Impact of maternal thyroid hormone in late pregnancy on adverse birth outcomes: A retrospective cohort study in China.

The purpose of this study was to explore the impact of maternal thyroid hormone dysfunction in late pregnancy on birth outcomes in a Chinese population. We retrospectively examined hospitalisation records and laboratory data between April 2016 and March 2017 and obtained results from 11,564 consecutive pregnant women with singleton births in which serum thyroid hormone had been examined together with birth outcomes. We assessed the association between maternal thyroid level and dysfunction with adverse birth outcomes based on regression analysis. Hyperthyroidism was associated with an increased risk of preterm birth (PTB, adjusted OR: 2.41, 95% CI: 1.83-3.17) and hypothyroidism was associated with an increased risk of small for gestational age (SGA, adjusted OR: 1.56, 95% CI: 1.10-2.22), while hyperthyroxinaemia was associated with a decreased risk of large for gestational age (LGA, adjusted OR: 0.64, 95% CI: 0.45-0.90). In addition, compared to women with normal FT3 and TSH (≥the 5th and ≤the 95th percentiles), women with high free triiodothyronine (FT3 >the 95th percentile) and low thyroid-stimulating hormone (TSH

Basal Serum Thyroxine Level should Guide Initial Thyroxine Replacement Dose in Neonates with Congenital Hypothyroidism

Objective: Initial high-dose sodium levothyroxine (Na-LT4) (10-15 µg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels. Methods: Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT4) levels. Time taken to achieve target hormone levels was compared within groups. Results: Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 µg/kg/day. Serum fT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016). Conclusion: Not all patients diagnosed with CH require high-dose Na-LT4. Initial dose of Na-LT4 may be selected on the basis of pre-treatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

Hyperthyroxinemia with a non-suppressed TSH: how to confidently reach a diagnosis in this clinical conundrum.

Disorders of thyroid function are among the commonest referrals to endocrinology. While interpretation of thyroid function testing is usually straightforward, accurate interpretation becomes significantly more challenging when the parameters do not behave as would be expected in normal negative feedback. In such cases, uncertainty regarding further investigation and management arises. An important abnormal pattern encountered in clinical practice is that of high normal or raised free thyroxine (fT4) with inappropriately non-suppressed or elevated thyroid-stimulating hormone (TSH). In this short review using two clinical vignettes, we examine the diagnostic approach in such cases. A diagnostic algorithm is proposed to ensure that a definitive diagnosis is reached in these challenging cases.

Optimizing Levothyroxine Dose Adjustment After Thyroidectomy With a Decision Tree.

BACKGROUND: After thyroidectomy, patients require Levothyroxine (LT4). It may take years of dose adjustments to achieve euthyroidism. During this time, patients encounter undesirable symptoms associated with hypo- or hyper-thyroidism. Currently, providers adjust LT4 dose by clinical estimation, and no algorithm exists. The objective of this study was to build a decision tree that could estimate LT4 dose adjustments and reduce the time to euthyroidism. METHODS: We performed a retrospective cohort analysis on 320 patients who underwent total or completion thyroidectomy at our institution. All patients required one or more LT4 dose adjustments from their initial postoperative dose before attaining euthyroidism. Using the Classification and Regression Tree algorithm, we built various decision trees from patient characteristics, estimating the dose adjustment to reach euthyroidism. RESULTS: The most accurate decision tree used thyroid-stimulating hormone values at first dose adjustment (mean absolute error = 13.0 µg). In comparison, the expert provider and naïve system had a mean absolute error of 11.7 µg and 17.2 µg, respectively. In the evaluation dataset, the decision tree correctly predicted the dose adjustment within the smallest LT4 dose increment (12.5 µg) 79 of 106 times (75%, confidence interval = 65%-82%). In comparison, expert provider estimation correctly predicted the dose adjustment 76 of 106 times (72%, confidence interval = 62%-80%). CONCLUSIONS: A decision tree predicts the correct LT4 dose adjustment with an accuracy exceeding that of a completely naïve system and comparable to that of an expert provider. It can assist providers inexperienced with LT4 dose adjustment.

Association between mild hyperthyrotropinemia and hypercholesterolemia in children with severe obesity.

Background Severe obesity is associated with a number of cardiometabolic risk factors. Thyroid-stimulating hormone (TSH) levels are often slightly increased in children with obesity. The clinical significance of the mild elevation in TSH in children with obesity is unclear. Objective To examine the association between TSH and lipids in children with severe obesity. Methods We performed a retrospective analysis of records of children with severe obesity with simultaneous measurements of TSH and lipids. Children with TSH <0.3 mIU/L and ≥10 mIU/L were excluded. The relationship between TSH and lipids was evaluated using univariate/multiple variable linear and logistic regression. Results The study included 834 children (age 13.8 ± 4.1 years, males 46%, body mass index [BMI]: 36.9 ± 7.6 kg/m2; BMI z-score 2.6 ± 0.4). Seventy-four (8.9%) children had TSH between 5 and <10 mIU/L (high TSH [HTSH]). TSH was positively associated with non-high-density lipoprotein (HDL) cholesterol (ß: 1.74; 95% confidence interval [CI] 0.29-3.20, p = 0.02). Total cholesterol and non-HDL cholesterol were higher in males with HTSH compared to those with normal TSH (175.5 vs. 163.5 mg/dL, p = 0.02 and 133.7 vs. 121.4 mg/dL, p = 0.02, respectively). The odds of elevated non-HDL cholesterol (≥145 mg/dL) was higher in males with HTSH relative to those with normal TSH (odds ratio [OR]: 2.78; 95% CI 1.35-5.69, p = 0.005). Conclusions TSH levels were positively associated with non-HDL cholesterol in children with severe obesity. Males with mildly elevated TSH had higher total cholesterol and non-HDL cholesterol compared to males with normal TSH. Further studies are warranted to determine if levothyroxine therapy would result in improvement in total cholesterol or non-HDL cholesterol in children with severe obesity with mildly elevated TSH.

Hyperthyroxinemia is positively associated with prevalent and incident type 2 diabetes mellitus in two population-based samples from Northeast Germany and Denmark.

BACKGROUND AND AIMS: A potential causal relationship between thyroid function and type 2 diabetes mellitus is currently under debate, but the current state of research is limited. Our aim was to investigate the association of thyroid hormone levels with prevalent and incident type 2 diabetes mellitus (T2DM) in two representative studies. METHODS AND RESULTS: Analyses are based on data from the Study of Health in Pomerania (SHIP), a German population based cohort with 4308 individuals at baseline and 3300 individuals at a five-year follow-up, and from INTER99, a Danish population-based randomized controlled trial with 6784 individuals at baseline and 4516 individuals at the five-year-follow-up. Serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentrations were measured in both studies, while free triiodothyronine was measured in SHIP only. T2DM was defined by self report or intake of anti-diabetic medication. Neither in SHIP nor in INTER99 we detected significant associations of serum TSH levels with prevalent or incident T2DM. Serum fT4 levels were significantly positively associated with prevalent T2DM in SHIP and INTER99. In longitudinal analyses baseline levels of fT4 were significantly positively associated with incident T2DM in SHIP (RR per pmol/L = 1.07; 95%-CI = 1.05-1.10), while this association barely missed statistical significance in INTER99 (RR per pmol/L = 1.03; 95%-CI = 0.99-1.06). In SHIP baseline fT3 levels were significantly associated with incident T2DM (RR per pmol/L = 1.21; 95%-CI = 1.16-1.27). CONCLUSION: We demonstrated positive associations of thyroid hormones with prevalent and incident type 2 diabetes mellitus suggesting that hyperthyroxinemia may contribute to the pathogenesis of this condition.

A case of thyroid hormone resistance: a rare mutation / Caso de resistência aos hormônios tireóideos: mutação rara

Reduced sensitivity to thyroid hormones (RSTH) is a rare disease that affects about 3,000 individuals, belonging to about 1,000 families. It results from reduced intracellular action of thyroid hormones (TH) genetically determined and manifests as persistent hyperthyroxinemia with non-suppressed thyroid-stimulating hormone (TSH). We describe a 67-years old, Caucasian woman, with past history of subtotal thyroidectomy due to diffuse goiter, who presents with a recurrence of goiter. Although she is clinically euthyroid, laboratory evaluation shows persistent hyperthyroxinemia with non-suppressed TSH. Response to thyrotropin releasing hormone (TRH) test was normal and TSH concentrations were not suppressed during oral administration of suprafisiologic doses of levothyroxine (L-T4). Peripheral blood DNA was extracted from the patient and a mutation was found localized in cluster one, at codon 346 of the ligand binding domain of the THRB gene. The patient’s son underwent thyroid function testing (TFT) and genetic study, both negative, suggesting a sporadic mutation. RSTH should be considered in all hyperthyroxinemic patients who are clinically euthyroid. Mutations interfering with three major steps required for TH action on target tissues have been, so far, identified (TR-β, TR-α, MCT8, SPB2). Each mutation is associated with a distinctive syndrome. Goal of management is to maintain a normal serum TSH level and a eumetabolic state and offer appropriate genetic counselling and prenatal diagnosis. Inappropriate treatment of eumetabolic patients results in hypothyroidism and need for TH replacement.

A sensibilidade reduzida aos hormônios tiroidianos (RSTH) é uma doença rara que afeta cerca de 3.000 indivíduos em 1.000 famílias. Ela resulta de uma ação intracelular reduzida de hormônios tiroidianos (TH), é geneticamente determinada e se manifesta como hipertiroxinemia persistente com hormônio tireoestimulante (TSH) não suprimido. Descrevemos o caso de uma mulher caucasiana de 67 anos de idade com histórico de tiroidectomia subtotal por bócio difuso e que apresentou recorrência do bócio. Embora ela fosse clinicamente eutiroide, a avaliação laboratorial mostrou hipertiroxinemia persistente com TSH não suprimido. A resposta ao hormônio liberador da tireotrofina (TRH) foi normal e as concentrações de TSH não foram suprimidas durante a administração oral de doses suprafisiológicas de levotiroxina (L-T4). Foi extraído DNA de sangue periférico da paciente e encontrada uma mutação no cluster um do códon 346 do domínio de ligação do ligante do gene THRB. O filho da paciente foi submetido a um teste de função da tiroide e a um estudo genético, ambos negativos, o que sugeriu uma mutação esporádica. O RSTH deve ser considerado em todos os pacientes hipertiroxinêmicos que sejam clinicamente eutiroides. Foram identificadas, até hoje, mutações que interferem com os três passos principais necessários para a ação do TH sobre os tecidos-alvo (TR-b, TR-α, MCT8, SPB2). Cada mutação está associada com uma síndrome distinta. O objetivo do manejo é manter o nível sérico normal de TSH e um estado eumetabólico, além de se oferecer aconselhamento genético adequado e diagnóstico pré-natal. O tratamento inadequado de pacientes eumetabólicos leva ao hipotireoidismo e requer reposição de TH.

A case of thyroid hormone resistance: a rare mutation.

Reduced sensitivity to thyroid hormones (RSTH) is a rare disease that affects about 3,000 individuals, belonging to about 1,000 families. It results from reduced intracellular action of thyroid hormones (TH) genetically determined and manifests as persistent hyperthyroxinemia with non-suppressed thyroid-stimulating hormone (TSH). We describe a 67-years old, Caucasian woman, with past history of subtotal thyroidectomy due to diffuse goiter, who presents with a recurrence of goiter. Although she is clinically euthyroid, laboratory evaluation shows persistent hyperthyroxinemia with non-suppressed TSH. Response to thyrotropin releasing hormone (TRH) test was normal and TSH concentrations were not suppressed during oral administration of suprafisiologic doses of levothyroxine (L-T4). Peripheral blood DNA was extracted from the patient and a mutation was found localized in cluster one, at codon 346 of the ligand binding domain of the THRB gene. The patient's son underwent thyroid function testing (TFT) and genetic study, both negative, suggesting a sporadic mutation. RSTH should be considered in all hyperthyroxinemic patients who are clinically euthyroid. Mutations interfering with three major steps required for TH action on target tissues have been, so far, identified (TR-ß, TR-α, MCT8, SPB2). Each mutation is associated with a distinctive syndrome. Goal of management is to maintain a normal serum TSH level and a eumetabolic state and offer appropriate genetic counselling and prenatal diagnosis. Inappropriate treatment of eumetabolic patients results in hypothyroidism and need for TH replacement.

Rising serum thyroxine levels and chorea in graves' disease.

A 15-year-old girl presented with chorea as a first sign of Graves' hyperthyroidism. Chorea abated with antithyroid drug treatment and reappeared when hyperthyroidism recurred but not when thyrotropin receptor antibodies increased after administration of (131)I. Therefore, chorea in this patient is associated with hyperthyroxinemia and not with autoantibodies.

Dysthyronemia in normal concentrations of thyrotropin--analytical and clinical consequences.

This article discusses the conditions that may lead to a phenomenon called dysthyronemia. Here, the thyroid gland has concentration of thyrotropin in circulation within the reference range, but the concentrations of free or total fractions of thyroid hormones are outside the reference range. Normal values of thyrotropin (TSH) and increased values of THs are referred to as hyperthyroxinemia, while normal values of thyrotropin and decreased values of thyroid hormone are hypothyroxinemia. As shown by our observations, it is a relatively frequent situation in the parallel determinations of TSH and free thyroxine, when results verging on hyperthyroxinemia were found in 7% of cases (6.74%, n=259,590), and also in the parallel sets of TSH and total triiodothyronine when hypotriiodothyroninemia reached 8.5% (8.48%, n=73,143). We are assuming that the main cause of hyperthyroxinemia in the free thyroxine and TSH system is the presence of autoantibodies against thyroxine in patients with autoimmune thyroid disease. The reason of hypotriiodothyroninemia in the system of triiodothyronine and TSH is a decreased concentration of thyroid binding globulin in postmenopausal women. Manufacturers of immunoanalytical kits should take into account the potential adverse effects of autoantibodies against thyroid hormones when measuring the results of immunoassay determination of the free fraction of these hormones.

Thrombin-activatable fibrinolysis inhibitor in hypothyroidism and hyperthyroxinaemia.

Endocrine disorders affect both the coagulation and fibrinolytic systems, and have been associated with the development of cardiovascular diseases. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a link between coagulation and the fibrinolytic system. The aim of this study was to determine the effect of thyroid hormone excess and deficiency on TAFI levels and function. The effect of hyperthyroxinemia on TAFI was studied in healthy volunteers who were randomised to receive levothyroxine or no medication for 14 days in a crossover design. The effect of hypothyroidism on TAFI was studied in a multicentre observational cohort study. Blood was drawn before treatment of patients with newly diagnosed hypothyroidism and when euthyroidism was achieved. Plasma clot-lysis times, activated TAFI (TAFIa)-dependent prolongation of clot-lysis and TAFI levels were measured. Thyroid hormone excess resulted in a hypofibrinolytic condition and in an enhanced TAFIa-dependent prolongation of clot lysis. A trend towards decreased plasma TAFI levels was observed in healthy volunteers who used levothyroxine. Hypothyroidism resulted in hyperfibrinolysis and a reduced TAFIa-dependent prolongation of clot lysis. In conclusion, alterations of TAFIa-dependent prolongation of clot lysis in patients with thyroid disorders may cause an impaired haemostatic balance. The disturbed haemostatic balance in patients with hyperthyroidism might make them prone to thrombosis, while the risk for bleeding may increase in patients with hypothyroidism.

Thyroid hormone receptor ß mediates thyroid hormone effects on bone remodeling and bone mass.

Excess thyroid hormone (TH) in adults causes osteoporosis and increases fracture risk. However, the mechanisms by which TH affects bone turnover are not elucidated. In particular, the roles of thyroid hormone receptor (TR) isotypes in the mediation of TH effects on osteoblast-mediated bone formation and osteoclast-mediated bone resorption are not established. In this study we have induced experimental hypothyroidism or hyperthyroidism in adult wild-type, TRα- or TRß-deficient mice and analyzed the effects of TH status on the structure and remodeling parameters of trabecular bone. In wild-type mice, excess TH decreased bone volume and mineralization. High TH concentrations were associated with a high bone-resorption activity, assessed by increased osteoclast surfaces and elevated concentrations of serum bone-resorption markers. Serum markers of bone formation also were higher in TH-treated mice. TRα deficiency did not prevent TH action on bone volume, bone mineralization, bone formation, or bone resorption. In contrast, TRß deficiency blocked all the early effects of excess TH observed in wild-type mice. However, prolonged exposure to low or high TH concentrations of TRß-deficient mice induced mild modifications of bone structure and remodeling parameters. Together our data suggest that TRß receptors mediate the acute effects produced by transient changes of TH concentrations on bone remodeling, whereas TRα receptors mediate long-term effects of chronic alterations of TH metabolism. These data shed new light on the respective roles of TRs in the control of bone metabolism by TH.

What should be done when thyroid function tests do not make sense?

Interpretation of thyroid function tests (TFTs) is generally straightforward. However, in a minority of contexts the results of thyroid hormone and thyrotropin measurements either conflict with the clinical picture or form an unusual pattern. In many such cases, reassessment of the clinical context provides an explanation for the discrepant TFTs; in other instances, interference in one or other laboratory assays can be shown to account for divergent results; uncommonly, genetic defects in the hypothalamic-pituitary-thyroid axis are associated with anomalous TFTs. Failure to recognize these potential 'pitfalls' can lead to misdiagnosis and inappropriate management. Here, focusing particularly on the combination of hyperthyroxinaemia with nonsuppressed thyrotropin, we show how a structured approach to investigation can help make sense of atypical TFTs.

Thyroid function in the nutritionally obese child and adolescent.

PURPOSE OF REVIEW: In recent years, there has been an increasing focus on thyroid function in obese children. There is controversy concerning whether the changes in the levels of thyroid hormones and thyroid-stimulating hormone (thyrotropin - TSH) in obesity are causes or consequences of weight status and whether these subtle differences merit treatment with thyroxine. This review aimed to study the prevalence of disturbed thyroid hormone and TSH values in childhood obesity and the underlying pathophysiologic mechanisms linking obesity to thyroid function. RECENT FINDINGS: In the past 18 months, four studies demonstrated moderate elevation of TSH concentrations in 10-23% of obese children, which was associated with normal or slightly elevated thyroxine and triiodothyronine values. Two studies reported ultrasonographic hypoechogenicity of the thyroid in obese children with hyperthyrotropinemia, which was not caused by autoimmune thyroiditis; therefore, the authors hypothesized a link to chronic inflammation in obesity. Weight loss led to a normalization of elevated TSH levels in two studies. The adipokine leptin is the most promising link between obesity and hyperthyrotropinemia since leptin stimulates the hypothalamic-pituitary-thyroid. SUMMARY: The elevated TSH levels in obesity seem a consequence rather than a cause of obesity. Therefore, treatment of hyperthyrotropinemia with thyroxine seems unnecessary in obese children.

Elevated free thyroxine levels detected by a neonatal screening system.

In Sapporo city of Japan, neonatal screening for congenital hypothyroidism has used the measurement of free thyroxine (T4) and thyroid-stimulating hormone (TSH) in the filter-paper blood spot. This system has enabled us to identify hyperthyroxinemic diseases. Filter papers were collected from neonatal infants born at 4-6 d of age and neonates who showed elevated free T4 (>4.0 ng/dL, 4 SD above the mean) were studied. Between January 2000 and December 2006, 83,232 newborns were screened. Eleven infants demonstrated persistent hyperthyroxinemia. One patient with slightly elevated free T4 and normal TSH was diagnosed as having familial dysalbuminemic hyperthyroxinemia (FDH). The other two patients with elevated free T4 without suppressed TSH were considered as having resistance of thyroid hormone (RTH), and analysis of thyroid hormone receptor (TR) beta gene confirmed the diagnosis. The remaining eight patients were diagnosed as having neonatal Graves' disease (NGD). Seven of eight pregnant women were treated with antithyroid drug and thus only one unrecognized NGD during pregnancy was detected by screening. Our screening system enables for early awareness of RTH and FDH. Regarding Graves' disease, the benefit of elevated free T4 screening is small, because most pregnant women with Graves' disease were managed.

[Human serum albumin: isoforms and analbuminemia]. / Humant serumalbumin: isoformer og analbuminaemi.

Persons with human serum albumin and a genetic variant are relatively common, whereas variant homozygotes are rare. About 65 structurally different variants are known. There is no clear relationship between bisalbuminemia and disease, and therefore isoforms are detected either because of a very pronounced increase in ligand binding or because of a modified electrophoretic mobility. The latter albumins may have modified binding and/or immunological properties. Analbuminemia is a rare but relative benign, homozygote condition in which especially the lipid metabolism is affected.

Transient hyperthyroxinemia in newborns from women with autoimmune thyroid disease and raised levels of thyroid peroxidase antibodies.

OBJECTIVE: Although it is well established that maternal thyroid disease and increased levels of thyrotropin receptor antibodies (TRab) during pregnancy are associated with a number of complications, is the significance of increased levels of thyroid peroxidase antibodies (TPOab) alone a matter for discussion? The aim of the present study was to examine whether transplacental passage of TPOab from women with autoimmune thyroid disease (AITD) interferes with thyroid function in the neonate. METHODS: Pregnant women with AITD (raised levels of TPOab) and their neonates were monitored with regard to variations of thyroid hormones, thyrotropin (TSH), and TPOab. Pregnant women with non-AITD served as controls. RESULTS: The neonates from mothers with AITD, independently of the presence also of TRab in the mothers, had a transient hyperthyroxinemia one week following birth. Neonatal TPOab correlated with that of the mothers at gestation and was cleared concomitantly with normalization of thyroxine. A high frequency (21%) of severe hyperbilirubinemia was observed in neonates from mothers with AITD. CONCLUSION: Children of mothers with raised levels of TPOab, have a transient hyperthyroxinemia one week after birth accompanied by a high frequency of hyperbilirubinemia suggesting that clinical examination and blood testing should be performed consecutively during the first postnatal week.

Artifactually elevated serum-free thyroxine levels measured by equilibrium dialysis in a pregnant woman with familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia (FDH) is a familial autosomal dominant syndrome caused by abnormal albumin with an increased affinity for thyroxine (T4). Two types of mutations in the albumin gene, replacing the normal arginine 218 with a histidine (R218H) or a proline (R218P), have been reported to cause FDH. Here, we report a pregnant Japanese woman with FDH caused by the mutant albumin R218P. She had extremely elevated total T4 levels but normal TSH. While the majority of T4was bound to albumin, T4 binding to thyroxine-binding globulin (TBG) was progressively increased throughout pregnancy. Her infant also had elevated serum T4 but normal thyrotropin (TSH). The presence of a guanine to cytosine transition in the second nucleotide of codon 218 of the albumin gene, resulting in a substitution of proline for the normal arginine (R218P), was revealed in the proband. Serum free thyroxine (FT4) levels were increased when measured with some commercial kits including equilibrium dialysis followed by radioimmunoassay (RIA) but not when determined by RIA after ultrafiltration of sera. These results indicate an increased T4 binding to TBG during pregnancy in the patients with FDH. Furthermore, our results suggest that normal serum FT4 determined by equilibrium dialysis is not an ultimate standard for the diagnosis of FDH in the patients with the mutant albumin R218P.