A Renewed Focus on the Association Between Thyroid Hormones and Lipid Metabolism

Duntas, Leonidas H.; Brenta, Gabriela

doi:10.3389/fendo.2018.00511

Cited by 113 publications

(90 citation statements)

References 105 publications

(111 reference statements)

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“…H ypothyroidism is a common condition (1,2) associated with an increased cardiovascular risk profile (3)(4)(5) and poor quality of life (6,7). The goal of its therapy is the relief of symptoms and restoration of normal thyroid hormone levels by administration of synthetic thyroxine (T4), levothyroxine (LT4), which is then converted in the periph-eral tissues into the hormonally active triiodothyronine (T3) (8).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal

Wohlford

et al. 2019

Thyroid

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Background: L-triiodothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer (TC) patients during the preparation for nuclear medicine procedures, and it is used in combination with LT4 in patients who do not respond to the standard treatment for hypothyroidism. This therapy is commonly done by using fixed doses, potentially resulting in supraphysiologic levels of triiodothyronine (T3). A good understanding of the LT3 pharmacokinetics (PK) is necessary to design combination treatment schemes that are able to maintain serum T3 levels within the reference range, but data on the PK of LT3 are conflicting. Here, we present a study designed to characterize the PK of LT3 in patients devoid of endogenous thyroid hormone production, and not receiving LT4 therapy. Methods: We performed an open-label, PK study in patients undergoing thyroid hormone withdrawal in preparation for nuclear medicine procedures for the evaluation and treatment of follicular-derived TC. LT3 was substituted for LT4 at a 1:3 mcg/mcg dosage ratio thrice daily for at least 30 days. PK of the last LT3 dose while at steady state and terminal elimination was assessed over 11 days. Thereafter, a PK study was performed following the nuclear medicine procedure in patients who volunteered for a second study. Results: Fourteen patients age 48.5-16.0 years completed the last dose study and five completed the second PK study. PK analysis indicates a time to maximum serum concentration of 1.8-0.32 hours and two distinct phases of linear elimination, with a fast distribution phase and slow elimination phases with half-lives of 2.3-0.11 hours and 22.9-7.7 hours, supporting a two-compartment model. PK modeling predicts that a twicedaily administration of low-dose LT3 (0.07 mcg/kg twice daily) in combination with LT4 can predictably increase the serum T3 concentration without significant peaks above the reference range. Conclusions: The PK of LT3 is well described by a two-compartment model that assumes elimination only from the sampling compartment, with a rapid distribution phase and a slow elimination phase. This information will contribute to design therapeutic strategies for LT3/LT4 combination therapies directed to maintain stable T3 serum levels.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal

Wohlford

et al. 2019

Thyroid

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“…The hallmark of subclinical hypothyroidism-related dyslipidemia is reduced synthesis of liver LDL receptors and the mechanisms behind this effect have been extensively studied and explained. Emerging evidence suggests that the levels of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9), a serin-protease responsible for downregulation of liver LDL receptors, is also increased in subclinical hypothyroidism (64), paving the way for innovative lipid-lowering therapy in this category of patients (5). However, data on PCSK9 in children are sparse and the studies examining efficacy, safety, and tolerability of PCSK9 inhibitors in pediatric patients are underway (65).…”

Section: Hashimoto Thyroiditis and Dyslipidemiamentioning

confidence: 99%

“…The lack of thyroid hormones is associated with reduced clearance of TG-rich particles, due to attenuated lipoproteinlipase (LPL) and hepatic lipase (HL) activities, and increased production of very-low density lipoprotein (VLDL) particles (5). Hence, apart from the impact on LDL-C level, thyroid dysfunction may affect qualitative characteristics and functional properties of LDL particles.…”

Section: Hashimoto Thyroiditis and Dyslipidemiamentioning

confidence: 99%

“…As a result, plasma lipid and lipoprotein levels are sensitive to changes in the thyroid hormones concentrations. The alterations in lipid profile accompanying AIT worsen along with the advancement of hypothyroidism, ranging from discrete pro-atherogenic markers in euthyroid AIT, to full-blown dyslipidemia in many patients with the overt hypothyroidism (5)(6)(7). Furthermore, autoimmune disease itself has significant impact on lipid profile, as evidenced by a high prevalence of dyslipidemia in patients with autoimmune diseases (8)(9)(10), which may account, at least in part, to the increased cardiovascular disease (CVD) risk.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, autoimmune disease itself has significant impact on lipid profile, as evidenced by a high prevalence of dyslipidemia in patients with autoimmune diseases (8)(9)(10), which may account, at least in part, to the increased cardiovascular disease (CVD) risk. Thus, it could be regarded as convenient that the efficacy of L-thyroxine (L-T4) treatment in the normalization of lipid status is directly proportionate to the degree of thyroid dysfunction, being highest in the overt hypothyroidism (5,7,11,12). However, the waist majority of data linking autoimmune thyroid disease with dyslipidemia were gained from the studies in adults (13), whereas data in pediatric populations are limited.…”

Section: Introductionmentioning

confidence: 99%

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Hashimoto Thyroiditis and Dyslipidemia in Childhood: A Review

et al. 2019

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Hashimoto autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in the pediatric population. Development of AIT is mediated mainly by cellular immune response directed toward thyroid autoantigens, leading to inflammation and impaired function of thyroid gland. Both thyroid dysfunction and inflammation affect the metabolism of plasma lipoproteins. The alterations in lipid profile worsen with the advancement of hypothyroidism, ranging from discrete changes in euthyroid AIT patients, to atherogenic dyslipidemia in the overt hypothyroidism. In this review, characteristics of dyslipidemia in pediatric AIT patients, and the consequences in respect to the risk for cardiovascular disease (CVD) development are discussed. Additionally, benefit of L-thyroxine treatment on serum lipid profile in pediatric AIT patients is addressed. Finally, potential usefulness of novel lipid biomarkers, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), non-cholesterol sterols, low-density lipoprotein particle size and number, and high-density lipoprotein structure and functionality in AIT patients is also covered. Further longitudinal studies are needed in order to elucidate the long-term cardiovascular outcomes of dyslipidemia in pediatric patients with Hashimoto AIT.

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Apolipoprotein B as a New Link Between Cholesterol and Alzheimer Disease

Ishii

2019

JAMA Neurol

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Advanced age is the largest risk factor for developing Alzheimer disease (AD), with the incidence of AD increasing dramatically with age, and nearly all patients with AD manifesting symptoms after age 65 years (late-onset AD [LOAD]). 1 However, approximately 5% of those with AD experience onset before age 65 years and are classified as having early-onset AD (EOAD). 2 Despite the low prevalence of EOAD compared with LOAD, studying EOAD has led to seminal discoveries in AD. The most famous example is Dr Alois Alzheimer's examination of the brain of Auguste D., a patient who initially presented with symptoms of dementia at age 51 years, which led to the histopathological findings of extracellular neuritic plaques and intracellular neurofibrillary tangles that remain the neuropathological hallmarks of AD. 3 Several decades later, genetic studies in familial EOAD with autosomal dominant transmission resulted in the discovery of the 3 genes currently known to be causative for AD (amyloid precursor protein, presenilin 1, and presenilin 2). 2 Unfortunately, many recent AD studies have excluded patients with EOAD because of the low prevalence of this condition or the belief that EOAD may be a distinct form of dementia from LOAD owing to the higher frequency of atypical presentations in EOAD. 4 This has resulted in the underinvolvement of patients with EOAD in recent AD studies, leading to missed opportunities and several unanswered questions.While EOAD has a considerably higher genetic predilection than LOAD, with an estimated heritability between 92% and 100%, 5 the exact genes contributing to EOAD are unknown, because the AD-causing autosomal dominant mutations in the 3 genes identified thus far account for onset of only 11% or less of all EOAD cases. 4 This suggests that genetic studies in EOAD could yield novel AD susceptibility genes, which may also be involved in LOAD. Additionally, since patients with EOAD were found to have decreased cerebrovascular risk factors compared with LOAD, 6,7 it is not clear if these cerebrovascular risk factors such as hyperlipidemia that are associated with an increased risk for developing LOAD similarly affect patients with EOAD.In this issue of JAMA Neurology, Wingo et al 8 report the results of a study that investigated the association of circulating cholesterol levels with EOAD and its underlying genetic mechanisms. The study population included individuals recruited from 29 US Alzheimer's Disease Research Centers (ADRCs), with Emory University ADRC samples serving as a discovery data set and the samples in the University of California, San Francisco and other ADRCs (excluding Emory and University of California, San Francisco) serving as 2 separate replication data sets. Cases of EOAD were defined as having either probable or defi-

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A Renewed Focus on the Association Between Thyroid Hormones and Lipid Metabolism

Cited by 113 publications

References 105 publications

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal

Hashimoto Thyroiditis and Dyslipidemia in Childhood: A Review

Apolipoprotein B as a New Link Between Cholesterol and Alzheimer Disease

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