A Thyroid Hormone-Independent Molecular Fingerprint of 3,5-Diiodothyronine Suggests a Strong Relationship with Coffee Metabolism in Humans.

Background: In numerous studies based predominantly on rodent models, administration of 3,5-diiodo-L-thyronine (3,5-T2), a metabolite of the thyroid hormones (TH) thyroxine (T4) and triiodo-L-thyronine (T3), was reported to cause beneficial health effects, including reversal of steatohepatosis and prevention of insulin resistance, in most instances without adverse thyrotoxic side effects. However, the empirical evidence concerning the physiological relevance of endogenously produced 3,5-T2 in humans is comparatively poor. Therefore, to improve the understanding of 3,5-T2-related metabolic processes, we performed a comprehensive metabolomic study relating serum 3,5-T2 concentrations to plasma and urine metabolite levels within a large general population sample. Methods: Serum 3,5-T2 concentrations were determined for 856 participants of the population-based Study of Health in Pomerania-TREND (SHIP-TREND). Plasma and urine metabolome data were generated using mass spectrometry and nuclear magnetic resonance spectroscopy, allowing quantification of 613 and 578 metabolites in plasma and urine, respectively. To detect thyroid function-independent significant 3,5-T2-metabolite associations, linear regression analyses controlling for major confounders, including thyrotropin and free T4, were performed. The same analyses were carried out using a sample of 16 male healthy volunteers treated for 8 weeks with 250 µg/day levothyroxine to induce thyrotoxicosis. Results: The specific molecular fingerprint of 3,5-T2 comprised 15 and 73 significantly associated metabolites in plasma and urine, respectively. Serum 3,5-T2 concentrations were neither associated with classical thyroid function parameters nor altered during experimental thyrotoxicosis. Strikingly, many metabolites related to coffee metabolism, including caffeine and paraxanthine, formed the clearest positively associated molecular signature. Importantly, these associations were replicated in the experimental human thyrotoxicosis model. Conclusion: The molecular fingerprint of 3,5-T2 demonstrates a clear and strong positive association of the serum levels of this TH metabolite with plasma levels of compounds indicating coffee consumption, therefore pointing to the liver as an organ, the metabolism of which is strongly affected by coffee. Furthermore, 3,5-T2 serum concentrations were found not to be directly TH dependent. Considering the beneficial health effects of 3,5-T2 administration observed in animal models and those of coffee consumption demonstrated in large epidemiological studies, one might speculate that coffee-stimulated hepatic 3,5-T2 production or accumulation represents an important molecular link in this connection.

Chavibetol corrects thyrotoxicosis through alterations in thyroid peroxidase.

Thyrotoxicosis is a clinical syndrome that commonly results from excess secretion and/or release of thyroid hormones in the circulation. It affects most of the body systems and if not treated properly may lead to serious health problems. In this investigation, we isolated a phenolic compound, chavibetol (CHV) from Piper betel leaf and evaluated its possible ameliorative effects in thyrotoxicosis of rats. Adult female rats were rendered thyrotoxic by the administration of L-thyroxine (L-T4) at 500 µg/kg/day, i.p., for 12 days, and then chavibetol (20.0 mg/kg, p.o.) was administered for 2 weeks. L-T4 administration elevated the concentration of serum thyroxine and triiodothyronine, activities of alanineaminotransferase and aspartate aminotransferase, and decreased the thyrotropin level as well as the expression of thyroid peroxidase (TPO). Further, it increased the activities of hepatic 5'mono-deiodinase-I, glucose-6--phosphatase, sodium-potasium-ATPase, and lipid peroxidation, and depleted the cellular antioxidants. However, chavibetol treatment to thyrotoxic rats normalized almost all these indices including TPO and also preserved the integrity of thyroid tissues suggesting its potential to correct thyrotoxicosis. Effects of CHV were more or less similar to a conventional antithyroid drug, propylthiouracil (PTU).

The multiple effects of thyroid disorders on bone and mineral metabolism.

Differently from most hormones, which commonly are specialized molecules able to influence other cells, tissues and systems, thyroid hormones (TH) are pleiotropic peptides, whose primordial function is difficult to identify. The complex action of TH on human economy can be easily witnessed by examining the diverse consequences of TH excess and deficiency during development and after maturity. In particular, different manifestations in bone modeling and remodeling reflect the circumstantial consequences of thyroid disturbances, which are age dependent. While hyperthyroidism during childhood enhances bone mineralization and accelerates epiphyseal maturation, in adults it induces bone loss by predominant activation of osteoclast activity. Furthermore, the syndrome of TH resistance is a multifaceted condition in which different sites exhibit signs of hormone excess or deficiency depending on the configuration of the TH receptor isoform. The investigation of the impact of TH resistance on the skeleton still remains to be elucidated. We present here a thorough review of the action of TH on bone and of the impact of thyroid disorders, including hyper- and hypothyroidism and the syndrome of TH resistance, on the skeleton.

The multiple effects of thyroid disorders on bone and mineral metabolism / Os múltiplos efeitos das disfunções tireoidianas sobre o metabolismo osteomineral

Differently from most hormones, which commonly are specialized molecules able to influence other cells, tissues and systems, thyroid hormones (TH) are pleiotropic peptides, whose primordial function is difficult to identify. The complex action of TH on human economy can be easily witnessed by examining the diverse consequences of TH excess and deficiency during development and after maturity. In particular, different manifestations in bone modeling and remodeling reflect the circumstantial consequences of thyroid disturbances, which are age dependent. While hyperthyroidism during childhood enhances bone mineralization and accelerates epiphyseal maturation, in adults it induces bone loss by predominant activation of osteoclast activity. Furthermore, the syndrome of TH resistance is a multifaceted condition in which different sites exhibit signs of hormone excess or deficiency depending on the configuration of the TH receptor isoform. The investigation of the impact of TH resistance on the skeleton still remains to be elucidated. We present here a thorough review of the action of TH on bone and of the impact of thyroid disorders, including hyper- and hypothyroidism and the syndrome of TH resistance, on the skeleton.

Diferentemente da maioria dos hormônios, que usualmente são moléculas especializadas capazes de influenciar outras células, tecidos e sistemas, os hormônios da tireoide (HT) são peptídeos pleiotrópicos, cuja função primordial é difícil de identificar. A ação complexa dos HT na fisiologia humana pode ser facilmente reconhecida ao observar as diversas consequências do excesso e da deficiência de HT durante e após o pleno desenvolvimento. Em particular as diferentes manifestações na modelação e remodelação óssea refletem que as consequências esqueléticas das disfunções tireoidianas dependem das circunstâncias e variam com a idade. Enquanto o hipertireoidismo durante a infância aumenta a mineralização óssea e acelera a maturação epifisária, em adultos induz a perda óssea pela ativação predominante da ação osteoclástica. Além disso, a síndrome de resistência ao HT é uma condição multifacetada na qual diferentes tecidos apresentam sinais de excesso ou deficiência hormonal, dependendo da predominância da expressão das diversas isoformas do receptor de HT. O impacto da resistência ao HT sobre o esqueleto ainda é motivo de investigação. Apresentamos aqui uma revisão abrangente sobre as ações ósseas dos HT e o impacto no esqueleto dos distúrbios da tireoide, incluindo hipo e hipertireoidismo e síndrome de resistência ao HT.

[Application of herbal medicine alba in treatment of patients with the pathology of thyroid].

High prevalence of hyperplastic and autoimmune diseases of thyroid in Ukrainian population is determined by endemic deficit of iodine and selenium. The aim of this research was to assess the place of biologically-active additions on the basis of herbal material containing an iodine and selenium in prophylaxis and treatment of thyroid pathology. During the six month period 55 patients received herbal preparation Alba twice a day. The levels of TSH, volume of thyroid, the sizes of nodular goiter (ultrasound investigation) were measured before and at the end of the investigation. The levels of thyroid stimulating antibodies to TSH receptor (AB-r TSH) were evaluated in patients with hyperthyroidism. The results of Alba application showed that in patients with thyroid pathology (diffuse nontoxic goiter, hyperthyroidism and chronic thyroiditis) it was possible to reduce the volume of thyroid, normalize its function, and decrease the level of AB-r TSH in diffuse toxic goiter. We also found approximately 20 % shortening of the time needed to get target level of TSH and finally the duration of treatment of thyrotoxicosis.

[Features of osteopenic syndrome in diffuse toxic goiter].

AIM: To characterize action of thyroid hormones overproduction on bone mineral density. MATERIAL AND METHODS: Pain intensity was graded according to 4-score scale, atraumatic fractures in the past were recorded, mineral bone density (MBD) was studied, TTH and T4 levels and biochemical indices of calcium-phosphorus and bone metabolism were studied, thyroid volume was calculated by J. Brunn (1981) and USI data in 116 patients with diffuse toxic goiter aged 20-65 years compared to 200 healthy controls matched by gender and age. RESULTS: Pain in bones was registered in 79% examinees (1.8 +/- 0.2 scores, on the average). Atraumatic bone fractures were in 9.5% (8% in the controls). MBD reduction was revealed at densitometry in 71% patients with thyrotoxicosis. It was most frequent and severe (in UD--1.78 +/- 0.1 SD, in MD--2.1 +/- 0.1 SD) in patients with severe disease associated with intensive bone remodeling. Loss of MBD does not depend on DTG duration. Mild thyrotoxicosis had no negative effect on bone tissue. Significant differences between patients with thyrotoxicosis and drug euthyrosis by rate and severity of osteopenia were not observed. CONCLUSION: Patients with DTG, especially in severe DTG, demand prophylactic measures concerning osteopenia immediately after diagnosis of thyrotoxicosis.

Hypothalamic neuropeptide Y/Y1 receptor pathway activated by a reduction in circulating leptin, but not by an increase in circulating ghrelin, contributes to hyperphagia associated with triiodothyronine-induced thyrotoxicosis.

Food intake is regulated by hypothalamic neuropeptides which respond to peripheral signals. Plasma ghrelin and leptin levels reflect peripheral energy balance and regulate hypothalamic neuropeptides such as neuropeptide Y (NPY), pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and orexins. Thyroid hormone stimulates food intake in humans and rodents. However, the mechanisms responsible for this stimulation have not been fully elucidated. To investigate the hyperphagic response to triiodothyronine (T(3))-induced thyrotoxicosis, adult male rats were studied 7 days after daily intraperitoneal injections of T(3) or vehicle. T(3)-treated rats were markedly hyperphagic. During this hyperphagia, plasma leptin levels were markedly decreased. However, the expression of the ghrelin gene in the stomach and the plasma ghrelin concentrations did not differ between the 2 groups. Hypothalamic NPY mRNA levels were significantly increased and associated with a marked decreased in both hypothalamic POMC and CART mRNA levels in the T(3)-treated rats. Hypothalamic MCH and orexin mRNA levels did not differ between the 2 groups. In addition, hyperphagia was partially reversed by intracerebroventricular administration of the NPY Y1 receptor antagonist BIBO3304. Therefore, the decreased plasma leptin levels could contribute to hyperphagia in T(3)-induced thyrotoxicosis. However, plasma ghrelin levels did not contribute to this hyperphagia.

Reduced myo-inositol and total choline measured with cerebral MRS in acute thyrotoxic Graves' disease.

Neuropsychiatric symptoms in the acute thyrotoxic phase of Graves' disease suggest involvement of brain processes. Short-echo-time proton MRS was used to measure the cerebral metabolite profile in newly diagnosed and untreated Graves' disease. Sixteen patients with Graves' disease and 18 age- and sex-matched healthy volunteers were studied. The patients had significantly reduced total choline and myo-inositol in the acute phase of Graves' thyrotoxicosis compared with the healthy volunteers.

Effect of propranolol on calcium, phosphorus, and magnesium metabolic disorders in Graves' disease.

The purpose of this study was to determine whether propranolol alone can improve mineral metabolic disorders in thyrotoxicosis. Ten Graves' disease patients and 11 normal age- and sex-matched controls participated in the study. In the untreated Graves' patients, serum levels of calcium (Ca), calcium x phosphorus product (Ca x P), urinary Ca, phosphorus (P), magnesium (Mg), and hydroxyproline (Hp) were higher than in control subjects (P less than .05), intestinal Ca absorption was lower than in control subjects (P less than .05), and Ca, P, and Mg balance were negative (P less than .05). After 40 mg propranolol four times per day (qid) for 28 days, serum triiodothyronine (T3) had decreased (P less than .05), serum reverse triiodothyronine (rT3) increased (P less than .05), serum thyroxine (T4) remained unchanged (P greater than .05), serum Ca and urine Ca and Mg decreased (P less than .05), intestinal Ca absorption increased, Ca balance was corrected, and P and Mg balance was improved (P less than .05). Our results indicate that propranolol can improve the metabolic disorders in addition to the symptomatic manifestations of Graves' disease. The mechanism responsible for the improved mineral balance is unclear, but may be related to beta-adrenergic blockade, increased membrane stability, or a decrease in the thyrotoxic state caused by the therapeutically induced decrease in serum T3.

[The effect of convaflavin on lipid peroxidation in the heart in experimental thyrotoxicosis]. / Vliianie konvaflavina na perekisnoe okislenie lipidov v serdtse pri éksperimental'nom tireotokiskoze.

The effect of convaflavin in doses of 30 and 45 mg/kg on lipid peroxidation in the heart was studied in white rats with experimental thyrotoxicosis. A noticeable decrease of the concentration of diene conjugates and malonic dialdehyde was revealed as was activation of catalase and peroxidase under the influence of convaflavin administered in a dose of 45 mg/kg.

The perchlorate discharge test with and without supplement of potassium iodide.

The purpose of the study was to compare the discharge of radioactive iodine from the thyroid after po administration of perchlorate with and without supplement of 2 mg potassium iodine (Kl) in 42 euthyroid controls, 26 patients with nontoxic goiter, 39 patients with thyrotoxicosis treated with radioactive iodine, and 39 patients with Pendred's syndrome. The discharge test was found to have a satisfactory specificity with supplement of 2 mg Kl, and was more sensitive to detect an organification defect than the standard perchlorate discharge test without Kl. In all groups of patients a significant discharge occurred after addition of Kl in contrast to healthy persons. Only in the group of patients with Pendred's syndrome a discharge of iodine was found in the perchlorate test without Kl.