Abstract
Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.
SUBCLINICAL HYPERTHYROIDISM (SHyper) is defined as normal serum free thyroxine (fT4) and free triiodothyronine (fT3) levels with subnormal serum thyrotropin (TSH) levels, which is generally considered as a mild hypermetabolic state [1]. Pathogenically, SHyper can be categorized as endogenous and exogenous [1, 2]. The major causes of endogenous SHyper are toxic multinodular goiter or Graves’ disease [1, 3]. Exogenous SHyper is mainly caused by overzealous thyroid hormone replacement therapy with levothyroxine (LT4), or intentional thyroid hormone suppressive therapy [2]. The degree of disease is often classified by the level of TSH suppression [2]. Athyreotic patients receiving TSH suppression therapy with LT4 (TSTL) after total thyroidectomy are usually regarded as being in an exogenous subclinical thyrotoxicosis state; therefore, it is generally considered as a mild thyrotoxic condition.
Among the two thyroid hormones, thyroxine (T4) and triiodothyronine (T3), T3 is the biologically active thyroid hormone. In normal participants, 100% of circulating T4 and approximately 20% of circulating T3 are secreted from the thyroid gland, and approximately 80% of T3 is derived from the conversion of T4 to T3 in extrathyroidal peripheral tissues [4]. Thus, a relative T3 deficiency may be present in athyreotic patients during LT4 monotherapy. We and other investigators have reported earlier that in athyreotic patients receiving TSTL, serum T4 levels are relatively higher than those in healthy participants, but serum T3 levels are not high [5-7]. On the other hand, it is well established that in endogenous SHyper, such as Graves’ disease or multinodular toxic goiter, there is a predominant increase in serum T3 levels compared to serum T4 levels [8, 9].
Although SHyper is considered as a mild form of overt hyperthyroidism, the underlying pathology related to thyroid function may differ between endogenous SHyper patients with relatively high fT3 levels, and athyreotic patients receiving TSTL without high fT3 levels, even with similar TSH levels. To the best of our knowledge, no previous study has compared the differences in thyroid hormone profiles and pathophysiology between endogenous SHyper patients and athyreotic patients receiving TSTL.
The present study is a retrospective cross-sectional study, in which we compared the thyroid hormone balance and peripheral indices related to thyrotoxicosis (serum creatinine [Cre], serum alkaline phosphatase [ALP], and pulse rate) among athyreotic patients receiving TSTL, endogenous SHyper patients, and healthy participants, to determine whether athyreotic patients receiving TSTL are thyrotoxic. We considered that serum Cre reflects renal function, since both serum Cre and cystatin C are altered even in mild thyroid dysfunction states, such as subclinical hyperthyroidism [10]. Serum ALP and pulse rate each reflects bone metabolism and heart rate.
Materials and Methods
Patients
Untreated endogenous SHyper patients and athyreotic patients receiving TSTL after total thyroidectomy for papillary thyroid carcinoma at Kuma Hospital between January 2012 and December 2018 were retrospectively sampled. There were 540 (466 females, 74 males) endogenous SHyper patients and 1,024 (830 females, 194 males) athyreotic patients receiving TSTL. All sampled patients had normal levels of fT4 (0.7–1.6 ng/dL) and fT3 (1.7–3.7 pg/mL), with suppressed levels of TSH (<0.3 μIU/mL). Graves’ disease was diagnosed based on the following clinical features: diffuse goiter, increase in thyroid radioiodine uptake (RAIU) or 99m technetium-pertechnetate (99mTc) thyroid uptake, and positive anti-TSH receptor antibodies (TRAb). Toxic multinodular goiter or adenoma was diagnosed by a single or multinodular goiter, an increase in RAIU matching the nodule(s) with suppression of the background thyroid gland, and negative TRAb. The exclusion criteria were as follows:1) patients taking medications that affect thyroid function or thyroid hormone peripheral indices; 2) patients with a history of chronic or severe diseases; 3) patients with arrhythmia, such as atrial fibrillation, and who were receiving antihypertensive drugs, such as β-blockers; 4) pregnant or breastfeeding women; 5) patients with a body mass index (BMI) of <18 or >30 kg/m2; and 6) patients with any physical disability.
Destructive thyroiditis was excluded from the endogenous SHyper group, which was diagnosed based on a decrease in thyroid RAIU or 99mTc thyroid uptake and negative TRAb. Athyreotic patients receiving TSTL with metastasis were excluded. Based on the degree of TSH suppression, endogenous SHyper patients and athyreotic patients on TSTL were each divided into two groups, 1) those with TSH <0.03 μIU/mL (strongly suppressed TSH), and 2) those with TSH between 0.03 and 0.3 μIU/mL (mildly suppressed TSH).
This study was approved by the Ethics Committee of Kuma Hospital (No. 20200709-1). All the patients were informed and agreed to participate in the study.
Matched controls
Participants showing normal thyroid function with negative anti-thyroid peroxidase, anti-thyroglobulin, and TRAb were selected as healthy controls. Blood tests for the healthy participants were performed at Kuma Hospital during the same period as the test participants. Participants with thyroid nodules or goiter (total volume: male ≥20 mL and female ≥18 mL) [11] were excluded from the healthy control group. The same exclusion criteria as the test participants were applied to the healthy participants. The total sample size of the healthy participants was 2,064 (1,693 females, 371 males). Considering the different age distributions and backgrounds, the participants in the one-by-one comparisons were matched by age, sex, body weight, and BMI by 1:1 matching.
Laboratory tests and measurements
Blood samples from patients taking LT4 were obtained in the morning or afternoon after the daily oral administration of LT4. Serum TSH, fT4, and fT3 levels were measured using chemiluminescent immunoassay (ARCHITECT i2000; Abbott Japan, Tokyo). The intra- and inter-assay coefficients of variability for TSH assay were 1.1–5.0% and 1.7–5.3%, for fT4 assay were 2.3–5.3% and 3.6–7.8%, and for fT3 assay were 1.4–4.2% and 2.3–5.0%, respectively. Serum TRAb levels were measured using electrochemiluminescence immunoassay (Elecsys 2010; Roche Diagnostics Japan, Tokyo). The normal range for TRAb is ≤1.9 IU/L. The total volume of the thyroid gland was measured using ultrasonography as previously reported [12]. Serum Cre was measured by an enzyme assay, and ALP by p-nitro-phenyl phosphate (p-NPP) assay.
The pulse rate was measured by palpation of the radial artery.
Statistical analyses
We conducted one-way analysis of variance (ANOVA) to compare the clinical characteristics among healthy participants, endogenous SHyper (mildly and strongly suppressed TSH), and athyreotic patients receiving TSTL (mildly and strongly suppressed TSH), using Bonferroni correction for multiple comparisons. The paired grouped data with parametric distribution are shown as mean ± standard deviation and were analyzed using t-test. The paired grouped data with nonparametric distributions are shown as median and interquartile range (IQR) and were analyzed using the Wilcoxon signed-rank test. A p value of <0.05 (two-sided) was defined as statistically significant. StatFlex (version 7; Artech Co., Ltd., Osaka, Japan) was used for statistical analyses.
Results
Clinical characteristics of healthy participants, endogenous SHyper patients, and athyreotic patients receiving TSTL
The clinical characteristics of the five groups (healthy participants, endogenous SHyper patients with strongly suppressed TSH, endogenous SHyper patients with mildly suppressed TSH, athyreotic patients on TSTL with strongly suppressed TSH, and athyreotic patients on TSTL with mildly suppressed TSH) are presented in Table 1. There were no significant differences in sex; however, other parameters (age, BMI TSH, fT4, fT3, fT3/fT4, ALP, Cre, and pulse rate) were significantly different among the five groups (Table 1A). In the multiple comparisons, all groups except endogenous SHyper with strongly suppressed TSH vs. endogenous SHyper with mildly suppressed TSH group showed significant differences in any of the patient background categories (age, BMI, and sex) (Table 1B).
Table 1
Clinical characteristics of healthy participants, endogenous subclinical hyperthyroid patients, and athyreotic patients receiving TSH suppression therapy with LT4
A.
| Subgroups |
G1 |
G2 |
G3 |
G4 |
G5 |
p-Value |
| Groups |
Healthy participants |
Endogenous subclinical hyperthyroidism (strongly suppressed TSH) |
Endogenous subclinical hyperthyroidism (mildly suppressed TSH) |
Athyreotic patients on TSTL (strongly suppressed TSH) |
Athyreotic patients on TSTL (mildly suppressed TSH) |
| Number of participants |
2,064 |
240 |
300 |
509 |
515 |
|
| Age (years)* |
35.6 (14.5) |
44.3 (15.7) |
41.5 (15.0) |
52.7 (13.7) |
53.0 (14.1) |
<0.001a |
| BMI (kg/m2)* |
21.74 (2.65) |
21.74 (2.58) |
21.85 (2.64) |
22.51 (2.72) |
23.13 (2.89) |
<0.001a |
| Sex (female/male) |
1,693/371 |
210/30 |
256/44 |
417/92 |
413/102 |
0.088χ2 |
| TSH (μIU/mL)** |
1.4570 (3.6561) |
0.0040 (0.0240) |
0.1335 (0.2550) |
0.0100 (0.0250) |
0.0850 (0.2466) |
<0.001a |
| fT4 (ng/dL)* |
1.027 (0.120) |
1.192 (0.169) |
1.067 (0.147) |
1.406 (0.128) |
1.328 (0.153) |
<0.001a |
| fT3 (pg/mL)* |
2.803 (0.357) |
3.175 (0.384) |
2.930 (0.368) |
2.926 (0.333) |
2.742 (0.320) |
<0.001a |
| fT3/fT4* |
2.750 (0.381) |
2.700 (0.421) |
2.784 (0.435) |
2.096 (0.288) |
2.087 (0.314) |
<0.001a |
| ALP (U/L)* |
196.4 (85.6) |
224.1 (82.4) |
200.0 (61.7) |
224.4 (62.6) |
218.3 (80.2) |
<0.001a |
| Cre (mg/dL)* |
0.651 (0.133) |
0.592 (0.127) |
0.627 (0.142) |
0.632 (0.147) |
0.676 (0.239) |
<0.001a |
| Pulse rate (beats/min)* |
76.8 (12.1) |
80.2 (12.9) |
78.1 (12.5) |
76.7 (11.9) |
78.3 (12.6) |
<0.001a |
B.
|
p-Value |
| G1 vs. G2 |
G1 vs. G3 |
G1 vs. G4 |
G1 vs. G5 |
G2 vs. G3 |
G2 vs. G4 |
G2 vs. G5 |
G3 vs. G4 |
G3 vs. G5 |
G4 vs. G5 |
| Age (years)a |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
0.28 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
1.00 |
| BMI (kg/m2)a |
1.00 |
1.00 |
<0.001 |
<0.001 |
1.00 |
<0.01 |
<0.001 |
<0.01 |
<0.001 |
<0.01 |
| Sex (female/male)χ2 |
0.43 |
1.00 |
1.00 |
1.00 |
1.00 |
0.68 |
0.18 |
1.00 |
0.8 |
1.00 |
| TSH (μIU/mL)a |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
0.20 |
1.00 |
0.64 |
0.071 |
1.00 |
0.26 |
| fT4 (ng/dL)a |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
| fT3 (pg/mL)a |
<0.001 |
<0.001 |
<0.001 |
<0.01 |
<0.001 |
<0.001 |
<0.001 |
1.00 |
<0.001 |
<0.001 |
| fT3/fT4a |
0.44 |
1.00 |
<0.001 |
<0.001 |
0.085 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
1.00 |
| ALP (U/L)a |
<0.001 |
1.00 |
<0.001 |
<0.001 |
<0.01 |
1.00 |
1.00 |
<0.001 |
<0.05 |
1.00 |
| Cre (mg/dL)a |
<0.001 |
0.11 |
0.14 |
<0.01 |
0.086 |
<0.01 |
<0.001 |
1.00 |
<0.001 |
<0.001 |
| Pulse rate (beats/min)a |
<0.001 |
0.75 |
1.00 |
0.24 |
0.52 |
<0.01 |
0.67 |
1.00 |
1.00 |
0.63 |
* Mean (SD)
** Median (IQR)
a ANOVA test
Abbreviations: TSH: thyrotropin; LT4: levothyroxine; TSTL: TSH suppression therapy with levothyroxine; BMI: body mass index; χ2: chi-square test; fT4: free thyroxine; fT3: free triiodothyronine; ALP: alkaline phosphatase; Cre: creatinine
Reference range: TSH 0.3–5.0 μIU/mL, fT4 0.7–1.6 ng/dL, fT3 1.7–3.7 pg/mL
To precisely analyze thyroid hormone levels and peripheral indices, we matched the backgrounds (age, BMI, and sex) between the groups. Compared to healthy participants, regardless of their TSH suppression levels, endogenous SHyper patients showed significantly lower levels of TSH (p < 0.001) and significantly higher levels of fT3 and fT4 (p < 0.001 and p < 0.001, respectively); however, there was no significant difference in the fT3/fT4 ratio (Table 2). Among the peripheral indices related to thyrotoxicosis, endogenous SHyper patients with strongly suppressed TSH levels showed significantly lower serum Cre levels, as well as significantly higher serum ALP levels and pulse rates than healthy controls (p < 0.001, p < 0.001, and p < 0.05, respectively). Although endogenous SHyper patients with mildly suppressed TSH levels showed significantly lower serum Cre levels than healthy controls (p < 0.05), there were no significant differences in serum ALP levels or pulse rate (p = 0.249 and p = 0.814, respectively) (Table 2).
Table 2
Comparison of clinical characteristics between healthy participants and endogenous subclinical hyperthyroid patients matched for age, BMI, and sex
|
Healthy participants |
Endogenous subclinical hyperthyroidism (strongly suppressed TSH) |
p-Value |
Healthy participants |
Endogenous subclinical hyperthyroidism (mildly suppressed TSH) |
p-Value |
| Number of participants |
237 |
237 |
|
297 |
297 |
|
| Age (years)* |
44.0 (15.2) |
44.3 (15.2) |
ns |
41.4 (14.7) |
41.6 (14.6) |
ns |
| BMI (kg/m2)* |
21.73 (2.57) |
21.72 (2.56) |
ns |
21.82 (2.62) |
21.83 (2.62) |
ns |
| Sex (female/male) |
207/30 |
207/30 |
ns χ2 |
254/43 |
254/43 |
ns χ2 |
| TSH (μIU/mL)** |
1.5260 (1.1410) |
0.0040 (0.0080) |
<0.001 |
1.5020 (1.3018) |
0.1330 (0.1525) |
<0.001 |
| fT4 (ng/dL)* |
1.006 (0.125) |
1.194 (0.169) |
<0.001 |
1.013 (0.124) |
1.066 (0.147) |
<0.001 |
| fT3 (pg/mL)* |
2.740 (0.332) |
3.174 (0.383) |
<0.001 |
2.766 (0.34) |
2.932 (0.36) |
<0.001 |
| fT3/fT4* |
2.750 (0.369) |
2.696 (0.421) |
ns |
2.754 (0.373) |
2.787 (0.435) |
ns |
| ALP (U/L)* |
196.0 (74.50) |
222.1 (80.80) |
<0.001 |
193.4 (64.8) |
199.3 (61.5) |
ns |
| Cre (mg/dL)* |
0.648 (0.125) |
0.592 (0.127) |
<0.001 |
0.651 (0.129) |
0.625 (0.137) |
<0.05 |
| Pulse rate (beats/min)* |
77.2 (12.7) |
80.2 (12.9) |
<0.05 |
78.3 (12.6) |
78.1 (12.6) |
ns |
* Mean (SD)
** Median (IQR)
Abbreviations: TSH: thyrotropin; ns: not significant; BMI: body mass index; χ2: chi-square test; fT4: free thyroxine; fT3: free triiodothyronine; ALP: alkaline phosphatase; Cre: creatinine
Reference range: TSH 0.3–5.0 μIU/mL, fT4 0.7–1.6 ng/dL, fT3 1.7–3.7 pg/mL
To precisely analyze thyroid hormone levels and peripheral indices, we matched the backgrounds (age, BMI, and sex) between the groups. Compared to healthy participants, athyreotic patients receiving TSTL with strongly suppressed TSH levels showed significantly lower levels of TSH (p < 0.001), as well as significantly higher levels of fT4 and fT3 (p < 0.001 and p < 0.001, respectively) (Table 3). Compared to healthy participants, athyreotic patients receiving TSTL with mildly suppressed TSH levels showed significantly lower levels of TSH (p < 0.001) and significantly higher levels of fT4 (p < 0.001), whereas there was no significant difference in fT3 levels (p = 0.093) (Table 3). The fT3/fT4 ratio was significantly lower in athyreotic patients receiving TSTL than in healthy participants, regardless of TSH suppression levels (p < 0.001) (Table 3). Among the peripheral indices related to thyrotoxicosis, although serum Cre levels were significantly lower in athyreotic patients receiving TSTL with strongly suppressed TSH levels than in healthy participants (p < 0.001), there were no significant differences in serum ALP levels or pulse rate (p = 0.095 and p = 0.404, respectively). Furthermore, there were no significant differences in the peripheral indices related to thyrotoxicosis between athyreotic patients receiving TSTL with mildly suppressed TSH levels and healthy participants (ALP, p = 0.629; Cre, p = 0.174; pulse rate, p = 0.958) (Table 3).
Table 3
Comparison of clinical characteristics between healthy participants and athyreotic patients receiving TSH suppression therapy with LT4 matched for age, BMI, and sex
|
Healthy participants |
Athyreotic patients on TSTL (strongly suppressed TSH) |
p-Value |
Healthy participants |
Athyreotic patients on TSTL (mildly suppressed TSH) |
p-Value |
| Number of participants |
377 |
377 |
|
382 |
382 |
|
| Age (years)* |
54.5 (13.2) |
54.5 (13.1) |
ns |
54.3 (13.4) |
54.5 (13.3) |
ns |
| BMI (kg/m2)* |
22.53 (2.67) |
22.55 (2.70) |
ns |
22.88 (2.84) |
22.88 (2.84) |
ns |
| Sex (female/male) |
296/81 |
296/81 |
ns χ2 |
296/86 |
296/86 |
ns χ2 |
| LT4 dose (μg/kg/day) |
— |
2.12 (0.36) |
|
— |
2.04 (0.38) |
|
| TSH (μIU/mL)** |
1.8110 (1.3710) |
0.009 (0.0110) |
<0.001 |
1.6535 (1.3100) |
0.0830 (0.1050) |
<0.001 |
| fT4 (ng/dL)* |
1.019 (0.119) |
1.409 (0.128) |
<0.001 |
1.021 (0.122) |
1.325 (0.157) |
<0.001 |
| fT3 (pg/mL)* |
2.783 (0.355) |
2.938 (0.344) |
<0.001 |
2.794 (0.358) |
2.752 (0.316) |
ns |
| fT3/fT4* |
2.757 (0.404) |
2.098 (0.285) |
<0.001 |
2.763 (0.406) |
2.101 (0.318) |
<0.001 |
| ALP (U/L)* |
213.7 (70.0) |
221.5 (64.2) |
ns |
210.7 (72.5) |
213.3 (78.1) |
ns |
| Cre (mg/dL)* |
0.697 (0.148) |
0.633 (0.148) |
<0.001 |
0.699 (0.146) |
0.678 (0.256) |
ns |
| Pulse rate (beats/min)* |
78.1 (13.5) |
76.4 (11.7) |
ns |
78.0 (13.2) |
77.9 (12.5) |
ns |
* Mean (SD)
** Median (IQR)
Abbreviations: TSH: thyrotropin; LT4: levothyroxine; TSTL: TSH suppression therapy with LT4; ns: not significant; BMI: body mass index; χ2: chi-square test; fT4: free thyroxine; fT3: free triiodothyronine; ALP: alkaline phosphatase; Cre: creatinine
Reference range: TSH 0.3–5.0 μIU/mL, fT4 0.7–1.6 ng/dL, fT3 1.7–3.7 pg/mL
To precisely analyze thyroid hormone levels and peripheral indices, we matched the backgrounds (age, BMI, and sex) and serum TSH levels between the groups. Compared to athyreotic patients receiving TSTL, regardless of their TSH suppression level, endogenous SHyper patients showed significantly lower levels of fT4 (p < 0.001), as well as significantly higher levels of fT3 and fT3/fT4 ratio (p < 0.001 and p < 0.001, respectively) (Table 4). TSH levels were matched between the two groups to exclude the effect of TSH differences on each parameter; therefore, there was no significant difference in TSH levels. Among the peripheral indices related to thyrotoxicosis, although endogenous SHyper patients with strongly suppressed TSH showed significantly higher ALP levels and pulse rates than athyreotic patients receiving TSTL with strongly suppressed TSH (p < 0.05, and p < 0.05, respectively), there was no significant difference in serum Cre (p = 0.909) (Table 4). On the other hand, there were no significant differences in any of the peripheral indices between endogenous SHyper patients and athyreotic patients receiving TSTL with mildly suppressed TSH levels (ALP, p = 0.491; Cre, p = 0.462; pulse rate, p = 0.328) (Table 4).
Table 4
Comparison of clinical characteristics between endogenous subclinical hyperthyroid patients and athyreotic patients receiving TSH suppression therapy with LT4 matched for age, BMI, sex, and serum TSH levels
|
Endogenous subclinical hyperthyroidism (strongly suppressed TSH) |
Athyreotic patients on TSTL (strongly suppressed TSH) |
p-Value |
Endogenous subclinical hyperthyroidism (mildly suppressed TSH) |
Athyreotic patients on TSTL (mildly suppressed TSH) |
p-Value |
| Number of participants |
142 |
142 |
|
108 |
108 |
|
| Age (years)* |
51.3 (13.7) |
51.5 (13.6) |
ns |
50.7 (13.1) |
50.9 (13.1) |
ns |
| BMI (kg/m2)* |
21.94 (2.46) |
21.86 (2.41) |
ns |
21.76 (2.25) |
21.84 (2.29) |
ns |
| Sex (female/male) |
125/17 |
125/17 |
ns χ2 |
101/7 |
101/7 |
ns χ2 |
| LT4 dose (μg/kg/day) |
— |
2.16 (0.36) |
|
— |
2.06 (0.37) |
|
| TSH (μIU/mL)** |
0.0040 (0.0080) |
0.0060 (0.0060) |
ns |
0.0835 (0.0875) |
0.0830 (0.0845) |
ns |
| fT4 (ng/dL)* |
1.191 (0.160) |
1.404 (0.127) |
<0.001 |
1.089 (0.159) |
1.317 (0.142) |
<0.001 |
| fT3 (pg/mL)* |
3.201 (0.362) |
2.934 (0.317) |
<0.001 |
3.009 (0.344) |
2.698 (0.299) |
<0.001 |
| fT3/fT4* |
2.729 (0.456) |
2.102 (0.286) |
<0.001 |
2.807 (0.439) |
2.065 (0.274) |
<0.001 |
| ALP (U/L)* |
230.1 (74.2) |
210.9 (59.3) |
<0.05 |
206.0 (65.0) |
199.8 (71.0) |
ns |
| Cre (mg/dL)* |
0.605 (0.122) |
0.604 (0.118) |
ns |
0.611 (0.148) |
0.625 (0.137) |
ns |
| Pulse rate (beats/min)* |
80.4 (12.8) |
77.4 (12.0) |
<0.05 |
79.3 (12.6) |
76.9 (11.1) |
ns |
* Mean (SD)
** Median (IQR)
Abbreviations: TSH: thyrotropin; LT4: levothyroxine; TSTL: TSH suppression therapy with LT4; ns: not significant; BMI: body mass index; χ2: chi-square test; fT4: free thyroxine; fT3: free triiodothyronine; ALP: alkaline phosphatase; Cre: creatinine
Reference range: TSH 0.3–5.0 μIU/mL, fT4 0.7–1.6 ng/dL, fT3 1.7–3.7 pg/mL
Discussion
To investigate the difference in pathophysiology between patients with endogenous SHyper and athyreotic patients receiving TSTL, we first compared the thyroid hormone profile. Patients with endogenous SHyper had higher fT3 levels than the healthy participants; however, there was no significant difference in the fT3/fT4 ratio (Table 2). Generally, serum fT3 is predominantly elevated in endogenous SHper, such as Graves’ disease, resulting in a high fT3/fT4 ratio [8, 9]. However, some researchers have reported that an increase in the fT3/fT4 ratio is not observed in mild hyperthyroidism, such as endogenous SHyper [13, 14]. When athyreotic patients receiving TSTL were compared to healthy participants, fT4 levels were elevated in athyreotic patients receiving TSTL regardless of the degree of TSH suppression, whereas fT3 levels were higher in athyreotic patients receiving TSTL only when TSH was strongly suppressed (Table 3). In other words, the fT3 levels in athyreotic patients receiving TSTL under mild TSH suppression were similar to those in healthy participants. Previous studies have shown that in athyreotic patients receiving LT4 with normal serum TSH levels, fT4 levels were higher, whereas fT3 levels were lower than those in their preoperative state and healthy controls [5-7]. Furthermore, we previously reported that in athyreotic patients on LT4, after total thyroidectomy, postoperative fT3 levels under strongly suppressed TSH levels were higher than their preoperative state, whereas fT3 levels were similar to their preoperative state when TSH was mildly suppressed [7]. The present results are consistent with those of previous studies. Moreover, in the present study, there was a decrease in the fT3/fT4 ratio in athyreotic patients receiving TSTL compared to healthy participants. This suggests a reduction in conversion of T4 to T3 owing to the athyreotic state [15]. Lastly, when endogenous SHyper patients and athyreotic patients receiving TSTL were compared, regardless of the degree of TSH suppression, fT3 levels were higher in the former and fT4 levels were higher in the latter (Table 4). These results indicate that fT3 levels were predominantly higher in patients with endogenous SHyper, and fT4 levels were predominantly higher in athyreotic patients receiving TSTL. In a recent review article, Biondi and Cooper [16] stated that the total T3 or fT3 levels are usually in the middle or lower part of the reference range for exogenous subclinical thyrotoxicosis. Thus, endogenous and exogenous subclinical thyrotoxicosis are not biochemically comparable because of the differences in the severity and pattern of circulating thyroid hormones, suggesting that the pathophysiology of the two groups may be different.
Next, we investigated the peripheral indices related to thyrotoxicosis. Compared to healthy participants, patients with endogenous SHyper showed a trend towards a hyperthyroid state. It has been reported that TSH levels <0.10 mIU/L are associated with a higher risk of atrial fibrillation, coronary heart disease, and bone fractures [17, 18]. This is consistent with the present data, in which patients with endogenous SHyper with strongly suppressed TSH had significantly higher ALP and pulse rates than healthy participants (Table 2). Furthermore, hyperthyroidism alters kidney function, and untreated overt hyperthyroidism or SHyper shows low serum Cre levels [10, 19]. This is also consistent with the present data showing that serum Cre levels are significantly lower in patients with endogenous SHyper than in healthy participants (Table 2).
In athyreotic patients receiving TSTL with strongly suppressed TSH and relatively high fT3 levels, there was a trend toward a hyperthyroid state compared to healthy participants. On the other hand, athyreotic patients receiving TSTL with mildly suppressed TSH and fT3 levels similar to those of healthy participants showed a similar trend as healthy participants (Table 3). Werneck de Castro et al. [20] reported that in athyreotic rats treated with T4-monotherapy with high serum T4 and low serum T3 levels, despite normal serum TSH levels, showed signs of hypothyroidism as a result of thyroid hormone action in the brain, liver, and skeletal muscle. Moreover, in our previous study, all metabolic markers related to thyroid function remained equivalent to their preoperative levels when TSH was mildly suppressed [21]. This is consistent with the results of our present study, in which we compared peripheral indices between athyreotic patients receiving TSTL with mildly suppressed TSH and healthy participants (Table 3). Recently, in a large LT4-treated cohort with normal serum TSH, participants had lower serum T3 levels, and thyroid status markers differed both objectively and subjectively compared to healthy euthyroid controls [22]. Overall, the presence of biochemical markers of thyroid function in animal and human studies of LT4-treated athyreotic conditions suggests that patients with normal TSH levels may not be eumetabolic in all tissues, whereas those with slightly low TSH levels are less likely to have hyperthyroid symptoms than those with considerably low TSH levels.
There are several reports on the cardiovascular effects of TSH suppressive therapy in patients with differentiated thyroid cancer after total thyroidectomy [23, 24]. An interesting observational study showed that both cardiovascular and all-cause mortality rates increased with complete TSH suppression but not with mild TSH suppression [25]. These findings suggest that mild TSH suppression does not cause thyrotoxicosis in patients on LT4 after total thyroidectomy, which is consistent with the present study, where there was no significant difference in pulse rate between athyreotic patients receiving TSTL with mildly suppressed TSH and healthy participants (Table 3).
According to the American Thyroid Association (ATA) and European Thyroid Association (ETA) guidelines, disease management for SHyper, including treatment, differs according to severity (TSH <0.1 μIU/mL or not), age (65 years or older or not), existence of symptoms related to hyperthyroidism, and risk of complications such as cardiovascular disease or osteoporosis [26, 27]. The present study showed that thyroid hormone levels and peripheral indices differ depending on differences in the pathogenesis of SHyper, suggesting that different disease management indices are needed for athyreotic patients receiving TSTL.
This study has several limitations. First, it was retrospective and uncontrolled. Second, the sample size was reduced through the matching process. Third, Japan is an iodine-rich region; therefore, there is a possibility that the results may differ due to differences in iodine intake. Fourth, we divided the patients with suppressed TSH levels into two groups by TSH levels below or above 0.03 μIU/mL based on our previous study [7]; however, since the TSH cutoff in the current guidelines is 0.1 μIU/mL, there is a discrepancy with the guideline cutoff. Fifth, since the present study was retrospective, aspartate aminotransferase, alanine aminotransferase, ALP isozymes, creatine kinase, and low-density lipoprotein cholesterol were not measured in most patients, which should be assessed in future prospective studies. Finally, because the data was acquired at a particular point in time, the long-term implications are unknown.
In summary, endogenous SHyper and athyreotic patients receiving TSTL have distinct pathophysiology. Athyreotic patients receiving TSTL with mildly suppressed TSH levels are not thyrotoxic, even though the thyroid hormone profile is analogous to the thyrotoxic state. Complications associated with different degrees of TSH suppression in athyreotic patients receiving TSTL have not yet been studied and require further investigation.
Acknowledgments
Data collection and analyses were assisted by Izumi Otsuka and Makoto Kawakami.
Disclosure
None of the authors have any potential conflicts of interest associated with this research.
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