Liothyronine Administration Research Articles

Changes in Thyroid Metabolites after Liothyronine Administration: A Secondary Analysis of Two Clinical Trials That Incorporated Pharmacokinetic Data.

We examined relationships between thyroid hormone (TH) metabolites in humans by measuring 3,5-diiodothyronine (3,5-T2) and 3-iodothyronamine (3-T1AM) levels after liothyronine administration. In secondary analyses, we measured 3,5-T2 and 3-T1AM concentrations in stored samples from two clinical trials. In 12 healthy volunteers, THs and metabolites were documented for 96 h after a single dose of 50 mcg liothyronine. In 18 patients treated for hypothyroidism, levothyroxine therapy was replaced by daily dosing of 30–45 mcg liothyronine. Analytes were measured prior to the administration of liothyronine weekly for 6 weeks, and then hourly for 8 h after the last liothyronine dose of the study. In the weekly samples from the hypothyroid patients, 3,5-T2 was higher by 0.033 nmol/L with each mcg/dL increase in T4 and 0.24 nmol/L higher with each ng/dL increase in FT4 (p-values = 0.007, 0.0365). In hourly samples after the last study dose of liothyronine, patients with T3 values higher by one ng/dL had 3-T1AM values that were lower by 0.004 nmol/L (p-value = 0.0473); patients with 3,5-T2 higher by one nmol/L had 3-T1AM values higher by 2.45 nmol/L (p-value = 0.0044). The positive correlations between weekly trough levels of 3,5-T2 and T4/FT4 during liothyronine therapy may provide insight into 3,5-T2 production, possibly supporting some production of 3,5-T2 from endogenous T4, but not from exogenous liothyronine. In hourly sampling after liothyronine administration, the negative correlation between T3 levels and 3-T1AM, but positive correlation between 3,5-T2 levels and 3-T1AM could support the hypothesis that 3-T1AM production occurs via 3,5-T2 with negative regulation by T3.

Acute Effects of Liothyronine Administration on Cardiovascular System and Energy Metabolism in Healthy Volunteers.

ContextThe pharmacokinetics of liothyronine causes concerns for cardiovascular toxicity. While the effects of sustained increase in serum T3 concentrations are well described, little is known on the effects of acute changes in T3 concentrations due to rapid action of thyroid hormone.ObjectiveTo assess the clinical relevance of transient increase of T3 levels on cardiovascular system and energy metabolism.SettingDouble-blind, three arms, placebo controlled, cross-over study (ClinicalTrials.gov Identifier: NCT03098433).Study ParticipantsTwelve volunteers (3 females, 9 males), age 27.7 ± 5.1 years.InterventionOral administration of liothyronine 0.7 mcg/kg, equimolar dose of levothyroxine (0.86 mcg/kg), or placebo in three identical study visits. Blood samples for total T3, free T4 were collected at times 0’, 60’ 120’ 180’ 240’. Continuous recording of heart rate, blood pressure, and hemodynamic data was performed using the volume clamp method. Resting energy expenditure was measured by indirect calorimetry. An echocardiogram was performed on each study visit at baseline and after the last blood sampling.Main Outcome MeasuresChanges in cardiovascular function and energy expenditure.ResultsFollowing the administration of liothyronine, serum T3 reached a Cmax of 421 ± 57 ng/dL with an estimated Tmax of 120 ± 26 minutes. No differences between study arms were observed in heart rate, blood pressure, hemodynamics parameters, energy expenditure, and in echocardiogram parameters.ConclusionsThe absence of measurable rapid effects on the cardiovascular system following a high dose of liothyronine supports the rationale to perform long-term studies to assess its safety and effectiveness in patients affected by hypothyroidism.

Late Breaking Abstracts

Late Breaking Abstracts

TRH Stimulation Testing in Older Individuals with Persistent Subclinical Hypothyroidism: A Randomized, Double-Blind, Cross-Over Study of Levothyroxine and Liothyronine Administration

Abstract Background: Subclinical hypothyroidism is common in older individuals. To better understand the underlying physiology, we examined the pituitary-thyroid axis using thyrotropin releasing hormone (TRH) stimulation testing both at baseline and after levothyroxine (LT4) and liothyronine (LT3) supplementation. Methods: We conducted a randomized, double-blind, cross-over study in men and women aged 70 years and over without anti-thyroid peroxidase antibodies with persistent subclinical hypothyroidism, defined as having a TSH level between 4.5 and 19.9 µIU/mL with a normal free thyroxine (FT4) level at two consecutive time points. The primary outcome measures were TSH serum concentration area under the curve (AUC), maximum TSH serum concentration (Cmax), and change in free thyroxine (∆FT4) and total triiodothyronine (∆TT3) levels following TRH stimulation, each measured at three time points: once at baseline and once each after achieving euthyroid TSH levels with the two thyroid preparations. The maximal change in TSH (∆TSH); FT4 and TT3 AUCs; and time to maximal TSH, FT4, and TT3 (Tmax) were also analyzed. Results: Thirteen participants [mean (SD) age 77 (5) years], 4 women and 9 men, completed TRH stimulation testing at baseline and after achieving a TSH level of 0.5-1.5 µIU/mL with each therapy. Baseline mean TSH was 4.84 (1.29) µIU/mL. The mean LT4 dose was 105 (36) µg/day and LT4 dose was 34 (9) µg/day. After TRH stimulation, the mean TSH AUC (0-180) at baseline was 3099.5 (1424.4) µIU*min/mL, and significantly decreased after both LT4 [631.4 (315.2), p<0.001] and LT3 [631.5 (317.3), p<0.001]. There was no difference in TSH AUC (0-180) between LT4 and LT3 treatment arms. Baseline mean TSH Cmax was 27.2 (14.5) µIU/mL and significantly decreased after LT4 [5.5 (3.0), p<0.001] and LT3 [5.4 (2.9), p<0.001], with no difference between the LT4 and LT3 treatment arms. The ∆FT4 was 0.11 (0.07) ng/dL at baseline and decreased significantly on LT3. The ∆TT3 was 0.32 (0.09) ng/mL at baseline and significantly decreased on both LT4 and LT3, with no difference between treatment arms. Conclusions: Older individuals with antibody-negative persistent subclinical hypothyroidism have a heterogeneous TSH response to TRH stimulation. Our data show a significantly diminished response to TRH stimulation after thyroid hormone replacement, and they support the pharmacodynamic equivalence of LT4 and LT3 treatment.

Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along the Human Male Line

Background: Evidence for transgenerational epigenetic inheritance in humans is still controversial, given the requirement to demonstrate persistence of the phenotype across three generations. A previous study showed that exposure of human and mouse embryos to high maternal thyroid hormone (TH) concentrations not only affects the newborns but also subsequently reduces thyrotroph sensitivity to TH during adult life. The current investigation set out to determine if this epigenetic effect is transmitted by humans not exposed in utero to high TH levels to their offspring. Methods: The study took advantage of the high frequency of intrauterine exposure to high TH in the Azorean wild-type population born to healthy mothers with high TH levels because of a heterozygous TH receptor beta gene mutation. Wild-type individuals from F2 (second) and F3 (third) generations were studied, whose parents and grandparents, respectively, were not exposed to high maternal TH levels. Twenty-six individuals belonging to 17 nuclear families were tested for their sensitivity to TH using their thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) after administration of liothyronine (LT3). Results: Preservation of reduced sensitivity to TH (RSTH) was found in descendants of males but not of females with likewise RSTH. In F2, offspring of fathers but not of mothers exposed to high TH levels had RSTH (TRH-stimulated TSH of 6.39 ± 0.63 vs 1.58 ± 0.41 mIU/L [p < 0.001], respectively, after treatment with LT3). In F3, whose parents nor themselves were exposed to TH excess during their fetal life, descendants of fathers and not mothers had RSTH (TRH-stimulated TSH of 4.60 ± 0.61 vs 1.37 ± 0.23 mIU/L [p < 0.01], respectively, after pretreatment with LT3). Conclusions: Since intrauterine total body and gonadal exposure to elevated TH can potentially affect only the F1 and F2, respectively, the results obtained from F3 confirm a true inheritance of an epigenetic effect, scarcely observed in humans. While the exact mechanism underlying the inheritance of this epigenetic effect remains unknown, it correlates with type 3 deiodinase overexpression demonstrated in pituitary glands of mice born to dams with high TH. This enzyme inactivates TH, and is encoded by an imprinted gene with specific parent of origin expression.

SUN-550 Pressor Refractory, Liothyronine Responsive Myxedema Cardiogenic Shock without Myxedema Coma

Introduction: Typical features of severe hypothyroidism include myxedema coma with or without associated cardiogenic shock which manifests as persistent hypotension, hypothermia, and hypoventilation in the setting of other typical features of myxedema coma to include confusion and swelling in the face and extremities. No prior reports of myxedema cardiogenic shock without other features of myxedema coma have been described. Treatment with liothyronine is controversial in the setting of severe hypothyroidism as it is associated with coronary artery disease and worse cardiovascular outcomes. This case report introduces a 66 year old male with subtle findings of myxedema cardiogenic shock without features of myxedema coma who remained on vasopressors until administration of liothyronine. Case Presentation: This is a 66 year old male with a history of hypertension, ischemic cardiomyopathy with an ejection fraction of 35%, right MCA stroke with residual hemiparesis, expressive aphasia, and dementia as well as primary hypothyroidism. Medications included telmisartan 40mg daily, atorvastatin 40mg daily, levothyroxine 0.125mg Monday-Friday, 0.25mg Saturday and Sunday, and valproic acid 250mg three times daily. He was brought to the emergency department after experiencing a 5 minute long witnessed tonic clonic seizure. Initial laboratory studies showed a mild leukocytosis with left shift, elevated lactate, TSH of 136.9, and an undetectable free T4 and valproic acid levels. Urine culture ultimately grew E. coli with negative blood cultures and the remainder of the workup was unremarkable. Admission vital signs showed a blood pressure of 107/70, heart rate 83, respiratory rate 15, and oxygenation 95% on 2L by nasal cannula. Physical exam only revealed a cachectic older male with baseline neurologic deficits to include orientation to person only. There were no features of myxedema or myxedema coma. IV fluids and antibiotics were started as well as 100mg IV hydrocortisone and 0.112 mg IV levothyroxine every 8 hours. The patient developed fluid refractory hypotension requiring ICU transfer for pressor support with vasopressin and norepinephrine without improvement of his MAPs. A bedside echocardiogram completed in the ICU showed a significantly reduced ejection fraction. After 12 hours of inability to maintain MAPs >65, he was started on 10mcg oral liothyronine every 8 hours. Within 4 hours of starting liothyronine pressors were successfully discontinued. Echocardiogram obtained after discontinuation of pressors showed an ejection fraction of 40%. Discussion: Pressor refractory shock with concomitant hypothyroidism should bring up concerns for myxedema cardiogenic shock, even without features of myxedema coma. In this patient with existing cardiomyopathy, liothyronine was successfully used to treat severe hypothyroidism without decrease in the patient’s ejection fraction.

Combination therapy of propranolol, levothyroxine, and liothyronine was effective in a case of severe consumptive hypothyroidism associated with infantile hepatic hemangioma.

.Infantile hepatic hemangioma (IHH) can be accompanied by consumptive hypothyroidism. We report the case of a 4-mo-old boy who showed massive hepatomegaly, peripheral coldness, lethargy, and failure to thrive. An enhanced computed tomography scans demonstrated multiple hemangiomas in both lobes of the liver, and a thyroid function tests showed severe hypothyroidism: TSH 561.5 µIU/mL, free triiodothyronine (fT3) 1.0 pg/mL, and free thyroxine (fT4) < 0.7 ng/dL. IHH gradually regressed following propranolol treatment and fT4 increased to a low normal level (1.0 ng/dL) by high dose replacement of levothyroxine, while fT3 remained very low (< 1.0 pg/mL), even following high doses of levothyroxine; fT3 eventually normalized following the administration of liothyronine. We suggest that treatment strategies should be individualized based on thyroid function, and that the combination therapy of propranolol for anti-tumor treatment and levothyroxine and liothyronine for respective thyroid hormone replacement is effective, particularly in cases of severe consumptive hypothyroidism due to multiple IHHs.

Therapeutic effects of oral liothyronine on aluminum phosphide poisoning as an adjuvant therapy: A clinical trial.

In aluminum phosphide (AlP) poisoning, death is mainly due to cardiovascular failure and refractory acute heart failure. There is a lot of evidence showing thyroid hormones have cardioprotective effects. The purpose of this study was to evaluate the effect of oral liothyronine in the treatment of AlP poisoning. Twenty-four patients from intensive care unit of Baharloo Hospital, Tehran, Iran, were included based on the inclusion and exclusion criteria. They were randomly divided into two parallel groups of 12 cases and 12 controls. Intervention in the case group was administration of 50 µg liothyronine via nasogastric tube after gastric lavage, in the first 6 h of poisoning. In both groups, the routine treatment of AlP poisoning was performed. Blood samples were prepared at the beginning of the study and after 12 h. Patients were followed up till discharge from the hospital or death. The findings demonstrated that oral liothyronine was able to significantly improve systolic blood pressure, arterial blood pH, and total thiol molecules and also could decrease lipid peroxidation, increase catalase activity, and prevent further decline in total antioxidant capacity. Liothyronine administration is effective in controlling AlP poisoning and can improve patients' outcome.

Daily Administration of Short-Acting Liothyronine Is Associated with Significant Triiodothyronine Excursions and Fails to Alter Thyroid-Responsive Parameters.

Although most studies of levothyroxine-liothyronine combination therapy employ once-daily hormone administration, the kinetics of once-daily liothyronine have been studied infrequently. The aim of this study was to document both the peak and trough serum triiodothyronine (T3) levels that occur with once-daily liothyronine administration, along with changes in thyroid-responsive parameters. Participants with hypothyroidism were studied prospectively at an academic institution. Patients were switched from levothyroxine monotherapy to liothyronine monotherapy with 15 μg liothyronine for two weeks, and then continued liothyronine at doses of 30-45 μg for a further four weeks in an open-label, single-arm study. Weekly trough levels of T3 were documented. In addition, hourly T3 concentrations immediately following liothyronine tablet administration were documented for eight hours during the sixth week of therapy. Serum thyrotropin (TSH) and free thyroxine (fT4) concentrations were documented. Biochemical markers, markers of energy metabolism, anthropometric parameters, well-being, and hyperthyroid symptoms were also assessed. Mean serum TSH levels increased from 1.56 ± 0.81 mIU/L at baseline to 5.90 ± 5.74 mIU/L at two weeks and 3.84 ± 3.66 mIU/L at six weeks. Trough T3 levels decreased from 99.5 ± 22.9 to 91.9 ± 40.2 at two weeks and recovered to 96.1 ± 32.2 at six weeks. The peak T3 concentration after dosing of liothyronine during week 6 was 292.8 ± 152.3 ng/dL. fT4 levels fell once levothyroxine was discontinued and plateaued at 0.44 ng/dL at week 4. The sex hormone binding globulin (SHBG) concentration decreased at week 2 (p = 0.002). Hyperthyroid symptoms and SF36-PCS scores increased significantly at weeks 4-5 of liothyronine therapy (p = 0.04-0.005). Preference for liothyronine therapy increased from 6% to 39% over the study period. Once-daily dosing of liothyronine at doses of 30-45 μg did not return serum TSH to the values seen during levothyroxine therapy. There were significant excursions in serum total and free T3 concentrations with once-daily therapy. Trials of combination therapy are likely to be associated with similar excursions, albeit of a lesser magnitude. Only the physical component score of the SF36 questionnaire and hyperthyroid symptoms changed significantly with conversion to liothyronine monotherapy. Sustained release preparations with stable serum T3 profiles may have entirely different outcomes.

Use of liothyronine in preventing electroconvulsive therapy-induced memory impairment: evaluation

Aims and methodTo evaluate the effect of liothyronine administration on the cognitive side-effects of electroconvulsive therapy (ECT), 30 participants with major depressive disorder that were suitable candidates for ECT were randomly allocated to either a liothyronine or a placebo group. Participants in the liothyronine group received a daily 50 μg dose for the whole period of receiving ECT starting the day before ECT, whereas the other group received a placebo. The Hamilton Rating Scale for Depression (HRSD) and the Wechsler Memory Scale – revised (WMS-R) were used for evaluating mood and memory before the first ECT session and after the sixth session (the HRSD was also used after the third session).ResultsThe results indicated that after the sixth ECT session, participants that received liothyronine achieved significantly better scores on the HRSD and WMS-R.Clinical implicationsFurther studies with a larger number of participants, through multicentre research projects, are indicated to obtain adequate data for meta-analysis and systematic review.

Use of the triiodothyronine suppression test for diagnosis of hyperthyroidism in ill cats that have serum concentration of iodothyronines within normal range

Summary Administration of triiodothyronine (liothyronine, 15 μg, q 8 h, for 6 treatments) caused marked decrease in serum concentration of thyroxine (T4) and estimates of free T4 (fT4) concentration in clinically normal cats. A prospective clinical study was done to evaluate the use of this suppression test for diagnosis of hyperthyroidism in cats with clinical signs suggestive of the disease, but lacking high serum concentration of iodothyronines. Twenty-three cats were confirmed as hyperthyroid on the basis of histologic changes in the thyroid gland or clinical improvement in response to administration of methimazole. Mean ± sd serum concentration of T4 (34.3 ± 12.7 to 31.3 ± 11.5 nmol/L) and estimate of fT4 concentration (26.6 ± 6.4 to 25.6 ± 6.9 pmol/L) did not change after administration of liothyronine to these cats. Twenty-three cats were classified as nonhyperthyroid by histologic confirmation of other disease, abnormal results of other diagnostic tests that strongly supported primary disease other than hyperthyroidism, or spontaneous remission of weight loss without treatment. Mean ± sd serum concentration of T4 (27.9 ± 10.3 to 11.7 ± 6.4 nmol/L) and estimate of fT4 concentration (21.7 ± 5.4 to 10.4 ± 4.4 pmol/L) decreased significantly (P &lt; 0.001) in response to administration of liothyronine. Discriminant analysis was used to identify variables from iodothyronine assays (eg, absolute concentration of T4 or absolute estimate of fT4 concentration, or changes of T4 or fT4 concentration) that provided the best diagnostic sensitivity and specificity. The endocrine end points that best differentiated hyperthyroid vs nonhyperthyroid cats were the concentration of T4 or estimate of fT4 concentration in serum obtained after liothyronine administration and predictive values ues calculated from postliothyronine serum concentration of T4 or fT4 and percentage decrease of T4 concentration. Difference in diagnostic sensitivity among endocrine end points compared was not apparent. Use of postliothyronine estimate of fT4 concentration alone or as part of a predictive value improved diagnostic specificity for differentiation of hyperthyroid vs non-hyperthyroid cats (P ≤ 0.081). Results of this study further confirm existence of hyperthyroidism in cats that do not have high serum concentration of iodothyronines. We concluded that the triiodothyronine suppression test is a safe and accurate test for diagnosis of hyperthyroidism in cats with suggestive clinical signs of the disease, but lacking high serum concentration of iodothyronines.

Triiodothyronine (T3) Suppression Test

The purpose of this study was to develop a T3 suppression test to help in the diagnosis of mild hyperthyroidism in cats. We evaluated the response in circulating T4 concentrations to exogenous T3 (liothyronine) administration in 44 clinically normal cats, 77 cats with hyperthyroidism, and 22 cats with nonthyroidal disease. The test was performed by first collecting blood samples for basal serum T4 and T3 determinations, administering liothyronine at an oral dosage of 25 micrograms three times daily for seven doses, and, on the morning of the third day, again collecting serum samples for T4 and T3 determinations 2 to 4 hours after the seventh dose of liothyronine. The mean basal serum concentrations of T4 (53.1 nmol/L) and T3 (1.8 nmol/L) were significantly higher in the cats with hyperthyroidism than in the normal cats (T4 = 25.3 nmol/L, T3 = 1.3 nmol/L) and the cats with nonthyroidal disease (T4 = 29.5 nmol/L, T3 = 1.4 nmol/L); however, there was a great deal of overlap of basal values between the three groups of cats. Of the 77 cats with mild hyperthyroidism, 41 (53%) had serum T4 values and 55 (71%) had T3 values that were within the established normal ranges. After administration of liothyronine, mean serum T4 concentrations fell much more markedly in the normal cats and the cats with nonthyroidal disease than in the hyperthyroid cats.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of Euthyroid Solitary Autonomous Nodule of the Thyroid Gland

The euthyroid autonomous nodule of the thyroid may escape diagnosis if only the usual criterion of less than 50% suppression of radioactive iodine uptake, (RAIU) after administration of liothyronine sodium is employed. This was the case in four patients who had thyrotoxic response to suppressive therapy, which had been given as a result of the improper conclusion that a nodule was hyperplastic, after the RAIU had fallen. We studied 95 patients with a solitary functioning nodule and found ten euthyroid persons (11 tests) in whom scintiscans showed persistent function in the nodule in spite of suppression of the RAIU by more than 50%. A thyrotropin-releasing hormone test demonstrated lack of thyroid-stimulating hormone responsiveness after administration of liothyronine, proving adequacy of the suppressive dose. Diagnosis of an autonomous nodule should not be excluded unless a scintiscan reveals that its function, in distinction to the rest of the gland, is curtailed by adequate suppression.

Triiodothyronine-Induced Thyrotoxicosis in Ophthalmic Graves Disease

A euthyroid woman with ophthalmic Graves disease developed endogenous hyperthyroidism coincident with T3 suppression test. There is a putative role of liothyronine administration in precipitating or activating hyperthyroidism. Aberrancies in T3 suppression testing in graves disease occur.

The time course of changes in TRH responsiveness in man following a single dose of liothyronine

The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH, 100 μg i.v.) was evaluated prior to and at various times following the oral administration of single doses of liothyronine (100 μg) given at weekly intervals. The TSH response to TRH was mildly depressed when TRH was given 1 hr after liothyronine administration when the serum triiodothyronine (T 3) concentration was strikingly elevated, was markedly reduced 16 and 24 hr after liothyronine, was essentially abolished 3 days after liothyronine when the serum T 3 concentration was normal, and was normal 7 days after liothyronine administration. These findings suggest that the more prolonged suppression of TRH responsiveness, observed following the withdrawal of long-term excess endogenous or exogenous thyroid hormones, cannot be ascribed to the intrinsic duration of action of the hormone present at the time of withdrawal, but rather to the prolonged extent of the suppression itself.