LT4 Therapy Research Articles

Combined LT3 and LT4 therapy for precision medicine: easier with TTCombo system.

Hypothyroidism is typically treated with levothyroxine monotherapy. However, despite normalized serum thyroid-stimulating hormone levels, 5-10% of patients continue to experience persistent symptoms, raising concerns about the adequacy of thyroxine monotherapy. Combination therapy with levothyroxine and liothyronine has been proposed as an alternative, but it presents practical challenges, including dosing complexity, the short half-life of triiodothyronine, increased monitoring requirements, and potential adverse effects. Moreover, there is no clear consensus within the medical community regarding the superiority of combination therapy over levothyroxine monotherapy, although some studies indicate potential benefits in specific patient populations. Genetic factors, such as polymorphisms in the DIO2 gene, may influence individual responses to therapy, further complicating treatment. To address the limitations of combination therapy, we propose a novel approach: TTCombo. This digital health technology delivers personalized doses of levothyroxine and liothyronine, improving treatment adherence and optimizing outcomes. By providing individualized, physiologically tailored hormone replacement, TTCombo has the potential to revolutionize hypothyroidism management and enhance patient quality of life.

7276 Hypothyroid Patients With Gastric Diseases In Treatment With Liquid L-T4: An Observational Study

Abstract Disclosure: P. Fallahi: None. F. Ragusa: None. A. Patrizio: None. V. Mazzi: None. C. Botrini: None. G. Elia: None. E. Balestri: None. E. Barozzi: None. L. Rugani: None. E. Palmisano: None. M. Cosenza: None. G. Varricchi: None. S. Ulisse: None. S. Benvenga: None. S. Ferrari: None. A. Antonelli: None. We have conducted an observational and retrospective study, by enrolling patients with hypothyroidism and gastric diseases in treatment with liquid L-T4 (L-LT4) or tablet L-T4 (T-LT4). The aim of the study was to compare the stability of TSH in these patients. Eighty-four patients were in treatment with L-LT4, and 120 patients with T-LT4; all of them assumed L-T4 30 minutes before breakfast. The patients were affected by different types of gastric disease: a) in T-LT4 group: 74 chronic gastritis (CG); 4 gastrectomy for gastric cancer (GTx); 42 gastro-plastics (GP); b) in L-LT4 group: 60 CG; 3 GTx; 21 GP (p>0.05). In the T-LT4 group 66% of the patients were chronically treated with PPI, against 51% in the L-LT4 group (p>0.05). The frequency of Helicobacter Pylori infection was 17% in both T-LT4 and L-LT4 groups. The gender distribution, mean age and body weight were similar in the two groups (p>0.05). The mean L-T4 dosage in the T-LT4 group at the basal evaluation was 1.22+/-0.27 μg/kg/die, in the L-LT4 group was 1.36+/-0.22 μg/kg/die (p>0.05). At the basal evaluation the prevalence of patients with a TSH > 3.5 μIU/mL in the T-LT4 group was 36%, whereas in the L-LT4 group was of 46% (p<0.05). After adjustment of the dosage of the LT-4 therapy, the patients were re-evaluated with an interval range of 5-9 months, for 4 times, during an overall period ranging from 23 to 31 months. At the first re-evaluation, the prevalence of patients with a TSH>3.5 μIU/mL was 13% in both groups. At the second re-evaluation, the prevalence of patients with a TSH > 3.5 μIU/mL in the T-LT4 group was 26%, and of 13% in the L-LT4 group (p<0.05). At the third re-evaluation, the prevalence of patients with TSH>3.5 μIU/mL in the T-LT4 group was 19%, and of 9% in the L-LT4 group (p=0.05). At the fourth and last re-evaluation, the prevalence of patients with a TSH > 3.5 μIU/mL in the T-LT4 group was 18%, and of 5% in the L-LT4 group (p<0.05). Mean FT4 and FT3 circulating levels were not significantly different in the two group at each visit. These data highlight a more stable control of TSH levels in hypothyroid patients with gastric disorders in the long-term follow-up, by using a liquid L-T4 formulation therapy with respect to a tablet L-T4. Presentation: 6/3/2024

The Natural Course of Newborns with Transient Congenital Hypothyroidism.

The incidence of congenital hypothyroidism (CH) has increased worldwide over the last decades mainly due to the lowering of screening thresholds, resulting in an increased identification of newborns with transient CH. Several studies reported the prevalence and the predictive parameters of transient CH but reports on the long-term outcome are rare. This study aimed to assess the long-term course of neonates with transient CH. Neonates diagnosed with transient and permanent CH between the years 1998 to 2018 at the Pediatric Endocrine Institute of Ha'Emek Medical Center were enrolled in the study. Data were retrieved retrospectively from medical files. Included in the study were 76 newborns (45M,59%) with transient CH and 53 (25M,47%) with permanent CH. The major cause of transient CH was prematurity (29%) and subclinical hypothyroidism (30%). During retrospective follow-ups of up to 23 years, reinitiation of LT4 therapy was not required apart from four patients with underlying syndromic etiologies. Neurodevelopmental impairment occurred in 16% of children with transient CH compared with 29.4% in the permanent CH group. Transient CH is frequent among preterm infants but is limited to infancy. SCH frequently presents as overt hypothyroidism at birth but in most cases the requirement for LT4 supplemental therapy is limited to the first years of life, suggesting that long-term follow-up of thyroid function tests may be unnecessary for non-syndromic children. The high rate of neurodevelopmental impairment in newborns with transient CH emphasizes the need for neurodevelopmental monitoring in these patients.

Analysis of factors influencing the dose of levothyroxine treatment in adequately controlled hypothyroid patients of different etiologies

ObjectiveThe mainstay therapy of hypothyroidism is levothyroxine (LT4). In most cases lifelong treatment is warranted, therefore, choosing adequate doses are of paramount significance. The purpose of this study was to assess several factors that have been proposed to influence LT4 therapy including etiology of hypothyroidism, gender, age, bodyweight, BMI, concomitant drug use, disease severity and time since diagnosis in patients with stable, adequately controlled hypothyroidism. MethodsIn this cross-sectional study we analysed past medical history, anthropometric data and biochemical parameters reflecting thyroid function of patients with chronic hypothyroidism who were adequately treated (TSH levels in normal range) with LT4 for at least 6 months. Potential predictors of LT4 requirement were evaluated using uni- and multivariate linear modelling. Results191 individuals were enrolled in this study, who were divided into autoimmune (n=147) and post-surgery (n=44) groups. Mean age, time since diagnosis and LT4 dose (1.3 versus 1.1 mcg/kgBW) were significantly lower in the autoimmune group. In the post-surgery group age was the only significant (p=0.016) predictor of LT4 dose. In the autoimmune group BMI (p=0.001), time since diagnosis (p=0.023), as well as their interaction (p=0.012) turned out to be significant predictors of LT4 requirement. ConclusionsOur results implicate the necessity of differentiating between etiologies of hypothyroidism when starting or changing thyroxine replacement therapy. Patient in both groups required significantly lower doses of LT4 replacement, than previous reports suggest, to maintain stable euthyroidism. Distinctly different factors predicted hormone requirement in the two study groups.

Thyroidectomized patients on LT-4 therapy with advanced medullary thyroid carcinoma treated with selpercatinib show peculiar variations of thyroid function tests

Thyroidectomized patients on LT-4 therapy with advanced medullary thyroid carcinoma treated with selpercatinib show peculiar variations of thyroid function tests

Diagnosis of Thyroid Nodules in Children and Adolescents with Subclinical Hypothyroidism and Their Outcomes after Early Thyroxine Treatment-A Longitudinal Study.

Pediatric thyroid nodules (TNs) present a higher malignancy rate compared to adults. We sought to diagnose the frequency and characteristics of TNs in children and adolescents with subclinical hypothyroidism (SH) and their outcomes after levothyroxine (LT4) therapy. A total of 256 children with TNs and SH were followed every semester from 2006 to 2018. All patients were treated with LT4. Clinical and radiologic findings, such as the size and texture of the nodules, were documented. Analysis included one-way ANOVA, Kruskal-Wallis, Chi-square, and Fisher's exact tests. After initial LT4 therapy, TNs disappeared in 85.5% and did not reappear throughout follow-up. In 14.5%, TNs remained the same or increased in size, but they decreased after subsequent LT4 administration with an increased dose. Thyroid disease family history (FHTD) was documented in 77.0%. In total, 64.5% developed a goiter, 46.0% exhibited thyroid heterogeneity on ultrasound, 23.4% had positive Anti-Tg, and 25.4% had positive anti-TPO autoantibodies. Our findings support the possible premise that early pharmacologic intervention with LT4 may be beneficial in children and adolescents with TNs and SH. The increased frequency of FHTD, goiter, thyroid heterogeneity, and Hashimoto in our patients emphasizes that thyroid ultrasounds may be warranted in children and adolescents with these characteristics in order to rule out the presence of TNs.

Effects of levothyroxine treatment on serum thyroid hormone levels in euthyroid patients with papillary thyroid microcarcinoma

We recently reported that lowering serum thyroid stimulating hormone (TSH) levels with levothyroxine (LT4) may be associated with decreased tumor growth during active surveillance (AS) of papillary thyroid microcarcinoma (PTMC). Most clinicians might believe that low serum TSH levels following LT4 therapy indicate subclinical thyrotoxicosis. This study aimed to evaluate the effects of TSH-lowering therapy using small doses of LT4 on serum thyroid hormone levels in euthyroid patients with PTMC. We retrospectively analyzed data from 28 patients with low-risk PTMC who had undergone measurement of both FT4 and FT3 consecutively and received LT4 to achieve serum TSH levels of < 0.5 μIU/mL and > 0.05 μIU/mL between January 2012 and May 2018 at Kuma Hospital. There were 24 females and 4 males (aged 55 ± 12 years [mean ± standard deviation {SD}]). We compared their serum FT4 and FT3 levels at diagnosis with those following TSH-lowering therapy with LT4. Following LT4 therapy, the patients’ serum FT4 levels were significantly increased (P < 0.001). Serum FT3 levels, however, remained unchanged (P = 0.10). The proportions of patients whose FT3 levels increased by more than 1 SD, remained unchanged, and decreased by more than 1 SD were 11 %, 57 %, and 32 %, respectively. Our study indicated that mild TSH-lowering doses of LT4 for euthyroid patients with PTMC increased serum FT4 levels but did not increase serum FT3 levels in most cases, suggesting that a mild TSH-lowering therapy for euthyroid patients may not necessarily cause thyrotoxicosis.

Impact of hormone replacement therapy on cardiovascular risk in patients with hypothyroidism: a systematic review

Hypothyroidism, which is developed in 4-10 % of the population, and subclinical hypothyroidism found in more than 10 % of people which are highly associated with cardiovascular pathophysiology at some level. Hypothyroidism, which is the most frequent endocrine disorder with a lack of enough thyroid hormones, presents a wide range of cardiovascular complications, including coronary artery disease, heart failure, and dyslipidemia. Thyroid hormone replacement therapy, particularly levothyroxine (LT4), continues to be the central management of hypothyroidism, which aims to restore euthyroidism and other cardiac comorbidities as well as relieving symptoms. Nonetheless, the complex interworking of thyroid function and cardiovascular health requires a detailed clarification of the processes associated with disease development and drug therapy. Hypothyroidism triggers a chain of cardiovascular alterations such as aberrant lipid metabolism, endothelial dysfunction, and lessened cardiac contractility primarily by lowering the thyroid hormone level. Besides, these modifications eventually lead to raised rates of atherosclerosis, myocardial infarction, and heart failure. LT4 replacement therapy achieves normalization of hyperthyroidism with the replacement of thyroid hormone deficiency, which restores the cardiovascular system to normal by doing so. LT4 modulates lipid metabolism, improves endothelial function, and stimulates myocardial contractility via several different mechanisms. LT4 therapy acts on systemic inflammation and oxidation to accentuate the protective effects of the cardiovascular system. Apart from this, there is an increasing awareness about the use of new thyroid hormone formulations, like LH4, in the therapy of hypothyroidism. LH4, the thyromimetic compound, demonstrated a similar binding affinity at the thyroid hormone receptor as T3 (triiodothyronine) but with better tissue selectivity and more metabolic stability. Clinical trials have proven the potency of LH4 in lowering symptoms of hypothyroidism, for example, fatigue, weight gain which are leading cause of cardiovascular disorders. LH4 administration has been safe for up to six months, and only mild adverse effects have been reported when it is used more than a year.

One sip of water with LT-4 supplementation—a key to euthyroidism in Hashimoto’s thyroiditis

PurposeRecommended pharmacotherapy for hypothyroidism in Hashimoto’s thyroiditis (HT) is oral supplementation with levothyroxine (LT-4). However, serum thyrotropin (TSH) levels within normal range are not consistently achieved with LT-4 medication.Patients and methodsWe report on 35 HT patients with LT-4 therapy in this retrospective evaluation. In general, we recommend that a maximum of two sips of water, which would then amount to < 50 mL, be ingested at the same time as LT-4. We report on follow up examinations measuring TSH and antibodies against thyroid peroxidase (TPOAb) after 6 months to five years.ResultsAfter median time of 643 days (range 98-1825) we found in 35 HT patients a statistical significant reduction of serum TSH (p < 0.001) and TPOAb (p = 0.006). The patients median body weight was 71 kg (range 48–98) and a daily LT-4 dosage was used with median 69.1 µg (range 25–150). This results in a daily LT-4 dose of median 1.01 µg/kg bodyweight (range 0.3–2.3).ConclusionsThe reduction of water ingestion to a maximum of two sips, which is <50 mL, combined with LT-4 supplementation helps to achieve euthyroidism in HT. In addition, it reduces the L-T4 medication dosage needed to lower TSH serum levels and decreases TPO antibodies in HT.

Thyroid Hormone Homeostasis in Levothyroxine-treated Patients: Findings From ELSA-Brasil.

The effectiveness of levothyroxine (LT4) in restoring thyroid hormone (TH) homeostasis, particularly serum thyroxine (T4) and triiodothyronine (T3) levels, remains debatable. This work aimed to assess TH homeostasis in LT4-treated individuals using data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) study. The ELSA-Brasil study follows 15 105 adult Brazilians (aged 35-74 years) over 8.2 years (2008-2019) with 3 observation points assessing health parameters including serum thyrotropin (TSH), free T4 (FT4), and free T3 (FT3) levels. We analyzed 186 participants that initiated treatment with LT4 during the study, and 243 individuals continuously treated with LT4 therapy. Initiation of therapy with LT4 resulted in an 11% to 19% decrease in TSH, an approximately 19% increase in FT4, and a 7% reduction in FT3 serum levels (FT3 dropped >10% in ∼40% of the LT4-treated patients). This was associated with an increase in triglyceride levels and utilization of hypolipidemic and antidiabetic medications. Participants continuously treated with LT4 exhibited a stable elevation in serum FT4 and a reduction in serum FT3 and TSH levels. While 115 participants (47.3%) had at least 1 serum FT4 levels above the control reference range (>1.52 ng/dL), 38 participants (15.6%) had at least 1 serum FT3 below the reference range (<0.23 ng/dL). The present results challenge the dogma that treatment with LT4 for hypothyroidism restores TH homeostasis in all patients. A substantial number of LT4-treated patients exhibit repeated FT4 and FT3 levels outside the normal reference range, despite normal TSH levels. Further studies are needed to define the clinical implications of these findings.

Use of thyroid hormones in hypothyroid and euthyroid patients: A survey of members of the Endocrine Society of Australia.

Hypothyroidism is a common endocrine condition usually managed with levothyroxine (LT4). However, controversy remains around the use of liothyronine (LT3). We aimed to investigate the practices of Australian endocrinologists when managing patients with hypothyroidism, their use of LT3 + LT4 combination therapy and use of thyroid hormones in euthyroid patients. Members of the Endocrine Society of Australia (ESA) were invited to participate in an online questionnaire. We analysed questionnaires that had complete demographic data. Eighty-seven questionnaires fulfilled the criteria. LT4 was used as first line treatment for hypothyroidism by all respondents. Only 45% reported that their patients were dispensed the brand of LT4 that they recommend. LT3 (alone or in combination) was prescribed by 44% in their clinical practice. Although 49% of respondents would consider LT3 + LT4 in patients with normal TSH who had ongoing symptoms of hypothyroidism, the inability of LT4 to restore normal physiology was ranked the least likely explanation for persistent symptoms and only 32% would consider it for themselves if they were diagnosed with hypothyroidism. The majority (55%), in accordance with evidence, would not prescribe thyroid hormone to euthyroid individuals but 39% would consider use in euthyroid female infertility with high levels of thyroid antibodies and 11% in euthyroid patients with a simple goitre growing over time. LT4 use in pregnancy was variable among members. Australian endocrinologists mostly follow international guidelines when prescribing thyroid hormone therapy and many prescribe combination LT3 and LT4 therapy, particularly for patients who remain symptomatic on LT4 monotherapy. Prescribing practices are largely similar to other countries who have completed similar questionnaires.

Patients' Persistent Symptoms, Clinician Demographics, and Geo-Economic Factors Are Associated with Choice of Therapy for Hypothyroidism by European Thyroid Specialists: The "THESIS" Collaboration.

Background: Hypothyroidism is common, however, aspects of its treatment remain controversial. Our survey aimed at documenting treatment choices of European thyroid specialists and exploring how patients' persistent symptoms, clinician demographics, and geo-economic factors relate to treatment choices. Methods: Seventeen thousand two hundred forty-seven thyroid specialists from 28 countries were invited to participate in an online questionnaire survey. The survey included respondent demographic data and treatment choices for hypothyroid patients with persistent symptoms. Geo-economic data for each country were included in the analyses. Results: The response rate was 32.9% (6058 respondents out of 17,247 invitees). Levothyroxine (LT4) was the initial treatment preferred by the majority (98.3%). Persistent symptoms despite normal serum thyrotropin (TSH) while receiving LT4 treatment were reported to affect up to 10.0% of patients by 75.4% of respondents, while 28.4% reported an increasing such trend in the past 5 years. The principal explanations offered for patients' persistent symptoms were psychosocial factors (77.1%), comorbidities (69.2%), and unrealistic patient expectations (61.0%). Combination treatment with LT4+liothyronine (LT3) was chosen by 40.0% of respondents for patients who complained of persistent symptoms despite a normal TSH. This option was selected more frequently by female thyroid specialists, with high-volume practice, working in countries with high gross national income per capita. Conclusions: The perception of patients' dissatisfaction reported by physicians seems lower than that described by hypothyroid patients in previous surveys. LT4+LT3 treatment is used frequently by thyroid specialists in Europe for persistent hypothyroid-like symptoms even if they generally attribute such symptoms to nonendocrine causes and despite the evidence of nonsuperiority of the combined over the LT4 therapy. Pressure by dissatisfied patients on their physicians for LT3-containing treatments is a likely explanation. The association of the therapeutic choices with the clinician demographic characteristics and geo-economic factors in Europe is a novel information and requires further investigation.

Stijgend gebruik van levothyroxine in België

Increasing use of levothyroxine in Belgium In the past decades, increased prescription of levothyroxine (LT4) has been observed in Belgium, different countries in Western Europe and North America. The increased screening for thyroid dysfunction, longer life expectancy and lower threshold for the initiation of LT4 therapy are believed to play a role. The goal of this article is to present a data overview on the prevalence of hypothyroidism, LT4 use and screening for hypothyroidism in Belgium and other countries. The Belgian data are in line with those from other countries, where an increase in LT4 prescriptions has been observed. The threshold for the initiation of LT4 seems to have lowered. Not only the indication to start LT4, but also follow-up of the serum thyroid-stimulating hormone (TSH) are important to avoid complications. The elderly deserve special attention because of an age-related increase of the serum TSH level. This may increase the risk of overdiagnosis of hypothyroidism and overtreatment with LT4, which is associated with iatrogenic thyrotoxicosis, atrial fibrillation and osteoporosis. In the elderly, the decision whether or not to start LT4 needs to be individualized, particularly in cases with mild TSH elevation. If LT4 is initiated, the principle ‘start low, go slow’ should be followed. There is a need for a better knowledge and implementation of guidelines, adopting age-specific reference ranges for TSH in order to optimize the use of LT4.

Selenium supplementation and placebo are equally effective in improving quality of life in patients with hypothyroidism.

We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479). We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 μg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after six weeks, three, six, 12, and 18 months. In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 [95%CI:24.5-33.6] and 28.0 [24.5-33.1], respectively; P=0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 [95%CI:1512-2512] vs. 2344 kIU/L [1862-2951]; P=0.016) but did not influence LT4 dosage or free triiodothyronine/free thyroxin ratio. In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 μg selenium or placebo for 12 months improved QoL to the same extent.

Liquid L-T4 therapy in hypothyroid patients with gastric diseases, an observational study.

This is an observational and retrospective study, in which we have analyzed data from patients affected by gastric diseases (p) who have been treated with liquid L-T4 (L-LT4;84 p), or tablet L-T4 (T-LT4;120 p), for the replacement therapy of hypothyroidism. The aim of the study is to compare the stability of TSH [normal range, 0.3-3.5 μIU/ml] in these patients. All p assumed L-T4 30 minutes before breakfast. The types of gastric disease were: a) T-LT4 group: 74 chronic gastritis (CG); 4 gastrectomy for gastric cancer (GTx); 42 gastro-plastics (GP); b) L-LT4 group: 60 CG; 3 GTx; 21 GP (p>0.05). 66% p in T-LT4 group were chronically treated with proton pump inhibitors (PPI), against 51% in L-LT4 group (p>0.05). The frequency of Helicobacter Pylori infection was 17% in both T-LT4 and L-LT4 groups. The gender distribution, mean age and body weight were similar in the 2 groups (p>0.05). The mean L-T4 dosage in T-LT4 group at the basal evaluation was 1.22+/-0.27 μg/kg/die, in the L-LT4 group 1.36+/-0.22 μg/kg/die (p>0.05). At the basal evaluation the prevalence of patients with a TSH>3.5 μIU/mL in T-LT4 group was 36%, in L-LT4 group 46% (p<0.05). After adjustment of the dosage of the LT-4 therapy, the p were re-evaluated in an interval range of 5-9 months, for 4 times, during an overall period ranging from 23 to 31 months. At the first re-evaluation, the prevalence of p with a TSH>3.5 μIU/mL was 13% in both groups. At the second re-evaluation, the prevalence of p with a TSH>3.5 μIU/mL in T-LT4 group was 26%, in L-LT4 group 13% (p>0.05). At the third re-evaluation, the prevalence of p with TSH<3.5 μIU/mL in T-LT4 group was 19%, in L-LT4 group 9% (p=0.05). At the fourth and last re-evaluation, the prevalence of patients with a TSH>3.5 μIU/mL in T-LT4 group was 18%, in L-LT4 group 5% (p<0.05). Mean FT4 and FT3 circulating levels were not significantly different in the two group at each visit. These data suggest that the liquid L-T4 formulation therapy can result in a more stable control of TSH levels in hypothyroid patients with gastric disorders in the long-term follow-up.

Real Practice Assessment of Persistent Symptoms After Initiation of Levothyroxine

ObjectiveLevothyroxine (LT4) is the standard treatment for hypothyroidism. However, certain patients experience persistent symptoms even after achieving euthyroid status with LT4 therapy. We aimed to determine the frequency of persistent or new symptoms in patients with hypothyroidism after initiating LT4. MethodsThis retrospective study included patients with hypothyroidism who started on LT4 between January 2017 and December 2019 at Mayo Clinic in Rochester, Minnesota, USA. Five hundred patient charts were randomly selected for review. Patients with at least 1 documented follow-up encounter after LT4 initiation were evaluated for ≤3 follow-up visits regarding their biochemical status and symptoms. ResultsWe included 356 patients, a majority of whom were female (66.6%), white (92.3%), and obese (71.9%), with an average age of 59.5 years. At the baseline visit, approximately one-half of the patients (177/356, 47.7%) reported hypothyroid symptoms, with fatigue being the most common symptom. During the follow-up periods, we observed that 17.8% (28/157), 17.9% (19/106), and 19.3% (11/57) of patients had normal thyroid stimulating hormone (TSH) values but persistent symptoms, while 12.3% (19/156), 19.9% (16/107), and 8.9% (5/56) had normal TSH values but new symptoms. Overall, during each respective follow-up period, 26.7% (42/157), 27.3% (29/106), and 28% (16/57) of patients experienced persistent or new symptoms alongside normal TSH values, with fatigue being the most constant symptom. ConclusionOur findings indicate that approximately 1 in every 4 patients with hypothyroidism receiving LT4 therapy and achieving normal TSH levels experience persistent or new hypothyroid symptoms. The cause of these symptoms remains unclear, emphasizing the need for a better understanding of their underlying causes and the development of effective management strategies.

FRI482 Severe Hypothyroidism: A Lack Of Standardized Care For Patients At Risk Of Myxedema Coma

Abstract Disclosure: S. Abdurrahman: None. P. Thakkar: None. E. Kasiri: None. L. Belalcazar: None. Introduction: Myxedema coma (MC) is a rare complication of severe hypothyroidism (HT). MC is diagnosed clinically and often precipitated by a major acute event. While most physicians support rapid and aggressive management of MC to reduce mortality, there is no consensus on how to approach patients with severe HT at risk of MC. We present two cases that illustrate this treatment gap. Case Presentation: CASE 1: A 76-year-old woman with 9 years of primary HT presented to the hospital after a recent fall; she was found to have an intertrochanteric fracture. The patient reported fatigue, anorexia, and inability to perform activities of daily living. On exam, she was malnourished and intermittently somnolent. Her pulse rate was 84/min; she had no hypothermia. Labs were significant for TSH of 195 mIU/L (0.45 - 4.70 mIU/L) and an undetectable Free T4 (FT4) at &amp;lt;0.07 ng/dL (0.78 - 2.20 ng/dL). She was started on her prescribed home dose of levothyroxine (LT4) of 100 mcg PO daily (1.9 mcg/kg Ideal body weight [IBW]). Given the severe HT and risk of MC, surgery was deferred. More aggressive LT4 therapy begun the next day with 200 mcg orally and an additional dose of 100 mcg IV; concern for malabsorption was raised. On Day 3, she received 150 mcg IV of LT4 and her FT4 level was 0.75 ng/dL the following morning (average equivalent PO LT4 dose: 204 mcg/day, ∼2X replacement dose). She was given another dose of LT4 150 mcg IV and underwent surgical fixation the next day without complication. CASE 2: 27-year-old woman with 10 years of primary HT and non-adherence to LT4 therapy due to fear of palpitations. The patient presented to the hospital, after a recent miscarriage, with diarrhea due to clostridium difficile infection. On exam, she was alert and without hypothermia, but had a pericardial effusion. EKG was abnormal; labs showed hyponatremia, TSH of 147 mIU/L and an undetectable FT4 level. She refused LT4 on admission but agreed subsequently. An LT4 dose of 150 mcg IV daily was administered for 2 days with a follow-up FT4 level of 0.5 ng/dL (average equivalent PO LT4 dose: 187.5 mcg/day, ∼2.5 X replacement dose). Her LT4 dose was decreased to 100 mcg IV on Day 3. Given improvement of diarrhea, she was started on PO LT4 at a maintenance dose of 75 mcg daily (1.6 mcg/kg IBW per day) and discharged. Repeat labs 2 weeks later showed a TSH: of 5.52 mIU/L (0.45 - 4.70 mIU/L) and a free T4 of 1.17 ng/dl (0.78 - 2.20 ng/dL). Discussion: There remains a gap on how to systematically approach thyroid replacement in individuals with severe HT who present with an acute stressor and are at risk of MC. Our patients tolerated initial daily LT4 doses equivalent to 2-2.5 times their PO maintenance dose, with improvement in clinical status and circulating hormone levels. Our cases suggest that 3-4 days of LT4 approximating 2 times maintenance dose may expedite recovery of euthyroidism and reduce the risk of MC in these high-risk patients. Further studies are needed to inform practice. Presentation: Friday, June 16, 2023

SAT330 Recurrence of Acth Independent Cushing Syndrome In Patient With Previously Operated On For Primary Bilateral Macronodular Adrenal Hyperplasia And Co-existence Of Papillary Thyroid Carcinoma

Abstract Disclosure: N. Vashakmadze: None. D. Nikoleishvili: None. Background: Cushing syndrome is a rare and usually sporadic endocrine disorder. Herein we describe a case of ACTH-independent Cushing syndrome and ACTH-dependent Cushing disease in non-identical twins. Moreover, recurrence of Cushing syndrome after 25 years of non-complete resection of adrenal glands and co-existence of papillary thyroid cancer. Clinical Case: A 57-year woman presented with hypertension, depression, easy bruising, proximal muscle weakness, fatigue, and facial plethora. According to the patient, Cushing’s syndrome caused by bilateral macronodular adrenal hyperplasia was diagnosed in 1997. Surgical treatment - left adrenalectomy and right adrenal gland resection was performed. She was receiving HRT during the first 6 months, since then she was not receiving HRT and her cortisol was normal. It is extremely interesting that her nonidentical twin sister was diagnosed with ACTH-dependent Cushing disease in 2006 and was successfully treated with transsphenoidal surgery. In 2019 patient was diagnosed with papillary thyroid cancer (PTC), thyroidectomy was performed and multifocal PTC pT1b(m)N0M0 was diagnosed. Patient received adjuvant therapy with 80 mCi of RAI. In 2019 cortisol and ACTH levels were routinely evaluated, ACTH was undetectable &amp;lt;3 ng/dl (N: 7.2-63); 1 mg dexamethasone suppression test showed no suppression of cortisol 116 ng/ml (N: &amp;lt;1.8 ng/ml). However, patient did not consult an endocrinologist with the results of the mentioned investigations. She admitted to our clinic in December 2022 with above-mentioned complains to determine the tactics of further investigation/treatment. The data obtained during our consultation was consistent to recurrence of Cushing syndrome: midnight salivary cortisol– 0.46 mcg/dl (0.02-0.34), ACTH– 4.2 ng/l (7.2-63), 1 mg of dexamethasone suppression test – 217 nmol/l (&amp;lt;50). CT showed right adrenal noduls (2.5 cm and 1.2 cm). These data confirmed the diagnosis of recurrence of Cushing’s syndrome and right adrenalectomy with steroid coverage and postoperative hormone replacement therapy was recommended. Other data showed normal OGTT, moderate hypercholesterolemia, taking into account Cushing’s syndrome and smoking, statins were initiated. DXA showed osteoporosis (forearm T-score = -3.9 SD). 25(OH)D3 – 22.35 ng/ml, Ca – 1.09 mmol/l (1.1-1.3). Denosumab, calcium and vitamin D supplements were started to the patient. In addition, TSH was markedly suppressed on 125 mcg LT4 therapy, TSH – 0.005 mIU/l (0.4-3.8); Tg &amp;lt;0.17 g/l, anti-Tg - N and neck ultrasound was normal, that is consistent with excellent response and the target TSH was established 0.5-2.0 mIU/l. The dose of LT4 was reduced to 100 mcg. Conclusion: To our knowledge existence of Cushing syndrome and Cushing disease in non-identical twins has not been reported yet. Also, co-existence of Cushing syndrome and thyroid cancer is rare, and no connection is established yet. Presentation: Saturday, June 17, 2023

FRI527 Timing Of Thyroxine Dose During Ramadan: A Randomized Controlled Trial

Abstract Disclosure: R.M. Alamoudi: None. S.M. Nawar: None. H.S. Alharbi: None. A.A. Al Qarni: None. A. Alzahrani: None. A.K. Almulla: None. W.T. Busaad: None. N.F. Alahmari: None. N.D. Alshamrani: None. L. Alkhalifa: None. Y.M. Saleh: None. M. Ramadan: None. A. Borai: None. Background: The effect of Ramadan fasting on the thyroid profile, and the best time for L-thyroxine (LT4) intake in relation to fasting during Ramadan remains undetermined. Objectives: To compare two different time points of taking LT4 therapy during fasting the month of Ramadan in regards to thyroid profile and patient satisfaction. Methods: A multicenter open-label randomized controlled trial. Patients with primary hypothyroidism were recruited from three centers in three cities in Saudi Arabia (Jeddah, Riyadh, and Alhasa). Patients with thyroid cancer were excluded. TSH and FreeT4 (FT4) were measured two weeks before Ramadan, and four to six weeks after Ramadan. Results: 303 patients with primary hypothyroidism were randomized; 156 to take the LT4 dose at sunset with sips of water at the time of breaking fast and wait 30-60 minutes to eat the main Iftar meal (pre-Iftar), and 147 to take the LT4 dose just before the start of fasting (pre-dawn) regardless of their last meal intake. There were no significant differences between the two groups in demographics or comorbidities. The mean age was 49 ±12 years, 87% were female, and the average duration of hypothyroidism was 9.7 ±8.25 years. The mean weekly LT4 dose in the pre-Iftar vs. pre-dawn group was 753.3 ±349.4 vs. 733.2 ±265.6 mcg, p=0.001, and the Pre-Ramadan thyroid profile was: TSH 2.56 ±2.16 vs. 2.46 ±1.72 mIU/L, p=0.3, FT4 13.45 ±2.1 vs 13.08 ±2.4 pmol/L, p=0.16. Post-Ramadan thyroid profile values were: TSH 3.64 ± 4.1 vs. 4.07 ±4.17 mIU/L, p=0.78, FT4 12.96 ±0.1 vs. 12.64 ±0.22 pmol/L, p=0.003. The estimated difference within the group means post-Ramadan was - 0.41 ±0.51 mIU/L, p=0.43 for TSH, and 0.32 ±0.28 pmol/L, p=0.24 for FT4. Generalized linear model repeated measures analysis of variance showed no significant difference over time in TSH or FT4 within or between groups (p = 0.47 vs. 0.81). Patient compliance and satisfaction with the regimens were similar between groups. Conclusion: There is no significant change nor difference in thyroid profile between the two regimens related to the change in LT4 intake during the fasting months of Ramadan. Both regimens can be utilized depending on patient preferences. ClinicalTrials.gov: NCT05421468. Saudi FDA: SCTR # 22041002 Presentation: Friday, June 16, 2023

FRI526 Geographic Trends In Thyroid Hormone Prescribing In The US: 2010 - 2020

Abstract Disclosure: M.D. Ettleson: None. N. Laiteerapong: None. W. Wan: None. A.C. Bianco: Consulting Fee; Self; Abbvie, Acella, Synthonics, Thyron, Madrigal. Introduction: Levothyroxine (LT4) is the first line treatment of hypothyroidism. However, some clinical guidelines suggest a trial of adding triiodothyronine (T3) therapy if LT4 monotherapy does not adequately resolve symptoms despite a normal thyrotropin (TSH) level. It is unknown how patterns of thyroid hormone (TH) prescribing (LT4 vs T3-containing therapy) differ across the US. Methods: We conducted a cross-sectional study of TH prescription data from a large, US-based claims database from January 1, 2010 to December 31, 2020. TH type (LT4, liothyronine [LT3], or desiccated thyroid extract [DTE]), geographic, and clinical data were collected. Only patients with a new TH prescription and a diagnosis of hypothyroidism were included. The study population was subdivided into 4 TH treatment classes: 1) LT4 monotherapy, 2) LT3 therapy with or without LT4, 3) DTE therapy with or without LT4, and 4) other. Statewide physician density and urban-rural classification were the primary geographic covariates analyzed. Other covariates included in the analytical models were age, sex, comorbidities, and co-prescribed medications. Results: A total of 524,818 adult patients accounted for 537,594 new TH prescriptions over the 11 year study period. Of the total population, 89.0% received LT4 monotherapy, 8.8% received DTE therapy, and 2.0% received LT3 therapy. The proportion of patients receiving DTE increased from 5.4% to 10.2% during the study period. DTE and LT3 prescriptions were not uniformly distributed throughout the US, with higher rates in the West and South regions. Residence in a state with higher endocrinologist density (3.0/100k population) was associated with a decreased likelihood of receiving LT3 or DTE therapy (adjusted OR 0.33, 95% CI [0.20 – 0.55], p &amp;lt;0.001; adjusted OR 0.18, 95% CI [0.08 – 0.41], p &amp;lt;0.001, respectively). Residence in large central metro zones was associated with an increased likelihood of receiving LT3 or DTE therapy (adjusted OR 1.32, 95% CI [1.22 – 1.42]; p &amp;lt;0.001; adjusted OR 1.05, 95% CI [1.01 – 1.10], p = 0.008, respectively). Conclusions: There do appear to be geographic disparities in the patterns of TH prescribing in the US. Differences in access to endocrine care may contribute to these disparities. Also, patients in more urban zones were more likely to receive LT3 or DTE therapies. Further investigation is necessary to understand the patient and physician-level factors underlying the geographic disparities identified. Presentation: Friday, June 16, 2023