Therapy of Graves’ hyperthyroidism with thionamide anti-thyroid drugs is accompanied by a gradual remission of the autoimmune aberration in the majority of patients. The most likely mechanism behind this remission has been considered to be a direct immunosuppressive effect of thionamide drugs. However, a number of findings in clinical studies of patients with Graves’ disease indicate that remission is probably not caused by a special effect of thionamide drugs. Many studies have shown that remission is linked to restoration of the euthyroid state, and that it is independent of drug dose and type. Moreover, similar remission is observed when patients become euthyroid after thyroid surgery. In an explanatory model described, it is assumed that the autoimmune aberration of Graves’ disease is often basically quit mild and self-limiting. Patients may become ill by the running of a vicious cycle of hyperthyroidism worsening the autoimmunity, and autoimmunity worsening the hyperthyroidism. Once patients are made euthyroid by one or the other drug or by thyroid surgery, the majority of patients will gradually enter remission of the disease. The conclusion that remission is associated with restoration of the euthyroid state, and that it is not a special drug effect, highlights the importance of making and keeping patients with Graves’ disease euthyroid.
A method for once-through perfusion of the canine thyroid isolated in situ is described. The perfusion medium was a modified Krebs Ringer buffer with 4 % dextran added. In 4 control experiments the T4 and T3 concentrations in effluent were stable or slightly falling during 3 h perfusion. There were no significant alterations in the T4/T3 ratio in the effluent during these experiments.
A 10-min infusion of bovine TSH (1 mU/ml) caused an increase in the release of T4 and T3 after 15–25 min. The T4/T3 ratio in the effluent was significantly reduced after TSH stimulation. However, the ratio returned to pre-stimulation values while the hormone release was still very high. T4 and T3 content of the contralateral thyroid was determined after homogenation and hydrolysis with pronase. The T4/T3 ratio in the homogenate was twice as high as the T4/T3 ratio in the effluent during control perfusion. Thus there was a preferential secretion of T3 from the perfused canine thyroid and this was increased after TSH stimulation.
Previous studies on the secretion of thyroxine (T4), 3,5,3'-triiodothyronine (T3), and 3,3',5'-triiodothyronine (rT3) from perfused dog thyroids have indicated that a differential rate of secretion of various iodothyronines may take place.
The aim of the present study was to evaluate whether the proteolysis of thyroglobulin taking place during secretion could be involved in this phenomenon. Homogenate from the same dog thyroid was incubated either at pH 3.6 for 18 h without added protease or with pronase at pH 8.4 for 18 h. Iodothyronines were measured radioimmunologically in ethanol extracts of the hydrolysates. No significant deiodination of T4 to T3 and rT3 took place during incubation. During acid autolysis 17.5 ± 3.5% (mean ± SE, n = 5) of the T4 found after pronase hydrolysis was liberated, while 31.6 ± 4.8% of the T3 and 21.2 ± 4.2% of the rT3 were liberated (both values were significantly higher than that found for T4). Since iodothyronines in thyroglobulin are released nearly quantitatively during pronase hydrolysis, the results indicate that thyroid proteases acting at acid pH, liberates T3 and rT3 more easily than T4 from thyroglobulin.
This could be the mechanism behind the relatively high secretion of T3 and rT3 observed during acceleration of secretion from perfused thyroid lobes, and the relatively high secretion of T4 observed during deceleration of secretion.
Thyroglobulin fractions rich and poor in new thyroglobulin were separated by means of DEAE-cellulose chromatography of dog thyroid extracts and by zonal ultracentrifugation in a sucrose gradient of guinea pig thyroid extract incubated at low temperature. The distribution of thyroxine, triiodothyronine and 3,3′,5′-(reverse)-triiodothyronine in hydrolysates of the different fractions was estimated by radioimmunoassays. Following DEAE-cellulose chromatography there was a small but statistically significant increase in the T4/T3 ratio in thyroglobulin fractions eluted at high ionic strength - that is fractions relatively rich in stable iodine but poor in fresh thyroglobulin. There were no differences in the T4/rT3 ratios between the different fractions. The ratios between iodothyronines were almost identical in the various thyroglobulin fractions following zonal ultracentrifugation in a sucrose gradient of cold treated guinea pig thyroid extract.
These findings lend no support to the possibility that a relatively high content of triiodothyronines in freshly synthesized thyroglobulin modulates the thyroid secretion towards a preferential secretion of triiodothyronine and 3,3′,5′-(reverse)-triiodothyronine at the expense of the secretion of thyroxine.
Peter Laurberg and Jørgen Weeke
Blood samples for determination of serum total and free reverse triiodothyronine (rT3), triiodothyronine (T3) and thyroxine (T4) were obtained daily in 6 previously untreated thyrotoxic patients during periods of propylthiourazil (PTU) (600 mg per day) or methimazol (MMI) (45 mg per day) administration.
PTU induced about 60 per cent increase in both total and free serum rT3. This was accompanied by a rapid decrease in serum T3 and a more gradual decline in serum T4. MMI administration to untreated patients was followed by a gradual parallel decrease in rT3, T3 and T4. Turn from PTU to MMI produced a rapid decrease in serum rT3 and increase in serum T3 in all 6 patients. The relative variations in the free and total concentrations of iodothyronines were practically identical.
The increase in serum rT3 after PTU is most likely explained either by enhanced deiodination of T4 to rT3 or by an inhibitory effect of PTU on rT3 degradation.
Jørgen Weeke and Peter Laurberg
In a previous study we found a night surge in serum free T3 varying in parallel with that of serum TSH. In order to evaluate whether diurnal alterations in peripheral iodothyronine monodeiodination may be involved we have measured two products of peripheral deiodination, 3,3',5'-T3 (rT3) and 3,3'-T2 in serum samples obtained at short intervals during a 24-h period in 5 normal male subjects. Serum rT3 was rather stable during the period albeit with a trend towards lower levels during the night when the subjects were in bed. In order to obtain a measure of free rT3 a free rT3 index was calculated using the combined variations in per cent free T4 and free T3. Night and day levels of this rT3 index were found identical, suggesting a lack of diurnal variation in serum free rT3. Likewise serum 3,3'-T2 levels were identical during the day and night periods.
The results suggest that variations in peripheral iodothyronine deiodinations are not involved in the night increase in serum free T3.
Jesper Karmisholt and Peter Laurberg
To explore the possibility of predicting decline or improvement in thyroid function over 1 year, and to investigate the correlations of serum TSH (s-TSH) with hypothyroidism-related symptoms and signs, serum thyroid peroxidase antibody (s-TPO-Ab) and urinary iodine excretion in individual patients with untreated subclinical hypothyroidism (SH).
Monthly repeated measurement study without intervention.
Twenty-one patients without former thyroid disease who had been identified with s-TSH between 5 and 12 mU/l and normal serum thyroxine (s-T4) at two occasions were enrolled. Subsequently, 13 monthly measurements of s-TSH, hypothyroidism-related symptoms and signs, serum free T4, s-TPO-Ab and urinary iodine excretion were performed.
Over the study year, s-TSH increased significantly in 5 patients, 16 had unchanged s-TSH, whereas none improved. From clinical and biochemical inclusion data, it was not possible to predict who would later increase in s-TSH. In individual patients, a highly significant correlation between s-TSH and s-TPO-Ab was found (r=0.37, P<0.0001) and also between s-TSH and urinary iodine excretion (r=0.14, P=0.034). No correlation between s-TSH and clinical symptoms and signs was observed. Time shift showed best correlation between s-TSH and s-TPO-Ab measured at the same time point, whereas urinary iodine excretion correlated best to s-TSH and s-TPO-Ab obtained 1 month later.
At the time of inclusion, it was not possible to identify the 24% of SH patients who would show deterioration in thyroid function over the following year. Impairment in thyroid function varied in parallel with thyroid autoimmunity, whereas high urinary iodine excretion predicted high s-TSH and s-TPO-Ab 1 month later.
Stine Linding Andersen and Peter Laurberg
Peter Laurberg and Stine Linding Andersen
Antithyroid drugs (ATDs) may have teratogenic effects when used in early pregnancy.
To review the association between the time period of ATD exposure in early pregnancy and the development of birth defects.
We identified publications on birth defects after early pregnancy exposure to the ATDs methimazole (MMI; and its prodrug carbimazole (CMZ)) and propylthiouracil (PTU). Cases of birth defects after ATD treatment had been initiated or terminated within the first 10 weeks of pregnancy were identified and studied in detail.
A total of 92 publications were read in detail. Two recent large controlled studies showed ATD-associated birth defects in 2–3% of exposed children, and MMI/CMZ-associated defects were often severe. Out of the total number of publications, 17 included cases of birth defects with early pregnancy stop/start of ATD treatment, and these cases suggested that the high risk was confined to gestational weeks 6–10, which is the major period of organogenesis. Thus, the cases reported suggest that the risk of birth defects could be minimized if pregnant women terminate ATD intake before gestational week 6.
Both MMI and PTU use in early pregnancy may lead to birth defects in 2–3% of the exposed children. MMI-associated defects are often severe. Proposals are given on how to minimize the risk of birth defects in fertile women treated for hyperthyroidism with ATDs.