LT4 Therapy Research Articles

Managing symptoms in hypothyroid patients on adequate levothyroxine: a narrative review.

The current standard of care for hypothyroidism is levothyroxine (LT4) monotherapy to reduce levels of thyrotropin (thyroid-stimulating hormone, TSH) within its reference range and amelioration of any symptoms. A substantial minority continues to report hypothyroid-like symptoms despite optimized TSH, however. These symptoms are not specific to thyroid dysfunction and are frequent among the euthyroid population, creating a therapeutic dilemma for the treating clinician as well as the patient. We present a concise, narrative review of the clinical research and evidence-based guidance on the management of this challenging population. The clinician may endeavor to ensure that the serum TSH is within the target range. However, the symptomatic patient may turn to alternative non-evidence-based therapies in the hope of obtaining relief. Accordingly, it is important for the clinician to check for conditions unrelated to the thyroid that could account for the ongoing symptoms such as other autoimmune conditions, anemia or mental health disorders. Systematic and thorough investigation of the potential causes of persistent symptoms while receiving LT4 therapy will resolve the problem for most patients. There may be some patients that may benefit from additional treatment with liothyronine (LT3), although it is unclear as yet as to which patient group may benefit the most from combined LT4 + LT3 therapy. In the future, personalized treatment with LT4 + LT3 may be of benefit for some patients with persistent symptoms of hypothyroidism such as those with polymorphisms in the deiodinase enzyme 2 (DIO2). For now, this remains a subject for research.

Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?

It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist, and what is the role of combination therapy with LT4 and liothyronine (LT3), are questions that remain unclear. Here we explore evidence of abnormal thyroid hormone (TH) metabolism in LT4-treated patients, and offer a rationale for why some patients perceive LT4 therapy as a failure. This review is based on a collection of primary and review literature gathered from a PubMed search of "hypothyroidism," "levothyroxine," "liothyronine," and "desiccated thyroid extract," among other keywords. PubMed searches were supplemented by Google Scholar and the authors' prior knowledge of the subject. In most LT4-treated patients, normalization of serum thyrotropin levels results in decreased serum T3/T4 ratio, with relatively lower serum T3 levels; in at least 15% of the cases, serum T3 levels are below normal. These changes can lead to a reduction in TH action, which would explain the slower rate of metabolism and elevated serum cholesterol levels. A small percentage of patients might also experience persistent symptoms of hypothyroidism, with impaired cognition and tiredness. We propose that such patients carry a key clinical factor, for example, specific genetic and/or immunologic makeup, that is well compensated while the thyroid function is normal but might become apparent when compounded with relatively lower serum T3 levels. After excluding other explanations, physicians should openly discuss and consider therapy with LT4 and LT3 with those hypothyroid patients who have persistent symptoms or metabolic abnormalities despite normalization of serum thyrotropin level. New clinical trials focused on symptomatic patients, genetic makeup, and comorbidities, with the statistical power to identify differences between monotherapy and combination therapy, are needed.

Differences in food consumption between patients with Hashimoto\u2019s thyroiditis and healthy individuals

Food is considered as important environmental factor that plays a role in development of Hashimoto's thyroiditis (HT). The goal of our study was to identify food groups, assessed by food frequency questionnaire, that differ in consumption frequency between 491 patients with HT and 433 controls. We also analysed association of food groups with the wealth of HT-related clinical traits and symptoms. We found significantly increased consumption of animal fat (OR 1.55, p < 0.0001) and processed meat (OR 1.16, p = 0.0012) in HT cases, whereas controls consumed significantly more frequently red meat (OR 0.80, p < 0.0001), non-alcoholic beverages (OR 0.82, p < 0.0001), whole grains (OR 0.82, p < 0.0001) and plant oil (OR 0.87, p < 0.0001). We also observed association of plant oil consumption with increased triiodothyronine levels in HT patients (β = 0.07, p < 0.0001), and, association of olive oil consumption with decreased systolic blood pressure (β = − 0.16, p = 0.001) in HT patients on levothyroxine (LT4) therapy. Analysis of food consumption between HT patients with and without LT4 therapy suggest that patients do not tend to modify their diet upon HT diagnosis in our population. Our study may be of relevance to nutritionists, nutritional therapists and clinicians involved in developing dietary recommendations for HT patients.

Long-Term Follow-Up and Outcomes of Autoimmune Thyroiditis in Childhood.

Background: Autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in children. The natural outcome of AIT in childhood has been reported previously however follow-up duration is generally short and results variable.Objectives: To characterize clinical and biochemical findings at presentation of AIT, evaluate long-term outcomes and assess which factors at presentation predict evolution over time.Study cohort: 201 children under 18 years of age at presentation (82% female) were enrolled. Subjects were divided into five subgroups according to thyroid stimulating hormone (TSH) level at referral.Results: Mean follow-up was 8.1 years (range 0–29 years). At presentation, 34% of patients had overt hypothyroidism, 32% subclinical hypothyroidism (SCH), 16% compensated hypothyroidism, 14% were euthyroid, and 3.7% had Hashitoxicosis. Children with overt hypothyroidism were younger (10.6 vs. 13.2 years) and had higher thyroid peroxidase antibody titers. At the time of the study, levothyroxine (LT4) therapy was required in 26% of children who were euthyroid at presentation, 56% of SCH patients, 83–84% of those with TSH above 10 mIU/L, and 57% of those with Hashitoxicosis. Over the years, 16% of children presenting with overt hypothyroidism stopped therapy. Free T4 at presentation was the only predictor of outcome over time.Conclusions: Our findings suggest that only 26% children who were euthyroid at presentation developed hypothyroidism, whereas over 50% of those with SCH went on to require treatment. Of those presenting with overt hypothyroidism, 16% recovered with time. The only predictive parameter for LT4 therapy at the end of the study was free T4 levels at presentation. Long-term follow-up is required to determine ongoing therapy needs and screen for additional autoimmune diseases.

Thyroglobulin Changes are Highly Dependent on TSH in Low-risk DTC Patients not Treated with Radioiodine

Low-risk differentiated thyroid cancer (DTC) is currently rarely treated with radioiodine (131I) to ablate the postoperative remnant. Therefore, the interpretation of the serum thyroglobulin (Tg) values should be reconsidered. The aim of our study was to evaluate the changes in Tg values during follow-up with regard to the changing values in thyroid stimulating hormone (TSH). We evaluated 271 low-risk DTC patients, treated with total thyroidectomy but not 131I. To be included, patients had to be negative for Tg antibodies and have at least 3 evaluations in our department. All patients were on levothyroxine (L-T4) therapy. After a median follow-up of 73 months, the overall Tg values were stable, while TSH values slightly increased. Therefore, we pooled data of Tg and TSH from all evaluations and a significant positive correlation was demonstrated (R = 0.2; P < 0.01), and was also demonstrated when we performed the analysis using time-weighted values (R = 0.14; P = 0.02). Moreover, when dividing patients into 3 groups according to first postoperative Tg (Group A [Tg < 0.2 ng/ml], Group B [Tg 0.2-1 ng/ml], and Group C [Tg > 1 ng/ml]) most patients showed stable values of Tg at the end of follow-up but TSH variations had a clear impact on the changes in Tg among the groups. We demonstrated that in low-risk DTC not treated with 131I, serum Tg remains substantially stable over time, and the variations observed were correlated with the concomitant variations of TSH levels, mainly due to the modification of LT-4 therapy performed according to the ongoing risk stratification.

Standard hypothyroid treatment did not restore proper metabolic response to carbohydrate

PurposeHypothyroidism is associated with a lower metabolic rate, impaired glucose tolerance, and increased responsiveness of sympathetic nervous system to glucose ingestion. The Levothyroxine (LT4) monotherapy is the standard treatment for hypothyroidism; however to what extent this treatment restores the patients’ metabolism has not been verified. The aim of this study was to test the hypothesis that standard LT4 therapy may not restore proper metabolic response to carbohydrate ingestion.MethodsEnergy expenditure, glucose tolerance, and catecholamine response to glucose ingestion were compared in 18 subjects with pharmacologically compensated hypothyroidism (PCH) and controls, at baseline and during oral glucose tolerance test conditions.ResultsMetabolic rate was significantly lower in PCH (P < 0.0001). Glucose tolerance was decreased in this group with no differences in insulin resistance indicators between both groups. Adrenergic activity (P < 0.05) as well as adrenergic reaction to glucose ingestion (P < 0.001) were stronger in PCH.ConclusionsStandard treatment for hypothyroidism does not restore the normal metabolic reaction to carbohydrate which is observed in healthy people.

Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism.

Background: The basis for the treatment of hypothyroidism with levothyroxine (LT4) is that humans activate T4 to triiodothyronine (T3). Thus, while normalizing serum thyrotropin (TSH), LT4 doses should also restore the body's reservoir of T3. However, there is evidence that T3 is not fully restored in LT4-treated patients. Summary: For patients who remain symptomatic on LT4 therapy, clinical guidelines recommend, on a trial basis, therapy with LT4+LT3. Reducing the LT4 dose by 25 mcg/day and adding 2.5-7.5 mcg liothyronine (LT3) once or twice a day is an appropriate starting point. Transient episodes of hypertriiodothyroninemia with these doses of LT4 and LT3 are unlikely to go above the reference range and have not been associated with adverse drug reactions. Trials following almost a 1000 patients for almost 1 year indicate that similar to LT4, therapy with LT4+LT3 can restore euthyroidism while maintaining a normal serum TSH. An observational study of 400 patients with a mean follow-up of ∼9 years did not indicate increased mortality or morbidity risk due to cardiovascular disease, atrial fibrillation, or fractures after adjusting for age when compared with patients taking only LT4. Desiccated thyroid extract (DTE) is a form of combination therapy in which the LT4/LT3 ratio is ∼4:1; the mean daily dose of DTE needed to normalize serum TSH contains ∼11 mcg T3, but some patients may require higher doses. The DTE remains outside formal FDA oversight, and consistency of T4 and T3 contents is monitored by the manufacturers only. Conclusions: Newly diagnosed hypothyroid patients should be treated with LT4. A trial of combination therapy with LT4+LT3 can be considered for those patients who have unambiguously not benefited from LT4.

Postpartum Thyroiditis in Women With Euthyroid and Hypothyroid Hashimoto's Thyroiditis Antedating Pregnancy.

Postpartum thyroiditis (PPT) is defined as the occurrence of de novo autoimmune thyroid disease accompanied by thyroid dysfunction in the first year postpartum. However, hormonal changes resembling the typical pattern of PPT have been reported to occur even in women with pregestational Hashimoto's thyroiditis (HT) on levothyroxine (LT4). To evaluate the risk of PPT in women with HT antedating pregnancy. Retrospective chart review of pregnant women with HT antedating pregnancy seen in a university hospital (2008-2017), who were followed from preconception up to 1 year after delivery. 167 women preconceptionally diagnosed with HT and classified as hypothyroid HT (hypo-HT; n = 98) or euthyroid HT (eu-HT; n = 69), according to their thyroid status at the time of diagnosis. PPT occurrence and associated clinical characteristics/risk factors. PPT occurred in 65/167 women, with a rate statistically greater in the eu-HT than in the hypo-HT group (68.1% vs 18.4%; odds ratio [OR] 9.49, 95% confidence interval [CI] 4.62-19.49). Most of the women experiencing PPT in both groups were euthyroid at the time of first-trimester evaluation (39/47 eu-HT [83%] and 16/18 hypo-HT [88.9%]). Multivariate regression analysis showed eu-HT group and first-trimester euthyroidism to be positively associated with PPT occurrence (ORs 10.71 and 3.89, respectively). PPT may occur in hypo-HT women on LT4 therapy, although significantly less frequently than in eu-HT women. The 4-fold higher risk of PPT in HT women maintaining euthyroidism at first -trimester of gestation suggests that the risk of PPT could be related to the amount of unaffected thyroid tissue.

LT4 and Slow Release T3 Combination: Optimum Therapy for Hypothyroidism?

ContextLevothyroxine (LT4) is recommended as replacement therapy for thyroid hormone deficiency. However, some hypothyroid patients receiving LT4 therapy do not feel as well as healthy subjects. This article aimed to review current knowledge regarding LT4 monotherapy versus LT4+LT3 combination therapy and propose future directions regarding LT4+slow release T3 combination treatment for hypothyroidism.Evidence AcquisitionWe searched PubMed and Scopus using related keywords.ResultsThe LT4 monotherapy causes higher serum free T4 (fT4), subnormal serum free T3 (fT3), and fT3/fT4 ratio in one-fourth of patients. The LT4+LT3 combination therapy increases serum T3 and fT3 concentrations and may normalize the fT3/fT4 ratio. However, the primary outcomes, including thyroid hormone deficiency, anxiety, depression, and quality of life, may not be better in LT4+LT3 combination therapy than in LT4 monotherapy. Recent surveys show that combination therapy is on the rise, in particular, due to patient demand. The LT4 plus slow-release LT3 preparation has shown promising results in improving serum thyroid hormone concentrations.ConclusionsThe beneficial effect of LT4+LT3 combination therapy is not clear, and the safety of long-term therapy is yet under question. More scientific well-designed research projects are required in this field.

Serum levels of advanced glycation end products (AGEs) are increased and their soluble receptor (sRAGE) reduced in Hashimoto's thyroiditis.

Advanced glycation end products (AGEs) are increased in conditions of oxidative stress and promote inflammation by interacting with their receptor RAGE on cell membrane. By contrast, the soluble receptor sRAGE exerts protective effects by competing with RAGE for ligand binding. AGEs/sRAGEs interaction is involved in the pathogenesis of several diseases related to oxidative stress. In the present study, we evaluated the AGEs/sRAGEs oxidative balance in Hashimoto' thyroiditis (HT). We measured the levels of sRAGE, by ELISA, and AGEs, by spectrophotometric method, in the serum of 50 HT patients (5 M, 45 F; mean age 38.5 ± 12years) and 50 age-, sex- and BMI-matched healthy controls. All subjects were euthyroid at recruitment and none was on LT-4 therapy. Serum sRAGEs were significantly lower (median 424 vs 738pg/ml; p = 0.001) and AGEs higher (205 vs 114AU/g prot; p = 0.001) in HT patients compared to controls, and the two parameters were inversely correlated (p = 0.016). Accordingly, the AGEs/sRAGEs ratio was threefold higher in HT patients than controls (0.48 vs 0.15; p = 0.0001). In regression analysis models, serum TPO-Ab were the main predictors for AGEs and sRAGEs levels and AGEs/sRAGEs ratio (p < 0.0001), irrespective of TSH and/or FT4 values. sRAGEs were decreased and AGEs increased, suggesting a dysregulation of AGE/sRAGEs-related oxidative homeostasis in HT patients, even when in euthyroid status. Autoimmunity per se seems to play an important role in AGEs/sRAGE imbalance, irrespective of thyroid function alterations.

Is There a Role for Levo-Thyroxine for the Treatment of Arterial Erectile Dysfunction? The Clinical Relevance of the Mean Platelet Volume

Background: Arterial erectile dysfunction (ED) is an early sign of vascular damage. Rare evidence has been published so far as to whether subclinical hypothyroidism (SCH) affects arterial erectile function. Therefore, the objective of this study was to fill this gap. Methods: Patients with arterial ED and SCH were consecutive enrolled and randomly divided into Group A (n = 20) and Group B (n = 20). Group A was treated with levo-thyroxine (LT4) at the dose of 1 µg/kg/day for six months, whereas patients of the group B did not receive any treatment. Thyroid stimulating hormone (TSH), free-thyroxine (FT4), peak systolic velocity (PSV), International Index of Erectile Function 5-item version (IIEF-5) score, mean platelet volume (MPV), and total cholesterol were evaluated at enrollment (T0) and after six months (T1). Patients without hypertension, diabetes mellitus, dyslipidemia, not on drugs, and with normal total testosterone (TT) values were included in this study. Results: Group A and B did not differ for age (61.2 ± 4.8 vs. 60.3 ± 5.6 years), body-mass index (28.7 ± 2.5 vs. 28.3 ± 2.6 Kg/m2), and serum TT levels (481.2 ± 54.0 vs. 492.1 ± 59.7 ng/dL). At T0, serum TSH levels (6.5 ± 1.2 vs. 6.0 ± 1.0 µIU/mL), FT4 (8.8 ± 0.6 vs. 8.8 ± 0.6 pmol/L), PSV (26.5 ± 1.4 vs. 25.8 ± 2.1 cm/s), IIEF-5 score (8.2 ± 1.7 vs. 9.0 ± 1.7), and total cholesterol (167.8 ± 21.7 vs. 171.6 ± 21.3 mg/dL) did not significantly differ in patients of Group A vs. those of Group B. MPV was significantly higher in Group A than in Group B (12.3 ± 0.3 vs. 11.8 ± 0.7 fL). At T1, Group A showed significantly lower TSH (2.26 ± 0.5 µIU/mL), MPV (9.5 ± 0.3 fL), and total cholesterol (137.8 ± 29.2 mg/dL) and significantly higher FT4 (9.3 ± 0.4 pmol/L), PSV (40.0 ± 2.6 cm/s), and IIEF-5 score (20.2 ± 3.6) compared to pre-treatment values. None of these endpoints showed significant change at T1 compared to T0 in patients of group B. Conclusions: Lt4 therapy is associated with an improvement of the erectile function at the vascular level, a decrease in MPV and total cholesterol. LT4 therapy should be considered in patients with arterial ED and SCH.

Resting Energy Expenditure in Obese Women with Primary Hypothyroidism and Appropriate Levothyroxine Replacement Therapy.

Growing evidence suggests that appropriate levothyroxine (LT4) replacement therapy may not correct the full set of metabolic defects afflicting individuals with hypothyroidism. To assess whether obese subjects with primary hypothyroidism are characterized by alterations of the resting energy expenditure (REE). Retrospective analysis of a set of data about obese women attending the outpatients service of a single obesity center from January 2013 to July 2019. A total of 649 nondiabetic women with body mass index (BMI) > 30 kg/m2 and thyrotropin (TSH) level 0.4-4.0 mU/L were segregated into 2 groups: patients with primary hypothyroidism taking LT4 therapy (n = 85) and patients with normal thyroid function (n = 564). REE and body composition assessed using indirect calorimetry and bioimpedance. REE was reduced in women with hypothyroidism in LT4 therapy when compared with controls (28.59 ± 3.26 vs 29.91 ± 3.59 kcal/kg fat-free mass (FFM)/day), including when adjusted for age, BMI, body composition, and level of physical activity (P = 0.008). This metabolic difference was attenuated only when adjustment for homeostatic model assessment of insulin resistance (HOMA-IR) was performed. This study demonstrated that obese hypothyroid women in LT4 therapy, with normal serum TSH level compared with euthyroid controls, are characterized by reduced REE, in line with the hypothesis that standard LT4 replacement therapy may not fully correct metabolic alterations related to hypothyroidism. We are not able to exclude that this feature may be influenced by the modulation of insulin sensitivity at the liver site, induced by LT4 oral administration.

Effects of levothyroxine therapy on bone mineral density and bone turnover markers in premenopausal women with thyroid cancer after thyroidectomy.

We investigated the impact of long-term levothyroxine (LT4) treatment on bone mineral density (BMD) and bone turnover markers (BTMs) in premenopausal women with differentiated thyroid cancer (DTC) after thyroidectomy. Sixty-five premenopausal women who received LT4 therapy at least one year (range, 1.5-9.0 years) after thyroidectomy for DTC and 50 premenopausal women without thyroid diseases were enrolled in this study. We measured the Z-scores of lumbar and hip BMD, serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), intact parathyroid hormone (iPTH), N-terminal propeptide of type 1 N procollagen (P1NP), C terminal telopeptide of type 1 collagen (CTX-1), calcium (Ca), phosphorus (P), vitamin D3, and alkaline phosphatase (ALP) in all participants. In DTC subjects, serum TSH levels were lower, and serum FT4, P1NP, CTX-1, and ALP levels were higher compared with controls. The prevalence of low BMD was higher in DTC subjects than in controls. Multivariate logistic regression analysis showed that serum TSH levels were negatively associated with CTX-1 and ALP. We found a high prevalence of low BMD among premenopausal women who received long-term LT4 therapy for DTC after thyroidectomy. Long-term TSH suppression therapy was a significant risk factor for decreased bone strength, mainly by increasing bone turnover.

Schilddrüse und Schwangerschaft

Pregnancy has a profound impact on the thyroid gland and its function. This has to be considered in the assessment of thyroid function tests on the basis of trimester-specific reference intervals during pregnancy and in the decision making when to start therapy.The adverse impact of overt thyroid disorders in pregnancy is well understood, while the relevance of subclinical thyroid disorders and presence of thyroid antibodies remains a bit controversial. In euthyroid pregnant women with positive thyroid antibodies, levothyroxine (LT4) therapy may be discussed individually in the case of recurrent abortions. Furthermore, the risk of adverse pregnancy outcomes seems to be increased in the presence of both thyroid-stimulating hormone (TSH)-elevation and positive thyroid antibodies. Therefore, in case of subclinical hypothyroidism, taking in consideration the thyroid peroxidase antibody (TPO-Ab)-status individual decision-making and liberal initiation of LT4 therapy is recommended. In contrast, overt hypothyroidism is a strong indication for LT4 administration, aiming at rapid achievement of euthyroidism.The most common cause of hyperthyroidism is transient gestational thyrotoxicosis mediated by human chorionic gonadotropin (hCG), which leads to a reduction or suppression of TSH in the first trimester that does not require antithyroid medication. In other causes of overt hyperthyroidism antithyroid drugs (propylthiouracil or thionamides) need to be considered carefully and require interdisciplinary management.The presented recommendations are based on the current guideline of the American Thyroid Association (ATA) and the European Thyroid Association (ETA) as well as recently published literature.

Age-Related Serum Thyroid-Stimulating Hormone Reference Range in Older Patients Treated with Levothyroxine: A Randomized Controlled Feasibility Trial (SORTED 1)

Introduction: Serum thyroid-stimulating hormone (TSH) increases with age but target TSH is similar in younger and older hypothyroid patients on treatment. It is unknown if quality of life (QoL), hypothyroid symptoms and cardiovascular risk factors change in older hypothyroid patients treated to an age-appropriate reference range. Objective: To assess if a higher target serum TSH of 4.01–8.0 mU/L is feasible in, and acceptable to, older treated hypothyroid patients. Methods: A single-blind (participant) randomised controlled feasibility trial involving 48 hypothyroid patients aged ≥80 years on established and stable levothyroxine (LT4) therapy with serum TSH levels within the standard reference range (0.4–4.0 mU/L) was conducted. Standard (0.4–4.0 mU/L) or higher (4.1–8.0 mU/L) TSH target (standard TSH [ST] or higher TSH [HT] groups) LT4 for 24 weeks was administered. The outcome measures evaluated were thyroid function tests, QoL, hypothyroid symptoms, cardiovascular risk factors and serum marker of bone resorption in participants that completed the trial (n = 21/24 ST group, n = 19/24 HT group). Results: At 24 weeks, in the ST and HT groups, respectively, median (interquartile range) serum TSH was 1.25 (0.76–1.72) and 5.50 (4.05–9.12) mU/L, mean (± SD) free thyroxine (FT4) was 19.4 ± 3.5 and 15.9 ± 2.4 pmol/L, and daily LT4 dose was 82.1 ± 26.4 and 59.2 ± 23.9 µg. There was no suggestion of adverse impact of a higher serum TSH in the HT group with regard to any of the outcomes assessed. Conclusions: In hypothyroid patients aged ≥80 years on LT4 therapy for 24 weeks, there was no evidence that a higher target serum TSH was associated with an adverse impact on patient reported outcomes, cardiovascular risk factors or bone resorption marker over 24 weeks. Longer-term trials assessing morbidity and mortality outcomes and health-utility in this age group are feasible and should be performed.

Thyroid hormone therapy for subclinical hypothyroidism.

Subclinical Hypothyroidism (SCH) is defined as a raised level of serum TSH level in the presence of normal circulating free thyroid hormones. SCH is a highly prevalent condition displaying some peculiarities, both in terms of the diagnostic and therapeutic approach, when specific population and/or concomitant diseases are taken into account. The debate upon whether LT4 therapy should be initiated or not in patients with SCH is a long lasting one and still it remains controversial. Current evidence supports the concept that the clinical consequences of SCH may be profoundly different in relation to several patient-specific characteristics. Aim of the present review is to provide updated indications for SCH treatment in specific clinical settings. These will include the management of SCH in obese and diabetic patients, in pregnant women, and in specific age groups. Treatment modalities, including LT4 doses and recommended follow-up strategy will also be discussed. In the era of "precision medicine" the decision to-treat-not-to-treat SCH should be individualized taking into account risks and beneficial outcomes of LT4 therapy. With this in mind, we reviewed the most relevant studies in the recent literature in order to provide evidence for or against LT4 replacement therapy for SCH in specific clinical settings.

Thyroid hormone therapy of hypothyroidism in pregnancy.

Hypothyroidism is the most frequent pregnancy-related thyroid dysfunction, including overt and subclinical hypothyroidism. Studies show that even mild hypothyroidism may eventuate in adverse gestational outcomes and intellectual impairment of offspring. Women with overt hypothyroidism (OH) must be treated by levothyroxine (LT4) pre- and during pregnancy, however, it is controversial that when and how to initiate LT4 therapy and further optimize dosing so that pregnant women and their offspring may truly benefit. In the review we will analyze the changes in thyroid hormone requirements in pregnant women, the timing of LT4 treatment and adjustment of LT4 dose according to etiology in patients with hypothyroidism during pregnancy, and adjustment of LT4 after delivery.

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal

Background: L-triiodothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer (TC) patients during the preparation for nuclear medicine procedures, and it is used in combination with LT4 in patients who do not respond to the standard treatment for hypothyroidism. This therapy is commonly done by using fixed doses, potentially resulting in supraphysiologic levels of triiodothyronine (T3). A good understanding of the LT3 pharmacokinetics (PK) is necessary to design combination treatment schemes that are able to maintain serum T3 levels within the reference range, but data on the PK of LT3 are conflicting. Here, we present a study designed to characterize the PK of LT3 in patients devoid of endogenous thyroid hormone production, and not receiving LT4 therapy. Methods: We performed an open-label, PK study in patients undergoing thyroid hormone withdrawal in preparation for nuclear medicine procedures for the evaluation and treatment of follicular-derived TC. LT3 was substituted for LT4 at a 1:3 mcg/mcg dosage ratio thrice daily for at least 30 days. PK of the last LT3 dose while at steady state and terminal elimination was assessed over 11 days. Thereafter, a PK study was performed following the nuclear medicine procedure in patients who volunteered for a second study. Results: Fourteen patients age 48.5 ± 16.0 years completed the last dose study and five completed the second PK study. PK analysis indicates a time to maximum serum concentration of 1.8 ± 0.32 hours and two distinct phases of linear elimination, with a fast distribution phase and slow elimination phases with half-lives of 2.3 ± 0.11 hours and 22.9 ± 7.7 hours, supporting a two-compartment model. PK modeling predicts that a twice-daily administration of low-dose LT3 (0.07 mcg/kg twice daily) in combination with LT4 can predictably increase the serum T3 concentration without significant peaks above the reference range. Conclusions: The PK of LT3 is well described by a two-compartment model that assumes elimination only from the sampling compartment, with a rapid distribution phase and a slow elimination phase. This information will contribute to design therapeutic strategies for LT3/LT4 combination therapies directed to maintain stable T3 serum levels.

Levothyroxine Replacement in Obese Adults: The Role of Metabolic Variables and Aging on Thyroid Testing Abnormalities.

General rates of over- and underreplacement in levothyroxine (LT4) users with primary hypothyroidism are variably high. No information on LT4 adequacy exists in obesity. We explored rates and factors relating to LT4 adequacy in obese patients with primary hypothyroidism. Tertiary care center. Among 4954 consecutive obese patients admitted between 2011 and 2014, 691 hypothyroid patients receiving LT4 therapy and 691 body mass index (BMI)-, age-, and sex-matched euthyroid controls underwent analysis of thyroid function, glucolipid profile, body composition, and indirect calorimetry. LT4 users were classified into low TSH (<0.27 mU/L), euthyroid (0.27 to 4.2 mU/L), and high TSH (>4.2 mU/L). LT4 users constituted 13.9% of the incident population. TSH was low in 7.5%, high in 17.2%, and normal in 75.2% of LT4 users. Overtreatment decreased with aging and more LT4 users ≥65 years of age had normal TSH than those <65 years of age (P < 0.05). Compared with the euthyroid obese group, LT4 users showed higher adiposity, similar insulin resistance, but a healthier lipid profile. In multivariable analyses, LT4 dose was predicted by fat-free mass, hypothyroidism cause, and sex (P < 0.0001 to < 0.05). Risk of LT4 overreplacement increased with younger age (OR 0.96; 95% CI 0.94 to 0.99), higher LT4 dose (OR 2.98; 95% CI 1.44 to 6.14), and lower BMI (OR 0.93; 95% CI 0.88 to 0.99). Male sex increased the likelihood of LT4 underreplacement (OR 2.37; 95% CI 1.10 to 5.11). Obesity is associated with milder rates of inadequate LT4 treatment compared with nonobese populations. LT4 adequacy increases with aging. Age, body composition, and sex are main determinants of LT4 requirements in obesity.

Body Composition, Resting Energy Expenditure, and Metabolic Changes in Women Diagnosed with Differentiated Thyroid Carcinoma.

Background: Thyroid hormones heavily impact energy expenditure, body mass, and body composition. Their role in the state of exogenous subclinical hyperthyroidism in differentiated thyroid carcinoma (DTC) patients, however, is less well defined. The first aim of this study was to assess changes in body weight, body composition, resting energy expenditure (REE), respiratory quotient (RQ), and metabolic parameters in female DTC patients, starting from the phase of a euthyroid state before total thyroidectomy through the subsequent year after thyrotropin (TSH) suppression. The second aim was to assess the relationship between these variables and thyroid function parameters. Methods: This observational case series analyzed changes in body composition, calorimetric, and metabolic parameters of 15 DTC female patients at 5 time points: (1) at initial DTC diagnosis (euthyroid state), (2) at 2-3 weeks after thyroidectomy (hypothyroid state), (3) at 2-3 months of levothyroxine (LT4) treatment (exogenous euthyroid state), (4) after 6-9 months, and (5) after 1 year of TSH suppressive LT4 therapy (exogenous subclinical hyperthyroid state). A generalized estimating equation (GEE) analysis was performed to estimate the longitudinal correlations of the total triiodothyronine (TT3)/free thyroxine (fT4) ratio (as an independent variable) with body composition, metabolic, and calorimetric parameter changes (as dependent variables). Results: REE, REE per kilogram of lean body mass (REE/LBM), pulse, and systolic and diastolic blood pressure were significantly higher after TSH suppressive LT4 therapy. The GEE analysis revealed longitudinal negative correlations between the TT3/fT4 ratio and systolic blood pressure, fasting blood glucose, body mass index, android (abdominal wall and visceral mesentery) fat distribution, trunk, and arm fat distribution, REE, and REE/LBM. There was a positive correlation with RQ. Conclusions: REE, REE/LBM, pulse, and systolic and diastolic blood pressure were significantly higher after thyroidectomy, radioiodine and TSH suppressive therapy in female DTC patients, while no changes were observed in body weight or body composition. A lower TT3/fT4 ratio longitudinally correlated with increases in REE, REE/LBM, abdominal fat distribution, systolic blood pressure, and fasting blood glucose, as well as with decreased RQ. These findings highlight the importance of judicial balancing of the benefits and detriments of TSH suppression with subsequent decreased TT3/fT4 ratios for female DTC patients.