Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report

Centanni, Marco; Benvenga, Salvatore; Sachmechi, Issac

doi:10.1007/s40618-017-0706-y

Cited by 81 publications

(120 citation statements)

References 116 publications

(131 reference statements)

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“…It remains unclear whether this resistance involves other tissues and if prolonged exposure to TH in adult life could have a similar effect. This is currently under investigation, as prolonged suppression of TSH was for many years advocated as standard treatment of differentiated thyroid cancer (16), and the mechanism of refractoriness to TH in some patients without THRB gene defects remains unresolved (17,18).…”

Section: Discussionmentioning

confidence: 99%

Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along the Human Male Line

Anselmo

Scherberg

Dumitrescu

et al. 2019

Thyroid

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Background: Evidence for transgenerational epigenetic inheritance in humans is still controversial, given the requirement to demonstrate persistence of the phenotype across three generations. A previous study showed that exposure of human and mouse embryos to high maternal thyroid hormone (TH) concentrations not only affects the newborns but also subsequently reduces thyrotroph sensitivity to TH during adult life. The current investigation set out to determine if this epigenetic effect is transmitted by humans not exposed in utero to high TH levels to their offspring. Methods: The study took advantage of the high frequency of intrauterine exposure to high TH in the Azorean wild-type population born to healthy mothers with high TH levels because of a heterozygous TH receptor beta gene mutation. Wild-type individuals from F2 (second) and F3 (third) generations were studied, whose parents and grandparents, respectively, were not exposed to high maternal TH levels. Twenty-six individuals belonging to 17 nuclear families were tested for their sensitivity to TH using their thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) after administration of liothyronine (LT3). Results: Preservation of reduced sensitivity to TH (RSTH) was found in descendants of males but not of females with likewise RSTH. In F2, offspring of fathers but not of mothers exposed to high TH levels had RSTH (TRH-stimulated TSH of 6.39-0.63 vs 1.58-0.41 mIU/L [p < 0.001], respectively, after treatment with LT3). In F3, whose parents nor themselves were exposed to TH excess during their fetal life, descendants of fathers and not mothers had RSTH (TRH-stimulated TSH of 4.60-0.61 vs 1.37-0.23 mIU/L [p < 0.01], respectively, after pretreatment with LT3). Conclusions: Since intrauterine total body and gonadal exposure to elevated TH can potentially affect only the F1 and F2, respectively, the results obtained from F3 confirm a true inheritance of an epigenetic effect, scarcely observed in humans. While the exact mechanism underlying the inheritance of this epigenetic effect remains unknown, it correlates with type 3 deiodinase overexpression demonstrated in pituitary glands of mice born to dams with high TH. This enzyme inactivates TH, and is encoded by an imprinted gene with specific parent of origin expression.

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Section: Discussionmentioning

confidence: 99%

Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along the Human Male Line

Anselmo

Scherberg

Dumitrescu

et al. 2019

Thyroid

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“…e fasting regimen is required to promote the absorption of LT4 tablet and its ingestion 30 minutes before breakfast is necessary [1]. It is well known that in addition to the coadministration with foods and beverages, gastrointestinal diseases (i.e., Helicobacter pylori gastritis, atrophic gastritis, celiac disease, lactose malabsorption/intolerance, and dysbiosis), and drugs (i.e., proton-pump inhibitors, aluminum-containing antacids, calcium carbonate, ferrous sulphate, sucralfate, raloxifene, bile acid sequestrants, and phosphate binders) may substantially impair the bioavailability of LT4 tablet preparation [4]. New LT4 formulations, namely, liquid solution (LS) and soft gel (SG) capsule, were manufactured to overcome the limitations of the tablet [4,5].…”

Section: Introductionmentioning

confidence: 99%

Different Formulations of Levothyroxine for Treating Hypothyroidism: A Real-Life Study

Trimboli

Scappaticcio

Bellis

et al. 2020

International Journal of Endocrinology

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Objective. Hypothyroid patients are treated by sodium levothyroxine (LT4). Tablet is the mostly used LT4 formulation, and the fasting regimen is required for the absorption of active principle. Also, gastrointestinal diseases and drugs may impair the LT4 bioavailability when tablet is used. Nonsolid LT4 formulations (i.e., liquid solution (LS) and soft gel (SG) capsule) were manufactured to overcome the limitations of LT4 tablet. This study was conceived to evaluate the performance of nonsolid LT4 formulations in a real-life scenario. Methods. Two institutions participated in the study that was conducted in two phases (i.e., enrollment and re-evaluation). Adults with autoimmune or postsurgical hypothyroidism and on LT4 from a few months were selected. A nonparametric statistical analysis for paired or unpaired data was performed. Results. 121 consecutive cases were included. At the enrollment phase, a 52% of patients took the therapy at least 30 min before breakfast with no difference between tablet and SG/LS users. TSH was 1.65 mIU/L (0.86–2.70) in patients on LT4 tablet and 1.70 mIU/L (1.10–2.17) in those on SG/LS (p=0.66). At the re-evaluation phase, among the patients using correct LT4 assumption, the TSH value was stable in the tablet group (p=0.22) and significantly reduced in SG/LS group (p=0.004); among the patients using incorrect LT4 assumption, TSH was significantly increased in those on tablet (p=0.0029) and stable in those on SG/LS (p=0.36). Conclusion. The performance of nonsolid LT4 formulations is not influenced by correct or incorrect use of therapy. On the contrary, LT4 tablet does not guarantee euthyroidism when it is ingested without waiting for at least 30 minutes before breakfast. These new data, obtained in a real-life scenario, suggest that LT4 SG/LS should be regarded as first-line therapy for treating adults with newly diagnosed hypothyroidism.

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“…The reason for this finding is unknown, yet it may reflect the current complexities of treating hypothyroidism in pregnancy as well as the fact that there is no consensus on treating subclinical hypothyroidism in pregnancy [33], possibly because of the increased risk of pregnancy-related adverse outcomes offsetting risk reductions in pregnancy loss [34]. Pregnant patients with high TSH despite levothyroxine therapy may be taking too low a dose, since dose requirements increase over the course of a pregnancy [35], or some portion of patients may have treatmentrefractory hypothyroidism, which can be caused by poor adherence, interactions between the levothyroxine and food, problems with digestion or absorption, autoimmune processes or other conditions [36,37]. The lack of monitoring found for a significant portion of our study population further complicates identification and treatment of these issues.…”

Section: Discussionmentioning

confidence: 99%

Levothyroxine Treatment of Pregnant Women with Hypothyroidism: Retrospective Analysis of a US Claims Database

et al. 2020

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Background: Approximately 2-4% of women of reproductive age have hypothyroidism. This study characterizes pregnant women with hypothyroidism and examines adherence to guidelines during pregnancy. Methods: Women age 18 to 49 who were pregnant in 2014 and identified with hypothyroidism (N = 3448) were included in the retrospective study. The analyses examined differences in characteristics and comorbidities between pregnant women treated with levothyroxine and untreated women and adherence to guidelines by measuring thyroidstimulating hormone (TSH) target achievement for women treated with levothyroxine. Results: The average age was 32.76 years, and the median TSH value was 1.97 mIU/l. Compared with untreated pregnant women, pregnant women treated with levothyroxine were significantly younger, had a lower Charlson Comorbidity Index score and had lower rates of comorbid type 2 diabetes and migraines. Among women treated with levothyroxine, 52.61% had a last recorded TSH value consistent with American Thyroid Association (ATA) guidelines, 23.85% were undertreated, 1.03% were overtreated, and 22.52% did not have TSH monitored during their pregnancy. Conclusions: A large percentage of pregnant women, including many treated with levothyroxine, was not treated in a manner consistent with clinical guidelines. Additionally, there were significant differences in general health and comorbidities between pregnant women treated with levothyroxine and those untreated.

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Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report

Cited by 81 publications

References 116 publications

Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along the Human Male Line

Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along the Human Male Line

Different Formulations of Levothyroxine for Treating Hypothyroidism: A Real-Life Study

Levothyroxine Treatment of Pregnant Women with Hypothyroidism: Retrospective Analysis of a US Claims Database

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