Ricardo Villela and Ricardo Correa | https://doi.org/10.1089/ct.2022;34.147-149
Review of: Fujita N, Ono Y, Sano A, Kimata M, Oyama S, Hashimoto K, Sato I, Kudo M, Miyashiro Y, Fujikata A, Tanaka Y, et al. 2022
Serum diiodotyrosine—A biomarker to differentiate destructive thyroiditis from Graves’ disease
Eur J Endocrinol 186:245–253. PMID: 34874894.
Clinicians have long struggled with the task of distinguishing between thyrotoxicosis caused by thyroiditis and that caused by Graves’ disease. It is crucial to make a correct diagnosis that differentiates between the types of hyperthyroidism, since their treatments are different (1,2). Graves' disease is an autoimmune condition caused by overstimulation of the thyroid due to the presence of autoantibodies; destructive thyroiditis, on the other hand, is caused by the destruction of thyroid follicles and the consequent release of thyroid hormones into the blood (3).
Conventional diagnostic testing parameters such as quantification of serum thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), thyroid stimulating immunoglobulin (TSI), and thyrotropin receptors antibody (TRAb) levels and imaging studies such as thyroid scintigraphy, Doppler ultrasonography, and radioactive iodine uptake, among others, have traditionally been used to distinguish between these two conditions. However, these methods have been shown to be imprecise (1,2). This study (1) aims to determine whether serum levels of diiodotyrosine (DIT) or monoiodotyrosine (MIT) can improve the differentiation between destructive thyroiditis and Graves' disease.
The authors conducted a cross-sectional study of patients seen between November 2019 and August 2021 in the Department of General Medicine at the National Defense Medical College Hospital in Tokorozawa, Japan. There were 49 individuals identified with biochemical hyperthyroidism (defined by undetectable serum TSH levels and elevated FT4 levels) and who had thyroid-related symptoms. From that group, 14 were excluded because of refusal to participate and iatrogenic hyperthyroidism, among other causes, leaving 35 patients in the study group. The causes of thyrotoxicosis included thyroiditis, postpartum thyroiditis, subacute thyroiditis, and Graves' disease, based on diagnostic criteria from the American Thyroid Association's thyrotoxicosis guidelines (4) and as clinically interpreted by three endocrinologists. The control group consisted of 54 patients presenting with hyperthyroid symptoms during the eligibility period, but who ultimately were confirmed to be biochemically euthyroid.
Serum DIT and MIT levels were assayed by tandem liquid chromatography–mass spectrometry, and receiver operating characteristic (ROC) analysis was used to determine sensitivity and specificity as biomarkers for distinguishing between thyroiditis and Graves’ disease.
Three groups were created from the study cohort: destructive thyroiditis (n = 13), Graves' disease (n = 22), and controls (n = 54). Sociodemographic characteristics showed that sex did not differ significantly between the groups, but those in the control group were significantly older than those in the other two groups (mean age for destructive thyroiditis, 47.0 years; range, 34.2–72.5; mean age for Graves’ disease, 42 years; range, 32.0–60.0; mean age for controls, 60 years; range, 38.8–77.0; P = 0.028).
Median serum DIT levels in those in the destructive thyroiditis, Graves' disease, and control groups were 1058.8 pg/ml (IQR, 683.3–1301.0), 117.1 pg/ml (IQR, 61.5–170.0), and 30.0 pg/ml (IQR, 30.0–96.1), respectively (P<0.001), while median serum MIT levels were 144.0 pg/ml (IQR, 125.8–233.3), 75.8 pg/ml (IQR, 30.0–130.6), and 30.0 pg/ml (IQR, 30.0–90.3) (P<0.001).
Areas under the curve for serum DIT and MIT levels were 0.993 (95% CI, 0.975–1.000) and 0.830 (95% CI,0.695–0.966), respectively. The optimal cutoff values for distinguishing between destructive thyroiditis and Graves' disease were 359.9 pg/ml (sensitivity, 100%; specificity, 95.5%; P = 0.001) and 119.4 pg/ml (sensitivity, 84.6%; specificity, 77.3%; P = 0.001). The sensitivity and specificity for DIT were 100.0% and 84.6% and for MIT 95.5% and 77.3%.
Serum DIT levels can potentially be used as a biomarker to distinguish between destructive thyroiditis and Graves' disease, with levels <359.9 pg/ml favoring Graves’ disease and ≥359.9 pg/ml favoring destructive thyroiditis.
To the best of our knowledge, this is the first study that uses serum DIT and MIT as novel biomarkers for distinguishing between different types of thyrotoxicosis. Even though there has been sparse research on DIT and MIT levels in this clinical scenario, higher concentrations of DIT have been found in hyperthyroid patients and low concentrations in hypothyroid patients (5).
Strengths of the study included having a control group and the measurement of DIT and MIT levels by rigorous assay methods (i.e., tandem liquid chromatography– mass spectrometry). Limitations of the study include a small sample size drawn from a single institution and that the etiologies of the hyperthyroidism were relatively heterogeneous (i.e., TRAb-negative transient Graves' disease and TRAb-positive toxic thyroid nodules were not excluded). Furthermore, the serum DIT samples were not matched to patients’ thyroid scintigraphy scans, the current gold standard for identifying destructive thyroiditis, because the scan was not universally obtained. Finally, the results may not be widely generalizable, as both MIT and DIT are regulated by multiple thyroid hormone cellular control mechanisms in normal and pathologic circumstances (5,6), are affected by iodine intake, and differ by race and ethnicity (7).
Currently, the clinical relevance of this study is low, as serum DIT and MIT levels are not routinely measured in daily clinical practice. On the other hand, the study is novel, and the findings suggest there is opportunity for further research to assess DIT and MIT as clinical biomarkers for thyroid dysfunction.
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