Diagnostic Dilemma: A Case of Undetectable TSH

Introduction: Under steady-state conditions, measurement of TSH is accepted as the best assessment of thyroid function. The widely used TSH chemiluminometric assays have very low limits of detection and can help distinguish between the various causes of subnormal TSH. However, when evaluating a patient with abnormal thyroid tests but without thyroid symptoms, an appraisal of the test should be considered. Clinical Case: A 63-year-old South Asian man was referred to endocrinology for evaluation of a non-detectable TSH (<0.01 µIU/mL) that was reproduced on repeat testing, both using Siemens ADVIA Centaur TSH3-UL immunoassay. The patient was clinically euthyroid and denied taking biotin supplements. Testing of thyroid hormone showed normal values for free T3, total T3, free T4, and total T4. Additional labs included normal studies for free thyroxine by equilibrium dialysis, thyroid stimulating immunoglobulin, and heterophilic antibodies. Thyroid uptake and scan showed uniform uptake of 5.1% and 15.1% at 2-hours and 24-hours, respectively, with no dominant nodules. Hypothalamic-pituitary hormonal testing and MRI pituitary were both normal as well. When TSH testing was repeated on a separate platform, Roche’s eCLIA immunoassay, detectable values were obtained (TSH 6.48 µIU/mL). Conclusions: Testing of serum TSH by commercially available immunoassays is based on the sandwich method in which one antibody binds to the β-subunit of TSH and the other to the α-β interface. Most assays use monoclonal antibody pairs to achieve high selectivity. Immunoassay tests are prone to interferences, particularly by way of altering the measurable concentration of the analyte or by altering antibody binding (1). In this case, the presence of detectable TSH depended on the platform by which it was measured. This finding suggests a TSH-β variant with impaired immunoreactivity but functionally normal bioactivity. Such a mutation has been previously reported to occur five times more frequently among South Asian individuals than the general population (2). Genetic testing was offered to the patient to confirm this suspicion but was declined. It is incumbent on the clinician to reconcile a test result that is discordant with the clinical presentation. Having a fundamental understanding of the principles of the testing platform can assist in identifying potential sources of error. Failing to recognize a possible interference can lead to unnecessary healthcare expenditures, misdiagnosis and inappropriate management, potentially at a cost to the patient’s wellbeing. When faced with an undetectable TSH with otherwise normal thyroid hormones and unremarkable clinical picture, it is best to repeat the TSH test using a different available platform. References: (1)Favresse J et al. Endocr Rev. 2018;39(5):830-850(2)Pappa T et al. Thyroid. 2015 Aug;25(8):869-76

Papillary Thyroid Carcinoma With Axillary Lymph Node Metastasis

Papillary thyroid carcinoma (PTC) is typically known to be a non-aggressive form of thyroid follicular epithelial-derived cancer. It is characterized histologically by classic and variant forms. Metastases are uncommon and spread mainly via lymphatic channels to cervical lymph nodes and less commonly via hematogenous spread to lungs and bone. Axillary lymph node (ALN) metastasis is a rare sequela of disease presentation. A 59-year-old female presented for evaluation of shortness of breath and chest pain for one week. She had a longstanding history of hypothyroidism due to chronic lymphocytic thyroiditis which was stable on levothyroxine. Her physical exam revealed a firm mass on the inferior aspect of the left neck. Computed tomography (CT) angiogram ruled out pulmonary embolism but noted a superior mediastinal mass and significant left axillary and subpectoral adenopathy. Mammogram was negative for breast malignancy. Left axillary ultrasound showed a 1.1 x 1.8 x 1.9 cm enlarged lymph node. Thyroid ultrasound showed a 3 mm nodule on the left lower pole and a 3.7 x 2.9 x 2.1 cm heterogeneous and irregular mass in the left neck. Positron emission tomography/CT showed increased uptake in left lower paratracheal, left supraclavicular and axillary lymph nodes. Fine needle aspiration of the left neck mass and left ALN confirmed metastatic papillary carcinoma. She underwent total thyroidectomy, left modified neck, central neck, and left ALN dissection along with partial esophageal wall excision. Intraoperatively, she was found to have a multifocal tumor in the left thyroid lobe with the largest dimension of 1 cm. Surgical pathology noted that the primary tumor in the left thyroid was classic type of papillary carcinoma, and the metastatic tumor in the lymph nodes was of tall cell variant. I-123 thyroid uptake and scan after surgery showed low residual thyroid uptake of 0.6%. She underwent adjuvant ablation with 155 millicuries (mCi) of radioiodine (RAI or I-131) following levothyroxine withdrawal protocol. Post ablation therapy thyroid uptake and scan showed no radiotracer uptake within the thyroidectomy bed. According to the American thyroid association (ATA) risk stratification system, she was categorized as high risk. This case illustrates that PTC may exceptionally spread to axillary lymph nodes. Physiologic flow is centripetal to the jugulosubclavian junction and there is no communication between cervical and axillary lymphatics. However malignant tumors can alter and partially block lymphatic pathways, resulting in ALN metastasis in a retrograde direction. This case also demonstrates that PTC can be transformed into aggressive forms associated with worse prognosis such as tall cell variant. Further comprehensive monitoring and management approaches are needed to plan treatment and gauge prognosis of patients with PTC who present with ALN metastasis.

Comparison of Tc-99m Pertechnetate Thyroid Uptake Rates by Gamma Probe and Gamma Camera Methods for Differentiating Graves’ Disease and Thyroiditis

Although technetium-99m (99mTc) pertechnetate thyroid uptake rate can be measured by gamma camera with scintigraphy as well as by gamma probe, the normal reference range known as quite different between them. This study was performed to compare their diagnostic accuracy for evaluating patients with hyperthyroidism. We retrospectively reviewed consecutive 371 patients (euthyroid 89, Graves 167, and thyroiditis 115) who had simultaneously measured data of thyroid uptake rates by both gamma probe and camera methods in our hospital from November 2019 to June 2020. The reference ranges in euthyroid patients were 2.0-4.7% and 0.3–1.9% for probe and camera methods, respectively. For differentiating Graves’ disease and thyroiditis, the area under the curve of the camera method was significantly greater than that of the probe method (0.988 vs 0.975, p = 0.030) on receiver operating characteristic curve analysis. With a cutoff value of 0.7%, the sensitivity and specificity for the camera method were 93.4% and 94.8%, respectively. With a cutoff value of 3.0%, those for the probe method were 92.2% and 91.3%, respectively. In conclusion, 99mTc pertechnetate thyroid uptake rate measured by the camera method with scintigraphy had higher diagnostic accuracy than the probe method for evaluating patients with hyperthyroidism.

Assessment of normal reference values for thyroid uptake of technetium-99m pertechnetate in a Saudi population

BACKGROUND: Thyrotoxicosis is a common medical problem. Thyroid nuclear imaging with either I 123 or technetium-99m (Tc-99m) pertechnetate are used to determine the cause. Although I 123 has been the standard technique, Tc-99m pertechnetate is now commonly used, acceptable and easier to perform. The commonly used normal value of Tc-99m pertechnetate is 1–4%, but lower normal values have been reported in different populations. OBJECTIVE: Determine normal reference range of Tc-99m pertechne-tate thyroid uptake for thyroid scintigraphy in Saudi Arabia. DESIGN: Retrospective, cross-sectional. SETTING: Nuclear medicine service at tertiary care center in Riyadh. PATIENTS AND METHODS: We used data from biochemically euthyroid patients who underwent a thyroid Tc-99m pertechnetate scan while having parathyroid scintigraphy for hyperparathyroidism between April 2009 to April 2019. Medical records and biochemical thyroid function tests were reviewed and Tc-99m pertechnetate thyroid uptake values were determined for each patient. MAIN OUTCOME MEASURES: Thyroid uptake of Tc-99m pertechne-tate in euthyroid patients. SAMPLE SIZE: 167 RESULTS: The mean and median uptake of Tc-99m pertechnetate in euthyroid patients were 0.86% and 1.0%, respectively, and the inter-quartile range was 0.0–1.0%. The normal reference range in the study population was 0.2-2%. Thyroid uptake inversely correlated with age in females (r=−0.37, P <.001), males (r=−0.46, P =.001), and for all patients (r=?0.39, P <.0001). CONCLUSION: The range for normal thyroid Tc-99m pertechnetate was lower than the standard 1-4% range. Moreover, uptake decreased with age. Further studies are needed to establish the normal age-adjusted uptake for the thyroid Tc-99m pertechnetate scan. LIMITATIONS: Single center and retrospective. CONFLICT OF INTEREST: None.