited no symptoms generally associated with thyroid hypofunction, whereas 47 patients (43.9%) complained of one or more symptoms.
Hormone assays
Fasting samples of venous blood were obtained from an antecubital vein between 0800 and 0900 h. Blood samples were centrifuged immediately, and the serum was stored at –20 C until assayed. Serum TSH and FT4 concentrations were determined by using a commercially available immunoenzymatic assay (AIA-PACK TSH and AIA-PACK FT4, respectively). Both assays were performed using the AIA-1200 system (Tosoh Corporation, Tokyo, Japan). For TSH assay, the sensitivity was 0.06 mU/liter, and the maximal intra- and interassay coefficients of variation were 3.3 and 3.4%, respectively. Normal range for TSH in euthyroid subjects older than 55 yr from our population was 0.4–5.0 mU/liter (24). For the immunoenzymatic assay of FT4, the maximal intra- and interassay coefficients of variation were 9.6 and 7.7%, respectively. The sensitivity of FT4 assay was 0.1 ng/dl (1.3 pmol/liter), and the normal range was 0.75–2.0 ng/dl (9.7–25.7 pmol/liter) (24).
Thyroid autoimmune status was studied by the measurement of serum levels of TPOAb using the Enzymun-test from Roche Molecular Biochemicals (Mannheim, Germany). The sensitivity of this test was 1 U/ml. Values obtained in normal subjects were lower than 6.2 U/ml. However, positivity for TPOAb was considered when the titer of this autoantibody was at least 20 U/ml.
Study design
Spontaneous subclinical hypothyroidism was defined by elevated TSH concentrations (>5.0 mU/liter) in the presence of normal concentrations of FT4 (0.75–2.0 ng/dl; 9.7–25.7 pmol/liter) in a patient with no known previous thyroid disease. Two measurements of these hormones with an interval of 1–3 months were required to enter in the follow-up period. Patients were prospectively evaluated every 6 months. At each visit, clinical and analytical (TSH and FT4) data were assessed. During the time of this study, it was our policy to administer therapy with thyroid hormone only to patients with TSH levels higher than 20 mU/liter or with FT4 levels lower than 0.75 ng/dl (9.7 pmol/liter). It was our intention to analyze the survival time of this cohort of patients, i.e. the time free of L-T4 therapy when patients with subclinical hypothyroidism are followed without medical intervention and the spontaneous course of the disease is observed. Therefore, in this study, patients were followed without therapy until they exhibited TSH concentrations higher than 20 mU/liter or FT4 concentrations lower than 0.75 ng/dl (9.7 pmol/liter).
The mean observation period was 31.7 months (range, 6–72 months). The total time of observation was 3390 patient-months (282.5 patient-years). There were no statistically significant differences in the observation period between women and men and between patients 55–64 yr old and 
65 yr old. For comparative purposes, patients were divided into three groups according to initial plasma TSH concentrations (i.e. 5.0–9.9, 10.0–14.9, and 15.0–19.9 mU/liter; Table 1
). As shown in Table 1, there were no statistically significant differences among groups in relation to sex, age, body mass index, cholesterol and triglyceride levels, and the presence of goiter, symptoms of hypothyroidism, diabetes mellitus, hypertension, or hyperlipidemia. However, TPOAb titer was significantly different among the groups because patients with higher TSH levels exhibited higher titer of these antibodies. As expected, FT4 concentrations were lower in patients with higher TSH levels.
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For quantitative variables, results are expressed as mean ± SD for normally distributed data and as median (interquartile range) for nonparametric data. Adjustment to normal distribution was tested by the Kolmogorov test. Categorical variables are described as ratios or percentages. For comparisons of means between two groups of patients, the Student’s t test was used for normally distributed data, and the Mann-Whitney test was used for nonparametric data. For comparisons of means in paired groups of data, the paired Student’s t test and the Wilcoxon signed-rank test were used, as necessary. A repeated measures ANOVA was used to compare more than two means. Individual comparisons were performed by the Scheffé test. The Kruskal-Wallis ANOVA by ranks was used to detect differences if data were nonparametric. For ratio comparisons, the 
2 test or Fisher’s exact test was used. The time free of L-T4 therapy (time to progression to overt hypothyroidism) was estimated by the Kaplan-Meier method, with the log-rank test used to compare arms. Univariate and stepwise multivariate Cox regression models were used to assess the independent effect of several quantitative and qualitative variables on the risk to progression to overt hypothyroidism. Two-sided tests were used, and differences were considered significant when P < 0.05.
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Results |
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During follow-up, 28 (26.2%) of 107 studied patients required replacement therapy with L-T4. Causes for starting therapy were TSH greater than 20 mU/liter in nine patients, FT4 lower than 0.75 ng/dl (9.7 pmol/liter) in 10 patients, and both biochemical alterations in nine patients. One patient with TSH greater than 20 mU/liter also presented with development of goiter and a marked increase (x80) in the TPOAb baseline concentration. Twenty-three (82.1%) of these 28 patients started therapy at the first or second visits, i.e. they developed overt hypothyroidism at 6–12 months of follow-up.
Incidence of overt hypothyroidism in the whole cohort of studied patients was 9.91 cases per 100 patient-years. Incidence rates were also calculated for groups of patients classified according to the following variables: sex, group of age, presence or absence of symptoms, goiter, autoimmune status, and serum concentrations of FT4 and TSH (Table 2). It is noteworthy that patients with the highest initial TSH levels (15.0–19.9 mU/liter) showed the greatest incidence rate values (73.47 cases per 100 patient-years).
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At the end of the follow-up study, 40 subjects (37.4%) showed normal serum TSH levels. Final hormonal values in this group of patients were as follows: median TSH, 3.53 mU/liter (interquartile range, 2.45–4.32 mU/liter) and FT4, 1.14 ± 0.19 ng/dl (14.7 ± 2.4 pmol/liter). There were no relationships between normalization of TSH and sex, age, and the presence of symptoms of hypothyroidism or goiter. Normalization of TSH was found in 16 (61.5%) of 26 patients with nonautoimmune hypothyroidism and in 24 (29.6%) of 81 patients (P < 0.01) with autoimmune thyroiditis. The percentage of normalization of TSH was also higher in patients with initial FT4 levels of 1.00–1.70 ng/dl (12.9–21.9 pmol/liter; 50.0%) compared with patients with FT4 levels between 0.75–0.99 ng/dl (9.7–12.7 pmol/liter; 25.9%; P < 0.05). We found a clear and statistically significant difference in the percentage of TSH normalization among groups of patients classified according to baseline TSH (Table 1
). In fact, the percentage of TSH normalization was found to be 52.1% in patients with initial TSH levels between 5.0 and 9.9 mU/liter; however, this percentage was 13.3 and 4.8% in patients with TSH levels between 10.0 and 14.9 mU/liter and between 15.0 and 19.9 mU/liter, respectively (P < 0.001).
Survival analysis
To assess the influence of putative risk factors for the development of overt hypothyroidism, we performed a survival analysis using the Kaplan-Meier curves (Fig. 1). Mean time free of L-T4 therapy was 55.8 ± 2.6 months (SEM) for the entire population. We analyzed again the influence of the seven previously mentioned variables on the time to progression to overt thyroid hypofunction. Sex and age of the patient (55–64 or 65 yr) had no influence on the time free of therapy. However, we found that the percentage of patients not requiring L-T4 therapy was lower in the subgroups of patients with symptoms of thyroid hypofunction, palpable goiter, and positive TPOAb (Fig. 1). Mean survival times were 48.1 ± 4.4 months for patients with symptoms (vs. 61.9 ± 2.9 months for patients without symptoms, P < 0.05), 39.3 ± 9.9 months for patients with goiter (vs. 57.4 ± 2.7 months for patients without goiter, P < 0.05), and 52.0 ± 3.2 months for patients with positive TPOAb (vs. 56.6 ± 2.3 months for patients with negative autoimmunity, P < 0.05).
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). In fact, this time was 67.0 ± 4.8 and 67.2 ± 3.3 months for patients with FT4 in the ranges of 1.30–1.70 and 1.00–1.29 ng/ml (16.7–21.9 and 12.9–16.6 pmol/liter), respectively, and clearly dropped to 40.7 ± 3.3 months for patients with the lowest levels of FT4 (P < 0.01). More clearly, time free of L-T4 therapy was 68.6 ± 1.6 months for patients with initial TSH levels between 5.0 and 9.9 mU/liter. This survival time decreased to 36.6 ± 11.6 months for patients with initial TSH levels between 10.0 and 14.9 mU/liter and to 15.1 ± 2.4 months for persons with the highest baseline TSH levels (P < 0.0001). Univariate and multivariate analysis
A stepwise Cox proportional hazards regression univariate and multivariate analysis was conducted to evaluate the relative importance of individual factors for the development of overt hypothyroidism (Table 3). In the univariate analysis, the risk of progression to overt hypothyroidism was significantly greater for patients with symptoms of hypothyroidism (P = 0.0146), positive TPOAb (P = 0.0350), lower concentrations of FT4 (P = 0.0217), or higher levels of TSH (P < 0.0001). In the multivariate analysis, the only significant factor for progression to overt hypothyroidism was the serum TSH concentration (P < 0.0001).
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Discussion |
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However, none of these studies aimed to analyze the evolution of TSH concentrations in a systematic way with periodic visits. On the contrary, Huber et al. (20) studied a cohort of 82 patients with subclinical hypothyroidism over a mean observation period of 9.2 yr and found that 28% of patients developed overt hypothyroidism, but only a few (4%) became normal. The calculated annual rate of developing overt hypothyroidism was 5.6% per year for patients with TSH levels greater than 6 mU/liter in this survey (20). Nonetheless, it has to be mentioned that criteria for selection of patients in the study of Huber et al. (20) were very different from ours. They evaluated only women with a mean age of 50.7 yr. Many of the women had been previously diagnosed with Graves’ disease or autoimmune thyroiditis, and a great number of the patients had been treated with radioiodine (32 patients) or surgery (55 patients). We studied only patients over age 55 yr and without previous thyroid disease or therapies affecting the thyroid gland.
A remarkable number of patients in our survey showed normalization of TSH values. Reversion to normal TSH values has also been observed in some intervention trials (25, 26) in about 15% of individuals. More recently, TSH levels declined to less than 5 mU/liter in 24% of patients in the placebo group reported by Kong et al. (27), and intermittent normal TSH values were also observed in 42% of placebo-treated subjects in another trial (28). The great percentage of reversion to normal TSH found in our survey may be accounted for by the fact that we studied only patients without previous history of thyroid disease and that most subjects exhibited mild subclinical hypofunction with TSH levels between 5 and 10 mU/liter. We acknowledge that there is a possibility that nonthyroidal disease contributed to the transient rise in TSH that was identified in some of our patients.
Survival analysis allowed us to identify some risk factors for the development of overt hypothyroidism. Sex and age seem to have no influence, whereas the presence of symptoms, goiter, and positive autoantibodies do have a significant relationship with the progression to thyroid failure. However, the most significant differences in survival time were found in patients classified according to their initial values of FT4 and TSH concentrations. These findings are in agreement with some data of the literature. In fact, the presence of thyroid antibodies has been considered as a risk factor for progression to thyroid failure in the elderly (9). In the Whickham study, women with high TSH levels and positive thyroid antibodies showed the highest probability to develop over hypothyroidism (19). The prospective study of Huber et al. (20) also identified serum TSH, thyroid reserve, and microsomal thyroid antibodies as the main risk factors for progression.
After having analyzed the risk factors individually, we performed a stepwise Cox proportional hazards regression univariate and multivariate analysis. In the univariate analysis, we found four significant variables (symptoms, autoimmunity, FT4 values, and TSH values). However, in multivariate analysis, the only significant variable in the model was TSH. Our analysis demonstrated that, in aged people without previous thyroid disease, all studied variables contributed much less to the risk of developing overt hypothyroidism than initial TSH levels. Our data clearly showed that patients with TSH values over 10.0 and over 15.0 mU/liter exhibited a hazard ratio of about 10 and 28, respectively, for the development of overt hypothyroidism compared with patients with mildly elevated TSH.
There are three main potential benefits of therapy for subclinical hypothyroidism, i.e. the improvement in lipid profile, the reversion of some symptoms of mild hypothyroidism, and the prevention of progression to overt thyroid failure (1). A reduction in total and low-density lipoprotein cholesterol levels have been demonstrated after L-T4 therapy in some intervention studies (11, 29). These reductions were greater in patients with high serum cholesterol values and in patients with inadequately treated overt hypothyroidism than in patients with spontaneous subclinical hypothyroidism (30). Nonsignificant effects on lipid levels have been reported in patients with TSH levels less than 10 mU/liter (11, 26, 31). Therefore, the benefit of therapy is uncertain in patients with moderately elevated serum cholesterol or with mildly elevated serum TSH (11, 30). A nonsignificant increment in the risk of myocardial infarction during an average follow-up of 4.6 yr has been described in elderly women with subclinical hypothyroidism in the Rotterdam study (13). However, it is not known whether L-T4 therapy in subclinical hypothyroidism may reduce the risk of ischemic heart disease (32).
Some double-blind studies have shown that replacement therapy in patients with subclinical hypothyroidism is accompanied by significant improvement in some symptoms (25), although other authors found only marginal benefit (26) or no benefit of therapy (27, 28). The two trials that reported significant benefits included patients with prior thyroid disease and with mean values of TSH concentrations higher than 10 mU/liter (25), whereas trials showing scarce or no benefits included patients with mildly elevated TSH (26, 27, 28). Treatment with L-T4 has also been associated with some drawbacks, especially in the elderly. These include the risk of development of iatrogenic thyrotoxicosis and its complications, such as atrial fibrillation and osteopenia. On the other hand, it is worth noting that the majority of subjects with subclinical hypothyroidism has TSH concentrations under 10 mU/liter, as shown in the large cohort studied by Canaris et al. (10) (74%) or in the present study (66%), and that these patients usually have few symptoms or only minimal metabolic abnormalities.
Taking into account all these facts, it is our opinion that the risk of progression to overt hypothyroidism is the main parameter to be evaluated before deciding to prescribe replacement therapy in these patients. Our study reports some useful information in this context. Eighteen of 21 patients with TSH 15 mU/liter, and six of 15 patients with TSH 10 mU/liter developed overt hypothyroidism. Therefore, overt hypothyroidism may be prevented if patients with TSH 15 mU/liter are treated regardless of their FT4 or TPOAb levels. In patients with TSH levels between 10.0 and 14.9 mU/liter, treatment should also be considered, especially if they have positive thyroid autoantibodies or mildly low FT4 levels. In patients with TSH concentrations less than 10 mU/liter, the benefits of therapy are more uncertain because only four of 71 patients developed overt thyroid failure, and they have a substantial probability of spontaneous normalization over time (52.1% in our study). A close monitoring of these subjects might be satisfactory. We think that clinical monitoring provides valuable information in a relatively short time because, in accordance with others (18), we observed that the majority of patients (82.1%) who progress to definitive hypothyroidism do so in the first months of follow-up. Also, we recognize that these recommendations may not be valid in other clinical settings, such as pregnant women, adolescents, and young adults, and in patients with a personal past medical history of thyroid disorders or those previously treated with thyroid surgery or radioiodine.
In summary, initial TSH concentration is the most powerful predictor of the outcome of spontaneous subclinical hypothyroidism in adult patients over age 55 yr. Our data suggest that patients with mildly elevated TSH (5.0–9.9 mU/liter) have a low risk of developing overt hypothyroidism and a great probability of normalizing their TSH values over time. We recommend follow-up with clinical and biochemical monitoring in these patients. However, patients with higher levels of TSH should be treated with L-T4 because the risk of overt hypothyroidism is definitely elevated. These opinions are in agreement with the recommendations by an expert committee in a recently reported scientific review and guidelines for diagnosis and management of subclinical thyroid disease (33).
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Footnotes |
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Abbreviations: FT4, Free T4; TPOAb, thyroid peroxidase antibody.
Received November 30, 2003.
Accepted June 1, 2004.
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