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.