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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 4  |  Page : 167-171

Subclinical hyperthyroidism


Department of Endocrinology, MS Ramaiah Medical College, BengaluruQ, Karnataka, India

Date of Submission28-Mar-2020
Date of Decision05-Apr-2020
Date of Acceptance24-Apr-2020
Date of Web Publication23-Oct-2020

Correspondence Address:
Dr. Mala Dharmalingam
Department of Endocrinology, MS Ramaiah Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJIM.AJIM_21_20

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  Abstract 


Subclinical hyperthyroidism (SH) is a relatively common disorder; it is defined as a condition in which the thyroid hormones thyroxine (T4) and triiodothyronine levels (T3) are normal with low or even undetectable thyroid-stimulating hormone (TSH) levels. SH may be caused by exogenous or endogenous factors with TSH suppressive therapy in differentiated thyroid cancer or unintentional over-replacement L-T4 therapy being the most common causes. Frank symptoms of hyperthyroidism is most often absent. Patients often present with goitre or for other symptoms of mild thyroid hormone excess such as headache, reduced feeling of well-being, and inability to concentrate. SH leads to increased risk of cardiovascular morbidity and mortality, it may accelerate the development of osteoporosis, and increase bone vulnerability to trauma, especially in postmenopausal women and elderly. It reduces the quality of life, affecting both the psycho and somatic components of wellbeing. Diagnosis of SH is confirmed by repeated testing of TSH spaced months apart in the presence of normal free T3 and T4 concentrations. Radionuclide uptake scan aids us in the diagnosis of the cause of SH. The treatment of SH is similar to the treatment of overt hyperthyroidism, it should be based on the underlying etiology.

Keywords: American Thyroid Association Guidelines, bone and mineral metabolism, cardiovascular effects, subclinical hyperthyroidism


How to cite this article:
Dharmalingam M, Bobba R. Subclinical hyperthyroidism. APIK J Int Med 2020;8:167-71

How to cite this URL:
Dharmalingam M, Bobba R. Subclinical hyperthyroidism. APIK J Int Med [serial online] 2020 [cited 2020 Nov 26];8:167-71. Available from: https://www.ajim.in/text.asp?2020/8/4/167/298933




  Introduction Top


Subclinical hyperthyroidism (SH) is an increasingly recognized biochemical condition, and its influence on health is not very clear. There are conflicting evidences about the benefits of its treatment in adults.

In this article, we have reviewed the literature on SH (from PubMed, Google Scholar), defined its clinical features, effects on health, and the benefits of treatment. SH causes a dilemma in the physician's mind whether as to treat or not. Our aim is to provide physicians clarity, with the most recent data and to help them to manage this condition according to the principles of evidence-based medicine.

SH is defined as a condition where the thyroid hormones thyroxine (T4) and triiodothyronine levels (T3) are normal, however, the thyroid-stimulating hormone (TSH) levels are low or even undetectable. Although called SH a better terminology would be mild hyperthyroidism.

SH is a relatively common disorder with prevalence ranging from 0.6% to 1.6%, in various studies conducted at different cities in India.[1] The prevalence of SH depends on age, sex, and iodine intake.

The availability of sensitive assays for TSH is one of the reasons for its increased prevalence. Iodine-deficient areas have a higher prevalence of thyroid autonomy.

SH may be caused by exogenous or endogenous factors and may be transient or persistent. TSH suppressive therapy in differentiated thyroid cancer or unintentional over replacement L-T4 therapy are the most common exogenous causes; the prevalence in these patients may be as high as 20%.[2] The other causes of SH or low TSH are shown in [Table 1]. In pregnancy, placental human chorionic gonadotropin stimulates thyroid hormone secretion, often decreasing maternal TSH concentrations, especially in the early pregnancy. TSH below the nonpregnant lower limit of 0.4 mU/L is observed in as many as 15% of healthy women during the first trimester of pregnancy.[3] The normal range of TSH during pregnancy is 0.1–2.5 mIU/L during the first trimester, 0.2–3 mIU/L in the second trimester, and 0.3–3 mIU/L during the third trimester, and this is not considered as SH.[4]
Table 1: Causes of subclinical hyperthyroidism (or low thyroid-stimulating hormone level)

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  Transient Subclinical Hyperthyroidism Top


Transient TSH suppression may be due to subacute or postpartum thyroiditis.

The natural history of SH is variable depending on the underlying disease process. In patients with toxic adenoma or multinodular goiter (MNG), SH is usually a slowly progressive disorder and may last several years before being diagnosed. Patients with Graves' disease (GD) as the cause of SH are more likely to spontaneously remit rather than a toxic MNG. Patients with SH due to GD may progress, normalize, or remain in the SH state. Older people and those with positive anti-thyroid peroxidase antibodies have a higher risk of progression of the disease.[5] In various studies, the annualized rates of progression to overt hyperthyroidism were 0.5%–7%, and reversion to normal TSH levels were 5%–12%.[6],[7],[8],[9],[10]

The progression from SH to overt hyperthyroidism appears more likely if the TSH is suppressed (<0.01 mU/L) rather than low (0.01–0.4 mU/L).[7],[11],[12],[13]


  Clinical Features Top


Signs, symptoms, and quality of life

Frank symptoms of hyperthyroidism are most often absent. The diagnosis is either for a goiter or for some other reason. Symptoms of mild thyroid hormone excess such as headache, reduced feeling of well-being, fear, hostility, and inability to concentrate may be present. In occasional cases, they can present with symptoms of hyperthyroidism such as palpitations, tremor, heat intolerance, sweating, nervousness, anxiety, and hyper defecation.

Effect on overall mortality

Several longitudinal studies have examined correlations between SH and overall mortality, with conflicting results. Some studies reported increased overall mortality rates, especially in older individuals, while others indicated no such relation. These studies had several limitations, such as small sample sizes, age ranges, length of follow-up, and diagnosis of SH by a single TSH measurement. A meta-analysis by Collet et al . analyzing individual-level data from 52,674 participants concluded that SH confers a 24% increased risk of overall mortality.[14]


  Quality of Life, Mood, and Cognitive Function Top


Physical and mental aspects of quality of life were thought to be affected in patients with SH. Approximately equal number of studies report significant associations between SH and measures of cognitive decline and the development of dementia versus no associations.[15],[16] At present, no conclusions regarding this issue can be reached.


  Physical Functioning Top


Three studies could find no correlation between SH and self-reported functional capacity or objective measures of physical functioning,[17],[18],[19] while one study found a correlation between SH and lower physical performance in men only.[20]

The deleterious effects of SH include mainly the cardiovascular effects and the bone. It also has an effect on metabolic parameters such as glucose, mood and cognition, and muscle strength and physical functioning.


  Cardiovascular Disease Top


Cardiovascular effects of SH are shown in [Table 2].[21],[22]
Table 2: Cardiovascular effects of subclinical hyperthyroidism

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The most consistent cardiac abnormality reported in patients with SH, regardless of the underlying etiology, is a significant increase in the left ventricular mass with unchanged or increased at-rest systolic function and impaired diastolic function.[23] Two recent meta-analyses, one of the individual-level data of 52,674 participants concluded that SH confers an increased risk of cardiovascular mortality.[14] The risk was greater in patients with TSH levels <0.1 mU/L compared to those with TSH levels of 0.1–0.4 mU/L. Functional implications of these cardiac abnormalities include significant reductions in the peak workload and exercise duration, decreased exercise tolerance, and oxygen uptake at peak exercise due to decreased ejection fraction.


  Atrial Fibrillation Top


Studies showed an increased risk of atrial fibrillation in those with TSH levels <0.1 mIU/L compared to 0.1–0.44 mIU/L, suggesting that the risk of atrial fibrillation inversely correlates with TSH levels.[24],[25]

In the largest study to date (586,460 people followed for a median of 5.5 years), the highest relative risk for atrial fibrillation occurred in younger patients, possibly because other causes predominate with age, and in patients with lower TSH levels.[26]

In other studies, absolute incidence rates of atrial fibrillation were much lower in younger patients (women under the age of 65 years) compared with women 65 years and older. Similar trends were seen for men.[27],[28],[29]

In conclusion, taken together these data provide a strong argument for the treatment of SH in older individuals to avoid dysrhythmias and possible subsequent stroke. The absolute risks of these events are very low in younger patients, so the risk–benefit ratio of treating younger SH patients is not clear, and treatment decisions should be individualized.


  Heart Failure Top


Increased left ventricular mass and impaired left ventricular function in SH contribute to the increased heart failure risk that improves with treatment.

The effect of SH on stroke is controversial, with two population-based studies showing increased risk, but a more recent meta-analysis failed to confirm the findings.[30]


  Osteoporosis and Fractures Top


SH is associated with increased bone turnover, negative calcium balance, decreased bone density (particularly in the cortical bone), and increased risk of fractures.[31]

Serum concentrations of several markers of bone synthesis and reabsorption, that is, osteocalcin, telopeptide type I, and urinary pyridinoline cross-links and hydroxyproline, are increased in patients with SH and negatively correlated to serum TSH concentrations.[32] The extent of bone loss depends on the magnitude of thyroid hormone excess and its duration. These effects are more pronounced in postmenopausal women.

A meta-analysis of 70,298 pooled participants found that compared with euthyroid patients, those with TSH levels <0.45 mIU/L had an increased risk of hip fracture and total fractures.[33]

Prospective studies in postmenopausal women with SH treated with radioactive iodine ablation or antithyroid drugs showed stable or improved bone mineral density, whereas untreated patients continued losing bone mass at a rate of 1%–2% per year.[34] Overall, these data favor treatment in the older population, but unfortunately, there are still no large, long-term randomized studies to allow evidence-based conclusions as to the risk–benefit ratio.

The negative effects of thyroid hormone on bone can be obviated by adequate dietary calcium intake, bisphosphonates, or by estrogen replacement therapy in postmenopausal women.[35],[36],[37]


  Diagnosis Top


SH is confirmed by repeated testing of TSH spaced months apart in the presence of normal free T3 and T4 concentrations. This is to avoid diagnosing patients with transient, functional disorders related to acute illness, drugs, and laboratory errors of low TSH as SH. Radionuclide uptake scan (I 123 or Tc 99) aids us in the diagnosis of the cause of SH, as it can differentiate between GD, toxic MNG, and toxic adenoma. Thyroid antibodies can help to distinguish GD from other causes of SH. The most specific antibody for GD is TSH. Thyroid ultrasound offers information about the overall structure and characteristics of the thyroid gland. In patients with GD or thyroiditis, the thyroid gland is usually enlarged and heterogeneous in appearance. In patients with MNG and/or solitary autonomously functioning nodule, the thyroid ultrasound can characterize the number and size of the nodules. The possibility of thyroid cancer should be ruled out by a fine-needle aspiration biopsy of hypofunctioning nodules.

Investigations such as two-dimensional echo, electrocardiogram, and Holter monitoring of the heart and dual-energy X-ray absorptiometry scanning help us in the management of cardiovascular disease and bone health, respectively.


  When to Consider Treatment Top


Should be treated

  1. Age >65 years with TSH levels persistently <0.1 mIU/L over a minimum period of 3 months
  2. Age <65 years with TSH levels <0.1 mIU/L and with comorbidities such as heart disease, osteoporosis, symptoms of hyperthyroidism, or postmenopausal women not on estrogen or bisphosphonates.



  Treatment Can Be Considered Top


  1. Age >65 years with TSH levels of 0.1–0.4 mIU/L
  2. Age <65 years with TSH levels of 0.1–0.4 mIU/L and with comorbidities such as heart disease, osteoporosis, symptoms of hyperthyroidism, or postmenopausal women not on estrogen or bisphosphonates
  3. Age <65 years, asymptomatic individuals with TSH <0.1 mU/L.


Individuals <65 years of age and those with TSH levels of 0.1–0.4 mIU/L and without any comorbidities can be observed without treatment.

These recommendations were based primarily on the studies showing an increased rate of atrial fibrillation[26] and altered skeletal health[41] in older individuals and with suppressed TSH levels.

Emerging epidemiologic data on risks for overall and cardiovascular-specific mortality[25],[38],[39],[40],[41],[42] have strengthened this argument, even in the absence of interventional data.


  Treatment Top


The treatment of SH is similar to the treatment of overt hyperthyroidism, it should be based on the underlying etiology.

In patients with toxic MNG or a solitary autonomous nodule, radioactive iodine ablation or surgery is a definitive treatment and is preferred. These patients can often be treated with a single dose of radioactive iodine. Either antithyroid drugs or radioactive iodine are appropriate treatment options in patients with GD depending on the clinical features and patient's preferences. Propylthiouracil has been linked to rare but fatal cases of hepatotoxicity (especially in children and pregnant women), hence, methimazole is the first-line antithyroid drug for use in patients with hyperthyroidism (except in pregnant patients during their first trimester). In treating SH, low-dose methimazole is usually sufficient.

Ablative therapy is generally safe but is avoided in asymptomatic patients due to risk of permanent hypothyroidism. In an asymptomatic patient with mild GD, watchful waiting for several years, awaiting a possible spontaneous remission, may be the best course of action in younger patients.[13] Symptomatic treatment with beta-blockers is required in patients with atrial fibrillation.


  Conclusion Top


SH is a relatively common disorder. SH leads to increased risk of cardiovascular morbidity and mortality, it may accelerate the development of osteoporosis and increase bone vulnerability to trauma, especially in postmenopausal women and elderly. It reduces the quality of life, affecting both the psycho and somatic components of well-being. These data provide a strong argument for the treatment of SH in older individuals. The absolute risks of these events are very low in younger patients, so the risk–benefit ratio of treating younger SH patients is not clear, and treatment decisions should be individualized, and one should be guided by common sense and not by the principle of simply treating an abnormal test result.[43]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Transient Subcli...
Clinical Features
Quality of Life,...
Physical Functioning
Cardiovascular D...
Atrial Fibrillation
Heart Failure
Osteoporosis and...
Diagnosis
When to Consider...
Treatment Can Be...
Treatment
Conclusion
References
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