The definition of subclinical hypothyroidism (sHypo) is biochemical in nature, namely elevated serum thyroid-stimulating hormone (TSH) levels combined with normal levels of serum free thyroid hormones (i.e., within the population reference range) [1]. Unlike overt hypothyroidism, patients with sHypo may present without any clinical features of hypothyroidism and are often identified through routine health examinations. It is a challenge to determine the clinical meaning of this “subclinical” state [2].

Clinically, there are several important aspects of sHypo to consider, including the diagnosis. The normal range for TSH is determined based on the 95% confidence interval of the healthy population (i.e., the reference population). Patient demographics or characteristics (e.g., age, sex, race, iodine intake, and pregnancy) can affect the upper limit of normal (ULN) for TSH [3]. Additionally, there are individual variations of the hypothalamus-thyroid axis set-point [4] that lead to patient-specific thresholds for sHypo status. Another key sHypo-related clinical aspect is the wide range of effects of thyroid hormone on various organs—in particular, the role of thyroid hormone in cardiovascular and cognitive function makes the potential health effects of sHypo worrisome. For an endocrinologist, sHypo-related health issues may focus solely on the thyroid itself, leading to several important questions: (1) is the occurrence a transient or persistent phenomenon, (2) what are the cause(s), (3) what is the risk of progression to overt disease, and (4) what should be done to address the health of the patient’s thyroid? While the most important issue may be the decision of whether to initiate levothyroxine treatment (LT4-Tx), the existing evidence is not clear-cut, making clinical decisions such as when to treat and the best course of follow-up challenging and a matter of debate.

In this review, recent clinical and epidemiological data for sHypo are introduced to discuss: (1) the diagnosis and prevalence of sHypo, (2) its natural course and etiology, (3) its health impact, and (4) treatment recommendations.

sHypo is a common disease with a reported overall prevalence of 3.1% in Korea (males 2.26%, females 4.04%; Korean National Health and Nutrition Examination Survey [KNHANES VI]), 4.3% in the USA (National Health and Nutrition Examination Survey [NHANES] III) [5,6], and as high as 20% depending on the study population [7]. In fact, the prevalence might be even higher than estimated as a considerable proportion of the population may have undiagnosed sHypo [8]. The reported prevalence of sHypo in different countries is presented in Table 1 [5,6,8-14]. Several factors may influence differences in prevalence. First, the normal range of serum TSH could vary across different countries or ethnic groups [15]. The mean level and ULN of serum TSH are 2.16 and 7.03 mIU/L, respectively, in Koreans (KNHANES), whereas the corresponding levels are 1.40 and 4.12 mIU/L, respectively, in the USA (NHANES III) [6,16]. The markedly higher levels of TSH in Koreans may be explained by the excess iodine intake or genetic differences in the TSH set-point [16] and this discrepancy provides a clear example of why a single international cut-off for TSH cannot be recommended for the diagnosis of sHypo. Age is another important factor to consider; serum TSH levels increase with age, meaning that a mild increase may be normal for older individuals [17]. Therefore, using a single ULN for TSH for all age groups may lead to the misclassification of elderly individuals as having sHypo, which in turn could impact prevalence estimates. Importantly, age-related differences vary by country; the TSH median and 97.5th percentile increased progressively with age in the United States population [18], but in Koreans, the TSH and age graph was U-shaped (higher in younger and older subjects) [19,20]. Certain other factors (e.g., pregnancy, obesity, and dwelling conditions) can also impact the TSH reference range. TSH levels are usually lower during pregnancy, especially in the first trimester, and gradually rise in the second and third trimesters [21]. The extent of this reduction varies significantly based on race and country. Compared to Western countries, Asian countries, including China and Korea, show a modest reduction in the ULN of TSH during the first trimester [22,23]. Thus, most guidelines recommend developing population-based, age-specific, and trimester-specific reference ranges for serum TSH based on local data [21].

When age and race-specific reference ranges for TSH are not available, the ULN for TSH can be considered 4.0 to 6.0 mIU/L. sHypo is often classified as grade 1 (TSH level between the ULN and 9.9 mIU/L) and grade 2 (TSH levels 10 mIU/L or higher) [24]. Grade 1 can also be subdivided into those with TSH levels below 7 and between 7.0 and 9.9 mIU/L in younger patients (<65 years) for classifying the benefit of LT4-Tx [25]. Most patients with sHypo (90%) have serum TSH levels below 10 mIU/L (i.e., grade 1).

Another factor to consider in the differential diagnosis for sHypo is the presence of inter-individual differences in the TSH set-point [26]. Everyone has a unique set-point of the hypothalamic-pituitary-thyroid axis, which is genetically determined [4]. This concept is useful for explaining the different signs and symptoms of patients who have the same level of TSH. Theoretically, it is possible that a particular TSH level may be abnormal for one individual’s set-point, but still be within the normal reference limit. Therefore, it would be important to interpret sHypo-relevant laboratory data considering not only the fixed TSH level, but also serial changes in TSH levels concurrently with a careful clinical assessment.

Although the rate of progression to overt hypothyroidism may vary depending on several factors [27], it is not high in those with grade 1 sHypo (2% to 4% per year) [3]. For women with positive thyroid peroxidase antibodies (TPOAbs) and a baseline TSH between 2.5 and 4 mIU/L, the risk of progression to overt hypothyroidism is roughly 1% per year [28]. In children and adolescents, chronic autoimmune thyroiditis (CAT) usually remains static for years and recovery is more common [29]. Without considering causative factors, the overall recovery rate for grade 1 sHypo is 30% over 3 years and 60% over 5 years [3,30]. These data reveal that there are many patients with transient sHypo. In response to various external and internal stimuli, serum TSH levels could change transiently without thyroid diseases. Iodine or food with high iodine levels, medications, or testing reagents are classic examples of external stimuli [16,31]. Serum TSH concentrations could fluctuate as a result of diurnal or seasonal variations [32,33], and transiently increase during the course of non-thyroidal illness or with several drugs. In patients who are taking LT4, an inadequate dosage or consumption of substances that prevent absorption or increase the clearance of LT4 could also lead to sHypo. In these transient cases, only a re-evaluation of thyroid function without LT4-Tx could be recommended [34]. Thus, the first step of sHypo management is to confirm the persistence of TSH elevation and exclude transient cases. The causative factors of sHypo are summarized in Table 2.

Persistent sHypo mainly implies CAT, and the tendency for progression to overt hypothyroidism might be related to the degree of immunological deterioration and thyroid reserve. The most important risk factors have been shown to be serum TSH levels and TPOAb positivity [35]. Higher TSH levels are associated with a higher rate of TPOAb positivity, especially in women [6,28]. In patients with existing thyroid disease [36] or without a history of thyroid disease, prospective studies demonstrated that the most important predictor of progression was the serum TSH concentration [37]. In addition, iodine intake [38], cigarette smoking [39], racial differences [6], and cold environmental temperatures [33] have been identified as risk factors. Thyroid sonographic findings, such as markedly decreased echogenicity and multifocal pseudonodular hypoechoic infiltration, could also be used as indicators of inflammatory activity in CAT [40]. There is no evidence that early LT4-Tx would help prevent the development of overt hypothyroidism. Thus, in terms of progression to overt hypothyroidism, the “wait and see” strategy would be acceptable in most individuals with sHypo (grade 1), especially in TPOAb-negative patients.

Several clinical guidelines have provided a path for clinical decision-making for sHypo (Table 3) [24,100-104]. These guidelines primarily integrate patient age and serum TSH levels. Other parameters such as the presence of TPOAb, symptoms, cardiac risk factors, and goiter also be included for reference. Even with these guidelines, however, clinicians are often confronted with difficult challenges in the management of sHypo. Since the guidelines do not apply age-adjusted reference ranges of TSH, the suboptimal use of a single TSH cut-point value may still be applied to patients. Although the adverse health impacts of sHypo have been reported, data confirming the benefits of LT4-Tx remain unclear [101]. When using LT4-Tx, the appropriate duration of treatment has not yet been empirically defined. When managing patients without LT4-Tx, the ideal duration and schedule of follow-up have likewise not been clearly defined. The cost-benefit effect or possible risks of LT4-Tx in sHypo are also unclear. The remaining uncertainties have caused persistent concerns and dissatisfaction among patients, regardless of whether they are treated.

Based on the paucity of high-quality evidence, a clear-cut path for all sHypo patients cannot be provided at this moment. However, in clinical situations, it is essential to stratify patients depending on their need for LT4-Tx and the appropriate approach to monitoring, including the cadence of visits. In this review, a recommendation is suggested based on the intensity of the intervention: conservative, aggressive, or intermediate (Table 4). These recommendations have been devised to guide management decisions. In the conservative approach, LT4-Tx could be postponed for a while, even up to a transition into the overt hypothyroid state, and the follow-up schedule could be less frequent. In contrast, in the aggressive approach, LT4-Tx should be applied not too late, and a tight follow-up schedule should be considered. The intermediate approach falls in between the other two approaches, but is closer to the conservative approach due to a lack of definitive evidence; the LT4-Tx and follow-up schedule could be decided based on discussions with patients. Exceptional cases and educational factors are also included.

A representative example of the conservative approach is furnished by elderly patients; there is no need to rush to treatment in elderly patients with sHypo. As reviewed above, the serum TSH level could rise with increasing age as a result of physiological adaptation [17]. The upper limit of the 95% confidence interval is around 6.0 mIU/L in >80-year-old untreated individuals and could reach up to 8.0 mIU/L in those over 90 [18]. Elderly patients are also more vulnerable to LT4 overtreatment with increased risks of atrial fibrillation, ischemic heart disease, and fractures [3,105,106]. The recent TRUST trial has provided relatively clear evidence suggesting an absence of benefits of LT4-Tx in older individuals with sHypo [46]. Thus, ‘wait-and-see’ is a wise strategy, especially in frail patients. LT4-Tx could be considered in those with grade 2 sHypo (TSH >10 mIU/L) and relatively young patients (65 to 70 years), but patients’ life expectancy and the presence of comorbid conditions should also be considered [101]. When treatment is initiated, a “start low, go slow” policy is recommended [101], starting with a low dose of LT4 (12.5 to 25 μg/day and slowly increased by 12.5 to 25 μg/day every 4 to 8 weeks).

Pregnant women provide a representative example of the aggressive approach. Based on population-based, trimester-specific reference ranges for serum TSH [21], if possible, LT4-Tx should be considered in pregnant sHypo patients, regardless of etiologic factors. LT4-Tx is strongly recommended in women who are: (1) TPOAb-positive with TSH levels greater than the pregnancy-specific reference range, or (2) TPOAb-negative with TSH levels greater than 10.0 mIU/L. In these instances, a higher-than-usual initial LT4 dose could also be considered. Even when not pregnant, in women with sHypo who are hoping to conceive soon, LT4 could be started before conception, especially in TPOAb-positive subjects. Women of child-bearing age who have sHypo and TPOAb should also receive active LT4-Tx treatment, close follow-up, and education about the possible risks of sHypo for maternity.

The intermediate approach would cover all other cases. In this group, the clinical decision-making would be made based on the severity and persistence of sHypo, and patients’ preferences. In relation to persistence, CAT (Hashimoto thyroiditis) is the main cause to focus on. A detailed diagnostic approach is important to discriminate CAT from transient or reversible conditions that are correctable by managing etiologic factors. The rationale for LT4-Tx could be set based on the possible benefit for CAT status itself, organ-specific considerations, and the potential of adverse risks. Although conclusive, large-scale, prospective evidence is lacking, young, and middle-aged people with grade 2 sHypo, TPOAb positivity, and/or marked progression in follow-up thyroid function tests or the presence of cardiac risk factors [25] could usually be good candidates for LT4-Tx. LT4-Tx might also be considered in patients with severe symptoms as a trial, though prescribing LT4 based only on patient symptoms seems to lack a clear rationale [69]. For individuals with CAT who are living in an iodine-rich area, education about iodine restriction (diet, medication, or health-related products containing high iodine levels) is essential. When the decision is made to treat sHypo, daily LT4-Tx is the treatment of choice. There is no evidence supporting the use of liothyronine (T3) or combined LT4/T3 for the treatment of sHypo. The initial dosage of LT4 should be individualized, approximating 1.5 μg/kg/day (except in elderly patients) and should be increased gradually by 25 μg/day every 14 to 21 days until a full replacement dose is reached. The goal of treatment is to normalize serum TSH levels. LT4 prescriptions have increased remarkably during the last decade and LT4 is most likely to be prescribed for the treatment of sHypo [107]. While over-treatment should be avoided, holding back LT4 initiation in patients who require it because of concerns of over-treatment is not advised [101].

sHypo is associated with adverse outcomes in terms of cardiovascular risk, metabolic conditions, and quality of life; however, the exact benefits of LT4-Tx in those with sHypo are unclear, especially in patients with grade 1 sHypo or elderly individuals. Given the paucity of evidence supporting the benefits of LT4-Tx, it is reasonable to refrain from immediate LT4-Tx while closely monitoring most patients with sHypo, except in pregnant women or in progressive cases. However, there are indeed certain groups of patients for whom the benefits of LT4-Tx have been established; identifying these groups is an urgent task for future research [108]. Additionally, well-designed studies focused on younger patients with sHypo are needed because direct evidence is scant and therefore greater uncertainty remains [108]. For the management of sHypo, practical considerations include not only the serum TSH level and age, but also the burdens that come from overtreatment, regular visits, blood testing, medical costs, and emotional well-being [104]. Comprehensive assessments of all these issues would be essential to identify the true nature of sHypo and to establish an ideal management path.