Received Date : 24-Jul-2016

Revised Date : 02-Aug-2016

Accepted Date : 09-Aug-2016
Article type : 11 Letter
Accepted Article
LETTER

Levothyroxine therapy in the subclinical hypothyroidism: a lifelong therapy? A long

term study

Pedro W. Rosario1, M.D.; Maria R. Calsolari1, M.D.

1
Postgraduate Program and Endocrinology Service, Santa Casa de Belo Horizonte, Minas

Gerais, Brazil.

Address for correspondence:

Dr. Pedro W. Rosario, M.D.

Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte

Rua Domingos Vieira, 590, Santa Efigênia. CEP 30150-240, Belo Horizonte, MG, Brasil.

Telephone: 55 (31) 3238838 Fax: 55 (31) 32388980

E-mail: pedrowsrosario@gmail.com

Short title: Subclinical Hypothyroidism

Keywords: Subclinical Hypothyroidism; Levothyroxine; Withdrawal.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/cen.13174
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 Dear Editor,

Approximately 80% of patients with subclinical hypothyroidism (SCH) have TSH ≤ 10

Accepted Article
mIU/L.1 Many of these subjects are treated with levothyroxine (L-T4) because they have anti-

thyroperoxidase antibodies (TPOAb), goiter, high cardiovascular risk, dyslipidemia,

depression, infertility, and symptoms of hypothyroidism. In the case of the first three

conditions and when there is a satisfactory response in the remaining, therapy is maintained.

In 20 to 50% of patients with SCH and TSH ≤ 10 mIU/L, the concentrations of this hormone

normalize spontaneously in the years after diagnosis.2-4 Nevertheless, there is no

recommendation to attempt thyroid hormone withdrawal (THW) in patients with SCH under

treatment.1,5 Many of these cases of functional recovery of the thyroid are probably not

recognized since, even in patients receiving L-T4, this recovery is not always accompanied

by a reduction in TSH.6

We previously reported the results of THW in women with SCH and initial TSH ≤ 10 mIU/L

and their status one year after the discontinuation of treatment.6 We have now increased the

number of patients evaluated and the period of follow-up after THW.

This was a prospective study. Women aged ≤ 65 years consecutively evaluated between May

2005 and May 2013, who fulfilled the following criteria, were initially selected: initial

diagnosis of SCH with TSH ≤ 10 mIU/L; undergoing L-T4 therapy for at least 2 years;2-4,6

TSH between 0.5 and 2.5 mIU/L in the last two assessments (interval ≥ 8 weeks). Patients in

whom the diagnosis of SCH was established during pregnancy, up to 12 months after

delivery, after partial thyroidectomy, therapy with 131I for hyperthyroidism and neck

radiotherapy, or associated with drugs, were excluded. Pregnant women and women planning

to get pregnant in the short term were also excluded. The final sample consisted of 182

subjects.

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 SCH was defined as two consecutive measurements of TSH ≥ 4.5 mIU/L (interval ≥ 8 weeks)

in the presence of normal free T4 and excluding other causes of elevated TSH (recovery from
Accepted Article
an acute illness, medications, known adrenal or renal insufficiency). Treatment with L-T4

was instituted in these patients based on the presence of TPOAb with or without goiter (n =

100), symptoms of hypothyroidism (n = 106), dyslipidemia (n = 20), depression (n = 18),

infertility (n = 8), or unknown reason (n = 6). Except for women treated only because of the

presence of TPOAb, improvement of the condition that led to the indication of therapy was

observed in the remaining patients and L-T4 was thus maintained.

All patients were submitted to TPOAb measurement and ultrasonography (US) of the thyroid.

First, the L-T4 dose was reduced by half and TSH was measured within 4 weeks. When TSH

remained ≤ 4 mIU/L, this procedure was repeated successively until a dose ≤ 12.5 µg/day

was reached and therapy was then discontinued.6 In the case of a TSH increase to levels > 10

mIU/L or > 4 mIU/L in two consecutive measurements (at intervals of 8 weeks), the initial L-

T4 dose was reestablished. Patients with TSH ≤ 4 mIU/L after THW were followed up for a

period of 24-120 months (median 62 months) at intervals of 3-6 months.

TSH, TPOAb and free T4 were measured with a chemiluminescent assay, with reference

values of 0.4-4 mIU/L, up to 35 kIU/L and 10.3-23 pmol/L, respectively. US was performed

with a multifrequency linear transducer and the examiner was unaware of the thyroid status

of the patient. Diffuse hypoechogenicity was used as a criterion for the definition of

autoimmune thyroiditis.1,4,6

We used the χ2 test and multivariate logistic regression and a p-value of less than 0.05 was

considered significant.

Patient age ranged from 19 to 63 years (median 42 years) at the time when THW was

attempted, with a duration of L-T4 therapy of 24 to 82 months (median 36 months) and a

daily dose of 25 to 100 µg (0.3-1.5 µg/kg). The last TSH measurement ranged from 0.56 to

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 2.5 mIU/L (median 1.4 mIU/L). Pretreatment TSH ranged from 4.6 to 10 mIU/L (median 7.1

mIU/L).
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TSH remained ≤ 4 mIU/L after THW until the last assessment (euthyroidism) in 42/182

patients (23%). Classification of the patients into two groups,4,6 one with positive TPOAb

and/or US (n = 142) and another in which both parameters were negative (n = 40), showed

that the rate of euthyroidism was lower in the first group (15.5% versus 50%, p = 0.0001).

These rates were similar in TPOAb-positive patients (n = 100) and patients with negative

TPOAb but with positive US (n = 42) (16% versus 12%, respectively). The concentration of

TSH at the time of diagnosis of SCH was also predictive of euthyroidism. In the analysis

using binary TSH data (TSH ≥ 6, 7, 8, and 9 mIU/L compared with TSH < 6, 7, 8, and 9

mIU/L, respectively), the greatest difference in the rate of euthyroidism was obtained with

the cut-offs of 8 and 9 mIU/L. Since no difference was observed between the last two values,

we used the cut-off of 8 mIU/L for analysis of the predictive value of TSH: 30%)of patients

with TSH < 8 mIU/L at the time of diagnosis versus 5.9%) with TSH ≥ 8 mIU/L remained

euthyroid (p = 0.0003). None of the patients with autoimmune thyroiditis and pretreatment

TSH ≥ 8 mIU/L remained euthyroid. Free T4 levels were normal in all patients with TSH > 4

mIU/L after dose reduction or THW, indicating that the protocol used did not result in

clinical hypothyroidism (low T4).

There is currently no recommendation for the withdrawal of L-T4 therapy.1,5 To our

knowledge, only our previous study has evaluated treatment discontinuation in adult patients

receiving L-T4 due to a diagnosis of SCH outside pregnancy,6 but the time of follow-up after

THW was only one year. This was a prospective study whose protocol was rigorously

followed. Subclinical hypothyroidism was carefully defined and L-T4 therapy was instituted

in agreement with current guidelines.1,5 A large number of patients were studied. In addition

to TPOAb measurement, US was performed on all patients to exclude chronic thyroiditis and

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 the examiner was unaware of the thyroid status of the patient. Finally, the minimum time of

follow-up of patients with normal TSH after THW was 2 years (median of 5 years).
Accepted Article
It should be noted that patients with hypothyroidism diagnosed in situations in which

reversibility of this dysfunction is well known were excluded.7 Likewise, patients with TSH <

0.5 mIU/L, indicating excess thyroid hormone, were not included. Nevertheless, the rate of

persistent euthyroidism found in the present study seems to be sufficient to justify the attempt

of THW. The persistence of euthyroidism after THW was compatible with spontaneous TSH

normalization, which is observed in a good part of SCH cases with slightly elevated TSH.2-4

Our results permit to draw some conclusions. First, during L-T4 use, the possibility of

functional recovery of the thyroid should not only be considered when TSH becomes low or

undetectable. Second, although a higher rate of euthyroidism has been observed in patients

without autoimmune thyroiditis, functional recovery occurred even in the presence of this

condition when TSH concentrations at diagnosis were less than 8 mIU/L. Third, a duration of

treatment of 2 years to attempt THW seems reasonable since approximately three-quarters of

spontaneous normalizations of TSH occur during this interval.2-4 Fourth, the protocol

consisting of a reduction of the L-T4 dose by half and early assessment of TSH (4 weeks) did

not cause clinical hypothyroidism (low T4), thus demonstrating its safety for clinical practice.

Finally, it should be emphasized that our results cannot be applied to patients with persistent

SCH after partial thyroidectomy, 131I therapy for hyperthyroidism or neck radiotherapy, when

functional reversibility seems to be unlikely. Since only women were included in the present

study, the results cannot be fully extrapolated to men with SCH.

We conclude that in patients receiving L-T4, with TSH between 0.5 and 2.5 mIU/L, due to an

initial diagnosis of SCH with only moderately elevated TSH, a progressive dose reduction

and even eventual THW should be attempted. We believe that many patients are receiving L-

T4 unnecessarily, including the risk of thyrotoxicosis.

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 Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing
Accepted Article
the impartiality of the research reported.

References

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therapy? Clinical Endocrinology, 72, 718-720.

7. Vanderpump, M.P., Ahlquist, J.A., Franklyn, J.A., Clayton, R.N. (1996) Consensus

statement for good practice and audit measures in the management of hypothyroidism

and hyperthyroidism. The Research Unit of the Royal College of Physicians of

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 London, the Endocrinology and Diabetes Committee of the Royal College of

Physicians of London, and the Society for Endocrinology. BMJ, 313, 539-544.
Accepted Article

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