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 PLOS ONE 2012; 7: e47770. Clin Biochem. 2013;46:133-8
• Presentation of thyroid cancer 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 not included.
MN-6 AM 6 AM - 7 PM 7 PM - MN0
102030405060708090
100
Patient N and Type by Time of Day
ED %OUTPT. %
%
803862
4754
190773
2169
7539
Circadian Variation
N TSH and FT4: 205,53 FT3: 58,993
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 230.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00Thyroid Tests vs Hour of Day
Hour Specimen Collected
TSH Mean (mIU/L)
TSH Median (mIU/L)
FT3 Mean (pg/mL)
FT4 Mean (ng/dL) FT4 Median (ng/dL)
Normalized Circadian Variation in TSH and FT3
Nocturnal TSH Surge by Gender, Age, Rx
Circannual Variation
N TSH and FT4: 164,094 FT3: 47,667
2010
06
2010
08
2010
10
2010
12
2011
02
2011
04
2011
06
2011
08
2011
10
2011
12
2012
02
2012
04
2012
06
2012
08
2012
10
2012
12
2013
02
2013
040.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
TSH FT4 FT3 by Month
FT3 Mean
TSH Median
TSH mean
FT4 Mean
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.