A multicenter randomized placebo-controlled trial of intravenous thyroxine for heart-eligible brain-dead organ donors

Background Brain death frequently induces hemodynamic instability and cardiac stunning. Impairments in cardiac performance are major contributors to hearts from otherwise eligible organ donors not being transplanted. Deficiencies in pituitary hormones (including thyroid-stimulating hormone) may contribute to hemodynamic instability, and replacement of thyroid hormone has been proposed as a means of improving stability and increasing hearts available for transplantation. Intravenous thyroxine is commonly used in donor management. However, small controlled trials have not been able to demonstrate efficacy. Methods This multicenter study will involve organ procurement organizations (OPOs) across the country. A total of 800 heart-eligible brain-dead organ donors who require vasopressor support will be randomly assigned to intravenous thyroxine for at least 12 h or saline placebo. The primary study hypotheses are that thyroxine treatment will result in a higher proportion of hearts transplanted and that these hearts will have non-inferior function to hearts not treated with thyroxine. Additional outcome measures are the time to achieve hemodynamic stability (weaning off vasopressors) and improvement in cardiac ejection fraction on echocardiography. Discussion This will be the largest randomized controlled study to evaluate the efficacy of thyroid hormone treatment in organ donor management. By collaborating across multiple OPOs, it will be able to enroll an adequate number of donors and be powered to definitively answer the critical question of whether intravenous thyroxine treatment increases hearts transplanted and/or provides hemodynamic benefits for donor management. Trial registration ClinicalTrials.govNCT04415658. Registered on June 4, 2020

Thyroxine Treatment During the Perinatal Stage Prevents the Alterations in the ObRb-STAT3 Leptin Signaling Pathway Caused by Congenital Hypothyroidism

Thyroid hormone deficiency during crucial stages of development causes congenital hypothyroidism. This syndrome alters hypothalamic pathways involved in long-term bodyweight regulation as ObRb-STAT3 leptin signaling pathway, which is associated with metabolic syndrome. This study aimed to determine if thyroxine treatment during pregnancy and lactation in hypothyroid mothers avoids, in the congenital hypothyroid offspring, the alterations in metabolic programming related to metabolic syndrome and the ObRb-STAT3 leptin signaling pathway in hypothalamus. Twenty-four virgin female Wistar rats were divided into euthyroid, hypothyroid, and hypothyroid with thyroxine treatment (20 μg/kg/day T4 since pregnancy until lactation). The bodyweight and energy intake, insulin resistance, glucose tolerance, metabolic and hormonal parameters were determined in offspring at 28 weeks after birth. Then, the rats were euthanized to obtain adipose tissue reserves and hypothalamus to measure the expression of ObRb, STAT3, pSTAT3, and SOCS3. Congenital hypothyroidism presented metabolic syndrome such as insulin resistance, glucose tolerance, dyslipidemias, an increase in cardiovascular risk (Castelli I males:166.67%, females: 173.56%; Castelli II males: 375.51%, females: 546.67%), and hypothalamic leptin resistance (SOCS3, Males: 10.96%, females: 25.85%). Meanwhile, the thyroxine treatment in the mothers during pregnancy and lactation prevents the metabolic disturbance. In conclusion, thyroxine treatment during the critical perinatal stage for metabolic programming prevents congenital hypothyroidism-caused metabolic syndrome and hypothalamic leptin resistance.

Less Favorable Lipid Profile and Higher Prevalence of Thyroid Antibodies in Women of Reproductive Age with High-Normal TSH—Retrospective Study

High-normal TSH can be associated with metabolic abnormalities and infertility. Aims of this study are to analyze retrospectively if routinely measured blood laboratory and anthropometric parameters differ between women of reproductive age with TSH < 2.5 mIU/L and with TSH ≥ 2.5 mIU/L. Retrospective analysis was performed in 466 female inpatients, aged 13–51, hospitalized in an endocrine department. The group of 280 patients with normal thyroid tests (TSH 0.27-4.2 mIU/L; normal FT3 and FT4) was selected and it was divided into two subgroups, i.e., with TSH < 2.5 mIU/L and TSH ≥ 2.5 mIU/L (n = 66; 23.6%). After excluding patients on L-thyroxine treatment (n = 240), those with TSH ≥ 2.5 mIU/L constituted 22.92% (n = 55). In the group of 280 patients with normal thyroid tests, an abnormally high concentration of triglycerides and an abnormally low HDLC/cholesterol ratio occurred more frequently in women with TSH ≥ 2.5 mIU/L than those with TSH < 2.5 mIU/L (17% vs. 7%, p = 0.017; 14% vs. 5%, p = 0.015, respectively). Increased concentration of thyroid antibodies, i.e., TPOAb, occurred more frequently in patients with TSH ≥ 2.5 mIU/L than those with TSH < 2.5 mIU/L (27% vs. 9%, p = 0.001). The same differences were found in the group of 240 patients after excluding those on L-thyroxine treatment. Blood lymphocyte concentration was the only independent linear parameter associated with TSH ≥ 2.5 mIU/L (OR = 1.551, p = 0.024) but only in the group of 280 patients with normal thyroid tests. TSH concentration correlated positively with blood lymphocyte (r = 0.129, p = 0.031) and TPOAb (r = 0.177, p = 0.005) concentrations but only in the group of 280 patients with normal thyroid tests. Less favorable lipid profiles and a higher prevalence of thyroid antibodies in women of reproductive age with high-normal TSH suggests that L-thyroxine treatment should be considered in such patients. The significance of a positive association between high-normal TSH and blood lymphocytes requires further evaluation.

Accelerated gastric ulcer healing in thyroxine-treated rats: roles of gastric acid, mucus, and inflammatory response

The roles of gastric acid, mucus, and inflammation on the pro-ulcer-healing effect of thyroid hormone were investigated. Male Wistar rats were randomly divided into four groups: control, thyroidectomised, thyroidectomised with thyroxine treatment (100 μg·kg–1·day–1), and sham-operated animals treated with thyroxine. Thirty-five days after thyroidectomy, sham surgery, or thyroxine treatment, an ulcer was experimentally induced. Healing was assessed 3, 7, and 10 days post-ulceration by measurement of the ulcer area, gastric mucus and acid secretion, and neutrophil lymphocyte ratio (NLR) as an index of inflammation. By day 10, the ulcer area had decreased in all groups. Recovery was significantly greater (P < 0.05) in thyroxine-treated rats (78.5% ± 1.6% reduction in ulcer area) than in controls (72.3% ± 1.2% reduction) or thyroidectomised rats (63.3% ± 1.9% reduction). Thyroxine-treated animals also had the highest reduction in NLR (65.0% ± 2.5%). Mucus secretion was significantly lower (P < 0.05) in thyroidectomised rats by days 3 and 7. Furthermore, by day 10, the concentration of basal acid decreased by 77.4% ± 2.6% in thyroxine-treated, 65.0% ± 0.0% in control, and 51.5% ± 3.3% in thyroidectomised rats. We conclude that thyroxine accelerates gastric ulcer healing by altering mucus and acid secretion and reducing NLR.