Does TSH Reliably Detect Hypothyroid Patients?

Research Article

Annals Thyroid Res. 2018; 4(1): 122-125.

Does TSH Reliably Detect Hypothyroid Patients?

Ling C¹, Sun Q¹, Khang J¹, Felipa Lastarria M¹, Strong J¹, Stolze B¹, Yu X¹, Parikh TP¹, Waldman MA¹, Welsh K¹, Jonklaas J², Masika L³ and Soldin SJ1,2*

¹Department of Laboratory Medicine, NIH, USA

²Department of Medicine, Georgetown University, USA

³Department of Laboratory Medicine and Pathology, Walter Sisulu University, South Africa

*Corresponding author: Soldin SJ, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, 10 Center Dr, Rm 2C306, Bethesda, MD 20816, USA

Received: January 02, 2018; Accepted: February 08, 2018; Published: February 20, 2018


Objectives: To evaluate the reliability of normal Thyroid Stimulating Hormone (TSH) as a thyroid function test and assess the effect of Adrenocorticotropic Hormone (ACTH) on serum TSH concentration.

Design and Methods: Patients presenting to the National Institutes of Health Department of Endocrinology outpatient clinic with symptoms consistent with hypothyroidism were identified. Thyroid hormone concentrations were measured by liquid chromatography/tandem mass spectrometry and immunoassay. Patients with normal TSH concentrations were assessed for both clinical and biochemical hypothyroidism.

We evaluated the effect of ACTH stimulation (performed on patients for assessment of adrenal function) on TSH concentration.

Results: Patients with symptoms consistent with hypothyroidism but with normal TSH values in the range of 1-4 IU/mL and normal free T4 (FT4) values by immunoassay measurements were confirmed to be biochemically hypothyroid following measurements of thyroid hormones by mass spectrometry. We present case studies of two patients, a 76-year-old male and a 58-year-old female. Improvement in the male patient’s hypothyroid symptoms, including afternoon fatigue, constipation, alopecia, dry skin and high cholesterol, was documented after initiating thyroid hormone replacement.

ACTH stimulation resulted in an average decrease of 17% in TSH between time 0 and 60 minutes post stimulation.

Conclusion: Although measurement of TSH is a convenient screen for thyroid function, it is influenced by many factors which may affect its overall reliability. We believe thyroid function should be assessed by more than a single test. We recommend measurement of thyroid hormone concentrations by mass spectrometry if the patient’s clinical presentation is discordant with their TSH levels.

Keywords: Thyroid; Hypothyroidism; TSH; Thyroid hormones; Mass spectrometry


TSH: Thyroid stimulating hormone; FT3: Free Triiodothyronine; FT4: Free Thyroxine; TT3: Free Triiodothyronine; TT4: Free Thyroxine; ACTH: Adrenocorticotropic Hormone; LC-MS/ MS: Liquid Chromatography-Tandem Mass Spectrometry; TBG: Thyroxine-Binding Globulin; HPLC: High-Performance Liquid Chromatography


Hypothyroidism is a disorder that affects an estimated 5%-10% of the population in the United States [1,2] and 5% of the population worldwide [2]. Individuals with hypothyroidism may also experience symptoms including fatigue, dry skin, decreased cognitive function and elevated cholesterol [3].

The clinical manifestations of hypothyroidism vary widely and are usually dependent on the age at onset, the duration, as well severity of the disease. Hence, the accurate measurement of thyroid function and the serum levels through accurate quantitation of thyroid hormones by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) is critical for the assessment, treatment and monitoring of patients with thyroid diseases as the diagnosis and management relies heavily on performing the correct laboratory tests [4].

Measurement of Thyroid Stimulating Hormone (TSH) concentrations by immunoassay is used by the majority of clinical laboratories to assess thyroid function [5]. These assays are subject to a number of interferences, including biologically inactive isoforms of TSH, heterophilic antibodies and biotin supplements [6-8]. In addition, the concentration of serum TSH is affected by a number of non-thyroid hormone factors, such as pregnancy, age, sex, exercise, individual thyroid hormone set points, the timing of levothyroxine administration, steroids, and drugs [9-17]. Additionally, TSH may also undergo seasonal and diurnal fluctuations [18]. We have conducted extensive comparisons in hypo- and hyperthyroid patients with both immunoassay and LC-MS/MS. In general, agreement is adequate for FT4, FT3 and TT3 in the hyperthyroid area but very poor in the hypothyroid area [19-21]. This is a significant clinical problem as two-thirds of patients with thyroid disease are hypothyroid [1,22], accounting for 20 million people in the USA alone. We have demonstrated a positive bias for TT3, FT3 and FT4 by IAs, particularly at low concentrations, which prevented the correct diagnosis of approximately 50% of these patients. These patients were tested to be biochemically hypothyroid by LC-MS/MS and showed hypothyroid symptoms [19,21].

We have previously reported the case study of a patient with a medical history of hypothyroidism complaining of lethargy despite treatment with T4 [21]. Her serum TSH levels were within the normal range as measured by IA, but measurements of thyroid hormones with LC-MS/MS revealed that she had low TT3 and low-normal Free T3 (FT3) [21]. Addition of T3 to this patient’s T4 regimen normalized her T3 levels, lowered her cholesterol, and resolved her symptoms, demonstrating that a normal serum TSH level does not rule out hypothyroidism.

We present two additional cases in which serum TSH measurements alone should not be the sole criteria in the diagnosis of hypothyroidism. In our clinic, several of our patients suspected of having hypothyroidism, were found to have normal serum TSH concentrations. Assessing thyroid function tests by LCMS/ MS illustrated that they did indeed suffer from biochemical hypothyroidism. One of the patients received low-dose thyroid hormones, which alleviated the patient’s hypothyroidism.

We also investigated effect of ACTH on TSH concentrations in patients undergoing ACTH stimulation to evaluate adrenal function.

Materials and Methods

Patients and samples

Patients with symptoms of decreased thyroid function were identified in the NIH outpatient clinic. Thyroid hormone measurements by mass spectrometry confirmed them to be biochemically hypothyroid.

The effect of ACTH administration on serum TSH levels was assessed in 21 patients who were undergoing adrenal function testing between 8AM and 9AM. TSH was measured before administration of ACTH and 1 hour after ACTH stimulation.

This study was approved by the National Institutes of Health institutional review board (IRB, clinical protocol number 93-CC- 0094) and the Georgetown IRB (Pro0000007-01).

Cholesterol, thyroid hormone and TSH measurements

Cholesterol, TSH, and thyroid hormones were measured using the Roche Cobas 6000 (Indianapolis, IN). FT3 and FT4 were measured by ultrafiltration isotope dilution LC-MS/MS using a SCIEX Triple- Quad-6500 System (AB Sciex, Concord, ON, CA) as previously described [19]. TT3, and TT4 were measured by atmospheric pressure photoionization liquid chromatography-tandem mass spectrometry using the Agilent 6460 triple-quadrapole mass spectrometer coupled to the Agilent 1200 Infinity Series HPLC (Agilent Technologies, Santa Clara, CA, USA) as previously described [23].


To date we have identified three patients who clinically presented with symptoms of hypothyroidism, yet had TSH measurements within the reference range (0.2-4 μIU/mL) (Table 1). A case presentation of the first patient identified was previously published by our group [21] and we now present two additional cases.

Citation: Ling C, Sun Q, Khang J, Felipa Lastarria M, Strong J, Stolze B, et al. Does TSH Reliably Detect Hypothyroid Patients?. Annals Thyroid Res. 2018; 4(1): 122-125.