Thyroid Hormone Circadian and Circannual
Variation in 475,000 Outpatients.
Joel Ehrenkranz MD
Dept of Medicine, Intermountain Healthcare, Salt Lake City, UT, United States
Phillip R. Bach Ph.D.
Dept. of Pathology, Intermountain Central Laboratory, Salt Lake City, UT, United States
Salvatore Benvenga M.D.
Dept. of Clinical and Experimental Medicine, The University of Messina, Messina, Italy.
DISCLOSURE: nothing to disclose.
Thyroid Chronobiology: Prior Observations
• Multiple studies have demonstrated a circadian variation in TSH and FT3.
JCEM 2008, 93(6):2300–2306
Clinical Chemistry 53, No. 2, 2007
• Small sample size
• Short study duration
• Many examples of seasonal variation in thyroid function and pathology:
•
•
•
•
•
Thyroid volume
Horm. Metabol. Res. 1987; 19: 391
Radioactive iodine uptake
JCEM. 1964; 24: 1084
TSH, total and free T3 and T4 levels Am. J. Human Biology. 2006;18: 99. Eur J Nutr. 2011 50:285
TSH response to TRH
Ann Clinical Biochemistry 1985; 22: 371
Seasonal alterations in T4 levels among Siberian miners
Int. J. Circumpolar Health 1997; 56: 134
• Neonatal TSH
• Presentation of thyroid cancer
PLOS ONE 2012; 7: e47770. Clin Biochem. 2013;46:133-8
British Journal of Cancer 1998 77, 1174.
We undertook a large scale retrospective analysis of temporal
variation in thyroid hormone levels measured in a controlled and
calibrated manner.
Methods and Materials
•
•
•
Data analysis extracted from
Intermountain Healthcare (Salt
LakeCity, Utah) Electronic Data
Warehouse.
• Data collected 6/2010-5/2013
Serum TSH, FT4, FT3 measured by
Abbott Architect immunoassay
• external controls performed
daily
Subjects
• 25% males, ages 0-103 years
• 75% females, ages 0-105 years
• Outpatients
• Outpatient clinics
• Emergency departments
• Same day surgery centers
• Specimen collection from
urban and rural clinics and
hospitals throughout Utah
and southern Idaho.
• Includes individuals on
any thyroid medication
• Neonatal TSH screening
%
Patient N and Type by Time of Day
100
190773
90
80
7539
70
60
803
862
ED %
50
40
2169
30
20
4754
10
0
MN-6 AM
6 AM - 7 PM
7 PM - MN
OUTPT. %
Circadian Variation
Thyroid Tests vs Hour of Day
8.00
TSH Mean (mIU/L)
7.00
6.00
5.00
FT3 Mean (pg/mL)
4.00
3.00
TSH Median (mIU/L)
2.00
1.00
0.00
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14
Hour Specimen Collected
FT4 Mean (ng/dL)
N
TSH and FT4: 205,53 FT3: 58,993
15
16
17
18
19
20
FT4 Median (ng/dL)
21
22
23
Normalized Circadian Variation in TSH and FT3
Nocturnal TSH Surge by Gender, Age, Rx
N
TSH and FT4: 164,094
FT3: 47,667
201305
201304
201303
201302
201301
201212
201211
201210
201209
201208
201207
201206
201205
201204
201203
201202
201201
201112
201111
201110
201109
201108
201107
201106
201105
201104
201103
201102
201101
201012
201011
201010
201009
201008
201007
201006
Circannual Variation
TSH FT4 FT3 by Month
5.00
4.50
4.00
3.50
3.00
FT3 Mean
2.50
TSH Median
2.00
TSH mean
1.50
FT4 Mean
1.00
0.50
0.00
Conclusions
• TSH
• rises significant at night and remains constant between 6 AM and 7 PM.
• nocturnal surge varies by age and gender and is present independent
of medication for thyroid disease.
• shows an inconsistent pattern of rising in November and December.
• FT3
• peaks following the 2-3 AM rise in TSH.
• remains constant throughout the year.
• FT4
• is constant throughout the 24 hour cycle.
• has no annual periodicity.
Clinical Implications
• Reference range for TSH needs to take into account time of day.
• Further studies are necessary to determine whether TSH has an annual
rhythm and if monthly reference ranges are needed.
• A single measure of TSH between 6 AM and 7 PM as an indicator of
TSH suppression may not be sufficient.