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Abstract
Laboratory assessment of thyroid function is now often initiated with a low pre-test probability, by clinicians who may not have
a detailed knowledge of current methodology or testing strategies. Skilled laboratory staff can significantly enhance the choice
of appropriate tests and the accuracy of clinical response; such involvement requires both appropriate training and relevant
information from the clinician. Measurement of the serum thyroid stimulating hormone (TSH) concentration with an assay of
adequate sensitivity is now the cornerstone of thyroid function testing; for untreated populations at risk of primary thyroid dysfunction, a normal TSH concentration rules out an abnormality with a high degree of certainty. However, in several
important situations, most notably pituitary abnormalities and early treatment of thyroid dysfunction, serum TSH can give a
misleading indication of thyroid status. An abnormal TSH concentration alone is never an adequate basis for initiation of
treatment, which should be based on the typical relationship between trophic and target gland hormones, based on serum TSH
and an estimate of serum free thyroxine (T4). Six basic assumptions, some clinical, some laboratory-based, need to be
considered, together with the relevant limiting conditions, for reliable use of this relationship. Current methods of free T4
estimation remain imperfect, especially during critical illness. Diagnostic approach differs significantly between initial
diagnosis and follow-up of treated thyroid dysfunction. In some situations, serum triiodothyronine (T3) is also required, but
serum T3 lacks sensitivity for diagnosis of hypothyroidism, and has poor specificity during non-thyroidal illness. Where assay
results are anomalous, most atypical findings can be resolved by attention to the clinical context, without further investigation.
(Clin Biochem Rev 2003; 24:110-23)
Introduction
This review summarizes principles for the appropriate use of
laboratory assays in the diagnosis and follow-up of thyroid
disorders. Symptoms, physical signs, imaging techniques and
cytological examination will not be considered in detail,
although it is self-evident that laboratory results should be
interpreted in this broader context. The recent monograph
Laboratory support for the diagnosis of thyroid disease
from the National Academy of Clinical Biochemistry, USA,
should be consulted for detailed guidelines on the
preparation, laboratory use and application of current thyroid
1
assays. References for specific points in this review are cited
2
at www.thyroidmanager.org.
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Stockigt J
Common to Both
Thyrotoxicosis
Hypothyroidism
Classical presentations
Goitre
Postpartum
Menstrual disturbance
Neonatal
Incidental finding
Heart failure
Arrhythmia
Eye disease
Anxiety state
Weight loss
Diarrhoea
Apathetic hyperthyroidism
Myopathy
Periodic paralysis
Dermopathy
Itch
Thyroid storm
Anaemia
Constipation
Depression
Dementia
Myalgia
Nerve entrapment
Hyperlipidaemia
Hypoventilation
Galactorrhoea
Infertility
Puberty, precocious or delayed
Delayed growth
Hypothermia, coma
110
111
Stockigt J
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Stockigt J
1.
Steady-state conditions
(N.B. difference in half-life of TSH and T4 )
Acute effects of medications
Early response to therapy
Evolution of transient thyroid dysfunction
Recovery from severe illness
2.
3.
4.
5.
6.
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Stockigt J
Clinical Applications
Application of diagnostic strategy will differ depending on
the test group, i.e. testing of untreated subjects in whom
clinical features suggest thyroid dysfunction, screening or
case finding in at risk groups, evaluation of the response to
treatment, or assessment when associated illness or drug
therapy are likely to complicate both clinical and laboratory
assessment.
Untreated Subjects
Assessment of untreated subjects now commonly begins with
measurement of TSH alone, with free T4 and/or free T3
added only if TSH is abnormal, or if an abnormality of TSH
secretion is suspected. According to this algorithm, free T4
should be measured to distinguish between overt and
subclinical hypothyroidism when serum TSH is elevated,
while a suppressed or subnormal TSH level should be
followed by assay of both free T4 and free T3 to distinguish
subclinical from overt thyrotoxicosis and to identify T3
toxicosis.
Table 8. Serum TSH alone can give a false or uncertain indication of thyroid status.
Condition
TSH
Free T4
Free T3
N-H
L-N
L-N
L
L
N,H
Thyrotoxicosis
Subclinical
Early Treatment
U
U
N
H-N-L
N
H-N-L
Hypothyroidism
Subclinical
Early Treatment
H
H
N
L-N
H
L-N-H
N
H
Medications
Dopamine
Glucocorticoids
L
L
N
N
Critical illness
Euthyroid subject
Hypothyroid subject
U,L
N
L,N
L,N
N
H
____________________________________________
U: undetectable TSH <0.03 mU/L; L: low; N: normal; H: high.
Response to Treatment
In patients with newly treated thyrotoxicosis, TSH may
remain suppressed for several months after normalisation of
serum free T4 and free T3; serious over-treatment may result
if TSH alone is used for adjustment of antithyroid drug
dosage. Furthermore, during drug treatment, thyrotoxicosis
may persist due solely to T3 excess. Hence, reassessment of
serum free T4 and free T3 levels is recommended after about
3-4 weeks drug treatment of thyrotoxicosis to allow
appropriate dose adjustment. During long-term treatment,
TSH generally gives a reliable guide to optimal drug dosage.
Similarly, during long-term replacement or suppressive
therapy with T4, serum TSH is the best single index of
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Stockigt J
17
Thyroglobulin
18
119
Stockigt J
Clinical context
Assay Results
Free T4
Free T3
Pregnancy
L*
L,N
Antithyroid drug treatment, initial months
H,N,L
H,N,L
Recent T4 therapy for hypothyroidism
N
N
Hypothyroidism, appropriate T4 dose
H
N
Hypothyroidism, intermittent compliance
H,N
Appropriate T4 suppressive therapy
H
N
Excessive T3 treatment
L
H,N
Recombinant TSH, suppressive T4
H
N
Hypopituitarism
L
Phenytoin
L*
Critical illness
L*
L
Heparin effect in critical illness
L,N,H*
L
Recovery phase of critical illness
L,N
Drugs that inhibit T4&T3 binding to TBG
L*
L*
Amiodarone effect in euthyroid subject
H
L
Acute T4 overdose
HH
H,N
___________________________________________________________
U undetectable; L low; N normal; H high;
* effect dependent on assay method
# typical reference intervals are shown in Table 10.
depends on interval between dosage and sampling
120
TSH
N
U
H
N
H
U,L
U
HH
L,N
L,N
L
L
H
L,N
N
N
References
1.
Hormone
Reference Range
60-140 nmol/L
Free T4
10-25 pmol/L
1.1-2.7 nmol/L
Free T3
3-8 pmol/L
TSH
0.4-4.0 mU/L
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
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Stockigt J
14.
15.
16.
17.
18.
19.
20.
21.
22
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