Effect of the presence of remnant thyroid tissue on the serum thyroid hormone balance in thyroidectomized patients

in European Journal of Endocrinology
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  • 1 Center for Excellence in Thyroid Care, Kuma Hospital, 8‐2‐35, Shimoyamate‐Dori, Chuo‐Ku, Kobe‐City, Hyogo 650‐0011, Japan

Objective

We and others recently reported that in total thyroidectomy (TT), serum triiodothyronine (T3) levels during levothyroxine (l-T4) therapy were low compared to the preoperative levels, suggesting that the presence of the thyroid tissue affects the balances of serum thyroid hormone levels. However, the effects of remnant thyroid tissue on these balances in thyroidectomized patients have not been established.

Methods

We retrospectively studied 253 euthyroid patients with papillary thyroid carcinoma who underwent a TT or hemithyroidectomy (HT). We divided the cases into the TT+supplemental l-T4 (+l-T4) group (n=103); the HT+l-T4 group (n=56); and the HT-alone group (n=94). We compared the postoperative serum levels of free T4 (FT4) and free T3 (FT3) and the FT3/FT4 ratio in individual patients with those of controls matched by serum TSH levels.

Results

The TT+l-T4 group had significantly higher FT4 (P<0.001), lower FT3 (P<0.01) and lower FT3/FT4 (P<0.001) levels compared to the controls. The HT+l-T4 group had FT4, FT3 and FT3/FT4 levels equivalent to those of the controls. The HT-alone group had significantly lower FT4 (P<0.01), equivalent FT3 (P=0.083), and significantly higher FT3/FT4 (P<0.001) ratios than the controls.

Conclusions

The presence of the remnant thyroid tissue was associated with different thyroid hormone balances in thyroidectomized patients, suggesting that T3 production by remnant thyroid tissue has a substantial effect on the maintenance of postoperative serum T3 levels.

Abstract

Objective

We and others recently reported that in total thyroidectomy (TT), serum triiodothyronine (T3) levels during levothyroxine (l-T4) therapy were low compared to the preoperative levels, suggesting that the presence of the thyroid tissue affects the balances of serum thyroid hormone levels. However, the effects of remnant thyroid tissue on these balances in thyroidectomized patients have not been established.

Methods

We retrospectively studied 253 euthyroid patients with papillary thyroid carcinoma who underwent a TT or hemithyroidectomy (HT). We divided the cases into the TT+supplemental l-T4 (+l-T4) group (n=103); the HT+l-T4 group (n=56); and the HT-alone group (n=94). We compared the postoperative serum levels of free T4 (FT4) and free T3 (FT3) and the FT3/FT4 ratio in individual patients with those of controls matched by serum TSH levels.

Results

The TT+l-T4 group had significantly higher FT4 (P<0.001), lower FT3 (P<0.01) and lower FT3/FT4 (P<0.001) levels compared to the controls. The HT+l-T4 group had FT4, FT3 and FT3/FT4 levels equivalent to those of the controls. The HT-alone group had significantly lower FT4 (P<0.01), equivalent FT3 (P=0.083), and significantly higher FT3/FT4 (P<0.001) ratios than the controls.

Conclusions

The presence of the remnant thyroid tissue was associated with different thyroid hormone balances in thyroidectomized patients, suggesting that T3 production by remnant thyroid tissue has a substantial effect on the maintenance of postoperative serum T3 levels.

Introduction

There are two thyroid hormones, thyroxine (T4) and triiodothyronine (T3). T3 is the biologically active thyroid hormone. In normal subjects, 100% of T4 is secreted by the thyroid, about 20% of T3 is secreted from the thyroid gland, and about 80% of T3 is derived from the conversion of T4 to T3 in extra-thyroidal peripheral tissues (1). A relative T3 deficiency may thus be present in athyreotic patients during T4 monotherapy. Several studies (2, 3, 4, 5) compared postoperative T3 levels in patients on l-T4 therapy with their own preoperative levels or those in euthyroid controls. We reported that serum T3 levels were inappropriately low in patients who had undergone a total thyroidectomy (TT) and were on l-T4 supplementation and that a moderately thyroid-stimulating hormone (TSH)-suppressive dose of l-T4 was required to achieve their preoperative native serum T3 levels (2). Jonklaas et al. (3) reported that there were no significant decreases in T3 levels in patients on l-T4 supplementation compared with their preoperative T3 levels within the group as a whole, although a higher ratio of free T4 (FT4) to T3 ratio was necessary to achieve this. Gullo et al. (4) studied 1811 athyreotic subjects with normal TSH levels and 3875 euthyroid controls, and they found that serum free T3 (FT3) levels of the athyreotic subjects were lower than those of the euthyroid controls, whereas the athyreotic subjects' serum FT4 levels were higher. Hoermann et al. (5) recently reported that in 50 carcinoma patients who underwent TT and showed normal TSH levels postoperatively, the FT3 levels were lower than those of controls, whereas the FT4 levels were higher than those of the controls. These findings suggest that the interrelation among serum T4, T3 and TSH levels might differ according to the postoperative presence or absence of thyroid tissue. However, to the best of our knowledge this hypothesis has not been investigated in detail.

Although hemithyroidectomy (HT) is associated with a risk of hypothyroidism, few studies have evaluated the thyroidal function including serum T3 levels of HT patients, because patients who had normal serum TSH and FT4 levels were generally considered to have euthyroidism (6). Some investigators reported that patients who underwent a HT had approximately the same serum T3 levels compared to their preoperative native levels or those in controls (7, 8), but another group did not obtain such results (9). Most of the previous studies have some flaws such as the heterogeneity of patients or a small sample size (n=28–35). The cases in Lombardi et al. (7) and Toft Kristensen et al. (9) were only identified as euthyroid goiter; therefore, the cases in these studies may contain follicular tumor, thyroid dyshormonogenesis, or giant Hashimoto thyroiditis. These diseases reveal normal thyroid hormone levels but high T3/T4 ratio. In the present study, our cases were identified as papillary thyroid carcinoma that did not affect the thyroidal conversion of T4 to T3 (10). Moreover, in these reports, the postoperative serum TSH levels were increased compared to preoperative native levels or those of controls (7, 8, 9). It is possible that TSH stimulates both type 1 (D1) and type 2 (D2) deiodinases, which convert T4 to T3 mediated by a cAMP signaling pathway (11, 12, 13).

In the present study, we first measured serum TSH, FT4, and FT3 levels and the FT3/FT4 ratios on three groups of euthyroid patients who underwent a thyroidectomy for papillary thyroid carcinoma: the patients who underwent a TT and received supplemental l-T4, the patients who underwent HT and received supplemental l-T4, and the patients who underwent a HT alone, both before and after stabilization of the thyroid profiles 12 months after the thyroidectomy. We also compared gender, age, BMI, and serum thyroid parameters among the groups. Postoperative TSH levels differed from the preoperative levels in two patient groups. Moreover, gender, age, and TSH levels differed among groups. Therefore, we further compared serum FT4 and FT3 levels and the FT3/FT4 ratio measured postoperatively in each patient group with those in a healthy control group matched by gender, age, and serum TSH level.

Subjects and methods

Patients

From their medical records, we identified 1012 consecutive patients who underwent a thyroidectomy for papillary thyroid carcinoma between October 2011 and February 2013 at Kuma Hospital and were followed at least for 18 months postoperatively. The inclusion criteria for the present study were as follows: the patient underwent a TT or HT; the patient had been diagnosed with papillary thyroid carcinoma; the patient had a preoperative TSH level within the laboratory reference range (0.3–5.0 μU/ml); and the patient had a final postoperative TSH level within the laboratory reference range.

The exclusion criteria were as follows: patients who underwent near-total or subtotal thyroidectomy; patients with thyroid malignancies other than papillary carcinoma; patients with Graves' disease, Hashimoto thyroiditis, thyroid dysfunction, thyroid dyshormonogenesis, or autonomously functioning thyroid nodules; patients with chronic or serious diseases such as cardiac, pulmonary, hepatic, and renal diseases; patients who were taking drugs known to affect thyroid function or thyroid hormone metabolism, such as a steroid, estrogen, amiodarone, lithium, β-blocker, sucralfate, iron, or iodine-containing drugs; patients who were pregnant or lactating; patients who were under ‘suppressive’ l-T4 treatment for high-risk thyroid cancer; and patients who did not achieve normal serum TSH levels. Finally, 253 consecutive patients were enrolled in the present study.

The patients who underwent a TT were initially administered 2.0 μg/kg of l-T4 daily after surgery. Thyroid function tests were performed 1 month after surgery and every 3–6 months thereafter. If necessary, l-T4 was administered and doses were adjusted with the intention to maintain the patient's target serum TSH values. On the other hand, the patients who underwent a HT were initially followed up without l-T4 after surgery. Thyroid function tests were performed 1 month after surgery and every 3–6 months thereafter. If a patient developed hypothyroidism, l-T4 was administered and doses were adjusted to maintain the patient's serum TSH values within the reference range. The ultimate mean daily doses of l-T4 administered were 2.02 μg/kg per day for the patients who underwent a TT and received supplemental l-T4 and 1.07 μg/kg per day for the patients who underwent a HT and received supplemental l-T4.

Of the 253 patients, 103 patients underwent a TT and 150 patients underwent a HT. Among the latter, 56 patients (37%) developed hypothyroidism postoperatively and received supplemental l-T4 treatment. Thus, the present patients were divided into three groups: 103 patients with TT+supplemental l-T4 therapy, 56 patients with HT+supplemental l-T4 therapy, and 94 patients with HT alone (Fig. 1).

Figure 1
Figure 1

Flow chart of study. PC, papillary carcinoma.

Citation: European Journal of Endocrinology 173, 3; 10.1530/EJE-15-0138

Matched control subjects

A continuous series of 951 euthyroid subjects who were examined at Kuma Hospital during the same period and who did not have clinical or laboratory signs of thyroid diseases served as controls. Subjects with positive anti-thyroid peroxidase (TPO) or anti-thyroglobulin (Tg) antibody test results or with abnormal findings on an ultrasound examination were excluded. The other exclusion criteria were the same as those used for the selection of the present patients described above. To balance the covariates including age, sex, and serum TSH levels between the patients and controls, we used Mahalanobis-metric matching for choosing the control subjects for each patient group, as described by Rubin (14). Control subjects for each group of patients were chosen from among the 951 subjects selected above by 1:1 matching.

The present study was approved by the Ethical Committee at Kuma Hospital, and all patients gave informed consent.

Thyroid function tests

Each patient's presurgical thyroid profile was obtained 2 days before the surgery. The postoperative thyroid profiles were obtained after stabilization of the thyroid profiles, usually 12 months after the thyroidectomy. For the patients who were taking l-T4, blood samples were obtained in the morning and after the ingestion of l-T4.

The patients' and controls' serum levels of TSH, FT4, and FT3 were measured with a chemiluminescent immunoassay (ARCHTECT i2000, Abbott Japan). The intra-assay coefficients of variation and the inter-assay coefficients of variation were 1.1–5.0 and 1.7–5.3% for the TSH assay, 2.3–5.3 and 3.6–7.8% for the FT4 assay, and 1.4–4.2 and 2.3–5.0% for the FT3 assay. The reference ranges in our hospital are 0.3–5.0 mU/l for TSH, 9.0–20.6 pmol/l for FT4, 2.61–5.68 pmol/l for FT3, and 0.21–0.39 for the FT3/FT4 ratio.

Statistical analysis

Treatment effects (pre-thyroidectomy or controls vs post-thyroidectomy) were analyzed by a paired t-test in case of normal distribution and by the Wilcoxon test in case of nonparametric distribution. The postoperative group comparisons were analyzed by an unpaired t-test in case of normal distribution and by the Mann–Whitney U test in case of nonparametric distribution, using Bonferroni corrections for multiple comparisons. Significance was accepted at P<0.05. Mahalanobis-metric matching was performed using R package (version 3.0.2. R Core Team, Vienna, Austria). Other statistical analyses were performed using StatFlex (version 6.0. Artech Co., Ltd, Osaka, Japan).

Results

Postoperative vs preoperative thyroid function profiles in the three patient groups

Table 1 shows the TSH, FT4, and FT3 levels and the FT3/FT4 ratios before and after thyroidectomy in each patient group. In the TT+l-T4 group, compared to their preoperative values, the patients' postoperative serum TSH values were significantly decreased (P<0.001), their postoperative FT4 levels were significantly increased (P<0.001), and their postoperative FT3 levels were significantly decreased (P=0.023), although all of these values were within their reference ranges (Table 1).

Table 1

Pre- and post-thyroidectomy serum levels of TSH, FT4, FT3, and FT3/FT4 in the three patient groups. Statistical significance (pre- vs post-thyroidectomy) was analyzed by paired t-test or by Wilcoxon signed-rank test. Values indicate median (25th to 75th percentiles).

Patients groupsTSH (mU/l)FT4 (pmol/l)FT3 (pmol/l)FT3/FT4
Total thyroidectomy+l-T4 (n=103)
 Pre-thyroidectomy1.52 (1.02–2.13)14.4 (13.3–15.4)4.45 (4.06–4.81)0.31 (0.28–0.34)
 Post-thyroidectomy0.78 (0.49–1.50)17.2 (15.7–18.9)4.29 (3.96–4.65)0.25 (0.22–0.28)
 P value<0.001<0.0010.023<0.001
Hemithyroidectomy+l-T4 (n=56)
 Pre-thyroidectomy1.84 (1.30–2.63)13.8 (12.6–14.7)4.38 (4.06–4.65)0.32 (0.29–0.34)
 Post-thyroidectomy1.86 (1.16–2.75)14.3 (13.2–15.4)4.35 (3.98–4.61)0.29 (0.27–0.33)
 P value0.1360.0240.4980.017
Hemithyroidectomy alone (n=94)
 Pre-thyroidectomy1.07 (0.73–1.51)14.4 (13.1–15.3)4.31 (3.89–4.77)0.30 (0.27–0.33)
 Post-thyroidectomy2.41 (1.67–3.37)12.9 (12.1–13.6)4.43 (4.04–4.65)0.34 (0.32–0.37)
 P value<0.001<0.0010.204<0.001a

TSH, thyroid-stimulating hormone; FT4, free thyroxine; FT3, free triiodothyronine.

Wilcoxon signed-rank test.

In the HT+l-T4 group, the postoperative FT3 levels and TSH levels did not show significant differences from their preoperative values, and the postoperative FT4 levels were slightly and significantly increased (P=0.024), although all of these values were within their reference ranges (Table 1).

In the HT-alone group, the patients' postoperative FT3 levels did not differ significantly from their preoperative values, whereas their postoperative serum TSH values were significantly increased (P<0.001) and the postoperative FT4 levels were significantly decreased (P<0.001), although all of the values were within their reference ranges. Thus, the three groups of patients showed different thyroid function profiles, although the values were all within their reference ranges (Table 1).

Regarding the FT3/FT4 ratio, the three groups showed different changes postoperatively: the TT+supplemental l-T4 patients showed significant decreases in the ratio (P<0.001); the HT+l-T4 patients had slight but significant decreases in the ratio (P=0.017), and the HT-alone patients showed increases in the ratio (P<0.001) (Table 1).

Clinical characteristics among the three patient groups

Characteristics among the three patient groups are given in Table 2. Gender ratios of the HT+l-T4 group were significantly different from those of the other two groups (P<0.001). Ages of the HT+l-T4 group were significantly higher than those of the HT alone group (P<0.05). BMI values of the three groups were similar among groups. Serum TSH levels in the TT+l-T4 group were significantly lower than those of the other two groups (P<0.001). Serum FT4 and FT3/FT4 levels of one of the three groups were different from those of the other two groups. Serum FT3 levels of the three groups were not significantly different among groups.

Table 2

Clinical characteristics among the three patients groups. Statistical significance was analyzed by the χ2 test (gender), unpaired t-test, or Mann–Whitney U test using Bonferroni corrections for multiple comparisons. Values indicate median and interquartile ranges.

ParametersTT+l-T4HT+l-T4HT aloneP value
TT+l-T4 vs HT+l-T4TT+l-T4 vs HT aloneHT+l-T4 vs HT alone
n1035694
Gender (M/F)27/768/4826/68<0.0010.96<0.001
Age (years)51 (40–63)58 (43–65)50 (41–60)0.241.00<0.05
BMI (kg/m2)23.0 (3.7)23.1 (3.6)23.6 (3.7)0.841.001.00
TSH (mU/l)0.78 (1.01)1.86 (1.59)2.41 (1.70)<0.001<0.0010.07a
FT4 (pmol/l)17.2 (3.2)14.3 (2.2)12.9 (1.5)<0.001<0.001<0.001
FT3 (pmol/l)4.29 (0.68)4.35 (0.63)4.43 (0.61)1.000.440.52
FT3/FT40.25 (0.05)0.29 (0.06)0.34 (0.05)<0.001<0.001a<0.001

TSH, thyroid-stimulating hormone; FT4, free thyroxine; FT3, free triiodothyronine; TT, total thyroidectomy; HT, hemithyroidectomy.

Mann–Whitney U test.

Postoperative thyroid function profiles of the patients compared to those of the control subjects matched with the Mahalanobis-metric method

In the TT+l-T4 group, the postoperative serum FT4 levels were significantly higher than those of the matched controls (17.2 (15.7–18.9) vs 14.3 (13.3–15.2) pmol/l respectively, P<0.001 (median (25th to 75th percentiles)) and the postoperative serum FT3 levels were significantly lower (4.29 (3.96–4.65) vs 4.42 (4.12–4.74) pmol/l respectively, P=0.008). The serum FT3/FT4 ratios were significantly lower than those of the matched controls (0.25 (0.22–0.28) vs 0.31 (0.28–0.34) respectively, P<0.001) (Fig. 2A).

Figure 2
Figure 2

Postoperative serum FT4, FT3, and FT3/FT4 levels of patients who underwent thyroidectomy and those of the euthyroid controls matched by age, sex, and serum TSH levels. (A) The total thyroidectomy+l-T4 group (n=103). (B) The hemithyroidectomy+l-T4 group (n=56). (C) The hemithyroidectomy-alone group (n=94). FT4, free thyroxine; FT3, free triiodothyronine. The top, bottom, and middle lines of the boxes correspond to the 75th, 25th, and 50th percentiles (median), respectively. The whiskers extend from the minimum to the maximum.

Citation: European Journal of Endocrinology 173, 3; 10.1530/EJE-15-0138

In the HT+l-T4 group, the postoperative serum FT4 and FT3 levels and FT3/FT4 ratios did not differ significantly from those of the matched controls (14.3 (13.2–15.4) vs 13.8 (12.7–14.9) pmol/l, P=0.094; 4.35 (3.98–4.61) vs 4.19 (3.77–4.47) pmol/l, P=0.082; and 0.29 (0.27–0.33) vs 0.32 (0.29–0.34) respectively, P=0.978) (Fig. 2B).

In the HT-alone group, the postoperative serum FT4 levels were significantly lower than those of the controls (12.9 (12.1–13.6) vs 13.6 (12.3–14.5) pmol/l, P=0.007), but the postoperative serum FT3 levels did not differ significantly from those of the matched controls (4.43 (4.04–4.65) vs 4.25 (3.92–4.56) pmol/l, P=0.083), and the serum FT3/FT4 ratios were significantly higher than those of the controls (0.34 (0.32–0.37) vs 0.32 (0.29–0.35), P<0.001) (Fig. 2C).

Discussion

The results of the present study demonstrate that in patients who underwent TT and showed normal TSH levels postoperatively, the postoperative serum FT3 levels were lower than their preoperative native levels and those of the matched euthyroid controls despite the increased FT4 levels. The results obtained for the patients with TT+supplemental l-T4 in the present study were consistent with those of our previous report (2) and the reports by Gullo et al. (4) and Hoermann et al. (5). These findings suggest that the reason underlying the decreased serum T3 levels in such patients is the lack of intra-thyroidal T3 production caused by the absence of the thyroid gland. These data suggest that TSH-suppressive doses of l-T4 are required to achieve normal T3 levels in patients who have undergone TT not only for thyroid cancer but also for other diseases such as Graves' disease, multinodular disease, and Hashimoto thyroiditis.

Here we studied a large number of patients with papillary thyroid cancer and observed that the postoperative serum FT3 levels of the patients who underwent a HT alone were substantially equivalent to those of the controls matched by serum TSH level, although the patients' serum FT4 levels were significantly lower, resulting in a higher FT3/FT4 ratio. The mechanism of this increased FT3/FT4 ratio in patients who have undergone a HT alone remains unknown. Lum et al. (15) reported that a non-thyroidal, non-TSH-mediated system exists for maintaining circulating T3 levels in a state of T4 deficiency.

Considered in conjunction with the decreased FT3/FT4 ratio in the present athyreotic patients who underwent a TT, this increased FT3/FT4 ratio in the patients who underwent HT seems to be caused by an increasing production of T3 in the remnant thyroid tissue. Maia et al. (16) reported that D2 is expressed in the human thyroid gland and is postulated to play an important role as a source of plasma T3. As a matter of fact, it has been suggested that the increased D2 in the thyroid gland may account for the status of a low FT4 with relatively high or normal circulating T3 levels in other thyroid diseases, such as follicular carcinoma (10), thyroglobulin gene abnormalities (17), and T3-predominant Graves' disease (18). Very recently, Hoermann et al. reported the association between thyroid volume and deiodinase activity. They investigated deiodinase activity in l-T4-treated patients from thyroid volume groups (cut-off 5 ml) and indicated that patients with a post-interventional lower residual volume (<5 ml) have significantly reduced deiodinase activity and lowered T3 levels compared to patients with a higher residual thyroid volume (19). This result suggests that residual thyroid capacity plays a significant role in the physiological process of T3 homeostasis in humans and is in good agreement with this study. A further proper study including the determination of D2 activity in the remnant thyroid tissue may be necessary to clarify the mechanism of the higher FT3/FT4 ratio in these patients.

In our patients who underwent a HT and were treated with l-T4 therapy, the postoperative serum FT4 and FT3 levels and FT3/FT4 ratio were substantially equivalent to those of the matched controls. The present findings thus demonstrate that the serum thyroid hormone balances in these patients are similar to the preoperative levels in the physiological normal condition and to those of euthyroid controls. Because the dose of l-T4 was less in the patients who underwent a HT than in the patients who underwent a TT, we speculate that the reason the decrease of T3 levels was not observed in these patients was the production of T3 in the remnant thyroid tissue.

Considerable controversy exists regarding the management of the thyroid function status in patients who have undergone a thyroidectomy and are receiving postoperative l-T4 therapy. Since the negative feedback relationship between serum T4 levels and serum TSH levels is a consistent inverse relationship, most endocrinologists consider the serum TSH level a very sensitive indicator of thyroid function. However, serum TSH levels only reflect the feedback effect of thyroid hormones at the hypothalamic–pituitary level. The TSH secretion from the pituitary is negatively regulated primarily by T3 produced locally via the conversion of T4 transported from the peripheral blood, which is in keeping with the view that serum T4 rather than T3 has a dominant role in regulating TSH secretion (20). On the other hand, T3 transported from the peripheral blood also has a role in regulating TSH secretion by the pituitary. This has been well documented in patients acutely given large amounts of propylthyouracyl, which inhibits the peripheral synthesis of T3 (21).

l-T4 alone administered to rats that had undergone a TT at doses to normalize the plasma TSH levels did not normalize the T3 contents in some tissues (22). Alevizaki et al. (23) reported that athyreotic patients with T4-treated hypothyroidism and normal TSH levels had lower T3 and lower sex hormone-binding globulin (SHBG) levels than controls. These data suggest that normal TSH levels cannot guarantee euthyroidism in peripheral tissues in post-thyroidectomized athyreotic patients under l-T4 therapy. Most clinicians generally believe that a low serum TSH level indicates subclinical thyrotoxicosis and is a risk factor for cardiac dysfunction or osteoporosis (24). However, such a clinical outcome in subclinical thyrotoxicosis seems to be unclear in patients with moderately low TSH levels (25). Thus, in patients who have undergone a TT, TSH-suppressive treatment by l-T4 for high-risk thyroid cancer may not necessarily cause thyrotoxicosis.

The present study has some possible limitations. First, it has been reported that serum FT4 and FT3 levels increased transiently after the ingestion of l-T4 (26, 27). In consideration of such an increment, the evaluation of diurnal variation or the area under the curve (AUC) by repeated blood sampling may be the best method; however, it is practically difficult to carry out such an examination in many patients. In the present study, we evaluated the blood sampling data after the ingestion of l-T4. The result (i.e., the FT3 levels were lower than the preoperative FT3 levels) suggests that the postoperative FT3 levels in the serum remained relatively low for most of the day. In contrast, the serum FT4 levels were higher than the preoperative levels, and this could be affected by the blood sampling after the consumption of l-T4. Second, in this retrospective study, we did not measure the thyroid volumes. In general, it is believed that about 20% of the T3 pool is secreted from the thyroid gland, while we found that a marked contribution that is attributed to the remnant would be at variance with this reported proportion in humans. It would be possible to put a rough quantitative estimate on thyroidal T3 contributions by comparing pre- and postoperative levels and changes in volume. Properly designed studies including measures of the thyroid volumes are needed to clarify the quantitative estimate on thyroidal T3 contributions in the postoperative patients. In addition, the present study is restricted to the patients with normal serum TSH levels. It might be interesting to get some additional comparisons with another large entity, thyroidectomized patients with advanced thyroid cancer maintained on a TSH-suppressive regimen.

In conclusion, the results of the present study showed that in thyroidectomized patients, the presence of thyroid tissue causes significant differences in the interrelation of FT4, FT3, and TSH levels. Our findings suggest that T3 production by the remnant thyroid tissue has a substantial effect on the maintenance of serum T3 levels in thyroidectomized patients. The question arises as to whether any of the patients in the three groups were in a euthyroid condition: those with normal TSH, mildly high FT4, and mildly low FT3 levels among the TT+l-T4 patients, those with mildly suppressed TSH, mildly high FT4, and mildly low FT3 in the TT+supplemental l-T4 group, or those with normal TSH, mildly low FT4, and normal FT3 among the HT-alone patients. These patients live in a chronic condition of abnormal thyroid hormone status for the remainder of their lives. Therefore, even if the thyroidal dysfunction may be subtle, its long-term effects cannot be overlooked.

In 2014, the American Thyroid Association stated in a guideline that patients with hypothyroidism treated with l-T4 to achieve normal serum TSH values may have serum T3 levels that are at the lower end of the reference range, or even below the reference range (28). The guideline also mentioned that there is insufficient beneficial evidence to recommend that treatment with l-T4 be targeted to achieve low-normal TSH values or high-normal T3 values in patients with hypothyroidism who are athyreotic (28). The major weakness of this study, and most of the studies like this, concerns its retrospective analysis that may eliminate the ability to obtain strong conclusions. Prospective studies including measures of the patients' well-being and/or metabolic markers such as lipid or bone markers are needed to clarify the best method of managing postoperative thyroid function in patients.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

M Ito and A Miyauchi constructed the study design. M Ito analyzed the data and wrote the manuscript. The other coauthors contributed by performing surgery and/or caring for the patients. All authors read and approved the final manuscript.

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    • Export Citation
  • 7

    Lombardi G, Panza N, Lupoli G, Leonello D, Carlino M, Minozzi M. Study of the pituitary–thyroid axis in euthyroid goiter after partial thyroidectomy. Journal of Endocrinological Investigation 1983 6 485487. (doi:10.1007/BF03348349).

    • Search Google Scholar
    • Export Citation
  • 8

    Lindblom P, Valdemarsson S, Lindergård B, Westerdahl J, Bergenfelz A. Decreased levels of ionized calcium one year after hemithyroidectomy: importance of reduced thyroid hormones. Hormone Research 2001 55 8187. (doi:10.1159/000049975).

    • Search Google Scholar
    • Export Citation
  • 9

    Toft Kristensen T, Larsen J, Pedersen PL, Feldthusen AD, Ellervik C, Jelstrup S, Kvetny J. Persistent cellular metabolic changes after hemithyroidectomy for benign euthyroid goiter. European Thyroid Journal 2014 3 1016. (doi:10.1159/000357943).

    • Search Google Scholar
    • Export Citation
  • 10

    Miyauchi A, Takamura Y, Ito Y, Miya A, Kobayashi K, Matsuzuka F, Amino N, Toyoda N, Nomura E, Nishikawa M. 3,5,3′-Triiodothyronine thyrotoxicosis due to increased conversion of administered levothyroxine in patients with massive metastatic follicular thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 2008 93 22392242. (doi:10.1210/jc.2007-2282).

    • Search Google Scholar
    • Export Citation
  • 11

    Toyoda N, Nishikawa M, Mori Y, Gondou A, Ogawa Y, Yonemoto T, Yoshimura M, Masaki H, Inada M. Thyrotropin and triiodothyronine regulate iodothyronine 5′-deiodinase messenger ribonucleic acid levels in FRTL-5 rat thyroid cells. Endocrinology 1992 131 389394. (doi:10.1210/endo.131.1.1319323).

    • Search Google Scholar
    • Export Citation
  • 12

    Murakami M, Kamiya Y, Morimura T, Araki O, Imamura M, Ogiwara T, Mizuma H, Mori M. Thyrotropin receptors in brown adipose tissue: thyrotropin stimulates type II iodothyronine deiodinase and uncoupling protein-1 in brown adipocytes. Endocrinology 2001 142 11951201. (doi:10.1210/endo.142.3.8012).

    • Search Google Scholar
    • Export Citation
  • 13

    Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews 2002 23 3889. (doi:10.1210/edrv.23.1.0455).

    • Search Google Scholar
    • Export Citation
  • 14

    Rubin DB. Using multivariate sampling and regression adjustment to control bias in observational studies. Journal of the American Statistical Association 1979 74 318328.

    • Search Google Scholar
    • Export Citation
  • 15

    Lum SM, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. Journal of Clinical Investigation 1984 73 570575. (doi:10.1172/JCI111245).

    • Search Google Scholar
    • Export Citation
  • 16

    Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. Journal of Clinical Investigation 2005 115 25242533. (doi:10.1172/JCI25083).

    • Search Google Scholar
    • Export Citation
  • 17

    Kanou Y, Hishinuma A, Tsunekawa K, Seki K, Mizuno Y, Fujisawa H, Imai T, Miura Y, Nagasaka T, Yamada C et al. . Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity. Journal of Clinical Endocrinology and Metabolism 2007 92 14511457. (doi:10.1210/jc.2006-1242).

    • Search Google Scholar
    • Export Citation
  • 18

    Ito M, Toyoda N, Nomura E, Takamura Y, Amino N, Iwasaka T, Takamatsu J, Miyauchi A, Nishikawa M. Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with 3,5,3′-triiodothyronine-predominant Graves' disease. European Journal of Endocrinology/European Federation of Endocrine Societies 2011 164 95100. (doi:10.1530/EJE-10-0736).

    • Search Google Scholar
    • Export Citation
  • 19

    Hoermann R, Midgley JE, Larisch R, Dietrich JW. Integration of peripheral and glandular regulation of triiodothyronine production by thyrotropin in untreated and thyroxine-treated subjects. Hormone and Metabolic Research = Hormon- und Stoffwechselforschung = Hormones et Métabolisme 2015 In press doi:10.1055/s-0034-1398616).

    • Search Google Scholar
    • Export Citation
  • 20

    Silva JE, Larsen PR. Contributions of plasma triiodothyronine and local thyroxine monodeiodination to triiodothyronine to nuclear triiodothyronine receptor saturation in pituitary, liver, and kidney of hypothyroid rats. Further evidence relating saturation of pituitary nuclear triiodothyronine receptors and the acute inhibition of thyroid-stimulating hormone release. Journal of Clinical Investigation 1978 61 12471259. (doi:10.1172/JCI109041).

    • Search Google Scholar
    • Export Citation
  • 21

    Geffner DL, Azukizawa M, Hershman JM. Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man. Journal of Clinical Investigation 1975 55 224229. (doi:10.1172/JCI107925).

    • Search Google Scholar
    • Export Citation
  • 22

    Escobar-Morreale HF, Obregón MJ, Escobar del Rey F, Morreale de Escobar G. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. Journal of Clinical Investigation 1995 96 28282838. (doi:10.1172/JCI118353).

    • Search Google Scholar
    • Export Citation
  • 23

    Alevizaki M, Mantzou E, Cimponeriu AT, Alevizaki CC, Koutras DA. TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wiener Klinische Wochenschrift 2005 117 636640. (doi:10.1007/s00508-005-0421-0).

    • Search Google Scholar
    • Export Citation
  • 24

    Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA et al. . Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. Journal of the American Medical Association 2004 291 228238. (doi:10.1001/jama.291.2.228).

    • Search Google Scholar
    • Export Citation
  • 25

    Biondi B. How could we improve the increased cardiovascular mortality in patients with overt and subclinical hyperthyroidism. European Journal of Endocrinology/European Federation of Endocrine Societies 2012 167 295299. (doi:10.1530/EJE-12-0585).

    • Search Google Scholar
    • Export Citation
  • 26

    Wennlund A. Variation in serum levels of T3, T4, FT4 and TSH during thyroxine replacement therapy. Acta Endocrinologica 1986 113 4749. (doi:10.1530/acta.0.1130047).

    • Search Google Scholar
    • Export Citation
  • 27

    Sturgess I, Thomas SH, Pennell DJ, Mitchell D, Croft DN. Diurnal variation in TSH and free thyroid hormones in patients on thyroxine replacement. Acta Endocrinologica 1989 121 674676. (doi:10.1530/acta.0.1210674).

    • Search Google Scholar
    • Export Citation
  • 28

    Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim B, Peeters R, Rosenthal MS et al. . Guidelines for the treatment of hypothyroidism. Thyroid 2014 24 16701751. (doi:10.1089/thy.2014.0028).

    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

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    Flow chart of study. PC, papillary carcinoma.

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    Postoperative serum FT4, FT3, and FT3/FT4 levels of patients who underwent thyroidectomy and those of the euthyroid controls matched by age, sex, and serum TSH levels. (A) The total thyroidectomy+l-T4 group (n=103). (B) The hemithyroidectomy+l-T4 group (n=56). (C) The hemithyroidectomy-alone group (n=94). FT4, free thyroxine; FT3, free triiodothyronine. The top, bottom, and middle lines of the boxes correspond to the 75th, 25th, and 50th percentiles (median), respectively. The whiskers extend from the minimum to the maximum.

  • 1

    Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R. Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. American Journal of Physiology 1990 258 715726.

    • Search Google Scholar
    • Export Citation
  • 2

    Ito M, Miyauchi A, Morita S, Kudo T, Nishihara E, Kihara M, Takamura Y, Ito Y, Kobayashi K, Miya A et al. . TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. European Journal of Endocrinology/European Federation of Endocrine Societies 2012 167 373378. (doi:10.1530/EJE-11-1029).

    • Search Google Scholar
    • Export Citation
  • 3

    Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. Journal of the American Medical Association 2008 299 769777. (doi:10.1001/jama.299.7.769).

    • Search Google Scholar
    • Export Citation
  • 4

    Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE 2011 6 e22552. (doi:10.1371/journal.pone.0022552).

    • Search Google Scholar
    • Export Citation
  • 5

    Hoermann R, Midgley JE, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R. Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clinical Endocrinology 2014 81 907915. (doi:10.1111/cen.12527).

    • Search Google Scholar
    • Export Citation
  • 6

    Verloop H, Louwerens M, Schoones JW, Kievit J, Smit JW, Dekkers OM. Risk of hypothyroidism following hemithyroidectomy: systematic review and meta-analysis of prognostic studies. Journal of Clinical Endocrinology and Metabolism 2012 97 22432255. (doi:10.1210/jc.2012-1063).

    • Search Google Scholar
    • Export Citation
  • 7

    Lombardi G, Panza N, Lupoli G, Leonello D, Carlino M, Minozzi M. Study of the pituitary–thyroid axis in euthyroid goiter after partial thyroidectomy. Journal of Endocrinological Investigation 1983 6 485487. (doi:10.1007/BF03348349).

    • Search Google Scholar
    • Export Citation
  • 8

    Lindblom P, Valdemarsson S, Lindergård B, Westerdahl J, Bergenfelz A. Decreased levels of ionized calcium one year after hemithyroidectomy: importance of reduced thyroid hormones. Hormone Research 2001 55 8187. (doi:10.1159/000049975).

    • Search Google Scholar
    • Export Citation
  • 9

    Toft Kristensen T, Larsen J, Pedersen PL, Feldthusen AD, Ellervik C, Jelstrup S, Kvetny J. Persistent cellular metabolic changes after hemithyroidectomy for benign euthyroid goiter. European Thyroid Journal 2014 3 1016. (doi:10.1159/000357943).

    • Search Google Scholar
    • Export Citation
  • 10

    Miyauchi A, Takamura Y, Ito Y, Miya A, Kobayashi K, Matsuzuka F, Amino N, Toyoda N, Nomura E, Nishikawa M. 3,5,3′-Triiodothyronine thyrotoxicosis due to increased conversion of administered levothyroxine in patients with massive metastatic follicular thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 2008 93 22392242. (doi:10.1210/jc.2007-2282).

    • Search Google Scholar
    • Export Citation
  • 11

    Toyoda N, Nishikawa M, Mori Y, Gondou A, Ogawa Y, Yonemoto T, Yoshimura M, Masaki H, Inada M. Thyrotropin and triiodothyronine regulate iodothyronine 5′-deiodinase messenger ribonucleic acid levels in FRTL-5 rat thyroid cells. Endocrinology 1992 131 389394. (doi:10.1210/endo.131.1.1319323).

    • Search Google Scholar
    • Export Citation
  • 12

    Murakami M, Kamiya Y, Morimura T, Araki O, Imamura M, Ogiwara T, Mizuma H, Mori M. Thyrotropin receptors in brown adipose tissue: thyrotropin stimulates type II iodothyronine deiodinase and uncoupling protein-1 in brown adipocytes. Endocrinology 2001 142 11951201. (doi:10.1210/endo.142.3.8012).

    • Search Google Scholar
    • Export Citation
  • 13

    Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews 2002 23 3889. (doi:10.1210/edrv.23.1.0455).

    • Search Google Scholar
    • Export Citation
  • 14

    Rubin DB. Using multivariate sampling and regression adjustment to control bias in observational studies. Journal of the American Statistical Association 1979 74 318328.

    • Search Google Scholar
    • Export Citation
  • 15

    Lum SM, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. Journal of Clinical Investigation 1984 73 570575. (doi:10.1172/JCI111245).

    • Search Google Scholar
    • Export Citation
  • 16

    Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. Journal of Clinical Investigation 2005 115 25242533. (doi:10.1172/JCI25083).

    • Search Google Scholar
    • Export Citation
  • 17

    Kanou Y, Hishinuma A, Tsunekawa K, Seki K, Mizuno Y, Fujisawa H, Imai T, Miura Y, Nagasaka T, Yamada C et al. . Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity. Journal of Clinical Endocrinology and Metabolism 2007 92 14511457. (doi:10.1210/jc.2006-1242).

    • Search Google Scholar
    • Export Citation
  • 18

    Ito M, Toyoda N, Nomura E, Takamura Y, Amino N, Iwasaka T, Takamatsu J, Miyauchi A, Nishikawa M. Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with 3,5,3′-triiodothyronine-predominant Graves' disease. European Journal of Endocrinology/European Federation of Endocrine Societies 2011 164 95100. (doi:10.1530/EJE-10-0736).

    • Search Google Scholar
    • Export Citation
  • 19

    Hoermann R, Midgley JE, Larisch R, Dietrich JW. Integration of peripheral and glandular regulation of triiodothyronine production by thyrotropin in untreated and thyroxine-treated subjects. Hormone and Metabolic Research = Hormon- und Stoffwechselforschung = Hormones et Métabolisme 2015 In press doi:10.1055/s-0034-1398616).

    • Search Google Scholar
    • Export Citation
  • 20

    Silva JE, Larsen PR. Contributions of plasma triiodothyronine and local thyroxine monodeiodination to triiodothyronine to nuclear triiodothyronine receptor saturation in pituitary, liver, and kidney of hypothyroid rats. Further evidence relating saturation of pituitary nuclear triiodothyronine receptors and the acute inhibition of thyroid-stimulating hormone release. Journal of Clinical Investigation 1978 61 12471259. (doi:10.1172/JCI109041).

    • Search Google Scholar
    • Export Citation
  • 21

    Geffner DL, Azukizawa M, Hershman JM. Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man. Journal of Clinical Investigation 1975 55 224229. (doi:10.1172/JCI107925).

    • Search Google Scholar
    • Export Citation
  • 22

    Escobar-Morreale HF, Obregón MJ, Escobar del Rey F, Morreale de Escobar G. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. Journal of Clinical Investigation 1995 96 28282838. (doi:10.1172/JCI118353).

    • Search Google Scholar
    • Export Citation
  • 23

    Alevizaki M, Mantzou E, Cimponeriu AT, Alevizaki CC, Koutras DA. TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wiener Klinische Wochenschrift 2005 117 636640. (doi:10.1007/s00508-005-0421-0).

    • Search Google Scholar
    • Export Citation
  • 24

    Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA et al. . Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. Journal of the American Medical Association 2004 291 228238. (doi:10.1001/jama.291.2.228).

    • Search Google Scholar
    • Export Citation
  • 25

    Biondi B. How could we improve the increased cardiovascular mortality in patients with overt and subclinical hyperthyroidism. European Journal of Endocrinology/European Federation of Endocrine Societies 2012 167 295299. (doi:10.1530/EJE-12-0585).

    • Search Google Scholar
    • Export Citation
  • 26

    Wennlund A. Variation in serum levels of T3, T4, FT4 and TSH during thyroxine replacement therapy. Acta Endocrinologica 1986 113 4749. (doi:10.1530/acta.0.1130047).

    • Search Google Scholar
    • Export Citation
  • 27

    Sturgess I, Thomas SH, Pennell DJ, Mitchell D, Croft DN. Diurnal variation in TSH and free thyroid hormones in patients on thyroxine replacement. Acta Endocrinologica 1989 121 674676. (doi:10.1530/acta.0.1210674).

    • Search Google Scholar
    • Export Citation
  • 28

    Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim B, Peeters R, Rosenthal MS et al. . Guidelines for the treatment of hypothyroidism. Thyroid 2014 24 16701751. (doi:10.1089/thy.2014.0028).

    • Search Google Scholar
    • Export Citation