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Improved Diagnosis of Mild Hypothyroidism Using Time-of-Day

Normal Ranges for Thyrotropin


Susan R. Rose, MD
Objective To assess clinical utility of time-of-day-based thyrotropin (TSH) ranges.
Study design Ranges for TSH at 8 AM, 4 PM, and AM/PM TSH ratio were developed from prior data in 94 typical
children (age, 5 to 18 years). Data for these values in 227 short children (1.5 to 18 years) were compared with those
in typical children.
Results Short children included idiopathic short stature (ISS, n = 153), central hypothyroidism (Central, n = 42),
and mild primary hypothyroidism (Primary, n = 32), referred for evaluation of growth. In typical children, ISS, and
Primary, 8 AM TSH was greater than 4 PM TSH (P < .05). In Primary, 8 AM TSH was greater than normal. Only 4
with Primary had elevated 4 PM TSH (using usual laboratory range of 0.5 to 4 mU/L). In contrast, only 63% of 4
PM TSHs in Primary were elevated. compared with 95% confidence limits in typical children. In Central, 8 AM TSH
and 4 PM TSH were within normal time-of-day range, and FT4 was in lowest one-third of normal. AM/PM TSH ratio
was less than 95% confidence limits in 76% of those with Central.
Conclusions Either 8 AM TSH or 4 PM TSH (compared with time-of-day normal range) can identify TSH elevation.
Low AM/PM TSH ratio (FT4 in lowest one-third of normal) confirms central hypothyroidism. Thus, time-of-day TSH
ranges should be used for accurate diagnosis and more appropriate cost-effective treatment of mild hypothyroidism. (J Pediatr 2010;157:662-7).

o review what is known about physiologic thyrotropin (TSH) secretion, TSH varies in a circadian pattern (highest values
occurring between 10 PM and 4 AM; lowest values occurring between 10 AM and 6 PM).1-8 This circadian variation of TSH is
not seen in newborn infants but is present by about 6 months of age.9 Fine variations in TSH concentration are superimposed on an overall sine wave pattern yielding lowest TSHs in the afternoon with 50% to 200% higher TSHs at night.1,10,11
TSH remains relatively high until 9 AM, followed by nadir values.1
Reference data for TSH in commercial laboratory assays do not make note of time of day variation and do not provide normative ranges for first morning and for afternoon samples. The rationale for this has been stated as follows: The amplitude of
the diurnal TSH variability across a 24-hour period is approximately 2-fold.5,6 However, because this magnitude of change lies
within the normal TSH reference interval for the population as a whole ( 0.4 to 4.0 mU/L), it does not compromise the utility of
a single TSH value for diagnosing thyroid dysfunction. . TSH is typically measured during the day in the outpatient setting
when the magnitude of TSH variability is the least.12 As a result, in spite of the known physiologic circadian variation in TSH
concentrations, most laboratory assays provide a single normal range, not time-based, currently considered to be 0.4 to 4 mU/
L.13,14
NHANES15,16 has collected TSH data from persons age 12 to 90 years. Excluding those with thyroid disease or thyroid antibodies, TSHs were 0.4 to 4.1 mU/L in 2131 12- to 19-year-old adolescents and 0.4 to 3.6 mU/L in 5182 21- to 39-year-old
adults.17 These samples were drawn without regard to time of day. A recent metanalysis made no mention of time-of-day
as influencing reference range.18 Analysis of TSH concentrations from typical healthy adults with no thyroid antibodies, thyroid
enlargement or family history of thyroid disease suggests that values >3 mU/L are not often seen.12,15,19-21 Other studies suggest
that children over age 5 years have a similar range of TSH concentrations as adults.1,22
Evidence in adults supports the use of thyroid hormone replacement if TSH is >10 mU/L.23-25 Therapy also may be beneficial
for those adults with TSH between 4 and 10 mU/L, although this is more controversial.24,25 Mild TSH elevation may result from
recovery phase from illness, medication, or laboratory artifact.25,26
In the pediatric age group, in contrast to adults, unrecognized mild hypothyroidism can have clinically important effects
including mental retardation26), slowed growth rate, and delayed puberty.24,28,29
We hypothesized that a significant number of children with mild primary hypothyroidism or central hypothyroidism are
misclassified as having have idiopathic short stature (ISS) when there is no attention paid to time-of-day TSH variability. Iden-

Central
ISS
Primary
TSH

Central hypothyroidism
Idiopathic short stature
Primary hypothyroidism
Thyrotropin

From the Cincinnati Childrens Hospital Medical Center


and University of Cincinnati, Cincinnati, OH
The author declares no conflicts of interest.
0022-3476/$ - see front matter. Copyright 2010 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2010.04.047

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tification of small variations from normal in TSH concentrations might have clinical utility, improve choice of appropriate therapy, and reduce the cost of treatment, particularly in
children. We studied the potential clinical utility of time-ofday-based normal ranges for TSH in children.

Methods
Normal ranges for TSH at 8 AM and at 4 PM were developed
from previously obtained data for TSH concentration in
samples obtained for 24 hours in 94 typical children (42 girls,
ages 5 to 18 years, 11.4  2.6 years). These children were recruited as typical volunteers (height and weight in the normal
range, no medical abnormalities). The original evaluations
were performed in an IRB-approved investigation at the
National Institutes of Health, with informed consent obtained from the parent and assent obtained from each child.
Circadian variation of TSH in these typical children and
adolescents was previously published.1 On the basis of these
studies, the TSH surge test was established as a standard clinical endocrine test.1,35
TSH results were available from a previously performed
TSH surge study in each child.1,30-32 Results in children
with short stature were compared with results in typical children. Short patients had been referred to endocrine clinic for
evaluation. Children with a non-endocrine cause of short
stature, or isolated growth hormone deficiency, were excluded. Short children had been evaluated with the TSH
surge if their height was below the 3rd percentile with growth
rate at or below the 25th percentile for age and sex.30-32 For
the current project, data from the remaining 227 short children (97 girls, ages 11.1  2.4 years, 1.5 to 18 years) were
analyzed from their prior clinical testing, including TSH at
8 AM (7 to 8:59 AM), TSH at 4 PM (3 to 4:59 PM), and AM/PM
TSH ratio.
Children with small stature were assigned to groups based
on their height, growth velocity, their 8 AM TSH concentration, and their prior TSH surge result. Growth rate was considered normal if above -1.0 SD for age and sex. Children
were considered to have ISS if height was below 5th percentile
but growth rate was normal (-0.7  0.3 SD, mean  SD) and
they had no endocrine abnormalities. Children were considered to have central hypothyroidism (Central) if FT4 was in
the lowest one-third of the normal range with blunted nocturnal TSH surge and slow growth rate (-1.6  0.5 SD).
Children were considered to have primary hypothyroidism
(Primary) if AM TSH was equal to or above 5 mU/L with normal TSH surge and slow growth rate for age (-1.5  0.6 SD).
Children with central hypothyroidism were also evaluated
for adequacy of other hormones including growth hormone.
Growth hormone stimulation tests were performed after adequate replacement with thyroid hormone, so children with
central hypothyroidism were euthyroid at the time of growth
hormone testing.
Samples for TSH assay had been assessed using ultrasensitive TSH assays: the Serono TSH Maiaclone IRMA kit (Se-

rono Diagnostics, Norwell, Massachusetts) (assay normal


range, 0.5 to 4.6 mU/L) and the Abbott Axsym (Abbott Laboratories, Abbott Park, Illinois) (on an immunofluorescence
instrument) (assay normal range, 0.32 to 5.0 mU/L). A similar proportion of each assay was used in each patient grouping, so that small differences in assays did not influence group
mean results.
Analysis
For prior assessment of TSH surge, TSH concentrations were
assessed for nadir (lowest mean of three sequential TSH
values before 8 PM), peak (highest mean of 3 sequential
TSH values after 10 PM), and TSH surge [(peak - nadir) 
nadir] expressed as percent rise over nadir. The normal range
for the TSH surge is 50% to 300%. Thus, nocturnal TSH below 50% was considered to be blunted and consistent with
central hypothyroidism.
For the current analysis, from each childs individual series of TSH values, the TSH result at 8 AM and the TSH result
at 4 PM were recorded, along with clinical data (age, sex, FT4
concentration, and clinical diagnosis). For each child, ratio
of 8 AM TSH to 4 PM TSH was calculated. Results within
each diagnostic group (typical children, ISS, Central, and
Primary) are represented as mean, SD, and SEM. In typical
children, 95% confidence limits (95% CL) were developed
for TSHs at 8 AM and 4 PM, AM/PM TSH ratio, and FT4.
Growth velocity data are expressed in Z scores (SD from
the mean for age).
Within each diagnostic group, paired t tests were performed to compare TSHs at 8 AM and 4 PM. Grouped data
for 8 AM TSH, for 4 PM TSH, and for AM/PM TSH ratios
were assessed by ANOVA among the 4 diagnostic groups.

Results
In typical children, 8 AM TSH was significantly higher than 4
PM TSH (P < .05) (Table I; available at www.jpeds.com).
Ninety-five percent confidence limits for 8 AM TSH were
1.3 to 4.5 mU/L (Figure 1), and for 4 PM TSH were 0.7 to
2.9 mU/L (Figure 2). Within individuals, TSH at 8 AM was
significantly higher than TSH at 4 PM (P < .05) (Figure 3).
AM/PM ratio of serum TSH values was 1.9  0.5 (95% CL,
1.3 to 3) (Figure 4).
Of the 227 short children, 32.6% were found to have hypothyroidism using time-of-day normal ranges for TSH. The
hypothyroidism had not been previously identified. Hypothyroid patients included 32 (14.1% of the short group of
227 children) with mild primary hypothyroidism and 42
(18.5%) with central hypothyroidism. Of children with central hypothyroidism, 20 had this as an isolated hormone deficiency, and 22 also had growth hormone deficiency.
In the 153 short children found to have no diagnosable
hormone abnormality (ISS) (63 girls, ages 2 to 18 years),
TSH at 8 AM, TSH at 4 PM, and AM/PM TSH ratio were not significantly different from those in typical children (Table I
and Figures 1-4). Within individuals, 8 AM TSH was
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Figure 1. TSH at 8 AM in children with idiopathic short stature


(ISS), central hypothyroidism (Central), and primary hypothyroidism (Primary) compared with values in typical children.
Solid line signifies upper limits of normal TSH for time of day in
typical children.

significantly higher than 4 PM TSH (P < .05) (Figure 3). AM/


PM TSH ratio was within 95% CL for typical children
(Figure 4).
In 42 children (22 girls, ages 1.5 to 18 years) confirmed
clinically to have central hypothyroidism, TSHs at both 8
AM and 4 PM were within time-of-day normal ranges (Table
I, Figures 1 and 2), but AM/PM TSH ratio was low in 76%
(Figure 4). Of note, within individuals with central
hypothyroidism, 8 AM TSH and 4 PM TSH were not
significantly different in contrast to findings in typical
subjects and those with ISS (Figure 3). Short-term (6
months) therapy with thyroid hormone in a subset of these
children with central hypothyroidism was described
previously.30 Growth velocity increased from -1.6  0.5 SD
(mean  SD) before thyroid hormone therapy, to +1.5 
0.6 SD during therapy, returning to baseline during the
6 months after thyroid hormone therapy.30 Formally
analyzed long-term growth response to thyroid hormone
therapy is not available.
In 32 children (12 girls, ages 3 to 18 years) confirmed to
have mild primary hypothyroidism, 8 AM TSHs were elevated
above normal (Table I, Figure 1). However, based on their
TSH results at 4 PM, only 4 would have been considered
elevated compared with the usual laboratory normal range
of 0.5 to 4 mU/L (Figure 2). In contrast, when compared
with 95% CL for 4 PM TSH, 63% would be identified as
elevated (Figure 2). Within individuals, 8 AM TSH was
significantly higher than 4 PM TSH (P < .05) (Figure 3).
AM/PM TSH ratio was within 95% CL for typical children
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Figure 2. TSH at 4 PM in children with idiopathic short stature


(ISS), central hypothyroidism (Central), and primary hypothyroidism (Primary) compared with values in typical children.
Solid line signifies upper limits of normal TSH for time of day in
typical children. Dashed line signifies upper limit of normal
TSH in commercial assay.

(Figure 4). Growth response to thyroid hormone therapy


was not formally analyzed in the primary hypothyroidism
group.

Discussion
In this analysis, 32.6% of short children had a mild hypothyroidism that would have been missed without attention to
time of day normal range data. TSH values at 8 AM in typical
children and typical short children were within the usual
commercial laboratory normal range. However, 8 AM TSH
was significantly higher than 4 PM TSH within individuals,
and upper 95% CL for 8 AM TSH in typical children (4.5
mU/L) was higher than that for 4 PM TSH (2.9 mU/L). In
short stature children who had no endocrinopathy, 8 AM
TSH, 4 PM TSH, and AM/PM TSH ratios were similar to findings in typical children.
In some patients with primary hypothyroidism (elevated 8
AM TSH), TSH at 4 PM would have missed the diagnosis. Persons with mild primary hypothyroidism (8 AM TSH 5 to 12
mU/L) may have TSH as low as 1.5 mU/L in the afternoon.
In contrast, the diagnosis of central hypothyroidism would
have been missed with either 8 AM TSH or 4 PM TSH, and
the FT4 may be clearly low or in the lowest third of the normal range.29 As a characteristic of central hypothyroidism,
the diurnal variation in TSH is often lost or blunted, so
morning and afternoon TSH may be similar. The ratio of
AM to PM TSH was below 1.3, suggestive of central
Rose

ORIGINAL ARTICLES

October 2010

Figure 4. AM/PM TSH ratio in children with idiopathic short


stature (ISS), central hypothyroidism (Central), and primary
hypothyroidism (Primary) compared with values in typical
children. Solid line signifies upper limits of normal AM/PM TSH
ratio in typical children.

Figure 3. TSH at 8 AM compared with 4 PM TSH in children


with idiopathic short stature (ISS), central hypothyroidism
(Central), and primary hypothyroidism (Primary) compared
with values in typical children.

hypothyroidism, in 76% of those with the diagnosis. Thus,


ratio of 8 AM TSH to 4 PM TSH may provide a practical screening test for central hypothyroidism in patients with FT4 in
the lowest one-third of the normal range. FT4 in mild primary or central hypothyroidism is often in the lowest onethird of the normal range, rather than being clearly below
lower limits of normal.31
In literature and practice, little attention has been paid to
time of day for obtaining the TSH sample for assay. Publications from NACB recognize that Serum TSH levels exhibit
a diurnal variation with the peak occurring during the night
and the nadir, which approximates to 50% of the peak value,
occurring between 10 AM and 4 PM.3,5,33,34 However, they
state that this biologic variation does not influence the diagnostic interpretation of the test result because most clinical
TSH measurements are performed on ambulatory patients
between 8 AM and 6 PM and TSH reference intervals are
more commonly established from specimens collected during this time period.33,34
In contrast, the current analysis shows that time-of-day
normal ranges for TSH are useful for diagnosis of mild alterations in thyroid function that have clinical importance, particularly in the pediatric age range. Clinical examples are

provided that illustrate this utility (Table II; available at


www.jpeds.com). Clinical samples drawn for TSH, either at
8 AM or 4 PM, can be used to identify TSH elevation compared
with time-of-day normal range. Repeat TSH at 7 to 8 AM may
be helpful. There may or may not be thyroid gland enlargement on physical examination.
Low AM/PM TSH ratio confirms central hypothyroidism
when FT4 is in the lowest third of the normal range. When
there remains suspicion of central hypothyroidism in persons
with a normal AM/PM TSH ratio, these patients should
undergo a formal TSH surge test for confirmation of the
diagnosis.35 Of note, in central hypothyroidism, TSH concentration will be suppressed during low dose thyroid
hormone therapy (70% to 80% of expected replacement
dose). Thus, a suppressed or relatively low 8 AM TSH value
after taking low dose thyroid hormone therapy for one
month serves to confirm central hypothyroidism.36
Isolated central hypothyroidism has been thought to be
rare. However, we have previously demonstrated central hypothyroidism in about 17% of children with heights below -2
SD not found to have other hormone deficiencies or other
etiology.31 Of course, central hypothyroidism is more commonly observed in association with other pituitary hormone
deficiencies, such as that of growth hormone. Isolated TSH
deficiency could occur as a result of hypothalamic pituitary
disruption related to genetic mutation of TSH-b, congenital
pattern of TRH deficiency, abnormal glycosylation of a-subunit or TSH-b subunit, birth injury, infection, hypophysitis,
head injury, cranial irradiation or other acquired cause.37-39

Improved Diagnosis of Mild Hypothyroidism Using Time-of-Day Normal Ranges for Thyrotropin

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Long-term follow-up of this cohort of children with central


hypothyroidism will be important, particularly in those in
whom the deficiency appears to be isolated. This long-term
follow-up will include assessment of growth response to
long-term therapy and re-assessment of the thyroid axis in
those in whom thyroid hormone therapy has been discontinued.
The purpose of this analysis was to encourage practitioners
to think about time of day when they interpret TSH results,
similar to the thinking that is done when interpreting cortisol
results. Improved diagnosis of mild thyroid disorders has
clinical importance in the pediatric age group because mild
hypothyroidism can lead to slowed growth rate or delayed
puberty. Ignoring the observation of time of day changes in
TSH can lead to missed diagnosis of mild primary hypothyroidism or central hypothyroidism and subsequent inappropriate treatment with growth hormone for presumed ISS.
The current analysis shows that use of time-of-day normal
ranges for TSH provide improved diagnostic sensitivity.
Mild hypothyroidism should be addressed and treated before resorting to more expensive therapy using growth hormone injections. In mild hypothyroidism, either primary
or central, re-evaluation of thyroid function is indicated at
one month off therapy in a few years or at adult height.40,41
Thyroid hormone therapy (which is oral and inexpensive)
for confirmed mild hypothyroidism in short children may
obviate the need for more costly therapies. n
I appreciate the contributions by Larry Dolan (receives funding from
the CDC and NIH for work in type 1 and type 2 diabetes and obesity),
Douglas Rose, James Kerrigan, Diamond Austin, and the endocrine
nurses who cared for the children and their families.
Submitted for publication Dec 11, 2009; last revision received Mar 22, 2010;
accepted Apr 26, 2010.
Reprint requests: Dr Susan R. Rose, 3333 Burnet Avenue, MLC 7012,
Cincinnati, OH 45242. E-mail: Susan.Rose@cchmc.org.

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Table I. TSH by time of day, AM/PM TSH ratios, and FT4 in children with idiopathic short stature, primary
hypothyroidism, and central hypothyroidism compared with typical children
Diagnosis

n (girls)

Age (y)

TSH 8 AM (mU/L)

TSH 4 PM (mU/L)

Typical
94 (40) 11.4  2.6 (5-18) 2.7  0.9 (1.3-4.5, 0.01)
Idiopathic short stature 153 (63) 11.4  3.2 (1.9 - 19) 2.6  0.9 (1.3-4.4, 0.01)
Central hypothyroidism 42 (22) 10.0  3.5 (1.5-21) 2.3  2.3 (0.1-8, 0.06)
Primary hypothyroidism 32 (12) 11.6  3.5 (3.4-25) 7.2  4* (5.0-12.0, 0.1)

AM/PM

TSH ratio

FT4 (ng/dL)

1.5  0.7 (0.7-2.9, 0.01) 1.9  0.5 (1.3-3.0, 0.01) 1.4  0.2 (1-1.8)
1.3  0.6 (0.5-2.8, 0.01) 2.1  0.7 (1.2-4, 0.01) 1.4  0.2 (0.9-2.2)
2.0  1.8 (0.1-6.8, 0.04) 1.1  0.3* (0.9-1.5, 0.01) 1.0  0.2* (0.5-1.2)
3.6  2.6* (1.5-7, 0.08) 2.1  0.8 (1.6-2.8, 0.02) 1.1  0.2 (0.9-1.5)

Mean  SD (range, or 95% CL in typical children, SEM).


*P < .05 compared with normal
P < .05 compared with TSH at 8 AM.

Table II. Examples of the utility of time of day normal ranges in 5 prepubertal 10-year-old girls provided as examples
Example

Height, growth rate

-2 SD
4 cm/y
-2 SD
4 cm/y

B
C
D
E

-2 SD
5.2 cm/y
+1 SD
5.2 cm/y
+1 SD
7.0 cm/y

8 AM TSH
(0.5-4 m U/L)

4 PM TSH
(0.5-3 m U/L)

FT4
(1-2.4 ng/dL)

Follow-up test

Conclusion

NA

3.5

1.1

8 AM TSH 7.0

Primary hypothyroidism

1.4

NA

1.1

Central hypothyroidism

NA

1.2

1.1

NA

0.3

2.3

4 PM TSH 1.2
AM/PM TSH ratio 1.17
TSH surge 42% (50%-300%)
8 AM TSH 1.6
TSH ratio 1.33
8 AM TSH 1.0

NA

<0.1

2.3

8 AM TSH <0.1

Normal
Normal
Hyperthyroidism

NA, not available.

667.e1

Rose