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| INVITED REVIEW |
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| Year : 2018 | Volume
: 16
| Issue : 2 | Page : 34-38 |
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Interpretation of thyroid function tests
Mathews Edatharayil Kurian1, Nitin Kapoor2
1 Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Endocrinology, Diabetes and Metabolism, Faculty of Medicine, Dentistry and Health Sciences, NCD Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
| Date of Web Publication | 20-Jun-2018 |
Correspondence Address:
Dr. Nitin Kapoor
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore - 632 004, Tamil Nadu, India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/cmi.cmi_17_18
Thyroid function tests are one of the most common endocrine panels in general practice because a good understanding of when to order them, interpretation of their results and indications for treatment are important for the optimal treatment of thyroid dysfunction. Thyroid-stimulating hormone (TSH) should be the first test to be performed on any patient with suspected thyroid dysfunction and in follow-up of individuals on treatment. It is useful as a first-line test because even small changes in thyroid function are sufficient to cause a significant increase in TSH secretion. Thyroxine levels may be assessed in a patient with hyperthyroidism, to determine the severity of hyperthyroxinemia. Antithyroid peroxidase measurements should be considered while evaluating patients with subclinical hypothyroidism and can facilitate the identification of autoimmune thyroiditis during the evaluation of nodular thyroid disease. The measurement of TSH receptor antibody must be considered when confirmation of Graves' disease is needed and radioactive iodine uptake cannot be done. Keywords: Anti-thyroglobulin, antithyroid peroxidase, free thyroxine, free triiodothyronine, primary hyperthyroidism, primary hypothyroidism, secondary hyperthyroidism, secondary hypothyroidism, serum thyroid stimulating hormone, serum thyroxine, serum triiodothyronine, thyroid function tests, thyroid-stimulating hormone receptor antibody
How to cite this article:
Kurian ME, Kapoor N. Interpretation of thyroid function tests. Curr Med Issues 2018;16:34-8 |
| Introduction | |  |
Thyroid dysfunction is a common condition encountered in clinical practice the world over and India is no exception.[4] Clinically, this condition may present with a wide range of symptoms.[1],[2],[3] This makes thyroid function tests (TFTs), one of the most ubiquitous endocrine panels in general practice. However, the interpretation of these can be rather challenging and can cause considerable bewilderment, more often than not. While not every abnormal value requires therapeutic intervention, a seemingly normal value may, in fact, warrant treatment. A good understanding of TFTs, when to order them, how to interpret their results as well as when to treat is, therefore, key to optimal treatment of thyroid dysfunction. The clinical status of the patient remains the most important deciding factor with respect to the treatment strategy that needs to be employed.
| Thyroid Physiology and Pathophysiology | | |
Normal
Normal physiology
The hypothalamus produces thyrotropin-releasing hormone (TRH) which acts on the pituitary gland.[5] This stimulates the pituitary to release thyroid-stimulating hormone (TSH), which in turn stimulates the thyroid gland to secrete thyroxine (T4) and triiodothyronine (T3)[6],[7] [Figure 1].
TSH demonstrates a negative feedback on the hypothalamus, while T4 and T3 have the same on the pituitary gland as well as the hypothalamus.[8]
Primary hypothyroidism and hyperthyroidism
As suggested by the nomenclature, the dysfunction is at the level of the thyroid gland in these disorders. In primary hypothyroidism, there is a deficiency in the secretion of thyroid hormones (T3/T4) which leads to raised levels of serum TSH. In most cases, the elevated levels of TSH drive the thyroid gland to try and maintain normal thyroid hormone levels. Meanwhile, in primary hyperthyroidism, the increased secretion of thyroid hormones causes a negative feedback, resulting in a suppression of the levels of serum TSH [Figure 1].
Secondary hypothyroidism and hyperthyroidism
The abnormality is at the level of the hypothalamus or the pituitary gland, in these disorders. Surgery on sellar or on suprasellar masses are an important cause of secondary hypothyroidism.[9] It is essential to remember that, even though the levels of T4 are low, those of TSH may be well within the normal range. Such a patient would require thyroid hormone replacement. The apparently normal value of TSH is, in fact, an inappropriately low value. In these patients, the levels of T4 have to be monitored so that the dose of thyroxine may be adjusted accordingly [Figure 1].
| Thyroid Function Tests | | |
Thyroid-stimulating hormone
TSH should be the first test to be performed on any patient with suspected thyroid dysfunction. It is useful as a first-line test because even small changes in thyroid function are sufficient to cause a significant increase in TSH secretion. Hence, TSH may be elevated even when thyroid dysfunction is inconspicuous. The assays done for the determination of TSH levels are reliable. Third-generation chemiluminescent assays can detect both elevation as well as significant lowering of levels of serum TSH.[10],[11] In many situations, normal levels of TSH may be sufficient to halt further testing for thyroid function.[12]
Serum thyroxine
T4 levels may be assessed in a patient with hyperthyroidism, to determine the severity of hyperthyroxinemia. T4 levels are elevated in most patients suffering from hyperthyroidism. During the course of treatment, levels of serum TSH may continue to be suppressed for an extended period of time and so fail to be a good indicator of thyroid function. Despite appearing to be euthyroid clinically, a patient may have subclinical hyperthyroidism. This can only be detected with the help of serum T4 levels. Serum T4 levels also become of use during any suspicion of secondary hypothyroidism, where levels of serum TSH may be within normal range in spite of low levels of serum T4. A low value of T4 levels concomitant with normal levels of TSH should, therefore, alert the treating physician of the possibility of secondary hypothyroidism in the patient. This may also warrant the assessment of other pituitary functions.
Serum triiodothyronine
Estimation of T3 levels is not advised in routine clinical practice. The measurable levels of T3 usually remain normal not only due to its short half-life but also because of the maintenance of the same by various homeostatic mechanisms. T3 levels, however, must be measured in a patient with suppressed levels of serum TSH as well as normal levels of T4 but displaying clinical features of hyperthyroidism. This is to rule out T3 toxicosis, which is seen in about 5% of patients with Graves' disease (GD). T3:T4 ratio >20 ng/mg is suggestive of GD.
Free triiodothyronine and free thyroxine
The measurement of levels of free T3 and those of free T4 is useful in conditions associated with changes in thyroid-binding globulin (TBG). An increase in the levels of TBG may be mirrored by an increase in the levels of total T4 and total T3 without any actual augmentation in hormone activity. The levels of serum T4 as well as serum T3 may thus show falsely hiked values in conditions with elevated TBG and conversely, falsely reduced values in conditions with reduced TBG [Table 1]. | Table 1: Conditions associated with altered binding of thyroxine-binding globulin
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Antithyroid antibodies
Several antibodies against thyroid antigens have been described. These are the antithyroid peroxidase (anti-TPO) antibody, antithyroglobulin antibody, and the TSH receptor antibodies. Anti-TPO measurements should be considered while evaluating patients with subclinical hypothyroidism. Anti-TPO testing can facilitate the identification of autoimmune thyroiditis during the evaluation of nodular thyroid disease. Meanwhile, the measurement of TSH receptor antibody (TSHR-Ab) must be considered when confirmation of GD is needed and radioactive iodine uptake cannot be done. TSHR-Ab can also be helpful in predicting the course and the therapeutic response in GD. This assay can also help in the assessment of the risk of fetal thyrotoxicosis in pregnant women who suffer from GD, and also, in the diagnosis of euthyroid ophthalmopathy.[13]
| Pregnancy and Thyroid Function | | |
During pregnancy, there is increase in the levels of T4 and also a corresponding decrease in levels of serum TSH. There exist three principal physiological processes that bring about this shift:
- HCG, which is produced by the placenta during pregnancy, possesses an alpha subunit which is similar to that of TSH. Therefore, it is able to bind to TSH receptors in the thyroid gland, resulting in an increase in the secretion of T4.[14] This leads to negative feedback on the pituitary causing a reduction in the secretion of TSH [Figure 2]
- The placenta also secretes estrogen, which acts on the liver to cause increased secretion of sex hormone-binding globulin (SHBG). SHBG acts on the thyroid increasing the production of T4. A similar phenomenon can be seen in women who use estrogen-containing oral contraceptives
- Pregnancy is a state of increased glomerular filtration rate which brings about a magnified demand on the thyroid to secrete T4 due to the enhanced excretion of T4.
 | Figure 2: Increased T4 and reduced TSH in pregnancy. Abbreviations: T4: Thyroxine, T3: Tri-iodothyronine, TSH: Thyroid-stimulating hormone, SHBG: Sex hormone-binding globulin.
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The trimester-wise cutoff levels for TSH are given [Table 2].
Recommendations in pregnancy
The following are the recommendations in pregnancy.[15],[16]
- T4 should be one and a half times the upper limit of normal
- Thyroid functions to be assessed every 6 weeks during pregnancy.
| Sick Euthyroid Syndrome/nonthyroid Illness Syndrome | | |
Sick euthyroid syndrome is a clinical entity displaying abnormal TFTs, despite no real thyroid dysfunction, in a patient with a coexisting serious nonthyroid illness [Table 3]. The levels of both T4 and T3 are elevated, while levels of serum TSH may be normal or low. In conditions associated with high metabolic demand such as critical illnesses, the body attempts to conserve energy by decelerating metabolism and by repressing energy expenditure in tissues so that the much-needed energy is available to the vital organs. One such mechanism involved is the reduction in the production of thyroid hormone. This agendum translates to a reduction in the levels of T3, and concurrently, an increase in the levels of T4. There is also a simultaneous increase in the levels of reverse T3, which is an inactive form of T3 [Figure 3]. According to latest guidelines, replacement therapy with levothyroxine is not recommended in such patients.[17],[18]
| Subclinical Hypothyroidism | | |
In subclinical hypothyroidism, the levels of TSH are suppressed while those of T4 are normal in subclinical hyperthyroidism. The patient may also be clinically euthyroid.[15] [Table 4] and [Table 5][14],[19],[20] elucidate the clinical conditions when subclinical hypothyroidism should be treated.
Case discussions
To illustrate the precedence of clinical presentation over the mere physical values determined by thyroid function assays, two sets of TFTs have been presented, each juxtaposed to two unique clinical scenarios.
Case scenario 1
A 32-year-old female having no previous history of any thyroid dysfunction visits the outpatient department concerned about abnormal results of TFTs done elsewhere. The results are as follows [Table 6].
The level of TSH is elevated but total, as well as free thyroxine levels, are normal. Let us consider two distinctive clinical scenarios with the same TFT results. In the first one, the patient had been recently treated for infertility and is currently into the 2nd month of gestation. She had had two pregnancy losses earlier and the current pregnancy was achieved by in vitro fertilization. The second scenario involves the patient being under evaluation for obesity with a body mass index of 36 kg/m 2. She leads a sedentary life and gives no history suggestive of any secondary cause for obesity.
The first scenario involves a patient with subclinical hypothyroidism, who is also pregnant. The upper limit for TSH levels is 2.5 μIU/mL in the first trimester and she needs thyroid hormone replacement to normalize thyroid function. It is essential to remember that, in pregnancy, correction of thyroid dysfunction is inescapable. On the other hand, the second case is that of a patient who – while also having subclinical hypothyroidism – does not fall into any criteria for the treatment of the same. She may, perhaps, imagine that the elevated levels of TSH are responsible for her obesity. Nevertheless, she will not benefit from thyroxine replacement and requires counseling to reinforce better diet and exercise.
Case scenario 2
A 57-year-old gentleman with no prior history of thyroid dysfunction presents with the following reports [Table 7].
The levels of serum TSH are within normal limits, but the level of T4 as well as free T4 is below normal. Consider a clinical scenario where the gentleman gives a past history of surgery on the pituitary gland 2 years earlier and has now come for follow-up evaluation. He does not complain of any symptom of hypothyroidism. In a different scenario, an obese patient undergoes emergency surgery for acute appendicitis with sepsis and is put on inotropes, postoperatively. The treating doctor asks for TFTs to rule out hypothyroidism as a cause for obesity.
The patient, in the first case, is suffering from secondary hypothyroidism following surgery to the pituitary gland and needs treatment. The levels of T4 and free T4 need to be monitored, and the normalization of these levels is important rather than the levels of serum TSH. In the second scenario, the patient is obese and is recovering from sepsis that developed secondary to appendicitis. The most appropriate differential for his thyroid dysfunction is sick euthyroid syndrome which requires no thyroxine replacement. TFTs may be repeated following his recovery from sepsis. Assays for the thyroid hormones are not recommended in very sick patients unless there is considerable suspicion of severe hypothyroidism or thyrotoxic storm.
| Conclusion | | |
The fundamental testing to be done in any patient with suspected thyroid dysfunction is the determination of the level of serum TSH. Whereas the measurement of T4 levels is recommended in patients with hyperthyroidism, the same is seldom required for T3. The assessment of free thyroid hormones is recommended in situ ations where thyroid binding globulin levels may be altered, such as oral contraceptive use or in nephrotic syndrome. In a pregnant woman, overtreatment may be more beneficial than undertreatment. The levels of serum TSH during the first trimester must never be allowed to go beyond 2.5 μIU/L and should be monitored every 6 weeks. The clinical presentation remains the most important component of the deciding process in terms of the initiation of therapy. When in doubt – supposing the results from biochemical evaluation are not in line with the clinical status of the patient – it is imperative that treatment is based on clinical assessment after confirming with the laboratory for any possible analytical error.[21],[22]
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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