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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 2149-2156
Copyright © 2007 by The Endocrine Society

Sources of Circulating 3,5,3'-Triiodothyronine in Hyperthyroidism Estimated after Blocking of Type 1 and Type 2 Iodothyronine Deiodinases

Peter Laurberg, Henrik Vestergaard, Soren Nielsen, Stig E. Christensen, Torben Seefeldt, Kjeld Helleberg and Klaus M. Pedersen

Departments of Endocrinology and Internal Medicine, Aalborg Hospital (P.L.), DK-9000 Aalborg, Denmark; Herlev Hospital (H.V.), DK-2730 Herlev, Denmark; Aarhus Hospital (S.N., T.S.), DK-8000 Aarhus, Denmark; Aabenraa Hospital (S.E.C.), DK-6200 Aabenraa, Denmark; Viborg Hospital (K.H.), DK-8800 Viborg, Denmark; and Hobro Hospital (K.M.P.), DK-9500 Hobro, Denmark

Address all correspondence and requests for reprints to: Peter Laurberg, M.D., Department of Endocrinology and Medicine, Aalborg Hospital, Aarhus University Hospital, DK-9000 Aalborg, Denmark. E-mail: peter.laurberg{at}rn.dk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Graves’ hyperthyroidism and multinodular toxic goiter lead to high serum T3 compared with serum T4. The source of this high T3 has not been clarified.

Objective: Our objective was to assess the role of iodothyronine deiodinase type 1 (D1) and type 2 (D2) for T3 production and to estimate the sources of T3 in hyperthyroidism.

Design and Setting: The study was a prospective, randomized, open-labeled study in a secondary care setting.

Patients and Methods: Consecutive patients with hyperthyroidism caused by Graves’ disease or by multinodular toxic goiter were randomized to be treated with high-dose propylthiouracil (PTU) to block D1, PTU plus KI, or PTU plus sodium ipodate to additionally block D2. T3 and T4 were measured in serum, and we estimated the sources of T3.

Results: PTU reduced the T3/T4 in serum to 47.7 ± 2.5% (mean ± SEM) of the initial value on d 4 of therapy in patients with Graves’ disease. The addition of KI to PTU led to a greater fall in T3 and T4, but the balance was unaltered. After PTU plus ipodate, T3/T4 on d 4 was lower, 34.1 ± 1.2% of the initial value. Similar variations were observed in patients with multinodular toxic goiter. Thus, the major source of the excess T3 was D1-catalyzed T4 deiodination, with a minor role for D2. It was estimated that the majority of this D1-catalyzed T3 production takes place in the hyperactive thyroid gland.

Conclusion: Although thyroidal T3 contributes only around 20% of total T3 production in normal individuals, this is much higher in patients with a hyperactive thyroid, ranging up to two thirds. The major part is produced from T4 deiodinated in the thyroid.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THYROID HORMONES ARE important for development and growth, and in the adult individual, they participate in the regulation of metabolism and activity of probably every single cell. Thyroid hormone secretion depends on the function of the hypothalamic-pituitary-thyroid axis, and hormone effects on tissues are modulated by a complex system of hormone transport over membranes and enzymatic activation and inactivation of the iodothyronines in peripheral tissues.

In hyperthyroidism, thyroid hormone production is no longer targeted to physiological needs; rather, it is driven by one of a number of abnormalities. In Graves’ disease (GD), the abnormality is generation of TSH receptor-stimulating antibodies. In multinodular toxic goiter (MNTG), it is the constitutive activation of part of the thyroid follicular cells.

It is well established that hyperthyroid patients suffering from GD or MNTG have a disproportionate increase of T3 in serum compared with the increase in serum T4 (1, 2, 3). The high T3 may bypass some of the normal regulatory mechanisms operating in peripheral tissues, thus worsening the thyrotoxic state. To study the sources of this T3, we randomized patients with GD and MNTG to receive various combinations of drugs that can be used to treat hyperthyroidism. In particular, we used high-dose therapy with propylthiouracil (PTU) to block type 1 iodothyronine deiodinase (D1) (4) and sodium ipodate to additionally block type 2 iodothyronine deiodinase (D2) (5). In normal euthyroid subjects, these two enzymes catalyze the major part of T3 production by way of outer ring deiodination of T4 taking place in peripheral tissues (6).

Recently, Maia et al. (7) used cultures of human cells transfected with D1 or D2, as well as other in vitro systems, to study T3 production from T4 at various levels of ambient T4. According to their calculations, D2-catalyzed T3 generation may be responsible for around two thirds of peripheral T3 production in humans in the normal state. On the other hand, D1 may be more important in hyperthyroidism (7). Our study of patients with hyperthyroidism confirmed their notion on T3 production by D1-catalyzed T4 deiodination in hyperthyroidism. Moreover, we subsequently estimated from this and previous studies that a large part of the T3 production by deiodination of T4 that takes place in patients with a hyperactive thyroid occurs within the thyroid gland.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Consecutive patients submitted to hospital with newly diagnosed hyperthyroidism caused by GD (n = 27) or MNTG (n = 15) were stratified according to type of disease and randomly assigned to one of three types of medical therapies: 1) PTU, 400 mg four times daily; 2) PTU, 400 mg four times daily, plus KI, 400 mg three times daily; and 3) PTU, 400 mg four times daily, plus sodium ipodate, 500 mg three times daily. After 7 d, all therapies were changed to methimazole (MMI), 10 mg four times daily for 14 d. The first dose of KI or sodium ipodate was given with the second dose of PTU. Medication was taken at 0700, 1200, 1700, and 2300 h (PTU and MMI) and 0700, 1700, and 2300 h (iodide and ipodate). Blood samples were obtained at 0830–0900 h on d 0 (before the first dose of PTU) and after 1, 2, 4, 7, 8, 9, 11, 14, and 21 d of treatment. Samples were centrifuged at 4 C and sera stored at –20 C until analyses. PTU was obtained from Nycomed (Roskilde, Denmark), methimazole from Gea (Copenhagen, Denmark), potassium iodide tablets were from Marcopharma (Copenhagen, Denmark), and sodium ipodate was Biloptin from Schering (Berlin, Germany).

The diagnoses of GD and MNTG were based on the appearance of the Tc-scintigram of the thyroid with high diffuse uptake in GD and multinodular uptake with suppression of remaining thyroid tissue in MNTG, in patients being clearly clinically and biochemically hyperthyroid. Patients receiving medication affecting thyroid function or serum concentrations of thyroid hormones or who suffered from severe diseases or took iodine-containing supplements were excluded from the study. Serum T4 and T3 were measured by in-house RIAs (8, 9) known from many studies to give reliable measures over a wide range of serum concentrations. Normal ranges were 77–148 nmol/liter for T4 and 1.23–2.46 nmol/liter for T3, and the average normal T3 in percentage of T4 (nmol/nmol x 100) was 1.65. As part of the initial patient evaluation, a T3-uptake test was performed. None of the patients had signs of thyroid hormone-binding protein abnormalities, and no additional T3-uptake tests were performed.

One patient with GD treated with PTU plus KI felt mildly sick after KI and left the study. One patient with GD treated with PTU plus sodium ipodate was excluded on d 3 because of suspicion of the beginning of a cutaneous reaction. However, no significant reaction developed. One patient with MNTG treated with PTU was excluded due to lack of blood sampling by mistake. During the treatment period, regular analyses of blood leukocyte, thrombocyte, and erythrocyte counts as well as serum creatinine and liver function tests were performed and found unchanged. Informed consent was obtained from all patients, and the protocol was approved according to national ethical regulations.

Statistical analyses and data handling were performed with SPSS version 13.0.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Some basic characteristics of the 25 patients with GD and the 14 patients with MNTG who completed the study are given in Table 1Go. Patients with GD were on average younger [45 ± 12 yr of age (mean ± SD)] than those with MNTG (60 ± 11 yr of age) (P = 0.001, independent-samples t test) and had a higher serum T3 (6.36 ± 2.67 nmol/liter) than patients with MNTG (4.28 ± 1.79) (P = 0.013) and a higher ratio between T3 and T4 in serum (T3 nmol per liter/T4 nmol per liter in percent) (T3/T4%) (2.70 ± 0.63 vs. 2.01 ± 0.40) (P = 0.001). The difference in serum T4 (231 ± 58 vs. 209 ± 47 nmol/liter) was not statistically significant (P = 0.23). For comparison of treatment types, subsequent analyses were performed after stratification into the two subtypes of disease or in multivariate models including type of disease as an explanatory variable. Despite the random allocation to treatment groups, there were significant differences between groups in serum T4 (P = 0.014, ANOVA) and T3 (P = 0.008) before therapy in the patients with GD but not in the patients with MNTG (Table 1Go).


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  		TABLE 1. Characteristics of patients and response to therapy

 
Changes in serum T3 and T4

The absolute mean values of serum T3 and T4, and the calculated T3 percentage of T4 at various time points of the study, are given in Table 1Go, and the variation relative to the untreated condition is shown in Figs. 1Go (GD) and 2Go (MNTG).


Figure 1
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  		FIG. 1. Serum T4, T3, and T3 percentage of T4 (nmol/nmol x 100) in percentage of values from the untreated condition in 25 patients with hyperthyroidism caused by GD. Patients were randomly allotted to one of three types of antithyroid therapy: PTU, 400 mg four times per day (n = 9); PTU plus KI, 400 mg three times per day (n = 8); and PTU plus sodium ipodate, 500 mg three times per day (n = 8). After 7 d of therapy, all therapies were changed to MMI, 10 mg four times per day as indicated by the vertical dotted line. Values are mean, and error bars are SEM.

 

Figure 2
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  		FIG. 2. Serum T4, T3, and T3 percentage of T4 (nmol/nmol x 100) in percentage of values from the untreated condition in 14 patients with hyperthyroidism caused by MNTG. Patients were randomly allotted to one of three types of antithyroid therapy: PTU, 400 mg four times per day (n = 4); PTU plus KI, 400 mg three times per day (n = 5); and PTU plus sodium ipodate, 500 mg three times per day (n = 5). After 7 d of therapy, all therapies were changed to MMI, 10 mg four times per day as indicated by the vertical dotted line. Values are mean, and error bars are SEM.

 
In patients with Graves’ hyperthyroidism, PTU led to a rapid and sustained fall in serum T3, but after a shift from PTU to MMI, a reciprocal increase in serum T3 occurred. Serum T4 declined gradually and moderately during the study period. The addition of KI to PTU gave a more rapid decline in both serum T4 and T3 (for statistical analyses, see below), but after a shift from PTU plus KI to MMI, a rebound of T4 and T3 occurred.

Therapy with PTU plus sodium ipodate gave a T4 response intermediate between the two other types of therapy, whereas the fall in T3 was the largest observed. After a shift to MMI, an increase in T3 was seen that was considerably slower than in the other treatment groups.

Therapy of patients with hyperthyroidism caused by MNTG gave much the same type of responses (Fig. 2Go), but the overall pattern over the entire 21 d was that thyroid function responded more slowly to therapy (Table 1Go).

When tested in a multivariate linear regression model with serum T4 on d 7 in percentage of d 0 as a measure of the fall in T4 during therapy as dependent variable and type of therapy (PTU or PTU plus KI), type of disease, and T4 before therapy as explanatory variables, type of therapy had a significant association with the fall in T4 (P < 0.001). Similar results were obtained when PTU plus KI was tested against PTU plus ipodate in the model (P = 0.002). Type of therapy had no significant effect on percent T4 on d 21 (P = 0.07; P = 0.66). In these models, type of disease (GD or MNTG) was always a significant predictor of T4 response, whereas serum T4 before therapy was not.

When the T3 responses to therapy were entered in similar models, type of therapy predicted the percent T3 on d 7 (P < 0.001 in both models) and had a borderline association on d 21 (PTU vs. PTU plus KI, P = 0.051; PTU plus KI vs. PTU plus ipodate, P = 0.047). Both type of disease and serum T3 before therapy (with a higher relative response when serum T3 was higher) predicted the T3 response at all times (P values ranging from <0.001–0.029).

Changes in the balance between T3 and T4 in serum

Figure 3Go illustrates the association between the balance between T3 and T4 in serum and the degree of biochemical hyperthyroidism in the untreated patients. A clear positive correlation was observed with T3/T4% in serum ranging from normal (which is on average 1.65 with the assays employed) in patients with mild hyperthyroidism to above 4 in severe cases. Apart from the milder hyperthyroidism in patients with MNTG, no systematic difference between patients with GD and MNTG was apparent.


Figure 3
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  		FIG. 3. Scatter plots of the association between degree of biochemical hyperthyroidism as evaluated by untreated serum T3 (left) and T4 (right) and the balance between T3 and T4 in serum (measured as T3 percentage of T4 molar concentrations). Open circles are patients with MNTG, closed circles are patients with GD. R2 and P values are given for the linear regressions.

 
In patients with GD, a considerable decrease was observed in the T3/T4% in serum during PTU therapy to 47.7 ± 2.5% (mean ± SEM) of the initial value on d 4 (Fig. 1Go). Addition of KI to PTU did not modify the PTU-induced changes in the balance between T3 and T4 in serum (T3/T4% in serum on d 4 was 44.7 ± 4.5% of the initial value; P = 0.56 vs. PTU alone, independent-samples t test). After PTU plus ipodate, the fall in the T3/T4% in serum was considerably larger than after the two other types of therapy (T3/T4% on d 4 was 34.1 ± 1.2%; P < 0.001 vs. PTU; P = 0.04 vs. PTU plus KI). The pattern was similar in patients with MNTG (Fig. 2Go). On d 4 of therapy, the T3/T4% was for PTU, 53.3 ± 3.8% of initial value; PTU plus KI, 56.6 ± 6.5%; and PTU plus ipodate, 36.4 ± 3.6% (P = 0.01 vs. PTU; P = 0.03 vs. PTU plus KI).

In multivariate models, the change in the balance between T3 and T4 in serum was independent of type of disease and of T3/T4% before therapy and not different between the PTU and the PTU plus KI group. The T3/T4% after 7 and 9 d of therapy was significantly associated with type of therapy in models including PTU or PTU plus KI vs. PTU plus ipodate (P < 0.001), with no statistically significant difference after 21 d of therapy.

To evaluate whether the response in T3/T4 in serum to therapy depended on the degree of hyperthyroidism, we plotted associations between the percent fall in T3/T4 from d 0 to d 4 against the untreated serum T3 and T4 in the three treatment groups (Fig. 4Go). As illustrated, the response was high in the more hyperthyroid patients in some of the treatment groups but difficult to evaluate in the group PTU plus ipodate with no severely hyperthyroid patients (despite random allocation). In the estimation of sources of T3 in serum (Table 2Go), we did not include differences in responses depending on severity of hyperthyroidism in the models.


Figure 4
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  		FIG. 4. Correlations between the degree of biochemical hyperthyroidism as evaluated by untreated serum T3 (left) and T4 (right) and the change in balance between T3 and T4 in serum from untreated (d 0) to d 4 of therapy. The change in T3/T4 in serum is given as the value on d 4 as a percentage of the value on d 0 for each individual patient and plotted according to the type of therapy given. R2 and P values are given for the linear regressions.

 

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  		TABLE 2. Estimated sources of T3 in the normal state and in two hypothetical patients with Graves’ hyperthyroidism

 
Estimation of sources of T3 in hyperthyroidism

Based on the results of the present and previous studies, we estimated the sources of T3 in serum in hyperthyroidism (Table 2Go). An important assumption to be discussed was that fractional deiodination of T4 to T3 in peripheral tissues is unchanged in hyperthyroidism (although the enzyme catalyzing the deiodination may be different). Values for normal euthyroid subjects were taken from other studies as indicated in the footnote to Table 2Go. The results of the present study were used to estimate values for two hypothetical hyperthyroid patients: patient A with average GD and patient B having more severe disease.

The overall balance of T3 produced by D1-catalyzed and D2-catalyzed deiodination of T4 in hyperthyroidism (three to one) was calculated from the present findings of a 50% decrease in T3/T4% after PTU plus KI and a 66% decrease after PTU plus ipodate therapy.

The main result of the estimation was that thyroidal T3 production was much higher in hyperthyroidism (47% of total T3 production in patient A, 68% in patient B) than in the euthyroid state (20%) and that the main cause was a high thyroidal deiodination of T4 to T3 (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
We studied the balance between T3 and T4 in serum in patients with untreated GD and MNTG and the response to various types of therapy. High-dose PTU led to a rapid fall in serum T3 and a decrease in the ratio between T3 and T4 in serum to around 50% of initial. This is a well-known effect of PTU caused by inhibition of the type 1 T4 deiodinase (D1) (10, 11). The dose of PTU used gives a sustained inhibition of D1 as judged from our previous studies (12) and dose-response evaluations by Abuid and Larsen (10). The rapid fall in serum T3 is associated with a fall in peripheral effects of thyroid hormones (13), which makes high-dose PTU the preferred thionamide therapy of patients with manifest or impending thyrotoxic crisis. Our results illustrate that this type of therapy is equally effective in patients with GD and MNTG.

Addition of KI to PTU did not modify the balance between T3 and T4 in serum, but it led to a more rapid decrease in overall thyroid secretion with a parallel fall in T3 and T4 in serum. Excess iodide leads to rapid inhibition of several processes involved in thyroid hormone production and secretion. The exact mechanism behind this autoregulation is unknown, but the effect seems to be mediated via generation of iodine-containing organic intermediates (14). Because thionamide drugs inhibit organification of iodide in the thyroid, it might be questioned whether KI therapy would lead to an additional decrease in thyroid hormone secretion during high-dose therapy with a thionamide drug (14). The results of the present study show that, indeed, both T4 and T3 in serum decreased more rapidly when KI was added to PTU.

Ipodate is an effective inhibitor of both D1 and D2 (5, 15). Furthermore, ipodate contains 64% iodine, part of which is released as iodide after ingestion. Thus, PTU plus ipodate would be expected to give the same effect as PTU plus KI but with the additional effect of inhibition of D2.

The greater fall in serum T4 during PTU plus KI than during PTU plus ipodate therapy would presumably be caused by an ipodate-induced decrease in T4 clearance.

Ipodate or similar compounds have been found useful for short-term therapy of hyperthyroidism (16, 17) and for special indications (18) but less effective for prolonged therapy (19). In our study, PTU plus ipodate gave the most profound decrease in serum T3 with a decrease in the T3/T4% in serum to around one third of the initial value. After a change to MMI therapy alone, the increase in serum T3 came much later when ipodate had been used. This is in accordance with the prolonged inhibitory action of such compounds on T3 generation found by St. Germain (5, 15).

The block of D1 in one group of patients and D1 plus D2 in another group, with a control group for evaluation of the additional effect of iodide, enabled us to evaluate the sources of circulating T3 in hyperthyroidism. Turnover rates of T4 and T3 increase similarly in hyperthyroidism with 2-fold increases in metabolic clearance rates in the average GD patient (2). Assuming that D1 was nearly totally blocked by PTU and that the additional effect of ipodate was caused by a near total block of D2, our results suggest that the relative contribution of D1 and D2 to T3 production from T4 in hyperthyroidism is around three to one. This is a confirmation of the D1/D2 balance suggested by Maia et al. (7) from their in vitro studies.

We estimated in more detail the sources of T3 production in hyperthyroidism (Table 2Go). The generally accepted values for normal subjects are that around 80% of T3 originates from deiodination of T4 in peripheral tissues and 20% from the thyroid (6). We split the small thyroidal contribution into two thirds originating from hydrolysis of thyroglobulin (Tg), and one third originating from deiodination of T4 in the thyroid (20). The human thyroid contains both D1 (21) and D2 (22).

To understand T3 production in hyperthyroidism, it is helpful first to consider patients who are thyrotoxic but with no or little function of the thyroid gland. Peripheral D2, which seems to be the enzyme responsible for the major part of T3 production in euthyroid individuals (7), is up-regulated when T4 is low and down-regulated when T4 is high (6). This variation in D2 may explain why serum T3 tends to vary much less than does serum T4 in patients with little function of the thyroid gland when observed in states of thyroid insufficiency or during sufficient or excessive L-T4 replacement therapy. The phenomenon was labeled "peripheral auto-regulation of T4 to T3 conversion" by Nicoloff et al. (23). These authors also observed that no autoregulation of T4 to rT3 conversion occurred and that autoregulation was associated with serum T4 and not with the metabolic state of the patients (23), which is in accordance with D2 activity being responsible for autoregulation (6).

In the presence of excessive amounts of thyroid hormones, D1 activity in liver and kidney increases and peripheral T3 production may switch from being D2 to D1 dependent (7). However, overall fraction of T4 deiodinated to T3 in the periphery is unchanged or even lower when levels of thyroid hormones are high. When excessive amounts of L-T4 are given (23, 24, 25, 26, 27, 28, 29) and in thyrotoxicosis factitia caused by L-T4 intoxication (30), a relatively low T3/T4% in serum has been a consistent finding. Moreover, patients with thyrotoxicosis caused by passive release of hormones from the thyroid have no increase in their T3/T4% in serum (31).

Accordingly, the excess T3 compared with T4 in serum in thyrotoxic patients with a hyperactive thyroid, such as those in the present study, is not produced in peripheral tissues, and it has to originate from the thyroid gland.

Hyperstimulation of the thyroid gland leads to synthesis of Tg with a high T3 content and a T4 content similar to normal (32, 33, 34). This shift may be related to high thyroid peroxidase activity leading to changes in iodotyrosine coupling (33). In patients with untreated GD, the T3 content of Tg is around twice as high as normal (34), but this explains only a small part of the excessive T3 production in untreated patients (Table 2Go).

The remaining source is thyroidal deiodination of T4 to T3. According to our estimations, this contributed only 6% of daily T3 production in the normal state, but it was increased to around 25% in the average GD patient and to around 50% in the patient with severe disease. Such high production of T3 from T4 in the thyroid is not unrealistic. Both D1 and D2 are up-regulated in the hyperactive human thyroid (22, 35, 36). In severe GD, thyroid volume and blood flow may increase manyfold, and thyroid cell fraction is high. The thyroid may deiodinate both T4 released from Tg (20) and T4 taken up from the vascular bed (37). D1 and D2 activities are often relatively low in thyroid follicular cell cancers. However, when D1 or D2 contents are preserved, metastases from thyroid cancer may lead to a state characterized by excess T3 production from T4 (38, 39), similar to patients with active GD.

In the study by Maia et al. (7), it was calculated that a 10-fold increase in peripheral tissue T4 would lead to a state where D1 and D2 contributed around 2:1 to peripheral T3 production (vs. 1:2 in the normal state). An increase in T4 from around 100 (normal) to 200–300 nmol/liter as seen in our patients (Fig. 4Go) would by interpolation be associated with about equal contributions of D1 and D2 to T3 production in the periphery. In the context of the present study, this leads to the conclusion that nearly all T3 generation from T4 in the hyperactive thyroid is catalyzed by D1 (calculations not shown). This conclusion is different from that given by Salvatore et al. (22) based on their studies of D2 and D1 in samples of human thyroid tissue.

Conclusion

We confirmed the usefulness of combinations of high-dose PTU, KI, and ipodate to induce a rapid fall in serum T3 in hyperthyroidism caused by GD and MNTG and that D1 is more important than D2 for T3 production in hyperthyroidism. We estimated that the major source of T3 production in hyperthyroidism is the thyroid gland, which contributed around half of T3 in the average GD patient and two thirds in severely affected patients. The major part of this T3 originated from deiodination of T4 in the thyroid. Recognition of the high thyroidal production of T3 in hyperthyroidism is important for understanding some of the responses that may occur to therapy of hyperthyroidism, for example, the pattern of persistently high serum T3 with low serum T4 that may develop in the minority of GD patients who do not improve autoimmune abnormalities during medical therapy (40).


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online March 27, 2007

Abbreviations: D1, Type 1 iodothyronine deiodinase; GD, Graves’ disease; MMI, methimazole; MNTG, multinodular toxic goiter; PTU, propylthiouracil; Tg, thyroglobulin.

Received January 24, 2007.

Accepted March 15, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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