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Parathyroid adenoma is the most common cause of primary hyperparathyroidism (PHPT). We present the preoperative detection of a giant parathyroid adenoma (GPA) using (99mTc)-sestamibi parathyroid scintigraphy in a patient presenting with severely elevated parathyroid hormone, hypercalcemia, hypophosphatemia, and vitamin D insufficiency. The patient complained of cerebral symptoms and intermittent abdominal discomfort without constipation. After surgical removal of the hyperactive parathyroid gland and D vitamin supplementation, all blood tests were normalized. The clinical and paraclinical characteristics of GPA may raise the suspicion of parathyroid carcinoma, but not absolutely in this case.

Objective Thyroid disease in women of reproductive age is mainly of autoimmune origin, and thyroid peroxidase antibodies (TPO-Ab) as well as thyroglobulin antibodies (Tg-Ab) are key markers. Adding to this, much focus in pregnancy is on euthyroid women who are thyroid antibody positive. Evidence to substantiate the cut-offs for the definition of thyroid autoantibody positivity in early pregnant women is warranted. Methods Stored serum samples from 14,030 Danish pregnant women were used for the measurement of TPO-Ab, Tg-Ab, TSH, and free thyroxine (ADVIA Centaur XPT, Siemens Healthineers). Among all women, a reference cohort of 10,905 individuals was identified for the establishment of antibody cut-offs. Percentile cut-offs for TPO-Ab and Tg-Ab were determined using regression on order statistics (the reference cohort). The established cut-offs were then applied (the full cohort), and frequencies of early pregnancy as well as later diagnosis of hypothyroidism were evaluated. Results The highest established cut-offs (95th, 97.5th, and 99th percentiles) were 59, 68, and 81 U/mL for TPO-Ab and 33, 41, and 52 U/mL for Tg-Ab. When the cut-offs were applied in the full cohort, 11.0, 10.2, and 9.7% were TPO-Ab positive, whereas 13.3, 12.3, and 11.2% were Tg-Ab positive. Antibody-positive women (TPO-Ab and/or Tg-Ab) had higher median TSH and were more likely to have hypothyroidism in early pregnancy and to be diagnosed with hypothyroidism during follow-up. Conclusions This large study established and evaluated pregnancy-specific cut-offs for TPO-Ab and Tg-Ab. The findings are important regarding the classification of exposure in pregnancy and assessment of thyroid autoimmunity per se.

Objective: A transient rise in the occurrence of hyperthyroidism ensued the introduction of iodine fortification (IF) of salt in Denmark. Older adults are at risk of complications to hyperthyroidism that could prove fatal to vulnerable individuals. We evaluated the association between thyroid function and mortality in older adults before and after nationwide implementation of IF. Design: Retrospective cohort study. Patients: All 68-year-olds from the general population in the city of Randers were invited to participate in a clinical study in 1988 and followed until death, emigration or end of study (31 December 2017) using Danish registries. Measurements: Baseline measures comprised of a questionnaire, physical examination and blood and urine samples. Kaplan–Meier survival curves and Cox regression were used to determine the association between thyroid function and death before and after IF. Time-stratification of results before and after IF was employed due to violation of proportional hazards assumptions in Cox regression. Results: Median urinary iodine concentration was 42 µg/L at baseline consistent with moderate iodine deficiency. Hyperthyroidism (thyrotropin < 0.4 mIU/L) occurred in 37 (9.1%) participants. Kaplan–Meier survival curves showed an increase in mortality among participants with hyperthyroidism after IF. There was no significant association between hyperthyroidism and mortality before IF compared to euthyroid participants, but after IF hyperthyroid subjects had an increased mortality (adjusted hazard ratio: 2.22, 95% confidence interval: 1.44–3.44). Conclusions: IF was associated with raised mortality among older adults with a history of hyperthyroidism and moderate iodine deficiency. Our results highlight the need for cautious iodine supplementation and for monitoring of IF.

Introduction Thyroid disorders have been linked to abnormalities in the coagulation system, and a hypocoagulant state has been proposed in hypothyroidism. The assessment of thyroid function is, however, not routinely recommended as part of the assessment for coagulation disorders. Case presentation We present a 32-year-old woman who had no history of thyroid disease and who recently gave birth preterm because of severe preeclampsia and intrauterine growth restriction. Due to severe placental dysfunction, she underwent a routine biochemical assessment of the coagulation system 6 months postpartum, and a prolonged activated partial thromboplastin time (APTT) (43 s) was identified along with a low level of coagulation factor VIII (0.44 IU/mL), and a low level of von Willebrand factor (vWF) antigen (0.35 IU/mL), vWF activity (0.38 IU/mL) as well as reduced generation of thrombin. The assessment of thyroid function in the patient identified autoimmune, overt hypothyroidism with a thyroid-stimulating hormone (TSH) concentration of 139 mIU/L, low levels of the peripheral thyroid hormones (total thyroxine: 43 nmol/L, total triiodothyronine: 0.9 nmol/L), and high levels of thyroid peroxidase antibodies (296 U/mL) as well as thyroglobulin antibodies (927 U/mL). Conclusion In this case, prolonged APTT provided a diagnostic clue for the assessment of thyroid function in a young woman with a recent history of severe placental dysfunction. The identification of autoimmune, overt hypothyroidism emphasizes that measurement of TSH may be of clinical importance in cases of unexplained prolonged APTT or other biochemical signs of abnormalities in the coagulation system. Established facts Hypothyroidism has been associated with alterations of the coagulation system suggesting a hypocoagulant state. At present, measurement of thyroid-stimulating hormone is not routinely recommended as part of the assessment for coagulation disorders. Novel insights In this case, biochemical assessment of the coagulation system was routinely performed following a pregnancy complicated by severe placental dysfunction. Overt hypothyroidism of autoimmune origin was identified secondary to prolonged activated partial thromboplastin time (APTT) postpartum along with low levels of coagulation factor VIII, von Willebrand factor, and thrombin generation. Measurement of thyroid-stimulating hormone may be considered in cases of unexplained prolonged APTT.

Background: Weight gain during treatment of hyperthyroidism is a frequent and for many patients unwanted outcome. With this repeated measurement study, we explored the timing of weight changes during the first year of antithyroid drug (ATD) treatment and assessed the correlation between body weight changes and changes in thyroid hormones, resting energy expenditure (REE), physical activity level, and energy efficiency. Methods: Patients with new onset hyperthyroidism were investigated every second month during the first year of ATD treatment. At each investigation, the following were measured: body weight, thyroid hormone concentrations, physical activity level, and daily number of steps, REE, and exercise performance. Results: Two men and eleven women, all sedentary, mean age 49(SD: 9.3) years were included. Significant changes after 1 year occurred for body weight (68.9–74.1 kg), thyroid hormones (free T3 [fT3] 17.5 to 4.42 pmol/L), REE (1,630–1,484 kcal/24 h), and energy efficiency at lower (50 W) workloads (16.0–17.6%). In individual patients, only REE and fT3 correlated to changes in body weight. Physical activity level did not change during treatment. Conclusion: In this study, treatment of hyperthyroidism was associated with marked increase in body weight in the patients. This increase correlated to a decrease in REE and only to a negligible extent to changes in energy efficiency and not at all to changes in physical activity level of daily living.

Oral levothyroxine (LT4) is the standard therapy for patients with hypothyroidism. Oral LT4 is available in several formulations, including tablets, soft gel capsules and oral solution. Multiple brand-name and generic LT4 tablets are available. In the US, the Food and Drug Administration (FDA) has developed a protocol for establishing bioequivalence of LT4 formulations based on serum thyroxine (T4) levels after a single oral dose administered to healthy volunteers. This protocol has been criticized by professional endocrinology associations for using healthy individuals and ignoring serum thyroid-stimulating hormone (TSH) levels. In addition, the protocol did not initially correct for baseline T4 levels, although this was changed in a later version. There are concerns that the FDA’s protocol could allow products with clinically significant differences in bioavailability to be declared therapeutically equivalent and interchangeable. Once a generic LT4 has been shown to be bioequivalent to a brand-name LT4, it may be substituted for that brand-name LT4 with no need for dose adjustment or follow-up therapeutic monitoring. Often, the substitution is made by the pharmacy without the physician’s knowledge. Even small differences between LT4 formulations can cause significant changes in TSH levels. This may be a particular concern in vulnerable populations, including elderly, pregnant, and pediatric patients. Problems that can be encountered when switching between formulations or when original products are reformulated are discussed in this review. These problems include altered efficacy and adverse events, some of which can be caused by excipients. Patients should be maintained on the same LT4 preparation if possible. If the LT4 preparation is changed, TSH levels should be evaluated and, if necessary, the dose of LT4 adjusted. Funding: Merck. Plain Language Summary: Plain language summary available for this article.

Background: Physiological changes in maternal thyroid function during pregnancy necessitate the use of pregnancy-specific reference ranges. Dynamic changes in thyrotropin (TSH) within the first trimester of pregnancy have been reported, but more evidence is needed to substantiate the findings. The objective of this study was to estimate pregnancy week-specific reference ranges for maternal TSH and free thyroxine (fT4) in early pregnancy. Methods: The study consecutively recruited serum residues from blood samples collected as part of the prenatal screening in the North Denmark Region, 2011-2015. TSH, fT4, thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were measured using an ADVIA Centaur XPT immunoassay. The reference cohort included 10,337 pregnant women who had no thyroid disease or other autoimmune diseases and were TPOAb- and TgAb negative. The main outcome measures were lower and upper reference limits (2.5th and 97.5th percentiles) for TSH and fT4 stratified by week of pregnancy. Results: Blood samples were drawn in pregnancy weeks 4-20 (median week 10), and 92% of the pregnancies ended with a live birth. TSH varied considerably in the first trimester of pregnancy, and the levels were highest in early pregnancy (weeks 4-6: 0.6-3.7 mIU/L) followed by a gradual decline to lower levels in weeks 9-11 (0.1-2.8 mIU/L) and 12-14 (0.03-2.8 mIU/L). Maternal fT4 showed less variation (weeks 4-6: 12-20 pmol/L; weeks 9-11: 13-21 pmol/L; weeks 12-14: 13-20 pmol/L). Conclusions: The results corroborate dynamic week-specific changes in maternal TSH in early pregnancy. The use of uniform lower and upper reference limits for TSH in early pregnancy may be too simple.

OBJECTIVE: To monitor the impact of a cautious iodine fortification (IF) on the incidence of overt hypothyroidism in two subpopulations with different levels of preexisting iodine deficiency (ID). DESIGN: A 20-year (1997 to 2016) prospective population-based study identified all new cases of diagnosed overt biochemical hypothyroidism in two open cohorts: a western cohort with moderate ID (n = 309,434; 1 January 1997) and an eastern cohort with mild ID (n = 224,535; 1 January 1997). A diagnostic algorithm was applied to all thyroid function tests performed within the study areas, and possible new cases were verified individually. Mandatory IF of salt was initiated in mid-2000 (13 ppm). The current study is a part of the DanThyr study. RESULTS: At baseline, standardized incidence rates (SIRs) of hypothyroidism were 32.9 and 47.3/100.000/y in the cohorts with moderate and mild ID, respectively. The SIR of hypothyroidism increased significantly in both cohorts after implementing mandatory IF, with peak values of 150% in 2014 to 2016 for the moderate ID cohort and 130% in 2004 to 2005 for the mild ID cohort. Significant increases in SIR were seen among the young and middle-aged participants of both cohorts, whereas no changes were seen among the elderly participants (≥60 years). The follow-up period for the mildly iodine-deficient cohort was restricted up to and including 2008. CONCLUSION: The cautious initiation of the IF program in Denmark caused a sustained increase in hypothyroidism incidence among subjects residing in areas of moderate and mild ID but only among the young and middle-aged participants.

Iodine intake affects the occurrence of thyroid disorders. However, the association of iodine intake with longevity remains to be described. This led us to perform a 20 years’ follow-up on participants from the Randers–Skagen (RaSk) study. Residents in Randers born in 1920 (n 210) and Skagen born in 1918–1923 (n 218) were included in a clinical study in 1997–1998. Mean iodine content in drinking water was 2 µg/l in Randers and 139 µg/l in Skagen. We collected baseline data through questionnaires, performed physical examinations and measured iodine concentrations in spot urine samples. Income data were retrieved from Danish registries. We performed follow-up on mortality until 31 December 2017 using Danish registries. Complete follow-up data were available on 428 out of 430 of participants (99·5 %). At baseline, the median urinary iodine concentration was 55 µg/l in Randers and 160 µg/l in Skagen residents. Participants were long-term residents with 72·8 and 92·7 % residing for more than 25 years in Randers and Skagen, respectively. Cox regression showed that living in Skagen compared with Randers was associated with a lower hazard ratio (HR) of death in both age- and sex-adjusted analyses (HR 0·60, 95 % CI 0·41, 0·87, P = 0·006), but also after adjustment for age, sex, number of drugs, Charlson co-morbidity index, smoking, alcohol and income (HR 0·60, 95 % CI 0·41, 0·87, P = 0·008). Residing in iodine-replete Skagen was associated with increased longevity. This indicates that long-term residency in an iodine-replete environment may be associated with increased longevity compared with residency in an iodine-deficient environment.

BACKGROUND: Few studies have scrutinized the spectrum of symptoms in subclinical hypothyroidism.METHODS: From 3 Danish Investigation on Iodine Intake and Thyroid Diseases (DanThyr) cross-sectional surveys performed in the period 1997 to 2005, a total of 8903 subjects participated in a comprehensive investigation including blood samples and questionnaires on previous diseases, smoking habits, alcohol intake, and education. From the 3 surveys we included patients with subclinical hypothyroidism (n = 376) and euthyroid controls (n = 7619). We explored to what extent patients with subclinical hypothyroidism reported 13 previously identified hypothyroidism-associated symptoms (tiredness, dry skin, mood lability, constipation, palpitations, restlessness, shortness of breath, wheezing, globus sensation, difficulty swallowing, hair loss, dizziness/vertigo, and anterior neck pain). In various uni- and multivariate regression models we searched for circumstances predicting why some patients have more complaints than others.RESULTS: Subclinically hypothyroid patients did not report higher hypothyroidism score [(median, interquartile range), 2 (0-4) vs 2 (0-4), P = .25] compared with euthyroid controls. Within the group of subclinical hypothyroid patients, comorbidity had the highest impact on symptoms (tiredness, shortness of breath, wheezing; all P < .001); TSH level had no impact on symptom score; and younger age was accompanied by higher mental burden (tiredness, P < .001; mood lability, P < .001; restlessness, P = .012), whereas shortness of breath was associated with high body mass index (P < .001) and smoking (P = .007).CONCLUSION: Patients with a thyroid function test suggesting subclinical hypothyroidism do not experience thyroid disease-related symptoms more often than euthyroid subjects. In subclinical hypothyroidism, clinicians should focus on concomitant diseases rather than expecting symptomatic relief following levothyroxine substitution.

Objective: To investigate the impact of mandatory iodine fortification (IF) on the incidence of nosological subtypes of overt thyrotoxicosis and hypothyroidism. Design: We identified and scrutinized all possible new cases of overt thyrotoxicosis and hypothyroidism in an open cohort in Northern Jutland (n = 309 434; 1 January 1997) during the years 2014-2016. Individual medical history was evaluated to verify and detail the incidence of overt thyroid dysfunction and for classification into nosological subtypes. A number of cases were excluded during final verification due to spontaneous normalization of thyroid function, as they had no medical history suggesting a known condition, which could transiently affect thyroid function (subacute/silent thyroiditis, PPTD and iatrogenic thyroid dysfunction). An identical survey was conducted in 1997-2000 prior to mandatory IF of salt (13 µg/g) that was in effect from year 2001. Results: The standardized incidence rate (SIR) of verified overt thyrotoxicosis decreased markedly from 97.5/100 000/year in 1997-2000 to 48.8 in 2014-2016 (SIRR: 0.50 [95% CI: 0.45-0.56]). This was due to a distinct decrease in the SIR of multinodular toxic goitre (SIRR: 0.18 [0.15-0.23]), solitary toxic adenoma (SIRR: 0.26 [0.16-0.43]) and to a lesser degree Graves’ disease (SIRR: 0.67 [0.56-0.79]). SIR for overt hypothyroidism was unaltered by 2014-2016 (SIRR: 1.03 [0.87-1.22]). However, age distribution shifted with more young and fewer elderly cases of verified overt hypothyroidism. Conclusion: Mandatory IF caused a substantial reduction in SIR of verified overt thyrotoxicosis (especially of nodular origin) while avoiding an increase in SIR of verified overt hypothyroidism.

Hypothyroidism affects up to 5% of the general population, with a further estimated 5% being undiagnosed. Over 99% of affected patients suffer from primary hypothyroidism. Worldwide, environmental iodine deficiency is the most common cause of all thyroid disorders, including hypothyroidism, but in areas of iodine sufficiency, Hashimoto’s disease (chronic autoimmune thyroiditis) is the most common cause of thyroid failure. Hypothyroidism is diagnosed biochemically, being overt primary hypothyroidism defined as serum thyroid-stimulating hormone (TSH) concentrations above and thyroxine concentrations below the normal reference range. Symptoms of hypothyroidism are non-specific and include mild to moderate weight gain, fatigue, poor concentration, depression, and menstrual irregularities, while the consequences of untreated or under-treated hypothyroidism include cardiovascular disease and increased mortality. Levothyroxine has long been the main tool for treating hypothyroidism and is one of the world’s most widely prescribed medicines. In adults with overt hypothyroidism, levothyroxine is usually prescribed at a starting dose of 1.6 µg/kg/day, which is then titrated to achieve optimal TSH levels (0.4–4.0 mIU/L), according to the therapeutic target. We here summarise the history of levothyroxine and discuss future issues regarding the optimal treatment of hypothyroidism. Because nearly one-third of patients with treated hypothyroidism still exhibit symptoms, it is important that levothyroxine is used more appropriately to achieve maximum benefit for patients. In order to ensure this, further research should include more accurate assessments of the true prevalence of hypothyroidism in the community, optimisation of the levothyroxine substitution dose, proper duration of treatment, and identification of patients who may benefit from combination therapy with levothyroxine plus levotriiodothyronine. Funding: Merck. Plain Language Summary: Plain language summary available for this article.

Purpose. To study predictors of attaining (part 1) and sustaining (part 2) remission in patients with Graves’ hyperthyroidism (GH) treated with antithyroid drugs (ATD). Methods. In the prospective first part, the included patients were treated with ATD until a prespecified definition of remission (thyrotropin > 0.4 mU/L and TSH-receptor antibodies (TRAb) ≤ 1. 0 IU/L in a patient receiving a methimazole dose ≤ 5 mg/day, on two occasions two months apart) was met, or for 24 months. In the second part, patients attaining remission in part 1 were randomized to treatment or observation and followed until relapse or for 24 months. Results. 173 patients completed study 1 and 53% attained remission. TRAb and age were the only significant predictors of remission. Patients with baseline TRAb below vs above 10 IU/L attained remission in 63% compared to 39%, and 5 months priorly (p Conclusion. Baseline TRAb was prognostic for attaining remission in GH. Consecutive TRAb measurements during treatment were not worthwhile, but a single measurement after 6-8 months in patients with initial TRAb < 10 IU/L could substantially shorten the treatment period in a subgroup of patients. Only 3.6% of the patients in remission experienced relapse during follow-up when treated with a combination of fixed low dose methimazole and L-T4. ClinTrial.gov registration number is NCT00796913.

Objective: To investigate the association between reproductive history and later development of various nosological subtypes of overt hyperthyroidism. Study Design: From the Danish population, we included incident hyperthyroid women, and for each case we recruited 4 euthyroid age-sex-region-matched controls from the same sub-population. Hyperthyroid cases/controls were: Graves' disease (GD, n = 232/928), multinodular toxic goitre (MNTG, n = 91/364), solitary toxic adenoma (STA, n = 21/84). Patients diagnosed with hyperthyroidism within 1 year after delivery including post-partum GD were excluded. In multivariate conditional regression models (reference: no reproductive events), we analysed the association between development of GD/MNTG/STA and reproductive factors such as age at menarche/menopause, reproductive span, number of pregnancies/childbirths/abortions, investigations for infertility, and years on oral contraceptives. We adjusted for possible confounders such as alcohol intake, smoking, co-morbidity, and education. Age was studied as a potential effect measure modifier. Results: GD patients diagnosed before the age of 40 years had given births more often than control subjects (OR [95% CI] for 1/2/3+ births [ref.: nulliparous] were 1.57 [0.80-3.11]/2.06 [1.001-4.22]/3.07 [1.50-6.26]), and they had induced abortions performed more often (OR for 1/2+ induced abortions [ref.: no: events] were 0.99 [0.54-1.84]/2.24 [1.12-4.45]). No associations were observed between any reproductive factor and the development of MNTG or STA. Conclusions: Childbirths and induced abortions may be followed by development of Graves' hyperthyroidism after the post-partum period. This was not the case for the non-autoimmune subtypes of hyperthyroidism.

BACKGROUND: Clinic-based studies have indicated that older hypothyroid patients may present only few symptoms.METHODS: In this population-based study of hypothyroidism, we investigated how the power of symptom presence predicts overt hypothyroidism in both young and older subjects. We identified patients newly diagnosed with overt autoimmune hypothyroidism in a population (n = 140, median thyroid-stimulating hormone, 54.5; 95% confidence interval [CI], 28.3-94.8; median total T4, 37; 95% CI, 18-52) and individually matched each patient with 4 controls free of thyroid disease (n = 560). Participants filled out questionnaires concerning the presence and duration of symptoms. We compared the usefulness of hypothyroidism-associated symptoms in predicting overt hypothyroidism in different age groups (young: RESULTS: In young hypothyroid patients, all 13 hypothyroidism-associated symptoms studied were more prevalent than in their matched controls, whereas only 3 of those (tiredness, shortness of breath, and wheezing) were more prevalent in old patients. The mean numbers of symptoms presented at disease onset were 6.2, 5.0, and 3.6 at the ages of 0 to 49 years, 50 to 59 years, and 60+ years, respectively. In young versus old people with 0 to 1 symptoms, the odds ratio for being hypothyroid was 0.04 (95% CI, 0.007-0.18) versus 0.34 (95% CI, 0.15-0.78) (reference all other groups). In young versus old subjects reporting ≥4 symptoms, the odds ratio for being hypothyroid was 16.4 (95% CI, 6.96-40.0) versus 2.22 (95% CI, 1.001-4.90). Receiver operating characteristic analyses revealed that the symptom score was an excellent tool for predicting hypothyroidism in young men (area under the receiver operating characteristic curve, 0.91; 95% CI, 0.82-0.998), whereas it was poor in evaluating older women (area under the receiver operating characteristic curve, 0.64; 95% CI, 0.54-0.75).CONCLUSION: Hypothyroid symptom score is a good discriminating tool to identify hypothyroidism in young patients but fails to identify hypothyroidism in the elderly. Thus, thyroid function should be tested on wide indications in old age.

OBJECTIVE: Monitoring the influence of cautious iodine fortification (IF) on the incidence rate of overt thyrotoxicosis in Denmark with formerly frequent multinodular toxic goitre.DESIGN: A 21 year (1997-2017) prospective population-based study identified all new cases of overt biochemical thyrotoxicosis in two open cohorts: a Western cohort with moderate iodine deficiency (ID) and an Eastern cohort with mild ID (total n=533,969 by January 1st , 1997). A diagnostic algorithm was applied to all thyroid function tests performed within the study areas. Mandatory IF of salt was initiated in mid-2000 (13 p.p.m.). The present study is a part of DanThyr.RESULTS: The standardized incidence rate (SIR) of thyrotoxicosis at baseline (1997-1998) was 128.5/100.000/year in the cohort with moderate ID and 80.1 in the cohort with mild ID. SIR increased markedly in both cohorts during the initial years of IF (moderate/mild ID: +39/+52% in 2000-01/2004-05) and subsequently decreased to baseline level (mild ID) or below (moderate ID) by 2008. The decline was due to a marked decrease in the incidence rate among elderly subjects and a moderate decrease among the middle aged. The follow-up period for the mildly iodine deficient cohort was restricted to 2008. A continuous decline in SIR was observed for the remainder of the study period in the area with moderate ID (33% below baseline in 2016-17).CONCLUSION: The rise in thyrotoxicosis incidence with cautious mandatory IF returned to baseline level after 7-8 years and levelled out at 33% below baseline in the population with previously moderate ID after 16-17 years. This article is protected by copyright. All rights reserved.

Context: Hyperthyroidism in women of reproductive age is predominantly caused by Graves' disease. Pregnancy associated changes in the immune system may influence the onset of disease, but population-based incidence rates in and around pregnancy have not been reported. Objective: To estimate the incidence of maternal hyperthyroidism (defined by redeemed prescription of antithyroid drugs) in and around pregnancy and to compare this with the incidence of other autoimmune diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Design: Population-based cohort study. Setting: Danish nationwide registers. Participants: Women giving birth to singleton liveborn children in Denmark from 1999-2008 (n=403,958). Main outcome measure(s): Incidence rates (IR) of maternal hyperthyroidism during a four-year period beginning two years before and ending two years after the date when the mother was giving birth first time in the study period. Results: Altogether 3,673 women (0.9%) were identified with onset of hyperthyroidism from 1997-2010, and the overall IR of maternal hyperthyroidism was 65.0/100,000/year. The IR of hyperthyroidism in and around pregnancy varied widely and was high in the first three months of pregnancy (incidence rate ratio (IRR) versus the remaining study period: 1.50 (95% CI 1.09-2.06)), very low in the last three months of pregnancy (0.26 (0.15-0.44)), and reached the highest level 7-9 months postpartum (3.80 (2.88-5.02)). The incidence variation in and around pregnancy was different for RA and IBD. Conclusion: These are the first population-based data on the incidence of hyperthyroidism in and around pregnancy. The incidence of hyperthyroidism was high in early pregnancy and postpartum whereas such particular pattern was not observed for other diseases of autoimmune origin.

OBJECTIVES: In previous studies, around half of all hypothyroid patients preferred levo-thyroxine (L-T4) + levo-triiodothyronine (L-T3) combination therapy, 25% preferred T4, and 25% had no preference. The reason for this is yet to be explored.METHODS: A total of 45 overtly autoimmune, hypothyroid patients - now euthyroid on ≥6 months' L-T4 therapy - participated in a prospective, double-blind, cross-over study. The patients were randomized into 2 groups of either 3 continuous months' L-T4 therapy followed by 3 months' combination therapy or vice versa. In all periods, 50 μg L-T4 was blindly replaced by either (identical) 50 μg L-T4 or by 20 μg T3. L-T4 was hereafter adjusted to obtain normal serum TSH values. We investigated 3 single nucleotide polymorphisms (SNPs) on the type II iodothyronine deiodinase (DIO2) gene (rs225014 (Thr92Ala), rs225015, and rs12885300 (ORFa-Gly3Asp)) and 1 SNP on the cellular membrane transport-facilitating monocarboxylate transporter (MCT10) gene (rs17606253), and asked in which of the 2 treatment periods patients felt better (i.e., which treatment was preferred).RESULTS: 27 out of 45 patients (60%) preferred the combination therapy. Two polymorphisms (rs225014 (DIO2, Thr92Ala) and rs17606253 (MCT10)) were combined yielding 3 groups: none vs. 1 of 2 vs. both SNPs present, and 42 vs. 63 vs. 100% of our patients in the 3 groups preferred the combined treatment (Jongheere-Terpstra trend test, p = 0.009).CONCLUSION: The present study indicates that the combination of polymorphisms in DIO2 (rs225014) and MCT10 (rs17606253) enhances hypothyroid patients' preference for L-T4 + L-T3 replacement therapy. In the future, combination therapy may be restricted or may be even recommended to individuals harbouring certain polymorphisms.

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.

Selenium deficiency may play an important role in the initiation and progression of autoimmune thyroid disease.To compare serum selenium (s-Se) values in patients with newly diagnosed autoimmune thyroid disease and controls from the Danish population.S-Se was measured in triplicate by a fluorimetric method.Patients with newly diagnosed Graves' disease (GD) (n = 97) or autoimmune overt hypothyroidism (AIH) (n = 96), euthyroid subjects with high serum levels of thyroid peroxidase antibody (TPO-Ab) (TPO-Ab 1500 U/ml, n = 92) and random controls (n = 830).Differences in s-Se values.S-Se was lower in patients with GD than in controls (mean (SD), GD: 89·9 μg/l (18·4); controls: 98·8 μg/l (19·7), P 0·01). This was confirmed in a multivariate logistic regression model adjusting for age, sex, mineral supplements, smoking, geographical region and time of sampling (P 0·01). In a linear model, s-Se was similar in patients with AIH (mean (SD): 98·4 μg/l (24·9)) and in controls (P = 0·86). In the multivariate model however, s-Se was marginally lower in patients with AIH compared to controls (P = 0·04). There was no significant difference in s-Se between euthyroid participants with high TPO-Ab and random controls (linear: P = 0·97; multivariate: P = 0·27).Patients with newly diagnosed GD and AIH had significantly lower s-Se compared with random controls. Our observation supports the postulated link between inadequate selenium supply and overt autoimmune thyroid disease, especially GD.

Fetal programming is a long-standing, but still evolving, concept that links exposures during pregnancy to the later development of disease in the offspring. A fetal programming effect has been considered within different endocrine axes and in relation to different maternal endocrine diseases. In this critical review, we describe and discuss the hypothesis of fetal programming by maternal thyroid dysfunction in the context of fetal brain development and neurodevelopmental disorders in the offspring. Thyroid hormones are important regulators of early brain development, and evidence from experimental and observational human studies have demonstrated structural and functional abnormalities in the brain caused by the lack or excess of thyroid hormone during fetal brain development. The hypothesis that such abnormalities introduced during early fetal brain development increase susceptibility for the later onset of neurodevelopmental disorders in the offspring is biologically plausible. However, epidemiological studies on the association between maternal thyroid dysfunction and long-term child outcomes are observational in design, and are challenged by important methodological aspects.

OBJECTIVE: To clarify which factors may influence the serum Tg level in an adult population and how this may affect Tg as a biomarker of iodine deficiency (ID).DESIGN AND METHODS: Two identical cross-sectional studies were performed before (C1a: 1997-98, n=4649) and after (C2: 2004-05, n=3570) the Danish mandatory iodine fortification (IF) of salt (2000). Additionally, a follow-up study of C1a was performed after IF (C1b: 2008-10, n=2465). The studies took place in two regions with mild (Copenhagen) and moderate (Aalborg) ID before IF. Serum Tg was measured by immunoradiometric method and investigated as outcome variable in multivariate models.RESULTS: Multiple factors were associated with serum Tg. Some were directly related to iodine intake (cohort, urinary iodine concentration (UIC) level and region), and some were likely mediators of iodine intake effects on Tg (thyroid nodularity, thyroid size and autonomy with low TSH). Others were caused by Tg assay interference (Tg-Ab positivity), aggravation of ID (childbirths and smoking) or TSH stimulation of the thyroid. Estimated 24-hour urinary iodine excretion was a more sensitive predictor of Tg than UIC. Iodine supplement users had low median Tg values compared with non-users both before and after IF.CONCLUSIONS: Multiple factors should be taken into consideration when evaluating Tg as a marker of ID in adult populations, and the Tg results may depend on the assay used. Still, Tg is a sensitive marker of ID. We suggest including a reference population with known sufficient iodine intake when Tg is used to evaluate ID. This article is protected by copyright. All rights reserved.

Objective Immunological changes in and after a pregnancy may influence the onset of autoimmune diseases. An increased incidence of hyperthyroidism has been observed both in early pregnancy and postpartum, but it remains to be studied if the incidence of hypothyroidism varies in a similar way. Design Population-based cohort study using Danish nationwide registers. Method All women who gave birth to a singleton live-born child in Denmark from 1999 to 2008 (n = 403 958) were identified, and data on hospital diagnosis of hypothyroidism and redeemed prescriptions of thyroid hormone were extracted. The overall incidence rate (IR) of hypothyroidism during 1997–2010 and the IR in three-month intervals before, during and after the woman’s first pregnancy in the study period were calculated and compared with the IR of hyperthyroidism. Results Altogether 5220 women were identified with onset of hypothyroidism from 1997 to 2010 (overall IR 92.3/100 000/year) and 1572 women developed hypothyroidism in the period from 2 years before to 2 years after birth of the first child in the study period. The incidence of hypothyroidism decreased during the pregnancy (incidence rate ratio (IRR) vs overall IR in the rest of the study period: first trimester: 0.89 (95% CI: 0.66–1.19), second trimester: 0.71 (0.52–0.97), third trimester: 0.29 (0.19–0.45)) and increased after birth with the highest level at 4–6 months postpartum (IRR 3.62 (2.85–4.60)). Conclusion These are the first population-based data on the incidence of hypothyroidism in and around pregnancy. The incidence declined during pregnancy followed by a sharp increase postpartum. Notably, hypothyroidism as opposed to hyperthyroidism showed no early pregnancy increase.

Background A role for female reproductive factors in the pathogenesis of thyroid autoimmunity has been suggested. We investigated the prospective association between parity, abortion, use of oral contraceptive pill (OCP), and use of hormone replacement therapy (HRT), and 11-year change in serum thyrotropin (TSH) as well as change in thyroid peroxidase autoantibody (TPO-Ab) status. Methods A random sample of 4,649 persons aged 18-65 years participated in a population-based study in the period 1997-1998. In the study presented here, we included 1,749 non-pregnant women with no history of thyroid disease who participated in the 11-year follow-up examination in the period 2008-2010. Gynecological exposures were reported in a self-administered questionnaire at baseline and follow-up. TSH and TPO-Ab were measured at baseline and follow-up. Increased TPO-Ab status during follow-up was defined as a TPO-Ab below assay cut-off (< 30 kU/L) at baseline and TPO-Ab ≥ 30 kU/L at follow-up. Multiple linear regression models were used, adjusted for age, smoking status, and urinary iodine excretion. Results An inverse association was found between the number of years on hormone replacement therapy and the risk (odds ratio) of increased TPO-Ab status during follow-up (0.735 (95% confidence interval, CI 0.558, 0.968), P=0.03). This association was however not statistically significant when applying the Bonferroni adjusted significance level. The remaining reproductive factors showed no statistically significant association with risk of increased TPO-Ab during follow-up. Also, parity, abortions, use of OCP, HRT use, age at menarche and being pre- or postmenopausal were not significantly associated with 11-year TSH change. Conclusions We found no statistically significant association between the studied female reproductive measures and 11-year risk of TSH or TPO-change. A possible protective role for hormone replacement therapy in the etiology of thyroid autoimmunity however deserves further research.

Context:Few data are available on the effect of iodine fortification on thyroid function development in a population.Objective:Our objective was to evaluate changes in thyroid function after iodine fortification in a population and to identify predictors for changes in serum TSH.Design and Setting:A longitudinal population-based study of the DanThyr C1 cohort examined at baseline (1997-1998) and reexamined 11 yr later (2008-2010). The mandatory program for iodization of salt was initiated in 2000.Participants:A total of 2203 individuals, with no previous thyroid disease, living in two areas with different levels of iodine intake, with measurement of TSH and participation in follow-up examination were included in the analysis.Main Outcome Measure:Change in serum TSH was evaluated.Results:During the 11-yr follow-up, mean TSH increased significantly from 1.27 mU/liter [95% confidence interval (CI) = 1.23-1.30] to 1.38 mU/liter (CI = 1.34-1.43) (P

Summary Autoantibodies against the thyroid gland with thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) as the most common can often be demonstrated in serum. The effect of public iodization programmes on antibody prevalence is uncertain. Aim To measure the concentrations of thyroid autoantibodies in the Danish population before and after mandatory iodization of salt. Methods Two identical cross-sectional population studies were performed before (Cohort 1 (C1), year 1997–1998, n = 4649, median urinary iodine 61 μg/l) and 4–5 years after (Cohort 2 (C2), year 2004–2005, n = 3570, median urinary iodine 101 μg/l) mandatory iodine fortification of salt was implemented in Denmark. Blood tests were analysed for TPO-Ab and Tg-Ab using sensitive assays. Results Antibodies were more frequent in C2 than in C1: TPO-Ab > 30 U/ml, C1 vs C2: 14·3 vs 23·8% (P 20 U/ml, C1 vs C2: 13·7 vs 19·9% (P

The diagnosis of subclinical hypothyroidism--serum TSH levels above and T(4) 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.

Udgivelsesdato: 2009-Mar Context: Primary overt autoimmune hypothyroidism is often divided into primary idiopathic hypothyroidism with thyroid atrophy (Ord's disease) and hypothyroidism with goitre (Hashimoto's disease). Objective: The aim of the present study was to characterize the two subtypes of disease. Design and Setting: This was a population-based study identifying patients newly diagnosed with overt autoimmune hypothyroidism. Patients: We prospectively identified all patients with incident overt autoimmune hypothyroidism in a Danish population cohort, and 247 patients were invited to join a comprehensive program including thyroid ultrasonography and measurements of thyroid autoantibodies. Of the 144 patients investigated (58% of all invited), 139 were compared with 556 sex-, age-, and region-matched controls from the cohort. Results: Patients had lower median (11.6 ml vs. 13.5 ml, P = 0.001) and a more dispersed distribution of thyroid volumes compared with controls (P < 0.001). Log thyroid volume showed a Gaussian distribution in both males and females with no bimodal pattern. Nearly all patients had measurable thyroid autoantibodies, but with increasing thyroid volume (quartile I, II, III, and IV), levels of circulating antibodies were higher (median thyroid peroxidase autoantibody 1540, 3122, 4686, and 7058 kU/liter; median thyroglobulin autoantibody 72, 143, 119, and 1195 kU/liter), and thyroid volume correlated negatively with echogenicity (r = -0.21, P = 0.011). Patients with the smallest volumes were biochemically more hypothyroid at diagnosis (median serum T(4) 21.0, 45.5, 45.0, and 36.7 nmol/liter; median serum TSH 81.0, 40.9, 45.4, and 55.6 mU/liter). No difference between groups was observed in prevalence of TSH receptor autoantibody (14.7, 5.6, 14.7, and 8.3%) or duration of symptoms before hypothyroidism was diagnosed. Conclusions: In primary autoimmune hypothyroidism, thyroid volume follows a normal distribution. Cases with thyroid atrophy and goiter are only extremes within this distribution and do not represent separate disorders. However, patients with low vs. high thyroid volume differ with respects to several characteristics.

Iodine deficiency is still common in some European countries. In Denmark an iodine fortification programme was introduced in 1998 and a monitoring programme was established prior to iodization. This study reports the change in urinary iodine excretion caused by fortification and investigates determinants of iodine intake after fortification. Iodine excretion in casual urine samples was assessed in 4649 subjects in 1997–8 and in 3570 comparable subjects in 2004–5 in women 18–22, 25–30, 40–45 and 60–65 years of age and in men 60–65 years of age living in Aalborg (western part of Denmark) or Copenhagen (eastern part of Denmark). These areas had moderate and mild iodine deficiency, respectively, before iodine fortification. All subjects filled in a FFQ and a questionnaire regarding lifestyle factors. Iodine excretion, expressed as the estimated 24 h urinary iodine excretion and as urinary iodine concentration, increased significantly in all age and sex groups. However, the iodine intake was still below the recommended in the youngest age groups in both cities and in women 40–45 years of age living in Aalborg. Intake of milk and salt had strong significant direct associations with iodine excretion (P

ObjectiveOur objective was to investigate individual serum thyroglobulin (Tg) changes in relation to iodine fortification (IF) and to clarify possible predictors of these changes.DesignWe performed a longitudinal population-based study (DanThyr) in two regions with different iodine intake at baseline: Aalborg (moderate iodine deficiency (ID)) and Copenhagen (mild ID). Participants were examined at baseline (1997) before the mandatory IF of salt (2000) and again at follow-up (2008) after IF.MethodsWe examined 2465 adults and a total of 1417 participants with no previous thyroid disease and without Tg-autoantibodies were included in the analyses. Serum Tg was measured by immunoradiometric method. We registered participants with a daily intake of iodine from supplements in addition to IF.ResultsOverall, the follow-up period saw no change in median Tg in Copenhagen (9.1/9.1 μg/l,P=0.67) while Tg decreased significantly in Aalborg (11.4/9.0 μg/l,PPP=1.00). Living in Aalborg (PP=0.001) predicted a decrease in Tg whereas baseline thyroid enlargement (P=0.02) and multinodularity (P=0.01) were associated with an individual increase in Tg during follow-up.ConclusionsAfter IF we observed a decrease in median Tg in Aalborg and the previously observed regional differences between Aalborg and Copenhagen had levelled out. Likewise, living in Aalborg was a strong predictor of an individual decrease in serum Tg. Thus, even small differences in iodine intake at baseline were very important for the individual response to IF.

OBJECTIVES: We examined the gender-specific symptom prevalences in hypothyroidism and in healthy controls, and explored the extent to which symptoms indicative of thyroid status may be different in women and men.DESIGN AND METHODS: Patients newly diagnosed with overt autoimmune hypothyroidism (n=140) and controls free of thyroid disease (n=560) recruited from the same population participated in a population-based study of The Danish Investigation on Iodine Intake and Thyroid Diseases (DanThyr). Participants underwent a comprehensive programme including blood tests and completion of questionnaires. The gender-specific distribution of 13 hypothyroidism-associated symptoms and a simple combined score (0-13) was explored in conditional uni- and multivariate models taking into account a broad spectrum of possible confounders. Diagnostic odds ratios (DORs) were calculated as measures for the association between participant status (case vs. control) and presence of symptoms (yes vs. no).RESULTS: In overt autoimmune hypothyroidism, 94.9% of women and 91.3% of men (p=0.62) reported at least one of the hypothyroidism-associated symptoms, with tiredness as the most common symptom followed by dry skin and shortness of breath. In contrast, women free of thyroid disease self-reported at least one hypothyroidism-associated symptom considerably more often than men (73.7% vs. 51.1%, pCONCLUSION: The presence of symptoms is more indicative for overt autoimmune hypothyroidism in men than in women, and presumably persistent symptoms after therapy of hypothyroidism will be more common in women. This article is protected by copyright. All rights reserved.

Context: Double vision (diplopia) is a major determinant of work disability in patients with Graves' orbitopathy (GO), but is not part of the classification NOSPECS classification of GO. Objective: The objectives of the study were to quantitate diplopia in patients with moderate to severe GO and to study associations with other disease and patient variables. Design: This was a single-center prospective study of consecutive patients at the time of referral. Setting: The study was conducted at the University Hospital Thyroid-Eye Clinic. Patients: Patients included 216 patients diagnosed with moderate to severe and active GO. Main Outcome Measures: Binocular diplopia in field of gaze and monocular fields of motility were prospectively recorded on diagrams and measured by planimetry. Fields of diplopia were correlated to other disease and patient variables. Results: Six patients had only one functional eye and were excluded. Among the remaining 210 patients, diplopia was present in 75.2%. In patients with diplopia, this ranged from 5% to 100% (observed in 11.4% of patients) of binocular field of gaze. The field of diplopia correlated positively with eye motility restriction and with asymmetrical affection of orbits but negatively with signs of inflammation and proptosis that often are the main outcome measures in clinical studies of GO therapy. Conclusion: Diplopia is very common in moderate to severe GO and a major cause for active therapy. In moderate to severe GO, the field of diplopia correlates negatively with some other indicators of disease activity, which may be explained by the physiological properties of binocular fusion.

Thyroid autoimmunity is a major cause for hypothyroidism. We describe thyroid auto-antibodies in patients with various nosological subtypes of hypothyroidism identified in a population study.Population-based follow-up study identifying all new cases of hypothyroidism in an open cohort.We established a monitoring system, and identified all new cases with primary overt hypothyroidism (n = 685) in a 4 year period in a well-defined population cohort (2,027,208 person-years of observation). Patients were sub-classified into: spontaneous hypothyroidism, presumably of autoimmune origin (n = 578); non-spontaneous hypothyroidism (associated with medication, delivery, neck-irradiation or subacute thyroiditis, n = 97); and congenital hypothyroidism (n = 10). A total of 186 adult patients (61% of those invited) underwent thyroid ultrasonography and measurements of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb).In spontaneously hypothyroid patients:99% were antibody-positive (TPOAb or TgAb), TPOAb were more often measurable than TgAb (95.9 vs. 80.7%, p0.001). A statistically significant but modest correlation was observed between the two antibodies (Pearson's r2 = 0.11, p0.001). In a multivariate regression model both TPOAb and TgAb were positively associated with thyroid enlargement (p0.001), whereas no association was found with sex, age, iodine deficiency level or serum TSH level. We found no differences in patient characteristics between those who mainly developed TPOAb vs. those who preferentially harboured TgAb.Autoimmunity played a dominant role in practically all patients classified as spontaneously hypothyroid. Thyroid enlargement was associated with high levels of TPOAb and TgAb. We found no clue to why some spontaneously hypothyroid patients predominantly developed TPOAb whereas others mainly generated TgAb.

Some degree of hypothyroidism is common in the elderly. It affects 5-20% of women and 3-8% of men. The occurrence varies with genetics with a high prevalence in Caucasians, and the disease is more common in populations with a high iodine intake. The common causes of hypothyroidism are autoimmune destruction of the thyroid gland and previous thyroid surgery or radioiodine therapy. Various types of medication, including amiodarone, cytokines and lithium, often induce hypothyroidism. Symptoms may be atypical and measurement of serum thyroid-stimulating hormone (TSH) levels should be part of biochemical testing for undiagnosed medical conditions in elderly subjects. The finding of an elevated serum TSH level should be confirmed by repeated testing and supplemented with measurements of serum levels of thyroxine (T(4)) and thyroid peroxidase antibodies to verify, quantify and subclassify the abnormality. The recommended and appropriate replacement therapy for hypothyroidism is levothyroxine sodium. The initial replacement dose should be low if heart disease is suspected. Because of the long half-life of levothyroxine sodium small dosage adjustments may be performed by adding or withdrawing a tablet once or twice weekly. Levothyroxine sodium is only partly absorbed after oral ingestion, and food, minerals, drugs and tablet composition influence absorption. Studies performed a few years ago suggested that a combination of levothyroxine sodium and liothyronine may improve clinical results, but recent more comprehensive studies have not supported this hypothesis. Accordingly, liothyronine replacement is not documented to be of benefit. If liothyronine is added to replacement, the liothyronine dose should be kept low, within the physiological range and, preferably be administered twice daily. Thyroid hormone therapy has no beneficial effect above placebo in elderly individuals with normal serum TSH levels and T(4) levels. The major risk of levothyroxine sodium therapy is over-replacement, with anxiety, muscle wasting, osteoporosis and atrial fibrillation as adverse effects. Subclinical hypothyroidism with elevated serum TSH levels but T(4) levels within the laboratory reference range is a mild variant of overt hypothyroidism. Patients with subclinical hypothyroidism should be informed about the disease and offered the possibility of replacement. Only some patients treated for subclinical hypothyroidism will feel better after therapy. In elderly patients on replacement therapy, care should include estimation of serum TSH level once or twice a year, with small dosage adjustments of levothyroxine sodium to keep serum TSH level within the normal range.

BackgroundIt is generally accepted that patients suffering from hypothyroidism may express few symptoms, but this has not been studied in a population-based study design.ObjectivesTo study the array of symptoms as they are reported in newly diagnosed overt autoimmune hypothyroidism using a population-based case–control design.MethodsPatients with new overt autoimmune hypothyroidism (n=140) and their individually matched thyroid disease-free controls (n=560) recruited from the same population underwent a comprehensive program and self-reported a number of symptoms. We identified the symptoms associated with overt hypothyroidism and calculated positive (LR+) and negative (LR−) likelihood ratios as well as diagnostic odds ratios (DORs) as measures for the association between disease state and symptoms.ResultsAmong 34 symptoms investigated, 13 symptoms were statistically overrepresented in hypothyroidism. Hypothyroid patients suffered mostly from tiredness (81%), dry skin (63%), and shortness of breath (51%). Highest DORs (95% CI) were reported for tiredness (5.94 (3.70–9.60)), hair loss (4.58 (2.80–7.51)), and dry skin (4.09 (2.73–6.16)). A hypothyroidism-component-score was defined as the number of hypothyroidism-associated symptoms (range: 0–13). LR+ for participants with a hypothyroidism-component-score of 0 was 0.21 (0.09–0.39), meaning that the post-test probability was lowered to 21% of what it was before asking for symptoms. LR+ for scores of 1–2/3/4–6/7–9/10–13 were: 0.47 (0.30–0.72)/1.16 (0.70–1.87)/1.90 (1.29–2.45)/3.52 (2.30–5.36)/6.29 (2.30–17.7).ConclusionsNone of the individual symptoms of hypothyroidism had high LRs or DORs. Thus, neither the presence nor absence of any individual hypothyroidism symptom was reliable in the decision making of who should have their thyroid function tested. Therefore, even minor suspicion should lead to a blood test.

Sir: We have read with great interest the recent publication by Schwartz et al. [1] on the incidence of silent or painless thyroiditis (PT) presenting with thyrotoxicosis in Denmark during the peri...

Context: The 1-year postpartum period is often accompanied by increased risk for thyroid disease. Objective: The objective of the study was to investigate the role of reproductive risk factors in the development of autoimmune overt hypothyroidism in the years after the 1-year postpartum period. Design, Setting, and Subjects: In a population study, we included Danish women with new autoimmune overt hypothyroidism not diagnosed within the first year after a pregnancy (n = 117; median age 53.0 y) and age- and region-matched euthyroid controls from the same population (n = 468). Main Outcome Measures: In conditional multivariate logistic regression models, we analyzed the associations between the development of autoimmune hypothyroidism and age at menarche/menopause, years of menstruations, pregnancies, spontaneous and induced abortions, live births, and years on oral contraceptives and postmenopausal hormone replacement therapy, also taking various possible confounders into account. Results: In multivariate regression models with no event as reference, the odds ratios (ORs) for hypothyroidism [95% confidence interval (CI)] after one/two/three or more live births were 1.72 (0.56-5.32)/3.12 (1.14-8.48)/4.51 (1.65-12.3) and 1.02 (0.57-1.81)/2.70 (1.27-5.75) after one/two or more induced abortions. Findings were valid only for women having hypothyroidism diagnosed before the age of 55 years. We found no association between disease development and other reproductive risk factors investigated. Conclusions: Previous live births and induced abortions were major risk factors for the development of autoimmune overt hypothyroidism in women aged up to 55 years. The increased risk for hypothyroidism after giving birth extends longer than just to the 1-year postpartum period, and numbers of previous pregnancies should be taken into account when evaluating the risk of hypothyroidism in a young women.

ObjectiveTo assess the individuals' thyroid volume changes after the mandatory nationwide iodine fortification (IF) program in two Danish areas with different iodine intake at baseline (Copenhagen, mild iodine deficiency (ID) and Aalborg, moderate ID).DesignA longitudinal population-based study (DanThyr).MethodsWe examined 2465 adults before (1997) and after (2008) the Danish IF of salt (2000). Ultrasonography was carried out by the same sonographers using the same equipment, after controlling performances. Participants treated for thyroid disease were excluded from analyses.ResultsOverall, median thyroid volume had increased in Copenhagen (11.8–12.2 ml, P=0.001) and decreased in Aalborg, although not significantly (13.3–13.1 ml, P=0.07) during the 11 years of follow-up.In both regions, there was an age-related trend in individual changes in thyroid volume from baseline to follow-up; thyroid volume increased in women 40 years of age.In a multivariate regression model, higher age at entry was a predictor (P20% during the follow-up period (women aged 40–45 years: odds ratio (OR) 4.3 (95% CI, 2.2–8.2); women aged 60–65 years: 5.8 (2.9–11.6)) and individuals of higher age were also less likely to have an increase in thyroid volume (women aged 40–45 years: OR 0.2 (0.1–0.3); women aged 60–65: OR 0.3 (0.2–0.4)).ConclusionsAge-dependent differences in thyroid volume and enlargement had leveled out after the Danish iodization program. Thus, the previously observed increase in thyroid volume with age may have been caused by ID.