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Peter Laurberg

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.

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Jesper Karmisholt and Peter Laurberg

Objective

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).

Design

Monthly repeated measurement study without intervention.

Methods

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.

Results

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.

Conclusion

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.

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Peter Laurberg and Stine Linding Andersen

Background

Antithyroid drugs (ATDs) may have teratogenic effects when used in early pregnancy.

Objective

To review the association between the time period of ATD exposure in early pregnancy and the development of birth defects.

Methods

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.

Results

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.

Conclusion

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.

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Peter Laurberg and Stine Linding Andersen

Thyroid hormones are essential developmental factors, and Graves’ disease (GD) may severely complicate a pregnancy. This review describes how pregnancy changes the risk of developing GD, how early pregnancy by several mechanisms leads to considerable changes in the results of the thyroid function tests used to diagnose hyperthyroidism, and how these changes may complicate the diagnosing of GD. Standard therapy of GD in pregnancy is anti-thyroid drugs. However, new studies have shown considerable risk of birth defects if these drugs are used in specific weeks of early pregnancy, and this should be taken into consideration when planning therapy and control of women who may in the future become pregnant. Early pregnancy is a period of major focus in GD, where pregnancy should be diagnosed as soon as possible, and where important and instant change in therapy may be warranted. Such change may be an immediate stop of anti-thyroid drug therapy in patients with a low risk of rapid relapse of hyperthyroidism, or it may be an immediate shift from methimazole/carbimazole (with risk of severe birth defects) to propylthiouracil (with less risk), or maybe to other types of therapy where no risk of birth defects have been observed. In the second half of pregnancy, an important concern is that not only the mother with GD but also her foetus should have normal thyroid function.

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Stine Linding Andersen, Jørn Olsen, and Peter Laurberg

Objective

Thyroid disorders are common in women of reproductive age, but the exact burden of disease before, during and after a pregnancy is not clear. We describe the prevalence of thyroid disease in women enrolled in the Danish National Birth Cohort (DNBC) and investigate some of its risk factors.

Design

Population-based study within the DNBC, which included 101 032 pregnancies (1997–2003).

Methods

We studied women enrolled in the DNBC who gave birth to a live-born child. Information on maternal thyroid disease (hyperthyroidism, hypothyroidism, benign goiter/nodules, thyroid cancer, and other) before, during and up to 5 years after the woman's first pregnancy in the cohort was obtained from self-report (telephone interview in median gestational week 17) and from nationwide registers on hospital diagnosis of thyroid disease/thyroid surgery (from 1977) and prescriptions of thyroid drugs (from 1995).

Results

Of the 77 445 women studied, 3018 (3.9%) were identified with an onset of thyroid disease before (2.0%), during (0.1%) or in the 5-year period after the pregnancy (1.8%). During the pregnancy, 153 (0.2%) women received antithyroid drugs and 365 (0.5%) received thyroid hormone for hypothyroidism (83 after previous hyperthyroidism, 42 after previous surgery for benign goiter/nodules or thyroid cancer). Significant risk factors for maternal thyroid disease were age, parity, origin, iodine intake, smoking, alcohol, and BMI.

Conclusions

Around 4% of Danish pregnant women had either a history of thyroid disease or thyroid disease during pregnancy or were diagnosed with thyroid disease for the first-time in the years following a pregnancy. The spectrum of thyroid disease was influenced by demographic and environmental factors.

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Jesper Karmisholt, Stig Andersen, and Peter Laurberg

Subclinical hypothyroidism (SCH) is a common condition that is often observed without therapy. However, no evidence-based recommendation exists with regards to how patients with untreated SCH should be monitored.

Monitoring involves regular assessment of symptoms and signs of hypothyroidism (HYPO) and biochemical tests of thyroid function. An important question when repeated tests of thyroid function are performed is how large a difference in test results is needed to be confident that the change is real and not just due to chance variation.

Recent data show that the least significant difference between two tests in SCH is 40% for TSH and 15% for free thyroxine and free triiodothyronine, with 90% confidence. Furthermore, monitoring has to be based on biochemical function testing because serial evaluation of symptoms and signs related to HYPO is rather insensitive in detecting worsening of thyroid insufficiency.

When the presence of thyroid peroxidase auto-antibodies (TPO-Ab) in serum has been demonstrated, repeated measurements do not add much useful information in the monitoring of individual subclinical hypothyroid patients, as levels of TPO-Ab vary in parallel with TSH in these patients.

Lastly, we discuss how differences in the monitoring procedure influence the diagnostic outcome, and we suggest a follow-up approach for untreated subclinical hypothyroid patients.

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Peter Laurberg, Claire Bournaud, Jesper Karmisholt, and Jacques Orgiazzi

Graves' disease is a common autoimmune disorder in women in fertile ages. The hyperthyroidism is causedby generation of TSH-receptor activating antibodies. In pregnancy both the antibodies and the antithyroid medication given to the mother pass the placenta and affect the foetal thyroid gland. Thyroid function should be controlled not only in the mother with Graves' hyperthyroidism but also in her foetus.The review includes two cases illustrating some of the problems in managing Graves' disease in pregnancy.

Major threats to optimal foetal thyroid function are inadequate or over aggressive antithyroid drug therapy of the mother. It should be taken into account that antithyroid drugs tend to block the foetal thyroid function more effectively than the maternal thyroid function, and that levothyroxin (l-T4) given to the mother will have only a limited effect in the foetus.

Surgical thyroidectomy of patients with Graves' hyperthyroidism does not lead to immediate remission of the autoimmune abnormality, and the combination thyroidectomy+withdrawal of antithyroid medication+l-T4 replacement of the mother involves a high risk of foetal hyperthyroidism.

Conclusion

Antithyroid drug therapy of pregnant women with Graves' hyperthyroidism should be balanced to control both maternal and foetal thyroid function. Surgical thyroidectomy of a pregnant woman with active disease may lead to isolated foetal hyperthyroidism.

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Stig Andersen, Kent Kleinschmidt, Bodil Hvingel, and Peter Laurberg

Objective

Adult man hosts brown adipose tissue with the capacity to consume energy and dissipate heat. This is essential for non-shivering thermogenesis and its activation depends on sympathetic activity and thyroid hormones. This led us to evaluate the impact of chronic cold exposure on thyroid activity and thyroid hormones in serum in Arctic residents.

Design

Comparative, population-based study (n=535) performed in Greenland.

Methods

Hunters were compared with other men, and Inuit in remote settlements in East Greenland with no modern housing facilities were compared with the residents of the capital city in West Greenland and residents of a major town in East Greenland in a cross-sectional study. We used interview-based questionnaires, measured TSH, free thyroxine, free triiodothyronine (fT3), thyroglobulin (TG) antibody and TG (a measure of thyroid activity) in serum, and iodine and creatinine in spot urine samples.

Results

Serum TG was the highest among hunters (P=0.009) and settlement dwellers (P=0.001), who were most markedly exposed to cold, even though they had the highest urinary iodine excretion (hunters, P<0.001; settlement dwellers, P<0.001). Hunters and settlement dwellers also had the lowest fT3 (hunters, P<0.001; settlement dwellers, P<0.001) after adjusting for gender, age, smoking habits, alcohol intake and iodine excretion in multivariate linear regression models. TSH was not influenced by measures of cold exposure (hunter, P=0.36; residence, P=0.91).

Conclusions

Cold exposure influenced thyroid hormones and TG in serum in Arctic populations consistent with consumption of thyroid hormone and higher thyroid hormone turnover. Findings emphasise that changes in thyroid activity are essential in cold adaptation in Arctic residents.

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Allan Carlé, Stine Linding Andersen, Kristien Boelaert, and Peter Laurberg

Subclinical thyrotoxicosis is a condition affecting up to 10% of the population in some studies. We have reviewed literature and identified studies describing prevalences, causes and outcomes of this condition. Treatment should be considered in all subjects if this biochemical abnormality is persistent, especially in case of symptoms of thyrotoxicosis or in the presence of any complication. In particular, treatment should be offered in those subclinically thyrotoxic patients with a sustained serum TSH below 0.1 U/L. However it is important to recognise that there are no large controlled intervention studies in the field and thus there is no high quality evidence to guide treatment recommendations. In particular, there is no evidence for therapy and there is weak evidence of harm from thyrotoxicosis if serum TSH is in the 0.1–0.4 IU/L range. In this review, we describe the different causes of subclinical thyrotoxicosis, and how treatment should be tailored to the specific cause. We advocate radioactive iodine treatment to be the first-line treatment in majority of patients suffering from subclinical thyrotoxicosis due to multinodular toxic goitre and solitary toxic adenoma, but we do generally not recommend it as the first-line treatment in patients suffering from subclinical Graves’ hyperthyroidism. Such patients may benefit mostly from antithyroid drug therapy. Subclinical thyrotoxicosis in early pregnancy should in general be observed, not treated. Moreover, we advocate a general restriction of therapy in cases where no specific cause for the presumed thyroid hyperactivity has been proven.