Download A Thyroid Testing Review December 2013

December 2013
A Thyroid Testing Review
Erin Grimm, MD—Hospital Pathology Associates
Do you fell tired, cold, and overall, just a general state of lethargy? Many of us
may respond in the affirmative as day length decreases and winter arrives in
full force. However, today we will address physiologic causes for these
symptoms, specifically thyroid disorders. This month’s laboratory update will
include a brief review of thyroid testing as well as new options for test ordering
provide by Allina Health Laboratory.
A quick review of physiology
The hypothalamus produces thyrotropin releasing hormone (TRH) which
stimulates the pituitary gland to release TSH, and TSH stimulates the thyroid
gland to secrete the biologically active thyroid hormones, T4 (Thyroxin) and T3
(Triiodothyronine). The only source of T4 is the thyroid gland; however, T3 is
both released from the thyroid and produced by peripheral tissues through the
deiodination of T4. T4 can also be transformed by diodination into reverse T3,
a biologically inert compound. A complex series of positive and negative
feedback loops regulate the amount of thyroid hormone in circulation. Both T3
and T4 are protein bound in the blood with <0.1% of either hormone existing
in their free (non-protein bound) states. Thyroid hormones are biologically
active only in their free states.
TSH
Testing for TSH is performed via a chemiluminometric assay that is sensitive to
the level of 0.01 mIU/mL. Older generations of TSH testing were unreliable at
levels <0.1 mIU/L and could give spurious results in hyperthyroid patients,
however, this is a much less frequently encountered problem with the current
testing methodology.
The reference range for TSH is an area of controversy, and this is due in part to
the variability of TSH secretion. TSH secretion varies by individual, by time of
day (it’s highest in the evening), season of the year, and by age of the person tested.1 For
example, the NHANES III study tested normal thyroid function in different age groups. Using
a population of 20-29 year olds, the upper limit for the reference range in this population is
3.56 mIU/mL. That same upper limit in a population >80 years old is 7.49 mIU/mL.2
Therefore, building a reference range from a mixed population generates larger variation in
thyroid hormone levels (a larger standard deviation) than is the variation in any one
individual.1 This hormone variability is seen in all thyroid hormone measurement (TSH, total
T4, Free T4 and Free T3). The extension of this argument is that it is feasible that a 20 year
old who is mildly hypothyroid following an viral illness would not have TSH (or total or free T4
or T3 testing) outside of the reference range derived from a population that contained 20-80
year olds participants. The significance of subclinical hypothyroidism is currently debated. In
the previous scenario, the 20 year old is likely to either recover or progress to overt
hypothyroidism.
Total T4, Free T4 and Free T3
Total (serum) T4 and total T3 testing measure both protein bound and unbound hormone. A
person’s total T4 and T3 can rise or fall due to illness or drugs; however, this can occur
without a change in the Free (unbound and active) hormone levels. For this reason, many
clinicians prefer Free T4 or Free T3 testing to total T4/T3 testing when working up an
abnormal TSH value.
Free T4 is measured via a ‘Direct’ method. However, the word ‘direct’ is a slight misnomer
because (since the amount of Free T4 is miniscule in a vial of blood), propriety assumptions
and calculations are built into the testing formula. These calculations can break down in
pregnant patients and patients with renal failure, and, particularly in pregnant patients,
specific reference ranges should be used. 5
Free T3 is measured in similar manner and since it is present in even smaller amounts in the
blood, similar testing limitations exist.
Thyroid function in inpatient settings
Acute and chronic diseases also affect thyroid hormones and thyroid hormone testing. Testing
is not recommended on hospitalized patients unless there is a very strong suspicion for thyroid
dysfunction based on clinical symptoms.4 Low TSH, low total T4, low free T4, low Free T3, or
high reverse T3 (rT3) are common results in hospitalized patients and are not thought to
represent a patient’s current or future thyroid function.3,4 Treatment of critically ill patient with
low serum T3 and/or low T4 concentrations and no other clinical signs of hypothyroidism has
shown no effect on mortality or outcome, and treatment with thyroid hormone is not
recommended (Grade 2B). In previously euthyroid patients undergoing CABG, treatment with
thyroid hormone in the immediate post-operative period is not recommended (Grade 1A). If
clinical symptoms of thyroid dysfunction are present and testing is necessary, generally the full
thyroid panel is recommended (total T4, Free T4, and T3).
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Clinical use:
Recommendations for thyroid testing are as follows:
1. Outpatients with suspected hyperthyroidism or hypothyroidism due to thyroid
dysfunction
A. Order TSH with reflex T4 (8960/TSR)
A normal serum TSH requires no further work-up. If the TSH is abnormal, reflex
testing with the addition of free T4 testing is automatic.
2. Outpatients with pituitary or hypothalamic disease suspected (ie other endocrine
abnormalities are present additionally)
A. Order serum TSH (258/TSH) and free T4 (251/FT4)
3. Inpatient – testing is not recommended without highly suspicious clinical symptoms of
hypothyroidism
Levothyroxine therapy:
TSH takes 4-6 weeks to reach a steady state; however, it continues to be the recommended
testing method to assess treatment efficacy. Testing of serum Free T4 is not recommended as
doses of levothyroxine high enough to cause TSH suppression can still result in Free T4 values
within the normal range. (Remember from the discussion above that population based
reference ranges are generally wider than an individual’s personal reference range).
In summary, testing for thyroid dysfunction has limitations, however, in the correct clinical
context, testing can be ordered judiciously.
References:
1. Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum
T(4) and T(3) in normal subjects: ... J Clin Endocrinol Metab 2002; 87:1068–72.
2. Ross, DS et al. Laboratory Assessment of thyroid function. In: UpToDate, Cooper, DS
(Ed), UpToDate, Waltham, MA, 2013.
3. Ross, DS et al. Diagnosis and Screening of hypothyroidism. In: UpToDate, Cooper, DS
(Ed), UpToDate, Waltham, MA, 2013.
4. Ross, DS et al. Thyroid Function in Nonthyroid Illness. In: UpToDate, Cooper, DS (Ed),
UpToDate, Waltham, MA, 2013.
5. Stricker R et al. Evaluation of maternal thyroid function during pregnancy: the
importance of using gestational age-specific reference intervals. Eur J Endocrinol. 2007
Oct;157(4):509-14
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