Article

Effect of Vitamin C on the Absorption of Levothyroxine in Patients With Hypothyroidism and Gastritis

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Abstract

Background: Malabsorption of l-T4 is a major clinical problem. Changes in gastric pH caused by several medical illnesses are associated with difficulties in the control of patients with hypothyroidism receiving the hormone. Means to correct these alterations would be of clinical value. Objectives: Our objective was to study the effect of vitamin C on the absorption of l-T4 in patients with hypothyroidism and gastritis. Design: Thirty-one patients with hypothyroidism, 28 females age 47.5 ± 13.5 (mean ± SD) years and 3 males age 55.7 ± 11.2 years ingested the dose of l-T4 in 120 mL water containing or not containing 500 mg vitamin C in a solution of pH 2.9 ± 0.1 (mean ± SD). Serum concentrations of free T4 and TSH were measured at the end of 3 periods of 2 months each, 2 controls and 1 vitamin C. Serum total T3 was measured in 16 of the patients, before and at the end of the vitamin C period. Serum TSH and free T4 and T3 were measured by a solid-phase, enzyme-labeled chemiluminescent competitive immunoassay All patients had gastrointestinal pathology and were not in good control when taking l-T4 before the study, and 23 had autoimmune thyroiditis or idiopathic hypothyroidism. The median l-T4 dose was 100 μg with an interquartile range of 50 μg. The protocol was reviewed and approved by our institution's ethics committee. Patients were asked to sign a written consent to participate in the study. Results: Serum concentrations of TSH, free T4, and T3 improved while on vitamin C. Serum TSH decreased in all patients (control, 11.1 [10.5] μIU/mL, median [interquartile range]), vitamin C 4.2 (3.7) μIU/mL, P = .0001), and it was normalized in 17 patients (54.8%). The average decrease was 69.2%. Serum T4 was higher with vitamin C in 30 of the 31 patients (control, 1.1 [0.3] ng/dL; vitamin C, 1.3 [0.3] ng/dL; P < .0001), and serum T3 increased as well in all 16 patients in whom it was measured (control, 60.5 [16.5] ng/dL; vitamin C, 70 [21] ng/dL; P < .005). Conclusions: In patients with hypothyroidism and gastrointestinal pathology, vitamin C improves the abnormalities in serum free T4, T3, and TSH concentrations. This approach is helpful in the management of these patients.

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... We did not find any evidence to suggest that the metabolism of T4 is significantly modulated by LT4-related pharmaceutical variables (formulation, dosing frequency, time of day, etc.). [141,142] Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
... For example, Antunez and Licht found that after 2 months of coadministration of LT4 tablets with 1 g of vitamin C, the patients' TSH levels had fallen by an average of around 70% for the same LT4 dose [141]. The effect of vitamin C was confirmed by Jubiz and Ramirez in a longitudinal study of 31 patients [142]. The researchers suggested that vitamin C might increase the solubility of LT4 in the stomach [142]. ...
... The effect of vitamin C was confirmed by Jubiz and Ramirez in a longitudinal study of 31 patients [142]. The researchers suggested that vitamin C might increase the solubility of LT4 in the stomach [142]. Thus, vitamin C is the only nutrient positively associated with LT4 absorption and can thus be proposed as a co-adjuvant in patients with gastrointestinal pathologies and LT4 malabsorption. ...
Article
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Levothyroxine (LT4) is a safe, effective means of hormone replacement therapy for hypothyroidism. Here, we review the pharmaceutical, pathophysiological and behavioural factors influencing the absorption, distribution, metabolism and excretion of LT4. Any factor that alters the state of the epithelium in the stomach or small intestine will reduce and/or slow absorption of LT4; these include ulcerative colitis, coeliac disease, bariatric surgery, Helicobacter pylori infection, food intolerance, gastritis, mineral supplements, dietary fibre, resins, and various drugs. Once in the circulation, LT4 is almost fully bound to plasma proteins. Although free T4 (FT4) and liothyronine concentrations are extensively buffered, it is possible that drug- or disorder-induced changes in plasma proteins levels can modify free hormone levels. The data on the clinical significance of genetic variants in deiodinase genes are contradictory, and wide-scale genotyping of hypothyroid patients is not currently justified. We developed a decision tree for the physician faced with an abnormally high thyroid-stimulating hormone (TSH) level in a patient reporting adequate compliance with the recommended LT4 dose. The physician should review medications, the medical history and the serum FT4 level and check for acute adrenal insufficiency, heterophilic anti-TSH antibodies, antibodies against gastric and intestinal components (gastric parietal cells, endomysium, and tissue transglutaminase 2), and Helicobacter pylori infection. The next step is an LT4 pharmacodynamic absorption test; poor LT4 absorption should prompt a consultation with a gastroenterologist and (depending on the findings) an increase in the LT4 dose level. An in-depth etiological investigation can reveal visceral disorders and, especially, digestive tract disorders.
... Hypothyroid patients treated with LT4 must be careful to avoid concomitant ingestion of substances such as coffee, fiber, calcium carbonate, ferrous sulfate, bile acid sequestrants, and raloxifene, all of which reduce absorption of LT4 (1)(2)(3). Vitamin C has also been reported to increase LT4 absorption in patients with gastritis, presumably due to alteration of gastric pH (4). ...
... Serum TT4 concentrations were measured for each subject at baseline and up to 6 h following LT4 administration. There was no significant difference in the median time-to-peak TT4 concentrations (4 h [4,4]; p = 0.19), or in the mean peak TT4 concentration before (12.03 -2.03 lg/dL) and following (11.63 -1.92 lg/dL) metformin administration ( p = 0.13) ( Table 2). The mean area under the TT4-time curve (AUC) before metformin administration was 3893.19 -567.58 lg/ dL-min, which was marginally, but not significantly, higher than the AUC (3765.45 ...
... Serum TT4 concentrations were measured for each subject at baseline and up to 6 h following LT4 administration. There was no significant difference in the median time-to-peak TT4 concentrations (4 h [4,4]; p = 0.19), or in the mean peak TT4 concentration before (12.03 -2.03 lg/dL) and following (11.63 -1.92 lg/dL) metformin administration ( p = 0.13) ( Table 2). The mean area under the TT4-time curve (AUC) before metformin administration was 3893.19 -567.58 lg/ dL-min, which was marginally, but not significantly, higher than the AUC (3765.45 ...
Article
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Levothyroxine (LT4) absorption is affected by concomitant ingestion of certain minerals, medications, and foods. It has been hypothesized that metformin may suppress serum thyroid-stimulating hormone (TSH) concentrations by enhancing LT4 absorption or by directly affecting the hypothalamic-pituitary axis. We examined the effect of metformin ingestion on LT4 absorption, as assessed by serum total T4 (TT4) concentrations. A modified Food and Drug Administration LT4 bioequivalence protocol was applied to healthy, metformin-naïve, euthyroid adult volunteers. Following an overnight fast, 600 μg LT4 was administered orally. Serum TT4 concentrations were measured at baseline and at 0.5, 1, 1.5, 2, 4, and 6 hours following LT4 administration. Measurements were performed before and after one week of metformin ingestion (850 mg three times daily). Peak serum TT4 concentrations, time to peak TT4 concentrations, and area under the concentration-time curve (AUC) were calculated. Twenty-six subjects (54% men, 27% white, age 33 ± 10 [standard deviation] years) were studied. There were no significant differences in peak serum TT4 concentrations (p = 0.13) and time to peak TT4 concentrations (p = 0.19) before and after one week of metformin use. We observed a trend toward reduced TT4 AUC after metformin ingestion (pre-metformin 3893 ± 568 [SD] mcg/dL-min, post-metformin 3765 ± 588, p = 0.09). LT4 absorption is unchanged by concomitant metformin ingestion. Mechanisms other than increased LT4 absorption may be responsible for the suppressed TSH concentrations observed in patients ingesting both drugs.
... Future developments have already occurred considering the availability of L-T4 formulations (liquid, softgel) that are refractory or much more resistant to IM than tablet L-T4 (9,14,98,100,(109)(110)(111)(112)(113)(114). In the author's opinion, their use seems preferable to the strategies of (i) increasing stepwise the dose of L-T4 (with associated frequent monitoring of TFTs and risk of iatrogenic thyrotoxicosis if the IM is decreased in dose or withdrawn); (ii) adding supplementation with either 1 g/d (115) or 0.5 g/d (116) vitamin C to acidify the intragastric pH. In the Argentinian study, the 28 patients had no known cause for UTH (115), while in the Colombian study, the 31 patients had endoscopy/gastritis-proven gastritis (116). ...
... In the author's opinion, their use seems preferable to the strategies of (i) increasing stepwise the dose of L-T4 (with associated frequent monitoring of TFTs and risk of iatrogenic thyrotoxicosis if the IM is decreased in dose or withdrawn); (ii) adding supplementation with either 1 g/d (115) or 0.5 g/d (116) vitamin C to acidify the intragastric pH. In the Argentinian study, the 28 patients had no known cause for UTH (115), while in the Colombian study, the 31 patients had endoscopy/gastritis-proven gastritis (116). Both 2-month-long trials with vitamin C (115,116) lack formal pharmacokinetics studies and challenge of patients with IM-associated UTH. ...
... In the Argentinian study, the 28 patients had no known cause for UTH (115), while in the Colombian study, the 31 patients had endoscopy/gastritis-proven gastritis (116). Both 2-month-long trials with vitamin C (115,116) lack formal pharmacokinetics studies and challenge of patients with IM-associated UTH. Indeed, coadministration of acidic beverages is one way of solving the problem of decreased bioavailability of drugs whose bioavailability under conditions of increased intragastric pH (117). ...
Article
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Pharmacological interference on L-thyroxine (L-T4) therapy can be exerted at several levels, namely from the hypothalamus/pituitary through the intestine, where the absorption of exogenous L-T4 takes place. A number of medications interfere with L-T4 therapy, some of them also being the cause of hypothyroidism. The clinician should be aware that some medications simply affect thyroid function tests with no need of modifying the dose of L-T4 that the patient was taking prior to their prescription. Usually, the topic of pharmacological interference on L-T4 therapy addresses the patient with primary hypothyroidism, in whom periodic measurement of serum thyrotropin (TSH) is the biochemical target. However, this minireview also addresses the patient with central hypothyroidism, in whom the biochemical target is serum free thyroxine (FT4). This minireview also addresses two additional topics. One is the costs associated with frequent monitoring of the biochemical target when L-T4 is taken simultaneously with the interfering drug. The second topic is the issue of metabolic/cardiovascular complications associated with undertreated hypothyroidism.
... In the same context, Baghcheghi et al. reported that thymoquinone significantly increased the T4 level in PTU-induced juvenile hypothyroid rats [25]. In addition, it was reported that antioxidant agents, such as vitamin C, improved the disturbed serum T4, T3, and TSH levels in patients with hypothyroidism [26]. Therefore, increasing the level of thyroid hormones could be a possible mechanism that indirectly contributed to the improving effects induced by TQ on the renal structure in the current experiment. ...
... A variety of factors is involved, either alone or in combination, in the modulation of expression of eNOS in hypothyroid rats. These factors include the direct impact of thyroxin on eNOS activity, changes in blood pressure, altered levels of vasoactive agents, and/or changes in shear stress due to hypodynamic circulation of hypothyroid rats [26]. Conversely, TQ administration increased eNOS expression in tubular epithelium possibly through its antioxidant properties. ...
Article
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Background: The association between hypothyroidism and renal diseases has been described in many studies. Nigella Sativa was among the recently reported natural product that has the potential to prevent renal tissue damage and fibrosis. The aim of this study was to evaluate the possible protective effect of thymoquinone on the structure of the renal cortex of hypothyroid rats and explore the mechanism behind it. Methods: An experimental model of hypothyroidism was induced in adult male Wistar rats by administration of propylthiouracil (6 mg/kg/body weight). One hypothyroid group was treated with thymoquinone at the dose of 50 mg/kg/body weight and compared to the untreated group. Thyroid function and oxidant/antioxidant status were assessed in the serum. Catalase gene expression was assessed using the real-time polymerase chain reaction. The kidney was assessed both histologically and immunohistochemically. Results: Administration of propylthiouracil resulted in a significant decrease in the serum levels of nitric oxide, reduced glutathione, and superoxide dismutase activity while the level of malondialdehyde significantly (p < 0.001) increased. Administration of thymoquinone alleviated this effect on the thyroid hormones and significantly increased the serum levels of antioxidants. Thymoquinone significantly (p < 0.001) upregulated catalase transcription by about 24-fold and could block the hypothyroidism-induced glomerular and tubular injury. Conclusion: Thymoquinone may have a potential protective effect against hypothyroidism-induced renal injury acting through the attenuation of the oxidative stress and upregulation of renal catalase gene expression.
... Jubiz et al. [99] conducted the study on 31 patients with hypothyroidism and gastritis. Participants swallowed L-T4 tablets, in a median daily dose of 100 µg, with 120 mL of water containing, or not, 500 mg vitamin C. Researchers measured serum levels of fT4 and TSH at the end of 2, 4, and 6 months. ...
... Vitamin C uncontrolled clinical study [100], non-randomized cross-over study [99] lowering of gastric pH enhanced absorption of L-T4 consider advising concomitant ingestion of vitamin C and L-T4 For L-T4 the knowledge gaps on drug-food interactions are clearly visible. Heuberger [106] and Paśko et al. [107] provided a few reasons for that, such as undefined framework study, hardly available appropriate samples, or measurement difficulties. ...
Article
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Levothyroxine (l-thyroxine, l-T4) is a drug of choice for treating congenital and primary hypothyroidism. Although clinically significant interactions between l-T4 and food can alter the safety and efficacy of the treatment, they still seem to be generally underestimated by patients, physicians and pharmacists. This review aimed to investigate the effects of meals, beverages, and dietary supplements consumption on l-T4 pharmacokinetics and pharmacodynamics, to identify the most evident interactions, and to perform the recommendations for safe co-administering of l-T4 and food. A total of 121 studies were identified following a systematic literature search adhering to PRISMA guidelines. After full-text evaluation, 63 studies were included. The results proved that l-T4 ingestion in the morning and at bedtime are equally effective, and also that the co-administration of l-T4 with food depends on the drug formulation. We found limited evidence for l-T4 interactions with coffee, soy products, fiber, calcium or iron supplements, and enteral nutrition but interestingly they all resulted in decreased l-T4 absorption. The altered l-T4 efficacy when ingested with milk, juices, papaya, aluminium-containing preparations, and chromium supplements, as well as observed enhancement effect of vitamin C on l-T4 absorption, shall be further investigated in larger, well-designed studies. Novel formulations are likely to solve the problem of coffee, calcium and iron induced malabsorption of l-T4. Maintaining a proper time interval between l-T4 and food intake, especially for coffee and calcium, or iron supplements, provides another effective method of eliminating such interactions.
... A number of factors can determine absorption of, and the therapeutic response to, levothyroxine in the individual patient, including gastrointestinal disorders, concomitant medications or vitamin supplements, diet, concurrent infections of comorbidities, weight gain, pregnancy, and others [18][19][20] . Levothyroxin NF, described above, has a more accurate and stable proportion of the active ingredient over time, in line with emerging regulatory requirements around the world. ...
... Thus, the new formulation will allow more precise and accurate dose titration of this NTI drug. This is relevant to all patients with hypothyroidism, but may be especially important for some patients with complex or unpredictable responses to LT4 therapy, as described above [18][19][20][21][22][23][24] . ...
Article
Background: Small variations in the dose of levothyroxine have been associated with marked variations in thyroid function in people with hypothyroidism. Accordingly, regulators have identified levothyroxine as a "narrow therapeutic index" drug subject to more stringent regulations compared with other drugs, in terms of the accuracy and stability of the amount of active drug in each tablet (typically required to be 95-105% of the labelled amount over its full shelf life), and its bioavailability geometric mean ratios (90% confidence intervals between 90-111.1%, including 100%). Review: This review describes a reformulation of a widely used levothyroxine product (Euthyrox.*). The new tablet fulfils all criteria according to the new specification regulations for dosage accuracy over a shelf life of 3 years in all climate zones, and for bioequivalence compared to the conventional formulation used for many years. In addition, a clinical trial demonstrated equivalent exposure between three different tablet strengths of the new formulation, amounting to the same total dose (dose form proportionality). As a consequence, switching from the conventional to the new formulation can be undertaken on a 1:1 dose-for-dose basis, without re-titration or additional thyroid function testing. Conclusion: The new formulation, which is more stable, will assist in the accurate dosage and titration of levothyroxine in the management of hypothyroidism.
... From a pharmacologic standpoint, the role of gastric pH was highlighted by Seng et al., who suggested that a bioequivalence in healthy volunteers might differ from the one in patients bearing altered gastric pH [50]. In a clinical study, a more efficient absorption of thyroxine has been observed when vitamin C was simultaneously taken in patients bearing both hypothyroidism and gastritis [51]. In these patients with impaired acid secretion, ascorbic acid may lower gastric pH thus facilitating the T4 absorption process [51]. ...
... In a clinical study, a more efficient absorption of thyroxine has been observed when vitamin C was simultaneously taken in patients bearing both hypothyroidism and gastritis [51]. In these patients with impaired acid secretion, ascorbic acid may lower gastric pH thus facilitating the T4 absorption process [51]. More recently, a pharmacokinetic study in healthy euthyroid subjects by Chon et al. [52] showed that simultaneous milk ingestion decreases oral levothyroxine absorption. ...
Article
Full-text available
Purpose Despite the absorption of oral thyroxine (T4) occurs in the small bowel, several patients with gastric disorders show an increased need for T4. In vitro evidence suggested that medium pH variations interfere with T4 dissolution. This study was aimed at finding the proof of concept of a direct relationship between the minimal effective dose of T4 and the actual gastric juice pH. Patients and methods Among 311 consecutively thyroxine-treated patients, 61 bearing Hashimoto’s thyroiditis (52 F/9 M; median age = 51 years) who complained persistent dyspepsia and/or upper abdominal symptoms following a noninvasive workup for gastrointestinal disorders, underwent EGDS with multiple biopsies and gastric juice pH measurement. All patients accepted to take thyroxine in fasting conditions, abstaining from eating or drinking for one hour. Results Thyroxine requirement increased along with the rising gastric pH (ρ = 0.4229; p = 0.0007). A multivariate analysis revealed that gastric pH was, beside body mass index, the far more important independent variable in determining the effective dose of T4 (p = 0.001). The ROC curve revealed that the pH threshold for an increased thyroxine requirement was at 2.28, being the AUC by 78%. Subdividing patients by the histologic findings, it appeared a significant increase (p = 0.0025) along with the progressive damage of gastric mucosa. Conclusion The in vivo measurement of gastric pH highlighted its key role in determining the minimal effective dose of oral T4 and may explain the interference of food, of some drugs and gut disorders on levothyroxine treatment
... Calcium supplements [74,75] and iron [76,77] also reduce absorption and thereby increase the levothyroxine dose requirement or increase serum TSH [52,53]. Vitamin C stands alone as an example of a supplement that may actually decrease the requirement for levothyroxine by enhancing its absorption, at least in patients with gastritis [78]. ...
Article
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Levothyroxine is the standard therapy for patients with hypothyroidism, a condition that affects up to 5% of people worldwide. While levothyroxine therapy has substantially improved the lives of millions of hypothyroid patients since its introduction in 1949, the complexity of maintaining biochemical and clinical euthyroidism in patients undergoing treatment with levothyroxine cannot be underestimated. Initial dosing of levothyroxine can vary greatly and may be based on the amount of residual thyroid function retained by the patient, the body weight or lean body mass of the patient, and thyroid-stimulating hormone levels. As levothyroxine is usually administered over a patient’s lifetime, physiological changes throughout life will affect the dose of levothyroxine required to maintain euthyroidism. Furthermore, dose adjustments may need to be made in patients with concomitant medical conditions, in patients taking certain medications, as well as in elderly patients. Patients who have undergone any weight or hormonal changes may require dose adjustments, and the majority of pregnant women require increased doses of levothyroxine. Optimal treatment of hypothyroidism requires a partnership between patient and physician. The physician is tasked with vigilant appraisal of the patient’s status based on a thorough clinical and laboratory assessment and appropriate adjustment of their levothyroxine therapy. The patient in turn is tasked with medication adherence and reporting of symptomatology and any changes in their medical situation. The goal is consistent maintenance of euthyroidism, without the patient experiencing the adverse events and negative health consequences of under- or overtreatment.
... En los pacientes reportados, aparte de la educación en la toma adecuada del medicamento, se trataron aquellas causas que fueron encontradas: el primero recibió tratamiento para gastritis crónica por H. pylori, además de antiparasitarios y suplemento con vitamina B12 para alcanzar niveles mayores de 400 pg/ml. El paciente 2 también recibió antiparasitarios, suplencia con vitamina B12 y un gramo diario de vitamina C efervescente, para mejorar la absorción de la levotiroxina (16) . En el caso 3 se evidenció en la paciente déficit de vitamina B12 y anticuerpos contra células parietales gástricas positivos 1:2.560, para lo cual recibió reposición mensual con 1.000 µg de cianocobalamina. ...
Article
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Se presentan cinco casos de pacientes con hipotiroidismo primario y altos requerimientos de levotiroxina, que luego de haber tenido un abordaje convencional en el ajuste de las dosis necesarias de levotiroxina por el peso y etiología de hipotiroidismo, recomendación y educación para el consumo adecuado de levotiroxina, optimización de la calidad del medicamento recibido, eliminación de interferencias con la absorción por medicamentos o alimentos, reposición de deficiencia de vitamina B12, desparasitación, descartar enfermedad celíaca y gastritis autoinmune atrófica, persisten con TSH elevada pese al uso de dosis altas de levotiroxina (mayores de 2,5 µg/kg/día). Se les practicó prueba de absorción de levotiroxina con 1.000 µg en dosis única de carga y evaluación de los incrementos de T4 libre a las 2 y 4 horas en cuatro pacientes y en uno con suministro semanal de la dosis de levotiroxina y evaluación semanal de T4 libre. Se confirmó en los cinco pacientes la capacidad de absorción de levotiroxina, constituyendo cinco casos de pseudomalabsorción de levotiroxina.Abstract Five patients with primary hypothyroidism and high levothyroxine dose requirements (>2.5 µg/kg/day) are presented. All patients had usual adjustment of the levothyroxine dose according to weight and hypothyroidism etiology. Patients were educated about the appropriate way of drug intake, the quality of the hormone replacement was assessed and withdrawal of all medications potentially interrupting with the levothyroxine absorption was done. All patients had vitamin B12 replacement, were treated for gastrointestinal parasites and celiac disease and autoimmune atrophic gastritis was ruled out. Despite correction of all this factors these patients had elevated TSH. To evaluate a potential mala-absorptive case all patients underwent a levothyroxine absorption test. In 4 cases, 1000 µg of levothyroxine was administered and free T4 was evaluated at 2 and 4 hours after intake of the drug. In 1 case, the levothyroxine was administered weekly with free t4 evaluation. Appropriate levothyroxine absorption was confirmed in all cases and the diagnosis of pseudo mal-absorption of levothyroxine was done.
... Previously, Pustylnik et al. (2013) demonstrated that vitamin C induces the expression of cell adhesion molecules and stimulates the differentiation of osteoblasts [61]. Furthermore, it has been previously reported that supplementation of vitamin C improves the thyroid hormone level in hypothyroidism patients [62]. Dysregulation of thyroid hormone is involved in various musculoskeletal pathologies such as osteoporosis [63,64]. ...
Article
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MicroRNAs (miRNAs) are small (18-25 nucleotides), noncoding RNAs that have been identified as potential regulators of bone marrow stromal cell (BMSC) proliferation, differentiation, and musculoskeletal development. Vitamin C is known to play a vital role in such types of biological processes through various different mechanisms by altering mRNA expression. We hypothesized that vitamin C mediates these biological processes partially through miRNA regulation. We performed global miRNA expression analysis on human BMSCs following vitamin C treatment using microarrays containing human precursor and mature miRNA probes. Bioinformatics analyses were performed on differentially expressed miRNAs to identify novel target genes and signaling pathways. Our bioinformatics analysis suggested that the miRNAs may regulate multiple stem cell-specific signaling pathways such as cell adhesion molecules (CAMs), fatty acid biosynthesis and hormone signaling pathways. Furthermore, our analysis predicted novel stem cell proliferation and differentiation gene targets. The findings of the present study demonstrate that vitamin C can have positive effects on BMSCs in part by regulating miRNA expression.
... The influence of the supplemental factors is consistent with recent research demonstrating iron and various vitamins interfere with LT4 therapy. 22,23 Although each ML algorithm used these same 7 predictors, their accuracy varied substantially, reflecting the importance of their varying assumptions. Poisson regression assumes a model most aligned with LT4 estimation, and is correspondingly the most accurate ML algorithm. ...
Article
Background: Patients often struggle to attain euthyroidism after thyroidectomy, and multiple dosing schemes have been proposed to supplant the standard weight-based approach for initial levothyroxine dosing after thyroidectomy. The objectives of this study were to review the literature for existing levothyroxine dosing schemes and compare estimation accuracies with novel schemes developed with machine learning. Methods: This study retrospectively analyzed 598 patients who attained euthyroidism after total or completion thyroidectomy for benign disease. A scoping review identified existing levothyroxine dosing schemes. Thirteen machine learning algorithms estimated euthyroid dose. Using 10-fold cross-validation, we compared schemes by the proportion of patients having a predicted dose within 12.5 µg/day of their euthyroid dose. Results: Of 264 reviewed articles, 7 articles proposed retrospectively implementable dosing schemes. A novel Poisson regression model proved most accurate, correctly predicting 64.8% of doses. Incorporating 7 variables, Poisson regression was significantly more accurate than the best scheme in the literature (body mass index/weight based) that correctly predicted 60.9% of doses (P = .031). Standard weight-based dosing (1.6 µg/kg/day) correctly predicted 51.3% of doses, and the least effective scheme (age/sex/weight based) correctly predicted 27.4% of doses. Conclusion: Using readily available variables, a novel Poisson regression dosing scheme outperforms other machine learning algorithms and all existing schemes in estimating levothyroxine dose.
... Higher intake of vitamin C appeared to be positively associated with thyroid cancer risk. Biologically, vitamin C has been shown to improve and mediate abnormalities seen in the levels of thyroid hormones and thyroid stimulating hormone in the serum of humans [50] and rats [51]. Previous studies have indicated both a positive and negative association between increased vitamin C intake and thyroid cancer [28]. ...
Article
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Background Selenium is an essential trace element that is important for thyroid hormone metabolism and has antioxidant properties which protect the thyroid gland from oxidative stress. The association of selenium, as well as intake of other micronutrients, with thyroid cancer is unclear. Methods We evaluated associations of dietary selenium, beta-carotene, calcium, vitamin D, vitamin C, vitamin E, folate, magnesium, and zinc intake with thyroid cancer risk in the National Institutes of Health – American Association of Retired Persons Diet and Health Study, a large prospective cohort of 566,398 men and women aged 50–71 years in 1995–1996. Multivariable-adjusted Cox proportional hazards regression was used to examine associations between dietary intake of micronutrients, assessed using a food frequency questionnaire, and thyroid cancer cases, ascertained by linkage to state cancer registries and the National Death Index. Results With the exception of vitamin C, which was associated with an increased risk of thyroid cancer (HRQ5 vs Q1, 1.34; 95% CI, 1.02–1.76; Ptrend, <0.01), we observed no evidence of an association between quintile of selenium (HRQ5 vs Q1, 1.23; 95% CI, 0.92–1.65; Ptrend, 0.26) or other micronutrient intake and thyroid cancer. Conclusion Our study does not suggest strong evidence for an association between dietary intake of selenium or other micronutrients and thyroid cancer risk. More studies are needed to clarify the role of selenium and other micronutrients in thyroid carcinogenesis.
... 46 Ascorbic acid determined in water hyacinth as 10.19 mg/100 g by cyclic voltammetry (CV) and 16.34 mg/100 g by titration with N-bromosuccinimide (NBS) in water hyacinth can thus highly relate its medicinal claim in goiter and related conditions. 47 In autoimmune thyroid disease, there is lymphatic infiltration that causes tissue damage further altering the normal functioning of thyroid gland in such conditions; drugs having immunomodulatory and antioxidant properties like Ashwagandha and Brahmi are prescribed along with the mainstream symptomatic management. 48 The paradigm of reverse pharmacology, however, is actually a rediscovery of the path, which founded modern pharmacology and evaluation of these herbal drug claims at the biomolecular level may further reveal its mechanism of action in providing the specific pharmacological actions. ...
Article
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Thyroid disorders have been one among the most challenging and most common endocrine disorders that we confront worldwide. Major thyroid disorders include hypothyroidism, hyperthyroidism, goiter/iodine deficiency, Hashimoto’s thyroiditis, and thyroid cancer. Among these, hypothyroidism is arguably the most challenging as its multifarious clinical presentation often goes unnoticed. Hypothyroidism can be attributed to the deficiency of thyroid hormones, triiodothyronine (T3) and thyroxine (T4), in the body. Mild or subclinical hypothyroidism refers to the condition where peripheral thyroid hormone levels are within normal range, but serum thyroid-stimulating hormone (TSH) levels are mildly elevated. Data to date are scarce that include direct experimental, pharmacological, or preclinical types of evidence of treating hypothyroidism with Ayurvedic and herbal drugs. The scope of this manuscript covers the utility of conventional Ayurveda or herbal drugs in ameliorating the pathophysiological symptoms of hypothyroidism. Treatment strategies have been evolving since the early and mid-twentieth century, starting from using the whole thyroid extract to the modern-day thyroxine monotherapy by L-thyroxine. Despite these advances, there remains a considerably large population who endure the symptoms of hypothyroidism. Various assortments of formulations are available for such conditions in Ayurveda system of medicine since the very early days of civilization. In Ayurveda, though there are not any direct reference of thyroid, Galaganda and Gandamala, which possess symptomatic similarities with thyroid disorders, have been mentioned frequently in the texts. With the present data available, it is concluded that natural resources around can be utilized for the prevention and amelioration of hypothyroidism in mammals.
... Gastritis causes L-T4 malabsorption, by altering the gastric juice pH, thereby affecting L-T4 tablet dissolution [8,16,17]. Recent studies have shown that vitamin C improves circulating concentrations of TSH, FT4, and total T3 in patients with gastritis and hypothyroidism receiving L-T4 replacement therapy in tablets, probably by increasing solubility of L-T4 in the stomach [18,19]. In fact, normal gastric acid secretion is necessary for effective absorption of L-T4 [5] by dissolution of tablets, and drug dissolution and solubility may be altered by restrictive procedures that increase gastric pH in the newly created stomach pouch; this may occur in gastric bypass [20]. ...
Article
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Background L-thyroxine (L-T4) malabsorption is a potential concern in patients with autoimmune atrophic gastritis. Methods We evaluated five patients with autoimmune gastritis, who showed high serum thyrotropin (TSH) levels (in the hypothyroid range) while in therapy with L-T4 in tablet. All patients were switched to receive an oral L-T4 liquid formulation maintaining the same dosage. Results In all patients who received L-T4 in tablet form after switching to an oral liquid formulation with the same L-T4 dosage, TSH circulating levels were normalized. In four patients who were switched back again to receive L-T4 in tablets, maintaining the dosage, TSH levels worsened again reaching levels in the hypothyroid range. Conclusions The fact that the change from tablets to liquid oral formulation normalised serum TSH levels, and that switching back to tablets caused thyrotropin levels to worsen, leads us to believe that absorption of L-T4 is greater with oral liquid formulations in these patients. These results suggest that the L-T4 oral liquid formulation could circumvent the pH alteration resulting from atrophic gastritis.
... Only a few small studies in the literature shed light on what may help in these circumstances. For example, triiodothyronine is absorbed better than thyroxine, and vitamin C has been shown to help with thyroxine absorption; therefore, giving either a combination of thyroxine and triiodothyronine or a combination of thyroxine and vitamin C may be more efficacious in these circumstances than giving thyroxine alone [8,9]. We however only have insufficient data to guide us on how to treat these patients. ...
Article
We present a case of myxedema coma refractory to traditional treatments. Morbidity and mortality from myxedema coma are frequently due to a missed or delayed diagnosis. It tends to respond very well to intravenous levothyroxine replenishment as long as this treatment is initiated early. We report a case of a 71-year-old man who presented with altered mental status and severe bradycardia who was promptly diagnosed with myxedema coma on laboratory studies sent in the emergency department (thyroid-stimulating hormone 94.74, free T4 0.17, and free T3 0.69). However, while the diagnosis was recognized immediately, and he was treated aggressively with intravenous thyroxine replacement, he strangely remained refractory to treatment for a prolonged period of time. While he did respond to intravenous thyroxine initially, he dramatically decompensated each time he was transitioned to oral therapy. This case brings to question why rarely certain patients fail the transition to oral therapy, and how to treat these patients.
... 5 µg/kg/d levothyroxine (Figure 1). Indeed, there is some evidence to suggest that vitamin C may enhance the intestinal absorption of levothyroxine (22,23). Furthermore, in a case series of ten infants with newly diagnosed cystic fibrosis and hyperthyrotropinemia, pancreas enzyme replacement normalized elevated TSH levels without levothyroxine substitution in nine of ten patients (24). ...
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Background Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3 . Almost 20 patients have been reported to date, with significant phenotypic variability. Case presentation We describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis. Conclusions Our report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range.
... Таким образом, ограничение потребления йода может быть методом лечения пациентов с СГ в регионах без йодного дефицита. 0,77, 1,46) и 0,99 (95% ДИ: 0,67, 1,47) для женщин с любым СГ и женщин с " мягким " СГ (уровень ТТГ сыворотки 4,69–6,99 мМЕ/л) по сравнению с женщинами в эутиреозе. Соотношение рисков для умеренного/тяжелого СГ (ТТГ ≥ 7,00 мМЕ/л) было немного повышенным (ОР: 1,22; 95% ДИ: 0,73, 2,05). ...
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The article is to overview papers:Effect of vitamin C on the absorption of levothyroxine in patients with hypothyroidism and gastritis.Management of neonates born to women with Graves’ disease: a cohort study.A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with Graves’ ophthalmopathy.Glucocorticoid regimens for prevention of Graves’ ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis.Smoking induces overexpression of immediate early genes in active Graves’ ophthalmopathy.Obesity and the risk of papillary thyroid cancer: A pooled analysis of three case-control studies.Differentiation of postpartum Graves’ thyrotoxicosis from postpartum destructive thyrotoxicosis using antithyrotropin receptor antibodies and thyroid blood flow.Follow-up of newborns of mothers with Graves’ disease.Severity of birth defects after propylthiouracil exposure in early pregnancy.The attitude toward hypothyroid- ism during early gestation: time for a change of mind?Effect of iodine restriction on thyroid function in subclinical hypothyroid patients in an iodine-replete area: A long period observa- tion in a large-scale cohort.Subclinical hypothyroidism and risk for incident ischemic stroke among postmenopausal women.Hashimoto’s thyroiditis pathology and risk for thyroid cancer.Anxiety and depression are more prevalent in patients with Graves’ disease than in patients with nodular goitre.The TRHR gene is associated with hypothalamo-pituitary sensitivity to levothyroxine.
... Chronic IDA is associated with palpitations, pallor, fatigue, poor exercise tolerance, decreased work performance, and can influence learning ability, cellular immunity and increase the frequency of premature and low birth weight deliveries [1,4]. Additionally, IDA secondary to gastropathy has been associated with refractoriness to iron supplementation and chronic atrophic gastritis has been associated with malabsorption of levothyroxine [15,45,46] which can be mitigated with clinical interventions addressing the achlorhydria [47,48]. Furthermore, atrophic gastritis has been associated with gastric cancer [6,49], gastric carcinoid [14,[49][50][51] and malt lymphoma [2]. ...
Article
Background: Graves' disease (GD) has been associated with iron deficiency anemia (IDA). Atrophic gastritis leads to IDA and has been associated with autoimmune thyroid disease. This study prospectively determined the prevalence of atrophic gastritis markers and the relationship between these markers and markers of IDA in GD subjects. Methods: Newly diagnosed GD patients (90) and controls (41) were studied. Of the newly diagnosed GD patients, 65 were consecutively enrolled and identified with GD irrespective of anemia, 25 had GD and IDA. Thyroid function, hematologic indices, and atrophic gastritis markers [parietal-cell antibodies (PCab), Helicobacter pylori antibodies (H. pylori ab), mean serum gastrin levels] were examined. Results: GD patients presenting with IDA were twice as likely (64% vs. 32%, P=0.049) to harbor PCabs when compared to all other GD subjects. Unselected GD subjects (n=65) had significantly higher PCab (37% vs. 7%, P<0.001) compared to controls. Gastrin levels were significantly elevated in all GD subjects compared to controls (105 vs. 39 pg/ml, P<0.0001). This difference was magnified in PCab+ subjects (202 vs. 64 pg/ml, P=0.003). In all GD subjects, PCabs were associated with increased gastrin levels (202 vs. 75 pg/ml, P=0.0004) and lower ferritin levels (52 vs. 95, P=0.05). In GD anemic subjects, PCabs were associated with lower mean corpuscular volume (75 vs. 81, P=0.001). Gastrin levels correlated inversely with ferritin levels in all GD subjects and positively with TIBC in GD anemic subjects. Conclusions: A significant subset of patients presenting with GD may suffer from IDA due to concurrent autoimmune atrophic gastritis.
... Vitamin C (ascorbic acid) is one of the essential vitamins due to its role as an antiaging agent, and because of its protective role against infections, autoimmune diseases, and the development of cancer [16]. There are indications that serum concentrations of thyroid-stimulating hormone (TSH) and free thyroid hormones (T3 and T4) have improved when patients have taken vitamin C [17]. It seems that vitamin C can reduce the adverse effect of heat stress [18]. ...
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Levothyroxine (LT4) is known for its use in various conditions including hypothyroidism. LT4 interaction with serum albumin may be influenced by the presence of vitamins. For this reason, we investigated the effect of vitamin C, vitamin B12, and folic acid on the complex of Bovine Serum Albumin with LT4 (BSA-LT4). UV-Vis spectroscopy was used to monitor the influence of vitamins on the BSA-LT4 complex. Fluorescence spectroscopy revealed a static quenching mechanism of the fluorescence of BSA-LT4 complex by the vitamin C and folic acid and a combined mechanism for vitamin B12. The interaction of vitamin C and folic acid with BSA-LT4 was moderate, while the binding of vitamin B12 was much stronger, extending the storage time of LT4 in blood plasma. Synchronous fluorescence found that the vitamins were closer to the vicinity of Trp than to Tyr and the effect was more pronounced for the binding of vitamin B12. The thermal stability of the BSA-LT4 complex was more evident, but no influence on the stability of BSA-LT4 complex was obtained for vitamin C. Molecular docking studies showed that vitamin C and folic acid bound the same site of the protein, while vitamin B12 bonded to a different site.
... In supporting of our data, it has been previously reported that administration of PTU during juvenile and growth period has a more pronounce effects on thyroid gland growth (Kikuyama et al. 1974). It has been previously reported that Vit C improved the abnormalities in serum free T4, T3, and thyroid stimulating hormone (TSH) concentrations in hypothyroid patients (Jubiz and Ramirez 2014). Therefore, the balancing effects of Vit C on thyroid hormones can be suggested as one of the possible mechanisms which indirectly contribute in learning and memory improving effects of Vit C in the present study. ...
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In this study the effects of Vitamin C (Vit C) on hypothyroidism-associated learning and memory impairment in juvenile rats was investigated. The pregnant rats were kept in separate cages. After delivery, they were randomly divided into six groups and treated: (1) Control; (2) Propylthiouracil (PTU) which 0.005% PTU in their drinking; (3–5) Propylthiouracil- Vit C groups; besides PTU, dams in these groups received 10, 100 and 500 mg/kg Vit C respectively, (6) one group as a positive control; the intact rats received an effective dose, 100 mg/kg Vit. C. After delivery, the pups were continued to receive the experimental treatments in their drinking water up to 56th day of their life. Ten male offspring of each group were randomly selected and tested in the Morris water maze (MWM) and passive avoidance (PA) which were started at 63th day (one week after stopping of the treatments). Brains were then removed for biochemical measurements. PTU increased time latency and traveled distance during 5 days in MWM while, reduced the spent time in target quadrant in MWM and step-trough latency (STL) in PA. PTU decreased thiol content, superoxide dismutase (SOD) and catalase (CAT) activities in the brain while, increased molondialdehyde (MDA). In MWM test, 10, 100 and 500 mg/kg Vit C reduced time latency and traveled distance without affecting the traveling speed during 5 days. All doses of Vit C increased the spent time in target quadrant in probe trail of MWM and also increased STL in PA test. Vit C increased thiol, SOD and CAT in the brain tissues while, reduced MDA. Results of present study confirmed the beneficial effects of Vit C on learning and memory. It also demonstrated that Vit C has protective effects on hypothyroidism-associated learning and memory impairment in juvenile rats which might be elucidated by the antioxidative effects.
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Purpose of review: Differentiated thyroid cancer is a malignancy that is rapidly increasing in frequency. As thyroidectomy plays a central role in the treatment of thyroid cancer, it is incumbent on physicians treating this patient group to be well versed in the intricacies of treating hypothyroidism. Recent findings: Treatment of hypothyroidism may be refined by careful attention to dose selection, monitoring of therapy and achievement of thyrotropin goals that are specific to the individual patient's overall clinical situation. These goals are common not only to patients with a sole diagnosis of hypothyroidism, as discussed in the recent American Thyroid Association Guidelines, but also to patients with hypothyroidism in the setting of thyroid cancer. Several recent studies have illuminated our understanding of the benefits and risks of thyrotropin suppression therapy in patients with differentiated thyroid cancer. Multiple studies of combination therapy with levothyroxine and liothyronine for treating hypothyroidism have not led to a clear conclusion about its benefits over levothyroxine monotherapy. Animal studies have advanced our understanding of the altered serum and tissue milieu that characterizes levothyroxine monotherapy. Crossing the bridge from this translational research into clinical research using sustained release triiodothyronine preparations may ultimately enhance the health of our patients. Summary: Continued refinement of our understanding of thyroid status and our ability to flawlessly implement thyroid hormone replacement is an active area of research.
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Congenital hypothyroidism (CH) is a relatively frequent congenital endocrine disorder, caused by defective production of thyroid hormones (THs) at birth. Because THs are essential for the development of normal neuronal networks, CH is also a common preventable cause of irreversible intellectual disability (ID) in children. Prolonged hypothyroidism, particularly during the THs-dependent processes of brain development in the first years of life, due to delays in diagnosis, inadequate timing and dosing of levothyroxine (l-thyroxine or l-T 4 ), the non-compliance of families, incorrect follow-up and the interference of foods, drugs and medications affecting the absorption of l-T 4 , may be responsible for more severe ID. In this review we evaluate the main factors influencing levels of THs and the absorption of l-T 4 in order to provide a practical guide, based on the existing literature, to allow optimal follow-up for these patients.
Article
Purpose: Levothyroxine (LT4) is a drug with a narrow therapeutic index, applied in small amounts (micrograms), which makes interactions in the absorption phase clinically significant. The main aim of this article was to review and present the latest information on factors that affect the gastrointestinal absorption of this drug. Methods: Relevant data were collected by using the MEDLINE, PubMed, EMBASE, Web of Science, Science Direct, and Scopus databases with the key words levothyroxine and absorption. Searches were not limited to specific publication types, study designs, dates, or languages. The reports were highly variable in the amount of information provided regarding study design and methods. Because of the heterogeneity of studies, no statistical analysis was performed. Findings: Many gastrointestinal disorders, such as celiac disease, atrophic gastritis, lactose intolerance, and Helicobacter pylori infection, may impede the absorption of levothyroxine. During treatment of these disorders, it is necessary to monitor serum thyroid-stimulating hormone and free T4 values to reduce the risk of developing iatrogenic hyperthyroidism. Soybeans and coffee have the greatest impact on the reduction of absorption, whereas vitamin C has the ability to increase it. Conversely, the effect of dietary fiber on the absorption of LT4 is not yet fully understood; further research is needed on this topic. A decrease in the absorption of LT4 is established and clinically significant when administered concomitantly with cholestyramine, colesevelam, lanthanum, calcium carbonate, calcium citrate, calcium acetate, iron sulfate, ciprofloxacin, aluminum hydroxide, sevelamer, or proton pump inhibitors. This effect should be taken into consideration when prescribing these drugs concomitantly with LT4. The effects of Giardia lamblia infection and the influence of orlistat, polystyrene sulfonate, raloxifene, and simethicone on absorption of LT4 have been poorly documented. For bariatric surgery, sucralfate and H2-antagonist interactions are not well founded or contradictory evidence is available regarding their existence; additional research should be conducted. Implications: The majority of the interactions are clinically significant. They are based on the LT4 adsorption on interfering substances in the digestive tract, as well as a consequently reduced amount of the drug available for absorption. These interactions can be avoided by separating the administration of LT4 and the interfering substance.
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In this study, the effect of thymoquinone (TQ) on propylthiouracil (PTU)-induced memory impairment was investigated in juvenile rats. The rats were grouped into control, Hypo, Hypo-TQ5 and Hypo-TQ10. Propylthiouracil increased latency time in the Morris water maze test and decreased delay in entering the dark compartment in the passive avoidance test. Both 5 mg/kg and 10 mg/kg doses of TQ decreased latency time in the Morris water maze test and increased delay in entering the dark compartment in a passive avoidance test. The PTU also increased malondialdehyde and nitric oxide metabolites in the brain while reduced the thiol content and superoxide dismutase and catalase activities and serum T4 level. Both doses of TQ decreased malondialdehyde and nitric oxide metabolites in the brain while enhanced the thiol content and superoxide dismutase and catalase activities and serum T4 level. The results of the present study showed that TQ protected against PTU-induced memory impairments in rats.
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PurposeSelenium (Se), an essential trace element, has been implicated in pathogenesis of autoimmune thyroiditis (AIT). Most studies attributed the immune modulating effects of Se to its antioxidant properties. However, there is insufficient evidence to support the use of selenium supplementation or other antioxidants in patients with AIT. This clinical trial was designed to investigate the impact of Se and vitamin C supplementation on antithyroid peroxidase antibody (TPO-Ab) level in patients with AIT. Methods One hundred and two subjects aged 15–78 years were randomized into three groups. Group one (GI) (n = 38) was treated with 200 μg/day sodium selenite, group two (GII) (n = 36) received 500 mg vitamin C/day, and group three (GIII) (n = 28) received placebo over a 3-month period. Thyroid stimulating hormone (TSH), TPO-Ab, antithyroglobulin antibody (Tg-Ab) and Se concentrations were once measured before treatment and at the end of the study. ResultsAfter 3 months, TPO-Ab concentrations decreased within Se and vitamin C-treated groups, but did not change in the placebo subjects. In this regard, there was no significant difference between the groups. We also did not find any statistically significant difference in TSH and Tg-Ab levels within and between the groups. At the end of the study, Se level was significantly higher in GI compared with GII and GIII. Conclusion Our findings supported the hypothesis of antioxidant beneficial effects of Se in AIT. However, it was not superior to vitamin C, regarding its effects on thyroid-specific antibodies.
Article
The present study was designed to evaluate the effects of boldenone undecylenate (BL) abuse alone and in combination with vitamin C (VC) on the immune responses and thyroid structure and function in rats. Thirty adult male Wistar rats were randomly divided into five equal groups and were subjected to various treatment regimens for eight weeks as follows: control group, vehicle control group, VC group orally received VC (120 mg/Kg BW/day), BL-treated group intramuscularly injected with BL (5 mg/kg BW, once/week), and BL+VC group received BL and VC. At the end of this experiment, blood and tissue samples (thyroid, thymus, and spleen) were subjected to hematological evaluation, biochemical analysis, histopathological, and immunohistochemical examinations. In comparison to controls, BL significantly increased the levels of serum proinflammatory interleukins (IL-1 β and IL-6), immunoglobulins (IgG and IgM), and complement 3 but reduced anti-inflammatory interleukin-10, lysosome, and nitric oxide. Besides, altered platelet count and leukogram were evident in BL-injected rats. BL notably disturbed thyroid profile as revealed by a significant increase of thyroid-stimulating hormone and thyroid peroxidase antibody. In contrast, both total and free forms of thyroid hormones (tri-iodothyronine and thyroxine), thyroglobulin, and thyroid peroxidase, were significantly decreased. Moreover, BL caused histopathological changes in the thyroid, thymus, and spleen tissues.CD4+ immuno-expression was reduced, but CD8+ immunolabelling was increased in both spleen and thymus. The daily dosing of VC to BL-exposed rats significantly corrected most of the deviations in immune parameters. It restored most of the thyroid architecture and function, revealing a significant protective effect of this vitamin. This experimental study demonstrates that BL abusing disrupts the immune system by different mechanisms and addresses BL, for the first time, as an autoimmune clinical hypothyroidism inducer drug. Additionally, VC is helpful in the management of BL abuse.
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Levothyroxine, a largely prescribed drug with a narrow therapeutic index, is often a lifelong treatment. The therapeutic efficacy of thyroxine may be marred by behavioral, pharmacologic and pathologic issues acting as interfering factors. Despite a continuous search for an optimal thyroxine treatment, a significant number of patients fail to show a complete chemical and/or clinical response to this reference dose of thyroxine. Gastrointestinal malabsorption of oral thyroxine represents an emerging cause of refractory hypothyroidism and may be more frequent than previously reputed. In this review article we aimed at examining the pharmacologic features of thyroxine preparations and their linkage with the intestinal absorption of the hormone. We have stressed the major biochemical and pharmacologic characteristics of thyroxine and its interaction with the putative transporter at the intestinal level. We have examined the interfering role of nutrients, foods, and drugs on thyroxine absorption at gastric and intestinal level. The impact of gastrointestinal disorders on thyroxine treatment efficacy has been also analyzed, in keeping with the site of action and the interfering mechanisms. Based on the evidence obtained from the literature, we also propose a schematic diagnostic workup for the most frequent and, often hidden, gastrointestinal diseases impairing thyroxine absorption.
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Patients on treatment with levothyroxine (T4) are informed to take this drug in the morning, at least 30 min before having breakfast. A significant decrease of T4 absorption was reported, in fact, when T4 solid formulations are taken with food or coffee. According to preliminary clinical study reports, administration of T4 oral solution appears to be less sensitive to the effect of breakfast beverages on oral bioavailability. In the present study, stability of T4 oral solution added to breakfast beverages was investigated. A 1 mL ampoule of single-dose Tirosint® oral solution (IBSA Farmaceutici Italia, Lodi, Italy) was poured into defined volumes of milk, tea, coffee, and coffee with milk warmed at 50 °C, as well as in orange juice at room temperature. Samples were sequentially collected up to 20 min and analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The results of the study demonstrated that T4 is stable in all beverages after 20 min incubation. Demonstration of T4 stability is a prerequisite for a thorough evaluation of the effect of breakfast beverages on the bioavailability of T4 given as oral solution and for a better understanding of the reasons underlying a decreased T4 bioavailability administered as solid formulations.
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Drug malabsorption is a potential concern after bariatric surgery. We present four case reports of hypothyroid patients who were well replaced with thyroxine tablets to euthyroid thyrotropin (TSH) levels prior to Roux-en-Y gastric bypass surgery. These patients developed elevated TSH levels after the surgery, the TSH responded reversibly to switching from treatment with oral tablets to a liquid formulation.
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As recently claimed, TSH-suppressive therapy with L-T4 may have adverse effects on the heart, but these results have not been consistently confirmed. We assessed cardiac function by clinical, echocardiographic, and ergometabolic criteria in 19 patients (16 women and 3 men) receiving long term L-T4 at a fixed daily dose ranging from 1.8-4.0 microg/kg. The results showed significant alterations in several cardiac parameters suggestive of subclinical hyperthyroidism. In particular, intraventricular septum thickness (10.0+/-1.4 vs. 8.1+/-1.1 mm), left ventricular posterior wall thickness (9.4 1.5 vs. 8.1+/-1.1 mm), end-diastolic dimension (47+/-4 vs. 44+/-3 mm), and left ventricular mass index (102+/-15 vs. 75+/-15 g/m2) were significantly increased compared to values in age- and sex-matched euthyroid controls. Exercise tolerance (expressed as maximal tolerated workload; 102+/-14 vs. 117+/-12 watts), maximal VO2 achieved at peak exercise (maximum VO2, 17.3+/-3.3 vs. 21.9+/-2.5 mL/min x kg), and anaerobic threshold (expressed as a percentage of VO2max, 46.5+/-8.4 vs. 56.2+/-6.6) were significantly reduced in L-T4-treated patients. The L-T4 dose was then reduced to the minimal amount able to keep the serum TSH concentration at 0.1 mU/L or less in 7 patients who were reevaluated 6 months after the initial study. This individual tailoring of the TSH-suppressive L-T4 dose was in all cases associated with normalization of all echocardiographic and ergometabolic parameters. In conclusion, our findings show that abnormalities of heart morphology associated with impaired exercise performance occur as a consequence of long term therapy with fixed TSH-suppressive doses of L-T4, but that these abnormalities improve or disappear after careful tailoring of TSH-suppressive therapy.
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Euthyroidism could not be achieved in a 41-year-old woman with primary hypothyroidism despite escalating doses of oral levothyroxine as high as 600 microg and 100 microg of triiodothyronine daily. Clinical and biochemical evidence of hypothyroidism persisted even with the administration of intramuscular levothyroxine. There was no history compatible with drug-induced malabsorption of levothyroxine. Evaluation of serum showed no thyroid hormone autoantibodies. After hospitalization, intravenous levothyroxine therapy returned thyroid hormone to normal concentrations. Moreover, thyroid hormone loading tests revealed normal oral absorption of both levothyroxine and triiodothyronine. Noncompliance with medical treatment leading to pseudomalabsorption of levothyroxine should be considered in patients who have persistent hypothyroidism with high-dose replacement therapy.
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As in some patients with hypothyroidism, because of unknown reasons, large doses of levothyroxine are required to achieve a therapeutic endpoint, and preliminary observations have indicated that an hypoacidic gastric environment is associated with a reduction in levothyroxine bioavailability, and that co-administration of vitamin C might enhance absorption of certain drugs, we assessed whether this effect would be obtained taking levothyroxine with vitamin C. Design: We studied 28 patients (24 women and 4 men, age range 26-76 years; mean 48.0 ±17.75) treated with levothyroxine at doses of >1.70 μg/kg but failing to achieve their target TSH level. During the control period, each patient had at least two determinations of TSH indicating inadequate dosage. Interfering factors that could alter levothyroxine absorption such as celiac disease, calcium, iron, or antacid use, among others, and non-compliance were excluded. During the study period, the patients continued on the same dose of levothyroxine but took the tablet with 1 g of vitamin C in 200 cc of tap water, instead of the same volume of water alone. Serum TSH levels were prospectively measured 6-8 weeks after starting co-administration with vitamin C, and two months later. Main outcome: After six-eight weeks of taking levothyroxine with vitamin C, serum TSH decreased in all 28 patients (average reduction 69.79 ±22.19 %), and the target or desired level of TSH was achieved in 19/28 patients. The difference between TSH levels before and after treatment with vitamin C was significant: Basal TSH (IFMA) was 9.01 ±5.51 mIU/L vs. a mean TSH on vitamin C treatment of 2.27 ±1.61mIU/L (p<0.0001). Conclusions: 1) Vitamin C enhances oral absorption of levothyroxine; 2) Co-administration of Vitamin C with levothyroxine should be considered in patients with difficulties in the absorption of levothyroxine. Copyright © 2011 por la Sociedad Argentina de Endocrinología y Metabolismo.
Article
Objective: To report a patient in whom the impaired absorption of tablet levothyroxine (L-T4) due to a proton pump inhibitor (PPI) use was corrected by switching the patient to the soft gel capsule. Methods: A woman with Hashimoto's thyroiditis-associated hypothyroidism (serum thyroid-stimulating hormone [TSH] 6.8-9.6 mU/L) had been treated with tablet L-T4 (100 μg/day). Because she used to take pantoprazole just before L-T4 in the morning, TSH failed to normalize (4.4-6.5 mU/L). Thus, the daily dose had been progressively increased to 125 and 150 μg/day, with serum TSH levels of 2.4 and 0.6 mU/L, respectively. Results: While maintaining pantoprazole, we switched the tablet L-T4 (150 g/day) to a soft gel capsule (125 μg/day; Tirosint® capsule, IBSA, Lugano, Switzerland) and after 2 months, to 100 μg/day. Serum TSH was lower than under the equivalent regimens with the tablet: 0.5 versus 2.4 mU/L (125 μg/day) and 2.4 versus 4.4 to 6.5 mU/L (100 μg/day). Upon switching back to the tablet (100 μg/day), serum TSH increased to 3.2 and 4.7 mU/L and then dropped to 2.7-3.0 mU/L when the dose was increased to 125 μg/day. We also acutely evaluated the intestinal absorption of L-T4 by administering 600 μg LT4 as a tablet or soft gel capsule while maintaining pantoprazole. Pharmacokinetic indices showed better and faster absorption for the soft gel capsule versus tablet (area under the curve [AUC]0-4h = 16,240 vs. 10,960 nmol/L x 4 hours, maximum absorption [Cmax] = 108 vs. 73 nmol/L, and time of maximum absorption [Tmax] = 120 minutes vs. 180 minutes). Conclusion: Confirming in vitro studies conducted by other authors, the soft gel capsule L-T4 is negligibly affected by changes in gastric pH compared to tablet L-T4.
Article
Levothyroxine (T4) is a narrow therapeutic index drug with classic bioequivalence problem between various available products. Dissolution of a drug is a crucial step in its oral absorption and bioavailability. The dissolution of T4 from three commercial solid oral dosage forms: Synthroid (SYN), generic levothyroxine sodium by Sandoz Inc. (GEN) and Tirosint (TIR) was studied using a sensitive ICP-MS assay. All the three products showed variable and pH-dependent dissolution behaviors. The absence of surfactant from the dissolution media decreased the percent T4 dissolved for all the three products by 26-95% (at 30 min). SYN dissolution showed the most pH dependency, whereas GEN and TIR showed the fastest and highest dissolution, respectively. TIR was the most consistent one, and was minimally affected by pH and/or by the presence of surfactant. Furthermore, dissolution of T4 decreased considerably with increase in the pH, which suggests a possible physical interaction in patients concurrently on T4 and gastric pH altering drugs, such as proton pump inhibitors. Variable dissolution of T4 products can, therefore, impact the oral absorption and bioavailability of T4 and may result in bioequivalence problems between various available products.
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A change in the formulation of the levothyroxine preparation Synthroid (Flint) in 1982 prompted us to reevaluate the replacement dose of this drug in 19 patients with hypothyroidism. The dose was titrated monthly until thyrotropin levels became normal. The mean replacement dose (+/- SD) was 112 +/- 19 micrograms per day, significantly less (P less than 0.001) than the dose of an earlier formulation--169 +/- 66 micrograms per day--used in a similar study (Stock JM, et al. N Engl J Med 1974; 290:529-33). The fractional gastrointestinal absorption of a tablet of the current formulation is 81 percent, considerably higher than the earlier estimate of 48 percent. Using high-performance liquid chromatographic analysis, we found that the current tablet contains the amount of thyroxine stated by the manufacturer. By measuring the bioavailability of the earlier type of tablet in five patients, we inferred that the strength of the previous tablet had been overestimated. In the present study, the thyrotropin levels of patients on replacement therapy returned to normal when serum triiodothyronine concentrations were not significantly different from those of controls (122 vs. 115 ng per deciliter [1.87 vs. 1.77 nmol per liter]), but when serum thyroxine levels were significantly above those of controls (11.3 vs. 8.7 micrograms per deciliter [145 vs. 112 nmol per liter], P less than 0.001). These findings suggest the possibility that in humans, serum triiodothyronine may play a more important part than serum thyroxine in regulating the serum thyrotropin concentration.
Article
To elucidate the role of gastric acid in iron absorption, six normal subjects and six with pernicious anemia were given ferric iron, mixed with ascorbate to form a chelate that remained soluble after alkalinization with sodium hydroxide, and ferric iron that had been precipitated with sodium hydroxide before the addition of ascorbate and remained insoluble. Either 59Fe or 55Fe was added to the iron preparations, and the absorption of 59Fe was measured with a whole-body counter. Achlorhydric subjects with pernicious anemia absorbed significantly (p less than 0.01) more iron from the solubilized chelates than from the precipitated preparation, but these differences were not found in the normal group. Normally, gastric acid appears to facilitate the chelation in the stomach of ferric salts with ascorbate and other exogenous or endogenous agents. Since these chelates then remain soluble in the more alkaline duodenum and jejunum, iron absorption is enhanced.
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Radioiron absorption tests in human volunteers demonstrated a modest but significant 28% reduction in the absorption of dietary nonheme iron from a meal that was preceded by the administration of 300 mg cimetidine. More pronounced decreases of 42% and 65% were observed with 600 and 900 mg cimetidine, respectively. Antacid caused a 52% decrease in iron absorption whereas pentagastrin had no significant effect. Since 300 mg cimetidine reduces gastric acid secretion by 60%-80% but iron absorption by only 28%, it appears that under normal conditions more gastric acid is secreted than is required for optimal iron absorption; absorption falls only when acid secretion is markedly reduced. Cimetidine in the doses currently recommended would not be expected to have a major effect on iron nutrition, although the combination of high doses of cimetidine with antacids would impair nonheme iron absorption significantly.
Article
To review the indications for and the proper monitoring of levothyroxine therapy in patients with thyroid disease. Relevant English language articles published from 1966 to 1992 were identified through a MEDLINE search and manual searches of both identified articles and selected endocrinology texts. Studies, case reports, and review articles that contained data on the pathophysiologic aspects of relevant thyroid disorders and on the pharmacologic aspects of, indications for, and administration of levothyroxine therapy. Data on the epidemiology, clinical manifestations, complications, and treatment of thyroid disorders were analyzed with respect to patient selection, methods, diagnostic criteria, and conclusions. These data were used to develop a rational approach to the management of such patients. Levothyroxine is a reliable and commonly prescribed drug to treat thyroid disease, but excessive dosage may have adverse effects. In patients with hypothyroidism, levothyroxine is used as replacement therapy. For most patients, therapy can be initiated with a full replacement dosage (1.6 micrograms/kg body weight), which is usually 75 to 100 micrograms/day for women and 100 to 150 micrograms/d for men. The goal is to normalize the serum thyroid-stimulating hormone concentration. Levothyroxine is also used to suppress the serum thyroid-stimulating hormone concentration. A trial of thyroid-stimulating hormone suppressive therapy is indicated for most patients with benign solitary nonfunctioning thyroid nodules and for those with a history of thyroid cancer. Levothyroxine in non-thyroid-stimulating hormone-suppressive doses may also be indicated for patients with nontoxic multinodular goiter and for certain patients after lobectomy for benign thyroid nodules. With proper patient monitoring, levothyroxine replacement therapy should be effective, inexpensive, and free of complications. Recommendations for thyroid-stimulating hormone suppression with levothyroxine are based on risk-benefit considerations of the biologic characteristics of the thyroid disorder and the individual patient.
Article
The thyroid hormone resistance syndromes are disorders in which the body's tissues are resistant to the effects of thyroid hormone. Generalized resistance to thyroid hormone (GRTH) is characterized by resistance in the pituitary gland and in most or all of the peripheral tissues. Affected individuals have elevated serum thyroid hormone levels and inappropriately normal or elevated thyroid-stimulating hormone (TSH) but are usually clinically euthyroid and require no treatment. Selective pituitary resistance to thyroid hormone (PRTH) is characterized by resistance in the pituitary gland but not in peripheral tissues. Patients have elevated serum thyroid hormone levels and normal or elevated TSH levels and are clinically thyrotoxic. Therapy is usually necessary, but current choices are not completely satisfactory. Selective peripheral resistance to thyroid hormone (PerRTH) is characterized by resistance in peripheral tissues but not in the pituitary. The only patient thus far described had normal serum thyroid hormone and TSH levels but was clinically hypothyroid and improved with thyroid hormone administration. All of these disorders are probably more common than is generally recognized and are often misdiagnosed and inappropriately treated. GRTH, in most cases studied, results from a mutation in the thyroid hormone receptor beta gene causing an amino acid substitution in or a partial or complete deletion of the thyroid hormone-binding domain of the receptor. The causes of PRTH and PerRTH remain to be determined.
Article
Biondi, Fazio, and colleagues recently reported that long term T4 treatment to suppress serum TSH markedly affects cardiac function. T4-treated patients had more symptoms [12.2 +/- 3.9 (+/-SD) vs. 4.2 +/- 2.3 by quantitative questionnaire], higher mean heart rate, increased incidence of atrial extrasystoles, increased interventricular septal thickness and left ventricular mass index (LVMi), and significant diastolic dysfunction. The severity of cardiac abnormalities was highly correlated with scores of a rating scale used for assessing symptoms of thyrotoxicosis. We have duplicated their studies in 17 athyreotic patients (mean age, 45 +/- 10 yr; range, 27-63 yr) without heart disease or hypertension whose dose of T4 was titrated to suppress serum TSH to less than 0.01 microU/mL. The mean duration of T4 treatment was 9.2 +/- 5.4 yr. Controls were healthy volunteers matched for sex and age (+/-3 yr). The mean T4 dose was 2.8 +/- 0.9 micrograms/kg (0.192 +/- 0.058 mg/day). By questionnaire, patients had minimal symptoms, although their symptom score was significantly greater than the control value (4 +/- 3 vs. 2 +/- 1; P < 0.05; maximum score, 36). No differences in mean heart rate or in atrial or ventricular extrasystoles were noted. In patients, indexes of systolic and diastolic function and interventricular septal thickness were similar to control values. The mean LVMi was normal in both groups. However, the mean LVMi in patients (117 +/- 35 g/m2) was higher than that in controls (92 +/- 31; P < 0.05). In conclusion, patients were minimally affected by TSH-suppressive doses of T4. They had few symptoms and no increase in extrasystoles or basal heart rate. Based on current knowledge, the increase in LVMi observed in patients without associated significant systolic or diastolic abnormalities does not have clinical or prognostic importance. Therefore, in the absence of symptoms of thyrotoxicosis, patients treated with TSH-suppressive doses of L-T4 may be followed clinically without specific cardiac laboratory studies.
Article
Malabsorption of thyroxine has been described in patients treated with drugs that modify an acidic environment. We determined whether there is an increased need for thyroxine in patients with euthyroid multinodular goiter and impaired secretion of gastric acid. We assessed the dose of thyroxine required to obtain a low level of thyrotropin (0.05 to 0.20 mU per liter) in 248 patients with multinodular goiter. Of these 248 patients, 53 also had Helicobacter pylori-related gastritis and 60 had atrophic gastritis of the body of the stomach (31 with evidence of H. pylori infection and 29 without such evidence). The reference group comprised 135 patients with multinodular goiter and no gastric disorders. In addition, variation in the level of serum thyrotropin was prospectively studied in 11 patients treated with thyroxine before and after H. pylori infection and both before and during treatment with omeprazole in 10 patients treated with thyroxine who had gastroesophageal reflux. The daily requirement of thyroxine was higher (by 22 to 34 percent) in patients with H. pylori-related gastritis, atrophic gastritis, or both conditions than in the reference group. In prospective studies, the occurrence of H. pylori infection in the 11 patients treated with thyroxine led to an increase in the level of serum thyrotropin (P=0.002), an effect that was nearly reversed on eradication of H. pylori infection. In a similar way, omeprazole treatment was associated with an increase in the level of serum thyrotropin in all 10 patients treated with thyroxine, an effect that was reversed by an increase in the thyroxine dose by 37 percent. Patients with impaired acid secretion require an increased dose of thyroxine, suggesting that normal gastric acid secretion is necessary for effective absorption of oral thyroxine.
Article
Recent milestones in the understanding of gastric acid secretion and treatment of acid-peptic disorders include the (1) discovery of histamine H(2)-receptors and development of histamine H(2)-receptor antagonists, (2) identification of H(+)K(+)-ATPase as the parietal cell proton pump and development of proton pump inhibitors, and (3) identification of Helicobacter pylori as the major cause of duodenal ulcer and development of effective eradication regimens. This review emphasizes the importance and relevance of gastric acid secretion and its regulation in health and disease. We review the physiology and pathophysiology of acid secretion as well as evidence regarding its inhibition in the management of acid-related clinical conditions.
Tratamiento del hipotiroidismo In: Endocrinología clínica. 6th ed. Cali, Colombia: Talleres de Litocencoa
  • W Jubiz
Jubiz W. Tratamiento del hipotiroidismo. In: Endocrinología clínica. 6th ed. Cali, Colombia: Talleres de Litocencoa; 2012:139 – 141.
Replacement dose, metabo-lism, and bioavailability of levothyroxine in the treatment of hypo-thyroidism. Role of triiodothyronine in pituitary feedback in hu-mans
  • Fish Lh
  • Schwartz Hl
  • Cavanaugh
Fish LH, Schwartz HL, Cavanaugh J. Replacement dose, metabo-lism, and bioavailability of levothyroxine in the treatment of hypo-thyroidism. Role of triiodothyronine in pituitary feedback in hu-mans. N Engl J Med. 1987;316:764 –770.
Noncompliance with medical treatment: pseudomalabsorption of levothyroxine
  • Eledrisi
Factores que afectan la absorción de levotiroxina
  • Jubiz
Tratamiento del hipotiroidismo
  • Jubiz