Latent Hypothyroidism in Adults

Background: The prevalence of latent/subclinical hypothyroidism is between 3% and 10%, according to epidemiologic studies that have been carried out in the USA, the United Kingdom, and Denmark. As persons with latent hypothyroidism are often asymptomatic, the diagnosis is often made incidentally in routine laboratory testing.

Methods: This review is based on a selective search in PubMed for publications on the diagnosis and treatment of latent hypothyroidism. All pertinent articles and guidelines published from 1 January 2000 to 31 July 2016 were included.

Results: The diagnosis of latent hypothyroidism is generally assigned after repeated measurement of a TSH concentration above 4.0 mU/L in a person whose fT4 concentration is in the normal range. The most common cause is autoimmune thyroiditis, which can be detected by a test for autoantibodies. L-thyroxin supplementation is a controversial matter: its purpose is to prevent the development of overt hypothyroidism, but there is a danger of overtreatment, which increases the risk of fracture. To date, no benefit of L-thyroxin supplementation has been demonstrated with respect to morbidity and mortality, health-related quality of life, mental health, cognitive function, or reduction of overweight. There is, however, evidence of a beneficial effect on cardiac function in women, and on the vascular system. At present, treatment is generally considered indicated only if the TSH level exceeds 10.0 mU/L.

Conclusion: Limited data are available on the relevant clinical endpoints and undesired side effects of supplementation therapy. Physicians should advise patients about the indications for such treatment on an individual basis after due consideration of the risks and benefits.

Technische Universität Dresden, Faculty of Medicine Carl Gustav Carus, Department of General Practice/MK3, Dresden, Germany: Jeannine Schübel, Prof. Dr. med. Bergmann, Dr. rer. medic. Dipl.-Soz. Voigt, MPH

Municipal Hospital Bielefeld, Department for Endocrinology and Diabetes, Bielefeld, Germany: PD Dr. med. Feldkamp

GesundheitsZentrum Kelkheim: Dr. med. Drossard

The diagnosis „subclinical hypothyroidism“ means in the first instance no more than that a blood test value has changed. According to the definition, it means that the concentration of thyroid-stimulating hormone (TSH), the main marker of thyroid dysfunction (1, 2), is above the reference range, but that free thyroxine (fT4) remains normal.

According to epidemiological data for the USA, Denmark, and the United Kingdom (no published figures are available for Germany), the prevalence of subclinical hypothyroidism in the general population can be estimated at between 3% and 10% (3–6), although analyzing the available data is not without its problems. TSH reference ranges vary according to differences in environmental factors (availability of iodine, etc.). Subclinical hypothyroidism is more common in women than in men, and in older people than in younger ones (3, 4).

Experience shows that, in daily clinical practice, subclinical hypothyroidism may be diagnosed in both the outpatient and the inpatient setting on the basis of TSH measurements, not always prompted by symptoms or any specific suspicion of disease (7). Thus, it is usually not symptoms reported by patients, but incidental findings of laboratory tests, that may lead to the diagnosis or suspected diagnosis „subclinical hypothyroidism.“ The moment when the diagnosis of subclinical hypothyroidism is documented in the medical records is the moment when the patient is defined as ill. In itself, a moderately raised TSH value (>4 <10 mU/L) on its own is not a health condition requiring treatment, but the risk does exist that the patient will go on to develop overt hypothyroidism with its potential for associated cardiovascular sequelae (8, 9, e1, e2). The treating physician must therefore decide whether to leave the patient untreated, or to treat the patient even though there is no clear indication for doing so and the risk is of triggering iatrogenic hyperthyroidism.

This example of clinical decision-making lays bare a medical dilemma faced today by physicians in all areas of medicine in countries like Germany that are rich and have a highly developed health care system: unlike in those more numerous parts of the world where medical undertreatment of large population groups is a big problem, in our part of the world protecting patients from overtreatment is also a big challenge for medical practitioners. In Germany, the need to protect the patient from both over- and undertreatment has come under discussion as an important issue in health care (e3–e5).

The question of treatment for subclinical hypothyroidism is a good example of the balancing act required between the fear of not carrying out an intervention that might be needed and the carrying out of unnecessary diagnostic and therapeutic procedures. A multitude of diagnostic options together with treatment that is regarded as simple, comparatively cheap, and with few undesired effects, will tend to give a false sense of safety for patients with subclinical hypothyroidism and their physicians, but this needs to be looked at more closely in terms of whether it is really necessary and whether it supports the autonomy of the patient (e6).

Method

This CME article is based on a selective search and review of the literature on the diagnosis and therapy of subclinical hypothyroidism in the PubMed database. The following inclusion criteria were applied:

• Publication date between 1 January 2000 and 31 July 2016
• Full text in English or German
• Patient groups: adults ≥ 19 years of age
• Study types: „clinical trial,“ „randomized controlled trial,“ „meta-analysis,“ „systematic review,“ „practice guideline,“ „guideline,“ „review.“
• In addition, cross-references to guidelines and articles were collected and followed up (snowball method). Publications identified through these manual searches were also included in the analysis.

For reasons of space, this article does not cover the special features of the diagnosis and treatment of subclinical hypothyroidism during pregnancy. The reference values that apply during pregnancy are different, as are recommendations for diagnosis and treatment. New international guidelines for this special case are currently in preparation.

Learning goals

This article should enable the reader to:

• Define subclinical hypothyroidism and assess the clinical significance of a raised TSH value in the individual case,
• understand the value of the various further diagnostic procedures, and
• gain confidence about when—under what conditions—subclinical hypothyroidism requires treatment.

Diagnosing subclinical hypothyroidism

Subclinical hypothyroidism is diagnosed when the TSH value is above the reference range but the fT4 value is within the normal range. Reference ranges for TSH vary from country to country and even within Germany. The upper limit lies between 2.5 and 5.0 mU/L (10). For years there has been a debate about whether to reduce the upper limit of all TSH reference ranges (11, e7). Based on study results in Germany, depending on the population and the test procedure, upper TSH reference values of 2.12 mU/L and 3.6 mU/L can be derived (12, 13). Lowering the TSH reference value would lead to a rise in the number of diagnoses, but they would have no clinical consequences (14). In studies in the USA, upper reference values for TSH of around 4.0 mU/L are recommended (3, 15); the recommendations are based on TSH value distributions in the normal healthy population for caucasian adults without diagnosed thyroid disease.

Defining subclinical hypothyroidism as a TSH value of over 4.0 mU/L with normal fT4 is also largely practicable in Germany and this definition is therefore in frequent use. Where the TSH value is higher than 10 mU/L while the fT4 value remains normal, the disorder is referred to as „severe“ subclinical hypothyroidism (16).

It is not necessary to measure fT3 for the diagnosis of (subclinical) hypothyroidism, since this provides no additional useful information (7, e8).

Diagnostic certainty

Depending on the method used to determine TSH in the laboratory, measured TSH values can vary, or for technical reasons the reference ranges provided may vary (e9). Direct comparison of TSH values (e.g., when monitoring a patient over time) is therefore only possible when the measurements have all been made using the same technique.

There are a number of factors that act on TSH concentrations and can affect their level. In the routine clinical setting, age, body weight, and medications are the most important non-thyroidal factors that can lead to a rise in TSH (Table).

Table

Non-thyroidal factors that can lead to a rise in TSH levels

Other non-thyroidal factors have also been described, but they will not be covered here because they

• become clinically overt due to other underlying diseases, e.g., adrenal insufficiency (e19), convalescence after non-thyroidal illness,
• very rarely occur, e.g., after excessive iodine intake, sleep deprivation, thyrotropin-secreting pituitary adenoma, or thyroid hormone resistance—both of the latter are also accompanied by raised T4 values,
• only cause clinically insignificant rises in TSH values, e.g., physiological daytime fluctuations due to the circadian rhythm of TSH secretion (e20).

Changes in reference range limits provided by laboratories should, unless there is good scientific evidence to support them (e.g., change in assay technique, epidemiology), be regarded with caution.

Intraindividual changes in serum TSH values of up to 40% do not necessarily reflect a change in thyroid function, but are within the range of random variation. In checking TSH values, therefore, only a difference of >40% from the preceding value should be definitely rated as showing a „true“ change in thyroid function (7, 18).

Given the multitude of ways in which TSH values can be influenced, to obtain TSH measurements that are as valid and comparable as possible, it is recommended that blood samples should always be taken under the same conditions (time of day [e20], medication intake). A single measurement of a TSH value above 4 mU/L should be confirmed by a repeat measurement.

There is no justification for diagnosing a pathological state solely on the basis of TSH values outside the reference range. On the contrary, individual TSH values should be assessed in the light of the possible influential factors alluded to above and the extent to which the patient's quality of life and general condition of health are or are not restricted (e21).

Measuring autoantibodies

The commonest cause of subclinical hypothyroidism is autoimmune thyroiditis (8). Measurement of thyroid autoantibodies is therefore often requested and should provide an answer to the question. Knowing that autoantibodies are present, however, has little clinical relevance because

• the risk of developing overt hypothyroidism is slightly increased in patients with thyroid autoantibodies: in a study of women with subclinical hypothyroidism, Vanderpump et al. found that antibody-positive patients had an increased relative risk of 1.7% per year compared to antibody-negative patients (6). However, follow-up laboratory tests will be required anyway for monitoring purposes when raised TSH values are found, and the intervals between tests are set according to the most up-to-date TSH value.
• patients with Hashimoto's thyroiditis are at increased risk of developing other autoimmune diseases (19); for example, Hashimoto's thyroiditis can be associated with autoimmune polyglandular syndrome (APS). However, patients with only autoimmune-related hypothyroidism are not normally expected to develop any other endocrine autoimmune disease (e22). Knowing that a patient is antibody-positive does not lead to earlier diagnosis of other autoimmune diseases; as in any other patients, the pathway to diagnosis of such diseases would be according to observed physical symptoms and changes.
• There is no reason to expect that demonstration of thyroid autoantibodies would alter the effectiveness of treatment compared to that in antibody-negative patients (14).

Raised levels of antibodies against thyroid peroxidase (TPO-AB) are found in 90% of patients with Hashimoto's thyroiditis, and raised antithyroglobulin antibody (TGAB) values in 70% (e23). To investigate suspected autoimmune thyroiditis, therefore, a single test for antibodies can be carried out. For this purpose, at primary physician level, generally TPO-AB can be determined; for individualized clinical questions in the specialist setting, TGAB may be determined in addition.

The question here is fundamentally one of the usefulness and the consequences of the laboratory findings for the individual patient. Being told you have an autoimmune disease triggers fear and uncertainty, thus reducing quality of life; this is something a diagnosis of „subclinical hypothyroidism“ does not justify.

The care that is best for the individual patient does not necessarily mean carrying out every medically possible diagnostic test, but should also be guided by the patient's own attitudes and expectations (20). This does, of course, require full explanation of the consequences of the investigations ordered, together with their significance for the patient.

Ultrasound

Patients with subclinical hypothyroidism do not require thyroid ultrasound unless one or more palpable nodules are present (7). Although the sensitivity of the hypoechoic thyroid for autoimmune thyroiditis is higher than that of TPO-AB, and the extent of Hashimoto's thyroiditis can be determined by experienced sonographers (e25), this has no relevance for decisions about treatment. In the endocrinological recommendations of the US „Choosing Wisely“ initiative, routine ultrasound scanning of the thyroid is classed as overdiagnosis (e26).

Diagnostic significance of symptoms

Patients with subclinical hypothyroidism do not usually report any symptoms (21, e1). In the literature, it has been reported that impaired working memory, decrements in mood status, and increased fatigue occur in patients with subclinical hypothyroidism. The study concerned, however, has considerable methodological defects and bears no relation to everyday patient care: in 19 patients with overt hypothyroidism, a subclinical stage was artificially induced through inadequate L-thyroxine replacement, and the patients' symptoms were documented (e27).

Guidelines on treating subclinical hypothyroidism often assume that symptoms are absent and that the diagnosis is therefore incidental. History taking in patients with diagnosed hypothyroidism aims primarily at investigating the possible development of overt hypothyroidism. To this end, a large number of possible symptoms are described, including fatigue, weight increase, constipation, alopecia, and dry skin (1, 2, 21, e23). However, because of their poor sensitivity and specificity, general symptoms of this kind are not much use in confirming a diagnosis of hypothyroidism, or distinguishing between subclinical and overt hypothyroidism (22, 23). It follows that asking about a list of „typical“ symptoms in a patient with hypothyroidism, in the setting of history taking from a patient with subclinical hypothyroidism, serves no purpose. If, on the other hand, a patient presents spontaneously reporting symptoms that could be associated with subclinical hypothyroidism, then further diagnostic tests should be undertaken. The most important recommendations regarding the next diagnostic steps in patients with subclinical hypothyroidism are listed in Box 1.

Box 1

Recommendations for diagnostic investigations

Treating subclinical hypothyroidism

The need for replacement therapy in patients with subclinical hypothyroidism is a matter of debate (21, 24–26, e6, e28, e29). The evidence in relation to clinically relevant endpoints or unwanted effects of hormone replacement in patients with subclinical hypothyroidism is limited; there are no randomized controlled studies (RCTs) (27). An international working group is currently studying the medical treatment of subclinical hypothyroidism in persons aged between 65 and 80 years in the TRUST project. However, the study is not expected to publish any results until 2018 at the earliest (e30).

The decision whether to treat or not should be made on an individual basis taking into account the patient's interests and potential side effects in the case that treatment is or is not initiated. Factors that have been described include an increased relative risk (RR) of arrhythmias of 1.6 in patients with a slightly raised TSH value and L-thyroxine treatment compared with patients without L-thyroxine treatment (e31). TSH vales that are too low as a result of overtreatment increase the relative risk of fractures (RR 1.9 to 2.0) (e32, e33). According to empirical studies, at 20% the proportion of patients with subclinical hypothyroidism whose TSH values fall below the normal range as a result of treatment is quite significant (3, 4). Some patients benefit from low-dose L-thyroxine therapy in terms of general well-being, improved performance, and improved mood, but the evidence for hormone-replacement-related improvement of psychological symptoms is inadequate (14, 28). In 2012, in a randomized, double-blind, placebo-controlled study, Reuters et al. investigated the effects of L-thyroxine treatment on psychiatric symptoms. At 6-month follow-up, no improvement in health-related quality of life and psychiatric symptoms was shown (28).

Recommendations for treatment of patients with TSH values >10 mU/L

In some studies, subclinical hypothyroidism has been shown to be an independent risk factor for the development and exacerbation of heart failure and coronary heart disease (9, e1, e2). However, a clear relationship was demonstrated only in the patient group ≤70 years of age with subclinical hypothyroidism and a TSH value >10 mU/L (29, 30, e1, e34–e36), so it is only for this patient group that a treatment recommendation can be made. In 2011, in a randomized, double-blind, placebo-controlled study, Martins et al. found indications that L-thyroxine replacement had a positive effect on cardiac function in women (40 to 60 years of age) with subclinical hypothyroidism. However, a limitation of the study was the very small size of the study groups (L-thyroxine n = 9, placebo n = 13) (30).

In starting replacement therapy in the patient group ≤70 years of age with subclinical hypothyroidism and TSH values >10 mU/L, low doses of L-thyroxine of 25 to 50 µg/day can be chosen initially (21).

For patients with subclinical hypothyroidism who are over the age of 70, treatment is indicated only if they are at high cardiovascular risk or have symptoms that may be associated with hypothyroidism (e2). In older patients, especially the very old (≥85 years) with subclinical hypothyroidism, overtreatment with L-thyroxine is suspected (31, e37). Against a background of rising multimorbidity and polypharmacy, it is always important to weigh up carefully whether L-thyroxine treatment is going to benefit the patient, especially if the patient is old or very old.

Recommendations for the treatment of patients with TSH values ≤10 mU/L

For the patient group with TSH values ≤10 mU/L, no generalized recommendation for treatment can be made, as there is insufficient evidence that L-thyroxine replacement benefits the patient (14, e38). The data to confirm whether a benefit exists are methodologically heterogeneous and difficult to compare because they employ different TSH reference ranges. Some studies showed improvements in surrogate parameters (lipid profile, echocardiographic parameters) (27, 32–34. e39–e42). In a randomized controlled study in 2011 of patients with subclinical hypothyroidism, Cabral et al. found indications at 12-month follow-up of a positive influence of L-thyroxine replacement (L-thyroxine group n = 14, observation group n = 18) on flow-mediated vasodilatation of the brachial artery (as a measure of endothelial function) (e39). No effects on clinically relevant parameters such as morbidity or mortality rates have been shown. As cardiovascular risk depends on lipid levels only to a small extent, other cardiovascular risk factors must be drawn into the calculation when deciding whether or not to treat subclinical hypothyroidism (35). There is no evidence that L-thyroxine treatment can achieve weight reduction in overweight female patients with subclinical hypothyroidism and a TSH value <10 mU/L (16). Similarly, the hope that thyroxine replacement could improve cognitive function has not been confirmed (27, 36). One study suggests that subclinical hypothyroidism with TSH values ≤ 10 mU/L in patients >85 years old is associated with longer life, and that therefore there should even be a recommendation against replacement therapy in patients with this set of characteristics (37).

The first thing that is required in making a decision for or against treating a patient with subclinical hypothyroidism and a TSH value ≤ 10 mU/L is to ensure that the patient is fully informed. The treating physician should explain that

• it is unclear whether any symptoms are being caused by thyroid dysfunction,
• it is possible, but not certain, that symptoms will improve with treatment (14),
• even if the patient feels an improvement in symptoms, it is difficult to say whether this is truly an effect of treatment or whether it stems from a placebo effect,
• regular blood tests will be necessary whether or not treatment is undertaken,
• possible overtreatment brings its own dangers.

If the patient agrees to replacement therapy, it can initially be started on a trial basis for a few months. Continuing treatment can be justified only if there is a marked improvement in symptoms; otherwise, there is no evidence-based foundation for continuing to prescribe L-thyroxine.

Treatment recommendations for patients with subclinical hypothyroidism who are TPO-antibody-positive

Given the slightly increased risk of overt hypothyroidism developing in patients who are autoantibody-positive (6), clinical guidelines of internal medicine always recommend hormone replacement in patients with subclinical hypothyroidism with proven Hashimoto's thyroiditis (2, 7, 24, e43, e44). The risk of developing overt hypothyroidism, however, correlates more strongly with the TSH value than with autoantibody-positive status (29). On the question of how to calculate the number needed to treat (NNT) in order to prevent the development of overt hypothyroidism in one patient (irrespective of antibody status), no randomized studies have been done. It has been estimated that it would be necessary to treat between 5 and 15 patients in order to prevent one case of overt disease (e29). Combining the results of all studies so far, treatment of patients with TSH values >6 mU/L and positive TPO-antibody status with the aim of preventing the development of overt hypothyroidism (even permanently) appears to be justified (2). The most important recommendations for treatment of patients with subclinical hypothyroidism are listed in Box 2.

Box 2

Test intervals during hormone replacement therapy

Once treatment with L-thyroxine has started, thyroid hormone tests should be carried out no earlier than after 8 weeks, as TSH values need 8 to 12 weeks to settle to a constant level after a change in L-thyroxine dose (21, 24, e43).

In the specialist endocrinology setting, clear recommendations exist for the choice of follow-up test intervals in subclinical hypothyroidism. If no treatment is started, it is recommended that for the first 2 years after diagnosis TSH should be tested every 6 months, and if levels remain stable they should then be tested once a year (14). In the primary care setting with an unselected patient population, testing intervals of 6 to 12 months appear to be adequate to rule out transient causes of increased TSH levels (e.g., acute disease, medication). However, little research has been carried out on the various strategies for choosing testing intervals. US authors working in general practice have stated that once a patient's TSH values have stabilized at normal on an L-thyroxine dosage of less than 125 µg/day, testing once every 2 years is adequate (38). At present, given findings of up to 20% of patients with subclinical hypothyroidism and iatrogenic TSH suppression (39, 40), testing once a year appears to be sensible.

The patient should also be actively involved in the choice of test intervals. So long as the patient has been given full information about the possible consequences of the various options, the intervals can be altered depending on his or her wishes and how well he or she feels.

Conflict of interest statement
Dr. Voigt, Jeannine Schübel and Prof. Bergmann are authors of the German College of General Practitioners and Family Physicians (DEGAM, Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin) guideline „Erhöhter TSH-Wert in der Hausarztpraxis [Raised TSH values in general practice]“ (AWMF no. 053–046).

Jeannine Schübel receives royalties from Elsevier

Dr. Drossard and PD Dr. Feldkamp represented respectively the German Society of Internal Medicine (Deutsche Gesellschaft für Innere Medizin) and the German Society of Endocrinology (Deutsche Gesellschaft für Endokrinologie) during the consensus process of the DEGAM guideline „Erhöhter TSH-Wert in der Hausarztpraxis [Raised TSH values in general practice]“

Manuscript received on 28 July 2016, revised version accepted on
18 January 2017.

Translated from the original German by Kersti Wagstaff, MA.

Corresponding author:
Jeannine Schübel
Medizinische Fakultät Carl Gustav Carus der Technischen Universität Dresden
Bereich Allgemeinmedizin/MK3
Fetscherstr. 74, 01307 Dresden, Germany

Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref2517

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