Prevalent Polymorphism in Thyroid Hormone-Activating Enzyme Leaves a Genetic Fingerprint That Underlies Associated Clinical Syndromes

McAninch, Elizabeth A.; Jo, Sungro; Preite, Nailliw Z.; Farkas, Erzsébet; Mohácsik, Petra; Fekete, Csaba; Egri, Péter; Gereben, Balázs; Li, Yanyan; Deng, Youping; Patti, Mary Elizabeth; Zevenbergen, Chantal; Peeters, Robin P.; Mash, Deborah C.; Bianco, Antonio C.

doi:10.1210/jc.2014-4092

Cited by 84 publications

(75 citation statements)

References 46 publications

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“…While acknowledging the role of genetically determined differences in deiodinase activity affecting conversion rates, the poor converter status described here appears to emerge mainly as a consequence of the T 4 monotherapy itself, induced by the mechanisms discussed above (42,43,44,45). Compared to untreated subjects, deiodinase activity and conversion efficiency tend to be diminished in L-T 4 treatment (20,22).…”

Section: Discussionmentioning

confidence: 65%

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

Midgley¹,

Larisch²,

Dietrich³

et al. 2015

Endocrine Connections

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Several influences modulate biochemical responses to a weight-adjusted levothyroxine (L-T 4 ) replacement dose. We conducted a secondary analysis of the relationship of L-T 4 dose to TSH and free T 3 (FT 3 ), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state L-T 4 replacement for autoimmune thyroiditis or after surgery for malignant or benign thyroid disease. Peripheral deiodinase activity was calculated as a measure of T 4 -T 3 conversion efficiency. In euthyroid subjects, the median L-T 4 dose was 1.3 mg/kg per day (interquartile range (IQR) 0.94,1.60). The dose was independently associated with gender, age, aetiology and deiodinase activity (all P!0.001). Comparable FT 3 levels required higher L-T 4 doses in the carcinoma group (nZ143), even after adjusting for different TSH levels. Euthyroid athyreotic thyroid carcinoma patients (nZ50) received 1.57 mg/kg per day L-T 4 (IQR 1.40, 1.69), compared to 1.19 mg/kg per day (0.85,1.47) in autoimmune thyroiditis (P!0.01, nZ76) and 1.08 mg/kg per day (0.82, 1.44) in patients operated on for benign disease (P! 0.01, nZ80). Stratifying patients by deiodinase activity categories of !23, 23-29 and O29 nmol/s revealed an increasing FT 3 -FT 4 dissociation; the poorest converters showed the lowest FT 3 levels in spite of the highest dose and circulating FT 4 (P!0.001). An L-T 4 -related FT 3 -TSH disjoint was also apparent; some patients with fully suppressed TSH failed to raise FT 3 above the median level. These findings imply that thyroid hormone conversion efficiency is an important modulator of the biochemical response to L-T 4 ; FT 3 measurement may be an additional treatment target; and L-T 4 dose escalation may have limited success to raise FT 3 appropriately in some cases.

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Section: Discussionmentioning

confidence: 65%

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

Midgley¹,

Larisch²,

Dietrich³

et al. 2015

Endocrine Connections

View full text Add to dashboard Cite

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“…In contrast, a more recent study showed that DR-92Ala has a longer half-life in transfected human embryonic kidney cells (22,38). Expression profiles of T3-responsive genes in the cerebral cortex of 19 D2-92Ala carriers were not affected but those of non-T3 responsive genes were, suggesting that the effects of the 92Ala variant on cognitive endpoints might not be mediated via changes in thyroid hormone levels (22,38). The most recent study showed no differences in protein stability between genotypes, but intracellular T4 to T3 conversion was lower in D2-92Ala than that in D2-Thr92 transfected myoblasts (24).…”

Section: Introductionmentioning

confidence: 89%

“…Patients with type 2 diabetes who were homozygous for D2-92Ala, had decreased D2 activity in muscle samples compared to D2-Thr92 carriers; however, decreased D2 activity was not observed in transfected D2-92Ala cells (22,37). In contrast, a more recent study showed that DR-92Ala has a longer half-life in transfected human embryonic kidney cells (22,38). Expression profiles of T3-responsive genes in the cerebral cortex of 19 D2-92Ala carriers were not affected but those of non-T3 responsive genes were, suggesting that the effects of the 92Ala variant on cognitive endpoints might not be mediated via changes in thyroid hormone levels (22,38).…”

Section: Introductionmentioning

confidence: 92%

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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“…Besides its association with QoL in millions of patients with hypothyroidism, Thr92Ala-D2, a common SNP, exhibits a strong susceptibility to ubiquitination and proteasomal degradation, which is regulated within the D2 molecule [27]. By accumulating in the Golgi, Ala92-D2 may, following oxidative stress, disrupt basic cellular functions, increase pre-apoptosis and cause disease [27].…”

Section: Genetic Variancementioning

confidence: 99%

New aspects of an old dilemma: treatment of hypothyroidism with L-thyroxine combined with L-triiodothyronine

Duntas¹

2017

Clin Exp Thyroid

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В данном обзоре приведена информация о последних исследованиях в области комбинированного лечения гипотиреоза L-тироксином и L-трийодтированином. Не смотря на то, что были опубликованы достоверные данные об эффективности комбинированной терапии Т3 и Т4 у крыс после тиреоидэктомии, последние исследования и мета-анализы не указывают на значимое преимущество комбинированной терапии по сравнению с монотерапией Т4. Более того, у пациентов, получающих комбинированную терапию, чаще развиваются побочные эффекты, такие как тахикардия, нервозность и общая слабость. Тем не менее, по сравнению с комбинированной терапией L-T4+L-T3, при монотерапии Т4 обычно наблюдается сниженный уровень свободного Т3 и повышенный уровень свободного Т4 сыворотки крови, при этом отношение свТ3/свТ4 ближе к показателям, характерным для здорового человека. Согласно рекомендациям ЕТА и АТА, на сегодняшний день монотерапия Т4 считается первоочередной в лечении гипотиреоза. Тем не менее, во многих случаях рекомендации не соблюдаются, и пациенты принимают высушенные экстракты щитовидной железы или разнообразные «препараты» Т3 доступные в интернете. Недавно было выявлено, что однонуклеотидный полиморфизм (ОНП) генов дейодиназы 1-го (Д1) и 2-го (Д2) типов, а также гена фосфодиэстеразы 8В ассоциированы со снижением уровня свободного Т3 и дисфункцией щитовидной железы. Данные наблюдения подчеркивают необходимость в дальнейших исследованиях эффективности применения готовых комбинированных препаратов, а также в разработке долгожданных формул L-T3 c отсроченным действием или низко-дозированных (капсулы или таблетки по 5 мкг) препаратов L-T3, с целью облегчения подбора правильной дозы при комбинированной терапии с препаратами L-Т4 в контексте персонализированного подхода к лечению. Последние данные о возможном влиянии ОНП генов дейодиназ или белков-переносчиков тиреоидных гормонов на концентрацию свободного Т3 в тканях открывают путь к генотипированию пациентов с тиреоидэктомией в анамнезе, предъявляющих характерные жалобы и имеющих низкое отношение свТ3/свТ4.

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Prevalent Polymorphism in Thyroid Hormone-Activating Enzyme Leaves a Genetic Fingerprint That Underlies Associated Clinical Syndromes

Cited by 84 publications

References 46 publications

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

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

New aspects of an old dilemma: treatment of hypothyroidism with L-thyroxine combined with L-triiodothyronine

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