CME Endocrinology Clinical Medicine 2013, Vol 13, No 3: 282–6

It is also important to consider whether

CME Endocrinology total (TT4 and TT3) or free (FT4 and FT3)
TH levels are being measured. If the
former, then changes in binding proteins
Edited by Dr Miles J Levy, consultant physician and endocrinologist, Department of can confound interpretation of results: T4
Endocrinology University Hospitals of Leicester NHS Trust; honorary senior lecturer, and T3 are heavily protein bound; thus,
Department of Medical Education, University of Leicester Medical School, UK total, but not free, hormone measure-
ments are affected by alterations in binding
protein status (eg exogenous oestrogen
therapy and pregnancy increase TT4 levels
Interpreting thyroid function through elevation of T4-binding globulin
How to interpret tests (TFTs) (TBG)).

thyroid function tests General considerations

Specific considerations
In any given individual, TH (thyroxine, T4;
Olympia Koulouri,1 academic clinical fellow; triiodothyronine, T3) levels remain rela- In all patients in whom thyroid function
Mark Gurnell,1,2 senior lecturer in tively constant and reflect the ‘set-point’ of testing is being considered, it is important
endocrinology and associate clinical dean the hypothalamic–pituitary–thyroid (HPT) to keep the following in mind.
1Institute of Metabolic Science, University
axis in that individual.3 Changes in thyroid
of Cambridge, Addenbrooke’s Hospital, status are typically associated with con- Thyroid status. Ideally, results of TFTs
Cambridge, UK; 2School of Clinical Medicine, cordant changes in TH and TSH levels (eg should confirm one’s clinical suspicion,
University of Cambridge, Addenbrooke’s raised T4 and T3 with suppressed TSH in namely that the patient is euthyroid,
Hospital, Cambridge, UK thyrotoxicosis; low T4 and T3 with elevated hypothyroid or hyperthyroid. Reassessment
TSH in hypothyroidism). However, the pop- of clinical status is particularly important
Disorders of thyroid function are common ulation reference ranges for TH are relatively when faced with an unexpected TFT result
(estimated UK prevalence is 1–4%). wide (especially for T4) and changes in TH because it provides an important clue to
Although thyroid disease in its most florid levels sufficient to render a patient hypo- or the test (TSH, T4 and/or T3) that is likely
form is easily recognised, patients often hyperthyroid might not necessarily be asso- to be discordant and guides further investi-
manifest symptoms and/or signs that are ciated with numerically abnormal T4 or T3 gation (see below).
non-specific, and present to clinicians in levels (as occurs in so-called ‘subclinical’ Levothyroxine therapy. Anomalous and/or
many different specialties.1,2 Accordingly, a hypo- or hyperthyroidism). Therefore, TSH discordant TFTs are not infrequently seen in
high clinical index of suspicion is required, has traditionally been recommended as a patients being treated with levothyroxine
and confirmation of diagnosis usually frontline screening test for thyroid dysfunc- (LT4) and can have several causes (Table 1).
depends on accurate measurement and tion, because relatively modest changes in
interpretation of thyroid function tests TH levels are associated with marked excur- Medications. Several commonly pre-
(TFTs). In most cases the results of TFTs sions in TSH. However, screening exclusively scribed drugs can cause thyroid dysfunc-
are straightforward and present a familiar with TSH means that some patients will be tion as an adverse effect and a careful
pattern that is easy to recognise. However, misdiagnosed, whereas other conditions medication history should be taken in all
in an important subgroup of patients, they might be missed altogether (by virtue of patients with thyroid disease (Table 2).4
can seem confusing, either by virtue of returning a TSH result that falls within the Other agents can interfere with some
being discordant with the clinical picture reference range despite overt HPT dysfunc- laboratory measurements, producing an
(eg inability of supraphysiological levothy- tion) (Box 1). Accordingly, many UK labo- apparently discordant TFT picture. For
roxine therapy to suppress thyroid stimu- ratories now routinely offer combination example, both fractionated and unfrac-
lating hormone (TSH; thyrotropin) in screening with T4 and TSH. tionated heparin activate endothelial
hypothyroidism) or because different assay
results appear to contradict each other (eg Box 1. Conditions in which measurement of TSH alone might be misleading.
raised thyroid hormone (TH) levels, but
with non-suppressed TSH; or low TH levels • Central hypothyroidism (eg hypothalamic and/or pituitary disorders)
with inappropriately normal or low TSH) • Non-thyroidal illness
(Fig 1). Here, we highlight the main causes • Recent treatment for thyrotoxicosis (TSH can remain suppressed even when thyroid hormone
of commonly encountered patterns of levels have returned to the reference range)
abnormal thyroid function, including so- • Resistance to thyroid hormone
called ‘anomalous/discordant TFTs’, and • TSH-secreting pituitary adenoma (thyrotropinoma or TSHoma)
propose a simple strategy for their investi-
TSH ⫽ thyroid-stimulating hormone; TSHoma ⫽ TSH-secreting pituitary adenoma.
gation.

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 CME Endocrinology

lipoprotein lipase with hydrolysis of trig- undetectable TSH in a patient taking T4 as levels. Accordingly, trimester-specific refer-
lycerides and an increase in circulating signifying over-replacement, or assuming that ence ranges for TH and TSH should be used
free fatty acid levels that, in some indi- a normal TSH level equates with euthy- whenever possible. Recently published
viduals, leads to displacement of T4 and roidism.5 guidelines offer useful advice on the man-
T3 from TBG, thus raising free (but not agement of suspected or confirmed thyroid
Non-thyroidal illness (‘sick euthyroid syn-
total) TH levels. Interestingly, such dysfunction in pregnancy.6
drome’). Intercurrent illness can affect thy-
changes are not generally associated with
roid function in several different ways Assay interference. In any patient in whom
clinical thyrotoxicosis, and TSH is usu-
(Fig 1). Commonly, TSH is low normal or anomalous or discordant TFTs are not
ally normal.
partially suppressed, with low or normal free readily explained by the above, consider-
Hypothalamic–pituitary disease. In the pres- TH. Therefore, it is generally advisable only ation must be given to whether one or
ence of suspected or confirmed central to check thyroid function in those patients other laboratory result could be erro-
HPT dysfunction, TSH should not be con- in whom primary disturbance of one or neous. Genetic and acquired causes of
sidered to be a reliable marker of thyroid other part of the HPT axis is suspected. interference in both TH and TSH assays
status and FT4 (⫾FT3) levels must be used are well recognised and can be screened
to guide management. Common pitfalls in Pregnancy. Physiological alterations during for (eg cross-reacting heterophilic anti-
this setting include misinterpreting a low or pregnancy lead to changes in TH and TSH bodies causing falsely low or elevated

Table 1. Causes of anomalous thyroid function tests in patients receiving levothyroxine therapy.12,13
Cause TFT patterns and LT4 dosage Comments
requirements
Normal physiological Normal TSH, mildly ↑FT4; ⫾ To abolish symptoms and normalise TSH, some individuals require a mildly
variant higher than predicted LT4 elevated FT4 (possibly reflecting less efficient deiodination of T4 to T3); FT3 is
requirements* typically normal
Inappropriate' ↑TSH, low normal or ↓FT4; LT4 should be taken on an empty stomach; certain foodstuffs (eg fibre or
administration requirement for high LT4 dosages espresso coffee) and some medication (eg iron, calcium, proton-pump
to normalise TSH* inhibitors, sucralfate, aluminium hydroxide and cholestyramine) might impair
absorption
Malabsorption ↑TSH, low normal or ↓FT4; LT4 malabsorption occurs with coeliac disease, achlorhydria, lactose intolerance
requirement for high LT4 dosages (lactose is a constituent of some LT4 preparations) and with certain medication
to normalise TSH* (see above)
Increased TH ↑TSH, low normal or ↓FT4; Phenytoin, carbamazepine, rifampicin and some tyrosine kinase inhibitors (eg
metabolism or excretion requirement for high LT4 dosages imatinib) increase LT4 requirements through enhanced metabolism; occasional
to normalise TSH* cases of increased urinary TH loss complicating nephrotic syndrome have also
been reported
Increased TH-binding ↑TSH, low normal or ↓FT4; Oral oestrogen therapy results in a marked increase in TBG levels and, hence, TH
capacity requirement for high LT4 dosages binding capacity, necessitating an increase in LT4 therapy
to normalise TSH*
Change in LT4 Increase or reduction in LT4 Not all LT4 preparations are of comparable potency and/or bioavailability;
preparation dosage required to maintain changes in preparation are generally best avoided but, if necessary, should
clinical and biochemical prompt more frequent TFT monitoring†
euthyroidism
TSH assay interference ↑TSH, normal FT4 Heterophilic antibody interference in the TSH assay can yield falsely elevated
results; FT4 and FT3 are normal, and the patient is clinically euthyroid
Poor compliance Persistent ↑TSH, ↓ ↑ or normal Owing to their differing half-lives, intermittent hormone ingestion can result in
FT4, despite treatment with high normal or even elevated TH levels, but fails to normalise TSH
LT4 dosages
Resistance to TH Supraphysiological LT4 required to Typically seen following inappropriate thyroid ablation in a patient harbouring a
normalise TSH, but with resultant mutation in the human TH receptor ␤ (THRB) gene
↑FT4 (and ↑FT3)
FT3 ⫽ free triiodothyronine; FT4 ⫽ free thyroxine; LT4 ⫽ levothyroxine; TFT ⫽ thyroid function test; TH ⫽ thyroid hormone; TSH ⫽ thyroid-stimulating hormone
(thyrotropin).
*In patients with athyreosis, total daily LT4 requirements can be estimated based on body weight and usually fall in the range 1.6–2.0 μg/kg (NB: older patients
typically require lower dosages and caution must be exercised when starting treatment in those with confirmed or suspected ischaemic heart disease or arrhythmias).
†The UK Medicines and Healthcare Products Regulatory Agency has recently suspended one preparation of levothyroxine following discovery that it yielded variable

control.14

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 CME Endocrinology

Table 2. Examples of drugs affecting thyroid function in previously euthyroid individuals.

Drug TFT patterns Comments
Amiodarone Average daily dosages of amiodarone provide a large excess of dietary' iodine; it is highly
lipophilic with a large volume of distribution, has structural similarity to TH, and inhibits T4→T3
conversion by type 1 DIO
Transient ↑TSH; ↑FT4, Short-lived rises in TSH are common during the first few months of treatment with amiodarone;
normal FT3 inhibition of type 1 DIO leads to persistent elevation of FT4, but normal FT3
↓TSH, ↑FT4 Two main types of thyrotoxicosis are recognised: type 1 (large iodine load precipitating latent
thyroid autonomy); and type 2 (destructive thyroiditis). Amiodarone inhibits T4→T3 conversion
such that T4 is typically more markedly elevated than T3
↑TSH, ↓FT4 Hypothyroidism occurs in up to 15% of patients (particularly women and those with positive
antithyroid antibodies); it can signify a failure to escape from the Wolff–Chaikoff effect*
Lithium ↑TSH, ↓ or normal FT4 Overt or subclinical hypothyroidism
↓TSH, ↑FT4 Thyroiditis occurs in a few patients and is typically self-limiting
Tyrosine kinase inhibitors ↑TSH, ↓FT4 Primary hypothyroidism (possibly owing to a direct toxic effect on the thyroid gland) has been
observed with some tyrosine kinase inhibitors (eg sunitinib and sorafenib)
↓TSH, ↑FT4 A prodromal thyrotoxic phase is occasionally seen in patients taking sunitinib
Immune modulators ↓TSH, ↑FT4 Graves' disease has been reported in patients receiving: alemtuzumab (a humanised
monoclonal antibody directed against CD52) for multiple sclerosis; HAART for HIV infection; or
INFα for chronic hepatitis C
↑TSH, ↓FT4 Hashimoto’s thyroiditis can complicate INFα therapy (± prodromal thyrotoxic phase)
DIO ⫽ deiodinase; FT4 ⫽ free thyroxine; FT3 ⫽ free triiodothyronine; HAART ⫽ highly active antiretroviral therapy; HIV ⫽ human immunodeficiency virus;
INFα ⫽ interferon alpha; T4 ⫽ thyroxine; T3 ⫽ triiodothyronine; TFTs ⫽ thyroid function tests; TSH ⫽ thyroid stimulating hormone (thyrotropin).
*The Wolff–Chaikoff effect is the temporary impairment of T4 and T3 synthesis by high intrathyroidal concentrations of iodine (eg following ingestion of a large iodine load).

• Graves’ disease Fig 1. Schematic

• toxic mulnodular goitre representation of
•toxic adenoma different patterns of
• thyroidis (post-viral, post-partum) thyroid function tests
• drugs (amiodarone); excess iodine intake and their causes. ATDs ⫽
• excess thyroxine ingeson antithyroid drugs; FDH ⫽
• pregnancy-related (hyperemesis gravidarum; familial dysalbuminaemic
• subclinical hyperthyroidism hydadiform mole) hyperthyroxinaemia;
• recent treatment for • congenital hyperthyroidism FT3 ⫽ free
• NTI
hyperthyroidism triiodothyronine; FT4 ⫽
• drugs (steroids, dopamine) • central hypothyroidism
• isolated TSH deficiency free thyroxine; NTI ⫽ non-
• assay interference thyroidal illness; TH ⫽
• NTI FT4/FT3 ↑ • assay interference
thyroid hormone; TKIs ⫽
TSH ↓* tyrosine kinase inhibitors;
FT4/FT3 ↔ FT4/FT3 ↓ TSH ⫽ thyroid-stimulating
TSH ↓* TSH ↔ or ↓* hormone (thyrotropin).
FT4/FT3 ↔ *signifies that TSH can be
TSH ↔ either fully suppressed (eg
FT4/FT3 ↔ FT4/FT3 ↑ as seen in classical primary
TSH ↑ TSH ↔ or ↑ hyperthyroidism) or
partially suppressed (ie
FT4/FT3 ↓
measureable, but below
• subclinical hypothyroidism TSH ↑ • assay interference; FDH the lower limit of normal).
• poor compliance with • thyroxine replacement therapy
thyroxine (including poor compliance)
• malabsorpon of thyroxine • drugs (amiodarone, heparin)
• autoimmune thyroidis (Hashimoto’s; atrophic) • NTI (including acute psychiatric
• drugs (amiodarone)
• post-radioiodine therapy/thyroidectomy disorders)
• assay interference
• hypothyoid phase of thyroidis • neonatal period
• NTI recovery phase
• drugs (amiodarone, lithium, TKIs, ATDs) • TSH-secreng pituitary adenoma
• TSH resistance
• iodine deficiency or excess • Resistance to thyroid hormone
• neck irradiaon • Disorders of thyroid hormone
• Riedel’s thyroidis transport or metabolism
• thyroid infiltraon (tumour, amyloid)
• congenital hypothyroidism

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 CME Endocrinology

TSH are readily detected through TSH Low TSH and normal FT4 and/or FT3 High TSH and normal FT4 (and FT3)
dilution studies, which return non-linear
results in this context). It is important to Subclinical hyperthyroidism (eg owing to a This pattern of results can signify so-called
note that simply sending a sample to ‘low-grade’ toxic multinodular goitre or ‘subclinical hypothyroidism’.8 Measurement
another laboratory does not necessarily adenoma) is characterised by apparently of antithyroid peroxidase (TPO) antibody
exclude assay interference (the same ‘normal’ TH levels, but low TSH.8 As titres is a useful adjunct to help guide deci-
interference can affect different assay described above, although within the refer- sion-making (eg surveillance vs LT4 therapy)
platforms) and specialist laboratory and/ ence range, TH levels in these individuals are because positivity predicts a higher risk of
or endocrine advice should be sought in higher than the normal set-point of the HPT subsequent progression to overt hypothy-
suspected cases.7 axis, resulting in TSH suppression. Most roidism. Again, confirmation that the TSH
endocrinologists consider that the term is persistently raised is generally advised,
‘subclinical hyperthyroidism’ should be although in certain circumstances (eg preg-
TFT patterns reserved for those patients in whom TSH is nancy) T4 replacement can be instituted
fully suppressed, because this is the group without delay. LT4 therapy should be par-
Fig 1 illustrates the different patterns of
for whom there is the greatest evidence of ticularly considered in: younger patients
TFTs that might be encountered in clinical
adverse sequelae (atrial fibrillation and oste- (especially when symptomatic); women
practice.
oporosis) if TSH remains suppressed in the who wish to become or who are pregnant;
long term (especially postmenopausal patients with positive TPO antibodies or a
Low TSH and high FT4 (and FT3) women and patients older than 65 years of rising trend in serial TSH levels; and the
This is the picture of primary hyperthy- age).8 When TSH is not fully suppressed, a presence of marked hypercholesterolaemia.8
roidism and, in this context, TSH is usually period of surveillance can reasonably be Raised TSH with normal TH levels is also
undetectable (typically ⬍0.03 mU/l for adopted, although emerging evidence sug- seen with assay interference and in patients
modern ultrasensitive TSH assays). In the gests that even these individuals will have taking exogenous T4, where it might reflect
UK, Graves’ disease (GD) and toxic multi- greater morbidity in the longer term. malabsorption, altered metabolism or poor
nodular goitre (MNG) are the two most However, in a significant proportion of compliance (Fig 1 and Table 1).
common causes (Fig 1). patients with subnormal TSH values, levels
return to normal during follow-up without
Low FT4 (and/or low FT3) with
intervention. Non-thyroidal illness (NTI) is
High TSH and low FT4 (and FT3) inappropriately normal or low TSH
another common cause of transiently low
This combination of TFTs suggests primary (but not fully suppressed) TSH, with resolu- This combination of TFTs is also seen in
hypothyroidism and, in the UK, is most tion following recovery,9 and emphasises the NTI and resolves with recovery.9 However,
usually the result of autoimmune thy- importance of not acting on a single TSH in the absence of a clear alternative diag-
roiditis (Hashimoto’s disease or atrophic result. In cases of exogenous T4 administra- nosis, central hypothyroidism must be con-
thyroiditis) or follows radioiodine or thy- tion, it is generally desirable to avoid full sidered and a full pituitary hormone profile,
roidectomy.2 Other more rare causes are TSH suppression, with the notable excep- including assessment for secondary hypoad-
shown in Fig 1. tion of thyroid cancer treatment. renalism, is mandatory. T4 therapy in
patients with untreated hypocortisolism can
be life threatening and failure to recognise a
Key points large pituitary mass compressing the optic
chiasm can result in irreversible visual loss.
The results of thyroid function tests (TFTs) must always be interpreted in light of the
clinical status of the patient: hypothyroid, euthyroid or hyperthyroid
High FT4 (±FT3) with inappropriately
Awareness of the conditions and/or disorders that can be associated with different
normal or high TSH
patterns of TFTs guides further investigation and management
This unusual pattern of TFTs is most com-
Confounding factors that may might influence thyroid status (eg intercurrent non-
thyroidal illness or medications) should be excluded before embarking on further monly accounted for by assay interference,
biochemical, radiological or genetic testing confounding effects of drugs (eg amio-
darone or heparin) or T4 replacement
Screening for interference in thyroid hormone (T4 and T3) and/or thyrotropin (TSH) therapy (including non-compliance) (Table
laboratory assays should be considered in any patient with apparently anomalous or
discordant TFTs 1).7 Once these have been excluded, two
rare but important conditions must be
Referral to a specialist laboratory and/or endocrine service is required when distinguished: resistance to TH (RTH) and
anomalous or discordant TFTs cannot be readily explained by confounding a TSH-secreting pituitary adenoma
intercurrent illness, medication or assay interference
(TSHoma), and referral to a specialist
KEY WORDS: Thyroid function tests (TFTs), interpretation, anomalous or discordant TFTs endocrine centre is advised.10,11

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Conclusions 5 Koulouri O, Auldin MA, Agarwal R et al. 12 Liwanpo L, Hershman JM. Conditions and
Clin Endocrinol 2011;74:744–9. drugs interfering with thyroxine
A structured approach, founded on careful 6 Stagnaro-Green A, Abalovich M, Alexander absorption. Best Pract Res Clin Endocrinol
clinical assessment, judicious use of TFTs and E et al. Guidelines of the American Thyroid Metab 2009;23:781–92.
Association for the diagnosis and manage- 13 Morris JC. How do you approach the
knowledge of the conditions and/or disorders
ment of thyroid disease during pregnancy problem of TSH elevation in a patient on
that are associated with different TFT patterns and postpartum. Thyroid 2011;21:1081–125. high-dose thyroid hormone replacement?
enables most TFTs to be reliably interpreted 7 Gurnell M, Halsall DJ, Chatterjee VK. What Clin Endocrinol 2009;70:671–3.
with avoidance of inappropriate investiga- should be done when thyroid function tests 14 Medicines and Healthcare Products
tions and/or treatment. do not make sense. Clin Endocrinol Regulatory Agency, 2012. [Link].
2011;74:673–8. uk/NewsCentre/Pressreleases/CON143688
8 Cooper DS, Biondi B. Subclinical thyroid [Accessed 4 April 2013].
References disease. Lancet 2012;379:1142–54.
1 Pearce EN. Diagnosis and management of 9 Mebis L, Van den Berghe G. Thyroid axis
thyrotoxicosis. BMJ 2006;332:1369–73. function and dysfunction in critical illness.
2 Vaidya B, Pearce SH. Management of Best Pract Res Clin Endocrinol Metab Address for correspondence:
hypothyroidism in adults. BMJ 2011;25:745–57. Dr M Gurnell, Metabolic Research
2008;337:a801. 10 Beck-Peccoz P, Persani L, Mannavola D, Laboratories, Institute of Metabolic
3 Andersen S, Pedersen KM, Bruun NH et al. Campi I. TSH-secreting adenomas. Best Science, University of Cambridge,
Narrow individual variations in serum T4 Pract Res Clin Endocrinol Metab
2009;23:597–606.
Box 289, Addenbrooke’s Hospital,
and T3 in normal subjects: a clue to the
understanding of subclinical thyroid dis- 11 Gurnell M, Visser T, Beck-Peccoz PB, Hills Road, Cambridge CB2 0QQ.
ease. J Clin Endocrinol Metab Chatterjee VKK. Resistance to thyroid Email: mg299@[Link]
2002;87:1068–72. hormone. In: Jameson JL, De Groot LJ
4 Barbesino G. Drugs affecting thyroid func- (eds), Endocrinology, 6th edn. Philadelphia:
tion. Thyroid 2010;20:763–70. Saunders Elsevier, 2010:1745–59.

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