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.
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Salman Razvi, Sanaa Mrabeti, and Markus Luster
L Johnsen, N B Lyckegaard, P Khanal, B Quistorff, K Raun, and M O Nielsen
We aimed to test, whether fetal under- or overnutrition differentially program the thyroid axis with lasting effects on energy metabolism, and if early-life postnatal overnutrition modulates implications of prenatal programming.
Twin-pregnant sheep (n = 36) were either adequately (NORM), under- (LOW; 50% of NORM) or overnourished (HIGH; 150% of energy and 110% of protein requirements) in the last-trimester of gestation. From 3 days-of-age to 6 months-of-age, twin lambs received a conventional (CONV) or an obesogenic, high-carbohydrate high-fat (HCHF) diet. Subgroups were slaughtered at 6-months-of-age. Remaining lambs were fed a low-fat diet until 2½ years-of-age (adulthood).
Serum hormone levels were determined at 6 months- and 2½ years-of-age. At 2½ years-of-age, feed intake capacity (intake over 4-h following 72-h fasting) was determined, and an intravenous thyroxine tolerance test (iTTT) was performed, including measurements of heart rate, rectal temperature and energy expenditure (EE).
In the iTTT, the LOW and nutritionally mismatched NORM:HCHF and HIGH:CONV sheep increased serum T3, T3:T4 and T3:TSH less than NORM:CONV, whereas TSH was decreased less in HIGH, NORM:HCHF and LOW:HCHF. Early postnatal exposure to the HCHF diet decreased basal adult EE in NORM and HIGH, but not LOW, and increased adult feed intake capacity in NORM and LOW, but not HIGH.
Conclusions: The iTTT revealed a differential programming of central and peripheral HPT axis function in response to late fetal malnutrition and an early postnatal obesogenic diet, with long-term implications for adult HPT axis adaptability and associated consequences for adiposity risk.
Xiujuan Su, Yan Zhao, Zhijuan Cao, Yingying Yang, Tony Duan, and Jing Hua
The effect of isolated maternal hypothyroxinaemia (IMH) on pregnancy complications and neonatal outcomes in human beings is still controversial.
This was a retrospective cohort study based on the electronic medical register system. The records of women with a singleton pregnancy who sought antenatal examination between January 2014 and December 2015 at Shanghai First Maternity and Infant Hospital were extracted from the electronic medical records system. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and anti-thyroperoxidase autoantibody (TPO-Ab) was measured before 20 gestational weeks, and a multiple logistic regression model was used to estimate the odds ratios of pregnancy complications and neonatal outcomes between euthyroid women and those with isolated hypothyroxinaemia.
A total of 8173 women were included in this study, of whom 342 (4.18%) were diagnosed with IMH. Regression analysis showed that IMH diagnosed in the second trimester (13–20 weeks) was associated with an increased risk of hypertensive disorders of pregnancy (OR = 2.66, 95% CI: 1.38–5.10) and placenta abruption (OR = 3.64, 95% CI: 1.07–12.41), but not with preterm delivery (OR = 1.09, 95% CI: 0.50–2.40), small or large gestational age of infant (OR = 0.91, 95% CI: 0.39–2.12; OR = 1.16, 95% CI: 0.72–1.86), macrosomia (OR = 1.71, 95% CI: 0.95–3.07), gestational diabetes mellitus (OR = 1.36, 95% CI: 0.86–2.15) and placenta previa (OR = 1.62, 95% CI: 0.39–7.37).
IMH could be a risk factor for hypertensive disorders of pregnancy.
Amir Bashkin, Eliran Yaakobi, Marina Nodelman, and Ohad Ronen
TSH routine testing in hospitalized patients has low efficacy, but may be beneficial in a selected subgroup of patients. Our aim was to evaluate the efficacy of routine thyroid function tests among patients admitted to internal medicine departments. It is a retrospective study. A randomly selected cohort of hospitalized patients with abnormal thyroid-stimulating hormone (TSH) blood tests drawn as part of admission protocol. Patient data were collected from the electronic medical files and analyzed for its efficacy. TSH as a screening test was proven unnecessary in 75% (174) of the study population. Leading causes were non-thyroidal illness syndrome, drugs affecting the test results and subclinical disorders. TSH testing was found to be clinically helpful in only 9 patients; however, all of them had other clinical need for TSH testing. We found a clinically abnormal TSH in 20 patients, hypothyroidism in 11 patients and thyrotoxicosis in 9 patients. Low efficacy ascribed to TSH screening test by this study correlates with recent recommendations that indicate TSH screening in admitted patients only with accompanying clinical suspicion. Most probably, the majority of patients found by screening to have thyrotoxicosis have non-thyroidal illness or drug effects so the threshold for FT4 to diagnose overt thyrotoxicosis should be higher than that in ambulatory patients. In elderly patients, clinically relevant TSH disturbances are more frequent and are harder to diagnose, therefore, TSH screening in this group of patients might be beneficial.
Alessandro Brancatella and Claudio Marcocci
Thyroid hormones stimulate bone turnover in adults by increasing osteoclastic bone resorption. TSH suppressive therapy is usually applied in patients with differentiated thyroid cancer (DTC) to improve the disease outcome. Over the last decades several authors have closely monitored the potential harm suffered by the skeletal system. Several studies and meta-analyses have shown that chronic TSH suppressive therapy is safe in premenopausal women and men. Conversely, in postmenopausal women TSH suppressive therapy is associated with a decrease of bone mineral density, deterioration of bone architecture (quantitative CT, QCT; trabecular bone score, TBS), and, possibly, an increased risk of fractures. The TSH receptor is expressed in bone cells and the results of experimental studies in TSH receptor knockout mice and humans on whether low TSH levels, as opposed to solely high thyroid hormone levels, might contribute to bone loss in endogenous or exogenous thyrotoxicosis remain controversial. Recent guidelines on the use of TSH suppressive therapy in patients with DTC give value not only to its benefit on the outcome of the disease, but also to the risks associated with exogenous thyrotoxicosis, namely menopause, osteopenia or osteoporosis, age >60 years, and history of atrial fibrillation. Bone health (BMD and/or preferably TBS) should be evaluated in postmenopausal women under chronic TSH suppressive therapy or in those patients planning to be treated for several years. Antiresorptive therapy could also be considered in selected cases (increased risk of fracture or significant decline of BMD/TBS during therapy) to prevent bone loss.
Muthiah Subramanian, Manu Kurian Baby, and Krishna G Seshadri
Antithyroid drugs (ATDs) have been shown to attenuate the effectiveness of radioiodine (radioiodine ablation, RIA) therapy in Graves' disease. We undertook a study to look at the impact of iodine uptakes on the outcome of 131I therapy. To determine the effect of prior ATD use on the duration of time to achieve cure in patients with high vs intermediate uptake Graves' disease who received a fixed dose (15 mCi) of 131I radioiodine. In a retrospective study of patients with Graves' disease, 475 patients who underwent RIA were followed-up on a two-monthly basis with thyroid function tests. Of the 123 patients with a documented preablation RAIU and consistent follow-up it was observed that 40 patients had an intermediate RAIU (10–30%) and 83 subjects had a distinctly increased uptake (>30%). Successful cure was defined as the elimination of thyrotoxicosis in the form of low free thyroxin and rising TSH levels. When a standard dose of 15 mCi 131I was administered, a cure rate of 93% was achieved. The median duration of time to cure (TC) was 129 days. Surprisingly, a direct proportional linear relationship (R 2=0.92) was established between time to cure and radioiodine uptake (TC> 3 0%=172days, TC10 – 3 0%=105 days, P<0.001). Patients who used ATD medications took a proportionately longer duration to achieve remission (TCNO ATD=102days, TCATD=253days, P<0.001). The effect of prior ATD therapy in delaying remission was amplified in the subset of patients with higher uptakes (TC> 3 0% + ATD=310days, TC> 3 0% + NO ATD=102days, P<0.001) compared to those with the intermediate uptakes (TC10 – 3 0% + ATD=126 days, TC10 – 3 0% + NO ATD=99 days, P<0.001). RIA, using a dose of 15 mCi achieved a high cure rate. Higher uptakes predicted longer time to achieve remission, with prior ATD use amplifying this effect.
Verônica Carneiro Borges Mioto, Ana Carolina de Castro Nassif Gomes Monteiro, Rosalinda Yossie Asato de Camargo, Andréia Rodrigues Borel, Regina Maria Catarino, Sergio Kobayashi, Maria Cristina Chammas, and Suemi Marui
Iodine deficiency during pregnancy is associated with obstetric and neonatal adverse outcomes. Serum thyroglobulin (sTg) and thyroid volume (TV) are optional tools to urinary iodine concentration (UIC) for defining iodine status. This cross-sectional study aims to evaluate the iodine status of pregnant women living in iodine-adequate area by spot UIC and correlation with sTg, TV and thyroid function.
Two hundred and seventy-three pregnant women were evaluated at three trimesters. All had no previous thyroid disease, no iodine supplementation and negative thyroperoxidase and thyroglobulin antibodies. Thyroid function and sTg were measured using electrochemiluminescence immunoassays. TV was determined by ultrasonography; UIC was determined using a modified Sandell–Kolthoff method.
Median UIC was 146 µg/L, being 52% iodine deficient and only 4% excessive. TSH values were 1.50 ± 0.92, 1.50 ± 0.92 and 1.91 ± 0.96 mIU/L, respectively, in each trimester (P = 0.001). sTg did not change significantly during trimesters with median 11.2 ng/mL and only 3.3% had above 40 ng/mL. Mean TV was 9.3 ± 3.4 mL, which positively correlated with body mass index, but not with sTg. Only 4.5% presented with goitre.
When pregnant women were categorized as iodine deficient (UIC < 150 µg/L), adequate (≥150 and <250 µg/L) and excessive (≥250 µg/L), sTg, thyroid hormones and TV at each trimester showed no statistical differences.
Iodine deficiency was detected frequently in pregnant women living in iodine-adequate area. sTg concentration and TV did not correlate to UIC. Our observation also demonstrated that the Brazilian salt-iodization programme prevents deficiency, but does not maintain iodine status within adequate and recommended ranges for pregnant women.
Norra Kwong, Ellen Marqusee, Michael S Gordon, P Reed Larsen, Jeffrey R Garber, Matthew I Kim, and Erik K Alexander
Well-differentiated thyroid carcinoma (WDTC) generally has a favorable prognosis. However, patients with distant metastatic disease experience progression of disease with a higher mortality. A subset of patients not previously described may challenge the conventional dogma regarding the progressive nature of all metastatic WDTC. Through analysis of our database, we identified patients with distant metastatic WDTC and persistent, minimally progressive disease. In all patients, persistent metastatic disease was confirmed via tissue biopsy, abnormal PET scan, and/or biochemical elevations in thyroglobulin or antibody levels. Progression of disease was monitored clinically and with repeat imaging. We describe five patients with WDTC and pulmonary metastases, aged 8–43 years at diagnosis. All patients underwent initial surgery and radioactive iodine (RAI) ablation, with some receiving multiple treatments. Persistent pulmonary metastatic disease was confirmed over decades (mean 22 years, range 8–42 years) with minimal progression despite no further treatment beyond thyroid hormone suppression. Persistent disease was biopsy-proven in all patients at a mean of 9.6 years from last RAI treatment. All patients had elevated thyroglobulin or anti-thyroglobulin antibody levels, while three demonstrated metabolically active disease with positive FDG uptake on PET scan, and one patient with persistent radioactive iodine avid pulmonary metastasis 36 years after her last RAI treatment. This case series demonstrates that some patients with distant metastases, even if metabolically active and radioactive iodine resistant, remain stable for decades without further treatment. Clinical awareness of such patients and continual reassessment of disease risk following initial therapy are crucial as aggressive treatment may not be necessary.
Isabel M Abreu, Eva Lau, Bernardo de Sousa Pinto, and Davide Carvalho
Previous studies suggested that subclinical hypothyroidism has a detrimental effect on cardiovascular risk factors, and that its effective treatment may have a beneficial impact on overall health. The main purpose of this review and meta-analysis was to assess whether subclinical hypothyroidism treatment is of clinical relevance, based on cardiovascular risk parameters correction. A systemic research of the literature using MEDLINE tool was performed to identify the relevant studies. Only placebo-controlled randomized control trials were included. A quantitative analysis was also performed. This systematic review and meta-analysis of randomized placebo-controlled trials assess the different impact of levothyroxine vs placebo treatment. A significant decrease in serum thyroid-stimulating hormone and total and low-density lipoprotein cholesterol was obtained with levothyroxine therapy (66, 9 and 14%, respectively) and, although modest, this could be significant in terms of reduction of the incidence of coronary artery disease. Other significant results of lipid parameters were not obtained. This systematic review provides a strong evidence-based data in favour of specific changes and beneficial effects of levothyroxine treatment.
Monika Schaffner, Ursula Rochau, Nikolai Mühlberger, Annette Conrads-Frank, Vjollca Qerimi Rushaj, Gaby Sroczynski, Eftychia Koukkou, Betina Heinsbaek Thuesen, Henry Völzke, Wilhelm Oberaigner, and Uwe Siebert
More than 30% of the German population suffers from mild to moderate iodine deficiency causing goiter and other iodine deficiency disorders (IDDs). The economic burden of iodine deficiency is still unclear. We aimed to assess costs for prevention, monitoring and treatment of IDDs in Germany.
We performed a comprehensive cost analysis.
We assessed direct medical costs and direct non-medical costs for inpatient and outpatient care of IDDs and costs for productivity loss due to the absence of work in 2018. Additionally, we calculated total costs for an IDD prevention program comprising universal salt iodization (USI). We performed threshold analyses projecting how many cases of IDDs or related treatments would need to be avoided for USI to be cost-saving.
Annual average costs per case in the year of diagnosis were € 211 for goiter/thyroid nodules; € 308 for hyperthyroidism; and € 274 for hypothyroidism. Average one-time costs for thyroidectomy were € 4184 and € 3118 for radioiodine therapy. Average costs for one case of spontaneous abortion were € 916. Annual costs of intellectual disability were € 14,202. In the German population, total annual costs for USI would amount to 8 million Euro. To be cost-saving, USI would need to prevent, for example, 37,900 cases of goiter/thyroid nodules.
USI potentially saves costs, if a minimum amount of IDDs per year could be avoided. In order to recommend the implementation of USI, a full health-economic evaluation including a comprehensive benefit-harm assessment is needed.