TITLE:
Free T3 or T4 Levels for Hypothyroidism: Clinical Effectiveness and Guidelines
DATE: April 21, 2015
RESEARCH QUESTIONS
1.
What is the clinical effectiveness of assessing free T4 or T3 levels to screen for
hypothyroidism?
2.
What is the clinical effectiveness of assessing free T4 or T3 levels to monitor and adjust
levothyroxine dose?
3.
What are the evidence-based guidelines regarding the assessment of free T4 or T3 levels
to screen for hypothyroidism?
KEY FINDINGS
Three non-randomized studies and nine evidence-based guidelines were identified regarding
the use of free T3 and T4 in the screening and treatment of hypothyroidism.
METHODS
A focused search (with main concepts appearing in title or major subject heading) was
conducted on key resources including PubMed, The Cochrane Library, University of York
Centre for Reviews and Dissemination (CRD) databases, Canadian and major international
health technology agencies, as well as a focused Internet search. No filters were applied to limit
the retrieval by study type. Where possible, retrieval was limited to the human population. The
search was also limited to English language documents published between January 1, 2010
and April 9, 2015. Internet links were provided, where available.
The summary of findings was prepared from the abstracts of the relevant information. Please
note that data contained in abstracts may not always be an accurate reflection of the data
contained within the full article.
Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in
Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to
provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time
allowed. Rapid responses should be considered along with other types of information and health care considerations. The
information included in this response is not intended to replace professional medical advice, nor should it be construed as a
recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality
evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for
which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation
of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect.
CADTH is not liable for any loss or damages resulting from use of the information in the report.
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SELECTION CRITERIA
One reviewer screened citations and selected studies based on the inclusion criteria presented
in Table 1.
Table 1: Selection Criteria
Population
Intervention
Comparator
Outcomes
Study Designs
Q1: Patients suspected of hypothyroidism
Q2: Patients with primary hypothyroidism
Free T4 or T3 levels
No free T4 or T3
Clinical effectiveness (benefits [reliable assessment of hypothyroidism or
usefulness to monitor levothyroxine dose]; harms)
Health technology assessments, systematic reviews, meta-analyses,
randomized controlled trials, non-randomized studies, evidence-based
guidelines
RESULTS
Rapid Response reports are organized so that the higher quality evidence is presented first.
Therefore, health technology assessment reports, systematic reviews, and meta-analyses are
presented first. These are followed by randomized controlled trials, non-randomized studies,
and evidence-based guidelines.
Three non-randomized studies and nine evidence-based guidelines were identified regarding
the use of free T3 and T4 in the screening and treatment of hypothyroidism. No relevant health
technology assessments, systematic reviews, or randomized controlled trials were identified.
Additional references of potential interest are provided in the appendix.
OVERALL SUMMARY OF FINDINGS
Three non-randomized studies1-3 and nine evidence-based guidelines4-12 were identified
regarding the use of free T3 and T4 in the screening and treatment of hypothyroidism.
One study1 evaluated the efficacy of FT4 screening in transient and thyroidal congenital
hypothyroidism with delayed TSH elevation and reported that screening with FT4 facilitated the
identification of these patient groups. A second study2 investigated the use of FT4 and TSH
steady-state concentrations (SSCs) as target values in guiding treatment decisions in congenital
hypothyroidism and reported that FT4 SSCs may be more valuable as individual target values
than TSH SSCs during clinical follow-up. A third study3 identified varying levels of free T3 and
free T4 concentrations, depending on the type of hypothyroidism.
A summary of the guidelines identified for this report are provided in Table 2.
Free T3 or T4 Levels for Hypothyroidism
2
Table 2: Summary of Guidelines and Recommendations
Author, Year
Recommendationsa
LeFevre (2015)
AHRQ (2014)
4
5
Leger et al. (2014)
6
Brenta et al. (2013)
Maciel et al. (2013)
7
8
Pearce et al. (2013)
Sgarbi et al. (2013)
Garber et al.
11
(2012)
Wiersinga et al.
12
(2012)
9
10
“The primary screening test for thyroid dysfunction is serum TSH testing. Multiple
tests over 3 to 6 mo should be performed to confirm or rule out abnormal findings.
Follow-up testing of serum thyroxine (T4) levels in persons with persistently
abnormal TSH levels can differentiate between subclinical (normal T4 level) and
“overt” (abnormal T4 level) thyroid dysfunction.” page 4
“Screening for congenital hypothyroidism is recommended. Two methods of
screening are used most frequently in the United States:
o Primary TSH with backup T4.
o Primary T4 with backup TSH.” Section on Congenital Hypothyroidism
 “The most sensitive test for detecting primary CH is TSH determination.”
Recommendation 1.2, page 81
 “If venous free T 4 (FT4) concentration is below norms for age, treatment
should be started immediately” Recommendation 2.3, page 81
“If the patient has clinical findings or a high probability of overt hypothyroidism, the
measurement of both TSH and free T4 are required. However, one must take into
account that clinical findings of hypothyroidism are very unspecific”. page 272
“Diagnostic confirmation is required dosing TSH and free T4 or total T4 in serum.”
Abstract
“In addition, measurement of serum FT4 is necessary to rule out overt
hypothyroidism.” Section on Investigation of raised serum TSH
Full text not available
“RECOMMENDATION 24: In patients with central hypothyroidism, assessments
of serum free T4 should guide therapy and targeted to exceed the midnormal
range value for the assay being used.” page 1015
“(13) It is recommended that L-T4 + L-T3 combination therapy should be
monitored by thyroid function tests in blood samples withdrawn before morning
medication has been taken, aiming at normal serum TSH, free T4, free T3 and
free T4/free T3 ratio.” pages 68-69
CH = congenital hypothyroidism; TSH = thyroid stimulating hormone.
a
Verbatim recommendations.
Free T3 or T4 Levels for Hypothyroidism
3
REFERENCES SUMMARIZED
Health Technology Assessments
No literature identified.
Systematic Reviews and Meta-analyses
No literature identified.
Randomized Controlled Trials
No literature identified.
Non-Randomized Studies
1.
Soneda A, Adachi M, Muroya K, Asakura Y, Yamagami Y, Hirahara F. Overall usefulness
of newborn screening for congenital hypothyroidism by using free thyroxine measurement.
Endocr J. 2014;61(10):1025-30.
PubMed: PM25088493
2.
Bongers-Schokking JJ, de Ridder MA, de Rijke YB, de Muinck Keizer-Schrama SM.
Experience in treating congenital hypothyroidism: implications regarding free thyroxine
and thyrotropin steady-state concentrations during optimal levothyroxine treatment.
Thyroid. 2013 Feb;23(2):160-5.
PubMed: PM23013069
3.
Sesmilo G, Simo O, Choque L, Casamitjana R, Puig-Domingo M, Halperin I. Serum free
triiodothyronine (T3) to free thyroxine (T4) ratio in treated central hypothyroidism
compared with primary hypothyroidism and euthyroidism. Endocrinol Nutr. 2011
Jan;58(1):9-15.
PubMed: PM21195684
Guidelines and Recommendations
4.
LeFevre ML. Screening for thyroid dysfunction: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med [Internet]. 2015 Mar 24 [cited 2015 Apr 20].
Available from :
http://www.uspreventiveservicestaskforce.org/Home/GetFile/1/1313/thyroiddysfinalrs/pdf
See: Screening tests, page 4
5.
U.S. Preventive Services Task Force. Guide to clinical preventive services, 2014
[Internet]. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2014 May
[cited 2015 Apr 20]. Section 3, Recommendations for children and adolescents. Available
from : http://www.ahrq.gov/professionals/clinicians-providers/guidelinesrecommendations/guide/section3.html#
See: Congenital Hypothyroidism
6.
Leger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, et al. European
Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and
management of congenital hypothyroidism. Horm Res Paediatr [Internet]. 2014 [cited
2015 Apr 20];81(2):80-103. Available from: http://www.karger.com/Article/FullText/358198
PubMed: PM24662106
See: Recommendations, page 81
Free T3 or T4 Levels for Hypothyroidism
4
7.
Brenta G, Vaisman M, Sgarbi JA, Bergoglio LM, Andrada NC, Bravo PP, et al. Clinical
practice guidelines for the management of hypothyroidism. Arq Bras Endocrinol Metabol
[Internet]. 2013 Jun [cited 2015 Apr 20];57(4):265-91. Available from:
http://www.lats.org/downloads/Hypothyroidism-en.pdf
PubMed: PM23828433
See Recommendation 2, page 272
8.
Maciel LM, Kimura ET, Nogueira CR, Mazeto GM, Magalhaes PK, Nascimento ML, et al.
Congenital hypothyroidism: recommendations of the Thyroid Department of the Brazilian
Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2013
Apr;57(3):184-92.
PubMed: PM23681264
9.
Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA
guideline: management of subclinical hypothyroidism. Eur Thyroid J [Internet]. 2013 Dec
[cited 2015 Apr 20];2(4):215-28. Available from:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923601
See: Investigation of raised serum TSH
10.
Sgarbi JA, Teixeira PF, Maciel LM, Mazeto GM, Vaisman M, Montenegro Junior RM, et al.
The Brazilian consensus for the clinical approach and treatment of subclinical
hypothyroidism in adults: recommendations of the thyroid Department of the Brazilian
Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2013
Apr;57(3):166-83.
PubMed: PM23681263
11.
Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical
practice guidelines for hypothyroidism in adults: cosponsored by the American Association
of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract [Internet].
2012 Nov [cited 2015 Apr 20];18(6):988-1028. Available from:
http://aace.metapress.com/content/611883025v735392/fulltext.pdf
PubMed: PM23246686
See: Recommendation 24, page 1015
12.
Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA guidelines:
the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J [Internet]. 2012
Jul [cited 2015 Apr 20];1(2):55-71. Available from:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821467
PubMed: PM24782999
See: Recommendation 13, pages 68-69
PREPARED BY:
Canadian Agency for Drugs and Technologies in Health
Tel: 1-866-898-8439
www.cadth.ca
Free T3 or T4 Levels for Hypothyroidism
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APPENDIX – FURTHER INFORMATION:
Clinical Practice Guidelines – Unclear Methodology
13.
Saskatchewan Disease Control Laboratory. Laboratory testing guidelines for the diagnosis
and monitoring of thyroid disease [Internet]. Regina: Government of Saskatchewan; 2014
Oct [cited 2015 Apr 20]. Available from: http://sdcltestviewer.ehealthsask.ca/SCI/Sample%20Collection%20and%20Packaging%20Informati
on/Laboratory%20Testing%20Guidelines%20for%20the%20Diagnosis%20and%20Monito
ring%20of%20Thyroid%20Disease.pdf
See: Recommended Testing Algorithm, page 2
14.
UK Newborn Screening Programme Centre; UK Newborn Screening Laboratories
Network; British Society for Paediatric Endocrinology and Diabetes. Congenital
hypothyroidism: initial clinical referral standards and guidelines [Internet]. [London]: UK
Newborn Screening Programme Centre; 2013 Jan [cited 2015 Apr 20]. Available from:
http://www.bsped.org.uk/clinical/docs/128977_Congenital_Booklet_A4_12pp-5LO.pdf
See: Clinical evaluation and confirmatory diagnostic tests, pages 4-5
15.
Best Practice Advocacy Centre New Zealand (bpacnz). Management of thyroid dysfunction
in adults. Best Practice Journal [Internet]. 2010 Dec [cited 2015 Apr 20];33:22-32.
Available from:
http://www.bpac.org.nz/BPJ/2010/December/docs/bpj_33_thyroid_pages_22-32.pdf
See: Diagnosis of Thyroid Function, page 23
16.
Guidelines and Protocols Advisory Committee. Thyroid function tests in the diagnosis and
monitoring of adults [Internet]. Victoria: British Columbia Ministry of Health Services; 2010
Jan [cited 2015 Apr 20]. Available from:
http://www2.gov.bc.ca/gov/DownloadAsset?assetId=581E65D32B7140E0A87E79002E94
BE1C&filename=thyroid.pdf
See: Algorithm for Thyroid Function Tests, page 3
Review Articles
17.
Vila L, Velasco I, Gonzalez S, Morales F, Sanchez E, Torrejon S, et al. Controversies in
endocrinology: on the need for universal thyroid screening in pregnant women. Eur J
Endocrinol. 2014 Jan;170(1):R17-R30.
PubMed: PM24128429
18.
Chang DL, Pearce EN. Screening for maternal thyroid dysfunction in pregnancy: a review
of the clinical evidence and current guidelines. J Thyroid Res [Internet]. 2013 [cited 2015
Apr 20];2013:851326. Available from:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671674
PubMed: PM23762776
19.
Vila L, Velasco I, Gonzalez S, Morales F, Sanchez E, Lailla JM, et al. Detection of thyroid
dysfunction in pregnant women: universal screening is justified. Endocrinol Nutr. 2012
Nov;59(9):547-60.
PubMed: PM23099114
Free T3 or T4 Levels for Hypothyroidism
6
20.
Gurevitz SL, Snyder JA, Peterson KL, Kelly KL. Hypothyroidism and subclinical
hypothyroidism in the older patient. Consult Pharm. 2011 Sep;26(9):657-64.
PubMed: PM21896472
21.
Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis [Internet].
2010 [cited 2015 Apr 20];5:17. Available from:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903524
PubMed: PM20537182
Free T3 or T4 Levels for Hypothyroidism
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