Hyperthyroxinemia and Hypercortisolemia due to Familial Dysalbuminemia.

A 23-year-old man and his grandmother with hyperthyroxinemia and hypercortisolemia were heterozygous for an ALB mutation (p. Arg218Pro), known to cause familial dysalbuminemic hyperthyroxinemia (FDH). However, serum-free cortisol levels in these individuals were normal and total cortisol concentrations fell markedly after depletion of albumin from their serum. We conclude that binding of steroid as well as iodothyronines to mutant albumin causes raised circulating cortisol as well as thyroid hormones in euthyroid euadrenal individuals with R218P FDH, with potential for misdiagnosis, unnecessary investigation, and inappropriate treatment.

Hyperthyroxinemia at birth: a cause of idiopathic neonatal hyperbilirubinemia?

BACKGROUND: Some neonates develop idiopathic hyperbilirubinemia (INHB) requiring phototherapy, yet with no identifiable causes. We searched for an association between abnormal thyroid levels after birth and INHB. METHODS: Of 5188 neonates, 1681 (32.4%) were excluded due to one or more risk factors for hyperbilirubinemia. Total thyroxine (TT4) and thyroid stimulating hormone values were sampled routinely at 40-48 hours of age and measured in the National Newborn Screening Program. RESULTS: Of the 3507 neonates without known causes for hyperbilirubinemia, 61 (1.7%) developed INHB and received phototherapy. Univariate analyses found no significant association between mode of delivery and INHB (vacuum-delivered neonates were a priori excluded). Nonetheless, in cesarean-delivered (CD) neonates, two variables had significant association with INHB: TT4 ≥ 13 µg/dL and birth at 38-38.6 weeks. In vaginally delivered (VD) born neonates, INHB was associated with weight loss > 7.5% up to 48 hours of age. Multivariate logistic regression analysis showed a strong effect of mode of delivery on possible significant association with INHB. In CD neonates, such variables included: TT4 ≥ 13 µg/dL [P = 0.025, odds ratio (OR) 5.49, 95% confidence interval (CI) 1.23-24.4] and birth at 38-38.6 weeks (P = 0.023, OR 3.44, 95% CI 1.19-9.97). In VD neonates, weight loss > 7.5% (P = 0.019, OR 2.1, 95% CI 1.13-3.83) and 1-min Apgar score < 9 (P < 0.001, OR 3.8, 95% CI 1.83-7.9), but not TT4, showed such an association. CONCLUSIONS: INHB was significantly associated with birth on 38-38.6 week and TT4 (≥ 13 µg/dL) in CD neonates, and with a weight loss > 7.5% in VD neonates. We herein highlight some acknowledged risk factors for neonatal hyperbilirubinemia, and thus minimize the rate of INHB.

Unfavorable Course of Subclinical Hypothyroidism in Children with Hashimoto's Thyroiditis Compared to Those with Isolated Non-Autoimmune Hyperthyrotropinemia.

Subclinical hypothyroidism (SCH) is a common problem in pediatric population, and the natural history of SCH varies depending on its etiology. Whether Hashimoto's thyroiditis (HT) negatively affects the natural course of SCH was investigated in pediatric patients without concomitant diseases. Predictors for levothyroxine medication were also evaluated. Medical records of 109 children with SCH (91 girls, 5?18 years) diagnosed between 2005 and 2014 were retrospectively reviewed. Patients were classified into HT (n = 37) and isolated non-autoimmune hyperthyrotropinemia (iso-NAHT, n = 72). During median 2 years of follow-up, only 10.1% of SCH patients eventually initiated levothyroxine, and HT patients showed a higher probability of requiring levothyroxine medication than iso-NAHT patients (21.6% vs. 4.2%). Underlying HT independently predicted deterioration of thyroid function, leading to levothyroxine medication (hazard ratios [HRs], 4.6 vs. iso-NAHT, P = 0.025). High titers of anti-thyroglobulin antibodies (TGAbs) predicted later medication in the HT group (HRs, 28.2 vs. normal TGAbs, P = 0.013). Most pediatric SCH showed benign and self-remitting courses. Underlying HT significantly increases the risk for levothyroxine medication, especially with high titers of TGAbs.

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.

Reversible atrioventricular blocks in thyroid storm.

Atrioventricular blocks or sinoatrial blocks are rarely described in patients with thyrotoxicosis or thyroid storm. The mechanism of these blocks remains obscure. Thyroid storm, being an emergency situation requires early diagnosis and management because if left untreated, it may prove fatal. Usually patients with AV blocks require pacing (temporary or permanent). Here we describe a case who developed AV blocks, did not undergo pacing, but recovered only on antithyroid treatment.

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.

La hipotiroxinemia gestacional se asocia al síndrome de déficit de atención e hiperactividad / Low maternal free thyroxine concentrations during pregnancy is associated with attention-deficit/hyperactivity disorder

Objetivo: El objetivo de este estudio es determinar si existe una relación entre la aparición del trastorno de hiperactividad y déficit de atención(THDA) y la hipotiroxinemia durante la gestación. Material y métodos: Se seleccionó a 59 pacientes con determinaciones de FT4 en el tercer trimestre de la gestación, entre los 15 meses y los 2 años después del parto. De estas mujeres, 34 tenían valores < 0,79 ng/dl (que es el percentil 10 de la distribución de T4 en gestantes normoyodadas de nuestra área).Se interrogó a la madre sobre la presencia de los18 síntomas que constituyen la prueba de HTDA. Las respuestas obtenidas se transformaron en una puntuación dependiendo de la frecuencia de aparición de los citados síntomas. Resultados: Tener una T4 anormal implica demedia 6,7 (intervalo de confianza [IC] del 95%,1,75-11,58) puntos más de la escala y esta diferencia resultó significativa (p = 0,009).Conclusión: Parece existir una relación positiva entre la hipotiroxinemia gestacional y una frecuencia aumentada en la aparición de síntomas de HTDA, aunque el diagnóstico del trastorno debería realizarlo un profesional cualificado (AU)

Objective: To investigate the relationship between ADHD test scores in children and mothers who had low levels of thyroxine while pregnant. Material and methods: A total of 59 women and their children were included in the study. In 28 of them a free thyroxine (FT4) lower than the percentile 10 of normal pregnancy values was detected in the third trimester of gestation. The control group (n = 30) was selected randomly from 442 pregnant women from an original cohort having normal FT4 values using the SPSS program. The ADHD test was administered to the mothers by a trained interviewer and a score was obtained covering two different dimensions, one on attention and the other related to hyperactivity impulsivity. Results: Children of mothers with gestational hypothyroxinaemia had an average of 7.3 more points in the ADHD global score (95% CI,2.6-12.05, P=.003). For the attention scale this revi difference was 2.2 (95% CI, 0.33-4.05, P=.022), and for hyperactivity-impulsivity it was 5.1 points (95%CI, 1.4-8.9, P=.008). Logistic regression analysis showed that the offspring of mothers with gestational hypothyroxinaemia had an adjusted odds ratio of 3.9 (95% CI, 1.1-14.2, P=.036) of having an abnormal ADHD test score. Conclusion: Low maternal FT4 in third trimester of gestation is associated with abnormal ADHD scores and a significant risk of ADHD in the offspring. Appropriate correction of gestational hypothyroxinaemia by means of sufficient iodine supply in the preconception period or thyroxine supplementation very early in pregnancy may prevent future development of ADHD in the progeny (AU)

Dysprealbuminemic hyperthyroxinemia in a patient with hyperthyroid graves disease.

Rare mutant forms of circulating albumin and prealbumin [transthyretin (TTR)] have increased binding affinity for thyroxine (T4). Patients with these variant plasma proteins, as a result of inherited mutations or as a paraneoplastic phenomenon, typically present with increased serum total T4 and, by some assay methodologies, an increased free T4 as well. Although these individuals are, in fact, euthyroid, nonspecific symptoms may lead to inappropriate treatment for hyperthyroidism. We present a 34-year-old woman in whom a mutant form of TTR with increased T4 binding affinity and coexisting Graves disease was present. Subsequent 131I therapy led to development of postablative hypothyroidism, which was obscured by her higher serum free T4 concentration. Circulating thyroid-binding globulin (TBG), albumin, and TTR concentrations were all within their respective reference limits. A T4-binding protein panel confirmed that TTR-bound T4 was significantly increased, whereas TBG- and albumin-bound T4 was normal, indicating that this patient had euthyroid dysprealbuminemic hyperthyroxinemia, which had been masked by the initial presentation of hyperthyroidism. These findings indicate that hypothyroidism can be masked by coexisting euthyroid dysprealbuminemic hyperthyroxinemia.

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.

[Hyperthyroxinemia and clinical euthyroidism. Report of one case]. / Hipertiroxinemia con eutiroidismo clínico: análisis a propósito de un caso.

The association of hyperthyroxinemia and euthyroidism is frequent and characterized by high plasma thyroxin concentrations, normal TSH values and absence of clinical signs of hyperthyroidism. We report an asymptomatic 28 years old male presenting with a serum total plasma thyroxin of 18.5 micrograms/dl (N 6.1-12.5), a free thyroxin of 2.9 ng/dl (N 0.8-1.4), a TSH of 3.4 microIU/ml (N 0.5-5), and a triiodothyronine of 128 ng/dl (N 80-180). Laboratory assessment did not find high thyroxin binding globulin, albumin or prealbumin concentrations or antithyroxin antibodies. The thyroxin binding capacity of albumin was elevated to 58.2 micrograms/dl (N 11.5-34.1). TSH responded normally to TRH stimulus and was suppressed with exogenous triiodothyronine, which caused an hyperthyroid syndrome. We concluded that this patient had a familial dysalbuminemia.

Immunologic and biochemical factors in hyperemesis gravidarum with or without hyperthyroxinemia.

OBJECTIVE: This study was set up to investigate the relationship between immune process and high levels of human chorionic gonadotropin-beta (betahCG) in hyperemesis patients with or without hyperthyroxinemia. METHODS: betahCG, immune parameters and thyroid related hormones were assayed in hyperemesis patients and in controls. RESULTS: Mean serum betahCG, fT4 and TSH levels were significantly higher in hyperemesis patients than in controls (p<0. 01, p<0.01, p<0.05, respectively). Further, immune parameters regarding IgG, IgM, C3, C4 and lymphocyte count were significantly higher in patients than in controls (p<0.05, p<0.01, p<0.01, p<0.05, p<0.01, respectively). In hyperemesis patients with hyperthyroxinemia, mean serum betahCG, IgG and IgM were significantly higher than in hyperemesis women without hyperthyroxinemia (p<0.001, p<0.05, p<0.05, respectively). BetahCG was positively correlated with fT4 (r = 0.45, p<0.05), with lymphocyte count (r = 0.47, p<0.01), with IgM (r = 0.38, p<0.05) and with C3 (r = 0.40, p<0.05) in hyperemesis patients. A negative correlation between betahCG and TSH (r = -0.43, p<0.05) was noted in the hyperemesis group. Free T4 showed a positive association to IgM (r = 0.49, p<0.01), to IgG (r = 0.40, p<0.05), to lymphocyte count (r = 0.45, p<0.05). CONCLUSION: Immunologic activity in pregnancy may have an effect or role on the stimulatory mechanism of betahCG in hyperemesis patients with or without hyperthyroxinemia.

Hipertiroxinemia con eutiroidismo clínico: análisis a propósito de un caso / Hyperthyroxinemia and clinical euthyroidism: report of one case

The association of hyperthyroxinemia and euthyroidism is frequent and characterized by high plasma thyroxin concentrations, normal TSH values and absence of clinical signs of hyperthyroidism. We report an asymptomatic 28 years old male presenting with a serum total plasma thyroxin of 18.5 µg/dl (N 6.1-12.5), a free thyroxin of 2.9 ng/dl (N 0.8-1.4), a TSH of 3.4 µIU/ml (N 0.5-5), and a triiodothyronine of 128 ng/dl (N 80-180). Laboratory assessment did not find high thyroxin binding globulin, albumin or prealbumin concentrations or antithyroxin antibodies. The thyroxin binding capacity of albumin was elevated to 58.2 µg/dl (N 11.5-34.1). TSH responded normally to TRH stimulus and was suppressed with exogenous triiodothyronine, which caused an hyperthyroid syndrome. We concluded that this patient had a familial dysalbuminemia

Inhibition of serum protein binding of thyroxine in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia.

OBJECTIVE: To investigate unusual free thyroxine (FT4) responses to T4 replacement doses in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia (FDH). METHODS: In this FDH hypothyroid patient, serum FT4 concentration by equilibrium dialysis and T4, triiodothyronine (T3), and thyroid stimulating hormone (TSH) determinations were supplemented by thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) measurements. RESULTS: Initial thyroid function tests were compatible with hypothyroidism and FDH (T4 = 78 nmol/L, T3 = 1.08 nmol/L, FT4 = 11.6 pmol/L, TSH = 45 mU/L). When she was initially treated with T4 (0.112-0.088 mg/day) there was an increase in FT4 concentration to hyperthyroid levels accompanied by TSH inhibition (FT4 = 31-51 pmol/L, TSH = <0.03 mU/L); the patient also complained of intolerance and nervousness, and T4 treatment was discontinued. Concentrations of thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) were normal. When T4 therapy was later resumed at a dosage of 0.075 mg/day, there was a marked increase in percent dialyzable T4. The elevation in percent dialyzable T4 during T4 replacement in a patient with FDH is unusual in view of the very large T4 binding capacity of FDH albumin. The presence of an inhibitor that reduced T4 binding by both TBG and FDH albumin probably explains the elevation in percent dialyzable T4 during T4 treatment. CONCLUSIONS: This FDH patient represents the first case of a putative inhibitor of T4 binding to both TBG and FDH albumin. The inhibition of T4 binding by these disparate proteins suggests that the inhibitor effect is mediated nonspecifically.

Familial dysalbuminaemic hyperthyroxinaemia and inherited partial TBG deficiency: first report.

BACKGROUND: Abnormalities of the serum thyroid hormone binding proteins are not uncommon but, when properly assessed, they do not present diagnostic difficulties. In contrast, the presence of two inherited defects of thyroid hormone transport, of the type presented in the family described here, may cause a major problem in diagnosis and has not been described previously. METHODS: All conventional thyroid function tests were carried out. In addition, thyroid hormone binding to serum proteins was assessed by agarose gel electrophoresis, and thyroxine binding globulin by immunoassays and by immunodiffusion. The affinity of TBG for thyroxine and its maximal binding capacity were assessed by Scatchard analysis. RESULTS: Tests carried out on 22 members of the family revealed familial dysalbuminaemic hyperthyroxinaemia in 10 family subjects. All five living siblings of the propositus had familial dysalbuminaemic hyperthyroxinaemia and two tested transmitted this trait to their children and grandchildren. This was not the case with the propositus. Partial thyroxine binding globulin deficiency only, inherited presumably from the propositus' mother, was found in two family members. Both thyroxine binding globulin deficiency and familial dysalbuminaemic hyperthyroxinaemia were detected in the propositus and in his male nephew, masking the typical laboratory abnormalities associated with each of these defects. CONCLUSIONS: Coexistence of two inherited defects of thyroid hormone transport proteins produce atypical thyroid function test abnormalities, which can be misinterpreted as thyroid hormone dysfunction.

Postpartum thyroiditis and familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia (FDH) is a syndrome associated with euthyroidism and increased binding of T4 to serum albumin. The combined occurrence of FDH and postpartum hyperthyroidism due to Graves' disease has only been reported in one patient. We now describe the first case of FDH and thyrotoxicosis due to postpartum silent thyroiditis. In a 19-yr-old woman, FDH, suspected on the basis of strikingly elevated analog free T4 (fT4) and total T4 values, but normal two-step fT4 and serum TSH values, was confirmed by [125I]T4 agarose-gel electrophoresis. When FDH and thyrotoxicosis, characterized by markedly elevated analog fT4, total T4, and two-step fT4 values and undetectable TSH values, coexist, the differential diagnosis may be confusing.

The effects of danazol on a patient with familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia, a syndrome involving an abnormal affinity of albumin for thyroxine, results in elevated total thyroxine and free thyroxine index levels but normal triiodothyronine resin uptake and thyroid-stimulating hormone levels. Danazol is a synthetic androgen that increases triiodothyronine resin uptake and decreases total thyroxine, secondary to a decrease in thyroid-binding globulin levels. A 35-year-old woman with familial dysalbuminemic hyperthyroxinemia who was given danazol, in whom nervousness, insomnia, and weight gain developed, is described. Thyroid tests performed after initiation of danazol therapy revealed an increase in triiodothyronine resin uptake, with persistently elevated total thyroxine and free thyroxine index levels, and normal thyroid-stimulating hormone levels. Once the danazol was withdrawn, the symptoms resolved, the triiodothyronine resin uptake returned to normal, and the thyroid-stimulating hormone remained normal. The effects of danazol on a patient with familial dysalbuminemic hyperthyroxinemia correlate well with the effects on normals, and the ultrasensitive thyroid-stimulating hormone was the most useful test in separating hyperthyroxinemia from hyperthyroidism.

Familial dysalbuminemic hyperthyroxinemia associated with multinodular goiter and elevated radioiodine uptake. A case report.

Familial dysalbumenic hyperthyroxenemia characterized by elevations in serum total thyroxine (T4) and free-thyroxine index and normal free T4 and radioiodine uptake has been previously described. This syndrome is secondary to an autosomal dominant inheritance in which affected individuals are mistakenly diagnosed as thyrotoxic because of the elevation of serum levels of total T4 and free T4. The excess T4 level is caused by the presence of an abnormal serum protein that binds excess T4, thereby raising the level of total T4. The authors report the case of a patient with familial dysalbumenic hyperthyroxenemia who presented with superimposed multinodular goiter and an elevated 24-hour radioiodide uptake.

Heterogeneity of serum prolactin in patients with menstrual disorder in conjunction with hyperthyroxinemia.

Since the secretion of PRL is regulated by the hypothalamic-pituitary axis, an increase in large molecular size PRL in the serum is most likely due to secretion by the pituitary itself. The present study was performed to investigate the possible occurrence of PRL heterogeneity in 128 subjects with menstrual disorder in conjunction with hyperthyroxinemia (88 with untreated Graves' disease, 40 with subacute thyroiditis) and 50 age- and sex-matched healthy controls. All 128 patients in this study were suffering from amenorrhea or oligomenorrhea at the time of their initial visit. PRL heterogeneity was found in the sera of 5 of 88 (5.7%) patients with untreated Graves' disease, in 2 of 40 (5.0%) patients with subacute thyroiditis, but in none of the normal controls. PRL heterogeneity remained essentially unchanged in patients with Graves' disease over 6 months of treatment; however, in patients with subacute thyroiditis, either big-big PRL or big PRL decreased significantly along with a corresponding increase in little PRL associated with recovery from the illness within 6 months. The menstrual disorders in all patients were restored to normal after restoration to a euthyroid state. The underlying cause of the occurrence of PRL heterogeneity in patients with menstrual disorder in conjunction with hyperthyroxinemia is not known.