Current status of the thyroid hormone measurement items in patients receiving levothyroxine monotherapy by the management based on the thyroid tissue volume

Abstract

We and other investigators reported that mild TSH suppression with levothyroxine (LT₄) was needed to achieve normal free triiodothyronine (FT₃) levels and metabolic euthyroid state in athyreotic patients. Consequently, management methods based on thyroid tissue volume have been implemented for patients receiving LT₄ at the Kuma Hospital. This retrospective study examined the composition of the thyroid hormone measurement items (serum-free thyroxine [FT₄], FT₃, and FT₄ + FT₃) in patients receiving LT₄ monotherapy. According to the etiology of hypothyroidism, 36% of the 25,523 patients included in this study underwent total thyroidectomy (TT). Thirteen percent and 14% had undergone ¹³¹I treatment for hyperthyroidism (RIT) and partial thyroidectomy (PT), respectively. Moreover, 37% of patients had received non-invasive treatment (NIT). The proportion of patients who underwent only FT₃ measurements was higher (TT, 93%; RIT, 61%) in the first two groups, whereas the proportion of patients who underwent only FT₄ measurements was higher (PT, 50%; NIT, 65%) in the remaining two groups. Only FT₃ measurements were performed in 58% of patients. Only FT₄ measurements were performed in 34% of patients. The serum TSH levels were suppressed in nearly half of the patients (46%). Thus, FT₃ was the major thyroid hormone measured in patients receiving LT₄ treatment, and the serum TSH levels were suppressed in nearly half of the patients. This may be attributed to the management guidelines at our hospital, a specialized facility for thyroid disease, wherein half of the patients present are athyreotic or have atrophic thyroid glands after TT or RIT.

1. Introduction

The thyroid gland secretes two hormones: thyroxine (T₄) and triiodothyronine (T₃; a biologically active hormone). The thyroid gland secretes 100% of T₄ and approximately 20% of T₃ in normal individuals. Thus, approximately 80% of T₃ is derived from the conversion of T₄ to T₃ in the extrathyroidal peripheral tissues [1]. Athyreotic patients may present with a relative T₃ deficiency while receiving levothyroxine (LT₄) monotherapy. Previous studies [2-5] have reported that patients with asthma who had normal serum thyroid-stimulating hormone (TSH) levels exhibited slightly lower serum-free triiodothyronine (FT₃) levels among athyreotic patients with asthma who underwent total thyroidectomy and received LT₄. The patients with mild and strong suppression of the serum TSH levels had normal and increased serum FT₃ levels, respectively. The serum-free thyroxine (FT₄) levels were significantly increased in all groups; however, the magnitude of the increase varied according to the TSH level. Relatively low serum FT₃ levels have been observed in patients with an atrophic thyroid who received LT₄ treatment after radioiodine treatment for Graves’ disease [6].

Werneck et al. reported that a combination of high serum T4 and low serum T₃ levels during T₄ monotherapy affected the action of thyroid hormones in rats, as reflected in the brain, liver, and skeletal muscle, which exhibited signs of hypothyroidism despite the serum TSH levels being normal [7]. Previous studies on humans have shown that the metabolic marker levels [8] and symptoms [9] related to thyroid function exhibited no significant increase following the mild suppression of TSH. However, lower serum T₃ levels that differed in terms of both objective and subjective measures were observed in participants with normal serum TSH levels who received LT₄ monotherapy [10]. Thus, the presence of biochemical markers of thyroid function observed in previous animal and human studies suggests that mild suppression of TSH must be induced to achieve normal FT₃ levels and a metabolic euthyroid state in patients who develop hypothyroidism after total thyroidectomy or an atrophic thyroid condition after radioiodine treatment. Such patients are less likely to experience symptoms of hyperthyroidism. The serum FT₃ levels in patients with sufficient thyroid tissue, such as those who have undergone hemithyroidectomy [11] and those with Hashimoto’s disease [5, 12], are equal to those of the patients in the preoperative or control groups with normal TSH levels.

LT₄ monotherapy is considered to be the standard of care for hypothyroidism [13]. LT₄ replacement is commenced to achieve the target TSH levels (which are low following TSH suppression therapy or normal following replacement therapy), normalize the thyroid hormone levels, and resolve symptoms and hypothyroid signs (including biological and physiological markers of hypothyroidism) [13]. The simultaneous measurement of TSH, FT₄, and FT₃ is not covered by insurance in several regions of Japan; consequently, only two items, TSH and FT₄, are generally measured. Thus, the following management strategies have been implemented at our hospital since 2021 for patients receiving LT₄ monotherapy: (1) The serum TSH and FT₃ levels of athyreotic patients, patients with an atrophic thyroid gland, and those requiring TSH suppressive therapy (e.g., patients with thyroid carcinoma) are measured. The treatment goal is to maintain the TSH levels (mild to complete; target values in each patient) and FT₃ levels within the reference range. (2) The serum TSH and FT₄ levels of patients with sufficient amounts of thyroid tissue (e.g., autoimmune thyroiditis) receiving replacement doses of LT₄ are measured. The treatment goal is to maintain the TSH and FT₄ levels within the reference range.

This study investigated the current protocol for managing patients receiving LT₄ therapy at our hospital by examining the composition of the thyroid hormone measurement items (measurement of FT₄ only, FT₃ only, and FT₄ + FT₃) according to the etiology of hypothyroidism, thyroid volume (in patients who underwent ultrasonography), and TSH levels.

2. Materials and Methods

2.1. Patients

The medical records of 25,523 consecutive patients with primary hypothyroidism who had received replacement therapy/TSH suppressive therapy with LT₄ only and undergone thyroid function tests between January 2022 and June 2022 at the Kuma Hospital were analyzed retrospectively. All patients had undergone thyroid function tests in stable condition at least 6 months after commencing LT₄ treatment. The data from the last visit were evaluated if the patients had undergone repeated thyroid function tests during the study period. Written informed consent was obtained from each patient for the collection and use of blood test data and medical records for research purposes. Each patient was informed of their right to participate and that their refusal would not result in disadvantages. Personal information, such as data and samples, was kept confidential by the deletion of identifiable information (name, address, age, etc.), anonymized, password-protected when taken outside the hospital, and encrypted for transmission or storage on external media. This study was approved by the Ethics Committee of Kuma Hospital (no. 20200709-1) and has been opted-out (https://www.kuma-h.or.jp/).

2.2. Guidelines for management of LT₄ monotherapy at Kuma Hospital

The following management methods have been recommended at the Kuma Hospital for patients receiving LT₄ monotherapy since only two thyroid function test items are approved by insurance.

(1) The serum TSH and FT₃ levels of athyreotic patients (e.g., post-total thyroidectomy), patients with an atrophic thyroid gland (thyroid volume ≤10 mL on ultrasonography; e.g., after radioiodine treatment for Graves’ disease or atrophic thyroiditis), patients requiring TSH suppressive therapy for thyroid carcinoma or large goiter (thyroid volume >80 mL on ultrasonography; e.g., Hashimoto’s disease with a large goiter) are measured. The treatment goal is to maintain the TSH levels (mild to complete; target levels in each patient) and FT₃ levels within the reference range. In older adults and patients with cardiac diseases or osteoporosis, serum TSH levels within the normal range are considered acceptable. (2) The serum TSH and FT₄ levels of patients with sufficient amounts of thyroid tissue (thyroid volume 10–80 mL on ultrasonography; e.g., post-hemithyroidectomy or autoimmune thyroiditis) receiving replacement doses of LT₄ are measured. The treatment goal is to maintain the TSH and FT₄ levels within the reference range. Mildly elevated TSH levels are acceptable in older adults and patients with cardiac disease or osteoporosis.

However, many cases that did not necessarily conform to the guidelines were included because the choice of measurement items was left to each physician’s judgment. There were also cases in which three items (TSH, FT₄, and FT₃) were measured at the physician’s discretion, although this was not recommended because it was not approved by insurance; these data were tabulated for this study.

2.3. Thyroid function tests

The thyroid profile of each patient was determined after stabilizing thyroid function for at least 6 months after treatment. Blood samples were collected in the morning or afternoon after administering LT₄. The serum TSH, FT₄, and FT₃ levels were measured via electrochemiluminescence immunoassay (ECLusys; Roche Diagnostics GmbH, Mannheim, Germany). The reference ranges followed at our hospital are as follows: TSH, 0.5–5.0 μIU/mL; FT₄, 0.9–1.7 ng/dL; and FT₃, 2.3–4.0 pg/mL. The intra-assay coefficients of variation were ≤10%, ≤8%, and ≤10% for the TSH, FT₄, and FT₃ assays, respectively. Thyroid volume was measured via ultrasonography. The maximum width (W), thickness (T), and length (L) of the lobes of the thyroid gland were measured. Thyroid volume was calculated using the following equation: thyroid volume = 0.70 × (WrTrLr + WlTlLl) wherein a constant of 0.70 was obtained for the comparison of the thyroid volume measured using this method and the actual thyroid volume in patients with Graves’ disease (X) [14].

2.4. Data analysis

Data on the thyroid hormone measurement items were summarized and represented using a pie chart as appropriate. Statistical tests of the proportions of thyroid hormone measurement items in each patient group were performed using the Kruskal–Wallis test. The statistical significance of the clinical characteristics by patient group controlled by thyroid hormone items for each thyroid volume was analyzed by an unpaired t-test or the Mann–Whitney U test using Bonferroni corrections for multiple comparisons. Significance was defined as a two-sided value of p < 0.05. The statistical analyses were performed using StatFlex software version 6.0 (Artech Co., Ltd., Osaka, Japan).

3. Results

Number of patients according to the factors leading to hypothyroidism

A total of 25,523 consecutive patients, comprising 21,469 women and 4,054 men, were retrospectively analyzed. According to the factors leading to hypothyroidism, 9,298 (36%), 3,235 (13%), and 3,499 (14%) patients were receiving LT₄ after total thyroidectomy (TT), ¹³¹I therapy (RIT) for hyperthyroidism (including those treated with ¹³¹I after surgery), and partial thyroidectomy (PT), respectively. The remaining 9,491 (37%) patients were receiving LT₄ for reasons other than postoperative or ¹³¹I therapy (non-invasive treatment; NIT), such as hypothyroidism due to Hashimoto’s disease (Fig. 1).

Fig. 1  Number of patients who underwent measurement of serum-free T₃ (FT₃), serum-free T₄ (FT₄), and FT₃ + FT₄ according to the factors that led to hypothyroidism

We retrospectively identified 25,523 consecutive patients. Among these patients, 36% were receiving LT₄ after total thyroidectomy (TT), as shown in yellow; 13% had undergone ¹³¹I therapy (RIT), as shown in brown; 14% were receiving LT₄ after partial thyroidectomy (PT), as indicated in gray; and 37% were receiving LT₄ as a non-invasive treatment (NIT), as shown in blue.

Thyroid hormone measurement items according to the factors leading to hypothyroidism

The thyroid function test items, in addition to TSH, were examined for each of these factors. Among the patients who underwent TT, 8,649 (93%), 434 (5%), and 215 (2%) underwent the measurement of only FT₃ (accounting for the majority), FT₄ + FT₃, and only FT₄, respectively (Fig. 2A). Among the patients who received RIT, 1,962 (61%), 804 (25%), and 469 (14%) underwent the measurement of only FT₃ (accounting for the majority), FT₄ + FT₃, and only FT₄, respectively (Fig. 2B). Among the patients who underwent PT, 1,755 (50%) underwent the measurement of only FT₄. The number of patients who underwent the measurement of FT₄ and FT₃ was similar (Fig. 2C). Among the patients with hypothyroidism who underwent NIT, 6,225 (65%), 2,621 (28%), and 645 (7%) patients underwent the measurement of only FT₄ (accounting for the majority), only FT₃, and FT₄ + FT₃, respectively (Fig. 2D). Overall, 14,781 (58%) and 8,664 (34%) patients underwent the measurement of only FT₃ (accounting for the majority) and only FT₄, respectively (Fig. 2E). The proportions of thyroid hormone measurements differed significantly among the patient groups (p < 0.001).

Fig. 2  Proportion of thyroid hormone measurement items according to thyroid volume

Among the patients who underwent total thyroidectomy (TT), only serum-free T₃ (FT₃) was measured in 8,649 patients (93%), accounting for the majority (beige); 5% had both FT₄ and FT₃ levels measured, as shown in violet; and 2% had only serum-free T₄ (FT₄) levels measured, as shown in blue (A). Among the patients who underwent RIT for hyperthyroidism, 61% had only FT₃ levels measured, accounting for the majority; FT₄ + FT₃ were measured in 25% of the patients; 14% had only FT₄ measured (B). Among the patients who underwent PT, only FT₄ was measured in 50% of patients. The number of patients who underwent FT₄ and FT₃ measurements was similar (C). Among the patients who did not receive invasive treatment, 65% had only FT₄ measurements, accounting for the majority; 28% had only FT₃ measurements; and 7% had FT₄ + FT₃ measurements (D). In the total patient population, 14,781 (58%) patients had only FT₃ measurements, accounting for the majority, whereas 8,664 (34%) patients had only FT₄ measurements (E). The Kruskal–Wallis test revealed a statistically significant difference in the proportion of thyroid hormone measurement items among the four patient groups (p < 0.001).

Thyroid hormone measurement items according to thyroid volume

The patients were evaluated subsequently according to thyroid volume. The patients who had undergone TT were considered to have a volume of 0 mL. A total of 21,977 patients (9,298 patients after undergoing TT and 12,679 with thyroid volume measured using thyroid ultrasound) were divided into three groups: athyreotic or atrophic thyroid group (n = 16,042), ≤10 mL; normal to moderately enlarged thyroid volume group (n = 5,202), 10–80 mL; and large goiter group (n = 283), >80 mL. Among the patients in the athyreotic or atrophic thyroid group, 11,968 (75%), 2,707 (17%), and 1,368 (8%) patients underwent the measurement of only FT₃ (accounting for the majority), only FT₄, and FT₄ + FT₃, respectively (Fig. 3A). Among the patients in the normal-to-moderately enlarged thyroid volume group, 3,868 (74%), 819 (16%), and 515 (10%) patients had undergone the measurement of only FT₄ (accounting for the majority), only FT₃, and FT₄ + FT₃, respectively (Fig. 3B). Among the patients in the large goiter group, 154 (54%), 84 (30%), and 45 (16%) patients had undergone the measurement of only FT₄, only FT₃, and FT₄ + FT₃, respectively (Fig. 3C). The proportions of thyroid hormone measurements differed significantly among the patient groups (p < 0.001). Serum TSH, FT₄, and FT₃ levels and total cholesterol levels of patients controlled by FT₃ alone, FT₄ alone, and FT₃ and FT₄ for each thyroid volume are shown in Table 1. In patients controlled by FT₃ alone, serum TSH levels of two patient groups with a thyroid volume ≤10 mL and a thyroid volume >80 mL were lower than normal. Other measured parameters were within the normal range for all patient groups.

Fig. 3  Proportion of thyroid hormone measurement items according to thyroid volume

Patients who underwent total thyroidectomy were considered to have a tumor volume of 0 mL. A total of 21,977 patients were divided into three groups: the athyroid or atrophic thyroid group (n = 16,042) with ≤10 mL, the normal to moderately enlarged thyroid volume group (n = 5,202) with 10–80 mL, and the large goiter group (n = 283) with >80 mL. In the athyroid or atrophic thyroid group (≤10 mL), 75% of patients had only serum-free T₃ (FT₃) measured, accounting for the majority, shown in beige; 17% had only serum-free T₄ (FT₄) measured, shown in blue; and 8% had FT₄ + FT₃ measured, shown in violet (A). In the normal-to-moderately enlarged thyroid volume group (10–80 mL), 74% had only FT₄ measurements, accounting for the majority; 16% had only FT₃ measurements; and 10% had FT₄ + FT₃ measurements (B). In the large goiter group (>80 mL), 54% had only FT₄ measured. Additionally, 30% had only FT₃ measured and 16% had FT₄ + FT₃ measured (C). The Kruskal–Wallis test revealed a statistically significant difference in the proportion of thyroid hormone measurement items among the three patient groups (p < 0.001).

Table 1 Serum TSH, FT₄, and FT₃ and total cholesterol levels of the patients who were controlled by FT₃ alone, FT₄ alone, both FT₃ and FT₄ for each thyroid volume

	No of Patients	TSH (μU/mL)	FT4 (ng/dL)	FT3 (pg/mL)	T-cho (mg/dL)
FT3 alone
TV ≤10	11,967	0.10 (0.58)*a	—	2.93 (0.48)a	209 (35)
TV 10–80	819	1.19 (2.19)*b	—	2.82 (0.43)	211 (37)
TV >80	84	0.45 (1.12)	—	3.09 (0.43)c	209 (30)
FT4 alone
TV ≤10	2,707	1.92 (2.39)	1.37 (0.25)a	—	213 (36)
TV 10–80	3,868	2.03 (2.29)*b	1.33 (0.23)b	—	210 (37)
TV >80	154	1.05 (1.88)*c	1.24 (0.25)c	—	211 (34)
FT3 and FT4
TV ≤10	1,368	0.76 (2.38)	1.54 (0.38)a	2.72 (0.58)a	210 (40)
TV 10–80	515	1.59 (3.02)	1.38 (0.33)b	2.88 (0.70)b	208 (39)
TV >80	45	1.09 (1.54)	1.11 (0.37)c	3.13 (0.81)c	199 (45)

TV, thyroid volume; TSH, thyroid-stimulating hormone; FT₄, free thyroxine; FT₃, free triiodothyronine; T-cho, total cholesterol. TSH values are shown as median (IQR). Other parameters are shown as mean (SD).

Statistical significance was analyzed by unpaired t-test, or *Mann–Whitney U test by using Bonferroni corrections for multiple comparisons.

TV ≤10 vs. TV 10–80, ^ap < 0.05; TV10–80 vs. TV >80, ^bp < 0.05; TV ≤10 vs. TV >80, ^cp < 0.05.

Thyroid hormone measurement items according to the intended target of serum TSH levels

The patients receiving LT₄ (n = 23,921) were evaluated according to the degree of TSH suppression (1,602 patients with high TSH levels were excluded). The serum TSH levels were reduced in nearly half of the patients (n = 11,723) (46%). Among the patients in the complete suppression of TSH group (n = 5,815), 5,353 (92%), 296 (5%), and 166 (3%) patients had undergone the measurement of only FT₃, FT₄ + FT₃, and only FT₄, respectively (Fig. 4A). Among the patients in the TSH mild suppression group (n = 5,908), 4,605 (78%), 821 (14%), and 482 (8%) patients had undergone the measurement of only FT₃ (accounting for the majority), only FT₄, and FT₄ + FT₃, respectively (Fig. 4B). Among the patients in the group with normal TSH (n = 12,198), 6,840 (56%), 4,312 (35%), and 1,046 (9%) patients had undergone the measurement of only FT₄ (accounting for the majority), only FT₃, FT₄ + FT₃, respectively (Fig. 4C). The proportions of thyroid hormone measurements differed significantly among the patient groups (p < 0.001).

Fig. 4  Proportion of thyroid hormone measurement items according to the intended target of serum TSH levels

A total of 23,921 patients receiving LT₄ were evaluated based on the degree of TSH suppression (1,602 patients with high TSH levels were excluded). In the TSH complete suppression group (n = 5,815), the majority of patients (92%) had only serum-free T₃ (FT₃) measured, shown in beige; 5% had FT₄ + FT₃ levels measured, shown in violet, and 3% had only serum-free T₄ (FT₄) levels measured, shown in blue (A). In the mild TSH suppression group (n = 5,908), 78% had only FT₃ measurements, accounting for the majority, 14% had only FT₄ measurements, and 8% had FT₄ + FT₃ measurements (B). In contrast, in the group with normal TSH (n = 12,198), 56% had only FT₄ measured, accounting for the majority; 35% had only FT₃ measured; and 9% had FT₄ + FT₃ measured (C). The Kruskal–Wallis test revealed a statistically significant difference in the proportion of thyroid hormone measurement items among the three patient groups (p < 0.001).

4. Discussion

The majority of patients receiving LT₄ in this study had undergone thyroidectomy or ¹³¹I treatment. Iodine deficiency is the primary cause of hypothyroidism in iodine-deficient geographic areas worldwide, whereas Hashimoto’s disease is the primary cause of hypothyroidism in iodine-sufficient regions [15]. The Kuma Hospital is a specialized hospital for thyroid disease; consequently, a large number of patients undergo follow-up at our hospital after undergoing thyroidectomy and ¹³¹I treatment. This could explain why the majority of patients did not have Hashimoto’s disease but developed hypothyroidism due to thyroidectomy and ¹³¹I treatment in this study.

Athyreotic patients and patients with atrophic thyroid predominantly underwent the measurement of only FT₃. In contrast, patients with sufficient thyroid tissue, such as those who underwent PT or patients with other diseases, predominantly underwent the measurement of only FT₄. The predominance of patients who predominantly underwent the measurement of only FT₃ in the first two groups could be attributed to the management guidelines of our hospital, which recommend the measurement of the TSH and FT₃ levels in these patients, with the TSH levels being suppressed and the FT₃ levels being normal. The predominance of patients who had predominantly undergone the measurement of FT₄ only in the latter two groups could be attributed to the guidelines of our hospital, which recommend the measurement of the TSH and FT₄ levels in these patients and maintaining the FT₄ levels within the normal range. The FT₃ levels were measured in a few patients in the latter group; however, the thyroid gland was judged to be atrophic via ultrasonography or palpation in these patients. The majority of patients in the total patient population underwent the measurement of only FT₃ levels. In addition to the management guidelines, this may be attributed to the majority of patients having undergone thyroidectomy and ¹³¹I treatment, as our hospital is a specialized hospital for thyroid disease.

The majority of athyreotic patients and patients with atrophic thyroid (≤10 mL) underwent the measurement of only FT₃; in contrast, the majority of patients with normal to mild enlargement (10–80 mL) underwent the measurement of only FT₄. The majority of patients with thyroid volume >80 mL underwent the measurement of only FT₄; however, the proportion of those who underwent the measurement of only FT₃ has been increasing. This may be attributed to the majority of patients with atrophic goiter undergoing the measurement of only FT₃ and the majority of patients with normal to mildly enlarged goiters undergoing the measurement of only FT₄ based on the aforementioned guidelines. The higher proportion of patients with huge goiters undergoing the measurement of FT₃ only compared with that of those with normal-to-mildly enlarged goiters may be attributed to the management guidelines recommending the measurement of the FT₃ levels in patients receiving TSH suppressive therapy. These were also supported by the finding that serum TSH levels in the two groups (thyroid volume ≤10 mL, thyroid volume >80 mL) of patients controlled with FT₃ alone were lower than normal.

The serum TSH levels were suppressed in nearly half of the patients; however, this could be attributed to the majority of patients undergoing radical treatment (with nearly half of the patients having athyreotic or atrophic thyroid glands owing to undergoing TT or RIT), including those who have undergone total thyroidectomy and ¹³¹I treatment, in addition to the management guidelines. Complete suppression of the TSH levels is mainly observed among those with a risk of developing thyroid carcinoma after thyroidectomy; however, it has been observed in patients with benign disease owing to the increased dosage of LT₄ and those with completely suppressed TSH levels owing to disturbance in the conversion from T₄ to T₃. Patients with suppressed TSH levels predominantly underwent the measurement of only FT₃. In contrast, patients with normal TSH levels predominantly underwent the measurement of only FT₄. The serum FT₃ levels were measured, rather than the FT₄ levels as per the guidelines, in a few patients with normal TSH levels. In LT₄ treatment, it is acceptable for TSH levels be mildly elevated in the elderly and patients with cardiac disease. The presence of normal serum TSH levels indicates a reasonable state of management in older adults and patients with cardiac disease or osteoporosis receiving LT₄, even in an athyreotic state. In addition, the serum FT₄ levels are often elevated in patients receiving LT₄ monotherapy with normal TSH levels. This reflects a transient increase in the serum FT₄ levels following the oral administration of LT₄ [16-18]. Thus, it is possible that serum FT₃ levels were measured instead serum FT₄ levels for this reason in some cases.

This study has certain limitations. First, this was a retrospective study. Second, the choice of measuring only FT₄, only FT₃, or FT₄ + FT₃ was at the discretion of the physician. Since measuring TSH and FT₄ is the standard method and thyroid volume was not measured in all cases, TSH and FT₄ may have been measured in cases in which TSH and FT₃ should have been measured according to our guidelines due to an atrophic thyroid or giant goiter. If the guidelines were more thorough, the proportion of TSH and FT₃ measurements may have been increased, whereas the proportion of TSH and FT₄ measurements may have been decreased. Third, it was difficult to determine whether the purpose of administering LT₄ was supplementation alone, TSH suppression alone, or both in several cases. Cases with suppressed TSH included those in which serum TSH levels were mildly suppressed to normalize serum FT₃ levels, those in which TSH suppressive therapy for carcinoma or huge goiter was administered, and those in which LT₄ was mistakenly overdosed with the intention of normalizing TSH levels. Lastly, metabolic indices, heart rate, and thyroid-related physical symptoms were not examined as the aim of the current investigation was to determine the status of thyroid hormone levels. Thus, further well-designed studies including these factors must be conducted in the future.

The FT₄ levels are generally measured in patients receiving LT₄ monotherapy for hypothyroidism. This study revealed that FT₃, rather than FT₄, was the major thyroid hormone measured in patients receiving LT₄ monotherapy at our hospital and that the management method was such that the serum TSH levels were suppressed in nearly half of the patients (Graphical Abstract). These findings may be attributed to the management guidelines being based on thyroid tissue volume and our hospital being a specialized hospital for thyroid disease, wherein many patients are treated radically, and nearly half of the patients have athyreotic or atrophic thyroid glands, including those who have undergone total thyroidectomy or ¹³¹I treatment. FT₃ is a biologically active hormone that can accurately reflect the thyroid function under these conditions [7-9]. Moreover, the measurement of only FT₃ may be superior to the measurement of only FT₄ in terms of agreement with reference ranges [19].

Graphical Abstract 

This study elucidated the current status of thyroid function tests for the application of an integrative approach by the measurement of FT₃ as a more reliable reflection of the thyroid hormone status in patients receiving LT₄ monotherapy, considering the peripheral conversion of T₄ to T₃ in these patients.

Declarations

Data Availability

The datasets generated and/or analyzed during the current investigation are available from the corresponding author, Ito M, upon reasonable request.

Disclosure

The authors have no relevant financial or non-financial interests to disclose.

Funding

None of the authors received any funding for this investigation.

Acknowledgments

Mitsuru Ito designed the study and analyzed the data. The other authors contributed by performing surgery and/or caring for the patients.

References

• 1   Pilo  A,  Iervasi  G,  Vitek  F,  Ferdeghini  M,  Cazzuola  F, et al. (1990) Thyroidal and peripheral production of 3,5,3'-triiodothyronine in humans by multicompartmental analysis. Am J Physiol 258: E715–E726.
• 2   Ito  M,  Miyauchi  A,  Morita  S,  Kudo  T,  Nishihara  E, et al. (2012) TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. Eur J Endocrinol 167: 373–378.
• 3   Jonklaas  J,  Davidson  B,  Bhagat  S,  Soldin  SJ (2008) Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA 299: 769–777.
• 4   Gullo  D,  Latina  A,  Frasca  F,  Le Moli  R,  Pellegriti  G, et al. (2011) Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One 6: e22552.
• 5   Hoermann  R,  Midgley  JE,  Giacobino  A,  Eckl  WA,  Wahl  HG, et al. (2014) Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clin Endocrinol (Oxf) 81: 907–915.
• 6   Ito  M,  Kawasaki  M,  Danno  H,  Kohsaka  K,  Nakamura  T, et al. (2019) Serum thyroid hormone balance in levothyroxine monotherapy-treated patients with atrophic thyroid after radioiodine treatment for Graves’ disease. Thyroid 29: 1364–1370.
• 7   Werneck de Castro  JP,  Fonseca  TL,  Ueta  CB,  McAninch  EA,  Abdalla  S, et al. (2015) Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest 125: 769–781.
• 8   Ito  M,  Miyauchi  A,  Hisakado  M,  Yoshioka  W,  Ide  A, et al. (2017) Biochemical markers reflecting thyroid function in athyreotic patients on levothyroxine monotherapy. Thyroid 27: 484–490.
• 9   Ito  M,  Miyauchi  A,  Hisakado  M,  Yoshioka  W,  Kudo  T, et al. (2019) Thyroid function related symptoms during levothyroxine monotherapy in athyreotic patients. Endocr J 66: 953–960.
• 10   Peterson  SJ,  McAninch  EA,  Bianco  AC (2016) Is a normal TSH synonymous with “euthyroidism” in levothyroxine monotherapy? J Clin Endocrinol Metab 101: 4964–4973.
• 11   Ito  M,  Miyauchi  A,  Kang  S,  Hisakado  M,  Yoshioka  W, et al. (2015) Effect of the presence of remnant thyroid tissue on the serum thyroid hormone balance in thyroidectomized patients. Eur J Endocrinol 173: 333–340.
• 12   Takahashi  S,  Ito  M,  Masaki  Y,  Hada  M,  Minakata  M, et al. (2021) Association between serum thyroid hormone balance and thyroid volume in patients treated with levothyroxine monotherapy for hypothyroidism. Endocr J 68: 353–360.
• 13   Jonklaas  J,  Bianco  AC,  Bauer  AJ,  Burman  KD,  Cappola  AR, et al. (2014) Guidelines for the treatment of hypothyroidism: American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 24: 1670–1751.
• 14   Murakami  Y,  Takamatsu  J,  Sakane  S,  Kuma  K,  Ohsawa  N (1996) Changes in thyroid volume in response to radioactive iodine for Graves’ hyperthyroidism correlated with activity of thyroid-stimulating antibody and treatment outcome. J Clin Endocrinol Metab 81: 3257–3260.
• 15   Taylor  PN,  Albrecht  D,  Scholz  A,  Gutierrez-Buey  G,  Lazarus  JH, et al. (2018) Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol 14: 301–316.
• 16   Wennlund  A (1986) Variation in serum levels of T₃, T₄, FT₄ and TSH during thyroxine replacement therapy. Acta Endocrinol (Copenh) 113: 47–49.
• 17   Ain  KB,  Pucino  F,  Shiver  TM,  Banks  SM (1993) Thyroid hormone levels affected by time of blood sampling in thyroxine-treated patients. Thyroid 3: 81–85.
• 18   Jansen  HI,  Bult  MM,  Bisschop  PH,  Boelen  A,  Heijboer  AC, et al. (2023) Increased fT4 concentrations in patients using levothyroxine without complete suppression of TSH. Endocr Connect 12: e220538.
• 19   Ito  M,  Takahashi  S,  Okazaki-Hada  M,  Minakata  M,  Kohsaka  K, et al. (2022) Proportion of serum thyroid hormone concentrations within the reference ranges in athyreotic patients on levothyroxine monotherapy: a retrospective study. Thyroid Res 15: 9.