Persistent Subclinical Hypothyroidism Research Articles

The Spectrum of Thyroid Function Tests and Autoantibodies During Hospitalization and After Six Months of Discharge in COVID-19 Patients: Does COVID-19 Trigger Autoimmunity?

ABSTRACT Objective The aim of the study was to investigate thyroid function test (TFT) results and anti-thyroid antibody titers in acutely infected COVID-19 patients, as well as the changes in TFT and autoantibody results during the 6-months recovery period among survivors. Patients and Design A total of 163 adult COVID-19 patients and 124 COVID-19 survivors were evaluated in terms of TFT (thyroid stimulating hormone [TSH], free triiodothyronine [fT3], and free thyroxine [fT4]) and anti-thyroid antibodies (anti-thyroglobulin [anti-Tg] and anti-thyroid peroxidase [anti-TPO]). Results Thyroid dysfunction was noted in 56.4% of patients on admission, including the non-thyroidal illness syndrome (NTIS) in most cases. Presence vs. absence of thyroid dysfunction on admission was associated with significantly higher rate of severe disease (p < 0.001), while severe vs. mild-to-moderate disease was associated with significantly lower serum fT3 levels (p = 0.001). Overall, 94.4% of survivors were euthyroid at the time of 6 months post-discharge, while in some patients, the post-COVID-19 recovery period was also associated with significantly increased anti-TPO titers and the presence of new-onset or persistent subclinical hypothyroidism. Conclusion This is one of the few studies to evaluate TFT and autoantibodies over a 6-month period after recovery from COVID-19. The presence of emergent or persistent subclinical hypothyroidism and the significantly increased anti-TPO titers in some patients during the convalescence period suggest the need for follow-up for development of thyroid dysfunction and autoimmunity among COVID-19 survivors.

Hypothyroidism in children with Hb E/β-thalassemia compared between those who received regular transfusion and those who underwent hematopoietic stem cell transplantation

The studies of hypothyroidism in children with transfusion-dependent hemoglobin E/β-thalassemia (TDT), especially in those who underwent hematopoietic stem cell transplantation (HSCT) are limited. We performed a longitudinal retrospective analysis of thyroid function test (TFT) results among TDT patients aged <25 years who received regular transfusion compared to those who underwent HSCT in Faculty of Medicine Siriraj hospital, Thailand during October 2003 to March 2019. Fifty patients (23 TDT, 27 HSCT) were included. The mean age at the last follow-up was 20.1 ± 2.8 vs. 14.5 ± 4.61 years, respectively. The median age at HSCT was 6 (range: 1.9–13.7) years. The prevalence of hypothyroidism among TDT and post-HSCT was 47.8% and 52.2%, respectively. No study patients showed symptoms or signs of hypothyroidism. Subclinical hypothyroidism was the most common type (63.6% of TDT, and 100% of post-HSCT). We found persistent hypothyroidism in 30.4% of TDT, and in 22.2% of post-HSCT. Thyroxine was given in 1 TDT patient with overt hypothyroidism, and in 3 of 6 post-HSCT patients with persistent subclinical hypothyroidism. The ex-thalassemia patients who underwent HSCT after the age of 10 years had a significantly higher risk of post-HSCT hypothyroidism compared to those who underwent HSCT at the age ≤10 years (hazard ratio: 12.01, 95% confidence interval: 1.65–87.41; p = 0.014). In conclusion, hypothyroidism was found to be common in both TDT and post-HSCT patients. Subclinical hypothyroidism without symptoms and signs was the most common type, and was diagnosed only by TFT screening. Long-term regular surveillance of TFT should be performed in both groups of patients.

Impact of persistent subclinical hypothyroidism on clinical outcomes in non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention.

Data on the association of subclinical hypothyroidism (SCH) with the severity of coronary artery disease and major adverse cardiovascular and cerebral events (MACCE) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) after percutaneous coronary intervention (PCI) are limited and conflicting. We established the baseline rate of SCH and followed the trajectory of thyroid-stimulating hormone (TSH) values during and after hospitalisation for PCI for up to six months and determined whether persistent SCH was associated with the severity of coronary artery disease and MACCE in patients with NSTE-ACS after PCI. Population-based prospective cohort study. We included patients with NSTE-ACS who underwent PCI with simple balloon angioplasty or stent implantation for coronary heart disease. Thyroid function tests of patients before PCI and 1 day, 1 week, 1 and 6 months after PCI were performed. Cases showing transient SCH were excluded. Patients were divided into two groups based on the results of four TSH tests: 0.27-4.2 mIU/L (n = 1472, 89.7%) and >4.2 mIU/L (n = 170, 10.4%). The risk factors for the severity of coronary artery lesions were estimated using multinomial logistic regression analysis. Univariate and multivariate Cox regression analyses were used to study the relationship between TSH and MACCE. Among 1642 patients, there were 1070 males (65.2%) and 572 females (34.8%), with an average age of 62.5 ± 9.6 years. SCH patients had a wider range of diseased vessels and a higher number of diseased vessels (p < .05). TSH level was an independent risk factor for moderate [odds ratio (OR) = 1.144, 95% confidence interval (95% CI): 1.057-1.237, p = .001] and severe (OR = 1.131, 95% CI: 1.043-1.226, p = .003) coronary artery lesions. After adjusting for covariates, the risk of MACCE [hazard ratio (HR): 4.067, p < .001], nonfatal myocardial infarction (HR: 14.724, p = .003), and unplanned PCI (HR: 5.028, p < .001) were higher in the SCH group than in the euthyroidism group. There were no significant differences in the incidence of heart failure (HR: 6.012, p = .175), nonfatal stroke (HR: 2.039, p = .302), unplanned coronary artery bypass grafting (CABG) (HR: 1.541, p = .57), or cardiac death (HR: 2.704, p = .375) between the two groups. Preoperative TSH levels and changes in thyroid hormone levels several months post-PCI in NSTE-ACS patients are highly significant in practice. Persistent SCH is associated with severe coronary artery lesions and MACCE, and may be a predictor for evaluating the prognosis of PCI-treated NSTE-ACS patients.

Transient high thyroid stimulating hormone and hypothyroidism incidence during follow up of subclinical hypothyroidism.

Objectives. Given the high prevalence of subclinical hypothyroidism (SCH), defined as high thyroid stimulating hormone (TSH) and normal free thyroxine (FT4), and uncertainty on treatment, one of the major challenges in clinical practice is whether to initiate the treatment for SCH or to keep the patients under surveillance. There is no published study that has identified predictors of short-term changes in thyroid status amongst patients with mild elevation of TSH (4.5-10 mIU/L). Subjects and Results. A cohort study was conducted on patients with SCH detected through a general population screening program, who were followed for six months. This project identified factors predicting progression to hypothyroid status, persistent SCH and transient cases. A total of 656 participants joined the study (431 controls and 225 were patients with SCH). A part of participants (12.2%) developed biochemical hypothyroidism during the follow-up, while 73.8% of the subjects became euthyroid and the remained ones (13.4%) stayed in the SCH status. The incidence of overt hypothyroidism for participants with TSH above 6.9 mIU/L was 36.7%, with incidence of 42.3% for females. Anti-thyroid peroxidase antibodies (TPO) positivity is an important predictor of development of hypothyroidism; however, it could be also positive due to transient thyroiditis. Conclusions. It can be concluded that females with TSH above 6.9 mIU/L, particularly those with free triiodothyronine (FT3) and FT4 in the lower half of the reference range, are more likely to develop biochemical hypothyroidism. Therefore, it is recommended to give them a trial of levothyroxine replacement. It is also recommended to repeat TSH after six months for male subjects and participants with baseline TSH equal or less than 6.9 mIU/L.

Physiologic Effects of Levothyroxine and Liothyronine in the in Older Individuals With Persistent Subclinical Hypothyroidism: A Randomized, Double-Blind, Cross-Over Study

Background: Subclinical hypothyroidism is common in older individuals, but the physiologic responses to treatment with levothyroxine (LT4) and liothyronine (LT3) are not well defined in this age group. Methods: We conducted a randomized, double-blind, cross-over study of LT4 and LT3 treatment in men and women aged 70 years and over without anti-thyroid peroxidase antibodies with persistent subclinical hypothyroidism, defined as having a TSH level between 4.5 and 19.9 µIU/mL with a normal free thyroxine (FT4) level at two consecutive time points. Physiologic outcome measures assessed after achieving a TSH level of 0.5-1.5 µIU/mL with each therapy included vital signs, weight and body composition, bone mineral content and bone density, lipids, resting energy expenditure (REE), cognitive function, quality of life, and thyroid symptoms. Results: Thirteen participants [mean (SD) age 77 (5) years], 4 women and 9 men, completed the study. Baseline mean TSH was 4.84 (1.29) µIU/mL. The mean LT4 dose was 105 (36) µg/day [1.4 (0.5) µg/kg/day] and LT4 dose was 34 (9) µg/day [0.4 (0.1) µg/kg/day]. Mean time on LT4 was 200 days and on LT3 was 231 days, with a 28 day washout period. Compared with baseline, participants had an average weight loss of 1.1 kg on LT4 (p<0.02) and 2.5 kg on LT3 (p<0.001), which was significantly different between the two treatments (p=0.01). Fat mass decreased by an average of 0.7 kg on LT4 (p=0.03 vs. baseline) and 1.5 kg on LT3 (p<0.01 vs. baseline) and differed between treatments (p=0.01). There was a significant difference in total cholesterol of 13.3 mg/dL (p<0.001) and in low-density lipoprotein cholesterol (LDL) of 10.8 mg/dL (p<0.001) between LT4 and LT3 treatment arms; for both, the levels were lower on LT3 than LT4. No differences were seen in the other assessed outcomes. Conclusions: In a cross-over study of treatment of LT4 or LT3 in persistent subclinical hypothyroidism, participants lost fat mass and weight after each treatment, with a greater decrease after treatment with LT3. These findings support different physiologic responses to LT4 compared with LT3.

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

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

Multinational Survey of Treatment Practices of Clinicians Managing Subclinical Hypothyroidism in Older People in 2019

Background: International societies have recommended that levothyroxine should not routinely be prescribed in older individuals for the management of mild subclinical hypothyroidism (SCH). However, it is unknown whether clinicians managing people with SCH are either aware of or adhere to these guidelines. Methods: A web-based survey of members of several international thyroid associations and general practitioners in North-East England was conducted. Respondents were presented with a vignette of an 80-year-old gentleman with mild persistent SCH experiencing tiredness. Multivariable logistic regression analyses were performed to evaluate predictors of awareness of guidelines and responses to treatment. Results: The survey response rate was 21.9% (565/2,583). Only 7.6% of clinicians were unaware of guidelines regarding management of SCH in older people. Twenty percent of clinicians stated that they would treat the older patient with mild SCH, whereas 13% were unsure. Clinicians from North America were more likely to treat the older person with mild SCH than clinicians from elsewhere (OR 2.24 [1.25–3.98]). Likewise, non-endocrinologists were also more likely than endocrinologists to treat the older person with mild SCH (OR 3.26 [1.45–6.47]). Conclusion: The majority of clinicians are aware of guidelines regarding management of SCH in older individuals. However, a considerable proportion of clinicians would still treat an older person with non-specific symptoms and mild SCH. These guidelines need to be disseminated more widely and more research is required to understand barriers to adherence to international recommendations.

Effect of Thyroid Hormone Therapy on Fatigability in Older Adults With Subclinical Hypothyroidism: A Nested Study Within a Randomized Placebo-Controlled Trial.

BackgroundFatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue.MethodThis study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged ≥65 and older, with persistent subclinical hypothyroidism (TSH 4.60–19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 μg (25 μg if weight <50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose.ResultsAmong 230 participants, the mean ± standard deviation (SD) TSH was 6.2 ± 1.9 mIU/L at baseline and decreased to 3.1 ± 1.3 with LT4 (n = 119) versus 5.3 ± 2.3 with placebo (n = 111, p < .001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI −1.8 to 2.1; p = .88), or mental fatigability (−1.0; 95% CI −2.8 to 0.8; p = .26). In participants with higher fatigability at baseline (≥15 points for the physical score [n = 88] or ≥13 points for the mental score [n = 41]), the adjusted between-group differences at 1 year were 0.4 (95% CI −3.6 to 2.8, p = .79) and −2.2 (95% CI −8.8 to 4.5, p = .51).ConclusionsLevothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability.

Annals for Educators - 2 June 2020

Annals for Educators - 2 June 2020

L-Thyroxine Therapy for Older Adults With Subclinical Hypothyroidism and Hypothyroid Symptoms: Secondary Analysis of a Randomized Trial.

L-thyroxine does not improve hypothyroid symptoms among adults with subclinical hypothyroidism (SCH). However, those with greater symptom burden before treatment may still benefit. To determine whether L-thyroxine improves hypothyroid symptoms and tiredness among older adults with SCH and greater symptom burden. Secondary analysis of the randomized, placebo-controlled trial TRUST (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial). (ClinicalTrials.gov: NCT01660126). Switzerland, Ireland, the Netherlands, and Scotland. 638 persons aged 65 years or older with persistent SCH (thyroid-stimulating hormone level of 4.60 to 19.9 mIU/L for >3 months and normal free thyroxine level) and complete outcome data. L-thyroxine or matching placebo with mock dose titration. 1-year change in Hypothyroid Symptoms and Tiredness scores (range, 0 to 100; higher scores indicate more symptoms) on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire among participants with high symptom burden (baseline Hypothyroid Symptoms score >30 or Tiredness score >40) versus lower symptom burden. 132 participants had Hypothyroid Symptoms scores greater than 30, and 133 had Tiredness scores greater than 40. Among the group with high symptom burden, the Hypothyroid Symptoms score improved similarly between those receiving L-thyroxine (mean within-group change, -12.3 [95% CI, -16.6 to -8.0]) and those receiving placebo (mean within-group change, -10.4 [CI, -15.3 to -5.4]) at 1 year; the adjusted between-group difference was -2.0 (CI, -5.5 to 1.5; P = 0.27). Improvements in Tiredness scores were also similar between those receiving L-thyroxine (mean within-group change, -8.9 [CI, -14.5 to -3.3]) and those receiving placebo (mean within-group change, -10.9 [CI, -16.0 to -5.8]); the adjusted between-group difference was 0.0 (CI, -4.1 to 4.0; P = 0.99). There was no evidence that baseline Hypothyroid Symptoms score or Tiredness score modified the effects of L-thyroxine versus placebo (P for interaction = 0.20 and 0.82, respectively). Post hoc analysis, small sample size, and examination of only patients with 1-year outcome data. In older adults with SCH and high symptom burden at baseline, L-thyroxine did not improve hypothyroid symptoms or tiredness compared with placebo. European Union FP7.

Thyroid disorders in Taiwanese children with Down syndrome: The experience of a single medical center

Thyroid disorders are common in children with Down syndrome (DS), however, such data have rarely been reported in Taiwanese children. This study presents our experience with the management of these children. Between 2006 and 2016, 51 children (31 boys and 20 girls) with DS were enrolled. Thyroid function was evaluated and natural course of thyroid status were analyzed. Of 51 patients with DS, 2 had congenital hypothyroidism due to dyshormonogenesis. Of the remaining 49 patients, 30 (61%) had euthyroidism (EuT), and 19 (39%) had subclinical hypothyroidism (SH). Eighteen (37%) had detectable thyroid antibodies. It occurred at any age and the incidence was not affected by sex. The mean follow-up duration for 39 DS children was 3.8±2.4 years. Of the 26 children who had EuT at enrollment and were followed up, 22 remained EuT, 2 developed SH, 1 developed overt hypothyroidism, and 1 developed overt hyperthyroidism. Of the 13 patients with SH who were followed up, 1 was treated for high thyroid-stimulating hormone levels, 8 became EuT, and 4 maintained SH status. Children with DS and persistent SH had significantly higher maximum thyroid-stimulating hormone levels during follow-up than did those with transient SH. Fluctuation in thyroid status during follow-up was not uncommon in children with DS. The prevalence of thyroid disorders is higher in Taiwanese children with DS than in the general population. Because symptoms of hypothyroidism overlap those inherent to DS, regular follow-up of thyroid function in children with DS is indicated.

Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80\xa0years and over

BackgroundSubclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base.MethodsThe IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over.The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years.Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure.DiscussionThe combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date.Trial registrationNederlands (Dutch) Trial Register: NTR3851 (12–02-2013), EudraCT: 2012–004160-22 (17–02-2013), ABR-41259.058.13 (12–02-2013).

Thyroid Stimulating Hormone Level at Diagnosis as a Predictor of Persistent Subclinical Hypothyroidism in Children with Down Syndrome

To evaluate subclinical hypothyroidism in a cohort of children with Down syndrome and identify a TSH level at the time of diagnosis to predict persistent hypothyroidism. 192 children (age <3 years) with Down syndrome, registered in the Genetic Clinic of a referral tertiary care Hospital from 2010 to 2015 were evaluated with thyroid function test at initial visits and subsequently based on standard protocol. Children with subclinical hypothyroidism were evaluated at 3 years of age after discontinuation of thyroxine for 3 months. 47 (24.5%) children had elevated TSH and among them 43 (91.5%) had subclinical hypothyroidism. Among the subclinical hypothyroidism group, 25 (73.5%) had transient hypothyroidism and 9 (26.5%) persistent hypothyroidism. Initial TSH level at the time of diagnosis was higher in persistent hypothyroidism group as compared to transient group (P= 0.003). The best cut-off level for prediction of persistent hypothyroidism for initial TSH level was 11.6 mIU/L. Subclinical hypothyroidism, especially transient, is the commonest form of thyroid dysfunction in children with Down syndrome. The initial TSH level may help to predict the possibility of persistence of hypothyroidism.

Natural history of mild subclinical hypothyroidism in a middle-aged and elderly Chinese population: a prospective study.

Subclinical hypothyroidism (SCH) has a high global prevalence. Most SCH patients have mild cases (thyrotropin ≤10 mIU/L). Treatment recommendations for mild SCH are controversial, which raises concerns about the natural history of mild SCH. We aimed to clarify the natural history of mild SCH. This is a prospective population-based study. We measured thyroid function in 11,000 participants in the REACTION study and followed 505 newly diagnosed mild SCH patients aged 40-years or older between 2011 and 2014. Logistic regression analysis was used to seek baseline parameters associated with the natural outcomes of mild SCH. Among 505 mild SCH patients, 221 (43.8%) had persistent SCH, 251 (49.7%) reverted to euthyroidism, and 17 (3.4%) progressed to overt hypothyroidism (OH). Patients with higher baseline total cholesterol (TC, between 201.0-240.0 mg/dL or >240.0 mg/dL vs. <201.0 mg/dL, p = 0.048 and 0.006, respectively) or positive thyroid peroxidase antibodies (TPOAb, p = 0.009) had higher risks of progression to OH, while those with higher baseline creatinine (CR, between 0.71-0.80 mg/dL or >0.80 mg/dL vs. ≤0.65 mg/dL, p = 0.031 and 0.004, respectively), higher baseline thyrotropin (≥7 mIU/L, p < 0.001) or older (>60 years vs. ≤50 years, p = 0.012) had lower odds of reverting to euthyroidism. In conclusion, TPOAb and TC seem to be more important predictors of progression to OH than initial thyrotropin, whereas high baseline thyrotropin or CR were negative correlated with reversion to euthyroidism. The prognostic value of TC and CR in mild SCH should be considered.

Subclinical Hypothyroidism in Childhood Cancer Survivors.

PurposeIn childhood cancer survivors, the most common late effect is thyroid dysfunction, most notably subclinical hypothyroidism (SCH). Our study evaluated the risk factors for persistent SCH in survivors.Materials and MethodsSurvivors (n=423) were defined as patients who survived at least 2 years after cancer treatment completion. Thyroid function was assessed at this time and several years thereafter. Two groups of survivors with SCH were compared: those who regained normal thyroid function during the follow-up period (normalized group) and those who did not (persistent group).ResultsOverall, 104 of the 423 survivors had SCH. SCH was observed in 26% of brain or nasopharyngeal cancer survivors (11 of 43) and 21.6% of leukemia survivors (35 of 162). Sixty-two survivors regained normal thyroid function, 30 remained as persistent SCH, and 12 were lost to follow-up. The follow-up duration was 4.03 (2.15–5.78) years. Brain or nasopharyngeal cancer and Hodgkin disease were more common in the persistent group than in the normalized group (p=0.002). More patients in the persistent group received radiation (p=0.008). Radiation to the head region was higher in this group (2394±2469 cGy) than in the normalized group (894±1591 cGy; p=0.003). On multivariable analysis, lymphoma (p=0.011), brain or nasopharyngeal cancer (p=0.039), and head radiation dose ≥1800 cGy (p=0.039) were significant risk factors for persistent SCH.ConclusionSCH was common in childhood cancer survivors. Brain or nasopharyngeal cancer, lymphoma, and head radiation ≥1800 cGy were significant risk factors for persistent SCH.

Diagnosis and Management of Subclinical Hypothyroidism in Elderly Adults: A Review of the Literature.

The estimated prevalence of subclinical hypothyroidism (SCH) in the general population is 3% to 8%. As the average age of the population in the United States and other countries continues to increase, the overall prevalence of SCH may also be expected to increase. Although age-related changes in thyroid function are well described, normal thyroid-stimulating hormone (TSH) reference limits, derived for age-specific populations, are not routinely used to identify thyroid dysfunction in elderly adults. Therefore, currently accepted values for the upper limit of normal of TSH may be inappropriate for diagnosing SCH in individuals aged 65 and older, resulting in potential overestimation of the prevalence of SCH in this population. This review discusses the current evidence of the effects of SCH on cardiovascular health and neuropsychiatric function in older adults. Although the results of some studies are conflicting, the overall evidence suggests that the consequences of SCH may be different for elderly adults than for younger populations. Treatment of SCH in older individuals requires special consideration with regard to thyroid hormone replacement therapy and expected clinical outcomes. Although careful identification of individuals with persistent SCH who could benefit from levothyroxine treatment is necessary, current evidence suggests that individuals with TSH levels greater than 10 mIU/L who test positive for antithyroid antibodies or are symptomatic may benefit from levothyroxine treatment to reduce the risk of progression to overt hypothyroidism, decrease the risk of adverse cardiovascular events, and improve their quality of life. After treatment is initiated, careful monitoring is essential.

Letter: the biochemical prognostic factors of subclinical hypothyroidism (endocrinol metab 2014;29:154-62, myung won lee et Al.).

Subclinical hypothyroidism is defined as a serum thyroid stimulating hormone (TSH) concentration above the upper limit of its reference range plus a serum free thyroxine (FT4) concentration within its reference range. There are several controversies regarding the effect of subclinical hypothyroidism on the risk of heart failure, cardiovascular disease risk, cholesterol metabolism and mortality, due to the lack of randomized prospective clinical trials [1]. Several studies have evaluated the natural course of overt hypothyroidism and risk factors for its development. In one previous United States study of elderly subjects (≥65 years old) [2], subclinical hypothyroidism remained in 56% of patients at a 2-year follow-up, while 35% showed euthyroidism and 2% overt hypothyroidism. In that study, higher TSH level and thyroid peroxidase (TPO) antibody (Ab) positivity were independently associated with persistent subclinical hypothyroidism, and a TSH level of 10 mU/L or higher was an independent risk factor for overt hypothyroidism. In another study, 36.4% of patients showed persistent subclinical hypothyroidism, 37.4% euthyroidism and 26.2% overt hypothyroidism after 6 to 72 months of follow-up (mean 31.7 months) [3]. TSH level was the only significant predictor of progression to overt hypothyroidism. Recently, Lee et al. [4] reported that the initial TSH level was the only definite prognostic factor for persistent subclinical hypothyroidism. Also, TPO Ab titer was a helpful prognostic factor for maintenance of subclinical hypothyroidism in patients with mildly elevated TSH levels (5 to 10 mU/L). This result is consistent with those reported previously. However, the authors needed to perform a multivariate Cox regression analysis to identify prognostic or risk factors for persistent subclinical hypothyroidism. Simple comparison of baseline characteristics seems insufficient to conclude that TSH is a risk factor. In addition, it might be helpful to perform a survival analysis according to TSH range using Kaplan-Meier curves. Determining the natural course and long-term clinical effects of subclinical hypothyroidism and identifying risk factors for persistent subclinical hypothyroidism would have implications for the follow-up and treatment of patients with subclinical hypothyroidism. Therefore, a long-term prospective study is needed.

Response: The Biochemical Prognostic Factors of Subclinical Hypothyroidism (Endocrinol Metab2014;29:154-62, Myung Won Lee et al.)

We sincerely thank the editors and reviewers for giving us the opportunity to publish this article. Our response to Professors Ahn and Chung's letter are included below. Previous studies of subclinical hypothyroidism (SHT) mainly focused on the aggravation of SHT to overt hypothyroidism [1,2]. However, the clinical significance of long-term, persistent SHT and clinically reliable prognostic factors for predicting the disease course of SHT, including aggravation, maintenance, and improvement, have not been established. Given our present clinical environment, in which increasing numbers of patients with SHT are consistently increasing, as well as our corresponding need to manage them as clinicians, we aimed to identify factors that influence the natural course of SHT. In line with this purpose, our study primarily focused on initial clues and evidence that enable us to predict whether newly-diagnosed SHT will improve spontaneously to a euthyroid state. In this retrospective study, we compared two groups according to thyroid function at follow-up: an SHT maintenance group and a spontaneous improvement group. The mean follow-up period was 10.1 months for the SHT maintenance group and 9.6 months for the spontaneous improvement group. By comparing initial parameters in patients with newly-diagnosed SHT between the two groups using t tests, this study presents evidence that only initial thyroid stimulating hormone (TSH) level was a definite prognostic factor for SHT, and that thyroid peroxidase antibody (TPO-Ab) titer was also a helpful prognostic factor for SHT in cases with mildly elevated TSH levels. As mentioned in the letter from the reviewers, multivariate Cox regression analysis would be a more concrete method to prove the prognostic value of a specific factor because it can correct for the influence of other confounding variables on prognosis. However, our data were determined to be inappropriate for a Cox regression model by the test of goodness of fit during the analysis. There are several possible reasons for this relating to the characteristics of our patients. The range of TSH levels was too narrow: subjects with TSH levels of 5 to 7 µIU/mL accounted for 59.5% of all subjects. When we also consider the short follow-up period in this study (less than 12.0 months), it was difficult to detect a significant odds ratio for SHT prognosis according to TSH range. Also, with regard to TPO-Ab, a large majority of subjects (79.3%) had TPO-Ab titers of <60 U/mL, i.e., within the normal range. With data for TSH and TPO-Ab with wider ranges and a longer follow-up period, we think that TSH level and TPO-Ab titer might have been shown to be strong prognostic factors for SHT in more powerful and sophisticated analyses, such as multivariate Cox regression analysis and survival analysis. In spite of these limitations, this study is useful for daily practice in clinics. Faced with patients with newly-diagnosed SHT, TSH level and TPO-Ab titer at initial presentation could be considered as evidence to predict spontaneous improvement. Also, another notable finding of this study is that TSH level was a very strong prognostic factor in SHT. As Professors Ahn and Chung mention, a large-scale, prospective study is needed to definitively identify prognostic factors for SHT. Thank you again for your insightful and comprehensive review of our paper.

Prospective Observation of 5-Year Clinical Course of Subclinical Hypothyroidism in Korean Population

Subclinical hypothyroidism (SCH) is a common clinical condition, whereas it's natural course has not been identified distinctly. We evaluated the natural history of 169 SCH patients over 5-yr and the prognostic factors including thyroid autoantibodies and thyroid ultrasonographic (USG) findings related to develop overt hypothyroidism. After 5 yr, 47.3% of patients showed normalization of TSH, while 36.7% of patients remained persistence of high level of TSH, and overt hypothyroidism developed in 11.2% of patients. There were painless thyroiditis (2.9%) and hyperthyroidism (1.7%) during 5 yr follow-up. The thyroid nodule was seen in 48.6% of patients. Most of patients had 1 to 2 nodules whereas only 3% of patients with thyroid nodule had more than 6 nodules. Overt hypothyroidism patients had more heterogenous echogenecity in USG compared to patients with normalization or persistent SCH (76.5% vs 50.0% vs 35.0%, P = 0.048) and higher prevalence positive anti-thyroid peroxidase (anti-TPO Ab) and anti-thyroglobulin antibody (anti-Tg Ab) and titer of anti-TPO Ab than other two groups. The cut off values for prediction of overt hypothyroidism were TSH > 7.45 µIU/mL, free T4 < 1.09 ng/dL and Anti-TPO Ab > 560 IU/mL. SCH has various courses and initial TSH, free T4, presence of thyroid autoantibody, titer of thyroid autoantibody; and thyroid USG findings can serve as a prognostic factor for progression of overt hypothyroidism. These parameters suggest consideration to initiate thyroid hormone treatment in SCH.

Persistent Subclinical Hypothyroidism and Cardiovascular Risk in the Elderly: The Cardiovascular Health Study

Use of a single set of thyroid function tests to define subclinical hypothyroidism may lead to misclassification over time and could influence findings from longitudinal studies. We assessed the risks of coronary heart disease (CHD), heart failure (HF), and cardiovascular (CV) death in older adults with persistent subclinical hypothyroidism. The study included 679 subclinically hypothyroid and 4184 euthyroid U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study and not taking thyroid preparations. We measured the 10-yr risk of incident CHD, HF, and CV death from persistent subclinical hypothyroidism, overall and stratified by degree of TSH elevation (4.5-6.9, 7.0-9.9, and 10.0-19.9 mU/liter). There was no association between persistent subclinical hypothyroidism and incident CHD [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.93-1.36], HF (HR, 1.05; 95% CI, 0.97-1.27), or CV death (HR, 1.07; 95% CI, 0.87-1.31) in adjusted analyses in which subclinical hypothyroidism was modeled as a time-varying exposure using up to four serial thyroid function tests. When subclinical hypothyroidism was stratified by degree of TSH elevation, no significant associations were found in any stratum. Findings were similar in fixed exposure analyses in which only participants with testing 2 yr apart were considered, with no association between persistent or transient subclinical hypothyroidism and incident CHD, HF, or CV death. Our data do not support increased risk of CHD, HF, or CV death in older adults with persistent subclinical hypothyroidism.