Abstract 16928: Amiodarone For Atrial Fibrillation In The Setting Of Cardiogenic Shock And Thyroid Storm

Case Presentation: A 29-year-old man with a history of hyperthyroidism presented to an outside hospital with altered mentation and palpitations in the setting of non-adherence to thyroid medications. He was found to be in atrial fibrillation with rapid ventricular response. Initial vital signs included a heart rate of 165 beats/min, respiratory rate of 43 breaths/min, blood pressure of 134/115 mmHg, and O2 saturation of 94% on 2L of oxygen. Point of care ultrasound showed an EF of 10% and a dilated IVC. Labs showed a creatinine of 0.7 mg/dL, total bilirubin of 3.9 mg/dL, ALT of 39 IU/L, AST of 62 IU/L, ALP of 181 IU/L, lactate of 7.6 mMol/L, TSH of < 0.01 uIU/mL, free T4 of > 5.00 ng/dL, and a T3 of > 30.00 pg/mL. He was treated with methimazole and then switched to propylthiouracil (PTU). Esmolol and diltiazem resulted in worsening cardiogenic shock and PEA arrest twice requiring VA ECMO cannulation. Upon transfer to our facility, he was started on potassium iodide (SSKI). He had electrical cardioversion twice with reversion back to atrial fibrillation. He was then started on amiodarone and digoxin. He remained in atrial fibrillation but achieved rate control with heart rates in the 100s. Discussion: Amiodarone is typically avoided in atrial fibrillation in the setting of thyrotoxicosis due to its high iodine content which can precipitate further thyroid hormone synthesis. However, in the setting of cardiogenic shock, treatment options are limited. We learned from our endocrinology colleagues that amiodarone can be beneficial when patients are treated with PTU and SSKI as amiodarone blocks the conversion of T4 to T3. Amiodarone should be started after PTU as PTU prevents thyroid hormone synthesis and blunts the effect of the iodine load of amiodarone. In conclusion, amiodarone can be considered earlier for the treatment of atrial fibrillation in the setting of thyrotoxicosis especially if treatment options are limited by cardiac dysfunction granted the patient has been started on PTU.

Next-Generation Sequencing Analysis Reveals Frequent Familial Origin and Oligogenism in Congenital Hypothyroidism With Dyshormonogenesis

ContextCongenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis.ObjectiveWe explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype.Patients, Design and SettingUsing the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed in silico for pathogenicity.ResultsAmong the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the TG, DUOX2, TPO, or SLC5A5 genes in 10 infants and heterozygous variants in DUOX2, TG, TPO, and TSHR in 19 others. In seven cases, a heterozygous variant in the TG gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them.ConclusionThe systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.

Resveratrol Alleviates the Inhibitory Effect of Tunicamycin-Induced Endoplasmic Reticulum Stress on Expression of Genes Involved in Thyroid Hormone Synthesis in FRTL-5 Thyrocytes

Recently, ER stress induced by tunicamycin (TM) was reported to inhibit the expression of key genes involved in thyroid hormone synthesis, such as sodium/iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), and their regulators such as thyrotropin receptor (TSHR), thyroid transcription factor-1 (TTF-1), thyroid transcription factor-2 (TTF-2) and paired box gene 8 (PAX-8), in FRTL-5 thyrocytes. The present study tested the hypothesis that resveratrol (RSV) alleviates this effect of TM in FRTL-5 cells. While treatment of FRTL-5 cells with TM alone (0.1 µg/mL) for 48 h strongly induced the ER stress-sensitive genes heat shock protein family A member 5 (HSPA5) and DNA damage inducible transcript 3 (DDIT3) and repressed NIS, TPO, TG, TSHR, TTF-1, TTF-2 and PAX-8, combined treatment with TM (0.1 µg/mL) and RSV (10 µM) for 48 h attenuated this effect of TM. In conclusion, RSV alleviates TM-induced ER stress and attenuates the strong impairment of expression of genes involved in thyroid hormone synthesis and their regulators in FRTL-5 thyrocytes exposed to TM-induced ER stress. Thus, RSV may be useful for the treatment of specific thyroid disorders, provided that strategies with improved oral bioavailability of RSV are applied.

Phenotypic Variability of Patients With PAX8 Variants Presenting With Congenital Hypothyroidism and Eutopic Thyroid

Purpose Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. Patients and Methods Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. Results We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. Conclusions Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.

Palmitic Acid Downregulates Thyroglobulin (Tg), Sodium Iodide Symporter (NIS), and Thyroperoxidase (TPO) in Human Primary Thyrocytes: A Potential Mechanism by Which Lipotoxicity Affects Thyroid?

Our previous studies suggested that the thyroid might be a target organ affected by lipotoxicity, which might be partially related to the increasing prevalence of subclinical hypothyroidism. However, the underlying molecular mechanism is not yet clearly established. This study aimed to assess the effect of palmitic acid stimulation on thyrocyte function. Upon palmitic acid stimulation, intracellular contents of lipids, as well as the expression and activity of three key molecules in thyroid hormone synthesis (i.e., thyroglobulin, sodium iodide symporter, and thyroperoxidase), were determined in human primary thyrocytes. The contents of BODIPY® FL C16 (the fluorescently labeled palmitic acid analogue) entering into the thyrocytes were gradually increased with time extending. Accordingly, the intracellular accumulation of both triglyceride and free fatty acids increased in dose- and time-dependent manners. The effect of palmitic acid stimulation on thyroid hormone synthesis was then determined. Both the mRNA and protein levels of thyroglobulin, sodium iodide symporter, and thyroperoxidase were decreased following palmitic acid stimulation. Consistently, upon palmitic acid stimulation, the secreted thyroglobulin levels in supernatants, 131I uptake, and extracellular thyroperoxidase activity were all decreased in a dose-dependent manner. Our results demonstrated that upon palmitic acid stimulation, the expressions of the key molecules (thyroglobulin, sodium iodide symporter, and thyroperoxidase) were reduced and their activities were suppressed, which might lead to impaired thyroid hormone synthesis.