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Lancet (London, England) Sep 2017Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The... (Review)
Review
Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and management; and highlight future directions for research.
Topics: Disease Management; Hormone Replacement Therapy; Hypothyroidism; Thyroxine
PubMed: 28336049
DOI: 10.1016/S0140-6736(17)30703-1 -
Endocrine Reviews Mar 2022Hypothyroidism is a common endocrinopathy, and levothyroxine is frequently prescribed. Despite the basic tenets of initiating and adjusting levothyroxine being agreed...
Hypothyroidism is a common endocrinopathy, and levothyroxine is frequently prescribed. Despite the basic tenets of initiating and adjusting levothyroxine being agreed on, there are many nuances and complexities to consistently maintaining euthyroidism. Understanding the impact of patient weight and residual thyroid function on initial levothyroxine dosage and consideration of age, comorbidities, thyrotropin goal, life stage, and quality of life as levothyroxine is adjusted can be challenging and continually evolving. Because levothyroxine is a lifelong medication, it is important to avoid risks from periods of overtreatment or undertreatment. For the subset of patients not restored to baseline health with levothyroxine, causes arising from all aspects of the patient's life (coexistent medical conditions, stressors, lifestyle, psychosocial factors) should be broadly considered. If such factors do not appear to be contributing, and biochemical euthyroidism has been successfully maintained, there may be benefit to a trial of combination therapy with levothyroxine and liothyronine. This is not supported by the majority of randomized clinical trials, but may be supported by other studies providing lower-quality evidence and by animal studies. Given this discrepancy, it is important that any trial of combination therapy be continued only as long as a patient benefit is being enjoyed. Monitoring for adverse effects, particularly in older or frail individuals, is necessary and combination therapy should not be used during pregnancy. A sustained-release liothyronine preparation has completed phase 1 testing and may soon be available for better designed and powered studies assessing whether combination therapy provides superior therapy for hypothyroidism.
Topics: Aged; Female; Hormone Replacement Therapy; Humans; Hypothyroidism; Pregnancy; Quality of Life; Thyroxine; Triiodothyronine
PubMed: 34543420
DOI: 10.1210/endrev/bnab031 -
Thyroid : Official Journal of the... Feb 2021Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these... (Review)
Review
Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 μg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.
Topics: Consensus; Drug Combinations; Evidence-Based Medicine; Humans; Hypothyroidism; Thyroxine; Treatment Outcome; Triiodothyronine
PubMed: 33276704
DOI: 10.1089/thy.2020.0720 -
Endocrine Reviews Apr 2010Cellular actions of thyroid hormone may be initiated within the cell nucleus, at the plasma membrane, in cytoplasm, and at the mitochondrion. Thyroid hormone nuclear... (Review)
Review
Cellular actions of thyroid hormone may be initiated within the cell nucleus, at the plasma membrane, in cytoplasm, and at the mitochondrion. Thyroid hormone nuclear receptors (TRs) mediate the biological activities of T(3) via transcriptional regulation. Two TR genes, alpha and beta, encode four T(3)-binding receptor isoforms (alpha1, beta1, beta2, and beta3). The transcriptional activity of TRs is regulated at multiple levels. Besides being regulated by T(3), transcriptional activity is regulated by the type of thyroid hormone response elements located on the promoters of T(3) target genes, by the developmental- and tissue-dependent expression of TR isoforms, and by a host of nuclear coregulatory proteins. These nuclear coregulatory proteins modulate the transcription activity of TRs in a T(3)-dependent manner. In the absence of T(3), corepressors act to repress the basal transcriptional activity, whereas in the presence of T(3), coactivators function to activate transcription. The critical role of TRs is evident in that mutations of the TRbeta gene cause resistance to thyroid hormones to exhibit an array of symptoms due to decreasing the sensitivity of target tissues to T(3). Genetically engineered knockin mouse models also reveal that mutations of the TRs could lead to other abnormalities beyond resistance to thyroid hormones, including thyroid cancer, pituitary tumors, dwarfism, and metabolic abnormalities. Thus, the deleterious effects of mutations of TRs are more severe than previously envisioned. These genetic-engineered mouse models provide valuable tools to ascertain further the molecular actions of unliganded TRs in vivo that could underlie the pathogenesis of hypothyroidism. Actions of thyroid hormone that are not initiated by liganding of the hormone to intranuclear TR are termed nongenomic. They may begin at the plasma membrane or in cytoplasm. Plasma membrane-initiated actions begin at a receptor on integrin alphavbeta3 that activates ERK1/2 and culminate in local membrane actions on ion transport systems, such as the Na(+)/H(+) exchanger, or complex cellular events such as cell proliferation. Concentration of the integrin on cells of the vasculature and on tumor cells explains recently described proangiogenic effects of iodothyronines and proliferative actions of thyroid hormone on certain cancer cells, including gliomas. Thus, hormonal events that begin nongenomically result in effects in DNA-dependent effects. l-T(4) is an agonist at the plasma membrane without conversion to T(3). Tetraiodothyroacetic acid is a T(4) analog that inhibits the actions of T(4) and T(3) at the integrin, including angiogenesis and tumor cell proliferation. T(3) can activate phosphatidylinositol 3-kinase by a mechanism that may be cytoplasmic in origin or may begin at integrin alphavbeta3. Downstream consequences of phosphatidylinositol 3-kinase activation by T(3) include specific gene transcription and insertion of Na, K-ATPase in the plasma membrane and modulation of the activity of the ATPase. Thyroid hormone, chiefly T(3) and diiodothyronine, has important effects on mitochondrial energetics and on the cytoskeleton. Modulation by the hormone of the basal proton leak in mitochondria accounts for heat production caused by iodothyronines and a substantial component of cellular oxygen consumption. Thyroid hormone also acts on the mitochondrial genome via imported isoforms of nuclear TRs to affect several mitochondrial transcription factors. Regulation of actin polymerization by T(4) and rT(3), but not T(3), is critical to cell migration. This effect has been prominently demonstrated in neurons and glial cells and is important to brain development. The actin-related effects in neurons include fostering neurite outgrowth. A truncated TRalpha1 isoform that resides in the extranuclear compartment mediates the action of thyroid hormone on the cytoskeleton.
Topics: Animals; Humans; Receptors, Thyroid Hormone; Thyroid Hormones; Thyroxine; Triiodothyronine
PubMed: 20051527
DOI: 10.1210/er.2009-0007 -
BMJ Clinical Evidence Feb 2014Hypothyroidism is six times more common in women, affecting up to 40 in 10,000 each year (compared with 6/10,000 men). (Review)
Review
INTRODUCTION
Hypothyroidism is six times more common in women, affecting up to 40 in 10,000 each year (compared with 6/10,000 men).
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for clinical (overt) hypothyroidism? What are the effects of treatments for subclinical hypothyroidism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found nine studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: levothyroxine, and levothyroxine plus liothyronine.
Topics: Drug Combinations; Humans; Hypothyroidism; Safety; Thyroxine; Treatment Outcome; Triiodothyronine
PubMed: 24807886
DOI: No ID Found -
Frontiers in Endocrinology 2020Oral levothyroxine sodium is absorbed in the small intestine, mainly in the jejunum and the ileum being lower the absorption rate at duodenal level. The time interval... (Review)
Review
Oral levothyroxine sodium is absorbed in the small intestine, mainly in the jejunum and the ileum being lower the absorption rate at duodenal level. The time interval between the ingestion of oral thyroxine and its appearance in the plasma renders unlike a gastric absorption of the hormone. However, several evidence confirm the key role of the stomach as a prerequisite for an efficient absorption of oral levothyroxine. In the stomach, in fact, occur key steps leading to the dissolution of thyroxine from the solid form, the process bringing the active ingredient from the pharmaceutical preparation to the aqueous solution. In particular, gastric juice pH, volume, viscosity, as well as gastric emptying time seem to be the most important limiting factors. These hypotheses are confirmed by the detection of an increased need for levothyroxine in patients with infection, chronic atrophic gastritis, gastroparesis, or in simultaneous treatment with drugs interfering with gastric acidic output. The aim of the present article is to focus on the knowledge of pathophysiologic events that determine the absorptive fate of traditional (tablet) and alternative thyroxine preparations (softgel capsule and liquid solution) in patients bearing gastric disorders.
Topics: Administration, Oral; Animals; Gastric Absorption; Gastric Emptying; Gastroparesis; Helicobacter Infections; Humans; Malabsorption Syndromes; Thyroxine
PubMed: 33584549
DOI: 10.3389/fendo.2020.621616 -
International Journal of Clinical... Sep 2021The approach to thyroid hormone replacement varies across centres, but the extent and determinants of variation is unclear. We evaluated geographical variation in...
INTRODUCTION
The approach to thyroid hormone replacement varies across centres, but the extent and determinants of variation is unclear. We evaluated geographical variation in levothyroxine (LT4) and liothyronine (LT3) prescribing across General Practices in England and analysed the relationship of prescribing patterns to clinical and socioeconomic factors.
METHODS
Data was downloaded from the NHS monthly General Practice Prescribing Data in England for the period 2011-2020.
RESULTS
The study covered a population of 19.4 million women over 30 years of age, attending 6,660 GP practices and being provided with 33.7 million prescriptions of LT4 and LT3 at a total cost of £90million/year. Overall, 0.5% of levothyroxine treated patients continue to receive liothyronine. All Clinical Commission Groups (CCGs) in England continue to have at least one liothyronine prescribing practice and 48.5% of English general practices prescribed liothyronine in 2019-2020. Factors strongly influencing more levothyroxine prescribing (model accounted for 62% of variance) were the CCG to which the practice belonged and the proportion of people with diabetes registered on the practice list plus antidepressant prescribing, with socioeconomic disadvantage associated with less levothyroxine prescribing. Whereas factors that were associated with increased levels of liothyronine prescribing (model accounted for 17% of variance), were antidepressant prescribing and % of type 2 diabetes mellitus individuals achieving HbA1c control of 58 mmol/mol or less. Factors that were associated with reduced levels of liothyronine prescribing included smoking and higher obesity rates.
CONCLUSION
In spite of strenuous attempts to limit prescribing of liothyronine in general practice a significant number of patients continue to receive this therapy, although there is significant geographical variation in the prescribing of this as for levothyroxine, with specific general practice and CCG-related factors influencing prescribing of both levothyroxine and liothyronine across England.
Topics: Diabetes Mellitus, Type 2; Female; General Practice; Hormone Replacement Therapy; Humans; Practice Patterns, Physicians'; Thyroxine; Triiodothyronine
PubMed: 33864324
DOI: 10.1111/ijcp.14228 -
Journal of Healthcare Engineering 2022To investigate the effect of levothyroxine sodium tablets (L-T4) on pregnancy outcome and offspring development quotient in patients with subclinical hypothyroidism...
OBJECTIVE
To investigate the effect of levothyroxine sodium tablets (L-T4) on pregnancy outcome and offspring development quotient in patients with subclinical hypothyroidism (SCH) during pregnancy. Pregnant women with gestational age less than 12 weeks who underwent the first prenatal examination in our hospital from January 2019 to December 2019 were prospectively selected as subjects. According to the level of thyroid hormone in pregnant women, they were divided into the treatment group (n = 63) and received L-T4 treatment, untreated group (n = 64), and control group (n = 54). Three groups of pregnancy outcomes, children's physical development, and the development of offspring were compared at when one full year of life.
RESULTS
After treatment, the contrast difference of the three groups about abortion and gestational diabetes mellitus (GDM) was statistically significant ( < 0.05). The abortion rate and gestational diabetes mellitus (GDM) in the untreated group were higher than those in the control group ( < 0.05). The contrast difference of the treatment group and control group about abortion and gestational diabetes mellitus (GDM) is not statistically significant ( > 0.05); The contrast difference of the three groups about a filial generation at birth and one-year-old body length is not statistically significant ( > 0.05). The contrast difference between the three groups of individual children who are one-year old having the individual action energy, material ability, speech ability, and human ability is statistically significant ( < 0.05). One-year-old developmental quotient (DQ) of the treatment group and control group was higher than that of the untreated group ( < 0.05); the Pearson correlation analysis showed that the treatment group TSH levels have no correlation between the offspring developmental quotient (DQ) level of one-year-old children ( > 0.05).
CONCLUSION
Levothyroxine sodium tablets (L-T4) can not only improve the pregnancy outcome of patients with SCH during pregnancy but also play a positive role in improving the neurointellectual development of their offspring.
Topics: Child; Diabetes, Gestational; Female; Humans; Hypothyroidism; Infant; Infant, Newborn; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Tablets; Thyroxine
PubMed: 35388329
DOI: 10.1155/2022/9001881 -
Clinical Pharmacology in Drug... May 2019A new formulation of levothyroxine sodium has been developed in the form of an oral solution contained in unit-dose ampules. A study has been conducted to compare the... (Comparative Study)
Comparative Study Randomized Controlled Trial
A new formulation of levothyroxine sodium has been developed in the form of an oral solution contained in unit-dose ampules. A study has been conducted to compare the bioavailability of levothyroxine sodium oral solution and levothyroxine sodium soft capsule in healthy volunteers under fasting conditions. The rate and extent of absorption of the new levothyroxine solution were also evaluated when administered on dilution in water or directly into the mouth without water. In each period, according to the randomization scheme, subjects were administered single oral doses of either test, as 4 × 150-μg unit-dose ampules, with or without water, or reference, as 4 × 150-μg capsules in a crossover design. Thirty-six subjects were randomized and dosed in this study; of these, 31 completed all study periods. When comparing the solution with the capsule (both products administered with water), the 90% confidence intervals for the ratio of log-transformed values of AUC and C were within 90.00% and 111.11%, respectively, for baseline-corrected levothyroxine. Moreover, the administration of levothyroxine oral solution without water did not affect the rate and extent of its absorption. In conclusion, levothyroxine oral solution unit-dose ampules were bioequivalent to the levothyroxine capsule when administered with or without water. All formulations were well tolerated, with no major side effects.
Topics: Administration, Oral; Adult; Biological Availability; Capsules; Cross-Over Studies; Fasting; Female; Healthy Volunteers; Humans; Male; Middle Aged; Solutions; Thyroxine; Young Adult
PubMed: 30153382
DOI: 10.1002/cpdd.608 -
Osteoporosis International : a Journal... May 2017No clinically important pharmacokinetic interference of alendronate occurred between a new effervescent formulation of alendronate and levothyroxine when coadministered.... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
No clinically important pharmacokinetic interference of alendronate occurred between a new effervescent formulation of alendronate and levothyroxine when coadministered. The combination does not materially affect levothyroxine absorption.
INTRODUCTION
Concurrent treatment of osteoporosis with alendronate (Aln) and hypothyroidism with levothyroxine (LT4) may be problematic because both drugs are to be taken separately after fasting overnight. The primary objective was to assess pharmacokinetic interactions between a new effervescent formulation of Aln (Aln-NEF) and LT4.
METHODS
A randomized, open-label, 3-way crossover study was conducted in 30 healthy adults (15 women). Subjects were dosed 3 times, separated by 35 days, after overnight fasts, with Aln-NEF alone (70 mg), LT4 alone (600 μg), or Aln-NEF and LT4 concurrently. Samples were analyzed for plasma Aln and serum LT4. Pharmacokinetic drug-drug interaction was assessed using 90% confidence intervals (CIs) for the test/reference ratio of the geometric means for area under the concentration-time curve from time zero to last measureable time point (AUC ) and maximum concentration (C ). Results were compared to the default no-effect boundaries of 80 to 125% for the ratio Aln-NEF and LT4 concurrently/Aln-NEF alone and the ratio Aln-NEF and LT4 concurrently/LT4 alone.
RESULTS
Geometric mean ratios (Aln-NEF with LT4/Aln-NEF alone) were 0.927 (90% CI 0.795-1.081) for AUC and 0.912 (90% CI 0.773-1.077) for C , demonstrating LT4 does not appreciably affect the pharmacokinetics of Aln. Geometric mean ratios (LT4 with Aln-NEF/LT4 alone) were 1.049 (90% CI 0.983-1.119) for AUC and 1.075 (90% CI 1.006-1.148) for C , demonstrating LT4 is bioequivalent between the 2 treatments. Coadministration of Aln-NEF and LT4 was well tolerated.
CONCLUSIONS
There was no clinically important pharmacokinetic interference between the Aln-NEF formulation and LT4. Aln-NEF does not materially affect LT4 absorption.
Topics: Administration, Oral; Adolescent; Adult; Alendronate; Bone Density Conservation Agents; Cross-Over Studies; Drug Administration Schedule; Drug Combinations; Drug Compounding; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Middle Aged; Therapeutic Equivalency; Thyroxine; Young Adult
PubMed: 28204953
DOI: 10.1007/s00198-017-3941-3