text:
July 2006
1. Introduction
1.1 Thyroid disease 11
1.2 Thyroid function tests 11
1.3 The patient perspective 11
1.4 The physician perspective 12
1.5 The laboratory perspective 12
1.6 The need for national guidelines 12
3. Hypothyroidism
3.1 Primary hypothyroidism 24
3.2 Subclinical (mild) hypothyroidism 27
3.3 Secondary hypothyroidism 28
3.4 Congenital hypothyroidism 30
4. Hyperthyroidism
4.1 Primary hyperthyroidism 32
4.2 Subclinical (mild) hyperthyroidism 36
4.3 Inappropriate TSH 37
Contents (continued)
Appendix 1 References 69
Use of thyroid function tests: guidelines development group
Notes on the development and use of the guidelines
The Use of Thyroid Function Tests Guidelines Development Group was formed in
2002 under the auspices of the Association for Clinical Biochemistry (ACB), the
British Thyroid Association (BTA) and the British Thyroid Foundation (BTF).
It is hoped that the document will provide guidance for primary care physicians,
specialist physicians, endocrinologists, and clinical biochemists. The accompanying
patient information sets have been especially designed to explain thyroid function
testing and to summarise the main recommendations in the guidelines in everyday
language. The purpose of the guidelines is to encourage a greater understanding of
thyroid function testing amongst all stakeholders with a view to the widespread
adoption of harmonised good practice in the diagnosis and management of patients
with thyroid disorders. The guidelines are also intended to provide a basis for local
and national audit and each section offers recommendations that are suitable for the
audit process.
The guideline development group met on several occasions. It was agreed to adopt
the literature review accompanying the 2002 publication of The National Academy of
Clinical Biochemistry entitled 'Laboratory support for the Diagnosis and Monitoring
of Thyroid Disease' and to supplement this with publications occurring during and
after 2001. Subgroups took responsibility for individual chapters and the whole group
considered each draft. Patient representatives were full members of the development
group throughout the development process.
After completion by the development group, the guidelines were subjected to external
refereeing by individuals with a range of interests, including patients, GP's,
physicians and laboratory specialists in district general hospitals and teaching centres
as well as international experts. In addition the draft guidelines were posted on the
websites of the ACB and BTA, with appropriate links, for a limited period, during
which comments were invited and received. Subsequent to this the development
group reviewed the comments and recommendations and appropriate revisions were
made. All members of the group approved the guidelines.
Mechanism for updating
The guidelines were completed in June 2006. Comments on their accuracy and
relevance are invited during the first year after publication and should be directed to
email@example.com. It is intended that a full review will take place after
three years.
Additional information
The format and style of the guidelines has been modelled on the complementary
document entitled 'Guidelines for the Management of Thyroid Cancer in Adults',
which was published in 2002 by The Royal College of Physicians.
The British Thyroid Foundation funded the project. No declarations of interest were
received from any of the professional members of the development group.
These guidelines and the accompanying patient information sets may be downloaded
from the ACB and BTA websites:
Types of evidence and the grading of recommendations
The definition of types of evidence and the grading of recommendations used in the
guidelines follows that of the Agency for Health Care Policy and Research (AHCPR),
as set out below:
Presentation Conventions
• The AHCPR level of evidence is included both in the main text and in the
recommendations of Chapters 2-7 as bold roman numerals I – IV in
parentheses. E.g. (III).
• Whenever the text refers to the hormones synthesised and secreted by the
thyroid gland the abbreviations T4 and T3 are used to describe thyroxine and
tri-iodothyronine, respectively.
• For the sake of consistency the term FT3 has been adopted to describe the
measurement of either free tri-iodothyronine (FT3) or total tri-iodothyronine
(TT3) in serum or other body fluids; wherever this is not the case the text
refers to the measurement of the specific form of tri-iodothyronine. In 2006,
UK NEQAS returns indicate that roughly equal numbers of UK laboratories
measure FT3 and TT3.
• At several points in the text numerical results are presented (e.g. 'a TSH level
of >10mU/L). These numerical results should be regarded as typical target
figures rather than as absolute cut-offs. The historical nature of some of the
evidence base together with uncertainty of the bias of the assays used in the
older studies means that absolute cut-offs cannot be presented. Individual
laboratories should use external quality assessment and other data to determine
if bias-related cut-offs are appropriate for the methods that they use. However,
in most cases it is unlikely that laboratories will have sufficient data to achieve
an accurate adjustment of the TSH cut-offs quoted in these guidelines.
Grateful thanks are expressed to:
• The British Thyroid Foundation for funding the project
• The Association for Clinical Biochemistry for hosting the meetings of the
guidelines development group
• The Executive Committee of the British Thyroid Association for helpful
comments during the formulation of the guidelines
• The individuals behind the 33 responses that were received as a result of the
consultation exercise
1. Introduction
Thyroid disorders are amongst the most prevalent of medical conditions, especially in
women. Disorders of the thyroid include both overt and mild/subclinical
hypothyroidism and hyperthyroidism, goitre and thyroid cancer.
Thyroid disorders are common and so thyroid function testing in blood samples is
also common with approximately 10 million requests each year in the UK at an
estimated cost of £30 million.2 The most commonly performed tests in serum are
used to establish if there is thyroid dysfunction or to monitor the response to therapy.
These tests include thyroid stimulating hormone (TSH), free thyroxine (FT4), and free
tri-iodothyronine (FT3). A range of other tests is also available to determine the
specific causes of thyroid disease.
The majority of thyroid disorders present to and are managed initially within General
Practice. Specialist thyroid physicians, who are usually hospital-based Clinical
Endocrinologists, and surgeons are involved at a later stage in many cases. Virtually
all thyroid function testing currently takes place in hospital laboratories in
departments of Clinical Biochemistry. Therefore, there are three main stakeholders in
thyroid function testing:
• The patient
• The physician (GP and specialist)
• The laboratory
Patients are becoming more informed about their health and any disorders from which
they suffer. They obtain this information from doctors, from patient support
organisations and from the Internet. There is a huge amount of information available
about thyroid disease but it can be confusing and it is not always consistent in terms
of content or implementation. Patients find it difficult to understand that the diagnosis
of thyroid disease is not always clear-cut or that individual patients respond
differently to treatment. They have an expectation that thyroid function testing across
the UK is uniform in terms of the tests performed, the results obtained and the
interpretations made. Some of the questions most frequently asked by patients are
listed in Table 1.1.
The symptoms of thyroid disease can be relatively non-specific and one of the first
challenges for the GP is to consider thyroid disease in the differential diagnosis of the
symptoms of the individual patient. Once this consideration has been made the GP
would like TFT either to exclude or confirm the diagnosis of thyroid disease. For
borderline cases the GP expects the laboratory to provide the combination of TFT that
provide the maximum information and they welcome an interpretation of the results in
difficult cases. For patients known to have thyroid disease GPs expect TFT to provide
information that assists with the optimisation of therapy. Some of the questions most
frequently asked by GPs are listed in Table 1.2a. Many laboratories provide
interpretive comments to GPs on all abnormal TFT results and user surveys indicate
that this service is appreciated.
The specialist thyroid physician receives referrals from GPs and from other sources.
In all cases the job of the thyroid physician is made much easier when the referral
notes include results of appropriate TFT performed at appropriate times. The thyroid
physician expects the laboratory to deliver a comprehensive range of TFT with
analytically valid results and finds it difficult to understand why laboratories offer
different test profiles and why results are not always transferable between
laboratories. Some questions most frequently asked by thyroid physicians are listed in
Table 1.2b.
Thyroid function testing is relatively expensive and laboratory budgets have struggled
to cope with the rapidly rising number of TFT over the last few years. Clinical
biochemists wish to work with physicians to ensure that all requests for TFT are
justified on clinical grounds and that there is not unnecessary repetition. They also
strive to obtain sufficient clinical information with each request to ensure that they
provide the optimal combination of TFT for each patient without performing
unnecessary or misleading tests. Some of the questions most frequently asked by
clinical biochemists are listed in Table 1.3.
It is clear from the previous sections that the different stakeholders are uncertain
about many aspects of thyroid function testing. Therefore, the need for national
guidelines for something as common as thyroid function testing is self-evident.
However, such guidelines do not exist in the UK, the nearest being the references
given to testing as part of the consensus statement for good practice and audit
measures in the management of hypothyroidism and hyperthyroidism.3 In the USA
the American Thyroid Association (ATA) has published guidelines for detection of
thyroid dysfunction 4; the ATA and the American Association of Clinical
Endocrinologists (AACE) have published guidelines on subclinical thyroid disease 5;
and the National Academy of Clinical Biochemistry (NACB) has published practice
guidelines on the laboratory support for the diagnosis and monitoring of thyroid
disease.6 However, none of these two sets of guidelines addresses the subject of
thyroid function testing from the perspective of all three stakeholders and neither uses
the rules of evidence based medicine 7 to support the recommendations.
As a result, the Association for Clinical Biochemistry (ACB), the British Thyroid
Association (BTA) and the British Thyroid Foundation (BTF) agreed to take the
initiative to produce a set of evidence-based guidelines that meet the requirements of
all three stakeholders. The model used for guidelines production has been that
employed by the BTA and the Royal College of Physicians (RCP) in the recently
published guidelines for the management of thyroid cancer.8
Table 1.2 Questions Frequently Asked by Physicians
a) General Practitioners
• What is the difference between total T4/T3 and free T4/T3 and which is better?
• Why do you attach so much significance to the TSH result?
• Why don't you always give me the same combination of tests?
• How long should it take for me to get results back?
• How accurate and precise are your results?
• What is the typical biological variability of thyroid hormones?
• Do thyroid hormones have a diurnal or seasonal rhythm?
• Why do I have to wait two months after adjusting the dose of thyroxine before I can
perform thyroid function testing?
• Should TSH always be 'normal' in patients taking thyroxine?
• What does a TSH result of 5-10mU/L mean?
• How should I interpret a positive thyroid antibody result?
• What is non-thyroidal illness (sick euthyroid syndrome)?
• What clinical question are you expecting to have answered with this request?
• Why have you asked for this combination of tests?
• What is the age/sex of this patient?
• Is the patient taking thyroxine / carbimazole?
• What medication is the patient taking?
• Why have you asked for thyroid function tests more than once this month?
• Why are you requesting thyroid function tests on all admissions?
• Do you really want thyroid function tests on this patient in ITU/HDU?
• Does this patient have non-thyroidal illness?
2. Indications for Thyroid Function Testing
2.1 Introduction
A strategy of first-line TSH may be cost effective for a wide range of clinical
purposes including screening and case finding, but it may be inappropriate in patients
being tested for the first time, and in some specific clinical settings. Throughout these
guidelines we have highlighted the clinical situations where measurement of both
serum TSH and FT4 is required; these are principally where the pituitary-thyroid axis
is not intact or is unstable. These situations include relatively common situations such
as optimising thyroxine therapy in newly diagnosed patients with hypothyroidism,
diagnosing and monitoring thyroid disorders in pregnancy and monitoring patients
with hyperthyroidism in the early months after treatment. Rare situations include
diagnosis and monitoring treatment for central hypothyroidism, end-organ thyroid
hormone resistance and TSH-secreting pituitary adenomas. It is the responsibility of
the requesting physician to provide clinical information to guide the laboratory in the
selection of the most appropriate TFT but if clinical details are not available that
allow the identification of the above categories of patient, then it may be prudent for
laboratories to measure serum TSH and FT4 on all specimens rather than embark on a
first-line serum TSH testing strategy followed by a cascade to include FT4 and FT3 if
Congenital hypothyroidism affects about one newborn in 3,500-4,000 births and is the
most treatable cause of mental retardation. There is an inverse relationship between
age at diagnosis and intelligence quotient (IQ) in later life. In iodine-replete areas,
85% of the cases are due to sporadic developmental defects of the thyroid gland
(thyroid dysgenesis) such as the arrested migration of the embryonic thyroid (ectopic
thyroid) or a complete absence of thyroid tissue (athyreosis). The remaining 15%
have thyroid dyshormonogenesis defects transmitted by an autosomal recessive mode
of inheritance. Clinical diagnosis occurs in less than 5% of newborns with
hypothyroidism because symptoms and signs are often minimal. As a result it is not
possible to predict which infants are likely to be affected. Without prompt diagnosis
and treatment most affected children gradually develop growth failure, irreversible
mental retardation and a variety of neuropsychological deficits.10,11.
nodule) at presentation to detect clinically unapparent hypothyroidism or
Women with type 1 diabetes are three times more likely to develop post-partum
thyroid dysfunction.21
• Women with type I diabetes should have their thyroid function, including
serum TSH, FT4 and thyroid peroxidase antibody status, established pre-
conception, at booking when pregnant and at 3 months post-partum (III,C)
The ageing UK population and the introduction of the General Medical Services
contract are providing GPs with more opportunity to consider thyroid dysfunction in
the normal community, especially in elderly subjects with few or no symptoms of
thyroid disease. The prevalence of unsuspected overt thyroid disease is low, but a
substantial proportion of subjects tested will have evidence of thyroid dysfunction,
usually subclinical hypothyroidism. In the absence of the confounding effects of non-
thyroidal illness or drugs, a normal serum TSH concentration has a high predictive
value in ruling out thyroid disease in healthy subjects. In unselected populations,
measurement of serum TSH has a sensitivity of 89 to 95% and specificity of 90 to
96% for overt thyroid dysfunction, as compared to cases confirmed by history,
examination and additional testing.22 Normal serum TSH concentrations are found in
some patients with hypothyroidism caused by pituitary or hypothalamic disease, but
both these situations are rare. In nearly all populations screened a serum TSH value
greater than 5mU/L is accepted as being raised. Different recommendations and
position papers have been reported by various physician organisations as to whether
subclinical thyroid disease is of sufficient clinical importance to warrant screening
and therapy.8,11,23-32
A cost-utility analysis using a computer decision model suggested that the cost-
effectiveness of screening for subclinical hypothyroidism compared favourably with
other preventive medical practices, such as screening for hypertension or breast
cancer, in women in the same age group, while providing a similar increase in quality
adjusted life years.33,34 Over half of the presumed benefit in the latter was accounted
for by preventing progression to overt hypothyroidism, 30% by improving associated
mild symptoms and 2% by preventing cardiovascular disease. The cost of detecting
subclinical hypothyroidism was $9223 for women and $22,595 for men per quality-
of-life year gained, but this cost was heavily dependent on the cost of the serum TSH
assay ($10 to 50). The cost-benefit analysis did not allow for the extra costs of
detecting, investigating and potentially treating subclinical hyperthyroidism. These
data led the American Thyroid Association to recommend population-based screening
for thyroid dysfunction by measurement of serum TSH, beginning at age 35 years and
every five years thereafter.35 Those organisations that assess screening programs, such
as the US Preventive Services Task Force11, have not recommended regular
assessment of thyroid function in adults. A recent US expert consensus development
conference recommended after review of the existing evidence that population
screening for subclinical thyroid disease was not warranted.30
There have been few trials to determine whether identification and treatment of
subjects with thyroid dysfunction, which would mostly be subclinical
hypothyroidism, results in any long-term benefit. A recent placebo- controlled double-
blind intervention study has demonstrated no difference in neuropsychological
function in subjects with subclinical hypothyroidism compared to controls, and
thyroxine treatment for one year did not alter neuropsychological function in a cohort
of the subjects with subclinical hypothyroidism.31 The potential benefits in terms of
decreased symptoms or other systemic effects are generally small and may not
enhance quality of life.36 In a recent observational cohort 10-year study, a low serum
TSH concentration (<0.5mU/L), but not a high serum TSH concentration, was
associated with an increase in all–cause mortality and cardiovascular mortality.37 Two
further studies have also observed that in elderly groups of subjects low FT4 and/or
raised TSH were associated with reduced mortality and it has been speculated that this
may reflect an adaptive mechanism to prevent excessive catabolism. 38,39 Despite this
growing evidence against thyroxine therapy it has recently suggested that individual
patients with subclinical hypothyroidism may be offered a three month therapeutic
trial of thyroxine as part of patient-centred care 32.
• If the serum TSH is greater than 10mU/L and the serum FT4 concentration is
low, then the subject has overt hypothyroidism and should be treated with
thyroxine (IV,C)
• If the serum FT4 concentration is normal, but the serum TSH concentration is
greater than10mU/L, then treatment with thyroxine is recommended (II,B)
• If the serum TSH concentration is above the reference range but <10mU/L,
then serum thyroid peroxidase antibodies should be measured. If the serum
antibody concentration is high, then serum TSH should be measured annually
or earlier if symptoms develop; thyroxine therapy should be started if the
serum TSH concentration rises above 10mU/L. If the serum antibody
concentration is not raised, then repeat measurement of serum TSH
approximately every three years is all that is required (IV,C) (See also
Chapter 3).
Few subjects screened will have overt hyperthyroidism, but the consequences of
finding subclinical hyperthyroidism have to be addressed.8,30 Patients with subclinical
hyperthyroidism can be categorised into those with low but detectable serum TSH
(0.1-0.4mU/L) and those with a clearly low serum TSH (less than 0.1mU/L). If a
subject has a serum TSH value below the reference range but >0.1mU/L, and is not on
thyroxine therapy, then the first step is to repeat the measurement together with FT4
and FT3 within one to two months to exclude overt hyperthyroidism (and also central
hypothyroidism). In most circumstances serum TSH will have returned to within the
reference range. If the repeat serum TSH measurement remains low but >0.1mU/L
with normal FT4 and/or FT3, then repeat testing every 6-12 months is required. In
those subjects with a serum TSH less than 0.1mU/L, FT4 and FT3 should be
measured to exclude overt hyperthyroidism. Usually, subclinical hyperthyroidism will
be confirmed. In addition to the risk of overt hyperthyroidism, the subject may be at
risk for atrial fibrillation 40 and osteoporosis.41 No consensus exists regarding the
treatment of subclinical hyperthyroidism30 but any potential benefits of therapy must
be weighed against the substantial morbidity associated with the treatment of
• If the serum TSH is less than 0.1mU/L then the serum FT4 and FT3 must be
measured to exclude overt hyperthyroidism (IV,C)
serum TSH concentrations that are suppressed (<0.10mU/L) or elevated (>20mU/L) but
less than half will have an underlying thyroid disorder.45 The reported point prevalence
rates for previously undiagnosed hyperthyroidism, between 0.3 and 1%, are consistent
with community surveys. An accurate diagnosis can be achieved if clinical indications
for measuring thyroid function exist, an accurate drug history is taken, the abnormal
serum TSH is subsequently confirmed and there is a reciprocal change in serum FT4.
The testing of hospital in-patients, predominantly elderly women, might be expected
to reveal a higher proportion of unsuspected hypothyroidism, but this is not supported
by the available studies, which confirm a prevalence of 2%.1 Unless clinically
indicated caution is also required in the investigation of thyroid function in acute
psychiatric disturbances and clinical depression since non-thyroidal illness and
medication that affects TFT are both common and may prompt inappropriate
intervention.27 (See also Chapter 7).
Women with a past history of postpartum thyroiditis have a risk of long-term risk of
permanent hypothyroidism and recurrence in subsequent pregnancies. 46 No
consensus exists on whether healthy women should be screened for the risk post-
partum thyroiditis pre-conception or during pregnancy.47 (See also Chapter 5).
• Patients with type-1 diabetes should have a check of thyroid function included
in their annual review. Patients with type-2 diabetes should have their thyroid
function checked at diagnosis but routine annual thyroid function testing is not
recommended. (III,B)
• All patients with Down Syndrome and Turner's Syndrome should have an
annual check of thyroid function (III,B)
2.3.4 Patients receiving Amiodarone and Lithium
Amiodarone contains 75mg iodine per 200mg tablet and is frequently associated with
iodide-induced thyroid dysfunction.52 Amiodarone-induced hyperthyroidism is
particularly prevalent (10%) in areas of iodine-deficiency and in patients with
underlying thyroid disease. Amiodarone-induced hypothyroidism is more common in
iodine-replete communities (up to 20%) and related to the presence of thyroid
autoimmunity. Lithium, used in the treatment of bipolar depression, is associated
with mild and overt hypothyroidism in up to 34% and 15% of patients respectively,
and can appear abruptly even after many years of treatment.53 Lithium-associated
thyrotoxicosis is rare and occurs mainly after long-term use. (See also Chapters 4,7).
• All patients on amiodarone therapy should have thyroid function tested before
commencing treatment and then should be routinely monitored every 6 months
thereafter whilst on treatment and up to 12 months after cessation of therapy
• All patients on lithium therapy should have thyroid function tested before
commencing treatment and then should be routinely monitored every 6-12
months whilst on treatment (III,B)
The incidence of hypothyroidism after surgery, external radiation therapy of the neck,
or both, in patients with head and neck cancer (including lymphoma) is as high as
50% within the first year after treatment, particularly in patients who underwent
surgery and received high doses of radiation.54-58 The effect is dose-dependent, the
onset is gradual, and subclinical hypothyroidism can be present for many years prior
to the development of overt disease.
occurs more frequently after partial thyroidectomy and follow-up should probe both
for hypothyroidism and recurrent hyperthyroidism.
Once hypothyroidism has been diagnosed and the appropriate dose of thyroxine has
been established, the dose remains constant in many patients. In pregnancy there may
be a need to increase the dose by at least 50µg daily to maintain a normal serum
TSH.63 Access to a computerised thyroid disease register improves the surveillance of
patients treated for thyroid dysfunction 64 and a register may assist GPs to meet the
targets in the General Medical Services contract. Patients with hypothyroidism who
are taking thyroxine may become hypothyroid if given drugs which decrease
thyroxine absorption, such as cholestyramine and iron salts, or increase its clearance,
such as phenytoin and carbamazepine.65 A recent report suggests that in women with
hypothyroidism treated with thyroxine, oestrogen therapy may increase the need for
thyroxine caused by an oestrogen-induced increase in the serum concentration of
thyroxine-binding globulin.66 (See Chapter 7). Poor compliance with thyroxine
therapy or suboptimal treatment may also result in hypothyroidism. There is evidence
from community studies that many treated hypothyroid patients have serum TSH
levels outside the normal range.3,7,67 In the Colorado Thyroid Disease Prevalence
Survey of 1525 subjects taking thyroid medication 17.6% had subclinical
hypothyroidism, 0.7% were overtly hypothyroid, 20.7% had subclinical
hyperthyroidism and over 90% had seen a health care provider in the previous year.3
Similar data are found in the UK community studies 7,67
• In pregnancy there may be a need to increase the dose by at least 50µg daily
to maintain a normal serum TSH, which should be measured in each trimester
3. Hypothyroidism
3.1.1 Diagnosis
Conversely, the symptoms of hypothyroidism are not specific for the disease; some
are present in a significant proportion of euthyroid subjects.4 Hypothyroidism cannot
be diagnosed accurately on symptoms alone.5 (III). The diagnosis of hypothyroidism
requires abnormal TFT results. A TSH greater than 10 mU/L combined with a FT4
below the reference range indicates the presence of overt primary hypothyroidism in
ambulant subjects.6-10 (III).
A TSH concentration above the reference range together with FT4 within the
reference range defines subclinical (mild) hypothyroidism (Section 3.2) (See also
Chapter 2). Subclinical hypothyroidism requires to be confirmed 3-6 months after the
initial results in order to exclude transient causes of a raised TSH. 11 (see also Chapter
7). Subclinical hypothyroid patients who are TPOAb or TgAb positive are more likely
to have higher serum TSH 12-15 and more likely to develop overt hypothyroidism 14-17
but do not have increased mortality or increased incidence of ischaemic heart disease.
If the serum TSH is within the reference range and the patient is not taking any
medication known to affect TSH (Chapter 7) then primary hypothyroidism is
excluded.6-10 (III). Secondary hypothyroidism may still be considered if the clinical
picture is suggestive (Section 3.3).
• Subjects with a TSH of >10mU/L and FT4 below the reference range have
overt primary hypothyroidism and should be treated with thyroid hormone
replacement (III,B).
Thyroid function tests have become the mainstay of optimising thyroxine replacement
therapy. The recommended approach in primary hypothyroidism is to titrate thyroxine
therapy against the TSH concentration whilst assessing clinical well-being. The target
is a serum TSH within the reference range. 18,19 (III). In the majority of patients 50-
100µg thyroxine can be used as the starting dose, although a higher starting dose may
be indicated in patients post-thyroidectomy. Thereafter alteration of the dose is
achieved by using 25-50µg increments and repeat measurement of TSH 2-3 months
after a change in dose. This will result in the majority of patients becoming clinically
euthyroid with a 'normal' TSH and having thyroxine replacement in the range 75-150
µg/day (1.6ug/Kg on average).20,21 (IIb). This strategy will prevent over-replacement
in patients and decrease possible adverse effects noted in terms of cardiovascular
outcome.22,23 In elderly patients and patients with with ischaemic heart disease
consideration should be given to commence replacement with 25µg thyroxine and
increase the dose in 25µg increments in an attempt to avoid cardiac complications.23-25
Other published guidelines recommend that the serum TSH during thyroxine therapy
should be targeted to be below 2.0mU/L26. It has been suggested that in a minority of
patients clinical well-being can only be achieved if the serum TSH is subnormal or
suppressed and that this is of no detriment to the patient as long as the serum FT3 is
unequivocally normal.27 However, the guidelines development group could find no
evidence to support a recommendation that in non-pregnant patients titrating the
serum TSH to the lower half of the reference range results in improved outcomes.
Serum FT4 test results can vary immediately following the daily dose of thyroxine,
but this is not clinically significant.28-30 (IIb). An even greater variability of serum
FT3 occurs in patients who are taking T3 therapy.31 It would, therefore, be ideal to
standardise the timing of thyroid function testing in relation to the daily dose of T4 or
T3 dose but clinic and surgery times make this ideal impracticable in most situations.
A minimum period of 2 months, and in some patients up to 3 months, is required to
restore stability in thyroid function tests after a change in dose.20 (IIb).
(III,B). The corresponding FT4 will be within or slightly above its reference
There has been considerable recent interest in using a combination of thyroxine and
tri-iodothyronine therapy. This interest was stimulated by an initial small study that
reported improved mood scores and self-reported wellbeing in the combined therapy
group compared with the thyroxine only group.36 However, a number of larger studies
have failed to confirm the initial finding and there is currently no consistent evidence
to suggest that combined therapy has advantages over therapy with thyroxine alone.
Most patients taking thyroxine will feel well when the serum TSH is maintained
within the reference range. However, some surveys have indicated that up to 21-59%
of patients receiving maintenance thyroxine therapy have TSH values below the
reference range. 16,22,43,44 There has been much debate regarding the possible
consequences for these patients remaining on doses of thyroxine that reduce TSH to
below the reference range27 because suppression of TSH may result in cardiac
problems.22,23 or bone loss 45,46. Therefore, it is recommended that a reduction in
thyroxine dose is made to bring the TSH within the reference range.23
Some patients on long term standard replacement doses of thyroxine, with thyroid
hormone values within the range for patients on T4, report an apparent psychological
benefit and general feeling of well being when TSH is undetectable.21 (III), although
this is not a universal finding. Although it may be difficult to reduce the thyroxine
dose in such patients it is recommended that the dose should be reduced until the TSH
is within the reference range, the use of small decremental changes of 25µg may make
this possible.47
cognitive symptoms in these patients. Indeed a lack of benefit has been demonstrated
from giving thyroxine to euthyroid patients with these symptoms.49 (Ib).
• The optimal dose of thyroxine for long-term therapy is assessed from the
results of thyroid function tests together with clinical findings. (9). In
determining the optimal dose of thyroxine the biochemical target is a TSH
result that is detectable, not elevated, and preferably within the reference
range (9).
Once stabilised on thyroxine all patients should have their serum TSH checked
annually as a change in requirement for thyroid hormone can occur with ageing. 50,51
(III). In some parts of the UK computerised thyroid registers have been established
and shown to be successful in ensuring excellent automated follow up for thyroid
patients on replacement therapy.52
3.2.1 Diagnosis
• If the serum FT4 concentration is normal but the serum TSH is >10mU/L,
then treatment with thyroxine is recommended (II,B).
• If the serum FT4 concentration is normal and the TSH is elevated but
<10mU/L then thyroxine therapy is not recommended as a routine therapy.
However, thyroxine may be indicated in non-pregnant patients with goitre;
also in patients who are seeking pregnancy (II,B).
The aim of treatment should be to restore and maintain TSH within the reference
range. Thyroxine should be given in doses increasing by 25-50µg daily titrated to
bring the TSH within the reference range. TSH should be measured 2-3 months
following a change in thyroxine dose.
A number of studies have used long term follow up in the community to define the
risk of progression from subclinical to overt hypothyroidism 14-16 (III) Establishing
treatment guidelines for individuals with elevated TSH or repeat testing protocols is
still a subject of significant debate 60,61 but it would appear prudent to measure TSH
on an annual basis.
The requirement for thyroxine can increase in patients treated for subclinical
hypothyroidism as they may develop overt hypothyroidism. TSH should be measured
annually and the thyroxine dose altered to maintain TSH within the reference range.
3.3.1 Diagnosis
vague and non-specific. Referral to an endocrinologist for additional pituitary
function tests (PRL, FSH, LH, ACTH/cortisol) may be required to make a diagnosis
and tests of adrenal function are mandatory in patients with a high index of suspicion
of hypopituitarism.. Very rarely a TRH test may help to establish the final diagnosis.
• First line TSH and FT4 are required to identify secondary hypothyroidism
Patients with secondary hypothyroidism usually also have a deficit of other anterior
pituitary hormones and the degree of hypopituitarism must be established before
commencing thyroxine replacement. This should include measurement of the
appropriate sex steroid. In particular thyroid hormone replacement should not be
commenced in patients with cortisol deficiency as this could provoke an Addisonian
crisis.65,66 Treatment with an appropriate glucocorticoid should be initiated in such
patients before commencing thyroxine therapy. (III).
In patients with secondary hypothyroidism, after a full diagnosis has been made and
steroid treatment initiated, thyroxine should be given in increasing 25µg doses and
optimised such that the thyroid hormone concentration is within the upper third of the
reference range 67,68 (III).
3.4 Congenital Hypothyroidism (see also Chapter 5)
3.4.1 Diagnosis
In neonates with an elevated TSH (>20 mU/L) formal clinical evaluation and testing
with measurement of serum TSH and FT4 should be performed immediately after the
TSH result is known (~2 weeks after birth).
It is important to perform TFT on the mother in cases with abnormal results; to ensure
that no anti-thyroid medication was ingested during the pregnancy and to exclude the
possibility of placental transfer of maternal antibodies that block the action of TSH. 71
Thyroxine is the replacement hormone of choice. The goals of treatment are to raise
the serum FT4 as rapidly as possible into the normal range, adjust the thyroxine dose
with growth to keep the serum FT4 in the upper half of the reference range and the
TSH normal, and maintain normal growth and development while avoiding
overtreatment.71 Monitoring of thyroxine replacement should take place 1-2 monthly
during the first year of life and 3-6 monthly thereafter until growth has been
completed. All infants should be re-evaluated at 3 years with a period of at least 2
weeks off thyroxine replacement therapy prior to repeat estimation of TSH and FT4 to
exclude the possibility of a transient effect of maternal antibodies.69
• The measurement of both TSH and FT4 are required to optimise thyroxine
replacement in infants. Age-related reference ranges should be used. (II,B).
4. Hyperthyroidism
4.1.1 Diagnosis
The finding of a serum TSH concentration below the reference range (in a reputable
second or third generation TSH assay) is not, however, specific for the diagnosis of
hyperthyroidism. Low serum TSH, especially if low but >0.10 mU/L, often reflects
"non-thyroidal illness" or therapy with a variety of commonly prescribed drugs 2,6
(Chapter 7).
The presence of a low serum TSH should prompt measurement of circulating thyroid
hormones (FT4 and FT3 concentrations).7 In most cases of hyperthyroidism a typical
biochemical picture of elevated FT4 and FT3 with associated undetectable serum
TSH will be evident. If FT4 is clearly elevated, then a diagnosis of thyrotoxicosis is
confirmed; in such circumstances measurement of FT3 may not provide clinically
useful additional information. If FT4 is not above the reference range in a patient with
low serum TSH, FT3 should be measured since in some cases the biochemistry
indicates a diagnosis of "T3-toxicosis" characterised by elevation of serum FT3 in the
absence of a rise in FT4. This biochemistry is typically observed in mild cases of
toxic nodular hyperthyroidism and early in the course of Graves' disease (either
primary presentation or relapse).4 In a few cases the converse is true in that a rise in
FT3 is absent despite elevation of FT4 and suppression of TSH in a patient thought
clinically to have thyrotoxicosis. The lack of rise in FT3 may reflect the presence of
"non-thyroidal illness", especially in elderly subjects; the explanation becoming
evident on re-testing once other morbidity is eliminated 8.
Once a biochemical diagnosis of hyperthyroidism has been made, other tests may be
needed to indicate the cause and specialist referral should be sought 9. Most cases of
hyperthyroidism in the UK are due to Graves' disease or toxic nodular goitre. In most
cases the clinical picture indicates the cause (e.g. ophthalmopathy, diffuse goitre in
Graves' disease, nodular goitre in toxic nodular hyperthyroidism), in which case
further investigations are not essential. If such clinical signs are absent, the presence
of thyroid peroxidase antibodies (TPOAb) is suggestive, but not diagnostic of,
Graves' disease.2,4 The presence of TSH-receptor antibodies (TSH-RAb) is a more
specific indicator of the diagnosis.10 Thyroid auto-antibodies are usually negative in
toxic nodular hyperthyroidism. Radioisotope scanning, using 99mtechnetium or
iodine, typically shows a diffuse pattern of uptake in Graves' disease, in contrast to
the presence of one or more "hot" nodules in toxic nodular hyperthyroidism 2,4. It is
not mandatory to differentiate between Graves' hyperthyroidism and toxic nodular
hyperthyroidism if the treatment plan is not altered (i.e. if 131iodine therapy is
considered the treatment of choice).
• If FT4 is not elevated in the patient with subnormal TSH, FT3 should be
measured to identify cases of T3-thyrotoxicosis (II,B)
• Patients with confirmed hyperthyroidism should be referred for specialist care
in order to establish the diagnosis and optimal management plan (III,B)
If the patient has marked adrenergic symptoms e.g. tremor, tachycardia, then
administration of beta-adrenergic blockers may be indicated for rapid relief of
symptoms (II). Propranolol is often used but beta-adrenergic blockers requiring only
once daily administration (e.g. atenolol, bisoprol) may be preferable. Beta-adrenergic
blockers are usually the sole form of treatment indicated/required in cases of
thyroiditis, although severe persistent symptoms/signs in "subacute" thyroiditis may
require additional therapy with salicylates and/or glucocorticoids.2
Most patients with hyperthyroidism require definitive treatment with 131iodine (II).
This reflects the low remission rate with thionamides alone in Graves' disease (<50%,
especially in cases with severe biochemical disease, large goitre and possibly in men)
and lack of curative effect of these drugs in toxic nodular hyperthyroidism.
All patients proceeding to surgery should be rendered euthyroid (normal FT4 and
FT3) with thionamides 3,4 (II). Preparation with beta adrenergic-blockers, iodine or
similar agents alone is considered inadequate unless thionamides are contraindicated.
• The degree of elevation of serum FT4 and FT3 provides an indication of the
severity of hyperthyroidism and should be interpreted in the context of clinical
symptoms and signs to direct first-line therapy (III,B).
serum TSH alone is not adequate since TSH may remain suppressed for weeks-
months after initiation of thionamides, especially in Graves' disease 2, so drug doses
should be titrated against measurements of FT4 (or FT3 in cases of T3-toxicosis).
Biochemistry should be checked every 4-6 weeks for the first few months after
initiation of thionamides.2,4 Once doses have been reduced to maintenance levels,
testing may be less frequent (approximately every 3 months). A fall in FT4 to low
normal or to below the normal range should prompt reduction in thionamide dosage.
A rise in serum TSH also indicates the development of hypothyroidism and the need
for dose reduction. Persistent suppression of serum TSH should not, in itself, prompt
an increase in thionamide doses.
Where patients are to be treated with a 'block and replace' regimen, a thionamide is
given alone for the first 4-6 weeks (e.g. carbimazole 40mg daily). Thyroxine (e.g.
125µg daily) is added in when the FT4 concentration has normalised while continuing
with the same dose of antithyroid drug. The TSH and FT4 should be checked 4-6
weeks thereafter and adjustments made to the dose of thyroxine if indicated. FT4 and
TSH should be checked again after 4-6 weeks; if the FT4 is in the reference range and
TSH not elevated, the same dose is continued and tests checked again after 3 months.
The serum TSH may remain suppressed for several months after initiation of
antithyroid drug treatment and decisions about adjustment of medication should be
influenced largely by the FT4 concentration. Once the FT4 and TSH have normalised
the required dose of antithyroid drug and thyroxine is unlikely to vary and TFT may
be checked less frequently (e.g. six monthly). Systematic review has shown that the
use of a 'block and replace regimen' is not superior to a dose titration regimen in
terms of remission rate in Graves' disease and may be associated with more adverse
events. 17,18
• Thyroid function tests should be performed every 4-6 weeks after commencing
thionamides. The frequency of testing should be reduced to every ~3months
once a maintenance dose is achieved (II,B)
b) Radioiodine therapy. Serum FT4 and TSH should be checked every 4-6 weeks for
several months after administration of 131iodine. A fall in serum FT4 to below normal
or rise in TSH should prompt reduction in dose or withdrawal of any thionamide
administered post-radioiodine therapy. In those not receiving thionamides, a mild and
transient rise in serum TSH may be observed in the first 6 months after 131iodine and
does not necessarily indicate the need for commencement of thyroxine replacement
therapy.21 A more marked or persistent rise in serum TSH (>20 mU/L for more than
one month), especially if associated with symptoms, should prompt thyroxine
prescription. Persistent elevation of FT4 six months after radioiodine therapy
indicates lack of cure and need for consideration of re-dosing.22 Suppression of serum
TSH may persist for weeks-months after radioiodine and does not, at present, indicate
the need for re-treatment (see Section 4.2). If FT4 is normal (off thionamides)
approximately 6 months after radioiodine, the frequency of testing may be reduced to
3 monthly and then 6 monthly. After an interval of euthyroidism (normal serum FT4)
of more than 12 months after radioiodine therapy, the patient may be transferred to
annual testing (see Section 4.1.4).
• Serum FT4 and TSH should be measured in all patients treated with
radioiodine. In most cases the FT4 result will be the marker of choice to
guide therapy (II,B)
• Thyroid function tests should be performed every 4-6 weeks for at least six
months following radioiodine therapy (II,B). The frequency of testing may be
reduced when the FT4 remains within the reference range, although an annual
TFT is still required (III,B).
• A fall in FT4 to below the reference range or a rise in TSH to above the
reference range should prompt reduction in thionamide dosage or drug
withdrawal in subjects prescribed these agents following radioiodine therapy,
followed by re-assessment off thionamaide therapy (III,B)
All patients who have received radioiodine therapy for hyperthyroidism or surgery
(partial thyroidectomy) require life-long follow-up to identify development of
hypothyroidism. Using a computerised recall system and testing of thyroid function
(TSH plus FT4) approximately every 12 months most efficiently achieves this.23
Measurement of serum TSH is the most sensitive and specific indicator of onset of
hypothyroidism. Follow-up may also indicate recurrence of hyperthyroidism; this is
rare in those previously rendered euthyroid by radioiodine but relatively common in
those previously treated by partial thyroidectomy.24 Regular thyroid function tests
should also be undertaken in any patient treated long-term with thionamides (testing
every 6-12 months).
• Life-long thyroid function testing is required for all patients who have
received radioiodine therapy or surgery for hyperthyroidism (II,B)
• Regular thyroid function testing is required for all patients being treated with
long-term thionamides (II,B)
4.2.1 Diagnosis
This is essentially a biochemical diagnosis based on the finding of low serum TSH in
association with normal serum concentrations of FT4 and FT3. Clinical symptoms
and signs are typically absent or mild/non-specific.25
It should be noted that a low serum TSH (especially if reduced but >0.1mU/L) can
reflect 'non-thyroidal illness' and various drug therapies (see Chapter 7). This is a
frequent finding in hospitalised patients. In primary care a serum TSH of <0.1mU/L is
more likely to indicate mild thyroid hormone excess 25.
The finding of a low serum TSH should prompt consideration of the cause. If non-
thyroidal illness and relevant drug therapies have been excluded then repeat
measurement of TSH (with serum FT4 and FT3) should be performed, to exclude
progression to overt hyperthyroidism and to determine if the biochemical abnormality
is persistent. The timing of repeat assessment should be based on the clinical picture;
more frequent testing may be appropriate if the subject is elderly or has underlying
vascular disease, otherwise repeat biochemical testing after 3-6 months may be
4.3.1 Diagnosis
Once the laboratory has excluded such explanations (Chapter 7) then the cause of
"true" inappropriate TSH should be considered (III). The major diagnoses are a TSH-
secreting pituitary tumour (TSH-oma) or a syndrome of thyroid hormone
resistance.29,30 The finding of an elevated serum sex hormone binding globulin
(SHBG) and circulating free alpha subunit may support the diagnosis of TSH-oma, as
may the finding of hyper- or hypo-secretion of other pituitary hormones. Pituitary
imaging usually confirms the diagnosis but should not be undertaken until the
appropriate biochemical confirmation has been made. A syndrome of thyroid
hormone resistance can be confirmed by family history; sequencing of the beta
thyroid hormone receptor (available through the Supraregional Assay Service
http://www.sas-centre.org/) confirms the diagnosis.
• The measurement of serum SHBG, alpha subunit and other anterior pituitary
hormones can help to distinguish TSH-oma from thyroid hormone resistance
5. Thyroid Function Testing in Pregnancy and Neonates
5.1 Introduction
In pregnancy there is an increased requirement for thyroxine, the reasons for which
are incompletely understood.4 In the first trimester of pregnancy the foetus is
dependent for normal development of the brain on maternal thyroid hormones; hence
it is vitally important that adequate maternal levels of thyroid hormones are
maintained. There is also an increased requirement for iodine through pregnancy,
which becomes clinically significant in areas of iodine deficiency. A daily intake of
200µg in pregnancy is recommended by the WHO; nutritional surveys indicate that
iodine deficiency is not generally a problem in the UK.
Changes in the immune system take place during and after pregnancy which influence
the course of existing autoimmune thyroid disease and also predispose to the relapse
or de novo development of autoimmune thyroid disease.
• Both TSH and FT4 (and FT3 also when TSH is below the detection limit of a
reputable assay) should be used to assess thyroid status and monitor
thyroxine therapy in pregnant patients. (III,B)
5.2 Hypothyroidism
and it is also suggested that early identification and treatment of mild (subclinical)
hypothyroidism may prevent the long-term effects of low thyroid hormone levels on
the psychomotor and auditory systems of the neonate. The impairment appears to
relate to the level of T4 rather than hypothyroidism per se 9 and even mild degrees of
hypothyroidism or presence of TPO-Ab are also incriminated.10
• The thyroid status of hypothyroid patients should be checked with TSH + FT4
during each trimester (II,B). Measurement of T3 is not appropriate.
The FT4 level should be maintained at the upper end of the non-pregnant reference
range in the first trimester, with the TSH at the lower end of the reference range or a
little below (0.4 – 2.0mU/L would be appropriate as this is normal for pregnancy).
Results should ideally be monitored against trimester-related reference ranges.
• Normal TSH and FT4 concentrations for the gestational age should be
maintained. (II,B)
• In hypothyroid patients the TSH should be checked and the thyroxine dose
should be adjusted as soon as pregnancy is diagnosed (II,B)
• The dose of thyroxine will usually require a small increase, to ensure that the
FT4 level is in the (upper) reference range and the TSH in the low/normal
range (0.4 – 2.0mU/L would be appropriate as this is normal for pregnancy)
• An increase in the dose of T4 is especially important for women who have been
treated for thyroid cancer, to ensure that the TSH remains fully suppressed
5.3 Hyperthyroidism
Patients being treated with antithyroid drugs will require the dose to be revised at the
diagnosis of pregnancy, as these drugs cross the placenta. The dose of anti-thyroid
drug is kept to the minimum consistent with maintaining euthyroidism.12,13 Patients
on a 'block and replace' regimen should be changed immediately to a maintenance
dose of anti-thyroid drug only 14. Patients on carbimazole may be switched to PTU
which it is claimed has some advantages in the pregnant patient 14,15 and is preferable
during breast feeding.
The FT4 level should be maintained at the upper end of the reference range.15 This is
particularly important in the first trimester, when even mild hypothyroidism must be
avoided, because of both the risk to the foetus, and also increased rates of spontaneous
miscarriage and premature delivery. Results should be monitored against trimester-
related reference ranges.
• The newly diagnosed hyperthyroid patient will require frequent testing during
pregnancy (e.g. monthly) until stabilised (II,B). FT4 rather than TSH is the
result that will guide therapy.
• Measurement of TSH-RAb at antenatal booking can be useful and if negative
or low need not be measured again. A very high titre can predict the chance of
intrauterine or neonatal thyrotoxicosis developing. (IV,C)
• The obstetrician must enquire about past history of thyroid disease, as women
who have had previous thyroidectomy for Graves' hyperthyroidism and are
currently euthyroid or hypothyroid may still have high titres of TSH-RAb with
concomitant risk of neonatal Graves' disease. (IV,C)
If the initial TFT show a thyrotoxic pattern, further tests are required to differentiate
postpartum thyroiditis from Graves' disease. These would include an isotope uptake ±
scan using either 99Tc or 123I (but not 131I), both of which necessitate temporary
cessation of breast feeding. Measurement of TSH-RAb may also be useful if
available. If the thyrotoxicosis is secondary to postpartum thyroiditis treatment is not
required but the TFT should be monitored to detect onset of hypothyroidism.
If the initial TFT show a thyrotoxic pattern, further tests are required to
differentiate postpartum thyroiditis from Graves' disease (II,B).
There is now substantial evidence that thyroid deficiency during pregnancy can result
in problems in development of the young child.7-10 In the early stages of pregnancy
the developing foetus is entirely dependent on the mother's thyroid hormone, so it is
vitally important that the pregnant woman's thyroid hormone levels are adequate.
The question therefore is whether all pregnant women should be screened.19,20 The
issues are well discussed 11 and the British Thyroid Association will be giving its
attention to these, but currently the recommendations are as follows:
• Thyroid function testing during pregnancy should comprise both TSH and FT4
(II,B). TPO-Ab should also be considered as this has predictive value for
both post-partum thyroiditis and foetal impairment (IV,C)
At delivery the normal full term neonate shows a marked and rapid increase in serum
TSH as a consequence of cutting the umbilical cord. The peak TSH surge occurs
within 30 minutes of birth reaching concentrations that would be diagnostic of
primary hypothyroidism in an adult. Serum TSH then starts to fall after 1-2 hours so
that by 2-3 days they have returned to concentrations typical of adults. Following the
TSH surge there is release of T4 and T3 and a progressive increase in serum FT4 and
FT3 during the first 24-36 hours of postnatal life followed by a gradual return over the
next few days to concentrations typical of normal adults.21 Similar, though less
pronounced changes occur in premature neonates such that premature neonates are in
a state of relative hypothyroxinaemia.22 Premature neonates may be considered as
having a specific form of non-thyroidal illness (NTI) (see Chapter 7) and as they
mature the TSH, FT4 and FT3 mimic the recovery phase from NTI. Few laboratories
will have definitive reference ranges for TFT in neonates and so there is reliance on
literature values.
• Unless there are compelling clinical reasons thyroid function testing should be
avoided during the first three days of life. Where testing is performed TFT
results should be interpreted with care and repeat testing after a few days is
recommended before any firm diagnosis is reached. (III,B)
This topic has already been addressed in Chapter 3. The recommendations are
repeated here for the sake of consistency. Details of policies and standards for
newborn blood spot screening in the UK are published 23.
Thyroxine is the replacement hormone of choice. The goals of treatment are to raise
the serum FT4 as rapidly as possible into the normal range, adjust the thyroxine dose
with growth to keep the serum FT4 in the upper half of the reference range and the
TSH normal, and maintain normal growth and development while avoiding
overtreatment.26 For a term neonate a high starting dose of 50µg per day (10-15
µg/kg) is typical and this dose may not need to be changed for many months.25
Smaller doses of 25-37.5µg per day may be more appropriate if the biochemical
abnormality is more subtle.
A neonate born to a mother with Graves' disease may have primary hypothyroidism
on biochemical testing because of the transfer of antithyroid drug or 'blocking' TSH-
RAbto the fetus.
Monitoring of thyroxine replacement should take place 1-2 monthly during the first
year of life and 3-6 monthly thereafter until growth has been completed.
• The measurement of both TSH and FT4 are required to optimise thyroxine
replacement in infants. Age-related reference ranges should be used. (II,B).
• Serum TSH and FT4 should also be measured in the mother of a neonate with
suspected congenital hypotrhyroidism. Measurement of maternal TSHRAb is
also helpful when transient hypothyroidism is a possibility (3)
Hyperthyroidism in most neonates subsides spontaneously over 3-12 weeks after birth
as the maternal TSH-RAb disappears from the infant's serum. However, a rarer form
of persistent neonatal hyperthyroidism is caused by germ line mutations in the TSH
receptor and the condition may also be associated with McCune Albright syndrome 26.
6 Thyroid Function Testing in Thyroid Cancer
6.1 Introduction
a) Diagnosis. Patients with thyroid cancer usually present with a nodule or goitre.
Thyroid function tests should be performed to aid the diagnosis of conditions such as
toxic nodular goitre or goitrous hypothyroidism. Thyroid function tests do not directly
aid the diagnosis of thyroid cancer, as patients are generally euthyroid.
c) Long term follow-up. After surgery the supervision of the replacement treatment is
best done by an endocrinologist. The aim of treatment is to maintain the serum TSH at
a level <0.1mU/L (III). General practitioners should be advised of the need for this
suppression and of the target TSH level.
• After thyroidectomy for thyroid cancer the TSH should be suppressed to and
maintained at a level of <0.1 mU/L in a reputable assay (III,B)
Details of the assay methodology for the measurement of thyroglobulin can be found
in Chapter 7 and also in Appendix 2 of ''Guidelines for the management of thyroid
cancer in adults''. 1 A recent article has reviewed the clinical impact of method
differences for the measurement of thyroglobulin (Tg) and thyroglobulin antibody
(TgAb) on the management of patients with differentiated thyroid carcinomas 2.
secreted by both normal and cancerous thyroid cells, therefore in patients who have
not had a total thyroidectomy and 131iodine ablation, the interpretation of serum Tg
measurements is limited by the inability to differentiate between tumour and thyroid
b) Assessing response and monitoring treatment. In patients who have been treated
with total thyroidectomy and 131iodine ablation, detectable serum Tg (>2ug/L) is
highly suggestive of residual or recurrent tumour, but could also indicate
persistence of a remnant of normal thyroid tissue.3 The sensitivity of serum Tg
measurements for detecting recurrence is enhanced by an elevated TSH
concentration. Therefore, Tg should preferably be measured when the serum TSH
is more than 30 mU/L, usually in conjunction with a whole-body radioiodine scan;
this can be achieved by either withdrawal of thyroxine or administering
recombinant TSH. To assess TSH status TFT should be performed whenever Tg is
being measured. The profile of the TFT will be determined by the nature of
thyroid hormone replacement (thyroxine or tri-iodothyronine).
Different assays for Tg can give different results depending on the assay antibody
specificity and the degree of interference from endogenous antibodies (Chapter 7).
Therefore, to ensure continuity in monitoring, clinicians should use the same
laboratory and Tg assay on a long-term basis. Laboratories should not change
methods without prior consultation with clinical users of the service 2.
• Samples for thyroglobulin assay should not be collected for at least 4-6 weeks
after thyroidectomy, or 131iodine therapy. (II,B)
• Thyroid function tests should be performed whenever thyroglobulin and
thyroglobulin antibodies are measured (II,B). The requesting clinician
should indicate on the form whether the patient is on thyroxine or tri-
iodothyronine therapy.
• For best sensitivity Tg should be measured when the serum TSH is >30
mU/L. (after thyroxine withdrawal or the use of recombinant human TSH)
(II,B). There is no need for TSH stimulation if the serum Tg is already
Although the rhTSH test has only recently been introduced, the evidence which is
evolving suggests that the test is probably as reliable as thyroxine withdrawal 5,
and that measurement of the thyroglobulin response may be adequate without the
need for 131iodine scan, particularly in low-risk patients.3,5,6
Details of the diagnosis and management of MTC can be found in ''Guidelines for
the management of thyroid cancer in adults''.1
6.3.1 Calcitonin
a) Diagnosis. Calcitonin is a useful tumour marker for medullary thyroid cancer.
Pre-operative diagnosis should include baseline values for calcitonin. There is a
positive correlation between the calcitonin level and the tumour mass. A
stimulation test with calcium/pentagastrin may also be indicated in the following
- To confirm a diagnosis of MTC pre-operatively when calcitonin levels are
only mildly elevated (<100ng/L)
- To detect C-cell disease in RET positive gene carriers (see Section 6.3.3)
- For pre-surgical assessment of RET positive children
- For post-operative monitoring for tumour recurrence
Thyroid function tests have no place in the diagnosis of MTC. However, TFT
should be monitored during follow-up in patients who have had thyroid ablation in
order to optimise thyroid hormone replacement. TSH suppression is not
appropriate for the treatment of MTC and so thyroid hormone replacement should
follow the guidelines for treating hypothyroidism.
Detailed recommendations for genetic investigation can be found in ''Guidelines
for the management of thyroid cancer in adults''.1
• RET mutation testing includes exons 10, 11, 13, 14,15 and 16; failure to
screen of exons 13-16 is an incomplete test. (III,B)
Thyroid function tests have no place in the diagnosis of anaplastic thyroid cancer.
However, TFT should be monitored during follow-up in patients who have had
thyroid ablation and the dose of thyroxine adjusted accordingly.
7. Laboratory Aspects of Thyroid Function Testing
7.1 Introduction
This chapter concerns itself with identifying the various hormone measurements that
are widely available for thyroid function testing and outlining the general principles of
how such tests should be selected, performed, reported and interpreted. The pitfalls of
thyroid function testing are discussed and recommendations given regarding how such
problems may be recognised or avoided. These recommendations have been
formulated from a number of sources but in particular from the detailed "Laboratory
Support for the Diagnosis and Monitoring of Thyroid Disease" guidelines published
by the National Academy of Clinical Biochemistry. 1
In the majority of cases there is no urgency for receipt of routine TFT but all
laboratories should be capable of issuing results for these tests within 48 hours from
receipt of the specimen.
Thyrotoxic crisis and myxoedema coma are medical emergencies with significant
morbidity and mortality if not treated promptly and adequately. Because of their rarity
few clinicians have first-hand experience of their diagnosis and management and
therefore rely heavily on biochemical proof of clinical suspicion. In these two
situations rapid provision of TFT is desirable but such requests should be supported
by an endocrinologist.
7.3.1 Thyrotrophin
• It is essential that laboratories use a reliable and sensitive method for TSH
that meets the following conditions:
- The functional sensitivity should be used to define the lowest concentration of
TSH that can be determined in routine use 5. (C)
- Functional sensitivity is defined from the 20% between-run coefficient of
variation (CV) determined by a recommended protocol 5(Section 7.11) (C)
- Laboratories should use a TSH method with a functional sensitivity of <0.02
mU/L 5 (C)
- Prior to the introduction of a TSH method, the laboratory should validate the
functional sensitivity quoted by the manufacturer. Quality assurance
procedures should be in place to ensure that the functional sensitivity of the
assay is regularly monitored (9)
Free (unbound) thyroid hormones are regarded by many as the biologically active
fraction of the total circulating thyroid hormone pool and are unaffected by changes in
the concentration and affinity of thyroid-hormone binding proteins. Free hormones
thus theoretically provide a more reliable means of diagnosing thyroid dysfunction
than measurement of total hormone concentrations. 6-9 (III). Free hormones are
normal in patients with mild (subclinical) thyroid disorders. 2
contrast many routine methods for FT4 show a marked decreases in the measured FT4
concentration on dilution. 6-13
• The nomenclature given to a method for free hormone measurement in no way
predicts its validity or agreement with equilibrium dialysis (IIa,B)
• Laboratories should obtain from kit manufacturers details of how their assay
compares with equilibrium dialysis in the clinical situations stated above (9)
• Free hormones can increase in some samples on storage 8,9 but because of
assay design (eg inclusion of albumin in reagents) not all free hormone
methods detect such changes. Laboratories should be aware of how storage
affects free hormone concentrations when measured by their own method.
Appropriate action should be taken to minimise such sample deterioration.
For example it may necessary to freeze samples that cannot be assayed within
48 hours of collection (9)
Total thyroid hormone concentrations are abnormal in patients with overt thyroid
dysfunction and also in euthyroid subjects in whom the concentration or affinity of
binding proteins are abnormal 14. Changes in plasma thyroid hormone binding
proteins may involve a change in concentration (e.g. as may occur in pregnancy) or
changes in affinity for hormone (e.g. in non-thyroidal illness or in patients taking
certain drugs such as salicylate). 14 It is thus common to find abnormal TT4 and TT3
in some euthyroid patients.
Many laboratories measure basal TSH as the initial test of thyroid function. This
strategy is not infallible but a normal TSH usually excludes primary thyroid
dysfunction. 1-4 (IIb). Initial measurement of both TSH and FT4 together can provide
a more satisfactory method of assessing thyroid status. However, it is essential to
understand and appreciate the factors that can affect the results of thyroid function
tests for correct interpretation. 4 (III).
• The use of first-line TSH will fail to identify some patients with thyroid
disorders (III,B)
• Measurement of TSH with FT4 should allow the detection of almost all causes
of thyroid dysfunction as long as the results of both tests are correctly
interpreted (III,B)
The secretion of TSH is pulsatile and night time concentrations are higher than during
the day. The concentrations of FT4 and FT3 in blood change little during a single day
but like TSH they do change throughout the year. Reference ranges for TFT are
derived from a reference population that comprises a large group of subjects who do
not have thyroid disease and are otherwise well. By convention, a reference range
usually only comprises 95% of a reference population. Thus 2.5% of "normal"
individuals will fall above the reference range and 2.5% will fall below the range. For
TSH the reference population shows a log normal distribution and has a diurnal
variation but for thyroid hormones a normal distribution is seen with no significant
diurnal variation. 15-22
For a number of reasons, reference ranges for TFT may show variation between
laboratories. Firstly the reference population studied may have included subjects with
subclinical hypothyroidism as indicated by the presence of thyroid antibodies. This
would have the effect of falsely increasing the calculated upper reference limit for
TSH. Secondly assays will have differences in standardisation, the matrix of the
calibrators and specificity of antibodies. These differences commonly give rise to
method-related biases which should be compensated for by the use of method-related
reference ranges. Thirdly, the measurement of free thyroid hormones is technically
difficult and differences in assay design may lead to significant method related
differences in hormone concentration even when measured in identical samples.
Recently, there has been a growing controversy about the upper limit of the reference
range for serum TSH. This culminated in a published debate in which one set of
authors argued in favour of reducing the upper limit of the reference range to
2.5mU/L23 while the other set of authors argued to retain the upper limit of the
reference range at 4.5mU/L24. The Guidelines Development Group recognizes the
controversy but it believes that the evidence in favour of narrowing the TSH reference
range is not convincing and cannot justify the large increase in the number of subjects
that would require regular investigation. This judgement is further influenced by the
established log-linear relationship between serum TSH and FT41 and by the lack of
evidence in favour of systematic thyroxine therapy in subclinical hypothyroidism (see
Chapters 2 and 3).
• Since TSH, free and total thyroid hormones change during pregnancy, trimester
related reference ranges should be available (see Chapter 5) (III,B)
• All laboratories must run IQC that comprise human serum pools (9)
• The analyte concentrations for the pools should be chosen to ensure that assay
performance is monitored within the euthyroid, hyperthyroid and hypothyroid
ranges (IV,C). Laboratories should define allowable limits of error for each of
these IQC pools.
• The minimum frequency with which IQC pools are run by laboratories will
usually be based on that recommended by the manufacturer for a particular
method. The laboratory should ensure that such recommendations are reasonable
and if not the laboratory should modify the IQC frequency accordingly (9)
7.7.1 Situations in which TSH Usually Provides the Correct Estimate of Thyroid
• In overt primary hyperthyroidism TSH is nearly always below 0.10 mU/L. 1-4
a) Assay interference. All assays are prone to interference from a range of substances
in blood including heterophilic antibodies. Heterophilic antibodies can interfere with
immunoassays for TSH and produce clinically misleading results (IIa). In most
circumstances assay interference produces a result that is higher than the true result
but the converse can also be found. 25-28
• Trimester-related reference ranges should be applied for TSH, total and free
thyroid hormones (III,B)
iv) Poor compliance. Some patients who are poorly compliant with thyroxine
therapy take excessive doses in the days prior to a clinic visit. These individuals
can be identified by the seemingly anomalous combination of a raised TSH and
FT4. Measurement of TSH alone is likely to lead to a recommendation for
increasing the daily dose of thyroxine when diligent adherence to the previous
drug regime is all that is required.
• The use of TSH alone is thus only adequate for patients on replacement
therapy once they are stable and compliant. (IV,C)
e) TSH secreting adenoma. Very rarely, the cause of the hyperthyroidism is a TSH-
secreting tumour. The persistent finding of hyperthyroid symptoms and elevated
thyroid hormones is consistent with the diagnosis once the common problems of assay
interference or non-thyroidal illness have been eliminated. 35,36 (III). (See also
Chapter 4).
f) End organ resistance. Certain patients with end organ resistance to thyroid
hormones may present with abnormal thyroid function tests. Some may have high
concentrations of thyroid hormone but normal TSH and others will have raised TSH
with normal thyroid hormones. 37, 38. Confirmation of the diagnosis can be made by
the thyroid hormone receptor β-gene sequence analysis available through the
Supraregional Assay Service (http://www.sas-centre.org). The decision to treat these
patients is often made on clinical grounds rather than the biochemical abnormality
(III). (See also Chapter 4).
g) "Non-thyroidal illnesses" and the "sick-euthyroid syndrome" Patients suffering
from any of a wide range of chronic or acute non-thyroidal illnesses, may show
abnormalities in thyroid function tests even though they are clinically euthyroid. This
has been described as the "sick euthyroid syndrome". 39-42 (III). In the majority of
these sick patients TSH will be normal and thus provide the best guide of thyroid
status. However in some patients, TSH concentrations may be suppressed in the acute
phase and on recovery TSH concentrations may rise transiently into the hypothyroid
range. 43 (III). Total T3 and FT3 concentrations usually fall as a result of impaired
tissue uptake of T4 and impaired conversion of T4 to T3. 39-42,44,45. However using
ultrafiltration or some commercial assays FT3 may be normal or sometimes raised. 39,
Illness modifies both the concentration and binding capacity of the plasma thyroid
hormone binding proteins 39-42,46 which in turn tends to diminish the total thyroid
hormone concentrations and raise the FT4 hormone fraction. When measured by a
reference method, FT4 concentrations usually remain within the reference range or
are modestly raised in the sick patient. 8,10-13,47,48 However many routine methods for
FT4 produce low values in the sick patient due to assay artefacts. 8,10-13,47,48
The contribution of each of the above mechanisms may vary with the severity and
stage of the illness and thus the pattern of thyroid function tests may be extremely
variable and may mimic the profile seen in primary or secondary thyroid disorders
• Although these procedures may clarify the cause of abnormal thyroid function
tests for some patients, clinical assessment by an endocrinologist may be
indicated (IV,C)
h) Drug treatment. Drugs may interfere with TSH secretion or the production,
secretion, transport and metabolism of thyroid hormones. 50,51 Some drugs modify
thyroid status whilst others produce abnormal thyroid function test results in
otherwise euthyroid subjects. In general, serum TSH is less affected by medication
than thyroid hormones, although glucocorticoids and dopamine in high doses inhibit
TSH release. 52,53
Certain agents will impair the absorption of thyroxine from the gut and patients on
thyroxine therapy should be advised to take their thyroxine at least 4 hours apart from
these medications. Patients taking thyroxine are likely to require an increase in
replacement dose if drugs such as phenytoin or carbamazepine are prescribed that
increase hepatic metabolism of T4. Propranolol may decrease TT3 and increase
TSH. 54 Phenytoin, carbamazepine, frusemide and salicylate compete with thyroid
hormone binding to serum binding proteins and may increase FT4. 55-58 In vivo
administration of heparin liberates free fatty acids, which displace thyroid hormones
from their binding proteins and also increase FT4. However it is important to note that
the influence of drugs on modifying free thyroid hormone concentrations may be
method specific. For example, depending on the method, FT4 may be measured as
normal or low in patients given heparin or taking phenytoin or carbamazepine 58,59
(IIa). Amiodarone and lithium can alter thyroid status and are discussed below.
Similarly the use of some cytokines such as interferon alpha for the treatment of
chronic hepatitis C can induce hypothyroidism or hyperthyroidism.
Section 7.12 lists some of the drugs that may produce abnormal thyroid function tests.
• For patients taking drugs known to modify thyroid function tests, the
laboratory must be able to provide appropriate interpretative advice (9)
• Certain drugs interfere with thyroid hormone absorption from the GI tract e.g.
ferrous sulphate, cholestyramine, cholestapol, and aluminium hydroxide.
Patients taking thyroxine should be advised against taking these drugs until at
least 4 hours after taking thyroxine. 60 (IIa,B)
• The dose of thyroxine may have to be increased in patients who are taking
drugs that increase thyroid hormone metabolism. For example
anticonvulsants induce drug metabolising enzymes (see Chapter 4) (III,B)
• Euthyroid subjects taking amiodarone for more than three months frequently
have increased FT4, decreased FT3 but normal TSH. During the first three
months of treatment, however, TSH may increase transiently (up to 20 mU/L)
particularly in patients receiving higher doses of amiodarone. 64- 67 (IIa,B)
Unusual combinations of TSH and thyroid hormone results may have a pathological
source but more commonly result from poor compliance or assay interference in one
or more assays. 68, 69
These are present in the serum of patients with a wide range of immunologically
mediated thyroid disorders (e.g. Hashimoto's thyroiditis, Graves' disease). They may
also be found in a small proportion of apparently healthy individuals but the
appearance of TPOAb usually precedes the development of thyroid disorders. 18,70
interleukin-2 or lithium. 73-76 (III,B).
- As a risk factor for thyroid dysfunction during lithium or amiodarone
therapy. 64-66, 77 (III,B)
• TPO results are method dependent and this should be recognised. (III,B)
• Functional sensitivity should be determined for the TPOAb method using the
same protocol as for TSH (Section 7.10) (IV,C)
• A reference interval for TPOAb should be derived using at least 120 subjects who
have no personal or family history of thyroid disorders and have no visible goitre
and are on no medication. They should have no autoimmune or systemic disease.
Young males <30 years with TSH between 0.5-2.0 mU/L may be a suitable source
of subjects (IV,C)
• A reference interval should be derived using at least 120 subjects who have no
personal or family history of thyroid disorders and have no visible goitre and
are on no medication. They should have no autoimmune or systemic disease.
• If TgAb is being used for monitoring purposes the method should not be
changed without consultation with the users. (IV,C)
Many differentiated papillary and follicular carcinomas of the thyroid synthesise and
secrete thyroglobulin. Detailed UK guidelines for the diagnosis and management of
thyroid cancer have been published recently 88, (also see chapter 6) and problems with
thyroglobulin assays have been widely reviewed. 89-92 It should be noted that marked
bias differences occur between Tg assays with up to four fold differences being seen
between the highest and lowest biased assays 78 It is important that the laboratory is
consulted to determine the appropriate bias-adjusted cut-offs for use in clinical
• The use of the Community Bureau of Reference standard for thyroglobulin
(CRM 457) is recommended. (IV,C)
7.9.5 Calcitonin
Detailed UK guidelines for the diagnosis and management of thyroid cancer and the
use calcitonin assays have been published recently. 88
Type of specimen
• Serum or plasma requirements should be confirmed with laboratories and/or
manufacturers' kit inserts. The effect of gel tubes should be known.
• Calcitonin results may be affected by visible haemolysis or lipaemia and assay
of such specimens should be avoided if possible
Specimen stability
• Calcitonin in serum or plasma is unstable and blood specimens should be kept
on ice. Red cells should then be separated within 30 minutes of collection and
serum or plasma frozen immediately.
• Assays should be standardised using WHO International Standard IS 89/620.
• Laboratories must decide whether to use a method that recognises primarily
monomeric calcitonin (IMA) or a method with broader specificity (RIA).
Assay sensitivity
• Laboratories and/or manufacturers should determine and quote the minimum
detection limit of their assay based on precision profiles derived from patient
Assay interferences
• Laboratories should have established protocols for identifying specimens that
may have 'hooked' and specimens that may contain interfering antibodies
Clinical assessment
• For a particular calcitonin method the results of a clinical assessment of the
assay performance should be available. The clinical sensitivity and specificity
(i.e. positive and negative predictive values) of the assays should be quoted.
Quality assurance
• Laboratories should run internal quality control at concentrations
appropriate for the range of results obtained. A pool with a calcitonin
concentration close to the minimum detectable limit should also be run to
ensure good baseline security.
• Laboratories should participate in a recognised and accredited external
quality assessment scheme
Assays for alpha subunit are performed in a few specialist laboratories in the UK. No
external quality assessment scheme is available. The specialist laboratory performing
the measurement should be consulted for interpretation of the results.
7.11 Drugs that Alter Thyroid Hormone Synthesis, Secretion and Metabolism
Decrease in TSH Decreased Thyroid Increased thyroid Decreased thyroidal Displacement of Impaired T4 to T3
Secretion Hormone Secretion Hormone secretion synthesis* Hormone from Plasma Conversion
Dopamine Dopaminergic Lithium Iodide Methimazole Frusemide Beta antagonists
agents Iodide Amiodarone Carbimazole Fenclofenac Glucocorticoids
Glucocorticoids Amiodarone Lithium (rare) Propylthiouracil Salicylates Amiodarone
Cytokines Lithium Mefenamic acid Propylthiouracil
Octreotide Carbamazepine Iopanoic acid
Non-steroidal AIDs Radiocontrast dyes
Increase TBG, Decrease TBG, Increased Hepatic Impaired Absorption of Alter autoimmunity*** Modify Thyroid
TT3, TT4 TT3, TT4 Metabolism of T4 Thyroxine ** Hormone Action
Oestrogens Androgens Phenytoin Cholestyramine Interleukin 1 Amiodarone
Tamoxifen Anabolic steroids Carbamazapine Cholestapol Interferon α
Heroin Glucocorticoids Barbiturates Aluminium hydroxide Interferon β
Methadone Rifampacin Ferrous sulphate TNF α
Clofibrate Sucralfate
Raloxifene Calcium carbonate
Soy protein
Proton pump inhibitors
*Drugs listed as causing a decrease in thyroid hormone synthesis or secretion thus leading to altered thyroid status.
** Drugs interfere with thyroid hormone absorption from the GI tract. Patients on thyroxine therapy should be advised to take their thyroxine at
least 4 hours apart from these medications..
***Treatment with these cytokines have been associated with cases of transient hypothyroidism and thyrotoxicosis. These usualy resolve several
months after treatment is stopped. The mechamism is unclear but the changes may be autoimmune
The other drugs listed are thought to produce abnormal thyroid function tests but patients maintain a euthyroid status. Amiodarone is an
exception (see main text).
8. Areas for further studies
Routine thyroid function testing has been available for more than thirty years.
Therefore, it may seem surprising that the quality of evidence to support the
recommendations in these guidelines is generally poor. The main reason for this
finding is that the early studies that were used to assess the value, validity and
effectiveness of thyroid function tests in a variety of clinical situations were
performed before the requirements for evidence based medicine were adopted. There
is a real need to conduct new studies that conform to the rules of evidence based
medicine in order to provide answers to some common but contentious issues in the
use of thyroid function testing.
The guideline development group highlights the need for additional studies on:
• The definition of age-related and trimester-related UK reference ranges for
serum TSH and FT4
• The appropriateness of using thyroid function tests in screening selected
categories of the normal healthy adult population for thyroid disease
• The appropriateness of using thyroid function tests for case finding for thyroid
disease in hospital inpatients
• The optimal use of thyroid function tests in the diagnosis, monitoring and
treatment of patients with subclinical hypothyroidism and subclinical
• The use of thyroid function tests to optimise thyroxine replacement therapy in
patients with primary hypothyroidism and secondary hypothyroidism
• The relative clinical outcome of patients on thyroxine therapy who have serum
TSH concentrations maintained within and below the reference range
• The relative effectiveness of thyroid function tests and tissue markers of
thyroid hormone action in the diagnosis and management of thyroid disorders
Appendix 1. References
References are numbered separately for each Chapter. Therefore, Reference 1.1 is
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Chapter 1
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practice and audit measures in the management of hypothyroidism and hyperthyroidism. Br
Med J 1996; 313: 539-544
1.4 Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association Guidelines for
detection of thyroid dysfunction. Arch Int Med 2000; 160: 1573-1575
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guidelines for diagnosis and management. JAMA 2004; 291: 228-238
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1.8 Guidelines for the management of thyroid cancer in adults. 2002; London: Royal College of
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Chapter 3
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hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in
elderly women: the Rotterdam Study. Ann Intern Med 2000;132: 270-278
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3.16 Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the
community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;
43: 55-68
3.17 Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of
abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin
Endocrinol (Oxf) 1991; 34: 77-83
3.18 Toft AD. Thyroxine therapy. N Engl J Med 1994; 331: 174-180
3.19 Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association Guidelines for
detection of thyroid dysfunction. Arch Int Med 2000; 160: 1573-1575
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responsiveness in hypothyroid patients receiving thyroxine replacement. J Clin Endocrinol
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3.22 Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for
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heart. Ann Intern Med 2002; 137: 904-914
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for the diagnosis and monitoring of thyroid disease. National Academy of Clinical
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3.28 Browning MC, Bennet WM, Kirkaldy AJ, Jung RT. Intra-individual variation of thyroxin,
triiodothyronine, and thyrotropin in treated hypothyroid patients: implications for monitoring
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than T4 alone in patients with hypothyroidism? Results of a double-blind randomized
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community: serum thyroid stimulating hormone level assays as an indicator of undertreatment
or overtreatment. Br J Gen Pract 1993; 43: 107-109
3.45 Faber J, Galloe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due
to L-thyroxine treatment: a meta-analysis. Eur J Endocrinol 1994; 130; 350-356
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suppressed serum TSH. Scot Med J 1995; 40: 171-173
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Decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med 1983;
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3.51 Young RE, Jones SJ, Bewsher PD, Hedley AJ.Age and the daily dose of thyroxine
replacement therapy for hypothyroidism. Age Ageing 1984; 13: 293-303
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3.55 Prentice LM, Phillips DI, Sarsero D, Beever K, McLachlan SM, Smith BR.
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highly sensitive direct assays for autoantibodies to thyroglobulin and thyroid peroxidase. Acta
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antibodies in the development of elevated serum TSH in middle-aged women: associations
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3.58 Kabadi UM. 'Subclinical hypothyroidism'. Natural course of the syndrome during a prolonged
follow-up study. Arch Intern Med 1993; 153: 957-961
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levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-
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3.60 McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should
be treated. J Clin Endocrinol Metab 2001; 86: 4585-4590
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321: 1275-1277
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line thyroid-function test. Lancet 2001; 357: 1013-1014
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hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin. J
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4.1 Nordyke RA, Gilbert FI, Jr., Harada AS. Graves' disease. Influence of age on clinical findings.
Arch Intern Med 1988; 148: 626-631
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4.4 Weetman AP. Graves' disease. N Engl J Med 2000; 343: 1236-1248.
4.5 Ross DS, Daniels GH, Gouveia D. The use and limitations of a chemiluminescent thyrotropin
assay as a single thyroid function test in an out-patient endocrine clinic. J Clin Endocrinol
Metab 1990; 71: 764-769
4.6 Wehmann RE, Gregerman RI, Burns WH, Saral R, Santos GW. Suppression of thyrotropin in
the low-thyroxine state of severe nonthyroidal illness. N Engl J Med 1985; 312: 546-552
4.7 Singer PA, Cooper DS, Levy EG et al. Treatment guidelines for patients with hyperthyroidism
and hypothyroidism. Standards of Care Committee, American Thyroid Association. JAMA
1995; 273: 808-812
4.8 Engler D, Donaldson EB, Stockigt JR, Taft J. Hyperthyroidism without triiodothyronine
excess: an effect of severe non-thyroidal illness. J Clin Endocrinol Metab 1978; 46: 77-82
4.9 Vanderpump MPJ, Ahlquist JAO, Franklyn JA, Clayton RN. Consensus statement for good
practice and audit measures in the management of hypothyroidism and hyperthyroidism. BMJ
1996; 313: 539-544.
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receptor antibodies has superior diagnostic sensitivity for Graves' disease. J Clin Endocrinol
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4.13 Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC, Franklyn JA. Age and gender
predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab 2000;
85: 1038-1042
4.14 Cooper DS. Antithyroid drugs. N Engl J Med 2005; 352: 905-917
4.15 Bonnema SJ, Bennedbaek FN, Veje A, Marving J, Hegedus L. Propothiouracil before 131I
therapy of hyperthyroid diseases; effect on cure rate evaluated by a randomized clinical trial.
J Clin Endocrinol Metab 2004; 89: 4439-4444
4.16 Andrade VA, Gross JL, Maia AL. The effect of methimazole pretreatment on the efficacy of
radioactive iodine therapy in Graves' hyperthyroidism: one-year follow-up of a prospective,
randomized study. .J Clin Endocrinol Metab 2001; 86: 3488-3493
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therapy for Graves' hyperthyroidism. Europ J Endocrinol 2005; 153: 489-498
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antithyroid drug dose in Graves' disease therapy. J Clin Endocrinol Metab 1993; 76: 1516-
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of relapse after antithyroid drug treatment in patients with Graves' disease. Acta Endocrinol
(Copenh) 1989; 120: 689-701
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iodine-131 treatment in hyperthyroid patients with Graves' disease: prevalence, mechanism
and prognosis. Clin Endocrinol (Oxf) 1997; 46: 1-5
4.22 Chiovato L, Fiore E, Vitti P et al. Outcome of thyroid function in Graves' patients treated with
radioiodine: role of thyroid-stimulating and thyrotropin-blocking antibodies and of
radioiodine-induced thyroid damage. J Clin Endocrinol Metab 1998; 83: 40-46
4.23 Franklyn JA, Daykin J, Drolc Z, Farmer M, Sheppard MC. Long-term follow-up of treatment
of thyrotoxicosis by three different methods. Clin Endocrinol (Oxf) 1991; 34: 71-76
4.24 Alsanea O, Clark OH. Treatment of Graves' disease: the advantages of surgery. Endocrinol
Metab Clin North Am 2000; 29: 321-337.
4.25 Surks MI, Ortiz E, Daniels GH et al. Consensus guidelines for the diagnosis and management
of subclinical thyroid disease. JAMA 2004; 291:228-238
4.26 Sawin CT, Geller A, Wolf PA et al. Low serum thyrotropin concentrations as a risk factor for
atrial fibrillation in older persons. N Engl J Med 1994; 331: 1249-1252
4.27 Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and
cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year
cohort study. Lancet 2001; 358: 861-865
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abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin
Endocrinol (Oxf) 1991; 34: 77-83
4.29 Beck-Peccoz P, Chatterjee VK. The variable clinical phenotype in thyroid hormone resistance
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1987; 16: 765-792
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Chapter 5
5.1 Burrow GN, Fisher DA, Larsen PR. Maternal and Fetal Thyroid Function. N Engl J Med
1994; 331: 1072-1078
5.2 Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation
from physiology to pathology. Endocr Rev 1997; 18: 404-433
5.3 Price A, Obel O, Cresswell J et al. Comparison of thyroid function in pregnant and non-
pregnant Asian and western Caucasian women. Clin Chim Acta 2001; 308: 91-98
5.4 Brent GA. Maternal hypothyroidism: recognition and management. Thyroid 1999; 9: 661-665
5.5 Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine during pregnancy
in women with primary hypothyroidism. N Engl J Med 1990; 323: 91-96
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increase in thyroxine dose requirement in pregnancy? Metabolism 2003; 52: 122-128
5.7 Haddow JE, Palomaki GE, Allan WC et al. Maternal thyroid deficiency during pregnancy and
subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549-555
5.8 Pop VJ, Kuijpens JL, van Baar AL et al. Low maternal free thyroxine concentrations during
early pregnancy are associated with impaired psychomotor development in infancy. Clin
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maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000;
85: 3975-3987
5.10 Pop VJ, de Vries E, van Baar AL et al. Maternal thyroid peroxidase antibodies during
pregnancy: a marker of impaired child development? J Clin Endocrinol Metab 1995; 80:
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women of childbearing age: Recent insights and consequences for antenatal and postnatal
care. Endocr Rev 2001; 22: 605-630
5.12 Burrow GN. The management of thyrotoxicosis in pregnancy. New Engl J Med 1985; 313:
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Thyroid 1999; 9: 647-652
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hypothyroidism? Lancet 1999; 354: 1224-1225
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2005; 58: 449-452
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newborn. N Engl J Med 1981; 304: 702-712
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Clin Perinatol 1998; 25: 999-1014
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Chapter 6
6.1 Guidelines for the management of thyroid cancer in adults. 2002; London: Royal College of
6.2 Spencer CA, Bergoglio LM, Kazarosyan M, Fatemi S, LoPresti JS. Clinical impact of
thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients
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response to recombinant human thyrotophin sufficient, by itself, to monitor for residual
thyroid carcinoma? J Clin Endocrinol Metab 2002; 87: 3242-3247
6.4 Spencer CA, Wang CC. Thyroglobulin measurement. Endocr Metab Clin N Am 1995; 24:
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thyroglobulin measurement after recombinant human thyrotropin. Thyroid 2002; 12: 583-590
6.6 Haugen BR, Chester-Ridgway E, McLaughlin BA, McDermott MT. Clinical comparison of
whole-body radioiodine scan and serum thyroglobulin after stimulation with recombinant
human thyrotropin. Thyroid 2002; 12: 37-43
Chapter 7
7.1 Demers LM, Spencer CA eds. Laboratory medicine practice guidelines: Laboratory support
for the diagnosis and monitoring of thyroid disease. National Academy of Clinical
Biochemistry 2002; URL: http//:www.nacb.org/monograph/Thyroid_index.htm
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detection of thyroid dysfunction. Arch Intern Med 2000; 160: 1573-1575
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7.5 Spencer CA, Takeuchi M, Kazarosyan M. Current status and performance goals for serum
thyrotropin (TSH) assays. Clin Chem 1996; 42: 141-145
7.6. Ekins R. The free hormone hypothesis and measurement of free hormones. Clin Chem 1992;
38: 1289-1293
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7.8 Stockigt JR. Free thyroid hormone measurement: a critical appraisal. Endocrinol Metab Clin
N Am 2001; 30: 265-289
7.9. Christofides ND Free Analyte Immunoassay In: The Immunoassay Handbook, second edition,
D.Wild ed, Nature Publishing Group, 2001: 61-77
7.10 Christofides ND, Wilkinson E, Stoddart M, Ray DC, Beckett GJ, Assessment of serum
thyroxine binding capacity-dependent biases in free thyroxine assays. Clin Chem 1999; 45:
7.11 Wang R, Nelson JC, Weiss RM, Wilcox RB. Accuracy of free thyroxine measurements across
natural ranges of thyroxine binding to serum proteins. Thyroid 2000; 10: 31-39
7.12 Sapin R. Serum thyroxine binding capacity-dependent bias in five free thyroxine
immunoassays: assessment with serum dilution experiments and impact on diagnostic
performance. Clin Biochem 2001; 34: 367-371
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non-isotopic two-step assay (Delfia) and an analogue radioimmunoassay (SimulTRAC) for
free thyroxine compared. Ann Clin Biochem 1991; 28: 335-344
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7.15 Tunbridge WMG, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community:
The Whickham survey. Clin Endocrinol 1977; 3: 481-493.
7.16 Hollowell JG, Staehling NW, Hannon WH, et al. Serum TSH, T4 and thyroid antibodies in
the United States Population (1988) to 1994): National Health and Nutrition examination
survey (NHANES III). J Clin Endocrinol Metab 2002; 87: 489-499
7.17 Vanderpump MPJ, Ahlquist JAO, Franklyn JA, Clayton RN. Consensus statement for good
practice and audit measures in the management of hypothyroidism and hyperthyroidism. Br
Med J 1996; 313: 539-544
7.18 Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T4
and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin
Endocrinol Metab 2002; 87: 1068-1072.
7.19 Fraser CG. Biological variation: from principles to practice. AACC Press, Washington DC;
7.20 Browning MCK, Ford RP, Callaghan SJ, Fraser CG. Intra-and inter-individual biological
variation of five analytes used in assessing thyroid function: implications for necessary
standards of performance and the interpretation of results. Clin Chem 1986; 32: 962-966
7.21 Fraser CG, Petersen PH. Desirable standards for laboratory tests if they are to fulfil medical
needs. Clin Chem 1993; 39: 1453-1455
7.22 Browning MC, Bennet WM, Kirkaldy AJ, Jung RT. Intra-individual variation of thyroxin,
triiodothyronine and thyrotropin in treated hypothyroid patients: implications for monitoring
replacement therapy. Clin Chem 1988; 34: 696-699
7.23 Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is
compelling. J Clin Endocrinol Metab 2005; 90: 5483-5488
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unchanged. J Clin Endocrinol Metab 2005; 90: 5489-5496
7.25 Howanitz PJ, Howanitz JH, Lamberson HV, Ennis KM. Incidence and mechanism of spurious
increases in serum thyrotropin. Clin Chem 1982; 28: 427-431
7.26 Boscato LM, Stuart MC. Heterophilic antibodies: a problem for all immunoassays. Clin Chem
1988; 34: 27-33
7.27 Levinson SS. The nature of heterophilic antibodies and their role in immunoassay
interference. J Clin Immunoassay 1992;15: 108-115
7.28 Kricka LJ. Human anti-animal antibody interference in immunological assays. Clin Chem
1999; 45: 942-956.
7.29 Gow SM, Kellett HA, Seth J, Sweeting VM, Toft AD, Beckett GJ. Limitations of new thyroid
function tests in pregnancy. Clin Chim Acta, 1985; 152: 325-333
7.30 Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation
from physiology to pathology. Endocr Rev 1997; 18: 404-433
7.31 Hershman JM. Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and
trophoblastic tumors. Thyroid 1999; 9: 653-657
7.32 Uy H, Reasner CA, Samuels MH. Pattern of recovery of the hypothalamic-pituitary thyroid
axis following radioactive iodine therapy in patients with Graves' disease. Am J Med 1995; 99:
7.33 Wardle CA, Fraser WD, Squire CR. Pitfalls in the use of thyrotropin concentration as a first-
line thyroid-function test. Lancet 2001; 357: 1013-1014
7.35 Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC, Weintraub BD. Thyrotropin-
secreting pituitary tumors. Endocr Rev 1996; 17: 610-638
7.36 Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL, Weintraub BD. Thyrotropin-
secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity and treatment
outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab
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7.37 Refetoff S. Resistance to Thyroid Hormone. In The Thyroid. Braverman LE and Utiger RD,
eds. Lippincott Williams & Wilkins, Philadelphia. 2000; 1028-1043.
7.38 Beck-Peccoz P, Chatterjee VKK. The variable clinical phenotype in thyroid hormone
resistance syndrome. Thyroid 1994;4: 225-232
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Clin Biochem 1998; 1: 9-15
7.41 LoPresti JS, Nicolof JT. Thyroid response to critical Illness. Contempory Endocrinology:
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7.42 Wiersinga WM, Boelen A, Thyroid hormone metabolism in non-thyroidal illness Current
Opin Endocrinol Diab 1996; 3: 422-428
7.43 Spencer CA, Eigen A, Duda M, et al. Sensitive TSH tests - specificity limitations for
screening for thyroid disease in hospitalized patients. Clin Chem 1987; 33: 1391-1396
7.44 Sapin R, Schliener JL, Kaltenbach G, et al. Determination of free triiodothyronine by six
different methods in patients with non-thyroidal illness and in patients treated with
amiodarone. Ann Clin Biochem 1995; 32: 314-324
7.45 Henneman G, Everts ME, de Jongt M. The significance of plasma membrane transport in the
bioavailability of thyroid hormones. Clin Endocrinol 1998; 48: 1-8
7.46 Wilcox RB, Nelson JC and Tomei RT. Heterogeneity in affinities of serum proteins for
thyroxine among patients with non-thyroidal illness as indicated by the serum free thyroxine
response to serum dilution. Eur J Endocrinol 1994; 131: 9-13
7.47 Nelson JC, Weiss RM. The effects of serum dilution on free thyroxine (T4) concentration in
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