ten year estimated risk of bone fracture in women with differentiated thyroid cancer under tsh suppressive levothyroxine therapy

Introduction: After thyroidectomy and radioiodine therapy, patients with differentiated thyroid cancer (DTC) are indefinitely treated with levothyroxine (L-T4). Osteoporosis is a debated consequence of hypothyroxinaemia. The aim of this study was to evaluate bone mineral density (BMD) and fracture risk assessed by FRAX in a cohort of DTC women. Material and methods: Seventy-four women with DTC (aged 56.5 ± 9.9 years) treated at the mean age of 51.9 ± 12.0 years were studied. Baseline BMD and FRAX were evaluated after 3.0 years (median). BMD and FRAX were further evaluated 5.5 years (median) after the baseline evaluation. A cohort of 120 euthyroid women, matched for age, BMI, and menopausal status, were evaluated as controls. Results: L-T4 dosages were 813.6 ± 208.8 μg/week and 782.1 ± 184.4 μg/week at the baseline and second evaluation, respectively. The risks of major osteoporotic fracture (MOF) and hip fracture (HF) were similar in DTC patients and in controls. In DTC women, significant changes in FRAX were found, with a higher increase in the probability of HF than of MOF. A similar change was found in controls. A significant inverse correlation (P < 0.001) between L-T4 dosage and HF/MOF probability on both first and second evaluations was found. A significant inverse correlation (P = 0.05) was found between fT4, TSH and duration of therapy and HF/MOF probability only on the second evaluation. Conclusions: FRAX increase is a multi-factorial, age-related phenomenon. The absence of correlations between L-T4 dosage, length of therapy or fT4 levels and FRAX does not enable us to attribute an increased fracture risk to DTC women with well-controlled disease on therapy. (Endokrynol Pol 2016; 67 (4): 350–358

Szacunkowe dziesięcioletnie ryzyko złamania kości u kobiet ze zróżnicowanym rakiem tarczycy stosujących terapię lewotyroksyną w celu supresji TSH

  Introduction: After thyroidectomy and radioiodine therapy, patients with differentiated thyroid cancer (DTC) are indefinitely treated with levothyroxine (L-T4). Osteoporosis is a debated consequence of hypothyroxinaemia. The aim of this study was to evaluate bone mineral density (BMD) and fracture risk assessed by FRAX in a cohort of DTC women. Material and methods: Seventy-four women with DTC (aged 56.5 ± 9.9 years) treated at the mean age of 51.9 ± 12.0 years were studied. Baseline BMD and FRAX were evaluated after 3.0 years (median). BMD and FRAX were further evaluated 5.5 years (median) after the baseline evaluation. A cohort of 120 euthyroid women, matched for age, BMI, and menopausal status, were evaluated as controls. Results: L-T4 dosages were 813.6 ± 208.8 μg/week and 782.1 ± 184.4 μg/week at the baseline and second evaluation, respectively. The risks of major osteoporotic fracture (MOF) and hip fracture (HF) were similar in DTC patients and in controls. In DTC women, significant changes in FRAX were found, with a higher increase in the probability of HF than of MOF. A similar change was found in controls. A significant inverse correlation (P &lt; 0.001) between L-T4 dosage and HF/MOF probability on both first and second evaluations was found. A significant inverse correlation (P = 0.05) was found between fT4, TSH and duration of therapy and HF/MOF probability only on the second evaluation. Conclusions: FRAX increase is a multi-factorial, age-related phenomenon. The absence of correlations between L-T4 dosage, length of therapy or fT4 levels and FRAX does not enable us to attribute an increased fracture risk to DTC women with well-controlled disease on therapy. (Endokrynol Pol 2016; 67 (4): 350–358)    Wstęp: Chorzy ze zróżnicowanym rakiem tarczycy (DTC) po tyroidektomi i terapii jodem radioaktywnym muszą do końca życia przyjmować lewotyroksynę (L-T4). Jednym z możliwych następstw hypertyroksynemii jest osteoporoza. Badanie przeprowadzono w celu oceny gęstości mineralnej kości (BMD) oraz ryzyka złamania na podstawie wskaźnika FRAX w kohorcie kobiet chorych na DTC. Materiał i metody: Badaniem objęto 74 kobiety z DTC (w wieku 56,5 ± 9,9 roku) poddane leczeniu w wieku 51,9 ± 12,0 lat. Wartości BMD i wskaźnika FRAX oceniono na początku badania oraz po upływie 3,0 lat (mediana). Następnie ponownie zbadano BMD i wskaźniki FRAX 5,5 roku (mediana) po początkowej ocenie. Grupę kontrolną stanowiła kohorta 120 kobiet z prawidłową czynnością tarczycy dobranych pod względem wieku, wskaźnika BMI i występowania menopauzy. Wyniki: Dawki L-T4 wynosiły 813,6 ± 208,8 μg/tydzień i 782,1 ± 184,4 μg/tydzień odpowiednio na początku badania i w trakcie drugiej oceny chorych. Ryzyko poważnego złamania osteoporotycznego (MOF) oraz złamania bliższego odcinka kości udowej (HF) było podobne u chorych z DTC i w grupie kontrolnej. U kobiet z DTC stwierdzono istotne zmiany wartości wskaźnika FRAX, przy czym wzrost wskaźnika był większy w przypadku prawdopodobieństwa HF niż u osób zagrożonych MOF. Podobne zmiany stwierdzono w grupie kontrolnej. Zaobserwowano istotną odwrotną korelację (p &lt; 0,001) między dawką L-T4 a prawdopodobieństwem HF/MOF zarówno przy pierwszej, jak i drugiej ocenie chorych. Natomiast istotną odwrotną korelację (p = 0,05) między dawką fT4, stężeniem TSH i czasem trwania terapii a prawdopodobieństwem HF/MOF stwierdzono tylko w czasie drugiej wizyty. Wnioski: Zwiększenie wartości wskaźnika FRAX jest związane z wiekiem i zależy od wielu czynników. Brak korelacji między dawką L-T4, czasem trwania terapii lub stężeniem fT4 a wartością wskaźnika FRAX wskazuje, że nie należy przypisywać zwiększonego ryzyka złamań pacjentkom z DTC, u których uzyskano dobre wyrównanie choroby za pomocą terapii. (Endokrynol Pol 2016; 67 (4): 350–358)

Metasomatic horizon sealing serpentinite-metasediments pair in the Zermatt-Saas metaophiolite (Northwestern Alps): record of a channel for focussed fluid flow during subduction

A metasomatic horizon (MH) occurs between the metaophiolite (serpentinite and metaophicarbonates) basement and metasedimentary sequence (chaotic rocks and calcschists) of the Lake Miserin Ophiolite, in the high pressure Zermatt-Saas Zone of the Northwestern Alps. Macro- and microstructural analyses combined with petrological and geochemical investigations of the MH and surrounding lithologies unravelled a polyphase blastesis-deformation history, which led to the formation of a complex fabric and minero-chemical alteration of the serpentinite basement-metasediments interface. Dehydration, decarbonation and carbonation interplayed from early Alpine subduction up to HP-LT metamorphic peak (T=550-630 °C, P=1.8-2.5 GPa), to produce a distinctive, pervasive amphibole (tremolite/actinolite) replacement both in carbonate-rich and serpentinite-rich domains pertaining to the MH protoliths, i.e. serpentinite and carbonate-bearing metabreccia of the chaotic rock unit. This characteristic amphibole metasomatism is more pronounced toward the contact with the metaophicarbonates, and the average δ18OVSMOW and δ13CVPDB values of dolomite within the MH (+14.4‰ and +0.7‰ respectively) lie between those of the metaophicarbonates and of calcschist. These results suggest that Mg- H2O-rich fluids from the dehydrating slab, CO2 released by decarbonation and SiO2-rich fluids evolved in calcschists mixed together and circulated mostly along the metaophiolite basement/metasediments interface, where the MH developed and recorded a preferential channel for mixed metamorphic fluid flow. These findings highlight and confirm that the study of metasomatic rocks in convergent systems is crucial to comprehend the behaviour of different fluids circulating, mixing and interacting with lithologies along slab-parallel discontinuities, which act as major fluid conduits for deep volatile recycling

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential

Human CD4(+)CD25(hi)FOXP3(+) regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/ glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation