|Year : 2016 | Volume
| Issue : 2 | Page : 69-74
Laboratory evaluation of thyroid function
M Suresh Babu, Rajendra Prasad Shivaswamy
Department of Medicine, JSS Medical College, JSS University, Mysore, Karnataka, India
|Date of Web Publication||14-Apr-2016|
M Suresh Babu
Department of Medicine, JSS Medical College, JSS University, Mysore, Karnataka
Source of Support: None, Conflict of Interest: None
Once diabetes is excluded, thyroid gland diseases form the main bulk of endocrine problems that the practicing physician encounters in their clinical practice. As patients with thyroid gland dysfunction may present with varied symptoms of different severity levels, physicians often have to identify such patients, so that appropriate treatment for thyroid disorders can be instituted at the earliest to prevent potential future complications. The current review will cover the evaluation and interpretation of thyroid function tests in the diagnosis of thyroid disorders.
Keywords: Thyroid, thyroid disorders, thyroid function test
|How to cite this article:|
Babu M S, Shivaswamy RP. Laboratory evaluation of thyroid function. Int J Health Allied Sci 2016;5:69-74
| Introduction|| |
The thyroid gland consists of two lobes that are connected by an isthmus and is located anterior to the trachea between the cricoid cartilage and the suprasternal notch. The normal thyroid gland is 12–20 g in size, highly vascular, and soft in consistency. The thyroid gland consists of numerous spherical follicles composed of thyroid follicular cells that surround secreted colloid, a proteinaceous fluid containing large amounts of thyroglobulin (Tg), the protein precursor of thyroid hormones (THs).
THs are derived from Tg, a large iodinated glycoprotein. After secretion into the thyroid follicle, Tg is iodinated on tyrosine residues that are subsequently coupled via an ether linkage. Reuptake of Tg into the thyroid follicular cell allows proteolysis and the release of newly synthesized T4 and T3. T4 is secreted from the thyroid gland in about 20-fold excess over T3. Both hormones are bound to plasma proteins, including thyroxine-binding globulin (TBG), transthyretin (TTR) formerly known as thyroxine-binding prealbumin and albumin. The hormone-binding proteins increase the pool of circulating hormone, delay hormone clearance, and may modulate hormone delivery to selected tissue sites. The concentration of TBG is relatively low (1–2 mg/dL), but because of its high affinity for THs (T4 > T3), it carries about 80% of the bound hormones. When the effects of the various binding proteins are combined, approximately 99.98% of T4 and 99.7% of T3 are protein-bound. Because T3 is less tightly bound than T4, the amount of unbound T3 is greater than unbound T4, even though there is less total T3 in the circulation. The unbound hormone is thought to be biologically available to tissues. T4 may be thought of as a precursor for the more potent T3. T4 is converted to T3 by the deiodinase enzymes. T3 is bound with 10–15 times greater affinity than T4, which explains its increased hormonal potency. Though T4 is produced in excess of T3, receptors are occupied mainly by T3, reflecting T4–T3 conversion by peripheral tissues, greater T3 bioavailability in the plasma, and receptors' greater affinity for T3.
Circulating THs enter cells by passive diffusion. After entering cells, THs act primarily through nuclear receptors α and β, although they also stimulate plasma membrane and mitochondrial enzymatic responses. Both TRα and TRβ are expressed in most tissues, but their relative expression levels vary among organs. TRα is particularly abundant in brain, kidney, gonads, muscle, and heart, whereas TRβ expression is relatively high in the pituitary and liver. The thyroid axis is a classic example of an endocrine feedback loop. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the pituitary production of thyroid stimulating hormone (TSH), which, in turn, stimulates TH synthesis and secretion. THs by negative feedback inhibit TRH and TSH production. The “set-point” in this axis is established by TSH. TSH is released in a pulsatile manner and exhibits a diurnal rhythm, its highest levels occur at night. However, these TSH excursions are modest in comparison to those of other pituitary hormones, in part because TSH has a relatively long plasma half-life (50 min). Acting through nuclear receptors, THs play a critical role in cell differentiation during development and help maintain thermogenic and metabolic homeostasis in the adult.
| Laboratory Assessment of Thyroid Status|| |
Laboratory assessment of thyroid status will help to arrive at a functional diagnosis and at times to an anatomical diagnosis. Laboratory tests can be divided into five major categories:
- Those that assess the state of the hypothalamic pituitary thyroid (HPT) axis
- Estimation of T4, T3 concentrations in the serum
- Tests that reflect the impact of TH on tissues
- Tests for the presence of autoimmune thyroid disease
- Tests that provide information about thyroidal iodine metabolism.
- Where possible manufacturers reference ranges should be confirmed locally using an adequate population size of at least 120 ambulatory subjects
- For TSH, reference ranges should be established using specimens collected between 08:00 h and 18:00 h and using 95% confidence limits from log transformed data
- Since TSH, free and total THs change during pregnancy, trimester-related reference ranges should be available with data generated locally or countrywise.
| Tests of Hypothalamic Pituitary Thyroid Axis|| |
TSH secretion is exquisitely sensitive to the plasma concentrations of free THs providing a precise and specific barometer of the thyroid status of the patient. Serum TSH level estimation is the single best test of thyroid function. Small changes in TH levels cause logarithmic amplification in TSH secretion. The most advanced (third-generation) chemiluminescent TSH assays can now detect both elevation and significant lowering of TSH levels, and are capable of reliably measuring values <0.1 mU/L, thus aiding detection of subclinical thyrotoxicosis. A normal TSH value is a sufficient indicator to stop further testing of thyroid function in most cases. However, in cases suggestive of possible hypothalamic-pituitary disease (central), a free T4 (FT4) level estimation is desirable. There is a diurnal variation of TSH secretion with peak values in the early evening and a nadir in the afternoon. A borderline abnormal value should always be repeated within a period of a week or so to be certain that it is representative.
The normal range of the serum TSH concentration by immunometric assay varies slightly in different laboratories but is most commonly 0.4–4.2 mU/L., Patients with hyperthyroidism will have a subnormal TSH. The values fall into two general categories – those between the lower limit of normal and 0.1 mU/L and those <0.1 mU/L. Individuals in the former category are asymptomatic (subclinical hyperthyroidism), whereas the latter usually has symptomatic thyrotoxicosis and a significant elevation in FT4. Patients with primary hypothyroidism have serum TSH concentrations that range from minimally elevated to 1000 mU/L. In general, the degree of TSH elevation correlates with the clinical severity of the hypothyroidism. Patients with serum TSH values in the range of 5–15 mU/L have few if any symptoms. Such individuals with modest elevation are said to have subclinical hypothyroidism if the serum FT4 is in the normal range. Patients with hypothalamic or pituitary hypothyroidism often have normal or even slightly elevated serum TSH. The circulating TSH generally has reduced biological activity due to abnormal glycosylation, reflecting the impaired access of TRH to the thyrotrophs., An elevation in both serum TSH and FT4 is unusual and indicates either autonomous TSH production as with a TSH secreting pituitary tumor, resistance to TH (RTH) or hyperthyroidism with an artifactual elevation in TSH. Consultation with the clinical chemistry laboratory to rule out an assay artifact should be done. If an artifactual error is ruled out, differentiating between these diagnoses may require magnetic resonance imaging of the hypothalmic pituitary region. The finding of an elevated serum sex hormone-binding globulin (SHBG) and circulating free α subunit may support the diagnosis of thyrotropinoma (TSH-oma), along with the finding of hyper- or hypo-secretion of other pituitary hormones.
The hypothalamic-pituitary axis may remain suppressed for up to 3 months after complete resolution of the thyrotoxic state in patients with Graves' disease after being treated with antithyroid drugs or I-131., The best test for assessing the physiologic state in that situation is the FT4 or FT4 index (FT4I). With time, the TSH feedback regulatory loop will normalize, and TSH secretion will return and become appropriate for the circulating free TH concentration. If the serum TSH is suppressed and the serum FT4 is low, ingestion of liothyronine (triiodothyronine) should be suspected. When mild thyrotoxicosis is present during early pregnancy, it may be due to gestational thyrotoxicosis secondary to human chorionic gonadotropin (hCG) stimulation of the thyroid gland. The alpha subunit of hCG is homologous to the alpha subunit of TSH. The serum hCG concentration is highest in the first trimester of pregnancy and hCG's thyroid stimulating activity can suppress the serum TSH level, but in most cases the TSH level remains within the “normal range” of pregnancy. In pregnant women who are not on T4 therapy for hypothyroidism, a persistently suppressed TSH (<0.1 μIU/mL) after the first trimester or elevations of the free THs at any point during pregnancy suggest that the suppressed TSH is secondary to autonomous thyroid function, like Graves' disease as toxic nodular goiters and hot nodules are uncommon in this age group. Detection of TSH receptor antibodies (TRAbs) can confirm the diagnosis. Iodine radioisotope imaging studies are forbidden during pregnancy. If the hCG concentration is markedly elevated and for a prolonged time, as in hyperemesis gravidarum and gestational trophoblastic disease (hydatidiform mole, a benign condition, and choriocarcinoma, a malignant condition), overt hyperthyroidism can develop, with elevated FT4 and free T3 (FT3)., In severe illnesses, with or without dopamine infusion or steroids, TSH is suppressed making an assessment of thyroid functional status difficult. Because FT4I may also be reduced in such patients, astute clinical judgment is required to know the thyroid status. In the absence of an abnormal thyroid gland by careful physical examination, a hospital in-patient with a mild or moderate (<20 mIU/L) increase in serum TSH and an estimated FT4 (by either a FT4 test ora FT4I) within the health-related reference interval can usually be followed without treatment and re-evaluated later. The same holds true for a patient with a subnormal serum TSH and estimated FT4 and serum T3 values that are not increased. In both cases, the great majority of patients do not have clinically significant thyroid disease.
Despite the utility and general efficacy of serum TSH measurement alone as a screening tool for identifying patients with thyroid dysfunction, a patient should not receive treatment for this dysfunction solely on the basis of an abnormal TSH. The TSH assay is an indirect reflection of TH supply and does not by itself permit a conclusive diagnosis of a specific disorder of TH production. Accordingly the TSH abnormality must be verified and an alteration in TH concentrations verified before initiating treatment.
| Estimation of T4, T3, Concentrations in the Serum|| |
Several laboratories measure the total T4 and total T3, which is not a true reflection of the thyroid status of an individual. The THs circulate in the body largely in the inactive form, bound to carrier proteins (TBG, TTR and albumin) while only the small unbound fraction is metabolically active. Moreover, in some clinical conditions, particularly those in which there is an alteration of the amount of carrier proteins, the total T3 and total T4 may be elevated while the thyroid functional state (FT3 and FT4 levels) may be normal. Such conditions include:
- Hereditary abnormalities of binding proteins: These include TBG deficiency or TBG excess, abnormal albumin, TTR levels
- Acquired deficiency of binding proteins: Nephrotic syndrome, liver disease, therapy with androgens or anabolic steroids may alter the levels of carrier proteins
- Drug-induced alterations in T4 binding to TBG: Therapy with salicylates, phenytoin, phenylbutazone
- Presence of T4 antibodies.
The development of newer immunoassay methods for determining FT3 and FT4 has overcome many of these problems. Radioimmunoassay measurement of total serum T4 levels is highly sensitive in reflecting the hyperthyroid (85–95%) and the hypothyroid status (80–90%) of patients.
Currently routine measurement of serum T3 is not carried out (only T4 is measured) in patients suspected of having thyroid disorders. About 25% of patients with hypothyroidism have low normal T3 values. FT3/total T3 measurements, however, should be performed in the following settings:
- In patients suspected of having T3 thyrotoxicosis. The combination of high T3, suppressed TSH and normal T4 is usually associated with toxic nodular goiter, whereas T3 and T4 are typically both elevated in Graves' disease (although T3 is usually more elevated than T4)
- In patients taking drugs that inhibit the peripheral conversion of T4 to T3 (such as dexamethasone, propranolol, propylthiouracil, amiodarone, and iodine-containing contrast media).
Testing both thyroid stimulating hormone and free T4 There are certain clinical situations where TSH testing must be coupled with testing the FT4 levels. Clinical situations where measurement of both serum TSH and FT4 is required are principally disorders where the pituitary thyroid axis is not intact or is unstable. These situations include:
- Optimizing thyroxine therapy in newly diagnosed patients with hypothyroidism
- Diagnosing and monitoring thyroid disorders in pregnancy
- Monitoring patients with hyperthyroidism in the early months after treatment
- Diagnosis and monitoring treatment for central hypothyroidism
- End-organ TH resistance
- Sick euthyroid state
- TSH-secreting pituitary adenomas
- Possible subclinical hypothyroidism: If screening is performed, and a high serum TSH concentration is found, and the FT4 is normal, the measurement should be repeated 3–6 months later, along with measurement of serum FT4, after excluding nonthyroidal illness and drug interference
- Overtly hypothyroid patients (who have serum TSH >10 mU/L and low FT4 concentrations) should be treated with thyroxine.
Free T4 or free T3 index
Is useful in estimating the FT4 or T3 levels indirectly and is obtained by multiplying the TH binding ratio by the total T4 (or T3). However, these tests are rarely used nowadays since better methods are routinely available to measure FT3 and FT4.
| Serum Thyroglobulin|| |
A major clinical value of measuring the level of serum Tg is in the management, but not in the diagnosis, of differentiated thyroid carcinoma., Serum Tg concentrations are increased in patients with both benign and differentiated malignant follicular-cell derived tumors of the thyroid and do not serve to distinguish between the two. After total thyroid ablation for papillary or follicular thyroid carcinoma, Tg should not be detectable, and its subsequent appearance signifies the presence of persistent or recurrent disease.
| Tests That Reflect the Impact of Thyroid Hormone on Tissues|| |
Abnormalities in the supply of TH to the peripheral tissues are associated with alterations in a number of metabolic processes that can be quantitated. Some of these may be useful in the rare patient in whom serum TSH is not an accurate barometer of thyroid status, such as those with TH resistance. These include basal metabolic rate, biochemical markers such as low-density lipoprotein cholesterol, creatine kinase MM isoenzyme, SHBG, ferritin, and osteocalcin.
| Tests for the Presence of Autoimmune Thyroid Disease|| |
Tests for antibodies against thyroid-specific antigens thyroid peroxidase (TPO), Tg and TSH receptors are used in the diagnosis of autoimmune thyroid disorders. Unfortunately, the diagnostic and prognostic value of these thyroid autoantibody measurements is hampered by differences in the sensitivity and specificity of current methods. Although autoantibody tests have inherent clinical utility in a number of clinical situations, these tests should be selectively employed.
| Thyroid Peroxidase Autoantibodies|| |
The principal antigen in the thyroid microsomes is the TPO enzyme, a 100kD glycosylated protein. An abnormal TPO autoantibody (TPOAb) is detected in 15–20% of “healthy” euthyroid subjects and even higher percentages of patients with various nonthyroid autoimmune disorders such as type 1 diabetes and pernicious anemia. Approximately 70–80% of patients with Graves' disease and virtually all patients with Hashimoto's, atrophic thyroiditis or postpartum thyroiditis have TPOAb detected. TPOAb is implicated as a cytotoxic agent in the destructive thyroiditic process. A euthyroid subject with detectable TPOAb is at increased risk of development of hypothyroidism. Detectable level of TPOAb typically precedes the development of an elevated TSH and is therefore a risk factor for hypothyroidism.
| Thyroglobulin Autoantibodies|| |
Anti-Tg autoantibodies (TgAbs) were the first thyroid antibodies to be recognized to circulate inpatients with autoimmune thyroid disorders. Autoantibodies against Tg are encountered in autoimmune thyroid conditions, usually in association with TPOAb. However, the recent NHANES III study found that 3% of subjects with no risk factors for thyroid disease had detectable TgAb without TPOAb. In these subjects with only TgAb detected, no association with TSH abnormalities was found so that the clinical significance of an isolated TgAb abnormality remains to be established. This suggests that it is unnecessary to measure both TPOAb and TgAb for a routine evaluation of thyroid autoimmunity. TPO Ab is the best choice if only a single test is ordered for detection of autoimmune thyroiditis.
| Thyroid Stimulating Hormone Receptor Autoantibodies|| |
TRAbs were first recognized as long-acting thyroid stimulator using mouse bioassays. These autoantibodies are directed against epitopes on the ectodomain of the TSH receptor. The prevalence of TRAb in Graves' disease is 80–95%. Two classes of TRAb can be associated with autoimmune thyroid disorders – (a) thyroid stimulating autoantibodies (TSAbs) that cause Graves' hyperthyroidism and (b) thyroid stimulation-blocking antibodies (TBAb) which block receptor binding of TSH. Each class of TRAb (TSAb and TBAb) may be detected alone or in combination in Graves' disease and Hashimoto's thyroiditis. The relative concentrations of the two classes of TRAb may modulate the severity of Graves' hyperthyroidism and may change in response to therapy or pregnancy. TRAb tests are used in the differential diagnosis of hyperthyroidism, the prediction of fetal and neonatal thyroid dysfunction due to transplacental passage of maternal TRAb and prediction of the course of Graves' disease treated with antithyroid drugs. A persisting high level of TRAbs is a useful predictor of relapse on cessation of the drug., Quantitation of TRAbs may be a useful indicator of the degree of disease activity in an individual patient and can confirm the clinical diagnosis of Graves' disease in a scientific manner. Demonstration of TRAbs may also be of diagnostic value in the euthyroid patient with exophthalmos, especially when it is unilateral. Graves patients usually test positive for TRAb, and they may have related ophthalmopathy, whereas patients with toxic nodular goiter are TRAb-negative and do not have Graves ophthalmopathy., Unfortunately, in patients with low or negative titers, the test is much less helpful. Furthermore, the presence of iodine deficiency may also interrupt the development of hyperthyroidism despite the presence of TRAbs. High TRAbs in a pregnant woman with Graves' disease increase the likelihood that neonatal thyrotoxicosis will be present in her offspring, and in this situation, a bioassay late in pregnancy is preferred.
| Tests That Provide Information About Thyroidal Iodine Metabolism|| |
Radioactive iodine uptake and scanning is a very useful tool in the diagnostic evaluation of thyrotoxicosis. After ingestion of the tracer usually I-131 or I-123, the emitted gamma radiation allows external detection, calculation of fractional uptake and scintigraphic imaging of the thyroid gland. The uptake is measured at 6 h and 24 h and the normal values range between 5% and 15% for the 6 h uptake and 5–25% for the 24 h uptake. Technetium-99 m pertechnetate imaging is preferably being used now, since it is actively trapped in thyroid follicular cells like iodine and has the advantage of a rapid turnover requiring the uptake and scan to be completed within 20–30 min with a much lower dose of radioactivity. However, it has limitations in terms of detecting organification defects.
Patients treated with radioiodine or those who undergo thyroidectomy should be screened indefinitely for the development of hypothyroidism or recurrence of hyperthyroidism. Assessment of thyroid function in these patients should be done 4–8 weeks after treatment, followed by quarter yearly assessments for the subsequent year and annually thereafter. In patients undergoing thyroxine therapy regardless of the cause, long-term follow-up with annual measurements of serum TSH are recommended. This helps to check compliance, verify the dosage and take account of variations in dosage requirements due to concomitant medications.
| Pitfalls in the Measurement and Interpretation of Thyroid Function Tests|| |
Most TFTs are straightforward to interpret and confirm the clinical impression of euthyroidism, hypothyroidism or hyperthyroidism. However, in an important subgroup of patients the results of TFTs can seem confusing, either by virtue of being discordant with the clinical picture or because they appear incongruent with each other (e.g., raised THs, but with nonsuppressed thyrotropin [TSH]; raised TSH, but with normal TH). In such cases, it is important first to revisit the clinical context, and to consider potential confounding factors, including alterations in normal physiology (e.g., pregnancy), intercurrent (nonthyroidal) illness, and medication usage (e.g., thyroxine, amiodarone, heparin). Once these have been excluded, laboratory artifacts in commonly used TSH or TH immunoassays should be screened for, thus avoiding unnecessary further investigation and/or treatment in cases where there is assay interference. In the remainder, consideration should be given to screening for rare genetic and acquired disorders of the HPT axis (e.g. RTH, TSH-oma).
| Thyroid Function Tests in Special Patient Populations|| |
Patients presenting with atrial fibrillation, hyperlipidemia, subfertility and osteoporosis, should undergo serum TSH estimations as assessment of thyroid function because:
- Atrial fibrillation may be secondary to thyrotoxicosis in about 5–10% of patients
- Osteoporosis may be secondary to hyperthyroidism and can be corrected by treating the underlying cause. Both hyper as well as hypothyroidism may be contributing factors in menstrual cycle disorders, fetal loss, and infertility.
| Conclusion|| |
- Thyroid disorders have varied clinical manifestations and hence every suspected case of thyroid disease needs to be evaluated with laboratory investigations
- The enhanced sensitivity and specificity of TSH assays have greatly improved the assessment of thyroid function tests. Since TSH levels change dynamically in response to the alterations of T3 and T4, the approach to evaluate whether the patient has thyroid disorder is to test the TSH levels first
- When hypothyroidism is suspected, a FT4 estimate is appropriate because total T3 and FT3 tests have in adequate sensitivity and specificity in this setting
- When hyperthyroidism is suspected, the combination of a FT4 estimate and a total T3 or FT3 estimate provides the most complete assessment of the severity of hyperthyroidism and identifies cases of “T3-toxicosis,” i.e., a selective increase of the serum T3 concentration.
JSS Hospital, Mysore, Karnataka, India.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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