The TSH Reference Range Wars, Part One by Jeffrey Dach MD

Click Here for Part Two

Click here for Part Three

I find it curious that  modern medicine continues to argue within itself on the proper reference range for the TSH test (Thyroid Stimulating Hormone) commonly used to assess thyroid function.  .This TSH test and reference range is the subject of continuous debate and even changing ranges throughout the history of medicine.

Above left image:  TSH Wars with Tank  convoy of Soviet T-72 battle tanks.  commons.wikimedia.org/wiki/File:Soviet_T-72_main_battle_tanks.JPEG

The New Reference Range for the TSH – The 2.5 cutoff

Here is a little history of the TSH reference range wars.  In 2002-2003, three professional organizations revised the TSH references range lower from the old 4.5 down to 2.5 or 3.0.  (10)  On the basis of this new range, a larger percentage of the population will be given a diagnosis of a low thyroid condition.

2002 – American Association of Clinical Endocrinologists narrowed the serum TSH reference range to 0.3-3.0 mIU/L, lowering the upper reference end to 3.0.
(Baskin et al. Endocrine Practice 8:457, 2002)

2003– The National Academy of Clinical Biochemistry, Recommends a TSH upper limit of 2.5 mIU/L. (Baloch et al. Thyroid 13:42, 2003 & www nacb.org)

2003 – the consensus panel (Endocrine Society, American Association of Clinical Endocrinologists, and American Thyroid Association) recommended a target TSH range of 1.0 to 1.5 mIU per liter in patients already receiving thyroxine therapy. (12)

In 2007, The endocrine Society issued new guidelines for pregnancy and preconception:

2007 – Endocrine Society Pregnancy Guidelines:
Preconception & 1st trimester – keep TSH below 2.5 mIU/L
2nd and 3rd trimesters – keep TSH below 3.0 mIU/L
(Abalovich et al. JCEM 92: S1-S47, 2007)

After all the above, it was a surprise to see a laboratory that had been using the lower TSH range (0.3 to 2.5) for many years, and then in 2010, switched back to the old range of  0.3 to 5.0. (2)  Many other labs, such as one in Ontario ignores the lower recommendations and continues using the older upper range for TSH of 4.5 (3)

Labs Using Differing Ranges

Another eye opener: When 30 labs were surveyed,  They found that 30% used the manufacturer recommended ranges, 10% used their own and 60 % used an “adapted” range.  Most of the 30 labs used differing reference ranges with the upper range varying from 3.8 to 6.0.  There was no single reference range in use.(10)  In addition, of 9 different manufacturers of TSH test kits used by the labs, they all had differing reference ranges.

Above Image: 40mm guns firing aboard the U.S. aircraft carrier USS Hornet (CV-12) on 16 February 1945, as the planes of Task Force 58 were raiding Tokyo. Note expended shells and ready-service ammunition at right.  16 February 1945. Courtesy Wikimedia commons. http://commons.wikimedia.org/wiki/File:40mm_guns_firing_aboard_USS_Hornet.jpg

TSH Reference Ranges Differ For 9 Different Manufacturers Assays (10)

TSH Kit                TSH Range

Roche Elecsys      0.27- 4.0

Immulite 2000     0.40- 4.0

Tosoh A1A           0.34- 3.8

Bayer Centaur      0.35- 5.5

Beckman Access   0.35- 3.5

Abbott AxSym      0.49- 4.7

Abbott Architect   0.35- 4.9

Ortho Eci             0.30- 3.1

 

Mary Shomon Reviews the TSH Wars

An excellent article by Mary Shomon summarizes the debate over what should be accepted as the TSH reference range. (6)  She cites Wartofsky as an advocate for the 2.5 cut off.  Wartofsky and Dickey say (7) :

“We will probably never have an absolutely cutoff value for TSH distinguishing normal from abnormal, but recognition that the mean of normal TSH values is only between 1.18 and 1.4 mU/liter and that more than 95% of the normal population will have a TSH level less than 2.5 mU/liter clearly imply that anyone with a higher value should be carefully assessed for early thyroid failure.”

Above left image: Vickers machine-guns 20 September 1944.  http://commons.wikimedia.org/wiki/File:Vickers_machine-guns_fire_in_support_of_troops_crossing_the_Maas-Schelde_Canal.jpg

Carole Spencer MD PHD –
How should the TSH reference range be determined?

Perhaps the most respected expert on the TSH test and reference range is Carole Spencer MD PhD, Professor of Research at the Keck School of Medicine at the University of Southern California. (9-10) Carole Spencer says:

“It is impossible to establish a range using population data.  The TSH upper reference limit is really a moving target. It depends upon the population being studied, the underlying pathology and iodine intake of that population, as well as the specificity of the assay for detecting the various TSH isoforms present in sera.”

She also says:

“It is not possible to establish a universal TSH upper limit from population data. An appropriate compromise would be to adopt an empiric TSH reference range approximating 0.3 to 3 mIU/L, as suggested by AACE. It is important to recognize that the upper TSH reference limit is not the therapeutic threshold for initiating levothyroxine replacement therapy. “

Treating Patients with Labs Within Normal Range  ??

The International Hormone Society has written extensively on this issue of Hypothyroidism with Labs in Reference Range, with a Consensus Panel Statement and listing of medical references supporting treatment in these cases (11)

In Addition, the American Academy of Anti-Aging Medicine issued a 2007 “White Paper Guidance” on interpretation of lab tests such as the TSH (12)

They state:

“The use of “natural” thyroid in patients whose TSH levels for example are not yet over 5.5 has stimulated controversial cases where the treating physician has been dragged into court to explain why a thyroid supplement was administered to a patient who is not yet sick? Several, often recent, studies have now been published that show that levels of TSH within the reference range, between 2 and 5.5, in certain categories of patients have been reported to be associated with pathological abnormalities and even diseases. It is therefore to no surprise that the American Association of Clinical Endocrinologists has therefore narrowed in 2002 the serum TSH reference range to 0.3-3.0 mIU/L, lowering the upper reference end to 3. The National Academy of Clinical Biochemistry, the world’s most respectful organisation for editing guidelines on laboratory test interpretation, reduced the upper end of the reference range from 5.5 to 4.1 mIU per liter in 2003. The latter group also stated that “more than 95% of healthy, euthyroid subjects have a serum TSH between 0.4 – 2.5 mIU per liter” and that “patients with a serum TSH above 2.5 mIU per liter, when confirmed by repeat TSH measurement made after three to four weeks, may be in the early stages of thyroid failure, especially if thyroid peroxidase antibodies are detected.” In 2003, the consensus panel (Endocrine Society, American Association of Clinical Endocrinologists, and American Thyroid Association) recommended a target TSH range of 1.0 to 1.5 mIU per liter in patients already receiving thyroxine therapy. “ (12)

Questioning TSH for Monitoring Thyroxine Treatment

To make matters worse, studies have shown TSH to be a poor indicator of thyroid status during thyroxine treatment.(13)  A 2005 study from Greece by Alevizaki concluded:

“Patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver. “(13)

They go on to say:

“TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect, provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels.” (13)

Others have questioned the value of T4 monotherapy because some individuals are poor converters and are unable to convert the T4 to T3. (14)

TSH Shifts Up With Age

One problem is that TSH ranges tend to shift up with age. (4)  Older individuals run higher TSH values and this may be “normal” based on gaussian distribution of lab values for the population.

TSH May Be Misleading In Certain Circumstances

In addition, there are clinical situations in which TSH levels may be misleading such as: (5)

1) abnormalities in hypothalamic or pituitary function, including TSH-producing pituitary tumors.

2)  transition periods such as early phase of treatment for hypothyroidism.  Specifically, it takes 6-12 weeks for pituitary TSH secretion to re-equilibrate to the new thyroid hormone status.

3) Following an episode of thyroiditis, including post-partum thyroiditis when discordant TSH and FT4 values may also be encountered.

4) Certain drugs that influence pituitary TSH secretion (i.e. dopamine and glucocorticoids) or thyroid hormone binding to plasma proteins, may also cause discordant TSH values

Articles With Related Content:

TSH Basics

The Unreliable TSH Test

TSH WARS Part Two

Jeffrey Dach MD

Links and References

(1) www.ncbi.nlm.nih.gov/pubmed/12625976?dopt=Abstract
Thyroid. 2003 Jan;13(1):3-126.
Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruf J, Smyth PP, Spencer CA, Stockigt JR; Guidelines Committee, National Academy of Clinical Biochemistry. Source Department of Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, USA.

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changing the reference range back up from 2.5 to 5.0

(2) www.allina.com/ahs/allinalabs.nsf/page/TSHRange10.pdf/$FILE/TSHRange10.pdf

Effective May 4, 2010, there is a new TSH reference range for adults:
Current Reference Range: 0.34 – 2.50 μU/mL
New Reference Range: 0.30 – 5.00 μU/mL

Why was the upper limit for TSH set at 2.5 μU/mL in the first place?
A national guideline published in 2003 recommended lowering the upper limit of TSH to 2.5 μU/mL (NACB in Thyroid. 2003 Jan;13(1):3-126). Based on a population study, this was felt to be the true upper limit for euthyroid individuals after rigorous exclusion of all patients with possible thyroid dysfunction.

Why is the laboratory now raising the upper limit of normal for TSH to 5.0 μU/mL?

More recent studies indicate that an upper limit of 2.5 μU/mL for TSH is too low. Kratzsch et al (Clin Chem. 2005 Aug;51(8):1480-6) showed that after rigorously excluding all patients with possible thyroid dysfunction, a normal range for TSH was 0.12-5.29 μU/mL. Massachusetts General Hospital uses a range of 0.5-4.7 μU/mL (New England Journal of Medicine 2004;351:1548-63) and Mayo Clinic uses a range of 0.3-5.0 μU/mL. Parallel tests of patient specimens at Allina and Mayo Clinic show the same TSH results and a recent reference range validation performed at AML indicates that the normal range for our population is consistent with the one used at Mayo Clinic.

(3) www.oaml.com/PDF/FINALTSH%20Guideline%20July%2018,%2007.pdf

Ontario Clinical Lab July 2007 Guidelines

5. TSH Reference Intervals In the literature, discussion is ongoing as to the appropriate TSH reference range; some laboratories report a lower value for the upper limit of normal (between 2.5‐3.0 mU/L). Ontario community laboratories have elected to continue to report the higher upper limit of normal (4.5 to 5.5 mU/L). The OAML Quality Assurance Committee and its Expert Panel on thyroid disease will update the reference range when there is evidence‐based literature supporting such a change.

Lowering the TSH Range to 2.5

TSH shifts up with age

(4) jcem.endojournals.org/content/92/12/4575.long

Age-Specific Distribution of Serum Thyrotropin and Antithyroid Antibodies in the U.S. Population: Implications for the Prevalence of Subclinical Hypothyroidism
Martin I. Surks and    Joseph G. Hollowell  The Journal of Clinical Endocrinology & Metabolism December 1, 2007 vol. 92 no. 12 4575-4582

Recently a discussion has begun concerning lowering the upper limit of the TSH reference range to 2.5 mIU/liter

Results: Without thyroid disease, 10.6% of 20- to 29-yr-olds had TSH greater than 2.5 mIU/liter, increasing to 40% in the 80+ group, 14.5% of whom had TSH greater than 4.5 mIU/liter. When TSH was greater than 4.5 mIU/liter, the percentage with antibodies was 67.4% (age 40–49 yr) and progressively decreased to 40.5% in the 80+ group. TSH frequency distribution curves of the 80+ group with or without antibodies was displaced to higher TSH, including TSH at peak frequency. The 97.5 centiles for the 20–29 and 80+ groups were 3.56 and 7.49 mIU/liter, respectively. Seventy percent of older patients with TSH greater than 4.5 mIU/liter were within their age-specific reference range.

Conclusion: TSH distribution progressively shifts toward higher concentrations with age. The prevalence of SCH may be significantly overestimated unless an age-specific range for TSH is used.

———————–
(5)
www.aacc.org/sitecollectiondocuments/nacb/lmpg/thyroid/thyroid-fullversion.pdf
LABORATORY MEDICINE PRACTICE GUIDELINES.

Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease.

It is important to recognize the clinical situations where serum TSH or FT4 levels may be diagnostically misleading (see Table 1).
These include abnormalities in hypothalamic or pituitary function, including TSH-producing pituitary tumors (27-29).

Also, as shown in Figure 2, serum TSH values are diagnostically misleading during transition periods of unstable thyroid status, such as occurs in the early phase of treating hyper- or hypothyroidism or changing the dose of L-T4.

Specifically, it takes 6-12 weeks for pituitary TSH secretion to re-equilibrate to the new thyroid hormone status (30). These periods of unstable thyroid status may also occur following an episode of thyroiditis, including post-partum thyroiditis when discordant TSH and FT4 values may also be encountered. Drugs that influence pituitary TSH secretion (i.e. dopamine and glucocorticoids) or thyroid hormone binding to plasma proteins, may also cause discordant TSH values [Section-3 B3(c)vi].

—————————————————————-
(6) thyroid.about.com/od/gettestedanddiagnosed/a/tshtestwars.htm

The TSH Reference Range Wars: What’s “Normal?”, Who is Wrong, Who is Right… And What Does It All Mean For You and Your Health? By Mary Shomon,
About.com Guide Updated June 19, 2006 3.

If your TSH test levels come in below 0.5, or above 2.5-3.0, and your doctor is saying these levels are normal, make him or her aware of the AACE and American Association for Clinical Chemistry Laboratory Medicine Practice Guidelines and their 0.3 to 3.0 new reference range. Ask the doctor if he or she will consider a different diagnosis and treatment based on this new information.

—————————-
(7) jcem.endojournals.org/content/90/9/5483.long
jcem.endojournals.org/content/90/9/5483/F1.expansion.html
The Evidence for a Narrower Thyrotropin Reference Range Is Compelling

The Evidence for a Narrower Thyrotropin Reference Range Is Compelling Leonard Wartofsky and Richard A Dickey Endocrinology & Metabolism September 1, 2005 vol. 90 no. 9 5483-5488 Drs.

Wartofsky and Dickey defend the shift to the new range, with some caveats. They say:

“We will probably never have an absolutely cutoff value for TSH distinguishing normal from abnormal, but recognition that the mean of normal TSH values is only between 1.18 and 1.4 mU/liter and that more than 95% of the normal population will have a TSH level less than 2.5 mU/liter clearly imply that anyone with a higher value should be carefully assessed for early thyroid failure.”

————————————-
(8) fpn.imng.com/fileadmin/content_pdf/fpn/archive_pdf/vol37iss20/71244_main.pdf
Upper Limit of TSH Reference Range Debated. BY SHERRY BOSCHERT. San Francisco Bureau. Providers looking for a defined upper limit of the statistically Family Practice News

———————————-
Carole Spencer MD PHD

(9) www.endocrinetoday.com/view.aspx?rid=28719
on June 10, 2008

How should the TSH reference range be determined?

It is impossible to establish a range using population data.  The TSH upper reference limit is really a moving target. It depends upon the population being studied, the underlying pathology and iodine intake of that population, as well as the specificity of the assay for detecting the various TSH isoforms present in sera. Its essential to ensure that individuals with any degree of thyroid dysfunction are excluded from reference range calculations. However, there are some individuals that are TPOAb-negative and yet have thyroid dysfunction. The inclusion of such individuals has the potential to skew the TSH reference limits to some extent. Carole Spencer, MD, PhD Carole Spencer Surks and Hollowell reported that the TSH reference range increased with age and concluded that perhaps a higher TSH is a natural consequence of aging. We interpret this finding differently. It is well known that in the United States the prevalence of autoimmune thyroid disease increases with age and not all affected individuals display TPOAb. In the SHIP study, there was a trend for a decrease in TSH with age, despite excluding individuals with nodules visible on ultrasound. Both the NHANES and SHIP studies did their best to screen out occult thyroid dysfunction yet opposite trends in TSH were seen with aging. These trends are less likely to be the physiological effect of aging, but more likely the influence of occult thyroid pathology specific to that population contaminating the data and causing these age-related shifts in TSH. It is not possible to establish a universal TSH upper limit from population data. An appropriate compromise would be to adopt an empiric TSH reference range approximating 0.3 to 3 mIU/L, as suggested by AACE. It is important to recognize that the upper TSH reference limit is not the therapeutic threshold for initiating levothyroxine replacement therapy. Instead, the clinical response to a confirmed mildly elevated TSH should be determined on an individual basis. Carole Spencer, MD, PhD, is a Professor of Research at the Keck School of Medicine at the University of Southern California.

(10)
www.aacc.org/events/expert_access/2009/July/Documents/AACC_Spencer_NoAnimOrNotes.pdf www.aacc.org/events/expert_access/2009/july/pages/default.aspx

Contemporary Issues in Thyroid Disease Measurements excellent review of varying TSH upper ranges for various labs, and societies based on iodine intake, ethnicity and age.

Dr. Carole Spencer received a 1st. Class Bachelor of Science degree in Applied Biochemistry from Bath University of Technology in England, U.K., and later a PhD from the Department of Medicine at Glasgow University, Scotland, U.K. In 1977, she immigrated to the United States and joined the University of Southern California in Los Angeles.

Dr. Spencer holds the rank of Professor of Medicine in the Department of Medicine at USC, where she is a licensed Medical Technologist, and directs the USC Endocrine Laboratories. Her research career has focused on the clinical and laboratory aspects of thyroid disease and treatment, and she has authored or co-authored more than 80 original papers, chapters and monographs on the clinical and laboratory aspects of thyroidology.

Dr. Spencer is a past President of the American Thyroid Association and a member of the ATA Laboratory Services Committee. She is the recipient of numerous outstanding speaker awards from the American Association for Clinical Chemistry, and she received the 2004 Distinguished Scientist Award from the National Academy of Clinical Biochemistry.

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(11)
www.intlhormonesociety.org/ref_cons/Ref_cons_9_thryoid_treatment_of_clinically_hypothyroid_biochemically_hypothyroid_patients.pdf

International Hormone Society Hypothyroidism with Labs in Reference Range References Supporting Treatment

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(12) www.worldhealth.net/pdf/WhitePaper_GuidancePhysicians-HRT.pdf

White Paper Guidance for Physicians on Hormone Replacement Therapy (HRT)
Released 27 April 2007; Updated 22 May 2007

The use of “natural” thyroid in patients whose TSH levels for example are not yet over 5.5 has stimulated controversial cases where the treating physician has been dragged into court to explain why a thyroid supplement was administered to a patient who is not yet sick? Several, often recent, studies have now been published that show that levels of TSH within the reference range, between 2 and 5.5, in certain categories of patients have been reported to be associated with pathological abnormalities and even diseases. It is therefore to no surprise that the American Association of Clinical Endocrinologists has therefore narrowed in 2002 the serum TSH reference range to 0.3-3.0 mIU/L, lowering the upper reference end to 3. The National Academy of Clinical Biochemistry, the world’s most respectful organisation for editing guidelines on laboratory test interpretation, reduced the upper end of the reference range from 5.5 to 4.1 mIU per liter in 2003. The latter group also stated that “more than 95% of healthy, euthyroid subjects have a serum TSH between 0.4 – 2.5 mIU per liter” and that “patients with a serum TSH above 2.5 mIU per liter, when confirmed by repeat TSH measurement made after three to four weeks, may be in the early stages of thyroid failure, especially if thyroid peroxidase antibodies are detected.” In 2003, the consensus panel (Endocrine Society, American Association of Clinical Endocrinologists, and American Thyroid Association) recommended a target TSH range of 1.0 to 1.5 mIU per liter in patients already receiving thyroxine therapy.

Questioning Use of TSH as marker for Thyroid Hormone Therapy

(13) http://www.ncbi.nlm.nih.gov/pubmed/16416346

Wien Klin Wochenschr. 2005 Sep;117(18):636-40.

TSH may not be a good marker for adequate thyroid hormone replacement therapy.

Alevizaki M, Mantzou E, Cimponeriu AT, Alevizaki CC, Koutras DA.
Source Endocrine Unit, Dept Medical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece.

The objective of this study was to evaluate parameters of thyroid function and indices of peripheral thyroid hormone action (such as SHBG) in patients whose hypothyroidism was considered well controlled under current criteria.

Eighty-five patients with T4-treated hypothyroidism, 28 of whom had athyria, were compared with 114 normal individuals with the same TSH levels. T3 levels were significantly lower in hypothyroidism although mean T4 and fT4 levels were significantly higher. Furthermore, mean SHBG levels were significantly lower in hypothyroidism independently of age. The difference remained when stricter criteria for adequate treatment were applied (TSH < 2.5 microgU/ml). Significant negative correlations were found between logTSH and T3. The slopes of the regression lines of T3 to TSH were significantly different in the control group and the hypothyroid group:

thus, for the same TSH levels, T3 levels were lower in the hypothyroid group.

We conclude that patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver.

TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect, provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels.

Questioning Levothyroxine Monotherapy

(14) www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0022552

Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients Damiano Gullo#*, Adele Latina#, Francesco Frasca, Rosario Le Moli, Gabriella Pellegriti, Riccardo Vigneri Endocrine Unit, Department of Clinical and Molecular Biomedicine, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy

(15)

mospace.umsystem.edu/xmlui/bitstream/handle/10355/3843/WhichLabTestsHypothyroidism.pdf?sequence=1
Which lab tests are best when you suspect hypothyroidism?

www.jfponline.com  VOL 57, NO 9 / SEPTEMBER 2008 Glenn D. Miller, MD, and Jared C. Rogers, MD University of Illinois College of Medicine and Methodist Medical Center of Illinois, Peoria Sandra L. DeGroote, MLIS University of Illinois College of Medicine Library of the Health Sciences, Peoria —

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