Peter Laurberg

Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

Iodine status of UK schoolgirls: a cross-sectional survey

BACKGROUND Iodine deficiency is the most common cause of preventable mental impairment worldwide. It is defined by WHO as mild if the population median urinary iodine excretion is 50-99 μg/L, moderate if 20-49 μg/L, and severe if less than 20 μg/L. No contemporary data are available for the UK, which has no programme of food or salt iodination. We aimed to assess the current iodine status of the UK population. METHODS In this cross-sectional survey, we systematically assessed iodine status in schoolgirls aged 14-15 years attending secondary school in nine UK centres. Urinary iodine concentrations and tap water iodine concentrations were measured in June-July, 2009, and November-December, 2009. Ethnic origin, postcode, and a validated diet questionnaire assessing sources of iodine were recorded. FINDINGS 810 participants provided 737 urine samples. Data for dietary habits and iodine status were available for 664 participants. Median urinary iodine excretion was 80·1 μg/L (IQR 56·9-109·0). Urinary iodine measurements indicative of mild iodine deficiency were present in 51% (n=379) of participants, moderate deficiency in 16% (n=120), and severe deficiency in 1% (n=8). Prevalence of iodine deficiency was highest in Belfast (85%, n=135). Tap water iodine concentrations were low or undetectable and were not positively associated with urinary iodine concentrations. Multivariable general linear model analysis confirmed independent associations between low urinary iodine excretion and sampling in summer (p<0·0001), UK geographical location (p<0·0001), low intake of milk (p=0·03), and high intake of eggs (p=0·02). INTERPRETATION Our findings suggest that the UK is iodine deficient. Since developing fetuses are the most susceptible to adverse effects of iodine deficiency and even mild perturbations of maternal and fetal thyroid function have an effect on neurodevelopment, these findings are of potential major public health importance. This study has drawn attention to an urgent need for a comprehensive investigation of UK iodine status and implementation of evidence-based recommendations for iodine supplementation. FUNDING Clinical Endocrinology Trust.

Environmental Iodine Intake Affects the Type of Nonmalignant Thyroid Disease

The relationship between the iodine intake level of a population and the occurrence of thyroid diseases is U-shaped with an increase in risk from both low and high iodine intakes. Developmental brain disorders and endemic goiter caused by severe iodine deficiency may seriously deteriorate overall health status and economic performance of a population. Severe iodine deficiency with a median 24-hour urinary iodine excretion of the population below 25 microg needs immediate attention and correction. Less severe iodine deficiency with median urinary iodine excretion below 120 microg per 24 hours is associated with multinodular autonomous growth and function of the thyroid gland leading to goiter and hyperthyroidism in middle aged and elderly subjects. The lower the iodine intake, the earlier and more prominent are the abnormalities. At the other end of the spectrum, severely excessive iodine intake starting at median urinary iodine excretion levels around 800 microg per 24 hours is associated with a higher prevalence of thyroid hypofunction and goiter in children. A number of studies indicate that moderate and mild iodine excess (median urinary iodine >220 microg per 24 hours) are associated with a more frequent occurrence of hypothyroidism, especially in elderly subjects. The exact mechanism leading to this has not been clarified, and more studies are needed to define the limits of excessive iodine intake precisely. Due to the frequent occurrence of thyroid disorders, proper monitoring and control of the population iodine intake level is a cost-effective alternative to diagnosing, therapy and control of the many individual cases of thyroid diseases that might have been prevented.

Iodine intake as a determinant of thyroid disorders in populations

UNLABELLED Depending on the availability of iodine, the thyroid gland is able to enhance or limit the use of iodine for thyroid hormone production. When compensation fails, as in severely iodine-deficient populations, hypothyroidism and developmental brain damage will be the dominating disorders. This is, out of all comparison, the most serious association between disease and the level of iodine intake in a population. In less severe iodine deficiency, the normal thyroid gland is able to adapt and keep thyroid hormone production within the normal range. However, the prolonged thyroid hyperactivity associated with such adaptation leads to thyroid growth, and during follicular cell proliferation there is a tendency to mutations leading to multifocal autonomous growth and function. In populations with mild and moderate iodine deficiency, such multifocal autonomous thyroid function is a common cause of hyperthyroidism in elderly people, and the prevalence of thyroid enlargement and nodularity is high. The average serum TSH tends to decrease with age in such populations caused by the high frequency of autonomous thyroid hormone production. On the other hand, epidemiological studies have shown that hypothyroidism is more prevalent in populations with a high iodine intake. Probably, this is also a complication to thyroid adaptation to iodine intake. Many thyroid processes are inhibited when iodine intake becomes high, and the frequency of apoptosis of follicular cells becomes higher. Abnormal inhibition of thyroid function by high levels of iodine is especially common in people affected by thyroid autoimmunity (Hashimotos thyroiditis). In populations with high iodine intake, the average serum thyroid-stimulating hormone (TSH) tends to increase with age. This phenomenon is especially pronounced in Caucasian populations with a genetically determined high tendency to thyroid autoimmunity. A small tendency to higher serum TSH may be observed already when iodine intake is brought from mildly deficient to adequate, but there is at present no evidence that slightly elevated serum TSH in elderly people leads to an increase in morbidity and mortality. CONCLUSION Even minor differences in iodine intake between populations are associated with differences in the occurrence of thyroid disorders. Both iodine intake levels below and above the recommended interval are associated with an increase in the risk of disease in the population. Optimally, iodine intake of a population should be kept within a relatively narrow interval where iodine deficiency disorders are prevented, but not higher. Monitoring and adjusting of iodine intake in a population is an important part of preventive medicine.

Goitre prevalence and thyroid abnormalities at ultrasonography : a comparative epidemiological study in two regions with slightly different iodine status

The association between severe iodine deficiency and endemic goitre is well established, but little information is available on the relation between milder degrees of iodine deficiency and goitre prevalence.

Biologic Variation is Important for Interpretation of Thyroid Function Tests

Large variations exist in thyrotropin (TSH) and thyroid hormones in serum. The components of variation include preanalytical, analytical, and biologic variation. This is divided into between- and within-individual variation. The latter consists of circadian and seasonal differences although there are indicators of a genetically determined starting point. The ratio of within- to between-individual variation describes the reliability of population-based reference ranges. This ratio is low for serum TSH, thyroxine (T(4)) and triiodothyronine (T(3)) indicating that laboratory reference ranges are relatively insensitive to aberrations from normality in the individual. Solutions are considered but reducing the analytical variation below the calculated analytical goals of 7%, 5% and 12% for serum T(3), T(4), and TSH does not improve diagnostic performance. Neither does determination of the individual set-point and reference range. In practice this means that population-based reference ranges are necessary but that it is important to recognize their limitations for use in individuals. Serum TSH responds with amplification to minor alterations in T(4) and T(3). A consistently abnormal TSH probably indicates that T(4) and T(3) are not normal for the individual even when inside the laboratory reference range. This underlines the importance of TSH in diagnosis and monitoring of thyroid dysfunctions. Also, it implies that subclinical thyroid disease may be defined in purely biochemical terms. Under critical circumstances such as pregnancy where normal thyroid function is of importance for fetal brain development, subclinical thyroid disease should be treated. Even TSH within the reference range may be associated with slightly abnormal thyroid function of the individual. The clinical importance of such small abnormalities in thyroid function in small children and pregnant women for brain development remains to be elucidated.

Dietary iodine intake and urinary iodine excretion in a Danish population: effect of geography, supplements and food choice

I deficiency diseases remain a health problem even in some developed countries. Therefore, measurement of I intake and knowledge about food choice related to I intake is important. We examined I intake in 4649 randomly selected participants from two cities in Denmark (Copenhagen and Aalborg) with an expected difference in I intake. I intake was assessed both by a food frequency questionnaire and by measuring I in casual urine samples. I excretion was expressed as a concentration and as estimated 24-h l excretion. Further, subgroups with low I intake were recognized. I intake was lower in Aalborg than in Copenhagen for all expressions, and lower than recommended in both cities if I intake from supplements was not included. Milk was the most important I source, accounting for about 44% of the I intake, and milk (P<0.001) and fish (P=0.009) intake was related to I excretion in a multiple linear regression model. Thus, risk groups for low I intake were individuals with a low milk intake, those with a low intake of fish and milk, those not taking I supplements and those living in Aalborg where the I content in drinking water is lower. Even individuals who followed the advice regarding intake of 200-300 g fish/week and 0.5 litres milk/d had an intake below the recommended level if living in Aalborg.

Risk Factors for Goiter and Thyroid Nodules

The occurrence of thyroid diseases is determined by interplay between genetic and environmental factors. The major environmental factor that determines goiter prevalence is iodine status, but other environmental factors influencing entire populations have been identified such as goitrogens in food and drinking water. Less focus has been on individual environmental factors and the interplay between factors. The goiter prevalence is higher in certain groups in the population. The variation in goiter prevalence between the genders is well known with a higher occurrence among women. The association with age is probably dependent on iodine status, because it seems that the zenith of goiter prevalence appears earlier in life the more severe iodine deficiency the population is exposed to. The association with individual risk factors has been investigated in some studies, especially the association with tobacco smoking. In iodine-deficient areas, a strong association between tobacco smoking and goiter prevalence is found, whereas the association is less pronounced in iodine-replete areas. This was predictable from experimental studies showing thiocyanate to be the mediator of the goitrogenic effect of tobacco smoke acting as a competitive inhibitor of iodine uptake. The association with alcohol intake has only been investigated in few studies, but a low occurrence of goiter among alcohol consumers has been found. The mechanism of this association is not known. Increased goiter prevalence during pregnancy has been reported, and recently a long-term goitrogenic effect of pregnancies has also been shown. As demonstrated for tobacco smoking, this association is dependent on iodine status, because the association has only been found in areas with a suboptimal iodine intake. This indicates pregnancy-induced goiter to be the result of exacerbation of existing iodine deficiency. Recently, the use of oral contraceptives has been shown to be associated with a markedly reduced prevalence of goiter, although experimental studies have previously shown proliferative effects of estrogens on thyrocytes. Some implications for prevention of thyroid disease could be suggested. Discussion of smoking habits should be included in a consultation for goiter with a motivation to quit smoking. Iodine deficiency has particularly strong goitrogenic effects during pregnancy and for the sake of the mother as well as the fetus, sufficient iodine supply should be ensured to all pregnant women. The difference in age maximum in goiter prevalence suggests that monitoring of iodine deficiency disorders should ideally include a spectrum of age groups.

Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency

background and aims Autoimmune thyroiditis is one of the most common autoimmune disorders. Autoantibodies against the thyroid gland, with thyroid peroxidase antibody (TPO‐Ab) and thyroglobulin antibody (Tg‐Ab) as the most common autoantibodies, can often be demonstrated in serum in population surveys. In the present study we evaluated if TPO‐Ab and Tg‐Ab tend to develop in parallel or whether one or the other may be more prevalent in subsets of the population.

Birth Defects After Early Pregnancy Use of Antithyroid Drugs: A Danish Nationwide Study

INTRODUCTION Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal complications, but teratogenic effects of antithyroid drug (ATD) treatment have been described. Evidence is still lacking in regard to the safety and choice of ATD in early pregnancy. OBJECTIVE Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects. METHODS This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008. Exposure groups were assigned according to maternal ATD use in early pregnancy: PTU (n = 564); MMI/CMZ (n = 1097); MMI/CMZ and PTU (shifted in early pregnancy [n = 159]); no ATD (ATD use, but not in pregnancy [n = 3543]); and nonexposed (never ATD use [n = 811 730]). Multivariate logistic regression was used to estimate adjusted odds ratio (OR) with 95% confidence interval (95% CI) for diagnosis of a birth defect before 2 years of age in exposed versus nonexposed children. RESULTS The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35-2.04]) and PTU (1.41 [1.03-1.92]) and maternal shift between MMI/CMZ and PTU in early pregnancy (1.82 [1.08-3.07]) were associated with an increased OR of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children (combined, adjusted OR = 21.8 [13.4-35.4]). CONCLUSIONS Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed. More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU. New ATD with fewer side effects should be developed.