A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats-an Investigational Therapy for ARDS.

Acute respiratory distress syndrome (ARDS) is a severe, life-threatening form of respiratory failure characterized by pulmonary edema, inflammation, and hypoxemia due to reduced alveolar fluid clearance (AFC). Alveolar fluid clearance is required for recovery and effective gas exchange, and higher rates of AFC are associated with reduced mortality. Thyroid hormones play multiple roles in lung function, and L-3,5,3'-triiodothyronine (T3) has multiple effects on lung alveolar type II cells. T3 enhances AFC in normal adult rat lungs when administered intramuscularly and in normal or hypoxia-injured lungs when given intratracheally. The safety of a commercially available formulation of liothyronine sodium (synthetic T3) administered intratracheally was assessed in an Investigational New Drug Application-enabling toxicology study in healthy rats. Instillation of the commercial formulation of T3 without modification rapidly caused tracheal injury and often mortality. Intratracheal instillation of T3 that was reformulated and brought to a neutral pH at the maximum feasible dose of 2.73 µg T3 in 300 µl for 5 consecutive days had no clinically relevant T3-related adverse clinical, histopathologic, or clinical pathology findings. There were no unscheduled deaths that could be attributed to the reformulated T3 or control articles, no differences in the lung weights, and no macroscopic or microscopic findings considered to be related to treatment with T3. This preclinical safety study has paved the way for a phase I/II study to determine the safety and tolerability of a T3 formulation delivered into the lungs of patients with ARDS, including coronavirus disease 2019-associated ARDS, and to measure the effect on extravascular lung water in these patients. SIGNIFICANCE STATEMENT: There is growing interest in treating lung disease with thyroid hormone [triiodothyronine (T3)] in pulmonary edema and acute respiratory distress syndrome (ARDS). However, there is not any published experience on the impact of direct administration of T3 into the lung. An essential step is to determine the safety of multiple doses of T3 administered in a relevant animal species. This study enabled Food and Drug Administration approval of a phase I/II clinical trial of T3 instillation in patients with ARDS, including coronavirus disease 2019-associated ARDS (T3-ARDS ClinicalTrials.gov Identifier NCT04115514).

Delayed diagnosis of T3 supplementation in a bodybuilder presenting with tachycardia and features of sepsis.

A 25-year-old man presented generally unwell to the emergency department. Initial assessment identified systemic inflammatory response syndrome markers with an insect bite as a potential source of infection and he was treated for presumed sepsis. Tachycardia persisted and baseline thyroid function testing showed undetectable free thyroxine and thyroid-stimulating hormone (TSH), prompting further endocrine investigation. Triiodothyronine (T3) was markedly raised with normal TSH receptor antibodies, and the patient later confessed to supplementary testosterone and T3 use as part of bodybuilding activities. Following counselling, thyroid function normalised and the patient returned to his usual health. This case describes the diagnostic work up in a case of persistent tachycardia caused by T3 supplementation, demonstrating the potential for endocrine supplementation by bodybuilders which may be poorly understood and recognised by clinicians. T3 supplementation should be considered and a thorough drug history obtained in bodybuilders presenting with symptoms of thyrotoxicosis and deranged thyroid function tests.

Combined administration of docosahexaenoic acid and thyroid hormone synergistically enhances rat liver levels of resolvins RvD1 and RvD2.

Supplementation with omega-3 fatty acids or thyroid hormone (T3) exhibit negative effects on inflammatory reactions in experimental animals. The aim of this work was to assess the hypothesis that docosahexaenoic acid (DHA) plus T3 co-administration enhances liver resolvin (Rv) levels as inflammation resolution mediators. Combined DHA (daily doses of 300 mg/kg for 3 consecutive days)-T3 (0.05 mg/kg at the fourth day) administration significantly increased the content of hepatic RvD1 and RvD2, without changes in that of RvE1 and RvE2, an effect that exhibits synergy when compared to the separate DHA and T3 treatments. Under these conditions, liver DHA levels increased by DHA administration were diminished when combined with T3 (p < 0.05), suggesting enhancement in resolvin D biosynthesis in extrahepatic tissues. It is concluded that co-administration of DHA and T3 rises the capacity of the liver for inflammation resolution by augmenting RvD1(2) availability, which represents an important protocol in hepatoprotection in the clinical setting.

Thyroxine-induced periodic paralysis: a rare complication of nutritional supplements.

The consumption of daily nutritional supplements has risen dramatically all over the world. Many people believe that dietary supplements, if not useful, are at least safe to fulfil small dietary gaps. Many nutritional supplements have not been approved by Federal Drug Administration due to their unregulated active ingredients, but they are available as over the counter. One of the active ingredients, exogenous triiodothyronine (T3), has been reported in dietary supplements. We present a case of sudden onset of tetraparesis. Laboratory workup showed hypokalaemia, low thyroid-stimulating hormone and thyroxine (T4) but normal T3 and thyroglobulin levels. The radioiodine uptake scan also showed reduced uptake. After aggressive serum potassium correction and stopping supplements, his condition got improved. So the suspicion of exogenous T3-induced thyrotoxic periodic paralysis was confirmed.

Muscle mania: the quest for the perfect body.

We describe the case of a young man with repeated hospital presentations for a variety of symptoms related to excessive bodybuilding and associated behaviours. He presented to our department (radiology) with right arm pain and loss of function. Ultrasound showed complete triceps rupture, rare in young patients and multiple cystic areas within the muscles of the arm. MRI revealed these to be multiple proteinaceous lesions within the muscle bellies and the possibility of self-innoculation was raised by the reporting radiologist. The patient subsequently admitted to injecting coconut oil to improve muscle contour lost secondary to injury. A review of his hospital presentations was then made and revealed further concerning practices performed by the patient to enhance his muscular appearance.

I lost weight, but I became weak and cannot walk--a case of nutraceutical (T3)-induced thyrotoxic periodic paralysis.

Thyrotoxic periodic paralysis (TPP) is a rare reversible cause of paralysis and cramping. TPP is usually precipitated by common causes of thyrotoxicosis such as Grave disease or multinodular goiter. TPP precipitated by exogenous triiodothyronine (T3) intake is an extremely rare occurrence with only 3 cases reported to date. We now report a 24-year-old healthy manual laborer who developed quadriparesis during a period of rest after heavy exertion and carbohydrate intake. He had severe hypokalemia (potassium level 1.9 mmole/L). Correction of his hypokalemia reversed the paralysis without rebound hyperkalemia. After a detailed history review, he reported that he had been consuming nutraceuticals containing T3 for 1 month to lose weight, and laboratory studies confirmed factitious T3 toxicosis. There was no evidence of renal or gastrointestinal potassium wasting. This episode of TPP was the first manifestation of thyrotoxicosis in this patient, and avoidance of T3 intake prevented more episodes.

Thyroxine and triiodothyronine content in commercially available thyroid health supplements.

BACKGROUND: As defined by the Dietary Supplement Health and Education Act 1997, such substances as herbs and dietary supplements fall under general Food and Drug Administration supervision but have not been closely regulated to date. We examined the thyroid hormone content in readily available dietary health supplements marketed for "thyroid support." METHODS: Ten commercially available thyroid dietary supplements were purchased. Thyroid supplements were dissolved in 10 mL of acetonitrile and water with 0.1% trifloroacetic acid and analyzed using high-performance liquid chromatography for the presence of both thyroxine (T4) and triiodothyronine (T3) using levothyroxine and liothyronine as a positive controls and standards. RESULTS: The amount of T4 and T3 was measured separately for each supplement sample. Nine out of 10 supplements revealed a detectable amount of T3 (1.3-25.4 µg/tablet) and 5 of 10 contained T4 (5.77-22.9 µg/tablet). Taken at the recommended dose, 5 supplements delivered T3 quantities of greater than 10 µg/day, and 4 delivered T4 quantities ranging from 8.57 to 91.6 µg/day. CONCLUSIONS: The majority of dietary thyroid supplements studied contained clinically relevant amounts of T4 and T3, some of which exceeded common treatment doses for hypothyroidism. These amounts of thyroid hormone, found in easily accessible dietary supplements, potentially expose patients to the risk of alterations in thyroid levels even to the point of developing iatrogenic thyrotoxicosis. The current study results emphasize the importance of patient and provider education regarding the use of dietary supplements and highlight the need for greater regulation of these products, which hold potential danger to public health.

Cardiac specific effects of thyroid hormone analogues.

There is significant interest in development of thyroid hormone analogues to harness specific properties as therapeutic agents for a variety of clinical indications including obesity, hypercholesterolemia, heart failure, and thyrotoxicosis. To date, most analogues have been designed to target liver specific effects, which can promote weight loss and lipid lowering through either tissue specific uptake or thyroid hormone receptor (TR) ß isoform selectivity at the same time minimizing the unwanted cardiac and bone effects. We have developed a molecular biomarker assay to study the induction of the transcription of the cardiac specific α-myosin heavy chain (MHC) gene as a more sensitive and specific measure of thyroid hormone action on cardiac myocytes. We tested 5 TRß and 1 TRα selective agonists as well as 2 putative TR antagonists in our α-MHC hnRNA assay. Using reverse transcription and polymerase chain reaction, we measured the induction of the α-MHC primary transcript in response to administration of drug. The TRα and only 2 of the TRß agonists were highly active, when compared to the effect of T3, at the level of the cardiac myocyte. In addition, our data suggests that the reason that the antagonist NH-3 is not able to block the T3-mediated induction of α-MHC is that it does not get transported into the cardiac myocyte. Our data suggest that this assay will be useful in preclinical studies of the potential cardiac specific effects of thyroid hormone analogues and that predictions of function based on structure are not necessarily accurate or complete.

Tiratricol-induced periodic paralysis: a review of nutraceuticals affecting thyroid function.

OBJECTIVE: To review the potential adverse effects of thyroid hormone-based nutraceuticals and describe a case of thyrotoxic periodic paralysis (TPP) after abuse of a dietary supplement containing 3,5,3'-triiodothyroacetic acid (tiratricol). METHODS: We review the literature on potential dangers and therapeutic misadventures of thyroid hormone-based nutraceuticals and present the clinical, laboratory, and radiologic data of a bodybuilder in whom hypokalemic TPP developed after use of "Triax Metabolic Accelerator". RESULTS: A 23-year-old white man developed lower extremity paralysis, diaphoresis, and palpitations in the setting of low serum potassium levels. Laboratory results showed suppressed thyroid-stimulating hormone, low levels of free and total thyroxine, low total triiodothyronine level, and very low 24-hour radioiodine uptake. The patient ultimately admitted to taking a supplement containing tiratricol for approximately 2 months, and hypokalemic TPP was diagnosed. He was treated with potassium supplementation and a ß-adrenergic blocking agent, which completely resolved his symptoms. Results of thyroid function tests normalized or approached normal 1 week after hospitalization, and future use of dietary supplements was strongly discouraged. Despite 2 warnings by the US Food and Drug Administration, products containing tiratricol are still available for sale on the Internet. CONCLUSION: This report illustrates both an unusual adverse effect of a nutraceutical containing tiratricol and the importance of educating our patients about the risks versus benefits of using these widely available but loosely regulated products.

Factitious thyrotoxicosis induced by mesotherapy: a case report.

CONTEXT: Mesotherapy consists of cutaneous injections of a mixture of compounds and has recently been used for cosmetic purposes to reduce local fat and cellulite. To date, several reports have described only local adverse events related to this therapy. We describe the first report of a female patient who developed thyrotoxicosis due to cosmetic mesotherapy with triiodothyroacetic acid in its formulation. Apart from mechanical rupture of the epidermal barrier, a disturbance of type III deiodinase activity or skin fibroblast paracrine function and vascular alterations related to simultaneously injected vasoactive compounds were observed. These findings could be related to thyroid hormone metabolite absorption and systemic consequences in the reported case. CONCLUSION: We describe factitious thyrotoxicosis induced by mesotherapy, to raise awareness of a systemic adverse effect resulting from this widespread cosmetic practice.

Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Antidepressant treatments that achieve a higher remission rate than those currently available are urgently needed. The thyroid hormone triiodothyronine may potentiate antidepressant effects. OBJECTIVE: To determine the antidepressant efficacy and safety of liothyronine sodium (triiodothyronine) when administered concurrently with the selective serotonin reuptake inhibitor sertraline hydrochloride to patients with major depressive disorder. DESIGN: Double-blind, randomized, 8-week, placebo-controlled trial. SETTING: Outpatient referral centers. PATIENTS: A total of 124 adult outpatients meeting unmodified DSM-IV criteria for major depressive disorder without psychotic features. INTERVENTIONS: Patients were randomized to receive sertraline hydrochloride (50 mg/d for 1 week; 100 mg/d thereafter) plus liothyronine sodium (20-25 microg/d for 1 week; 40-50 microg/d thereafter) or sertraline plus placebo for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was categorical response to treatment (> or =50% decrease in scores on the 21-item Hamilton Rating Scale for Depression from baseline to study end point). Remission rate (final Hamilton Rating Scale for Depression score, < or =6) was a secondary outcome measure. RESULTS: Intent-to-treat Hamilton Rating Scale for Depression response rates were 70% and 50% in the sertraline-liothyronine and sertraline-placebo groups, respectively (P = .02; odds ratio, 2.93; 95% confidence interval, 1.23-7.35); remission rates were 58% with sertraline-liothyronine and 38% with sertraline-placebo (P = .02; odds ratio, 2.69; 95% confidence interval, 1.16-6.49). Baseline T(3) values were lower in patients treated with sertraline-liothyronine who had remissions than in those without remissions (t(48) = 3.36; P<.002). Among patients treated with sertraline-liothyronine, remission was associated with a significant decrease in serum thyrotropin values (F(1,73) = 4.00; P<.05). There were no significant effects of liothyronine supplementation on frequency of adverse effects. CONCLUSIONS: These results demonstrate enhancement of the antidepressant effect of sertraline by concurrent treatment with liothyronine without a significant increase in adverse effects. The antidepressant effect of liothyronine may be directly linked to thyroid function.

Hypothyroidism in the elderly: pathophysiology, diagnosis and treatment.

Some degree of hypothyroidism is common in the elderly. It affects 5-20% of women and 3-8% of men. The occurrence varies with genetics with a high prevalence in Caucasians, and the disease is more common in populations with a high iodine intake. The common causes of hypothyroidism are autoimmune destruction of the thyroid gland and previous thyroid surgery or radioiodine therapy. Various types of medication, including amiodarone, cytokines and lithium, often induce hypothyroidism. Symptoms may be atypical and measurement of serum thyroid-stimulating hormone (TSH) levels should be part of biochemical testing for undiagnosed medical conditions in elderly subjects. The finding of an elevated serum TSH level should be confirmed by repeated testing and supplemented with measurements of serum levels of thyroxine (T(4)) and thyroid peroxidase antibodies to verify, quantify and subclassify the abnormality. The recommended and appropriate replacement therapy for hypothyroidism is levothyroxine sodium. The initial replacement dose should be low if heart disease is suspected. Because of the long half-life of levothyroxine sodium small dosage adjustments may be performed by adding or withdrawing a tablet once or twice weekly. Levothyroxine sodium is only partly absorbed after oral ingestion, and food, minerals, drugs and tablet composition influence absorption. Studies performed a few years ago suggested that a combination of levothyroxine sodium and liothyronine may improve clinical results, but recent more comprehensive studies have not supported this hypothesis. Accordingly, liothyronine replacement is not documented to be of benefit. If liothyronine is added to replacement, the liothyronine dose should be kept low, within the physiological range and, preferably be administered twice daily. Thyroid hormone therapy has no beneficial effect above placebo in elderly individuals with normal serum TSH levels and T(4) levels. The major risk of levothyroxine sodium therapy is over-replacement, with anxiety, muscle wasting, osteoporosis and atrial fibrillation as adverse effects. Subclinical hypothyroidism with elevated serum TSH levels but T(4) levels within the laboratory reference range is a mild variant of overt hypothyroidism. Patients with subclinical hypothyroidism should be informed about the disease and offered the possibility of replacement. Only some patients treated for subclinical hypothyroidism will feel better after therapy. In elderly patients on replacement therapy, care should include estimation of serum TSH level once or twice a year, with small dosage adjustments of levothyroxine sodium to keep serum TSH level within the normal range.

A report of hypothyroidism induced by an over-the-counter fat loss supplement (Tiratricol).

Prior to presentation, two physically fit adults, a 39-year-old male and 40-year-old female, began supplementation with an over-the-counter thyroid preparation marketed as a metabolic accelerator and fat loss aid, tiratricol. Both participants took the supplement for 5 weeks (3000-4000 mcg/d) and 3 weeks (6000 mcg/d), respectively. At presentation, both complained of lethargy, loss of appetite, and muscle weakness. Upon initial laboratory evaluation, results revealed low thyroid stimulating hormone with profoundly elevated T3 values in both patients. After an extensive review of the literature, the cause of the problem was found to be the nutritional supplement they consumed contained tiratricol. After discontinuation of the supplement, thyroid levels slowly returned to baseline 40 days and 5 months later, respectively.

Symptomatic hyperthyroidism in a patient taking the dietary supplement tiratricol.

An 87-year-old woman was referred for evaluation of nervousness, tremor, insomnia, and fatigue of 2 months' duration. Initial laboratory evaluation revealed a suppressed thyrotropin level and an elevated triiodothyronine level. A review of her medications revealed that she had started taking several dietary supplements at the recommendation of her chiropractor before the onset of symptoms. One of these was tiratricol (3,5,3'-triiodothyroacetic acid or Triac), a substance sold as a dietary supplement despite classification as a drug by the Food and Drug Administration. Tiratricol has weak thyromimetic effects, can inhibit pituitary thyrotropin secretion, and in higher doses can significantly stimulate metabolism. Such was the case with this patient who presented with signs, symptoms, and biochemical evidence of hyperthyroidism that promptly resolved after discontinuation of tiratricol therapy. To our knowledge, this is the first reported case of documented thyrotoxicosis secondary to tiratricol use. Because tiratricol is still available for sale on several Internet sites, this case emphasizes the importance of inquiring about the use of dietary supplements in all patients. The availability of such products on the Internet increases the already complex task of monitoring patients' use of dietary supplements.

The medical treatment of non-toxic goiter: several questions remain.

In this review it is concluded that thyroxine (T4), triiodothyronine (T3) and iodine (KI), singly or in combination, are all effective in reducing the goiter size, but there is insufficient evidence to prove which is the best (possibly the combination of T4 + KI?). Higher doses are more effective than smaller, but also lead to more side-effects. Thus, the optimal dose has yet to be found. The suppression of the pituitary thyroid axis plays a major role in the treatment of non-toxic goiter, but it is not definite that this is the only mechanism responsible for the beneficial effect of the agents mentioned. In view of the lack of better evidence, it is simply suggested that non-toxic goiters in young persons should be initially treated aggressively with 200 micrograms of T4/day or more for some months. If the goiter shrinks then the dose should be gradually decreased. If the goiter persists, it is futile to continue with large doses for more than 6-12 months. One may continue with smaller doses, maintaining the serum TSH in the low-normal range. The treatment of benign thyroid nodules with thyroxine is controversial. Probably thyroxine is beneficial in about a third of the cases. For both non-toxic goiters and nodules, autonomy should be excluded before starting thyroxine treatment, and old age, cardiac disease and a poor general condition are contraindications.

Vitamin E protects against thyroxine-induced acceleration of lipid peroxidation in cardiac and skeletal muscles in rats.

To determine whether vitamin E protects against thyroxine-induced oxidative stress in heart and soleus (slow oxidative) muscles, lipid peroxide (thiobarbituric acid-reactive substances) and antioxidant enzymes were measured in those tissues of hyperthyroid rats supplemented with vitamin E. The rats were rendered hyperthyroid by the administration of L-thyroxine in their drinking water. In experiment (EXPT) I, 30 mg/kg/dose of alpha-tocopheryl acetate was administered to the vitamin E-treated group. In EXPT II, the rats were fed a diet containing either less than 1 IU/kg (deficient diet), 20 IU/kg (control E diet), or 500 IU/kg (high E diet) of vitamin E and hyperthyroidism was induced. In EXPT I, hyperthyroidism induced an increase in oxidative enzymes, mitochondrial superoxide dismutase and lipid peroxide level, and a decrease in cytosolic superoxide dismutase, glutathione peroxidase and catalase in both tissues. Vitamin E treatment inhibited the increase in lipid peroxide level totally in the heart and partially in the soleus, with minimal changes in the other biochemical indices studied. In EXPT II, the lipid peroxide level was markedly increased in both tissues of the vitamin E-deficient group, and decreased in those of the group fed high E diet. There were some adaptive changes in the levels of cytosolic superoxide dismutase, glutathione peroxidase, and catalase in response to vitamin E deficiency, whereas neither oxidative enzymes nor mitochondrial superoxide dismutase were altered. These results suggest that vitamin E protects against lipid peroxidation in hyperthyroid heart and skeletal muscle independently of the changes in oxidative enzymes and antioxidant enzymes.