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Recommended reading – key published papers from 2017 as chosen by our Scientific Committee Members

PART OF Manage Thyroid Online FEATURE
Recommended reading – key published papers from 2017 as chosen by our Scientific Committee Members
  • Cardiometabolic
  • Thyroid disorder

Papers chosen by our Scientific Committee Members, Professor George Kahaly, Professor Nemencio Nicodemus and Dr Gabriela Brenta

2017 has been a rich and diverse year in terms of thyroid research and publications. We asked our Scientific Committee Members for Manage Thyroid Online, Professor George J Kahaly from Germany, Professor Nemencio A Nicodemus from The Philippines and Dr Gabriela Brenta from Argentina to highlight the papers from 2017 which, in their opinion, were the key papers of the year – those that have made the most impact on the scientific community.

These papers are in no particular order


Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017;376(18):1748-61.

An outstanding randomized double-blind, placebo-controlled trial demonstrating the excellent efficacy of a novel IgF1 receptor monoclonal antibody in the treatment of patients with active and severe thyroid eye disease. Inhibition of the IGF-IR with teprotumumab is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy.


Kahaly GJ, Riedl M, König J, et al. Double-blind, placebo-controlled, randomized trial of selenium in Graves’ hyperthyroidism. J Clin Endocrinol Metab 2017;102(11):4333-41.

The first randomized, double-blind, placebo-controlled trial of selenium supplementation in patients with autoimmune-induced Graves’ hyperthyroidism.


Stott DJ, Rodondi N, Kearney PM, et al.  TRUST Study Group. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med 2017; 376:2534-2544 June 29, 2017DOI: 10.1056/ NEJMoa1603825

In this double-blind, randomized, placebo-controlled, parallel-group trial, 737 adults ≥65 years old and who had persisting subclinical hypothyroidism were randomized to receive either placebo or levothyroxine with a TSH target of 0.40 to 4.60 mIU/L. The two primary outcomes were the change in the hypothyroid symptoms score and tiredness score on a thyroid-related quality-of-life questionnaire at 1 year. The authors found that levothyroxine had no consistent beneficial effect on thyroid-related symptoms nor on generic health-related quality of life. Other endpoints such as muscle function evaluated by hand-grip strength or executive cognitive function as measured by the letter-digit coding test did not change with levothyroxine treatment. Similarly, no effect of treatment on blood pressure, weight, waist circumference, body-mass index, or the Barthel Index or Instrumental Activities of Daily Living scores was observed. The study had sufficient number of participants to provide good statistical power regarding symptoms. However, few participants had a baseline TSH level of more than 10 mIU/L and it was underpowered to detect any effect of levothyroxine on the incidence of cardiovascular events or mortality.


Samuels MH, Kolobova IAntosik M,  et al. Thyroid function variation in the normal range, energy expenditure and body composition in L-T4-treated subjects. J Clin Endocrinol Metab 2017 Jul 1;102(7):2533-2542. doi: 10.1210/jc.2017-00224.

In this cross-sectional study the authors analyzed the effects of varying doses of levothyroxine on metabolic outcomes. Hypothyroid subjects (n=140) receiving chronic replacement therapy with levothyroxine who had TSH levels across the full span of the laboratory reference range (0.34 to 5.6 mU/L), underwent detailed tests of energy expenditure (total and resting energy expenditure, thermic effect of food, physical activity energy expenditure), substrate oxidation, diet intake and body composition. Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ in any of the outcome measures. However, across the entire group, serum free triiodothyronine levels were directly correlated with resting energy expenditure, body mass index, body fat mass and visceral fat mass.


Castagna MG, Dentice M, Cantara S, et al. DIO2 Thr92Ala reduces deiodinase-2 activity and serum-T3 levels in thyroid-deficient patients. J Clin Endocrinol Metab. 2017 May 1;102(5): 1623-1630. doi: 10.1210/jc.2016-2587.

In this study, the implication of polymorphisms of deiodinase type 2 (the enzyme which converts T4 to T3) was explored in thyroidectomized patients. The mean post-surgery FT3 levels were significantly lower in patients carrying the mutated allele(s) than in wild-type patients, in whom FT3 postsurgical levels were similar to presurgery levels. Thyroidectomized patients carrying Thr92Ala are at increased risk of reduced intracellular and serum T3 concentrations that are not adequately compensated for by levothyroxine, thus providing evidence in favour of customized treatment of hypothyroidism in athyreotic patients.


Lillevang-Johansen M,  Abrahamsen BJørgensen HL, et al. Excess mortality in treated and untreated hyperthyroidism is related to cumulative periods of low serum TSHJ Clin Endocrinol Metab. 2017 Jul 1;102(7):2301-2309. doi: 10.1210/jc.2017-00166.

This was a register-based cohort study of 235,547 individuals who had at least one serum thyroid-stimulating hormone (TSH) measurement in the period 1995 to 2011 (7.3 years median follow-up). It was shown that mortality is increased in hyperthyroidism. To understand the main reason for this, mortality rates for treated and untreated hyperthyroid subjects compared with euthyroid controls were calculated using multivariate Cox regression analyses, controlling for age, sex and comorbidities. Cumulative periods of decreased TSH increased mortality in both treated and untreated hyperthyroidism, implying that excess mortality may not be driven by lack of therapy, but rather the inability to keep patients euthyroid.


Diana T, Wüster C, Olivo PD, et al. Performance and specificity of 6 immunoassays for TSH receptor antibodies: A multicenter study. Eur Thyroid J 2017;6(5):243-9.

An excellent paper showing for the first time the significantly greater sensitivity and exclusive specificity of the cell-based bioassays for the measurement of TSH receptor autoantibodies in contrast to numerous conventional TSH receptor binding immunoassays.


Diana T, Krause J, Olivo PD, et al. Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease. Clin Exp Immunol 2017;189(3):304-9.

This important manuscript demonstrates the prevalence, clinical relevance and clinical utility of measuring TSH receptor autoantibodies in a very large collective of consequently tested patients with autoimmune thyroid disease


Mendoza A, Astapova I, Shimizu H, et al. NCoR1-independent mechanism plays a role in the action of the unliganded thyroid hormone receptor. Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):E8458-E8467. doi: 10.1073/pnas.1706917114. Epub 2017 Sep 18.

Repression and activation of target genes by T3 involves histone acetylation, as the corepressor complex is known to deacetylate target histones, while the coactivator complex does the opposite. In the absence of ligand, the thyroid hormone receptor (TR) recruits nuclear receptor corepressor 1 (NCoR1), forming a scaffold-binding surface for the multiprotein corepressor complex. NCoR1 is considered the major corepressor that mediates ligand-independent actions of the TR during development and in hypothyroidism. The authors recently demonstrated that abrogation of NCoR1 function did not reverse the ligand-independent action of the TR on many gene targets. Thus, many of the genomic changes mediated by the TR in hypothyroidism are independent of NCoR1, suggesting a role for additional signaling modulators in hypothyroidism.


Kim HI, Jang HW, Ahn HS, et al. High serum TSH level is associated with progression of papillary thyroid microcarcinoma during active surveillance. J Clin Endocrinol Metab 2017 Dec 1. doi: 10.1210/jc.2017-01775. 

TSH is a parameter that is used to measure the efficacy of levothyroxine suppression therapy among patients with differentiated thyroid cancer. This cohort study shows that the level of TSH achieved during levothyroxine suppression therapy, even among patients with papillary microcarcinoma, is also very important in predicting the course of this subgroup of differentiated thyroid cancer.


Tumino D, Frasca F, Newbold K. Front Endocrinol (Lausanne). Updates on the management of advanced, metastatic, and radioiodine refractory differentiated thyroid cancer. 2017 Nov 20;8:312. doi: 10.3389/fendo.2017.00312. eCollection 2017

This review highlights the approach to management of a subgroup of patients with differentiated thyroid cancer who have become refractory to the usual forms of management, which includes surgery and radioiodine therapy. Although relatively rare (5-10% of patients present with advanced, metastatic, radioiodine refractory disease), this subgroup requires a different approach that involves the use of newer targeted therapies, like tyrosine kinase inhibitors.  


Lamartina L, Borget I, Mirghani H, et al. Surgery for neck recurrence of differentiated thyroid cancer: outcomes and risk factors. J Clin Endocrinol Metab. 2017 Mar 1;102(3): 1020-1031. doi: 10.1210/jc.2016-3284.

Persistent/recurrent disease in the neck is frequent in patients with differentiated thyroid cancer (DTC). It is not known if the first neck reoperation in DTC is advantageous. In this retrospective study of consecutive patients undergoing neck reoperation for recurrent/persistent DTC, 161 DTC patients were followed after reoperation. After a median follow-up of 5 years, only 83 patients (53%) had complete remission without the need for further treatments. Age ≥45 years, aggressive histology and lymph node ratio ≥0.6 at initial surgery were independent risk factors for incomplete response after reoperation. Male sex, aggressive histology and ≥10 metastases at reoperation were independent risk factors of secondary relapse following CR achieved with reoperation. The authors concluded that a risk-benefit analysis should guide surgical decision in thyroid cancer patients with neck recurrence.


Lim H, Devesa SS, Sosa JA, et al. Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. JAMA. 2017 Apr 4;317(13):1338-1348. doi: 10.1001/jama.2017. 2719.

Thyroid cancer incidence has increased substantially in the United States over the last 4 decades, driven largely by increases in papillary thyroid cancer. It is unclear whether the increasing incidence of papillary thyroid cancer has been related to thyroid cancer mortality trends. Data from the Surveillance, Epidemiology and End Results-9 (SEER-9) cancer registry program was used to establish if thyroid cancer incidence had truly increased. An average 3.6% increase/year (95% CI: 3.2%-3.9%) during 1974-2013 was confirmed. Furthermore, this includes an increase in the incidence and thyroid cancer mortality rate for advanced-stage papillary thyroid cancer. These findings are consistent with a true increase in the occurrence of thyroid cancer in the United States.


Jeon MJ, Kim WG, Kwon H, et al. Clinical outcomes after delayed thyroid surgery in patients with papillary thyroid microcarcinoma. Eur J Endocrinol. 2017 Jul;177(1):25-31. doi: 10.1530/EJE-17-0160.

Active surveillance is an option for patients with papillary thyroid microcarcinoma (PTMC) and surgery can be deferred until it is deemed necessary. In this study, 2863 patients were assigned to three groups according to the delay period for surgery: ≤6 months, 6-12 months and >12 months. Delayed surgery was not associated with a higher risk of structural recurrent/persistent disease compared with immediate surgery. These findings support the notion that surgical treatment can be safely delayed in patients with PTMC under close monitoring.


Tuttle RM, Haugen B, Perrier ND. The updated AJCC/TNM staging system for differentiated and anaplastic thyroid cancer (8th edition): What changed and why? Thyroid. 2017 Jun;27(6):751-756. doi: 10.1089/thy.2017.0102

This article describes the new 8th edition of the AJCC/TNM cancer staging system released in October 2016 by the American Joint Committee on Cancer (AJCC; The main changes in the 8th edition include the classification of a significant number of patients into lower cancer stages that more accurately reflect their low risk of dying from thyroid cancer.

These modifications include raising the age cut-off from 45 years at diagnosis to 55 years, and removing regional lymph node metastases and microscopic extrathyroidal extension from the definition of T3 disease. By removing lymph node metastases and minor extrathyroidal extension from the definition of T3 disease, a significant number of patients (aged 45‐54 years, N1, M0) will be downstaged to stage I and older patients will be downstaged to either stage I (≥55 years, minor extrathyroidal extension, N0, M0) or stage II (≥55 years old, N1, M0).

The 8th edition also provides a list of additional clinical factors which aid risk stratification for routine clinical care. Additionally, stage III patients will now be characterized by tumours with gross extrathyroidal extension, so stage III is expected to have a significantly poorer disease specific survival than the 7th edition stage III category.


Pitoia F, Jerkovich F, Smulever A, et al. Should age at diagnosis be included as an additional variable in the risk of recurrence classification system in patients with differentiated thyroid cancer. Eur Thyroid J. 2017 Jul;6(3):160-166. doi: 10.1159/000453450.

The association between age at diagnosis and the initial and final response to treatment was assessed in a retrospective analysis of 268 patients with differentiated thyroid cancer (DTC) followed up for at least 3 years after initial treatment (total thyroidectomy and remnant ablation). Age at diagnosis was not associated with either an initial or final statistically significant different structurally incomplete response to treatment. Moreover, considering the classification of risk of recurrence, the proportion of structurally incomplete response was similar between different age groups. Thus, age does not seem to be critical for recurrence risk classification.


Bano A, Chaker L, Mattace-Raso FUS, et al. Thyroid function and the risk of atherosclerotic cardiovascular morbidity and mortality: The Rotterdam Study. Circ Res. 2017 Dec 8;121(12): 1392-1400. doi: 10.1161/CIRCRESAHA.117.311603.

The Rotterdam Study is a prospective population-based cohort study that investigates the determinants, occurrence and progression of chronic diseases in the middle-aged and elderly. In this study it was shown that higher FT4 levels in middle-aged and elderly subjects were associated with an increased risk of atherosclerosis, independently of cardiovascular risk factors. The association was consistent throughout the spectrum of atherosclerosis; from subclinical atherosclerosis to overt atherosclerosis to atherosclerotic mortality. These findings suggest that FT4 measurement can be a predictive marker of atherosclerotic mortality. The authors emphasized the need to re-evaluate TSH and FT4 reference ranges, which are currently based on arbitrary statistical approaches (2.5th and 97.5th percentiles) rather than on clinical outcomes. They also highlighted preventive strategies targeting thyroid function or certain mediators that could further lead to a reduction in atherosclerotic events.

In a further article by the same group (Chaker L, et al. Defining optimal health range for thyroid function based on the risk of cardiovascular disease. J Clin Endocrinol Metab 2017 Aug 1;102(8):2853-2861. doi: 10.1210/jc.2017-00410) the authors calculated the 10-year absolute risk of cardiovascular mortality in the same large population-based cohort study. They tried to define optimal health ranges of TSH and FT4 based on absolute risk estimates in the whole cohort as well as by sex and age groups. They described an absolute 10-year risk of 7.5% or higher with FT4 levels above the 90th percentile, corresponding to a cut-off level of FT4 of approximately 19 pmol/L (~1.5 ng/dL). However, they advised that this may be modified in participants <65 years of age compared with those >65 years and in men compared with women.


Giesecke P, Rosenqvist MFrykman V, et al. Increased cardiovascular mortality and morbidity in patients treated for toxic nodular goiter compared to Graves' disease and nontoxic goiter. Thyroid. 2017 Jul; 27(7):878-885. doi: 10.1089/thy.2017.0029.

This is an observational register study of subjects followed for a median period of 18.4 years treated for Graves' disease or toxic nodular goiter with either radioactive iodine or surgery (n=12,239). This group was compared with patients treated for nontoxic goiter (n=3685), with adjustments made for age, sex, comorbidities and time of treatment.

The hazard ratios (HR) for all-cause mortality and for cardiovascular mortality were 1.27 [confidence interval (CI) 1.20-1.35] and 1.29 [CI 1.17-1.42], respectively, for hyperthyroid patients compared with those with nontoxic goiter. Long-term risk of death and cardiovascular disease in hyperthyroid subjects is due to the hyperthyroidism itself and not an effect of confounding introduced by its treatment. Much of the excess risk is confined to individuals treated for toxic nodular goiter. Despite advances in cardiovascular care during recent decades, hyperthyroidism is still a diagnosis associated with increased cardiovascular morbidity and mortality.


Casey BM, Thom EAPeaceman AM, et al. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med. 2017 Mar 2;376(9):815-825. doi: 10.1056/ NEJMoa1606205.

The authors screened women with a singleton pregnancy before 20 weeks of gestation for subclinical hypothyroidism, defined as a TSH level of ≥4.00 mU/L and a normal free thyroxine (T4) level (0.86 to 1.90 ng/dL [11 to 24 pmol/L]), and for hypothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU/L) and a low free T4 level (<0.86 ng/dL). In separate trials for the two conditions, women were randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed monthly, and the levothyroxine dose was adjusted to attain a normal TSH or free T4 level (depending on the trial), with sham adjustments for placebo. Children underwent annual developmental and behavioural testing for 5 years. The primary outcome was the IQ score at 5 years (or at 3 years if the 5-year examination was missing) or death at an age <3 years. Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not significantly increase cognitive outcomes in children up to 5 years of age compared with no treatment for these conditions.


Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27(3): 315-389. doi: 10.1089/thy.2016.0457.

These guidelines for the management of thyroid disease in pregnant and postpartum women from the American Thyroid Association (ATA) were first published in 2011. This update contains evidence-based recommendations to inform clinical decision-making in the management of these patients, including thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules and cancer in pregnant women, fetal and neonatal considerations, thyroid disease and lactation, screening for thyroid dysfunction in pregnancy, and directions for future research.

The recommendation for iodine intake is that all pregnant women should ingest approximately 250 μg iodine daily. In most geographical regions this can be accomplished by adding a daily oral supplement to the diet that contains 150 μg of iodine in the form of potassium iodide, optimally started 3 months in advance of a planned pregnancy.

In patients with hypothyroidism, levothyroxine is recommended for TPO(+) with TSH greater than pregnancy specific reference range and TPO(-) with TSH >10 mUI/L. Levothyroxine may be considered for anti TPO(+) with TSH >2.5 mUI/L and below the upper limit of reference range and anti TPO(-) with TSH >reference range and <10 mUI/L. However, levothyroxine is not recommended for pregnant women with anti TPO(-) and TSH <4 mUI/L


Calsolaro V, Pasqualetti G, Niccolai F, et al.  Thyroid disrupting chemicals. Int J Mol Sci 2017 Dec 1;18(12).

The thyroid gland is very susceptible to environmental perturbations. In recent years, certain chemicals present in a lot of housewares and equipment have been associated with the development of thyroid dysfunction. This review looks into the different studies that link chemicals found in the environment with the development of thyroid abnormalities. The findings have been used by health authorities in Europe to restrict use of certain chemicals.


Sforza N, Rosenfarb J, Rujelman R, et al. Hypothyroidism in hospitalized elderly patients: a sign of worse prognosis. J Endocrinol Invest. 2017 Dec;40(12):1303-1310. doi: 10.1007/s40618-017-0690

The prevalence of hypothyroidism and its influence on mortality was studied prospectively in 451 hospitalized elderly patients, of whom 4% had overt hypothyroidism and 10% had subclinical hypothyroidism. In this population of hospitalized elderly patients, those with overt hypothyroidism showed significantly higher mortality (25%, P<0.05) than the rest of the groups (subclinical hypothyroidism, overt and subclinical hyperthyroidism, euthyroidism and non-thyroidal illness [NTI]). Furthermore, patients within the overt hypothyroid category showed a higher mortality rate than NTI patients in a model adjusted by stage of chronic kidney disease, Adult Comorbidity Evaluation-27, sex and age (HR 3.1 [1.14-8.41], P<0.026). Further studies would reveal if hypothyroidism should be diagnosed/treated in hospitalized elderly patients.

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