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Review Article

Laboratory evaluation of thyroid function:

Dilemmas and pitfalls
M. K. Garg, Namita Mahalle1, K. V. S. Hari Kumar2
Department of Endocrinology, Military Hospital, Shillong, Meghalaya, 1Department of Biochemistry, Deenanath Mangeshkar Hospital and Research
Center, Erandawane, Pune, Maharashtra, 2Department of Endocrinology, CH WC, Chandimandir, Panchkula, Haryana, India

ABSTRACT Access this article online

Among all endocrine disorders, thyroid dysfunction is possibly
most common endocrine disorder barring obesity. This
implies that thyroid function tests (TFT) are routinely ordered
for laboratory test for its evaluation. Furthermore, recently
laboratory values of thyroid function, thyroid-stimulating
hormone (TSH), free thyroxine (FT4), and free triiodothyronine
(FT3), have gathered importance in view of rapidly changing
cut-offs for treatment of thyroid disorders during pregnancy.
Most of the times, interpretation of TFT is easy, indicating
euthyroidism (normal FT4 and TSH), hypothyroidism (low FT4
or FT3 with high TSH), or thyrotoxicosis (high FT4 or FT3 with
low TSH). However, the normal ranges reflect two standard
deviations around the mean. Hence, 2.5% of the population may
show minor abnormalities on both side of normal range in spite
of being euthyroid. Sometimes interpretation becomes difficult
when there is an alteration in relation between thyroid hormones
and TSH. These pitfalls in investigations will cause dilemma
in physicians and patients mind alike. Problems in hormonal
evaluation can be preanalytical, analytical, and postanalytical.
In an ambulatory patient, TFTs have limited preanalytical
interferences such as age, pregnancy, medications, genetic
mutations, systemic diseases, and critical illnesses. Analytical
errors occur due to heterophile antibodies and macro-TSH.
Postanalytical errors include wrong entry of the result, mistakes
in the units of the parameter checked and failure to identify the
normal data.
Keywords: Hypothyroidism, thyroid function tests, thyroxine,
triiodothyronine
Quick Response Code:
Website:
www.mjdrdypu.org
DOI:
10.4103/0975-2870.186054
Prevalence of antithyroid peroxidase antibodies (TPOAb)
was around 3.7% among children and adolescents and 13.3%
among adults.[3,4] It is believed that in India alone there
are 42 million patients suffering from thyroid disorders.[5]
All this data implies that thyroid disorders are commonly
present in population, and their evaluation routinely
requires laboratory evaluation of thyroid function. In fact,
subclinical hypothyroidism and subclinical hyperthyroidism
are only laboratory diagnosis where patient usually has
no symptoms. Furthermore, recently laboratory values
of thyroid function have gathered importance in view
of rapidly changing cut-offs for the treatment of thyroid
disorders during pregnancy.[6]
Iodine is the main constituent of thyroid hormones,
which enters thyroid gland as inorganic or organic
form through sodium iodide symporter. In thyroid
gland, iodine get organized by peroxidase enzymes
at cell colloid interface and forms iodothyronines —

Introduction
Among all endocrine disorders, thyroid dysfunction
is possibly most common endocrine disorder barring
obesity. Almost one-third of the world’s population
lives in areas of iodine deficiency.[1,2] In recent studies in
Indian school children and adults, goiter rate was 15.5%
and 9.6%; hypothyroidism was present in 7.3% and 21%
and hyperthyroidism in 0.3% and 0.6%, respectively.
This is an open access article distributed under the terms of the
Creative Commons Attribution-NonCommercial-ShareAlike 3.0
License, which allows others to remix, tweak, and build upon the
work non-commercially, as long as the author is credited and the
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For reprints contact: reprints@medknow.com
How to cite this article: Garg MK, Mahalle N, Hari Kumar K.
Laboratory evaluation of thyroid function: Dilemmas and pitfalls. Med
J DY Patil Univ 2016;9:430-6.

Address for correspondence:

Dr. K. V. S. Hari Kumar, Department of Endocrinology, CH WC, Chandimandir, Panchkula, Haryana, India. E-mail: hariendo@rediffmail.com

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Garg, et al.: Thyroid function tests

monoiodothyronine, diiodothyronine, triiodothyronine All these advances and high prevalence of thyroid disorders
(T3), and thyroxin (T4). The thyroid gland is only source implies that thyroid function tests (TFTs) are performed
of T4, whereas T3 is secreted from thyroid gland and commonly. Most of the times, interpretation of TFT is
also generated in peripheral tissue by deiodinase enzyme easy, indicating euthyroidism (normal FT4 and TSH),
system. The same system also generates an inactive hypothyroidism (low FT4 or FT3 with high TSH), or
form of T3 — reverse T3. Thyroid hormones circulate thyrotoxicosis (high FT4 or FT3 with low TSH). However,
as protein-bound form (thyroid binding globulin [TBG], the normal ranges reflect two standard deviations around
transthyretin [TTR]/prealbumin [TBPA], and albumin) the mean. Hence, 2.5% of the population may show minor
and free form.[2] abnormalities on both side of normal range in spite of being
euthyroid. Sometimes interpretation becomes difficult when
Evaluation of thyroid functions consist of anatomical there is an alteration in relation between thyroid hormones
(ultrasonography, scintigraphy); physiological (total and TSH. These pitfalls in investigations will cause dilemma
T4 [TT4], total T3 [TT3], free thyroxine [FT4], free in physicians and patients mind alike. Variation or errors
triiodothyronine [FT3], thyrotropin [thyroid-stimulating in hormonal evaluation can be preanalytical, analytical,
hormone [TSH]] and thyroglobulin [Tg]); immunological and postanalytical. Out of these, we will discuss pitfalls in
(TPOAb, TSH receptor antibodies [TRAb], and anti Tg preanalytical and analytical factors.
antibodies [TgAb]); and pathological assessment (fine needle
aspiration). Preanalytical variations
The normal range of various thyroid hormones is given
Hormonal Tests in Table 1. Preanalytical variations are related to age,
pregnancy, medications, systemic, and genetic diseases.
Overview
In an ambulatory patient, TFTs have limited preanalytical
Over last 50 years, laboratory evaluation of thyroid disorder interferences [Table 2]. Physiological variables such as
has undergone sea of change. There has been gradual age, pregnancy, TSH/FT4 relationship, and biological
improvement in sensitivity and specificity of diagnostic tests differences can affect TFTs evaluation. The hypothalamo-
for thyroid. In the 1950s, only indirect estimate of the TT4 pituitary-thyroid unit matures from fetal life until the end
(free and protein-bound) concentration, using the protein-
bound iodide technique was available. The development
Table 1: Normal ranges of thyroid function tests
of competitive immunoassays in the early 1970s and more
recently, noncompetitive immunoradiometric assay methods Parameter Normal range
Total T4
have progressively improved the specificity and sensitivity
Adult (µg/dL) 5-12
of thyroid hormone testing. Presently, serum-based tests are Neonate (µg/dL) 6.4-12.6
available for measuring the concentration of both the total Total T3
(T4 and T3) and free (FT4 and FT3) thyroid hormones in the Adult (ng/dL) 70-190
circulation by radioimmunoassay and chemiluminescence Neonate (ng/dL) 100-470
assay.[7] In addition, measurements of the thyroid hormone TSH
Adult (mIU/L) 0.4-4.2
binding plasma proteins are available.[8] Improvements in the
Neonate (mIU/L) 1.0-39.0
sensitivity of assays to measure the pituitary TSH from first
First trimester (mIU/L) 0.1-2.5
generation assays to fifth generation assays with sensitivity Second trimester (mIU/L) 0.2-3
to detect TSH levels as low as <0.004 mIU/l, allow TSH to Third trimester (mIU/L) 0.3-3
be used for detecting both hyper- and hypo-thyroidism. As Free T4
a result, TRH stimulation test and T3 suppression test have Neonate (ng/dL) 0.9-2.2
become obsolete. Furthermore, measurement of the thyroid Adolescents (ng/dL) 0.8-2.0
Adults (ng/dL) 0.8-1.8
gland precursor protein, Tg as well as the measurement of
Free T3
calcitonin in serum, have become important tumor markers
Neonates (pg/mL) 2.4-4.2
for managing patients with differentiated and medullary Adolescents (pg/mL) 2.9-5.1
thyroid carcinomas (MTCs), respectively. Furthermore, Adults (pg/mL) 2.3-4.2
there has been development of more sensitive and specific Thyroglobulin (ng/mL) 5-25
tests for TPOAb, TgAb, and TRAb. Current thyroid tests are TBG (mg/L) 12-30
usually performed on serum by either manual or automated Prealbumin (mg/dL) 15.7-29.6
TSH: Thyroid stimulating hormone, TBG: Thyroid binding globulin, T4: Thyroxin,
methods that employ specific antibodies.[9] T3: Triiodothyronine

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Garg, et al.: Thyroid function tests

Table 2: Common causes of discrepant thyroid function test

Discrepancy Causes
Normal FT3 or FT4 and low Subclinical hyperthyroidism
TSH Pregnancy, hyperemesis gravidarum
Recent treatment of hyperthyroidism (anti-thyroid drugs or radioiodine therapy) (up to 3 months)
Drugs: Dopamine, steroids
Nonthyroidal illness: Acute psychosis, systemic illness
Normal FT3 or FT4 and high Subclinical hypothyroidism
TSH Poor compliance with T4 treatment
Malabsorption of T4: Coeliac disease, atrophic gastritis, iron, calcium or multivitamin tablets, sucralfate, sevelamer, proton pump inhibitor
Increased T4 metabolism: Phenytoin, rifampicin, carbamazepine, Imatinib, motesanib, sunitinib
Recovering subacute thyroiditis
Drugs: Amiadarone
Nonthyroidal illness: Recovery phase
Partial resistance to thyroid hormone
Adrenal insufficiency
Nephrotic syndrome
Assay interference with endogenous antibodies
Macro-TSH
High FT3 or FT4 and normal T4 replacement therapy
TSH Increased TBG: Pregnancy, neonatal period, drugs (estrogen therapy, tamoxifen, oral contraceptives), acute intermittent porphyria, acute
hepatitis, biliary cirrhosis, HIV infection, hereditary TBG excess
Drugs: Amiadarone, heparin
Familial dysalbuminemic hyperthyroxinemia
Transthyretin associated hyperthyroxinemia
De-iodinase deficiency
Allen-Herndon-Dudley syndrome (MCT-8 mutation)
Resistance to thyroid hormone due to mutation in TR-α
Nonthyroidal illness: Acute psychiatric illness
High FT3 or FT4 and high TSH TSH secreting pituitary adenoma
Resistance to thyroid hormone
Low FT3 or FT4 and low TSH Nonthyroidal illness
Central hypothyroidism
Congenital TSH deficiency
Low FT3 or FT4 and normal or Central hypothyroidism
high TSH Decreased TBG level: Androgens, glucocorticoids, acromegaly, nephritic syndrome, congenital TBG deficiency
Nonthyroidal illness: Recovery
TSH: Thyroid stimulating hormone, TBG: Thyroid binding globulin, MCT-8: Monocarboxylate transporter-8, TR-aα: Thyroid hormone receptor alpha, FT3: Free triiodothyronine,
FT4: Free thyroxine

of puberty.[10] Both TSH and FT4 concentrations are higher
in children, especially in the 1st week of life and throughout
the 1st year.[11] Failure to recognize this could lead to missing
and/or under-treating cases of congenital hypothyroidism.
Age-related normal reference limits should be used for all
TFTs.[12] Furthermore, with every decade there is rise of TSH
values as well as increased variability of TSH around mean;
however, the clinical significance of this is unclear as both
raised and suppressed TSH in elderly have been shown to
be associated with increased cardiovascular morbidity.[13,14]
During pregnancy owing to the increased estrogen levels
mean TBG concentration increases to 2-3 times the
prepregnancy level by 20 weeks of gestation. It results in a
shift in the TT4 and TT3 reference range to approximately
1.5 times the nonpregnant level by 16 weeks of gestation.[15]
Furthermore, during pregnancy there is rise in human
chorionic gonadotropin (HCG) levels which cross-react
partly with TSH receptor leading to mildly suppressed levels.
The peak rise in HCG and nadir in serum TSH level occurs
together at about 10-12 weeks of gestation.[16,17] Thus, higher
cut-offs for T4, T3 and lower cut-offs for TSH are suggested
during pregnancy, which should be standardized in local
laboratory. In patients with unstable thyroid function, such
as the first trimester of pregnancy, during the early course of
treatment for hypo- or hyper-thyroidism FT4 measurement
is a more reliable indicator of thyroid status than TSH.
Normally, there is inverse linear correlation between FT4
and TSH but each individual has a genetically determined
FT4 set-point for HPT axis.[18]
Another important source of preanalytical variation is
medications.[19] Drugs can cause both in vitro as well as
in vivo effects on TFTs estimation. Drugs such as estrogen
can increase TBG levels leading to falsely high TT4 levels
though free thyroid hormone levels and TSH stay normal.
Glucocorticoids can lead to suppressed TSH levels and
reduced conversion of T4 to T3 leading to lower T3 levels.
Metformin and dopamine too suppresses TSH secretion.[20]
Propranolol also inhibits deiodinase enzyme leading to
lower T3 levels and may be associated with a mild increase in

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TSH because of low T3 levels. Iodine and iodine-containing
drugs such as amiadarone can affect TFTs and cause both
hyperthyroidism as well as hypothyroidism.[21] Lithium can
also cause both hypothyroidism as well as hyperthyroidism.[22]
Drugs such as phenytoin, carbamazepine, furosemide, and
heparin may displace free thyroid hormones from TBG
leading to elevated free hormone levels. Many drugs increase
the metabolism of thyroxin and may increase requirements
such as phenytoin, carbamazepine, rifampicin, imatinib,
and sunitinib.[19]
Furthermore, patients who are critically sick suffer from
nonthyroidal illness syndrome (NTIS) also previously called
sick euthyroid syndrome, which is commonly associated
with low T3 levels and as clinical condition worsens even
T4 levels also go down.[23] TSH in the absence of dopamine
or glucocorticoid administration is more reliable test for
NTIS patients. Diagnosis of NTIS should be based on the
clinical condition of the patient if patient is not critically
sick low FT4 levels are unlikely, and one may be dealing
with hypothyroid case.[24] In nephrotic syndrome, there is
increases loss of T4 which is bound to albumin and TBG,
may lead to low T4 with normal or raised TSH.[25]
Noncompliant patients may exhibit discordant serum TSH
and FT4 values (high TSH/high FT4) because of persistent
disequilibrium between FT4 and TSH. Noncompliant
patients may consume thyroxin intermittently leading
to normal or near normal T4, T3 levels but persistently
raised TSH values. Noncompliance can be evaluated by
simultaneous oral and intravenous administration of the
thyroxin labeled with two different iodine isotope tracers.
Normally, approximately 80% of the T4 and 95% of the T3
administered orally are absorbed. Patients with absorption
defects due to interfering substances such as cholestyramine,
calcium, iron, or small bowel bypass or resection, celiac
disease, helicobacter pylori infection, atrophic gastritis,
achlorhydria, and isolated thyroxin absorption defect can
be evaluated by the administration of a single oral dose of
100 µg of L-T3 or 1 mg of levothyroxine (L-T4), followed
by their measurement in blood sampled at various intervals
and values plotted on graph and compared.[25]
In addition to pregnancy and neonatal period, increased TBG
levels due to systemic diseases such as acute intermittent
porphyria, acute hepatitis, biliary cirrhosis, HIV infection,
and hereditary TBG excess will lead to increased TT4
and normal TSH levels. A genetic mutation in albumin
(familial dysalbuminemic hyperthyroxinemia) and TTR
(TTR associated hyperthyroxinemia) which avidly bind to
T4 - also alters the relation between T4 and TSH similarly. In
contrast, low T4 and normal TSH can be found in conditions
Medical Journal of Dr. D.Y. Patil University | July-August 2016 | Vol 9 | Issue 4 433
associated with low TBG levels due to drugs or genetic
mutation in TBG gene. Inappropriately, normal TSH with
low T4 is also a feature of central hypothyroidism.[19]
Increased levels of thyroid hormone and TSH are
commonly found in patients with hypothyroidism, who
is noncompliant with therapy and consume medicine just
before the test. However, similar results can be observed
in rare conditions such as thyroid hormone resistance
syndrome and TSH-secreting pituitary tumor. These two
conditions can be differentiated by clinical feature, pituitary
imaging, measurement of serum α-subunit, sex hormone
binding globulin, measurement of thyroid hormones in
relatives, and genetic testing.[26]
A rare condition Allen Herndon Dudley syndrome due to
mutation in monocarboxylate transporter-8 gene, which is
required for thyroid hormone transportation into various
cells, leads to raised T3, low T4, and normal or elevated TSH
levels. A similar hormonal profile with raised T3, low T4,
and normal TSH levels has been reported in patients with
resistance to thyroid hormone due to mutation in thyroid
receptor-α.[27] Rarely, serum and urinary measurement of
monoiodothyronine and diiodothyronine is used to detect
rare genetic condition - iodotyrosine deiodinase deficiency,
which can also have raised T4, normal/low T3, and normal
TSH levels.[26]
Analytical variations
For estimation of TFTs, serum is preferred specimen and
ideally whole blood samples should be allowed to clot for
more than 30 min and then centrifuged and separated.
Serum can be stored at 4-8°C for up to 7 days. Storage
at −20°C is recommended if the assay is to be delayed
for more than 1 week. Collection of serum in barrier gel
tubes does not affect the results of most TFTs. Generally,
thyroid hormones are quite stable whether stored at room
temperature, in refrigerator or frozen. Furthermore, TSH
and T4 in dried whole blood spots used to screen for neonatal
hypothyroidism are also stable for months when stored
with a desiccant. Similarly, hemolysis, hyperlipidemia, and
hyperbilirubinemia do not produce interference in hormone
estimation by different assays.[18]
Equilibrium dialysis is gold standard for measurement of
free hormone assay. However, this assay is complex and
not widely available. Commonly used methods to measure
free hormones are one-step or two-step method. Two-step
method is more reliable than one-step method. Hence,
measurement of free thyroid hormone may vary from assay
methods. It is advisable to generate normative data for free
thyroid hormone in local laboratory with particular assay
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Garg, et al.: Thyroid function tests
method.[18] The thyroid hormone estimation, in most of the
laboratories currently, is done by the chemiluminescence
method. This modality has the least interference and the
normative data used from the population is derived using
the same test method.
Another important issue is the presence of heterophile
antibodies in serum which can lead to falsely high or
low TFTs. Heterophile antibodies are antibodies induced
by external antigens (heterophile antigens) that cross-
react with self-antigens. The best-known heterophile
antibodies are human anti-mouse antibodies (HAMA),
which can react with the mouse monoclonal antibodies
that are used in many immunometric assays, such as in
TSH estimation where if they are present they may lead
to erroneously high or low values of TSH. Manufacturers
are currently employing various approaches to deal
with the HAMA issue with varying degrees of success,
including the use of chimeric antibody combinations
and blocking agents to neutralize the effects of HAMA
on their methods.[26,28]
Macro-TSH is a rare condition where serum contains
antibodies against TSH (anti-TSH Ig) which binds to TSH
and neutralizes its activity, but leaves open epitope to
interact with assay antibodies leading to spuriously high
value.[28] This can be detected by:
1. Linearity test: Serum is tested with serial dilution. In
normal subjects, it shows a linear pattern (decreasing
TSH concentration with increasing dilution), but in
the presence of heterophile antibodies or macro-TSH it
shows nonlinear pattern (increase in TSH concentration
with dilution).
2. Polyethylene glycol (PEG) precipitation: Same amount
of PEG is added to serum of patient and normal
subject. It is centrifuged, and TSH is measured again.
In normal subjects, the decrease in TSH is proportional
to the dilution, whereas in patients TSH levels decrease
drastically due to the precipitation of antibodies.
3. TSH sequestration test: This is done to detect the
presence of anti-TSH antibodies. Patient’s serum is
mixed with serum of hypothyroid patient with known
high TSH in 1:1 ration and incubated for 4 h. TSH is
re-measured. In the absence of anti-TSH antibodies,
the TSH values will be average of these two. However,
in presence of anti-TSH antibodies this value will
decrease, because of sequestration of TSH by anti-TSH
antibodies.
4. Gel filtration chromatography: High molecular weight of
anti-TSH antibodies can be demonstrated by gel filtration
chromatography revealing TSH peak fraction belongs to
molecular weight of immunoglobulin.
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Postanalytical variations
Postanalytic errors are relatively less in frequency when
compared with the preanalytical and analytical variations.
This is subdivided into the intra-laboratory (procedures done
after conducting the test) and departmental (analysis of the
result by the user).[29] The sequential steps in the postanalytic
phase includes generation of the report, delivery of the
report to the concerned department, review of the result by
the treating doctor, interpretation of the result, and carrying
out appropriate therapy based on the test results. The errors
that may happen during postanalytical phase have been
summarized in the box no 1.
Postanalytical errors in interpretation of thyroid
function tests
• Intra-laboratory phase:
• Wrongful data entry — Reporting a correct value
in different patient.
• Wrong entry of the units — mg/L instead of mg/dL.
• Data entry errors — 20 instead of 2.0.
• Normal range not derived from the local population.
• Postlaboratory phase:
• Delayed access of the test results due to excessive
turnaround time.
• Underutilization of the test results for lack of
understanding.
• Failure to interpret correctly (high T4 is normal in
pregnancy).
• Failure to understand the physiology (delay in TSH
rise after antithyroid drugs).
Other Tests
Calcitonin
Calcitonin is secreted by “C” cells of thyroid. Currently,
it is measured with chemiluminescent immunometric
assays, which is highly specific and not affected by
interfering substance such as procalcitonin, which
is raised in many physiological and pathological
conditions. Calcitonin level is affected by age and
sex. Serum calcitonin levels are <40 ng/L in children
<6 months of age, <15 ng/L in children between 6 months
and 3 years, and <10 ng/L above 3 years and adults. It is
raised in MTC. It is used to screen multiple endocrine
neoplasia 2, planning treatment, and follow-up after
treatment for MTC. Mild elevation of calcitonin has been
observed in 3-10% normal adults, C-cell hyperplasia,
autoimmune thyroiditis, chronic renal failure, and
mastocytosis. Elevated calcitonin levels may also occur
from nonthyroidal neuroendocrine neoplasms and
heterophile antibodies.[30]
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Garg, et al.: Thyroid function tests
Thyroglobulin
Tg is a protein exclusively produced by thyroid follicular
cells. Most laboratories currently use immunometric assays
to measure serum Tg. Immunometric assays are prone to
interference from Tg autoantibodies, which commonly
cause falsely low serum Tg. Serum Tg levels are elevated in
most of thyroid diseases and are insensitive in the diagnosis
of thyroid dysfunction. However, its utility is to detect
functioning thyroid tissue after total thyroidectomy for
thyroid cancer and the diagnosis of thyrotoxicosis fictitia.
Fecal thyroxin estimation can also help in the diagnosis of
thyrotoxicosis fictitia. Tg levels basal and stimulated should
be undetectable after treatment for thyroid cancer. Serum
Tg levels <0.5 ng/ml after recombinant TSH stimulation
commensurate with 99% chances of disease-free state.
However, poorly differentiated thyroid cancer may still exist
with low serum Tg levels. A cut-off of <1.0 ng/ml levels of
serum Tg on thyroxin suppressive dose and >2.0 ng/ml after
TSH stimulation has been suggested for persistent disease.[31]
Immunological test
Measurement of TPOAb will be useful in the diagnosis of
autoimmune thyroid disease. Measurement of anti-TRAb
can be useful to diagnosis in suspected thyrotoxicosis
during pregnancy to differentiate gestational thyrotoxicosis
and Grave’s disease to predict neonatal thyrotoxicosis in
mother’s with present or past Grave’s disease.[32] Anti-TgAb
is measured in all patients with thyroid cancer to avoid
misinterpretation of high Tg levels during follow-up.[31]
Conclusion
Usually, interpretation of TFTs is straight forward, but
knowledge of commonly occurring pitfalls is essential to
avoid misinterpretation and mismanagement of the case.
For example, only emphasis on raised TSH may lead to the
prescription of thyroxin in a case of resistance of thyroid
hormone, and avoidance of thyroxin in patients treated with
radioiodine with low TSH and T4. It is prudent to interpret
TFT in relation to the clinical condition of patients than
merely treating the laboratory report.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
1. Zimmermann MB. Iodine deficiency. Endocr Rev 2009;30:
376-408.
Medical Journal of Dr. D.Y. Patil University | July-August 2016 | Vol 9 | Issue 4 435
2. Li M, Eastman CJ. The changing epidemiology of iodine
deficiency. Nat Rev Endocrinol 2012;8:434-40.
3. Marwaha RK, Tandon N, Garg MK, Desai A, Kanwar R,
Sastry A, et al. Thyroid status two decades after salt iodization:
Country-wide data in school children from India. Clin
Endocrinol (Oxf) 2012;76:905-10.
4. Marwaha RK, Tandon N, Ganie MA, Kanwar R, Sastry A,
Garg MK, et al. Status of thyroid function in Indian adults: Two
decades after universal salt iodization. J Assoc Physicians India
2012;60:32-6.
5. Available from: http://www.ias.ac.in/currsci/oct252000/n%20
kochupillai.PDF. [Last accessed on 2014 Apr 02].
6. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L,
Cobin RH, et al. Management of thyroid dysfunction during
pregnancy and postpartum: An Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab 2012;97:
2543-65.
7. Piketty ML, d’Herbomez M, Le Guillouzic D, Lebtahi R,
Cosson E, Dumont A, et al. Clinical comparison of three labeled-
antibody immunoassays of free triiodothyronine. Clin Chem
1996;42:933-41.
8. Robbins J. Thyroid hormone transport proteins and the
physiology of hormone binding. In: Gray CH, James VH,
editors. Hormones in Blood. London: Academic Press; 1996.
p. 96-110.
9. Demers LM. Thyroid function testing and automation. J Clin
Ligand Assay 1999;22:38-41.
10. Fisher DA, Nelson JC, Carlton EI, Wilcox RB. Maturation of
human hypothalamic-pituitary-thyroid function and control.
Thyroid 2000;10:229-34.
11. Nelson JC, Clark SJ, Borut DL, Tomei RT, Carlton EI.
Age-related changes in serum free thyroxine during childhood
and adolescence. J Pediatr 1993;123:899-905.
12. Surks MI, Boucai L. Age- and race-based serum thyrotropin
reference limits. J Clin Endocrinol Metab 2010;95:496-502.
13. Waring AC, Arnold AM, Newman AB, Bùzková P, Hirsch C,
Cappola AR. Longitudinal changes in thyroid function in the
oldest old and survival: The cardiovascular health study all-stars
study. J Clin Endocrinol Metab 2012;97:3944-50.
14. Boelaert K. Thyroid dysfunction in the elderly. Nat Rev
Endocrinol 2013;9:194-204.
15. Glinoer D. The regulation of thyroid function in pregnancy:
Pathways of endocrine adaptation from physiology to pathology.
Endocr Rev 1997;18:404-33.
16. Talbot JA, Lambert A, Anobile CJ, McLoughlin JD, Price A,
Weetman AP, et al. The nature of human chorionic gonadotrophin
glycoforms in gestational thyrotoxicosis. Clin Endocrinol (Oxf)
2001;55:33-9.
17. Hershman JM. Human chorionic gonadotropin and the thyroid:
Hyperemesis gravidarum and trophoblastic tumors. Thyroid
1999;9:653-7.
18. Demers LM, Spencer CA. Laboratory medicine practice
guidelines: Laboratory support for the diagnosis and
monitoring of thyroid disease. Clin Endocrinol (Oxf) 2003;58:
138-40.
19. Dayan CM. Interpretation of thyroid function tests. Lancet
2001;357:619-24.
20. Pappa T, Alevizaki M. Metformin and thyroid: An update.
Eur Thyroid J 2013;2:22-8.
[Downloaded free from http://www.mjdrdypu.org on Thursday, November 15, 2018, IP: 187.226.75.234]
Garg, et al.: Thyroid function tests
21. Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects
of amiodarone on the thyroid. Endocr Rev 2001;22:240-54.
22. Lazarus JH. The effects of lithium therapy on thyroid and
thyrotropin-releasing hormone. Thyroid 1998;8:909-13.
23. Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal
illness syndrome: An update. J Endocrinol 2010;205:1-13.
24. Stockigt JR. Guidelines for diagnosis and monitoring of thyroid
disease: Nonthyroidal illness. Clin Chem 1996;42:188-92.
25. Morris JC. How do you approach the problem of TSH elevation
in a patient on high-dose thyroid hormone replacement? Clin
Endocrinol (Oxf) 2009;70:671-3.
26. Gurnell M, Halsall DJ, Chatterjee VK. What should be done
when thyroid function tests do not make sense? Clin Endocrinol
(Oxf) 2011;74:673-8.
27. van Mullem AA, Chrysis D, Eythimiadou A, Chroni E,
Tsatsoulis A, de Rijke YB, et al. Clinical phenotype of a new type
of thyroid hormone resistance caused by a mutation of the TRa1
receptor: Consequences of LT4 treatment. J Clin Endocrinol
Metab 2013;98:3029-38.
Commentary
Thyroid function tests: Possible forgotten error
in testing
Thyroid function test is one of most commonly used
investigation in clinical endocrinology. There are many
patients with thyroid disorders that require thyroid
function tests. As noted, there are many dilemmas and
pitfalls regarding thyroid function tests.[1] The general
practitioner has to be well aware of these pitfalls. Based
on the concept of laboratory medicine, there are many
concerns regarding the quality of any laboratory testing.
For thyroid function tests also, the same holds good.
Theoretically, the quality of the testing has to start from
preanalytical step to postanalytical step.
Focusing on preanalytical step, the important considerations
are on the rational use of the test. For thyroid function
test, the problem of request without indication is not
uncommon. According to the recent report by Werhun and
Hamilton, “overused and under-evidenced” is common in
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DOI:
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436 Medical Journal of Dr. D.Y. Patil University | July-August 2016 | Vol 9 | Issue 4
28. Loh TP, Kao SL, Halsall DJ, Toh SA, Chan E, Ho SC, et al.
Macro-thyrotropin: A case report and review of literature. J Clin
Endocrinol Metab 2012;97:1823-8.
29. Plebani M. Errors in clinical laboratories or errors in laboratory
medicine? Clin Chem Lab Med 2006;44:750-9.
30. American Thyroid Association Guidelines Task Force, Kloos RT,
Eng C, Evans DB, Francis GL, Gagel RF, et al. Medullary
thyroid cancer: Management guidelines of the American Thyroid
Association. Thyroid 2009;19:565-612.
31. American Thyroid Association (ATA) Guidelines Taskforce on
Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS,
Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised
American Thyroid Association management guidelines for
patients with thyroid nodules and differentiated thyroid cancer.
Thyroid 2009;19:1167-214.
32. Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC,
Klein I, et al. Hyperthyroidism and other causes of thyrotoxicosis:
Management guidelines of the American Thyroid Association
and American Association of Clinical Endocrinologists. Endocr
Pract 2011;17:456-520.
primary care.[2] For the next step, preanalytical, the problem
on appropriate patients’ preparation, correct patient
identification and requesting, blood specimen collection,
and transportation should be discussed. According to the
report by Wiwanitkit, from an ISO certified laboratory,
preanalytical error is very common, and it is usually due
to human error.[3] For example, Zemlin et al. audited
laboratory request forms requesting thyroid function
tests and found that “medication/s used by the patient
and doctor’s contact number were the most commonly
incomplete parameters.”[4] Müller et al. studied the blood
collection technique on thyroid function test and found
that “a standardized and minimum compression time
when drawing blood samples is recommended in order
to eliminate this potential source of diagnostic error.”[5]
Focusing on analytical step, there are many concerns on
laboratory techniques, methodology, and interference.
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How to cite this article: Wiwanitkit V. Thyroid function tests: Possible
forgotten error in testing. Med J DY Patil Univ 2016;9:436-7.