Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine

Werneck-de-Castro, João Pedro; Fonseca, Tatiana L.; Ueta, Cintia B.; McAninch, Elizabeth A.; Abdalla, Sherine M.; Wittmann, Gábor; Lechan, Ronald M.; Gereben, Balázs; Bianco, Antonio C.

doi:10.1172/jci77588

Cited by 143 publications

(152 citation statements)

References 61 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…However, in this model the rT 3 effect was studied under rather artificial conditions in the absence of an abundant T 4 supply with elevated FT 4 levels that characterizes the treatment situation. In contrast, another recent experimental study has shown that escalating only the L-T 4 dose fails to normalize serum T 3 in the rat, and as a result, irrespective of local variations by type of deiodinase, all organs examined such as the brain, liver and skeletal muscle were hypothyroid at the tissue level in the presence of a normal serum TSH (29). This study suggests ubiquitination may be the limiting factor for T 4 alone to restore true tissue euthyroidism in the rodent (29).…”

Section: Discussionmentioning

confidence: 79%

“…In contrast, another recent experimental study has shown that escalating only the L-T 4 dose fails to normalize serum T 3 in the rat, and as a result, irrespective of local variations by type of deiodinase, all organs examined such as the brain, liver and skeletal muscle were hypothyroid at the tissue level in the presence of a normal serum TSH (29). This study suggests ubiquitination may be the limiting factor for T 4 alone to restore true tissue euthyroidism in the rodent (29). The lack of TSH stimulation and absence or functional deficiency of the thyroid gland may also impair T 4 -T 3 conversion (30).…”

Section: Discussionmentioning

confidence: 79%

See 1 more Smart Citation

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

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.

show abstract

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 79%

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

show abstract

“…T4 + T3 therapy but not T4 monotherapy in thyroidectomized rats restored serum cholesterol and mitochondrial content and α-glycerolphosphate dehydrogenase activity in liver and skeletal muscle (13). T4 + T3 therapy also normalized the expression of all studied T3-responsive genes in the brain, whereas T4 monotherapy restored gene expression partially (13).…”

Section: Introductionmentioning

confidence: 89%

“…High T4 levels inhibit D2 activity, which in D2-expressing tissues such as the brain may result in lower T3 content. D2 inactivation is by ubiquination, and tissue-specific differences in D2 ubiquitination account for the low serum T3/T4 ratio of T4 treatment after thyroidectomy in experimental animals (13). T4 administration decreases whole-body D2-dependent conversion of T4 into T3, but D2 activity in the hypothalamus is only minimally affected by T4.…”

Section: Introductionmentioning

confidence: 98%

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

Wiersinga

2017

European Journal of Endocrinology

View full text Add to dashboard Cite

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.

show abstract

“…In tanycytes, both WSB-1 and USP-33 are coexpressed with D2 . Recent studies, however, show that T 4 induced ubiquitination in tanycytes is minimal, probably to ensure the sensitivity of the TRH producing neurons in the PVN to fluctuations in serum TH concentrations (Werneck de Castro et al 2015). In line with these findings, there is no evidence that ubiquitination is involved in the regulation of D2 during inflammation.…”

Section: Type 2 Deiodinasementioning

confidence: 95%

The molecular basis of the non-thyroidal illness syndrome

Vries¹,

Fliers²,

Boelen³

2015

Journal of Endocrinology

145

116

View full text Add to dashboard Cite

The 'sick euthyroid syndrome' or 'non-thyroidal illness syndrome' (NTIS) occurs in a large proportion of hospitalized patients and comprises a variety of alterations in the hypothalamus-pituitary-thyroid (HPT) axis that are observed during illness. One of the hallmarks of NTIS is decreased thyroid hormone (TH) serum concentrations, often viewed as an adaptive mechanism to save energy. Downregulation of hypophysiotropic TRH neurons in the paraventricular nucleus of the hypothalamus and of TSH production in the pituitary gland points to disturbed negative feedback regulation during illness. In addition to these alterations in the central component of the HPT axis, changes in TH metabolism occur in a variety of TH target tissues during NTIS, dependent on the timing, nature and severity of the illness. Cytokines, released during illness, are known to affect a variety of genes involved in TH metabolism and are therefore considered a major determinant of NTIS. The availability of in vivo and in vitro models for NTIS has elucidated part of the mechanisms involved in the sometimes paradoxical changes in the HPT axis and TH responsive tissues. However, the pathogenesis of NTIS is still incompletely understood. This review focusses on the molecular mechanisms involved in the tissue changes in TH metabolism and discusses the gaps that still require further research.

show abstract

Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine

Cited by 143 publications

References 61 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?

The molecular basis of the non-thyroidal illness syndrome

Contact Info

Product

Resources

About