TFC Lay Summaries of Research Articles

Prepared by Hanista Premachandran, Director, Education & Research


Interpretation of TSH and T4 for diagnosing minor alterations in thyroid function: a comparative analysis of two separate longitudinal cohorts
Stig Andersen, Jesper Karmisholt, Niels Henrik Bruun, Johannes Riis, Paneeraq Noahsen, Louise Westergaard, and Stine Linding Andersen (2022)

Summary: Thyroid function tests are used to monitor and diagnose thyroid disorders. Minor changes or fluctuations in thyroid gland function appear to be common and as such may pose a challenge when interpreting thyroid tests. The current study compared how thyrotropin (TSH) and thyroxine (T4) varies and how this may affect the diagnosis and monitoring of thyroid disorders. When comparing monthly blood tests between participants with normal thyroid function and subclinical hypothyroid patients, the authors found that subclinical hypothyroid patients deviated or differed from control patients by 20% for total T4 levels, while subclinical patients deviated from control patients by 466% for TSH levels. This suggests that TSH testing is better able to detect slight differences in thyroid function. Go to article  



Hypothyroidism: To Screen or not to Screen, that is the Question?
Amit Bhargava (2016)

Summary: Physicians often encounter patients with subtle and non-specific complaints and must use their judgment to determine whether they screen for hypothyroidism. Several factors are considered when deciding whether to screen patients, such as symptoms suggesting thyroid failure, autoimmune disease diagnosis (e.g., type 1 diabetes mellitus), previous thyroid surgery or ablation, an abnormal thyroid exam, a psychiatric disorder, or adrenal insufficiency. Furthermore, certain demographics, such as those who live in iron deficient areas, have a greater risk of developing hypothyroidism. Notably, subclinical hypothyroidism appears to be more prevalent, and several clinical studies report higher prevalence in women and the elderly population. This article also discusses the limited research on the potential cost effectiveness and benefits of screening asymptomatic pregnant women. The author emphasizes the need for more randomized control trials to study maternal and neonatal outcomes as well as healthcare economics. Currently, there are no clear guidelines to specifically inform physicians of who to screen, but the factors influencing the decision to screen are the individual’s geographic location, medical history, and regional treatment patterns.  Go to article 



The thyroid gland and the process of aging; what is new?
Adam Gesing, Andrzej Lewiński & Małgorzata Karbownik-Lewińska (2012)

Summary: The process of aging is accompanied by changes to the endocrine system, which includes the thyroid gland. Symptoms of thyroid disorders can differ among younger versus older patients. As such, greater care is needed when monitoring and diagnosing older patients. Subclinical hypothyroidism, which is marked by increased thyrotropin (TSH) levels and normal free thyroxine (FT4) levels, is more frequently observed with aging. One study notes that the impairments to cognitive functions (e.g. attention, concentration, memory, and language) seen in overt hypothyroidism is not seen in subclinical hypothyroid patients that are 65 years and older. However, another study reported mild cognitive impairments in subclinical hypothyroid patients with an average age of under 65 years. Treatment for subclinical hypothyroidism is controversial due to unclear evidence of benefits to patients. Furthermore, the authors also review literature that suggests thyroid hypofunction in the elderly population may support increased lifespan or longevity. Conversely, subclinical hyperthyroidism (marked by decreased TSH levels and normal FT4 levels) is less frequently seen in the older population, but is associated with increased mortality, coronary heart disease, as well as atrial fibrillation, and thereby requires careful medical attention. Moreover, gender differences in thyroid function changes have been noted with aging. Specifically, aging in males was associated with decreased free thyroid hormone levels but not TSH levels, while aging in females resulted in increased TSH levels with no changes to the levels of free thyroid hormones. In addition, recent work suggests that increases in FT4 that were within the normal range was linked to frailty in men who are 70 years of age or older with normal thyroid functioning. In postmenopausal women, increased FT4 levels that are within the normal range were linked to lower hip bone mineral density, bone loss, and fracture risk. Further research is needed to understand the association between increased FT4 levels that are within the normal range and the health risks that it may pose to older individuals. Lastly, the authors discuss recent evidence suggesting increased prevalence of thyroid-related cancers among older patients. Go to article  



The Effect of Hypothyroidism on Insulin Sensitivity and Their Influence on the Serum Lipid Profile and Renal Function
Abdel-Gayoum AA* (2016)

Summary: Given that hypothyroidism is more common in patients diagnosed with diabetes mellitus, the current article studies the relationship between thyroid hormone levels and insulin resistance, as well as their influence on kidney function and cholesterol levels in recently diagnosed subclinical and overt hypothyroid patients. The author reports that serum insulin and glucose levels were higher in subclinical and overt hypothyroid patients compared to control patients (who visited for routine check-ups). The author also reports a negative correlation between free thyroxine (FT4) and insulin levels, suggesting that as FT4 levels rise, insulin decreases. Meanwhile, a positive correlation was found between TSH levels and insulin, suggesting that as TSH levels rise, insulin levels also rise. Additionally, serum creatinine, urea and uric acid levels were only increased in the overt hypothyroid patients, while cholesterol, TG and LDL-cholesterol were increased in both overt and subclinical hypothyroid patients. The article highlights the risk of developing insulin resistance, renal issues, and atherosclerosis in hypothyroid patients with increased TSH levels. Go to article  



People’s Experience with Thyroid DIsease (Survey Results)
Catia Montagna and Alexandros Zangelidis (2023)

Summary: A recent survey based in the United Kingdom details patients’ experience with thyroid disease from the onset of their symptoms to diagnosis and post-treatment. The authors reported that diagnosis takes 4.5 years on average and the diagnosis of hypothyroidism takes longer. Notably, thyroid treatment does not seem to benefit all patients and patients report feeling unheard by medical professionals. Specifically, over 90% of participants reported experiencing multiple thyroid-related symptoms after treatment (common symptoms include tiredness and slowness, cognitive deficits, muscle aches and weakness, weight changes and sensitivity to temperature and mental symptoms). Many participants reported that they did not feel involved during treatment decisions and did not feel empowered enough to provide their input. The authors discuss the significance of early diagnosis and support for patients with thyroid disease. Go to article



The upper limit for TSH during pregnancy: why we should stop using fixed limits of 2.5 or 3.0 mU/l
Franklin Neil Tessler (2021)

Summary: Provided that pregnancy involves physiological changes, it is not ideal to use the same TSH and FT4 reference ranges used for non-pregnant patients when diagnosing thyroid disease. Although it is common to use a TSH reference range with an upper limit of 2.5mU/l for the first trimester and 3.0 mU/l for the second and third trimester for diagnosis of subclinical and overt hypothyroidism, more recent studies suggest these ranges are too low. When the reference ranges are too low, overdiagnosis and overtreatment are possible. As a result, the 2017 American Thyroid Association (ATA) guidelines have updated their recommendations on the upper limit of TSH for pregnant patients. The author reports that among 14 studies that calculated pregnancy specific TSH ranges, 90% of the studies had an upper limit above 2.5 or 3.0 mU/l. The more recent ATA guidelines (2017) suggest to (1) calculate pregnancy-specific ranges for TSH and FT4, (2) if calculating ranges is not feasible, then a reference range from existing literature can be adapted, but if this is also not possible, then (3) a reference range that subtracts 0.5 mU/l from the non-pregnancy range should be used. The author states that it would be optimal to calculate reference ranges, as it can be performed at low costs and will improve the diagnosis of thyroid dysfunction in pregnancy. Go to article  



Diagnostic characteristics, treatment patterns, and clinical outcomes for patients with advanced/metastatic medullary thyroid cancer
Neha Janmohamed et al. (2021)

Summary: Medullary thyroid cancer (MTC) is a rare form of cancer involving a specific cell type (neural crest-derived calcitonin-producing parafollocular C cells). In the US, patients with symptomatic advanced, progressive, or recurrent MTC are treated with systemic therapies (e.g., vandetanib, cabozantinib, selpercatinib, and pralestinib). The authors aim to describe patient characteristics, biomarker testing, treatment patterns and clinical outcomes among patients with advanced/metastatic MTC to determine how treatment can be improved. This study recruited patients diagnosed with MTC who were 12 years and older (average age of 52 years) and had at least a year of systemic treatment. Results demonstrate that 37% of patients had RET mutation. Additionally, cabozantinib, vandetanib, sorafenib, and lenvatinib were common first-line treatments, while cabozantinib, vandetanib, lenvatinib, or sunitinib were common second-line treatments. Importantly, although testing for RET mutation is recommended by national guidelines, one-third of individuals diagnosed with advanced or metastatic MTC were not tested for RET mutation, which has been linked to negative clinical outcomes. Among patients with the RET mutation, vandetanib monotherapy was the common first-line treatment, which was followed by cabozantinib monotherapy. This study demonstrates that for advanced or metastatic MTC, there was no preference for systemic therapies. Additionally, given that RET inhibitors have been recently approved for treatment in the US, future research should focus on how treatment patterns and outcomes for RET-mutation MTC could be influenced by RET-targeting treatments.

Go to article  


Ultrasonographic Findings in Common Thyroid and Parathyroid Disorders—Advantages of Real Time Observation by the Endocrinologist with their Own Ultrasound Machine
Jack Wall et al. (2021)

 Summary: A recent article by Dr. Jack Wall and colleagues (2021) discusses how thyroid ultrasonography is used by endocrinologists in the diagnosis and management of thyroid and parathyroid disorders. Endocrinologists use a portable ultrasound machine to ultrasound images with clinical and blood test results. Below are a few examples of different thyroid disorders and their characteristic ultrasound features:

  •     Benign (or “colloid”) nodules are characterized by compressed blood vessels, which appears as a wide and black ring on ultrasonography;
  •     Follicular nodules also have a black ring surrounding its structure and appear more solid and white in colour;
  •     Hot (or toxic) nodules share similar characteristics with colloid nodules and may contain fluid n biopsy;
  •     Thyroid cysts share similar features with hot nodules but tend to be larger and rounder;
  •     Calcification in nodules, which is not found in normal thyroid glands, could be benign, however, if there are breaks in the wall of a calcified nodule, this may be indicative of cancer;
  •     Calcification may appear as spots or sheets throughout the thyroid gland. Calcification may also be present in Grave’s disease and Hashimoto thyroiditis; 
  •     Grave’s hyperthyroidism is marked by an enlarged gland with increased vascularity and the gland texture is noted to be “patchy.” Following radioiodine treatment, an increase in scar tissue will be seen. 

Overall, ultrasonography has become a common and very useful tool for the diagnosis and management of thyroid disorders. Importantly, novel ultrasound methods are currently being developed, such as shear wave elastography (which measures tissue stiffness), to aid with the identification of nodules that require biopsies. Go to article

An Explainable Artificial Intelligence Framework for the Predictive Analysis of Hypo and Hyper Thyroidism Using Machine Learning Algorithms
Damien Gruson, Pradeep Dabla,  Sanja Stankovic,  Evgenija Homsak,  Bernard Gouget,  Sergio Bernardini,  and Benoit Macq

Summary: Early disease detection and diagnosis are important for better health outcomes. Given that clinical diagnosis
is considered a difficult process, this article investigates whether artificial intelligence models can be used to predict
thyroid disease. The main aims of the current article are to find a machine learning model that predicts thyroid disease
with a limited number of features and identify ideal features to detect thyroid disease. Three datasets (hypothyroid,
hyperthyroid, and sick) from the UCI machine learning repository were combined for this study. Several features, such
as age, sex, and medication, were included in the analysis. Seven different machine learning algorithms were compared,
which included: Decision tree classifier, Random Forest Classifier, Gradient Boosting Classifier, Naive Bayes Classifier,
K-Nearest Neighbor, Logistic Regression, and Support Machine Vector. The main results suggest that each algorithm has
the capability of outperforming each other depending on whether a subset of features or full features were included.
Overall, the authors found that decreasing the number of features provided allowed for more algorithms to predict
thyroid disease more accurately. They also suggest that the Random Forest Classifier, Decision Tree Classifier, and
Gradient Boosting Classifier and feature importance techniques have the potential to predict thyroid disease more
reliably. The most important features to consider are thyroid stimulating hormone (TSH), triiodothyronine hormone
(T3), thyroxine hormone (TT4), thyroxine utilization rate (T4U), and free thyroxine index (FTI). Lastly, the authors discuss
potential limitations and biases of the limited data points that were used in this study. Go to article

Guidance in Subclinical Hyperthyroidism and Subclinical Hypothyroidism: Are We Making Progress? Wilmar M. Wiersinga

Summary: “Although the evidence of associations between SHyper or SHypo [S for subclinical] and adverse health outcomes has become much stronger in the last decade, evidence is lacking that restoration of the euthyroid state reverses the risk of adverse health outcomes. There are no long-term randomized clinical trials demonstrating that treatment will do more good than harm [4] … current guideline recommendations [are] to prescribe levothyroxine in [Subclinical] Hypo with TSH values of ≥ 10 mU/l (at least in subjects ≤ 70 years), but to be more conservative at TSH values between 4 and 10 mU/l [2] . My proposal would be to subdivide grade I (SHypo) into grade IA (TSH >4.0 to <10 mU/l) and grade IB ( ≥ 10 mU/l).

The population-based NHANES III Survey in the USA has been a hallmark study for establishing reliable TSH reference ranges [12] . In their so called ‘reference population’, the median TSH was 1.39 mU/l with a reference interval of 0.45–4.12 mU/l (P2.5P97.5). However, a clear age-dependent effect on TSH values was observed: median TSH values and their reference ranges in the age groups 20–29, 60–69, 70–79, and ≥ 80 years are 1.26 (0.40–3.56), 1.67 (0.49–4.33), 1.76 (0.45–5.90), and 1.90 (0.33–7.50) mU/l, respectively [12] . In view of the higher TSH values with advancing age, the prevalence of SHypo may thus be significantly overestimated unless an age-specific range for TSH is used [13] . The guidelines do not propose age-specific reference ranges (which I would have found quite logical), but recommend a very conservative attitude in prescribing levothyroxine in subjects with SHypo of 70 years and older, but based on other considerations than the upper normal limit of TSH that increases with age [2] .”   Go to article

2013 ETA Guideline: Management of Subclinical Hypothyroidism Simon H.S. Pearce, Georg Brabant, Leonidas H. Duntas, Fabio Monzani, Robin P. Peeters, Salman Razvi, Jean-Louis Wemeau

Summary:  “Even in the absence of symptoms, replacement therapy with L -thyroxine is recommended for younger patients (<65–70 years) with serum TSH >10 mU/l. In younger SCH [subclinical hypo] patients (serum TSH <10 mU/l) with symptoms suggestive of hypothyroidism, a trial of  L -thyroxine replacement therapy should be considered. For such patients who have been started on L -thyroxine for symptoms attributed to SCH, response to treatment should be reviewed 3 or 4 months after a serum TSH within reference range is reached. If there is no improvement in symptoms,  L -thyroxine therapy should generally be stopped. Age-specific local reference ranges for serum TSH should be considered in order to establish a diagnosis of SCH in older people. The oldest old subjects (>80–85 years) with elevated serum TSH  ≤ 10 mU/l should be carefully followed with a wait-and-see strategy, generally avoiding hormonal treatment. If the decision is to treat SCH, then oral  L -thyroxine, administered daily, is the treatment of choice. The serum TSH should be re-checked 2 months after starting  L -thyroxine therapy, and dosage adjustments made accordingly. The aim for most adults should be to reach a stable serum TSH in the lower half of the reference range (0.4–2.5 mU/l). Once patients with SCH are commenced on  L -thyroxine treatment, then serum TSH should be monitored at least annually thereafter.”

“Many patients with SCH do not need treatment, but if a decision is made to treat, then oral  L -thyroxine is the treatment of choice. Randomised clinical trials of SCH patients have shown that  L -thyroxine is effective in returning the biochemistry of a raised serum TSH into the reference range  [27, 29, 120–123] . Doses of  L -thyroxine used in these trials have varied substantially, but typical regimens have started with 25 or 50 μg daily, with subsequent monthly or 2-monthly dose adjustment to maintain serum TSH within reference range. Using this approach, a study of 94 >65-year-old patients found that serum TSH could be normalised with a median dose of 50 μg (interquartile range 50–75 μg)  L -thyroxine  [37] .Similarly, two smaller studies of younger SCH patients have found mean daily  L -thyroxine doses of 68 and 71 μg (range 50–125) were necessary to bring serum TSH into the reference range  [121, 123] . One study carefully titrated  L -thyroxine doses in 36 SCH patients to achieve serum TSH levels between 0.5 and 1.5 mU and found that mean daily doses around 100 μg (range 94–109) were necessary to achieve this  [27] . Nevertheless, a large study that started all SCH participants on 100 μg  L -thyroxine daily found that only 10% were overtreated as judged by subnormal serum TSH (only 2% with elevated serum FT 4 )  [29] . Thus, the evidence suggests that a daily dose of  L -thyroxine between 50 and 100 μg daily is adequate to normalise serum TSH in most SCH patients.”  Go to article

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