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Spontaneous Normalization of Thyrotropin Concentrations in Patients with Subclinical Hypothyroidism

Department of Endocrinology (J.J.D.), Hospital Ramón y Cajal, 28034 Madrid, Spain; Department of Endocrinology (P.I.), Hospital General, 40002 Segovia, Spain; and Endocrine Section (K.D.B.), Washington Hospital Center, Washington, D.C. 20010

Address all correspondence and requests for reprints to: Juan J. Díez, Department of Endocrinology, Hospital Ramón y Cajal, Carretera Colmenar km 9, 28034 Madrid, Spain. E-mail: mibarsd{at}infomed.es.

	Abstract

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Context: Patients with subclinical hypothyroidism may revert to normal TSH values.

Objective: The objective of this study was to examine the time course of the normalization of TSH levels in subclinical hypothyroidism.

Design: This was a prospective, observational study with no intervention, with a duration of follow-up of 12–72 months.

Setting: Outpatients visited an endocrinology clinic of a general hospital.

Patients: Forty patients (32 women, mean age 62.8 ± 8.2 yr) with spontaneous subclinical hypothyroidism (TSH > 5 mU/liter and normal free T₄) participated in the study. Each patient normalized their TSH values without T₄ therapy throughout the follow-up.

Measurements: TSH and free T₄ levels were evaluated every 6 months.

Results: Normalization occurred at a median time of 18 months (range, 6–60 months). Fifteen patients normalized their TSH levels during the first year of follow-up and 27 during the first 2 yr. Ten patients normalized their TSH values at the fourth or fifth year. Only four patients reverted to TSH values less than 2 mU/liter. Final TSH levels achieved by the patients were significantly correlated with the time elapsed until normalizing these levels (r = 0.367; P = 0.020).

Conclusions: There is no clear pattern of TSH normalization, although most patients normalize their TSH values early in the follow-up. The final TSH reached seems to be related to the time of normalization.

	Introduction

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SUBCLINICAL HYPOTHYROIDISM IS defined by elevation in TSH concentrations with normal circulating levels of thyroid hormones (1, 2, 3). The normalization of TSH levels in some patients with subclinical hypothyroidism is a well-known phenomenon, especially in those without previous history of thyroid disease and moderate elevations of TSH (4, 5, 6). In a prospective survey including patients with previous thyroid disorders, Huber et al. (7) reported that three of 82 patients (4%) normalized their TSH levels, whereas we observed normalization in 40 of 107 patients (37%) with spontaneous subclinical hypothyroidism (8). In our survey, normalization was more frequent in patients with moderate TSH elevation (5.0–9.9 mU/liter) and without thyroid autoimmunity, but there was no relationship between TSH normalization and gender, age, goiter, or symptoms of hypothyroidism.

The time interval with which serum TSH values normalized has not been studied. Therefore, we herein analyze the time course of this normalization, as well as the relationships between TSH values achieved and clinical and biochemical features in the group of 40 patients who showed normal serum TSH at the end of follow-up.

	Patients and Methods

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Patients and design

The patients here reported belong to a cohort of 107 patients with subclinical hypothyroidism whose details have been described previously (8). In summary, all of them were over age 55 yr and had no previous thyroid disease. The group of 40 patients who normalized their TSH values were eight men and 32 women, with mean age of 62.8 ± 8.2 yr. Three of them had palpable goiter, 15 had symptoms generally associated with hypothyroidism, and 24 of them were positive for thyroid peroxidase autoantibodies (TPOAbs). There were five patients with diabetes, 11 with hypertension, and 13 with hyperlipidemia.

All patients were studied as outpatients. We performed prospectively clinical and analytical evaluations every 6 months, including TSH and free T₄ (fT₄) determinations. Subclinical hypothyroidism was defined as elevated TSH levels (>5.0 mU/liter) in the presence of normal fT₄ (9.7–25.7 pmol/liter). We administered L-T4 therapy when TSH values were higher than 20 mU/liter or fT₄ values were lower than 9.7 pmol/liter. Patients who persisted with subclinical hypothyroidism or who normalized their TSH values (<5.0 mU/liter) were followed without intervention. All patients gave verbal informed consent after understanding the objective of follow-up.

Assays

Serum TSH and fT₄ concentrations were determined by immunoenzymatic assays (AIA-PACK TSH and fT₄, respectively), using the AIA-1200 system (Tosoh Corp., Tokyo, Japan). Thyroid autoimmune status was assessed by measurement of serum levels of TPOAb (Enzymuntest, Roche Molecular Biochemicals, Mannheim, Germany), and the titer was considered positive for values higher than 20 U/ml.

Statistical analysis

In this sample of patients, the Kolmogorov test showed that time to normalization and the titer of TPOAb were nonparametric data. Therefore, we expressed these results as median (interquartile range). Total time of follow-up, fT₄ and TSH levels, and the decrement in TSH concentrations were normally distributed data, and their results are expressed as mean ± SD. For comparisons of two means, the Student’s t test (normally distributed data) and the Mann-Whitney U test (nonparametric data) were used. 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. For ratio comparisons, the ² or Fisher exact test was employed. Correlations between quantitative variables were assessed using Pearson’s correlation analysis. Determinants for final TSH concentration were analyzed by using step-wise multiple linear regression analysis. Two-sided tests were used, and differences were considered significant when P < 0.05.

	Results

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Time course of TSH normalization

The mean (±SD) observation period in the 40 patients was 38.3 ± 17.0 months (range, 12–72 months). Time to normalization of TSH values was a nonnormally distributed variable, ranging from 6–60 months, with a median of 18 (interquartile range, 12–45) months. Fifteen patients (37.5%) normalized their TSH levels during the first year of follow-up and 27 (67.5%) during the first 2 yr. Ten patients (25%) normalized their TSH values at the fourth or fifth year of follow-up. Interestingly, patients who normalized their TSH late (48–60 months) showed higher initial and final TSH concentration and lower final fT₄ levels than patients who showed early normalization (6–24 months) (Table 1).

Initial TSH concentration were 7.48 ± 1.85 mU/liter and lowered to 3.37 ± 1.07 mU/liter at the end of follow-up (P < 0.001). fT₄ levels were 13.9 ± 2.4 pmol/liter at baseline and 14.7 ± 2.3 pmol/liter at the end of follow-up (P = 0.064). Figure 1 shows individual values of initial and final TSH in all patients. The mean decrement in TSH concentration was 4.12 ± 2.01 mU/liter. There was no relationship between the change in TSH levels and the presence of TPOAb, goiter, or the sex or age of the patients. The fall in TSH levels was similar in early and late normalizers (Table 1).

View larger version (53K): [in this window] [in a new window]   FIG. 1. Individual values of serum TSH concentrations. Each line represents a single patient; the top of the line represents the baseline value, and the bottom of the line represents the value at the end of follow-up. Patients are shown in order of initial TSH concentration and classified according to the presence (closed circles) or absence (open circles) of TPOAbs. The shaded area represents the normal range for TSH (0.4–5.0 mU/liter).

Only four patients (10%) reverted to TSH values less than 2 mU/liter, whereas most subjects (65%) achieved TSH values higher than 3 mU/liter. Twelve patients (30%) normalized to above 4.12 mU/liter, which is the upper limit of the normal range as defined by the National Health and Nutrition Examination Survey (NHANES) III survey (9). Final TSH levels were similar in patients with positive and negative TPOAb (3.41 ± 1.14 vs. 3.30 ± 0.98 mU/liter) and also in men and women and in patients with and without goiter. However, as shown in Table 1, patients with early normalization reached TSH values lower than those of patients who normalized late.

We found a significant correlation between final TSH and time to normalization (r = 0.367, P = 0.020). Final TSH was not significantly related to age, TPOAb titer, initial TSH, or initial fT₄. When classifying patients according to thyroid autoimmunity, we found that time of normalization and final TSH were significantly related in patients with positive TPOAb (r = 0.473; P = 0.019), but not in patients who lacked these autoantibodies (r = 0.142; P = 0.6). In a step-wise multiple regression analysis performed to evaluate the independent determinants of final TSH concentration, we found that the only significant variable in the model was time to normalization (ß± SE, 0.0228 ± 0.009; P = 0.020).

	Discussion

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To our knowledge, this is the first study that analyzes in a prospective way the time course of the spontaneous normalization of TSH values in patients with subclinical hypothyroidism. This phenomenon has been previously reported in 14.6% (10) and 17.6% (11) of patients entering two different intervention trials. In another study (12), 24% of patients in the placebo group exhibited reversion to TSH levels less than 5 mU/liter. Intermittent normal TSH values were also reported in 42% of placebo-treated subjects in the trial of Jaeschke et al. (13). The authors of other clinical trials did not mention normalization of TSH in the placebo group; however, these studies have been limited to 6 (14, 15) or 12 (16) months. Interestingly, a recent long-term prospective study by Gussekloo et al. (17) showed that 11 of 21 (52%) elder patients with subclinical hypothyroidism normalized their thyroid function in 3 yr, but the authors could not analyze the timing of normalization. Therefore, time course of TSH normalization cannot be discerned from any of these previous studies.

We have tried to answer three questions. What was the distribution of the normal values achieved? Did the return to a lower normal value relate to other factors? Was there a relationship between time of normalization and how low the values went into the normal range?

Firstly, only a minority of our patients achieved TSH values lower than 2 mU/liter. Approximately one third of the patients remained with TSH values over the upper limit of the normal range established by NHANES III (9). Some authorities have proposed to lower this upper limit to 2.5 mU/liter (http://www.endo-society.org/news/endocrine_news/2004/thyroid-april2004.cfm). This criterion has been criticized because it would result in an overdiagnosis of subclinical hypothyroidism and an increase in the number of patients on T₄ therapy (18). The NHANES III study removed subjects who had personal or family history of thyroid problems, goiter, or thyroid antibodies and who were taking medications that might influence thyroid function. Their normal range so defined was 0.45–4.12 mU/liter (2.5–97.5 percentile) (9). Furthermore, the recent guidelines published by an expert panel (3) selected the reference range of normal TSH as 0.45–4.5 mU/liter, which is very similar to our interval.

Secondly, we found no relationship between final TSH and thyroid autoimmunity, sex, age, and the presence of goiter. And thirdly, we encountered that early normalizers are more likely to reach lower TSH values than late normalizers. Interestingly, this phenomenon is more noticeable in patients with positive TPOAb.

In accordance with our results, TSH concentrations in 36 patients with initial elevated TSH levels but no antibodies tended to regress to the normal range over 4 yr in the study of Tunbridge et al. (4). Parle et al. (6) studied the evolution of 73 patients aged 60 yr and over with subclinical hypothyroidism and found that, after 12 months, 5.5% of these patients normalized their TSH levels, and 76.7% remained without progression to overt hypothyroidism. Our results also differ from those reported by Kabadi (19). In his prospective study (4–15 yr), 14 of 30 patients with subclinical hypothyroidism persisted with elevated TSH. He attributed this situation to a reset of the thyrostat. However, 11 of these subjects had a history of surgery or radiation, circumstances not present in our patients. The small percentage of normalization in the survey of Huber et al. (7) may be accounted for by the inclusion of 32 patients treated by radioiodine and 23 with surgery.

Our results did not allow us to determine whether some of these persons with final TSH levels between 3 and 5 mU/liter are euthyroid outliers and not true cases of subclinical hypothyroidism (2). The relatively small number of subjects is another limitation to detect associations between time course of TSH normalization and clinical features. We also acknowledge that natural history of subclinical hypothyroidism may be different in young adults and that variability in TSH assays may have influenced our and other authors’ results. The influence of nonthyroidal disease might contribute to a transient rise in TSH in some patients. Finally, our results do not allow us to infer the long-term evolution of these patients, that is, whether some of these patients might return to subclinical or overt hypothyroidism with time.

In summary, most patients who normalize their TSH values did so in the first 2 yr of follow-up. The final TSH reached by these patients tend to be in the range of 3–5 mU/liter, and only a minority of patients showed a reversion to TSH values <2 mU/liter. The final TSH achieved tended to be lower in patients with early normalization, but it is not related to thyroid autoimmunity or other clinical factors. These data have application to the difficult question of whether patients with subclinical hypothyroidism should be observed or treated. Long-term studies are needed to further characterize the spontaneous fall in TSH concentration in these patients.

	Footnotes

 
First Published Online April 5, 2005

Abbreviations: fT₄, Free T₄; NHANES, National Health and Nutrition Examination Survey; TPOAb, thyroid peroxidase autoantibody.

Received February 22, 2005.

Accepted March 28, 2005.

	References

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