Women with high early pregnancy urinary iodine levels have an increased risk of hyperthyroid newborns: the population-based Generation R Study.

OBJECTIVE: Iodine deficiency during pregnancy results in thyroid dysfunction and has been associated with adverse obstetric and foetal effects, leading to worldwide salt iodization programmes. As nowadays 69% of the world's population lives in iodine-sufficient regions, we investigated the effects of variation in iodine status on maternal and foetal thyroid (dys)function in an iodine-sufficient population. DESIGN, PARTICIPANTS AND MEASUREMENTS: Urinary iodine, serum TSH, free T4 (FT4) and TPO-antibody levels were determined in early pregnancy (13·3 (1·9) week; mean (SD)) in 1098 women from the population-based Generation R Study. Newborn cord serum TSH and FT4 levels were determined at birth. RESULTS: The median urinary iodine level was 222·5 µg/l, indicating an iodine-sufficient population. 30·8% and 11·5% had urinary iodine levels <150 and >500 µg/l, respectively. When comparing mothers with urinary iodine levels <150 vs ≥150 µg/l, and >500 vs ≤500 µg/l, there were no differences in the risk of maternal increased or decreased TSH, hypothyroxinaemia or hyperthyroidism. Mothers with urinary iodine levels >500 µg/l had a higher risk of a newborn with decreased cord TSH levels (5·6 ± 1·4 (mean ± SE) vs 2·1 ± 0·5%, P = 0·04), as well as a higher risk of a hyperthyroid newborn (3·1 ± 0·9 vs 0·6 ± 0·3%, P = 0·02). These mothers had newborns with higher cord FT4 levels (21·7 ± 0·3 vs 21·0 ± 0·1 pm, P = 0·04). Maternal urinary iodine levels <150 µg/l were not associated with newborn thyroid dysfunction. CONCLUSIONS: In an iodine-sufficient population, higher maternal urinary iodine levels are associated with an increased risk of a hyperthyroid newborn.

Low urinary iodine excretion during early pregnancy is associated with alterations in executive functioning in children.

The rare but deleterious effects of severe iodine deficiency during pregnancy on cognitive functioning of children are well known. Reports on possible associations between mild-to-moderate maternal iodine deficiency and child development, however, are scarce. In a population-based cohort we examined the association between maternal urinary iodine during early pregnancy and executive functioning in children at 4 y of age. In addition, we investigated the modification of this association by maternal diet and thyroid function. During pregnancy, we measured urinary iodine and thyroid hormone concentrations in 1156 women. In 692 of their children impairment of executive functioning was assessed by the Behavior Rating Inventory of Executive Function. Five hundred mothers of Dutch national origin completed an FFQ. Analyses were performed by using regression models. The children of mothers with low urinary iodine showed higher scores on the problem scales of inhibition [ß = 0.05 (95% CI: 0.01, 0.10), P = 0.03] and working memory [ß = 0.07 (95% CI: 0.02, 0.12), P = 0.003]. Although maternal dietary intake and thyroid hormone concentration did not significantly modify these associations, the associations between urinary iodine and problems of inhibition were attenuated after adjustment for maternal psychological symptoms. In addition, the consumption of bread [ß = 0.61 (95% CI: 0.27, 0.95), P < 0.001] and eggs (ß = 1.87 (95% CI: 0.13, 3.62), P = 0.04] was associated with higher urinary iodine. Thus, low maternal urinary iodine during pregnancy is associated with impaired executive functioning in children. Because these symptoms were subclinical and occurred at an early age, future studies are needed to show whether these children are more vulnerable to develop later clinical disorders.

Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 3: total thyroxine and total triiodothyronine.

BACKGROUND: Because total thyroid hormone testing is performed on many automated clinical chemistry instruments, the IFCC Scientific Division commissioned the Working Group for Standardization of Thyroid Function Tests to include total thyroxine (TT4) and total triiodothyronine (TT3) in its standardization efforts. METHODS: Existing SI-traceable reference measurement procedures (RMPs) were used to assign TT4 and TT3 values to 40 single-donor serum samples for subsequent use in a method comparison study with 11 TT4 and 12 TT3 immunoassays. Data from comparison of each immunoassay with the RMPs provided a basis for mathematical assay recalibration. RESULTS: Seven TT4 assays had a mean bias within 10% of the RMP, but 2 deviated by an average of -12% and another 2 by +17%. All TT3 assays showed positive biases, 4 within and 8 outside 10%, up to 32%. Mathematical recalibration effectively eliminated assay-specific biases, but sample-related effects remained, particularly for TT3. Correlation coefficients with the RMPs ranged from 0.82 to 0.97 for TT4 and from 0.32 to 0.92 for TT3. The within-run and total imprecision ranges for TT4 were 1.4% to 9.1% and 3.0% to 9.4%, respectively, and for TT3 2.1% to 7.8% and 2.8% to 12.7%, respectively. Approximately one-half of the assays matched the internal QC targets within approximately 5%; however, we observed within-run drifts/shifts. CONCLUSIONS: The study showed that of the assays we examined, only 4 TT4 but the majority of the TT3 assays needed establishment of calibration traceability to the existing RMPs. Most assays performed well, but some would benefit from improved precision, within-run stability, and between-run consistency.

Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 2: free thyroxine and free triiodothyronine.

BACKGROUND: Free thyroxine (FT4) and free triiodothyronine (FT3) measurements are useful in the diagnosis and treatment of a variety of thyroid disorders. The IFCC Scientific Division established a Working Group to resolve issues of method performance to meet clinical requirements. METHODS: We compared results for measurement of a panel of single donor sera using clinical laboratory procedures based on equilibrium dialysis-isotope dilution-mass spectrometry (ED-ID-MS) (2 for FT4, 1 for FT3) and immunoassays from 9 manufacturers (15 for FT4, 13 for FT3) to a candidate international conventional reference measurement procedure (cRMP) also based on ED-ID-MS. RESULTS: For FT4 (FT3), the mean bias of 2 (4) assays was within 10% of the cRMP, whereas for 15 (9) assays, negative biases up to -42% (-30%) were seen; 1 FT3 assay was positively biased by +22%. Recalibration to the cRMP eliminated assay-specific biases; however, sample-related effects remained, as judged from difference plots with biologic total error limits. Correlation coefficients to the cRMPs ranged for FT4 (FT3) from 0.92 to 0.78 (0.88 to 0.30). Within-run and total imprecision ranged for FT4 (FT3) from 1.0% to 11.1% (1.8% to 9.4%) and 1.5% to 14.1% (2.4% to 10.0%), respectively. Approximately half of the manufacturers matched the internal QC targets within approximately 5%; however, within-run instability was observed. CONCLUSIONS: The study showed that most assays had bias largely correctable by establishing calibration traceability to a cRMP and that the majority performed well. Some assays, however, would benefit from improved precision, within-run stability, and between-run consistency.

Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 1: thyroid-stimulating hormone.

BACKGROUND: Laboratory testing of serum thyroid-stimulating hormone (TSH) is an essential tool for the diagnosis and management of various thyroid disorders whose collective prevalence lies between 4% and 8%. However, between-assay discrepancies in TSH results limit the application of clinical practice guidelines. METHODS: We performed a method comparison study with 40 sera to assess the result comparability and performance attributes of 16 immunoassays. RESULTS: Thirteen of 16 assays gave mean results within 10% of the overall mean. The difference between the most extreme means was 39%. Assay-specific biases could be eliminated by recalibration to the overall mean. After recalibration of singlicate results, all assays showed results within the biological total error goal (22.8%), except for 1 result in each of 4 assays. For a sample with a TSH concentration of 0.016 mIU/L, 6 assays either did not report results or demonstrated CVs >20%. Within-run and total imprecision ranged from 1.5% to 5.5% and 2.5% to 7.7%, respectively. Most assays were able to match the internal QC targets within 5%. Within-run drifts and shifts were observed. CONCLUSIONS: Harmonization of TSH measurements would be particularly beneficial for 3 of the 16 examined assays. These data demonstrate that harmonization may be accomplished by establishing calibration traceability to the overall mean values for a panel of patient samples. However, the full impact of the approach must be further explored with a wider range of samples. Although a majority of assays showed excellent quality of performance, some would benefit from improved within-run stability.

Composite reference interval for thyroid-stimulating hormone and free thyroxine, comparison with common cutoff values, and reconsideration of subclinical thyroid disease.

BACKGROUND: Examination of the 2-dimensional probability distribution of thyroid-stimulating hormone (TSH) and free thyroxine (FT(4)) shows that the widths of the TSH and FT(4) reference intervals derived from this bivariate distribution are mutually interdependent, an aspect commonly ignored when interpreting thyroid testing results with separate reference intervals for TSH and FT(4). We desired to establish and critically evaluate a composite reference interval for TSH and FT(4) to allow bivariate classification of biochemical thyroid conditions. METHODS: FT(4) and TSH results of 871 healthy individuals [361 women and 510 men, 18-40 years old, without history of thyroid-related disease or medication, negative for anti-thyroid peroxidase (anti-TPO) antibody] were transformed to standard normal variables by logarithmic transformation with correction for skewness and subsequent normalization. We established a 95% reference interval of the distance of each FT(4)/TSH pair of values to the center of the 2-dimensional probability distribution. RESULTS: The bivariate 95% reference interval is enclosed by a circular profile with radius 2.45 SD. By contrast, conventional reference intervals comprise a square with the boundaries of -1.96 and +1.96 SD for both FT(4) and TSH that enclose only 90% of all data. Compared with the +/-1.96 SD square, the bivariate reference interval classified 4% fewer of 3651 healthy individuals older than 40 years as subclinically hyperthyroid and 14% fewer of 712 anti-TPO-positive healthy individuals as subclinically hypothyroid. CONCLUSIONS: Conventional application of separate cutoff values for FT(4) and TSH leads to overestimation of the incidence of subclinical thyroid disease. Application of a composite overall reference interval is recommended.

Assay bias may invalidate decision limits and affect comparability of serum thyroglobulin assay methods: an approach to reduce interpretation differences.

BACKGROUND: Thyroglobulin (Tg) assays are used to monitor patients after ablative therapy for differentiated thyroid carcinoma (DTC). Detectable Tg suggests persistence or recurrence of disease. However, even with very sensitive assays, false positive or false negative results are likely to occur depending on the presence of positive or negative assay bias. METHODS: We compared 6 different Tg immunometric assays in 53 treated DTC patients in whom serum Tg during TSH-suppression therapy was below an earlier established clinical decision limit of 3 pmol/l (2 ng/ml) by our routine Tg assay, which was one of these 6. Serum Tg was measured before and after administration of recombinant human TSH (r-TSH). Assay bias and confidence intervals for each assay were calculated from the pre-r-TSH Tg values in the patient subgroup in which no significant rise after r-TSH was observed by any method. RESULTS: Upper reference limits based on confidence intervals instead of functional sensitivity resulted in significant improvement of concordance between assays and prediction of Tg-rise after r-TSH. CONCLUSION: Confidence intervals in which assay bias are taken into account, form a better guideline for detection of possible persistence or recurrence of DTC than functional sensitivities.

Testicular tumors in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency show functional features of adrenocortical tissue.

CONTEXT: In male patients with congenital adrenal hyperplasia (CAH), testicular adrenal rest tumors are frequently found that may interfere with gonadal function. OBJECTIVE: Our objective was to determine steroid-producing features of testicular adrenal rest tumors. DESIGN AND SETTING: The study is descriptive and took place at a university medical center. PATIENTS: Eight adult CAH patients with bilateral testicular adrenal rest tumors were treated with testis-sparing surgery. INTERVENTIONS: In all but one patient, spermatic veins were cannulated during surgery and blood samples collected to measure the adrenal-specific steroid 21-deoxycortisol (21DF) and 17-hydroxyprogesterone (17OHP) and androstenedione (A). The same parameters were measured in simultaneously taken peripheral blood. mRNA concentrations of adrenal-specific enzymes CYP11B1 and CYP11B2 and ACTH and angiotensin II (AII) receptors were measured in tumor tissue. MAIN OUTCOME MEASURES: Adrenal-specific steroids/enzymes were assessed. RESULTS: 21DF, 17OHP, and A levels were measurable in all spermatic vein samples. The ratio (mean +/- SD) between spermatic vein and simultaneously taken peripheral blood samples was 37.8 +/- 56.3 (21DF), 132.0 +/- 249 (17OHP), and 57.0 +/- 68.2 (A). CYP11B1, CYP11B2, and ACTH and AII receptor mRNAs were detected in all tumors with a strong correlation between ACTH receptor mRNA in tumors and 21DF (r = 0.85; P = 0.015), 17OHP (r = 1; P = 0.01) and A (r = 0.89; P = 0.007) concentrations in peripheral blood. CONCLUSION: Testicular adrenal rest tumors produce adrenal-specific steroids and express adrenal-specific enzymes and ACTH and AII receptors, confirming the strong resemblance with adrenal tissue. Because AII receptors are present in tumor tissue, it can be hypothesized that AII may be an additional factor responsible for testicular adrenal rest tumor growth.

Comparison of human chorionic gonadotropin +beta and invasive trophoblast antigen disappearance rates in serum after evacuation of molar pregnancy.

After the evacuation of a hydatidiform mole, the spontaneous regression or the persistent trophoblastic disease (PTD) needing chemotherapy, is monitored by determining the serum human chorionic gonadotropin (hCG) concentration. Hyperglycosylated hCG (invasive trophoblast antigen, ITA) has been suggested to be of clinical value in the diagnosis and follow-up of gestational trophoblastic disease including PTD. To further document the relationship between ITA and hCG in spontaneous post-molar regression and during chemotherapy treatment of PTD, we used distinct immunoassays to measure the concentrations of hCG+beta and ITA in serum from three groups of patients after the evacuation of moles. For each group [uneventful post molar hCG regression, group 1; PTD treated with Methotrexate (MTX) (mono-chemotherapy), group 2; and PTD with MTX and poly-chemotherapy (EMA-CO), group 3], we compared the time course of the serum concentrations after evacuation, and determined the disappearance rates (half-lives) within and between treatment groups. Significantly longer mean serum half-lives for hCG+beta and ITA were found in the poly-chemotherapy (group 3: 3.02 and 2.51 weeks) as compared to the mono-chemotherapy group (group 2: 0.96 and 0.90 weeks) and the uneventful regression group (0.81 and 0.66 weeks) (each, p=0.003), but no differences were observed between the mono-chemotherapy and the uneventful regression group. Significantly shorter mean half-lives for ITA than those calculated for hCG+beta were observed in all three groups of patients. The implication and the possible clinical value of the more rapid regression of ITA to baseline levels as compared to hCG+beta remain to be investigated prospectively.

Evaluation of the highly sensitive Roche thyroglobulin II assay and establishment of a reference limit for thyroglobulin-negative patient samples.

OBJECTIVES: Thyroglobulin (Tg) measurements are used to monitor for residual thyroid tissue in patients with differentiated thyroid cancer (DTC) after thyroidectomy and radioiodine ablative therapy. In recent years highly sensitive Tg assays have been developed. In this study the analytical performance of the new Roche Elecsys Tg II assay was evaluated and compared with the well documented Access2 Tg assay (Beckman-Coulter). DESIGN AND METHODS: Analytical performance was examined using various Clinical and Laboratory Standards Institute (CLSI) evaluation protocols. Tg negative patient sera were used to establish an upper reference limit (URL) for the Elecsys Tg II assay. RESULTS: Non-linearity, drift and carry-over according to CLSI EP10 and EP6 in a measuring range of 0.04-500 ng/mL were non-significant. Total precision according to CLSI EP5 was 10% at a Tg concentration of 0.08 ng/mL. A patient serum comparison performed according to a modified CLSI EP9 protocol showed a significant difference of a factor of approximately 1.4, despite using an identical CRM calibrator. The Elecsys Tg II assay measured Tg with a two-fold higher sensitivity than the Access2 assay. Finally, using human sera without Tg, an URL of 0.05 ng/mL was determined. CONCLUSIONS: In our hands the highly sensitive Elecsys Tg II assay shows a good analytical performance and a higher sensitivity compared to the Access2 Tg assay. An URL of 0.05 ng/mL for the Elecsys Tg II assay was determined which may improve the clinical utility of the assay for the detection of residual DTC or disease recurrence.

Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter.

In patients with nodular goiter, radioiodine ((131)I) therapy results in a mean reduction in thyroid volume (TV) of approximately 40% after 1 yr. We have demonstrated that pretreatment with a single, low dose of recombinant human TSH (rhTSH) doubles 24-h radioactive iodine uptake (RAIU) in these patients. We have now studied the safety and efficacy of therapy with a reduced dose of (131)I after pretreatment with rhTSH. Twenty-two patients with nodular goiter received (131)I therapy, 24 h after im administration of 0.01 (n = 12) or 0.03 (n = 10) mg rhTSH. In preceding diagnostic studies using tracer doses of (131)I, 24-h RAIU without and with rhTSH pretreatment (either 0.01 or 0.03 mg) were compared. Therapeutic doses of (131)I were adjusted to the rhTSH-induced increases in 24-h RAIU and were aimed at 100 micro Ci/g thyroid tissue retained at 24 h. Pretreatment with rhTSH allowed dose reduction of (131)I therapy by a factor of 1.9 +/- 0.5 in the 0.01-mg and by a factor of 2.4 +/- 0.4 in the 0.03-mg rhTSH group (P < 0.05, 0.01 vs. 0.03 mg rhTSH). Before and 1 yr after therapy, TV and the smallest cross-sectional area of the tracheal lumen were measured with magnetic resonance imaging. During the year of follow-up, serum TSH, free T(4) (FT(4)), T(3), and TSH receptor antibodies were measured at regular intervals. TV before therapy was 143 +/- 54 ml in the 0.01-mg group and 103 +/- 44 ml in the 0.03-mg rhTSH group. One year after treatment, TV reduction was 35 +/- 14% (0.01 mg rhTSH) and 41 +/- 12% (0.03 mg rhTSH). In both groups, smallest cross-sectional area of the tracheal lumen increased significantly. In the 0.01-mg rhTSH group, serum FT(4) rose, after (131)I treatment, from 15.8 +/- 2.8 to 23.2 +/- 4.4 pM. In the 0.03-mg rhTSH group, serum FT(4) rose from 15.5 +/- 2.5 to 23.5 +/- 5.1 pM. Individual peak FT(4) levels, reached between 1 and 28 d after (131)I treatment, were above the normal range in 12 patients. TSH receptor antibodies were negative in all patients before therapy and became positive in 4 patients. Hyperthyroidism developed in 3 of these 4 patients between 23 and 25 wk after therapy. In conclusion, in patients with nodular goiter pretreatment with a single, low dose of rhTSH allowed approximately 50-60% reduction of the therapeutic dose of radioiodine without compromising the efficacy of TV reduction.

Dosimetry of radioiodine therapy in patients with nodular goiter after pretreatment with a single, low dose of recombinant human thyroid-stimulating hormone.

UNLABELLED: A single, low dose of recombinant human thyroid-stimulating hormone (rhTSH) doubles 24-h RAIU and causes a more homogeneous distribution of radioiodine on thyroid scintigrams of patients with nodular goiter. Pretreatment with rhTSH allows the therapeutic dose of (131)I to be reduced by 50%-60% without compromising the result of thyroid volume reduction. The present study focused on the dosimetric aspects of therapy with a reduced dose of (131)I after pretreatment with rhTSH in patients with nodular goiter. METHODS: Thirty-six patients were treated with (131)I to reduce thyroid volume. Nine patients were pretreated with a single dose of 0.01 mg of rhTSH, and 9 patients, with 0.03 mg of rhTSH. Two control groups of 9 patients, matched for thyroid weight and 24-h radioactive iodide uptake, were not pretreated with rhTSH. The therapeutic dose of (131)I was aimed at being sufficient to result in retention of 3.7 MBq of (131)I per gram of thyroid tissue at 24 h. Thyroid radioactivity after (131)I administration was measured every 24 h for 3 d and on days 7, 10, 14, 21, and 28. A model of iodine biokinetics was used to estimate absorbed doses in organs. Protein-bound (131)I activity was measured at 1, 2, 3, 7, and 10 d and at 2, 3, and 4 wk after (131)I therapy. RESULTS: The administered activities were 1.5 times lower in the 0.01-mg rhTSH group and 1.9 times lower in the 0.03-mg rhTSH group than in the control groups. The absorbed dose in the thyroid was similar in the rhTSH-pretreated groups and in the control groups. In the organs of excretion (bladder) and uptake (stomach) of inorganic iodide, the absorbed doses were 2- to 3-fold lower in the pretreated groups than in the control groups. The effective dose equivalent outside the thyroid was considerably lower in the rhTSH-pretreated groups than in their respective control groups (1.6-fold in the 0.01-mg rhTSH group and 2.3-fold in the 0.03-mg rhTSH group). The time course of protein-bound (131)I activity in serum and the cumulated protein-bound (131)I activity in serum did not differ significantly between rhTSH-pretreated and control groups. CONCLUSION: (131)I therapy after pretreatment with a single, low dose of rhTSH, with the dose reduced according to the rhTSH-induced increase in 24-h radioactive iodide uptake, caused lower radiation-absorbed doses in extrathyroidal organs and tissues, especially bladder and stomach, and no significant increase in the release of (131)I-labeled thyroid hormones into the circulation of patients with nodular goiter. Thus, this mode of therapy can be recommended, especially when the dose of radioiodine to be administered without rhTSH pretreatment is high.

Maternal urinary iodine concentration in pregnancy and children's cognition: results from a population-based birth cohort in an iodine-sufficient area.

OBJECTIVE: Reports from populations with an insufficient iodine intake suggest that children of mothers with mild iodine deficiency during pregnancy are at risk for cognitive impairments. However, it is unknown whether, even in iodine-sufficient areas, low levels of iodine intake occur that influence cognitive development in the offspring. This study investigated the association between maternal low urinary iodine concentration (UIC) in pregnancy and children's cognition in a population-based sample from a country with an optimal iodine status (the Netherlands). SETTING AND PARTICIPANTS: In 1525 mother-child pairs in a Dutch multiethnic birth cohort, we investigated the relation between maternal UIC<150 µg/g creatinine, assessed <18 weeks gestation and children's cognition. OUTCOMES MEASURES: Non-verbal IQ and language comprehension were assessed during a visit to the research centre using Dutch test batteries when the children were 6 years. RESULTS: In total, 188 (12.3%) pregnant women had UIC<150 µg/g creatinine, with a median UIC equal to 119.3 µg/g creatinine. The median UIC in the group with UIC>150 µg/g creatinine was 322.9 µg/g and in the whole sample 296.5 µg/g creatinine. There was a univariate association between maternal low UIC and children's suboptimum non-verbal IQ (unadjusted OR=1.44, 95% CI 1.02 to 2.02). However, after adjustment for confounders, maternal low UIC was not associated with children's non-verbal IQ (adjusted OR=1.33, 95% CI 0.92 to 1.93). There was no relation between maternal UIC in early pregnancy and children's language comprehension at 6 years. CONCLUSIONS: The lack of a clear association between maternal low UIC and children's cognition probably reflects that low levels of iodine were not frequent and severe enough to affect neurodevelopment. This may result from the Dutch iodine fortification policy, which allows iodised salt to be added to almost all processed food and emphasises the monitoring of iodine intake in the population.

Associations between thyroid function and mortality: the influence of age.

OBJECTIVE: The aim of this study was to investigate the influence of age on the association between thyroid function and mortality. DESIGN: The Nijmegen Biomedical Study is a population-based study, comprising 5816 randomly selected adults of all age groups without previously known thyroid disease. METHODS: TSH, free thyroxine (FT4) and peroxidase antibodies were measured in 2002-2003. The number of deaths were established in 2012 (median follow-up time 9.4 years). RESULTS: Subclinical thyrotoxicosis was associated with mortality in subjects aged <65 years (hazard ratio (HR) 2.5, 95% CI 1.1-5.7), but not in subjects aged >65 years. As for thyroid function within the normal range: in the 493 participants aged 80 years or older, an FT4 level in the high-normal range (18.5-22 pmol/l) was associated with a higher mortality in comparison with FT4 levels in the middle range (11.5-15.0 pmol/l): HR 1.7 (95% CI 1.0-2.9). In these elderly, TSH levels within the high-normal range (3.0-4.0 mIU/l) were also associated with a higher mortality in comparison with TSH levels within the middle range (1.0-2.0 mIU/l): HR 1.8 (95% CI 1.0-3.1). CONCLUSIONS: The relationship between thyroid function and mortality differs according to age. This finding might (partially) explain the discrepant results of previous studies examining the relationship between thyroid function and mortality in different age groups.

Longitudinal trends in thyroid function in relation to iodine intake: ongoing changes of thyroid function despite adequate current iodine status.

OBJECTIVE: Several cross-sectional studies on populations with iodine deficiency showed that TSH-levels are negatively associated with age, while in populations with high iodine intake TSH is positively associated with age. The question is whether such an age-thyroid function relation is an ongoing process apparent also in longitudinal studies and whether it reflects an actual iodine deficiency or an iodine insufficiency in the past. METHODS: In an area with a borderline iodine status in the past, we studied 980 participants of the Nijmegen Biomedical Study. We measured serum TSH, free thyroxine (FT4), total triiodothyronine (T3), peroxidase antibodies, and the urine iodine and creatinine concentration 4 years after our initial survey of thyroid function, in which we reported a negative association between TSH and age. RESULTS: within 4 years, TSH decreased by 5.4% (95% ci 2.58.3%) and FT4 increased by 3.7% (95% ci 2.94.6%). median urinary iodine concentration was 130 µg/l. estimated 24-h iodine excretion was not associated with TSH, T3, change of TSH, or FT4 over time or with the presence of antibodies against thyroid peroxidase. Only FT4 appeared to be somewhat higher at lower urine iodine levels: a 1.01% (95% CI 0.17-1.84%) higher FT4 for each lower iodine quintile. CONCLUSIONS: In this longitudinal study, we found an ongoing decrease in TSH and increase in FT4 in a previously iodine insufficient population, despite the adequate iodine status at present. This suggests that low iodine intake at young age leads to thyroid autonomy (and a tendency to hyperthyroidism) that persists despite normal iodine intake later in life.

Subclinical hypothyroidism after vascular complicated pregnancy.

OBJECTIVE: Women with a history of vascular complicated pregnancy are at risk for developing remote cardiovascular disease. It is associated with underlying cardiovascular risk factors both jeopardizing trophoblast and vascular function. Subclinical hypothyroidism may relate to both conditions. METHODS: In 372 women with a history of vascular complicated pregnancy, we assessed thyroid function. RESULTS: Subclinical hypothyroidism was diagnosed in 73/372 women (19.6%). It occurred more often when pregnancy ended before 32 weeks of gestation (p = 0.008). CONCLUSION: In this cohort, subclinical hypothyroidism is more common after very preterm delivery. It may contribute to the elevated risk of remote cardiovascular disease.

Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma.

BACKGROUND: Measurements of plasma normetanephrine and metanephrine provide a useful diagnostic test for phaeochromocytoma, but this depends on appropriate reference intervals. Upper cut-offs set too high compromise diagnostic sensitivity, whereas set too low, false-positives are a problem. This study aimed to establish optimal reference intervals for plasma normetanephrine and metanephrine. METHODS: Blood samples were collected in the supine position from 1226 subjects, aged 5-84 y, including 116 children, 575 normotensive and hypertensive adults and 535 patients in whom phaeochromocytoma was ruled out. Reference intervals were examined according to age and gender. Various models were examined to optimize upper cut-offs according to estimates of diagnostic sensitivity and specificity in a separate validation group of 3888 patients tested for phaeochromocytoma, including 558 with confirmed disease. RESULTS: Plasma metanephrine, but not normetanephrine, was higher (P < 0.001) in men than in women, but reference intervals did not differ. Age showed a positive relationship (P < 0.0001) with plasma normetanephrine and a weaker relationship (P = 0.021) with metanephrine. Upper cut-offs of reference intervals for normetanephrine increased from 0.47 nmol/L in children to 1.05 nmol/L in subjects over 60 y. A curvilinear model for age-adjusted compared with fixed upper cut-offs for normetanephrine, together with a higher cut-off for metanephrine (0.45 versus 0.32 nmol/L), resulted in a substantial gain in diagnostic specificity from 88.3% to 96.0% with minimal loss in diagnostic sensitivity from 93.9% to 93.6%. CONCLUSIONS: These data establish age-adjusted cut-offs of reference intervals for plasma normetanephrine and optimized cut-offs for metanephrine useful for minimizing false-positive results.