Jesper Karmisholt

Management of Graves' hyperthyroidism in pregnancy : focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy

Graves disease is a common autoimmune disorder in women in fertile ages. The hyperthyroidism is caused by 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-T(4)) 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-T(4) 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.

The TSH upper reference limit: where are we at?

The diagnosis of subclinical hypothyroidism—serum TSH levels above and T4 levels within the laboratory reference ranges—depends critically on the upper limit of the TSH reference interval. Calls have been made to lower the current upper TSH reference limit of 4.0 mU/l to 2.5 mU/l to exclude patients with occult hypothyroidism. However, data from population studies do not indicate that the distribution of TSH is altered owing to inclusion of such individuals. The opposite suggestion has also been put forward; the TSH upper reference limit is often too low, especially in the elderly, in women and in white individuals, which may lead to unnecessary or even harmful therapy. Studies in elderly individuals have shown that although aging may be associated with increased TSH levels, paradoxically, overt hypothyroidism in this population may be associated with a less robust TSH response than in young individuals. This Review highlights the interindividual and intraindividual variability of TSH levels and discusses the current controversy that surrounds the appropriateness of reference ranges defined on the basis of age, race, sex and amount of iodine intake. Moreover, the current evidence on lowering or increasing the upper limit of the TSH reference interval is reviewed and the need to individualize levothyroxine treatment in patients with elevated TSH levels is discussed.

Variation in Thyroid Function Tests in Patients with Stable Untreated Subclinical Hypothyroidism

OBJECTIVEnKnowledge of variation in thyroid function is important for interpretation of thyroid function tests. We aimed to describe intra-individual variation in thyroid function in patients with stable, untreated subclinical hypothyroidism (SCH) compared to euthyroid individuals to assess the importance of monitoring SCH patients.nnnDESIGNnWe measured thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) monthly for 1 year in a longitudinal study of 15 untreated SCH patients with initial TSH 5-12 mU/L, without trends in TSH, and compared findings with results from 15 euthyroid individuals.nnnMAIN OUTCOMEnCV% was 17.0, 6.1, and 6.2 for TSH, fT4, and fT3, respectively. Overall CV% for TSH was lower in SCH patients than controls. Contrary to euthyroid individuals, CV% in SCH patients increased with rising mean TSH (r2 = 0.29, p = 0.04). Individual disease set points were established with 45, 6, and 6 tests for TSH, fT4, and fT3, with 95% confidence. Differences required between two test results were 40%, 15%, and 15%, respectively, with 90% confidence.nnnCONCLUSIONnPercent variation in TSH was lower in SCH than in euthyroid controls, but increased with higher mean TSH. The number of tests needed to establish disease set points was high. The difference required between two tests to be truly different was 40% for TSH and 15% for fT4 and fT3.

Thyroid Function and Obesity

Important interaction exists between thyroid function, weight control, and obesity. Several mechanisms seem to be involved, and in studies of groups of people the pattern of thyroid function tests depends on the balance of obesity and underlying thyroid disease in the cohort studied. Obese people with a normal thyroid gland tend to have activation of the hypothalamic-pituitary-thyroid axis with higher serum TSH and thyroid hormones in serum. On the other hand, small differences in thyroid function are associated with up to 5 kg difference in body weight. The weight loss after therapy of overt hypothyroidism is caused by excretion of water bound in tissues (myxoedema). Many patients treated for hyperthyroidism experience a gain of more weight than they lost during the active phase of the disease. The mechanism for this excessive weight gain has not been fully elucidated. New studies on the relation between L-T3 therapy and weight control are discussed. The interaction between weight control and therapy of thyroid disease is important to many patients and it should be studied in more detail.

Weight Loss after Therapy of Hypothyroidism Is Mainly Caused by Excretion of Excess Body Water Associated with Myxoedema

CONTEXTnIn hypothyroidism, resting energy expenditure (REE) is reduced and weight gain is common. Physical activity contributes to the total daily energy expenditure, and changes in physical activity might contribute to hypothyroid-associated weight changes.nnnOBJECTIVEnThe objective of the present study was to evaluate mechanisms involved in body weight changes associated with hypothyroidism.nnnDESIGN, SETTING, AND PARTICIPANTSnWe conducted a 1-yr controlled follow-up study on outpatients newly diagnosed with hypothyroidism (n = 12) and a euthyroid measurement control group (n = 10). MAIN OUTCOME AND INTERVENTIONS: Changes in body mass and composition (dual-energy x-ray analysis scan), REE (indirect calorimetry), and spontaneous physical activity (pedometers and two different questionnaires) were studied before and after 12 months of L-T(4) therapy or observation (control group).nnnRESULTSnTSH changed from 102 (85) to 2.2 (2.1) mU/liter mean (SD) and free T(4) from 4.5 (2.1) to 18 (3.3) pmol/liter after 1 yr of treatment. Body weight decreased from 83.7 (16.4) to 79.4 (16.0) kg (P = 0.002) due to change in the lean mass subcompartment only (P = 0.001) because fat and bone mass was virtually unchanged. Significant increase was observed in REE and in physical activity measured with questionnaires but not measured as daily steps. No significant changes were observed in the control group.nnnCONCLUSIONnL-T(4) therapy of hypothyroidism associated with significant decrease in body weight and increase in REE. Physical activity measured with questionnaires increased significantly, but not number of daily steps. Despite changes in REE and body weight, fat mass was unchanged during the study. We propose that total body energy equilibrium is maintained during treatment of hypothyroidism and that weight loss observed during such treatment is caused by excretion of excess body water associated with untreated myxoedema.

Serum TSH and serum thyroid peroxidase antibody fluctuate in parallel and high urinary iodine excretion predicts subsequent thyroid failure in a 1-year study of patients with untreated subclinical hypothyroidism.

OBJECTIVEnTo 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).nnnDESIGNnMonthly repeated measurement study without intervention.nnnMETHODSnTwenty-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.nnnRESULTSnOver 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.nnnCONCLUSIONnAt 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.

Recommended number of participants in iodine nutrition studies is similar before and after an iodine fortification programme

BackgroundIodine fortification programs have been applied in many iodine deficient regions. Iodine excess is also unfavourable, and it is recommended to monitor iodine status by measuring urinary iodine concentration (UIC). The number of samples needed in such monitoring depends on the variation in UIC. However, it is not known if variation in UIC differs according to iodine levels.Aim and methodWe aimed to describe the effect of an iodisation program on the individual and group-based variation in UIC in spot urine samples. Group 1 (G1, nxa0=xa016) was studied before, and group 2 (G2, nxa0=xa021) was studied after an iodine fortification program was implemented. Individual urine samples were collected monthly for one year, 13 samplings.ResultsG1s (207 samples) median (interquartile range) UIC was 50 (37–67) μg/L, and G2 (265 samples) was 98 (69–139) μg/L. Median individual coefficient of variation (CV) was 38xa0% in G1 and 40xa0% in G2 (pxa0=xa00.55), whereas the group-based CV was 50xa0% in G1 and 53xa0% in G2. No trend was seen between mean UIC and variation in UIC, neither at the individual (pxa0=xa00.36) nor at the group level (pxa0=xa00.43). Based on data from both groups, approximately 100 samples were needed to reliably estimate the UIC in a population.ConclusionIn two groups studied before and after an iodine fortification program was implemented and with different UIC levels, variation in UIC was comparable both at the individual level and according to UIC level. When mild iodine deficiency is corrected, the number of samples needed to reliably estimate the UIC in a population is unaffected.

Antithyroid drug therapy of Graves’ hyperthyroidism: realistic goals and focus on evidence

Only a minority of patients with hyperthyroidism caused by Graves disease will experience cure of disease with a permanent euthyroid state without medication. Antithyroid drugs are useful in attaining euthyroidism, and most patients will gradually enter remission of the autoimmune abnormality after becoming euthyroid. A stable euthyroid state may be sustained by prolonged low-dose medication. The risk of relapse of hyperthyroidism after withdrawal of medication seems to be independent of duration of therapy, once remission has been induced. A number of risk factors influence the outcome of therapy and they should be evaluated when planning duration of therapy with antithyroid drugs.

Interval between Tests and Thyroxine Estimation Method Influence Outcome of Monitoring of Subclinical Hypothyroidism

CONTEXT/OBJECTIVEnMost patients with subclinical hypothyroidism are regularly monitored when treatment is not started. We have studied how interval between follow-up visits and how different T(4) estimates influence diagnostic outcome in a cohort of patients with untreated subclinical hypothyroidism, and studied whether assessment of clinical symptoms and signs aids evaluation of an individual subclinical hypothyroidism patient.nnnDESIGN/PATIENTSnDuring 1 yr, monthly measurements of TSH and three different T(4) estimates, and recording of hypothyroid symptoms and signs were performed in 21 patients with subclinical hypothyroidism confirmed on two occasions 3 months apart.nnnRESULTSnOne patient was euthyroid at all visits, and one started treatment for profound overt hypothyroidism. The remaining patients were subclinical hypothyroidism at 74%, overtly hypothyroid at 22%, and had normal thyroid function tests in 4% of the visits. Increasing frequency of visits associated significantly with decreasing number of patients characterized as subclinical hypothyroidism after 1 yr (P = 0.016). Diagnosis of overt hypothyroidism differed between T(4) estimates (P = 0.005) and was highly dependent on T(4) reference limits. The hypothyroid clinical score did not differ between biochemical diagnoses (P = 0.29).nnnCONCLUSIONSnThe monitoring procedure itself may influence the outcome of control of subclinical hypothyroidism. Specifically, the interval between visits, type of T(4) estimate used, and lower T(4) reference limit influenced the outcome when untreated subclinical hypothyroidism patients were followed for 1 yr. The hypothyroid clinical score did not aid the evaluation in individual subclinical hypothyroidism patients.

Association between TSH-Receptor Autoimmunity, Hyperthyroidism, Goitre, and Orbitopathy in 208 Patients Included in the Remission Induction and Sustenance in Graves' Disease Study

Background. Graves disease may have a number of clinical manifestations with varying degrees of activity that may not always run in parallel. Objectives. To study associations between serum levels of TSH-receptor autoantibodies and the three main manifestations of Graves disease (hyperthyroidism, goiter, and presence of orbitopathy) at the time of diagnosis of hyperthyroidism. Methods. We describe a cohort of 208 patients with newly diagnosed Graves hyperthyroidism. Patients were enrolled in a multiphase study of antithyroid drug therapy of Graves hyperthyroidism, entitled “Remission Induction and Sustenance in Graves Disease (RISG).” Patients were systematically tested for degree of biochemical hyperthyroidism, enlarged thyroid volume by ultrasonography, and the presence of orbitopathy. Results. Positive correlations were found between the levels of TSH-receptor autoantibodies in serum and the three manifestations of Graves disease: severeness of hyperthyroidism, presence of enlarged thyroid, and presence of orbitopathy, as well as between the different types of manifestations. Only around half of patients had enlarged thyroid gland at the time of diagnosis of hyperthyroidism, whereas 25–30% had orbitopathy. Conclusions. A positive but rather weak correlation was found between TSH-receptor antibodies in serum and the major clinical manifestation of Graves disease. Only half of the patients had an enlarged thyroid gland at the time of diagnosis.