No Effect of the Thr92Ala Polymorphism of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and Cognitive Functioning in a Large Population-Based Cohort Study

Wouters, Hanneke J C M; Loon, Hannah Constance Mathilde van; Klauw, Melanie M. van der; Elderson, Martin F.; Slagter, Sandra; Kobold, Anneke C. Muller; Kema, Ido P.; Links, Thera P.; Vliet-Ostaptchouk, Jana V. van; Wolffenbuttel, Bruce H. R.

doi:10.1089/thy.2016.0199

Cited by 84 publications

(72 citation statements)

References 46 publications

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“…Almost all studies have shown identical serum TSH and thyroid hormone concentrations in hypothyroid patients harbouring different DIO2 polymorphism in rs225014 [17, 25-37] and rs12885300 [27, 28, 30]. However, a few exceptions have also been published [25, 38, 39].…”

Section: Discussionmentioning

confidence: 99%

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

et al. 2017

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Objectives: In previous studies, around half of all hypothyroid patients preferred levo-thyroxine (L-T4) + levo-triiodothyronine (L-T3) combination therapy, 25% preferred T4, and 25% had no preference. The reason for this is yet to be explored. Methods: A total of 45 overtly autoimmune, hypothyroid patients – now euthyroid on ≥6 months’ L-T4 therapy – participated in a prospective, double-blind, cross-over study. The patients were randomized into 2 groups of either 3 continuous months’ L-T4 therapy followed by 3 months’ combination therapy or vice versa. In all periods, 50 μg L-T4 was blindly replaced by either (identical) 50 μg L-T4 or by 20 μg T3. L-T4 was hereafter adjusted to obtain normal serum TSH values. We investigated 3 single nucleotide polymorphisms (SNPs) on the type II iodothyronine deiodinase (DIO2) gene (rs225014 (Thr92Ala), rs225015, and rs12885300 (ORFa-Gly3Asp)) and 1 SNP on the cellular membrane transport-facilitating monocarboxylate transporter (MCT10) gene (rs17606253), and asked in which of the 2 treatment periods patients felt better (i.e., which treatment was preferred). Results: 27 out of 45 patients (60%) preferred the combination therapy. Two polymorphisms (rs225014 (DIO2, Thr92Ala) and rs17606253 (MCT10)) were combined yielding 3 groups: none vs. 1 of 2 vs. both SNPs present, and 42 vs. 63 vs. 100% of our patients in the 3 groups preferred the combined treatment (Jongheere-Terpstra trend test, p = 0.009). Conclusion: The present study indicates that the combination of polymorphisms in DIO2 (rs225014) and MCT10 (rs17606253) enhances hypothyroid patients’ preference for L-T4 + L-T3 replacement therapy. In the future, combination therapy may be restricted or may be even recommended to individuals harbouring certain polymorphisms.

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Section: Discussionmentioning

confidence: 99%

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

et al. 2017

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“…The absence of such an association in another study might be due to a smaller sample size (20). A recent large populationbased cohort study did not find an association between Thr92Ala and outcomes of T4 therapy such as quality of life and cognitive functioning (23). SNPs in the brain-specific thyroid hormone transporter OATP1C1 (also known as SLCO1C1) are associated with fatigue and depression in T4-treated patients, but not with neurocognitive test results or a preference for combination therapy (35).…”

Section: Introductionmentioning

confidence: 91%

“…The most studied variant is rs225014 (Thr92Ala), which also had no effects on serum TSH, FT4 or T3 (20,21) but interestingly has been associated with diabetes, psychological well-being, hypertension and the risk of osteoarthritis (22). A recent large study reports the presence of DIO2 Thr92Ala in 10.7% of the general population and in 11.3% of T4 users (23). In neither group was the polymorphism associated with differences in serum TSH, FT3, FT4, FT3/FT4 ratio, quality of life or cognitive functioning.…”

Section: Introductionmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?

Wiersinga

2017

European Journal of Endocrinology

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About 5%-10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03-≤0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients.

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“…Another study, in which participants taking LT4 were recruited by letter and then completed questionnaires assessing well-being, also showed lower scores in 2 different questionnaires in the euthyroid patients taking L-T4, although the comparison was with standard reference values, rather than a matched control group (8). In several more recent studies, treated female patients with hypothyroidism were found to have worse quality of life compared with control groups using the RAND-36 Short Form Survey Instrument (SF-36) (9), the ThyPRO and SF-36 questionnaires (10), the SF-36, the Hospital Anxiety and Depression Scale, and the multidimensional fatigue inventory questionnaire (11), and worse mental health using the General Health Questionnaire (GHQ) (12). One of these studies, which examined patients before and after initiation of LT4, showed improvement in some ThyPRO and SF-36 subscales as serum TSH was normalized from a median of 8.1 to 2.6 mIU/L.…”

Section: Patient-reported Outcomes During Levothyroxine Therapymentioning

confidence: 99%

Persistent hypothyroid symptoms in a patient with a normal thyroid stimulating hormone level

Jonklaas

2017

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of Review A subset of patients being treated for hypothyroidism do not feel well taking levothyroxine replacement therapy, despite having a normal TSH. Pursuing a relative triiodothyronine deficiency as a potential explanation for patient dissatisfaction, has led to trials of combination therapy with liothyronine, with largely negative outcomes. This review attempts to reconcile these diverse findings, consider potential explanations, and identify areas for future research. Recent Findings Patients being treated with levothyroxine often have lower triiodothyronine levels than patients with endogenous thyroid function. Linking patient dissatisfaction with low triiodothyronine levels has fueled multiple combination therapy trials that have generally not shown improvement in patient quality of life, mood, or cognitive performance. Some trials, however, suggest patient preference for combination therapy. There continues, moreover, to be anecdotal evidence that patients have fewer unresolved symptoms while taking combination therapy. Summary The fourteen trials completed to date have suffered from employing doses of liothyronine that do not result in steady triiodothyronine levels, and having insufficient power to analyze results based on baseline dissatisfaction with therapy and patient genotype. Future trials that are able to incorporated such features may provide insight to what thyroid hormone preparations will most improve patient satisfaction with therapy.

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No Effect of the Thr92Ala Polymorphism of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and Cognitive Functioning in a Large Population-Based Cohort Study

Abstract: The Thr92Ala polymorphism of D2 was not associated with thyroid parameters, HRQoL, and cognitive functioning in the general population and in participants on thyroid hormone replacement therapy.

Cited by 84 publications

References 46 publications

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?

Persistent hypothyroid symptoms in a patient with a normal thyroid stimulating hormone level

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