Thyroid disorders can be difficult to detect clinically, but thyroid function tests can assist in making a diagnosis. Measuring thyroid stimulating hormone is the first step. If it is abnormal, free thyroxine should be measured. A raised concentration of thyroid stimulating hormone with a low concentration of free thyroxine suggests hypothyroidism. A low concentration of thyroid stimulating hormone with a high concentration of free thyroxine suggests hyperthyroidism. Measuring thyroid autoantibodies may help establish the cause of the dysfunction. Different assays can give different results, and tests of thyroid function may be affected by drugs and intercurrent illness

Mortimer, Robin H.

University of Queensland eSpace

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Thyroid function tests 
Robin H Mortimer, Professor, Department ofEndocrinology, Royal Brisbane and Women's 
Hospital, and the University of Queensland, Brisbane 
Summary 
Thyroid disorders can be difficult to detect 
clinically, but thyroid function tests can assist 
in making a diagnosis. Measuring thyroid 
stimulating hormone is the first step. If it is 
abnormal. free thyroxine should be measured. 
A raised concentration of thyroid stimulating 
hormone with a low concentration of free 
thyroxine suggests hypothyroidism. A low 
concentration of thyroid stimulating hormone 
with a high concentration of free thyroxine 
suggests hyperthyroidism. Measuring thyroid 
autoantibodies may help establish the cause 
of the dysfuncti~n. Different assays can give 
different results, and tests of thyroid function 
may be affected by drugs and intercurrent illness. 
Key words: thyroxine, triiodothyronine, thyroid stimulating 
hormone. 
(Aust Preser 2011;34:12-15) 
Introduction
 
The thyroid gland secretes thyroxin~ (1'4) and triiodothyronine
 
(1'3)' These hormones are essential for normal growth,
 
development and metabolic function.
 
Altered thyroid function is common. For example, the
 
prevalence of hypothyroidism may be up to nearly 10% of the
 
general population.' As thyroid disorders may not present with
 
c!assical clinical signs, it is essentia: to have accurate assays of
 
thyroid function to assist in the diagnosis.
 
Thyroid physiology (Fig, 1)
 
The thyroid gland actively transports diet-derived iodide from
 
the bloed by means of a cell membrane iodide pump'called the
 
sodium-iodide symporter. Iodide then combines with tyrosines
 
in thyroglobulin, mediated by thyroperoxidase, to form 1'4
 
'(4 iodine atoms) or 1'3 (3 iodine atoms). The uptake of iodide and
 
the release o·f T,j and 1'3 are enhanced by thyroid stimulating
 
hormone iTSH~ which is secreted by the pituitary gland.
 
About 90% of thyroid hormone released is 1'4 and 10% is 1'3' In 
some hyperthyroid states the ratio of 1'3 to 1'4 is higher. Both 
hormones are co-secreted with thyroglobulin and circulate 
in blood bound to thyroid hormone binding proteins (thyroid 
binding globulin, transthyretin and albuminl. A very small 
unbound ('free') fraction is available for uptake by cells, Much 
of the 1'3 in the blood is generated by the liver after enzymatic 
removal of an iodine atom from 1'4' 
TSH secretion is mainly regulated by circulating 1'4 (which is 
deiodinated to 1'3 in the pituitary) and to a lesser extent by 
circulating 1'3' There is a classical negative feedback loop between 
1'4 and TSH. This is log-linear (log TSH is inversely proportional 
to free T4), which means that small changes in free 1'4 cause large 
Fig. 1 
Pituitary-thyroid physiology 
Bou nd to thyroxine 
binding globulin, 
transthyretin and 
albumin 
Somatostatin -
The hypothalamic horm.ones thyrotrophin releasing 
hormone and somatostatin stimulate or block secretion of 
thyroid stimulating hormone (TSH). TSH stimulates iodide 
uptake by the thyroid and synthesis of the thyroid hormones 
thyroxine (1'4) and triiodothyronine (T3)' 1'4 and T3 circulate 
bound to the thyroid hormone binding proteins (thyroxine 
. binding globulin, transthyretin and albumin). A very small 
I free fraction of thyroid hormone is available for cellular 
I action. 1'4 is deiodinated in liver and other tissues to form 
the more biol~gically active 1'3' 1'4 is also deiodinated in the 
pituitary to 1'3 which inhibits TSH secretion. l
12 Australian l'resniber IVOLUME 34 I NUMBER 1 IFEBRUARY 2011 www.australianpreseriber.eom 
inverse changes in TSH 'co JlceJltr-aii orjs, !SH stcretion is also -", 
regulated by the hypothalamic hormones thyrotrmphin releasing 
hormone (stimulating) and somatostatin (inhibitingJ. 
Blood tests relevant to thyroid disease" 
TSH is ~he hormone which is usually tested, It is the only test 
funded by the Medicare Benefits Scheme to screen' for thyroid 
disease when there is no history of thyroid problems, 
Thyroid stimulating hormone 
TSH is a sensitive marker of thyroid function because it is 
influenced by small changes in free T4 concentrations, A low 
TSH usually indicates hyperthyroidism whereas raised TSH 
usually means hypothyroidism. Over the years the lowest 
concentration of TSH which can be detected by assays has 
progressively fallen, allowing better separation of normal and 
hype rth yro id states. 
Thyroid hormone assays 
Only very small fractions of thyroid hormones are not bound 
to protein. These free thyroid hormones are the physiologically 
important thyroid hormones in blood. Modern immunoassays 
that estimate free hormone concentrations are widely available, 
Changes in serum albu,min concentrations, abnormal binding 
proteins, free fatty acids and drugs such as heparin, frusemide 
and phenytoin may interfere with these assays. Most 
laboratories now use chemiluminescent methods that are more 
(but not completely) resistant to such interference, When results 
do not fit into a recognised pattern the laboratory should be 
consulted to identify such interferences. 
Thyroid-related autoantibodies 
If a person has altered thyroid function, testing for thyroid 
antibodies helps to determine if they have, an a'utoimm'une 
condition. 
Th yroperoxidase autoantibodies 
Thyroperoxidase antibodies are also known as thyroid 
microsomal antibodies. They are present in autoimmune thyroid 
disease, but there is debate about whether low leve'rs'are' always 
patholo.gical, Unfortunately, there are significant djffer~nc.es, , 
between laboratories when the same sera are studied, and 
, ,. . '0": 
lower detection limits are variable. Assay sensi~vities and 
reference ranges can therefore vary quite widely. 
.'.... 
Thyroperoxidase antibodies can cause hypothyroidism in at 
least t'1\10 ways. Firs11y th ey can block thyroperoxidase th ereby 
inhibiting T4 and T3 synthesis and secondly through antibody­
dep.endent cell cytotoxicity and thyroid inflammation. Low 
concentrations may not be associated with 'evidence 'of thyroid' 
dysfunction, but the incidence of raised TSH increases as 
antibody levels rise. The prevalence of positive antibody levels 
www.australianprescriber.com 
::' ~hd mil9'hYPQthyroidism. incr,eases withag,e, ' , 
The concentration' of thyroperoxidase antibodies m'ay fluctuate 
in patients with autoimmune thyroid disease. This has no 
clinical significance and repeated measurements are not 
recommended. Maternal thyroperoxidase antibodies cross the 
placenta, but their effects on fetal thyroid function ~re unclear. 
Thyroglobulin autoantibodies ' 
. ' 
Thyroglobulin autoantibodies are also a marker of autoimmune 
thyroid disease, but are tess common than thyroperoxidase 
antibodies. Thyroglobulin autoantibodies do not inhibit 
thyroperoxidase or mediate antibody-dependent cell cytotoxicity 
'and are therefore markers' rather than mediators of autoimmune 
thyroid disease. There are considerable variations in sensitivity and 
reference ranges between assays. Other autoimmune diseases can 
also increase the concentration of thyroglobulin autoantibodies. 
TSH receptor autoantibodies 
TSH receptor autoantibodies may stimulate or less commonly 
block the TSH receptor, Stimulating antibodies cause Graves' 
disease and probably also cause the associated ophthalmopathy. 
Blocking antibodies can cause hypothyroidism. The assay of 
TSH receptor autoantibodies done in clinical laboratories cannot 
distinguish between stimulating or blocking antibodies. This is 
not usually relevant as clinical hyperthyroidism would suggest 
that the dominant antibody is stimulatory. 
Measuring TSH receptor autoantibodies can be useful if the 
cause of hyperthyroidism is not apparent. However. initial 
hopes' that remission of Graves' could be predicted by falling 
autoantibody levels have not been supported by most studies, 
Measurements of TSH receptor autoantibodies do have an 
important role in managing pregnant women with Graves' 
disease. High -concentrations of maternal TSH receptor 
autoantibodies can predict fetal and neonatal hyperthyroidism. 
, It is important to recognise that TSH receptor ,autoantibodies do 
not-always fall after successful treatment, so pregnant women 
with'a previous history of Graves' disease should be screened 
for TSH receptor autoantibodies, 
" Thyroglobulfn 
ThyroglobLllin, a,large glycoprotein, represents about 80% of 
.,the ~?t ~'V~ight. of the thyrOid and is co-sec.~eted with thyroid 
. ;,'hormone. Concentration$ are high in patients with raised TSH 
" cO,ncentrations or nodular goitres, but it is not clinically useful to 
'. mea~ure"thyrogl~bulin in these sltua'ti(;ns~" 
Most papillaly and follicular carcinomas synthesise and secrete 
thyroglobulin, but raised thyroglobulin levels--are not a reliable 
indicator or soreening test for thyroid malignancy. Thyroglobulin 
cdncentration becomes a useful marker of remaining or recurrent 
cancer in patients who have had a total thyroidectomy and remnant 
ablation'with radioiodine for papillary and foilicular carcinoma. 
Australian Prescriber I VOLUME 34 I NUMBER 1 IFEBRUARY 2011 13 
· Unfortunately, up to 20% of patie'lts with '<jiffe(ent~ated thyroid 
cancer. have thyroglobulin autoantibodies that inteifere with tlie 
thyroglobulin assay, leading to underestimation of thyroglobulin 
concentration. Thyroglobulin autoantibodies should therefore be 
measured, with a sensitive assay, on all thyroglobulin samples. 
Reference ranges 
As most commercial assays do not physically measure the analyte, 
results given are always an approximation of actual levels. Each 
assay, even for the same analyte, will therefore give slightly 
different results because of intrinsic v.ariations in the reagents used 
and the effects of interfering illnesses and substances. free T3 
levels are the most variable between assay methods. 
Reference ranges are altered by ethnicity, age and iodine intake. 
In Australia these factors are probably not clinically significant. 
Different ranges also apply in pregnancy, neonates and very 
young children. 
Reference ranges are defined as those into which 95% of a normal 
population fall. {Accordingly 2.5% of normals will have higher and 
2.5% will have lower results than the reference range.) Each assay 
must therefore be interpreted in terms of its own reference range. 
The practical implications of this are that blood test results from 
different laboratories may not be directly comparable and their 
interpretation requires examination of the reference ranges. 
Reference ranges change in pregnancy. In early pregnancy 
chorionic gonadotrophin is secreted by the placenta in large 
amounts. This is structurally similar to TSH (but is not measured 
by the TSH assay) and stimulates the maternal thyroid. This leads 
to increased maternal thyroid hormone secretion and a reduced 
maternal TSH. Occasionally women develop mild hyperthyroidism 
in the first trimester, especially if they have hyperemesis. 
Det~ctih9 and confirming thyroid dysfunction 
(Tab!e 11 
The inverse log-linear re'lationship between free T4 and TSH 
means that TSH concentrations are sensitive indicators of 
thyroid dysfunction. A raised TSH suggests hypothyroidism2 
while a low TSH suggests hyperthyroidism. There are other 
causes of low TSH com::entrations, notably hypothalamic­
pituitary disease, but this is very uncommon in the general 
population. The finding of an abnormal TSH should lead to 
measurement of free T4 levels. 
Interpretation of thyroid function tests may be particularly 
difficult if the patient is systemically ill. Starvation or severe 
illness can be associated with dysregulation of TSH secretion 
and reduced deiodination of T4 to T3 (the 'sick euthyroid' 
syndrome). Low TSH and T3 levels are typical and can cause 
diagnostic confusion. 
Very occasionally a raised TSH with a normal free T4 relates 
to interference in the TSH assay. Very rarely, thyroid hormone 
resistance or a pituitary TSH-secreting adenoma is associated 
with a mildly raised TSH in the presence of a raised free T4. 
Treatment with amiodarone is often associated with abnormal 
thyroid function tests. The most common finding is a raised 
TSH caused by inhibition of pituitary T4 to T3 conversion, but 
true hypothyroidism and hyperthyroidism can occur. Diagnosis 
and management may be complex and require expert advice. 
Hyperthyroidism 
A low TSH and raised free T4 indicate hyperthyroidism and 
should lead to consideration of causation and treatment. The 
majority of younger patients will have Graves' disease. but older 
patients are more likely to have nodular thyroid disease. 
Table 1 
Common results of thyroid function tests 
Thyroid 
stimulating 
horlYlone 
-
Free 
thyroxine 
"'~ 
Free tri­
iodothyronine 
-------_._-------­
+-l> 
Comment 
Normal 
Thyroptlfl)xidase 
and thyroglobulin 
autoantibodies 
t 
·t 
~ 
-
~ 
-
t 
t Subclinical hypothyroidism (Hashimoto'sl 
Primary hypothyroidism (Hashimoto's) 
t t t Hyperthyroidism {consider .Graves', measure TSH 
receptor autoantibodies) 
- - -
Subclinical hyperthyroidism (cons.ider nodular 
thyroid disease) 
~.. ~ 
-
Consider pituitary disease 
- normal 
-
t raised 
t 
t reduced 
variable 
-------------jT3 toxicosis . 
14 Australian Prescriber IVOLUME 3. I NUMBER 1 IFEBRUARY 2011 www.australianpreseriber.eom 
Transitory hyperthyroidism can be seen in patients with viral 
thyroiditis. Most have had a recent upper respiratory tract 
infection and present with neck tenderness and pain, which may 
be referred to the ear. 
Some patients have a low TSH but normal free T4. Measurement 
of free T3 can then be helpful as some patients will have T3 
toxicosis ca used by overproduction of T3' If T3 is not raised a 
repeat measurement of T4 and TSH is warranted. This may show 
normal values. but a persistently low TSH with a normal free 
T4 suggests autonomous thyroid function and a diagnosis of 
'subclinical hyperthyroidism'. which is usually associated with 
a nodular goitre (or, unusually, hypothalamic-pituitary disease}. 
Subclinical hyperthyroidism in the elderly is associated with an 
increased risk of atrial fibrillation, stroke and osteoporosis. 
Hypothyroidism 
A raised TSH and a low free T4 indicate primary 
hypothyroidism, almost always due to autoimmune thyroid 
disease but sometimes due to previous surgery or radioiodine 
administration. The incidence of raised TSH and thyroid 
antibody levels and hypothyroidism increases with age and is 
significantly more common in women. 
It is not uncommon to find a raised TSH but normal free T4. 
In most cases this suggests autoimmune thyroid disease. 
This subclinical hypothyroidism is more likely to progress to 
overt hypothyroidism when higher levels of TSH and thyroid 
autoantibodies are present. 
Asymptomatic patients with a raised TSH and normal free T4 
require regular monitoring, especially if they are elderly or have 
high levels of antithyroperoxidase autoantibodies. Every six 
months is probably sufficient. 
There is considerable debate about the normal upper limit of 
the TSH reference range. The high background prevalence of 
autoimmune thyroid disease as well as the age, iodine status, 
smoking prevalence and ethnicity of the 'normal' population has 
raised the 'normal' upper limit. In people without these factors 
the upper limit is probably 2.5 mIU/L. While mildly raised TSH 
levels rarely require treatment, a concentration above 4.0 mIU/L 
and the presence of thyroid antibodies is predictive of eventual 
hypothyroidism and indicates that these patients need to be 
followed up.3 
Adjusting thyroxine treatment 
Replacement thyrcxine in hypothyroid patients should be 
adjust~d to maintain TSH at about 2 mIU/L. It·takes about 
six weeks for a change in thyroxine dose to achieve stable 
concentrations of free T4' Changes to the dose of thyroxine. and 
tests of thyroid function. should not be done more frequently, 
unless clinically indicated. It is not uncommon for patients who 
are less than optimally compliant with recommended thyroxine 
treatment to take several tablets before a doctor's visit. This may 
be associated with a raised TSH. but normal free T4 . 
Many patients with a history of differentiated thyroid cancer 
are advised to take suppressive doses of thyroxine. Guidelines4 
suggest that with persistent disease TSH should be kept below 
0.1 mIU/l. Patients who presented with high-risk disease, but 
who are clinically free of disease, are advised to maintain 
TSH between 0.1 and 0.5 miU/l for 5-10 years. Advice from 
commercial pathology laboratories that thyroxine doses be 
reduced in these patients should be resisted. 
Adjusting treatment for hyperthyroidism 
TSH may remain suppressed for weeks or even months after 
a patient starts antithyroid medications. It is useful to monitor 
free T4 and free T3 every 6-12 weeks to jUdge the adequacy of 
treatment. A rise in TSH indicates overtreatment. Patients with 
severe hyperthyroidism may need more frequent monitoring. 
Conclusion 
Thyroid dysfunction is common in the general population and 
TSH measurements provide a sensitive method for detection. 
An abnormal TSH requires further investigation, including 
at least measurement of free T4. Interpretation of the results 
of thyroid function tests is facilitated by an understanding of 
thyroid hormone physiology, especially the normal inverse 
relationship between free T4 and TSH concentrations. 
Variations in assay performance mean that it may be helpful 
to consistently use the same laboratory for an individual 
patient. An understanding of the effects of severe illness and 
medications on test results is also important. 
References 
1.	 Canaris GJ, Manowit! NR, Mayor G, Ridgway EC. The 
Colcrado thyroid disease prevalence study. Arch Intern Med 
2000;160:526-34. 
2.	 Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, 
Levy EG, et 211. American Thyroid Association guidelines 
for detection of thyroid dysfunction. Arch Intern Med 
2000:160: 157.3-5. 
3.	 Waish JP, Bremner Ap, Feddema P, Leedman PJ, Brown SJ, 
O'Leary P. Thyrotropin and thyroid antibodies as predictors 
of hypothyroidism: a 13-year, longitudinal study of a 
community-based cohort using current immunoassay 
techniques. J Clin Endocrinol Metab ;2010;95:1095-104. 
4.	 Cooper DS, Doherty GM, Haugen SA. Kloos RT, Lee SL, 
Mandel SJ, et al. Revised American Thyroid Association 
mana!:lement guidelines for patients with thyroid'nodules 
and differentiated thyroid cancer. Thyroid 2009;19:1167-214, 
Conflict of interest: none declared 
www.australianprescriber.com	 Australian Prescriber I VOlUM~ 34 I NUMB~R 1 IFEBRUARY 2011 15 


Thyroid function tests

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