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Nuclear reverse T3 binding sites: an artefact of isolation?

R. Hartong and W. M. Wiersinga

Abstract. Binding of [125I]rT3 to rat liver nuclear extracts prepared in 0.25 m sucrose could be abolished by a prior wash of the nuclei with 2.4 m sucrose. Analysis of mixtures containing [125I]rT3 and nuclear extracts (0.25 m sucrose) showed that after incubation for 2 h at 22°C, degradation of rT3 into 3,3'-T2 and I- had taken place. It appears that the presence of 125I- in these mixtures can account for the previously observed 'binding' of [125I]rT3 to these nuclear extracts.

Further characterization of the deiodination process in nuclear extracts showed: 1) inactivation by heating, 2) production of equimolar amounts of I- and 3,3'-T2, 3) stimulation by sulfhydryl compounds and inhibition by propylthiouracil in a fashion similar to the microsomal iodothyronine 5'-deiodinase (ping-pong mechanism).

We conclude that the observed deiodination of rT3 in hepatic nuclear extracts is of enzymatic nature, due to contamination of the nuclear preparation by microsomal iodothyronine 5'-deiodinase. However, since the nuclei are prepared in the presence of the non-ionic detergent Triton X-100, a nucleus associated deiodinase activity cannot be totally excluded.

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The relation between gastrin, gastric acid and thyroid function disorders

W. M. Wiersinga and J. L. Touber

Abstract.

Hvpergastrinaemia was found in 11 out of 24 untreated hyperthyroid patients (Graves' disease or nodular goitre). Seven patients had a co-existent (autoimmune) atrophic gastritis. In the remaining 17 patients plasma T3 was positively related to plasma gastrin, and negatively to gastric acid output; there was no relation between gastrin levels and acid output. Acid instillation into the stomach revealed a normal negative feedback of acid upon gastrin release.

Sixteen hyperthyroid patients were restudied when euthyroid. Plasma gastrin decreased from 171 (51–1188) ng/l before treatment to 69 (39–392 ng/l after treatment (P < 0.002), and maximal acid output increased from 1.55 (0.00–22.75) to 8.03 (0.00–26.60) mmol H+/h (P < 0.01) (median values; range in brackets). However, in 4 patients with complete achlorhydria before and after treatment plasma gastrin decreased to the same extent as in the patients with gastric acid secretion.

We conclude that thyrotoxic hypergastrinaemia cannot be fully explained by the low gastric acid output in hyperthyroidism.

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ORPHENADRINE (DISIPAL), SERUM THYROXINE AND THYROID FUNCTION

W. M. Wiersinga, A. J. M. Fabius, and J. L. Touber

ABSTRACT

Studies were undertaken to elucidate whether orphenadrine influences thyroid function. Seven volunteers were given orphenadrine in weekly increasing dosage up to 300 mg per day; in 5 patients chronically treated with 300 mg orphenadrine daily the drug was gradually discontinued. No changes were found in PBI, RT3U, TT3 and TSH during or after orphenadrine medication; also TSH- and TT3-responses to 200 μg TRH iv were not influenced by the drug. Orphenadrine medication increased serum thyroxine values (P < 0.001) as measured with the competitive protein binding (CPB) technique, but did not influence serum thyroxine values measured by radioimmunoassay. Orphenadrine added to serum in vitro in the Murphy-Pattee assay did not increase thyroxine values; two out of eight tested metabolites however did. It is concluded that orphenadrine in a dosage up to 300 mg per day does not influence thyroid function. It increases serum thyroxine levels as measured by the competitive protein binding technique of Murphy and Pattee. This is due to an in vitro competition between ethanol-extractable orphenadrine metabolites and thyroxine for binding sites on the thyroxine binding globulin.

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Childhood Graves’ ophthalmopathy: results of a European questionnaire study

G E Krassas, M Segni, and W M Wiersinga

Objective: Evaluation of the frequency of Graves’ ophthalmopathy (GO) and its management in children and adolescents up to 18 years old with Graves’ hyperthyroidism.

Study design: This was a questionnaire study (QS) among members of the European Thyroid Association and the European Society for Paediatric Endocrinology. Approximately 300 QS were sent to members with electronic addresses and 110 QS were returned from 25 countries: 52 respondents said they had no experience with Graves’ disease in this age group, but 67 respondents (23 paediatric and 44 adult endocrinologists) completed the QS.

Results: Out of 1963 patients with juvenile Graves’ hyperthyroidism seen by respondents in the last 10 years, 641 (33%) had GO; about one-third of GO cases were ≤10 years old, and two-thirds were 11–18 years old. The prevalences of GO among juvenile Graves’ hyperthyroidism were 36.6, 27.3 and 25.9% in countries in which the smoking prevalence among teenagers was ≥25, 20–25 and <20% respectively (P < 0.0001 by χ2 test). When confronted with the standard case of a 13-year-old girl with Graves’ hyperthyroidism and moderately severe active GO, the diagnostic approach included on average 4.9 biochemical tests (TSH, free thyroxine (FT4) and TSH.R-Ab, 100-88% of respondents) and 2.4 specific investigations (thyroid ultrasound by 69%, orthopsy/visual fields/visual acuity by 64% and orbital magnetic resonance imaging or computed tomography by 63%). Antithyroid drugs were the treatment of choice for 94% of respondents; 70% recommended a wait-and-see policy and 28% corticosteroids for the co-existing GO. In variants of the standard case, a younger age did not affect therapeutic approach very much. Recurrent hyperthyroidism would still be treated with antithyroid drugs by 66%, and with 131I by 25%. Worsening of GO or active GO when euthyroid would convince about two-thirds of respondents to initiate treatment of GO, preferably with steroids.

Conclusion: GO occurs in 33% of patients with juvenile Graves’ hyperthyroidism; its prevalence is higher in countries with a higher prevalence of smoking among teenagers. The diagnostic approach to the standard case of a 13-year-old with Graves’ hyperthyroidism and moderately severe active GO involves on average five biochemical tests; thyroid as well as orbital imaging is done in 84% of cases. Antithyroid drugs remain the treatment of choice for 94% of respondents, and even so in case of recurrences (66%). For GO, 70% recommend a wait-and-see policy; intervention, preferably with steroids, is advocated by two-thirds of respondents in cases of worsening or still-active eye disease despite euthyroidism.

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Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death

N Benhadi, W M Wiersinga, J B Reitsma, T G M Vrijkotte, and G J Bonsel

Background

To examine the relationship between maternal TSH and free thyroxine (FT4) concentrations in early pregnancy and the risk of miscarriage, fetal or neonatal death.

Method

Cohort study of 2497 Dutch women. TSH, FT4, and thyroid peroxidase antibodies concentrations were determined at first booking. Child loss was operationalized as miscarriage, fetal or neonatal death. Women with overt thyroid dysfunction were excluded.

Results

Twenty-seven cases of child loss were observed. The mean TSH and FT4 level in the women with child loss was 1.48 mU/l and 9.82 pmol/l compared with 1.11 mU/l and 9.58 pmol/l in women without child loss. The incidence of child loss increased by 60% (OR=1.60 (95% confidence interval (CI): 1.04–2.47)) for every doubling in TSH concentration. This association remained after adjustment for smoking, age, parity, diabetes mellitus, hypertension, previous preterm deliveries, and previous preterm stillbirth/miscarriage (adjusted odds ratio=1.80 (95% CI: 1.07–3.03)). This was not true for FT4 concentrations (OR=1.41 (95% CI: 0.21–9.40); P=0.724).

Conclusion

In a cohort of pregnant women without overt thyroid dysfunction, the risk of child loss increased with higher levels of maternal TSH. Maternal FT4 concentrations and child loss were not associated.

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Graves' orbitopathy in a patient with adrenoleukodystrophy after bone marrow transplantation

Y Vardizer, A Lupetti, S Vandelanotte, A C Lankester, W M Wiersinga, and L Baldeschi

Objective

For many years, the treatment of X-linked childhood cerebral adrenoleukodystrophy (XALD) consisted of hydrocortisone replacement and a mixture of short chain-fatty acids, known as ‘Lorenzo's oil’. Recently, bone marrow transplantation (BMT) has also been used.

Case report

We report the case of a patient affected by XALD who developed Graves' hyperthyroidism (GH) and Graves' orbitopathy (GO) after BMT and who we could follow-up for 6.5 years afterwards.

Evidence synthesis

A boy affected by XALD was treated at the age of 6 years, with a whole BMT from his sister. One year after BMT, the transplanted patient presented TSH at the lower normal value and 3 years later he developed thyrotoxicosis. After a further 2 years, the patient developed GO, which showed clinical evidence of reactivation 5 years after its onset as a consequence of an attempt to treat thyrotoxicosis by means of I131 (300 MBq). Seven years after BMT, the donor showed alterations of thyroid autoimmunity and 1 year thereafter she developed GH. She never presented GO during a subsequent 5 year follow-up.

Conclusions

This case illustrates that autoimmunity originating from a pre-symptomatic donor can be transferred into the host during allogeneic stem cell transplantation. In cases where autoimmune phenomena are recognized in the donor prior to donation, alternative donors or T-cell manipulation of the graft might be considered.

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The effects of sex-steroid administration on the pituitary–thyroid axis in transsexuals

Peter H Bisschop, Arno W Toorians, Erik Endert, Wilmar M Wiersinga, Louis J Gooren, and Eric Fliers

Objective: Estrogen and androgen administration modulate the pituitary–thyroid axis through alterations in thyroid hormone-binding globulin (TBG) metabolism, but the effects of sex steroids on extrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion in humans are unknown.

Design and methods: We studied 36 male-to-female and 14 female-to-male euthyroid transsexuals at baseline and after 4 months of hormonal treatment. Male-to-female transsexuals were treated with cyproterone acetate (CA) 100 mg/day alone (n=10) or in combination with either oral ethinyl estradiol (or-EE) 100 μg/day (n=14) or transdermal 17β-estradiol (td-E) 100 μg twice a week (n=12). Female-to-male transsexuals were treated with i.m. testosterone 250 mg twice a week. A t-test was used to test for differences within groups and ANOVAwith post hoc analysis to test for differences between the groups.

Results: Or-EE increased TBG (100 ± 12%, P<.001) and testosterone decreased TBG (−14 ± 4%, P =0.01), but free T4 did not change. Td-E and CA did not affect TBG concentrations. TSH was not different between groups at baseline or after treatment. CA decreased T3/T4 ratios (−9 ± 3%, P=0.04), suggesting that T4 to T3 conversion was lower. Testosterone increased T3/T4 ratios (30 ± 9%, P=0.02), which probably reflects higher T4 to T3 conversion.

Conclusion: Oral but not transdermal estradiol increases TBG, whereas testosterone lowers TBG. Testosterone increases T3/T4 ratios. Estradiol does not affect T3/T4 ratios, irrespective of the route of administration.

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Pilot study on the assessment of the setpoint of the hypothalamus–pituitary–thyroid axis in healthy volunteers

N Benhadi, E Fliers, T J Visser, J B Reitsma, and W M Wiersinga

Objective

To determine the log-linear relationship between TSH and free thyroxine in healthy subjects, and the variation in baseline TSH/free thyroxine (FT4) combination in each individual.

Subjects and methods

Twenty-one healthy volunteers (nine males and 12 females; mean age 60 years, range 51–74) were randomized to receive at 2300 h with 2-week intervals a single dose of placebo, 125 μg T4 and 250 μg T4 (arm 1, n=10), or placebo, 25 μg triiodothyronine (T3) and 50 μg T3 (arm 2, n=11). Blood samples were taken in the morning (0800–1100 h) before and following the administration of the drug for the assessment of TSH, FT4 and T3.

Results

Intra- and inter-individual variation and the individuality index of the four baseline serum samples were respectively 21.6%, 41.9% and 0.52 for TSH; 9.9%, 16.5% and 0.60 for FT4; and 9.3%, 16.0% and 0.58 for T3. Substantial differences existed in the location of individual working points within the reference range. T4 administration increased FT4 (but not T3) and decreased TSH, resulting in a log-linear relationship (log TSH=1.50–0.059×FT4, P<0.05) for the whole group. T3 administration increased T3 and decreased TSH (but not FT4), resulting in a log-linear relationship (log TSH=0.790–0.245×T3, P<0.001) for the whole group. Log-linear relationships were not always significant when assessed for each subject separately.

Conclusion

Individuality indices of TSH, FT4 and T3 are all ≤0.6, thereby limiting the usefulness of the population-based reference values. Accurate assessment of individual setpoints of the HPT axis was not possible with the applied single doses of T4 or T3, and will require either prolonged administration or higher single doses of thyroid hormone.

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Some studies on the natural history of Graves' orbitopathy: increase in orbital fat is a rather late phenomenon

Peter W Potgieser, Wilmar M Wiersinga, Noortje I Regensburg, and Maarten P Mourits

Aim

To describe volumes of orbital fat (FV) and extraocular muscles (MV) in Graves' orbitopathy (GO) as a function of the duration of GO.

Patients

i) Cross-sectional survey among 95 consecutive patients with untreated GO who had been referred to the combined thyroid–eye clinics of our university hospital. ii) Longitudinal survey among 39 of the 95 patients who did not receive any therapeutic intervention and were followed for 1 year.

Methods

A computed tomography (CT)-based and well-validated method for calculating orbital soft tissues. In order to neutralize sex differences, results are expressed as ratios of FV:orbital volume (OV) and MV:OV.

Results

i) Patients with GO duration of >1 year had greater FV:OV (0.65 vs 0.55, P=0.004), similar MV:OV (0.22 vs 0.21, not significant (NS)), and more proptosis (22 mm vs 21 mm, P=0.03) as compared to those with shorter duration. ii) As compared to baseline, after 1 year, FV:OV had increased (0.56 vs 0.63, P=0.000), MV:OV had not changed (0.19 vs 0.19, NS), proptosis was higher (20 mm vs 21 mm, P=0.003), and clinical activity scores had become lower (2 vs 1, P=0.02) (median values).

Conclusion

CT images show that a longer duration of GO is associated with a higher orbital FV. Extraocular MV, however, is not associated with GO duration; rather, it is related to the severity of GO.

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Effect of amiodarone and dronedarone administration in rats on thyroid hormone-dependent gene expression in different cardiac components

I Stoykov, H C van Beeren, A F M Moorman, V M Christoffels, W M Wiersinga, and O Bakker

Objective: In view of their different actions on thyroid hormone receptor (TR) isoforms we set out to investigate whether amiodarone (AM) and dronedarone (Dron) have different and/or component-specific effects on cardiac gene expression.

Design: Rats were treated with AM or Dron and the expression of TRα 1, TRα 2, TRβ 1 and several tri-iodothyronine (T3)-regulated genes was studied in different parts of the heart, namely the right atrium (RA), left ventricular wall (LVW) and apex.

Methods: Rats were treated for 14 days with 100 mg/kg body weight AM or Dron. The expression of TRα 1, TRα 2, TRβ 1 and T3-regulated genes was studied using real-time PCR and non-radioactive in situ hybridisation.

Results: AM and Dron affected TR expression in the RA similarly by decreasing TRα 1 and β 1 expression by about 50%. In the LVW, AM and Dron decreased TRβ 1 and, interestingly, AM increased TRα 1. In the apex, AM also increased TRα 2. The changes seen in T3-dependent gene expression are reminiscent of foetal reprogramming.

Conclusion: Taken together, our results indicate that AM and Dron have similar effects on the expression of TR isoforms in the RA, which could partly contribute to their ability to decrease heart rate. On the other hand, the more profound effect of AM appears on TR- and T3-dependent gene expression in the left ventricle suggests foetal reprogramming.