Introduction 

Subclinical hyperthyroidism (SH) is characterized by a serum thy roid stimulating hormone (TSH, thyrotropin) concentration that is below the reference range, with circulating thyroid hormone levels (both thyroxine and triiodothyronine) that are within normal limits. In a minority of patients SH represents a state of mild thy roid autonomy or borderline hyperthyroidism. However, it is frequently an asymptomatic state and in many people it is also a transient biochemical finding that does not persist. In addition, a number of medications can cause SH or a low TSH: most obviously levothyroxine, but also glucocorticoids, opiates, and compounds containing iodine. The reference range for TSH in young adults is generally between 0.4 mU/ L and 4.0 mU/ L. With overt hyperthyroidism, the serum TSH concentration becomes undetectable in most assays, at levels of 0.05 mU/ L or less, which is often referred to as ‘fully suppressed’. This allows SH to be divided into two dif erent grades: those patients with a low but detectable serum TSH in the 0.05 to 0.4 mU/ L range (grade 1 SH), and those with a fully suppressed TSH <0.05 mU/ L (grade 2 SH) (Table 1). The former, less severe form is more frequently transient and will resolve over 1 year in around 70% of cases. The latter, grade 2 SH more closely resembles hyperthyroidism with a fully suppressed TSH and is more likely to be persistent, and in the absence of external precipitating factors is still present in 80% or more of patients after one year. It is therefore key to distinguish individuals who have mild or transient SH, as a consequence of medication, intercurrent illness or advanced age who will require no treatment, from those who have intrinsic thyroid disease causing mild thyroid autonomy who may benefit from specific management of their thyroid condition.

Table1. Subclinical hyperthyroidism in comparison to other thyroid states

Epidemiology and Biochemical Prognosis

SH prevalence increases with advancing age and is more frequent in women. Around 1% of a US population up to the age of 80 years who had no known thyroid disease and who were free of interfering medications were found to have a serum TSH below 0.4 mU/ L. The prevalence increased to 3% in participants over 80 years old. As SH is frequently a transient state, information based on a single measurement of TSH may overestimate the prevalence. In a UK study from Tayside in which TSH was measured twice, SH persisting for more than 4 months was found in 0.6% of adults, with a yearly incidence of 30 cases per 100 000 population. The peak prevalence of both grades of SH was in subjects between the ages of 75 and 85 years, and 77% occurred in women. The severity of SH could be divided, with approximately a quarter having grade 2 SH (TSH <0.1 mU/ L) and three- quarters with a serum TSH between 0.1 and 0.4 mU/ L. Despite the careful ascertainment of these cases with a persistent abnormality of serum TSH, there was still a significant spontaneous remission rate, with 40% of subjects with grade 1 SH and 30% of grade 2 SH subjects reverting to euthyroidism over 7 years of follow- up. Conversely, over the first year of follow- up progression to overt hyperthyroidism was found in 5% and 10% of patients with grades 1 and 2 SH, respectively. The rate of progression to overt hyperthyroidism is also dependent on aetiology, with 34% of SH patients who had positive TRAb antibodies diagnostic of Graves’ disease developing overt hyperthyroidism over a 3- year follow- up period. Thus, SH has a significant spontaneous remission rate, even after repeated ‘confirmatory’ measurements. The rate of progression to overt hyperthyroidism is low and dependent both on the grade of SH and any underlying intrinsic thyroid condition.

Thyroid Function: Physiology and Ageing

Even in healthy people, thyroid function as assessed with serum free thyroid hormones and TSH is not static over time. For instance, there is a circadian rhythm of TSH secretion, which is greater during the hours of darkness, with around a 25% variation in an individual’s serum TSH from the nocturnal peak to the midday trough. Furthermore, there is a seasonal variation of TSH among the population, with higher levels in winter months (7). With rising serum chorionic gonadotropin (hCG) levels in early pregnancy, there is also a physiological stimulation of the thyroid through the direct action of hCG on the TSH receptor. This leads to a low or even fully suppressed TSH during the first trimester of many pregnancies. T he degree of TSH suppression is proportional to hCG concentration leading to lower serum TSH levels in twin pregnancies. In addition, there are complex changes in serum TSH with advancing age, such that the reference interval expands both at the upper and lower limits. An Italian study of healthy community- dwelling elderly individuals showed that around one- fifth of Centenarians had a serum TSH below what would be considered the lower limit of the reference range for younger individuals. Thus, many apparently healthy older individuals might be considered to have subclinical thyroid disease, both SH and subclinical hypothyroidism based on TSH reference ranges derived from younger people.

There are several different changes in the thyroid axis with age. A conventional analysis is that TSH secretion by the pituitary gland is reduced with advancing age. A lower amplitude of nocturnal TSH pulses has been observed in healthy elderly volunteers, which may be as a result of decreased hypothalamic thyrotropin- releasing hormone (TRH) secretion. Indeed, a blunted TSH response to TRH stimulation has been demonstrated in elderly subjects, suggesting increased pituitary sensitivity to circulating thyroid hormone levels. However, in common with hepatic drug clearance, thyroid hormone clearance is also known to decrease with increasing age. In parallel, thyroxine secretion may also be reduced, resulting in unchanged total and fT4 concentrations. In contrast to this, total and fT3 levels decrease in older people, which is proposed to be due to reduced peripheral conversion of T4 to T3. Thus, either a central change in sensitivity to thyroid hormone feedback, reduced pituitary sensitivity to TRH or reduced peripheral hormone clearance leading to reduced axis tone and less throughput of thyroid hormone (i.e. less production, less clearance), or a combination of these mechanisms, contribute to the changes observed in the hypothalamic– pituitary– thyroid (HPT) axis with ageing.

Serum thyroid hormones, including TSH also change during acute or significant illnesses. In particular, any serious condition or one with an inflammatory or infective component can lead to the changes known as ‘non- thyroidal illness’ or sick- euthyroid syn drome (Table 1). A low serum fT3, or a reduction in fT3 that remains within the lower limit of the reference range, is the typical first change. However, with chronicity there is frequently a transient reduction in serum TSH, leading to the pattern of SH. This ‘non- thyroidal illness’ pattern of blood tests is the likely explanation for the significant spontaneous recovery rate seen in epidemiological studies of SH. Lastly, in patients who are hypopituitary, central hypothyroidism may be accompanied by a low serum TSH, which may precede any drop in serum free thyroxine concentration and mimic a state of SH. Thus, an understanding of these normal physiological and pathophysiological changes is needed to interpret low serum TSH levels, particularly in older people where intercurrent illness is common and low TSH is less likely to signify intrinsic thyroid disease.

Medications

Several drugs may cause a low serum TSH through different mechanisms (Table2). Minor levothyroxine or liothyronine (T3) overtreatment may cause a reduction or complete suppression of serum TSH without elevating serum fT4 or fT3. Several other drugs directly suppress TSH secretion at the hypothalamo- pituitary level including opiates, glucocorticoids, levodopa, and the retinoic acid derivative, etretinate. Whether these drugs actually cause a state of mild central hypothyroidism is unclear, but on occasions a low fT4 may be found during high- dose opiate treatment in conjunction with hypogonadotropic hypogonadism and/ or secondary adrenal insufficiency, suggesting that this might be the case. Metformin may also reduce serum TSH in some patient groups such as those with an underlying thyroid condition, type 2 diabetes, or polycystic ovarian syndrome. This effect is likely to be owing to adenosine monophosphate (AMP) kinase activation leading to a central inhibition of TSH secretion, but has not been robustly demonstrated in otherwise healthy people. Drugs containing iodine, including amiodarone and radiographic contrast media (iopaque) may also cause a transient reduction in serum TSH, or even frank thyrotoxicosis by augmenting the production of thyroid hormone in patients with pre- existing mild thyroid autonomy. This typically resolves spontaneously within 12 weeks of a dose of contrast media, but amiodarone has a much larger volume of distribution and its effects may linger for more than a year.

Table2. Factors that can cause low serum TSH

Aetiology

Once medication use and intercurrent illness are excluded, low TSH and SH can be the manifestation of mild hyperthyroidism. This is most typically due to a single or multiple autonomous follicular thy roid adenomas, which when thyrotoxicosis is more severe would be known as solitary toxic nodule or toxic multinodular goitre. However, in many individuals the degree of autonomy is mild and may commonly be fluctuant, with sometimes a serum TSH at the lower end of reference range, sometimes reduced but detectable (grade 1 SH) and sometimes a fully suppressed TSH (grade 2 SH). These fluctuations may depend upon changes in dietary iodine intake, and a transient period of grade 2 SH may also be seen in such a patient following iodinated radiographic contrast media, which later recovers. It is clear though that there is not inevitable progression to overt hyperthyroidism even in cases of persistent grade 2 SH. Therefore, it is incorrect to conceptualize SH as an ‘early’ manifestation of nodular thyrotoxicosis; even though there will be progression in a 2– 5% of cases each year, spontaneous remission is generally more probable than progression to overt disease. As well as autonomous thyroid nodules, SH is less commonly associated with Graves’ disease, demonstrable by its coexistence with detectable TSH receptor antibodies (TRAbs). Indeed, SH may be discovered when an apparently euthyroid patient is investigated for Graves’ orbitopathy. In these circumstances there is a higher risk of progression to overt hyperthyroidism, but a decline into overt hypothyroidism is also possible in the presence of high TRAb titres. As well as these potential thyroid diseases, as mentioned just now, other factors related to the fitness, chronological age and the ageing status of the patient need to be considered before making a judgement about the aetiology of SH. If the patient is frail, with multiple comorbidities or prematurely aged, it is more likely that SH is due to their ‘stage of life’ rather than any intrinsic thyroid disease.

Investigations

The most helpful investigation for SH is the passage of time, as many cases will resolve and some will worsen, unveiling an under lying intrinsic thyroid condition. Unless there are unusual circum stances following an initial low TSH measurement, it is satisfactory to repeat thyroid function testing including fT3 in 3 and 6 months’ time. If grade 2 hyperthyroidism persists, or there are other clues to the presence of intrinsic thyroid disease, then it is worth measuring TRAb antibodies and obtaining a ⁹⁹- Tc nuclide thyroid uptake scan to identify any potential ‘hot’ autonomous nodules. Pregnancy should be excluded where appropriate and interfering medications and coexisting non- thyroidal illnesses should be considered. With regards complications of SH, physical examination will reveal the presence of atrial fibrillation, but an electrocardiograph (ECG) or 24- hour Holter monitor record should be obtained if there is doubt or a suggestive history of paroxysmal palpitations. Similarly, measurement of bone mineral content by dual X- ray absorptiometry (DXA) may be helpful, although densitometry- defined osteoporosis is highly prevalent in older individuals rendering this test rather non- discriminatory.

Prognosis and Complications

 Several large epidemiological studies have shown that community- dwelling older people who have SH have a higher incidence of atrial fibrillation than euthyroid people during 10 or more years of follow- up. Furthermore, some but not all epidemiological studies have shown an increased mortality in SH people compared to euthyroid individuals (Figure 1). Indeed, meta- analysis confirms an increased risk of atrial fibrillation, heart failure, cardiovascular mortality, and all- cause mortality in populations with a TSH <0.1 mU/ L. Pertinently, there are numerous minor abnormalities of cardiac function that can be detected in younger patients with either SH due to endogenous thyroid autonomy or levothyroxine overtreatment. Similarly, bone mineral density, fractures, dementia, and cognitive impairment have all also been associated with low TSH in large epidemiological studies. A plausible case can therefore be made that there are clear adverse associations of SH at a population level and thus it should be aggressively treated. However, there are numerous caveats to this approach, not least that there is no good quality- controlled trial showing clinical benefit from treatment of SH. Therefore, we are a long way from being able to causally implicate SH in the adverse patient outcomes that it is epidemiologically associated with.

Fig1. Kaplan– Meier survival curves showing the relation between survival from circulatory disease and serum thyrotropin (TSH) concentration. The lowest serum TSH group (<0.5 mU/ L) has an excess mortality, but many people in this groups will have TSH at the lower end of the normal reference range; few will have grade 2 subclinical hyperthyroidism.

 Reproduced from Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all- cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10- year cohort study. Lancet, 2001; 358: 861– 5. Copyright © 2001 Elsevier.

One fundamental problem in extrapolating the results of epidemiological studies to an individual is that we know SH is commonly a transient state, so that after the 10 years of follow- up in an observational study, only a minority of people who initially had SH are likely to still have a low TSH. Furthermore, the majority of people who were categorized as SH in these studies had a low but not suppressed TSH (grade 1 SH), which is more compatible with a ‘non- thyroidal illness’ pattern of thyroid function than with true thyroid autonomy. Indeed, while cardiovascular disease and osteoporosis could be aetiologically linked to thyroid autonomy, the pathophysiological mechanism for dementia and Alzheimer’s disease is less clear. It therefore seems likely that in many patients low serum TSH is a marker for advanced biological age. When we compare these low TSH people to their euthyroid peers, there is an excess burden of many diseases associated with ageing, which include all the afore mentioned conditions, and which might wrongly be regarded as the direct complications of SH. Nevertheless, some patients with grade 2 SH will have genuine thyroid autonomy and identifying these individuals in order to treat their underlying thyroid condition and prevent complications is the key to appropriate management.

Management

 Most patients with grade 1 SH do not have thyroid autonomy and do not require specific treatment. Intermittent follow- up with once- or twice- yearly monitoring of serum TSH, fT4 and fT3 is sufficient to determine if there is remission of the biochemical abnormalities or if there is progression. A key indicator of likely thyroid autonomy in patients with grade 2 SH is the serum fT3 value. There is an age- related decline in the serum fT3 reference range, such that an fT3 value around 6.0 pmol/ L is at the upper limit of normal for an 85- year- old, as compared to 6.5 or 7.0 in younger people. In contrast, with frailty and comorbidity fT3 tends to be subnormal or at the lower limits of the reference range (≤4.0 pmol/ L). Thus, in the presence of persistent grade 2 SH and an fT3 ≥5.5pmol/ L, then thyroid autonomy is a serious consideration. The decision about whether to treat a patient will depend on the patient’s age, the presence of potential complications (atrial fibrillation in particular) and the degree of certainty about the diagnosis of their thyroid condition (Figure 2). If a decision is to treat, the choice is between antithyroid drug therapy (e.g. carbimazole or methimazole) and 131- I radioiodine therapy. In addition, β- blockers should be prescribed for people with atrial fibrillation or other tachyarrhythmias. If investigations suggest nodular thyroid disease, then radioiodine should be considered as a curative treatment. The downside to radioiodine is that it may precipitate a period of overt hyperthyroidism (in 5– 10%), or occasionally thyroid eye disease; both of which may be more troublesome to the patient than their original problem. In addition, 50% of people who receive radioiodine will ultimately become hypothyroid and dependent on daily levothyroxine. These are significant drawbacks and long- term low dose antithyroid drugs may be a superior choice, particularly for older patients. Furthermore, in the presence of TRAb antibodies, indicating Graves’ disease, then antithyroid drugs are the treatment of choice, as there is an excellent chance of long- term remission follow a 12- month course. Decision- making concerning the optimal choice of therapy is hindered by lack of randomized studies. However, two uncontrolled studies have shown improvement in cardiovascular abnormalities and two small studies have also shown improvement in bone mineral content, both following radioiodine and antithyroid drugs.

Fig2. Algorithm for management of subclinical hyperthyroidism.

 *First- line treatment should be antithyroid drugs in most cases.

Summary Points

 • SH is characterized by a low serum TSH with normal circulating fT4 and fT3.

• The commonest causes of SH are medication use and non- thyroidal illness.

• Large population studies of elderly people show that SH is associated with several adverse outcomes including atrial fibrillation (AF), heart failure, osteoporosis, and death.

 • There is no randomized controlled trial (RCT) evidence that demonstrates treatment of low TSH will improve outcome.

• Treatment should be considered in patients with a fully suppressed serum TSH ( <0.05 mU/ L), with evidence of thyroid autonomy (fT3 >5.5  pmol/ L) and complications that may be attributed to SH.

اخر الاخبار

اخبار العتبة العباسية المقدسة

متحف الكفيل يستعرض أحد مقتنياته العسكرية المزخرفة بالذهب

الزائرون يؤدون مراسم قراءة دعاء الندبة في صحن مرقد أبي الفضل العباس (عليه السلام)

جمعية العميد تبحث تعزيز التعاون العلمي مع كلّية العلوم الإسلامية في جامعة كربلاء

ضمن مشروعه الثقافي المستمر.. قسم الشؤون الفكرية يرفد مكتبات ذي قار بإصداراته

المزيد

الآخبار الصحية

عدد مرات التبرز يكشف أسرارا عن صحة الأمعاء

علامات جينية طويلة الأمد تتركها الرضاعة الطبيعية في دم الطفل

هل يمكن إعادة برمجة الجهاز المناعي لإنتاج أجسام مضادة نادرة؟

دراسة: أدوية الزهايمر "لا تحدث فرقا يذكر لدى المرضى"

المزيد

الآخبار التكنلوجية

روسيا تطور تقنية جديدة لتعديل خصائص البلاديوم

الصين: طاقم مهمة شينتشو-21 سيبقى في الفضاء شهرا آخر

"أبل" تهدد بحذف تطبيق "غروك" من متجرها وتكشف السبب

"أبل" تهدد بحذف تطبيق "غروك" من متجرها وتكشف السبب

المزيد

مواضيع ذات صلة

Absent Intrinsic Factor Secretion and Pernicious Anemia

Thyrotoxic Periodic Paralysis: Clinical Features

Nutritional Causes of Folate Deficiency

Neurologic Dysfunction with Cobalamin Deficiency

Sclerosing Thyroiditis (Riedel’s Thyroiditis) : Clinical Features

Infectious Thyroiditis

Leukopenia

Morphologic Expression of Megaloblastosis

Presentations Associated with Sideroblastic Anemia or Porphyrinuria

Sideroblastic Anemia and Porphyrinuria Caused by Drugs

Addison’s Disease

Cushing’s Disease