The TSH Reference Range Wars: What's "Normal?", Who is Wrong, Who is
Right..

From Mary Shomon,Your Guide to Thyroid Disease.
Dec 5 2005
And What Does It All Mean For You and Your Health?
http://thyroid.about.com/od/gettestedanddiagnosed/a/tshtestwars_p.htm
(Download a PDF copy of this article to print for your files, or to
give a
copy to your doctor)
Right now, a battle is waging in the endocrinology community
regarding the
so-called "reference range" for the Thyroid Stimulating Hormone (TSH)
test.
The importance of this controversy cannot be underestimated. The
majority of
practitioners -- including endocrinologists, the physicians who
specialize
in thyroid disease -- rely solely on the TSH test as the primary
test, the
supposed "gold standard" in fact, for diagnosing and managing most
thyroid
conditions.
There is ongoing controversy about whether reliance on the TSH test --
to
the exclusion of clinical symptoms and other tests such as Free T4,
Free T3,
and antibodies tests -- is medically sound. That is a controversy
that is
unlikely to be decided for years. The situation today, however, is
that the
majority of physicians do rely almost exclusively on the TSH test to
detect
thyroid disease, and monitor the effectiveness of treatment.
Surprisingly, however, while the medical community does rely on the
TSH test
there is complete disagreement within the community as to what
constitutes
the "normal range."
What is a Reference Range?
Reference range is a critical component, and the validity of the
entire TSH
test as diagnostic tool depends on it. A TSH reference range is
obtained by
taking a large group of people in the population, measuring their TSH
levels
and calculating a mean value. Supposedly, these people should be free
of
thyroid disease, so that the level represents the mean TSH of a
typical
thyroid disease-free person in the population. The reference range is
what
determines whether or not thyroid disease is even diagnosed at all,
much
less treated, and when it is diagnosed, how it is treated.
Currently, at most laboratories in the U.S., the reference range for
TSH
tests is approximately 0.5 to 5.0. Depending on the lab, you may seem
some
variations, I.e., 0.4 to 5.5, or 0.6 to 5.7, etc., but generally, 0.5
to 5.0
is considered typical of many labs.
Typically, doctors interpret levels below 0.5 as indicative of
hyperthyroidism (an overactive thyroid), and levels above 5.0 as
indicative
of hypothyroidism (an underactive thyroid.)
Changing the Reference Range
After noticing that patients who had TSH levels in the higher end of
the
normal range tended to go on to develop hypothyroidism more often
than those
in the lower end of the spectrum, researchers delved more fully into
understanding the validity of the reference ranges in use. They found
that
the upper TSH normal range has traditionally included people who have
mild
thyroid disease, and their higher TSH levels skewed the standard
curve,
potentially making the reference range wider than it should be, and
excluding some people who legitimately had a thyroid condition.
These findings led to the recommendation in January 2003 by the
American
Association of Clinical Endocrinologists (AACE) that doctors "consider
treatment for patients who test outside the boundaries of a narrower
margin
based on a target TSH level of 0.3 to 3.0. AACE believes the new
range will
result in proper diagnosis for millions of Americans who suffer from
a mild
thyroid disorder, but have gone untreated until now."
In a statement from the AACE, Hossein Gharib, MD, FACE, and president
of
AACE at the time, said, "The prevalence of undiagnosed thyroid
disease in
the United States is shockingly high...The new TSH range from the AACE
guidelines gives physicians the information they need to diagnose mild
thyroid disease before it can lead to more serious effects on a
patient's
health - such as elevated cholesterol, heart disease, osteoporosis,
infertility, and depression."
AACE cited as evidence the guidelines issued by the National Academy
of
Clinical Biochemistry, part of the Academy of the American
Association for
Clinical Chemistry (AACC), and presented in their Laboratory Medicine
Practice Guidelines for the Diagnosis and Monitoring of Thyroid
Disease.
Late in 2002, the group concluded that "it is likely that the current
upper
limit of the population reference range is skewed by the inclusion of
persons with occult thyroid dysfunction." In their guidelines, the
National
Academy of Clinical Biochemistry reported that: "In the future, it is
likely
that the upper limit of the serum TSH euthyroid reference range will
be
reduced to 2.5 mIU/L because 95% of rigorously screened normal
euthyroid
volunteers have serum TSH values between 0.4 and 2.5 mIU/L." They also
stated that "a serum TSH result between 0.5 and 2.0 mIU/L is generally
considered the therapeutic target for a standard L-T4 replacement
dose for
primary hypothyroidism."
>> What Would a Narrower Range Mean for Patients?
And What Does It All Mean For You and Your Health?
What Would a Narrower Range Mean for Patients?
At the time of the announcement, almost three years ago, AACE
estimated that
the new guidelines would double the number of people who have abnormal
thyroid function, bringing the total to as many as 27 million, up
from 13
million thought to have the condition under the old guidelines. These
new
estimates would make thyroid disease the most common endocrine
disorder in
North America, far outpacing diabetes.
The announcement from AACE was seen by many as a long-overdue and
much-needed improvement in the level of awareness of
endocrinologists. After
decades of denying that patients within the normal range of TSH could
in
fact have a thyroid condition, they were acknowledging what patients
and
advocates had been saying quite vocally for years: that the high and
low end
of the TSH normal range were not, in fact, normal for most people.
"...using a TSH upper normal range of 5.0, approximately 5% of the
population is hypothyroid. However, if the upper portion of the
normal range
was lowered to 3.0, approximately 20% of the population would be
hypothyroid
.."
More recently, researchers have looked at an important question: If
the
normal TSH range were narrowed, as has been recommended by AACE and
the
National Academy of Clinical Biochemistry, what are the implications?
One
2005 study found that using a TSH upper normal range of 5.0,
approximately
5% of the population is hypothyroid. However, if the upper portion of
the
normal range was lowered to 3.0, approximately 20% of the population
would
be hypothyroid! According to another study, an additional 12.8 to 16
million
people would be diagnosed with hypothyroidism if the TSH upper limit
was 3.0
and an additional 5.4% to 6.3% of the population --- 10.8 to 12.6
million
-- would be diagnosed as hypothyroid if the upper range for TSH was
2.5.
Clearly, these narrower ranges have huge implications for millions of
people
who are not being diagnosed or treated, because their test results
are being
evaluated according to the old reference range.
Untreated thyroid disease can severely compromise quality of life,
and in
some cases even be fatal. Untreated thyroid disease can cause or
contribute
to numerous debilitating symptoms and conditions, including, among
others:
weight problems and obesity
exhaustion and fatigue
depression and anxiety disorders
heart disease
stroke
infertility
miscarriage
birth defects
Some Experts Adopt the New Range
Interestingly, however, in the past three years, most laboratories in
the U
S., despite what are clear communications from both AACE and the
Laboratory
Medicine Practice Guidelines, have not revised their TSH reference
range,
and remain with the 0.5 to 5.0 range as their "normal range."
Some practitioners have adopted the new range for diagnostic and
treatment
purposes. Some physicians, who are aware of the new guidelines, have,
however, chosen not to follow them, and remain with the older
reference
range. Some of them have made this decision because they do not agree
with
the new range, medically. Others are attempting to "play it safe" and
protect themselves because the laboratories have not yet gone with the
change, and these doctors are reluctant to diagnose a thyroid
condition
unless the printed lab report flags a TSH test result as "high"
or "low."
There are also many doctors, general practitioners and even
endocrinologists
who are still routinely diagnosing and treating patients according to
the
old reference range simply because they aren't even aware of the new
reference range guidelines.
Interestingly, some patients who have asked for physicians to
diagnose and
treat them by the new reference range have been turned down, told
off, or
even fired by their physicians. This has led to even greater
controversy in
the medical community, as doctors are taking sides in the debate over
the
old and new reference ranges.
The Debate Goes Public
In September of 2005, two articles appeared in the Journal of Clinical
Endocrinology and Metabolism, presenting the two sides of the
argument.
Martin Surks, Gayotri Goswami and Gilbert Daniels argued that the
reference
range should remain the same in their article "Controversy in Clinical
Endocrinology: The Thyrotropin Reference Range Should Remain
Unchanged,"
while Leonard Wartofsky and Richard Dickey argued that "The Evidence
for a
Narrower Thyrotropin Reference Range is Compelling."
Surks, Goswami and Daniels base their argument on their assertion
that
because routine levothyroxine treatment is not recommended for
subclinical
hypothyroidism, it is certainly not warranted in individuals with
upper
reference range TSH [TSH 2.5 to 4.5]."
>> Surks and Company Say Don't Change the Range, But Wartofsky and
Dickey
Say the New Range is More Accurate...
And What Does It All Mean For You and Your Health?
Drs. Wartofsky and Dickey argue that the previously accepted reference
ranges are no longer valid because the reference populations
previously
considered normal were "contaminated" with individuals with various
levels
of thyroid disease. They argue that the benefits of treatment far
outweigh
any minimal risks.
Surks, Goswami and Daniels -- Don't Change the TSH Reference Range
How these researchers could come to such a definitive conclusion that
treatment is not warranted for subclinical hypothyroidism is
inexplicable,
given that in the same journal where their research is published, an
article
appeared just a few years earlier that demonstrated that treatment of
patients with subclinical hypothyroidism could help with cholesterol
levels
and potentially reduce cardiovascular mortality risk by 31%. [
TSH-controlled L-thyroxine therapy reduces cholesterol levels and
clinical
symptoms in subclinical hypothyroidism: a double blind, placebo-
controlled
trial (Basel Thyroid Study)," Journal of Clinical Endocrinology and
Metabolism, 2001 Oct;86(10):4860-6]
There is also evidence in the literature that levels above 2.0 during
pregnancy can potentially complicate pregnancy, and that upper level
normal
TSH levels can inhibit fertility. For example, in early 2005, Drs.
Casey and
colleague wrote in the journal Obstetrics and Gynecology
that "Pregnancies
in women with subclinical hypothyroidism were 3 times more likely to
be
complicated by placental abruption."
There is also a Norwegian study just published in the International
Journal
of Obesity that found that there is a positive association between
serum TSH
within the normal range and body mass index, and the higher the TSH
level,
the higher the body mass index and likelihood of overweight or
obesity.
These are just a few of the many examples of peer-reviewed literature
in
respected medical journals that discredit the argument that treatment
is not
recommended or warranted for subclinical hypothyroidism. The authors
also
state "The only documented adverse health outcome for individuals
with TSH
levels between 3.0 and 5.0 is progression to overt hypothyroidism.
Levothyroxine treatment would clearly prevent that outcome, but at
what
price?"
However, it must be asked, why is preventing progression to overt
hypothyroidism not a desired health objective, given that overt
hypothyroidism most definitely can contribute to obesity, heart
disease,
depression, infertility, and host of other health problems?
Prevention of disease is a major focus of much of today's medicine,
with
exercise, diet and medications to prevent heart disease, obesity,
stroke,
and many other conditions. Some of these preventative approaches,
particularly drug therapies, come with some risk factors, but the
risks are
presented along with benefits, so patients can make an informed
choice.
Even if there is a small risk to treatment of subclinical
hypothyroidism
(and the existence of such a risk is a theory, not a proven fact)
then why
is this same approach not used for thyroid patients, who could be
given the
opportunity to prevent overt hypothyroidism, realizing that the
prevention
also comes with some risk?
Wartofsky and Dickey: The New Range is More Accurate
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."
"...the decision as to whether to initiate a trial of levothyroxine
therapy
is based more upon the 'art of medicine' at this time than the
science."
In their article, they point to some key facts, including:
In an iodine-sufficient population, the mean TSH is 1.5
In African-Americans with low incidence of Hashimoto's thyroiditis,
the mean
TSH is 1.18, which suggests that "this is close to the true normal
mean for
a normal population"
When people with positive antithyroid antibodies or family history of
autoimmune thyroid disease are excluded from the "reference range"
cohort,
the normal reference range becomes .4 to 2.5
They argue that physicians are practicing a double standard --
considering
one level the "normal" for treatment, but another for diagnosis. The
authors
write:
We are also befuddled by the practice of supporters of the
recommendations
of the consensus panel [the panel that recommended that the reference
range
not be changed] who promote a target TSH range of 1.0-1.5 mU/liter in
patients already receiving T4 therapy, whereas they refuse to accept
TSH
levels of 3-10 mU/liter as abnormal in patients not receiving T4
therapy.
>> What IS Normal, Anyway?
And What Does It All Mean For You and Your Health?
According to Wartofsky and Dickey, opponents of the new range argue
against
treatment for subclinical thyroid problems because they are concerned
about
risks of subclinical hyperthyroidism due to overtreatment. Wartofsky
and
Dickey argue, however, that there is an equivalent risk of
undertreatment,
and that all of these risks can be minimized by educating doctors
about the
desirable TSH target and teaching them how to use various dosages to
reach
those targets in patients. They write:
To us, individual failure on the part of physicians to appropriately
monitor
levothyroxine therapy and adjust doses is not a rationale to withhold
the
indicated therapy. We find the reluctance of the consensus panel to
consider
treatment for mild TSH elevations puzzling when it is most likely
that they
would not argue with the wisdom and rationale for early therapeutic
intervention to mild diabetes mellitus with slight, but definite,
elevations
in blood glucose, mild elevations in low-density lipoprotein
cholesterol, or
mild elevations in blood pressure. After all, few endocrine disease
states
appear suddenly in an "on or off" or "black and white" manner.
Rather, the
disordered physiology must start at sub-intense level and then will
have the
potential to progress from mild to moderate to overt or severe. Just
as we
have revised downward our concept of normal range blood pressure and
cholesterol, we new now should consider the evidence for doing so
with TSH.
Given the wealth of data on the abnormalities present in untreated
subclinical hypothyroidism or hyperthyroidism and the demonstrated
benefits
of therapy to date, we are not disposed to have our hands tied by the
deficiencies inherent in analyses of this issue by evidence-based
medicine
and allow our patients to continue to be at risk as a consequence."
They also conclude their article with what may be the most sensible
statement of both arguments:
"...the decision as to whether to initiate a trial of levothyroxine
therapy
is based more upon the 'art of medicine' at this time than the
science."
What's Normal, Anyway?
There is also an argument regarding whether or not fluctuations with
the
normal range -- by whichever standard, old or new -- represent thyroid
dysfunction on an individual basis. Danish researchers found that each
person tends to have what's known as a "set point," a particular
level of T4
T3 and TSH that their body wants to return to automatically. We then
tend
to maintain thyroid levels around that set point, within a narrow
range -- a
range much narrower than the "reference range" for normal used by
laboratories for testing.
Because each of us has a distinct set point for TSH, T3 and T4
levels, the
general population references ranges are in fact too broad to detect
changes
to thyroid function that may represent disease in an individual.
The Danish researchers concluded that:
The distinction between subclinical and overt thyroid disease is
somewhat
arbitrary because it depends to a considerable extent on the position
of the
patient's normal set point for T3 and T4 within the laboratory
reference
range...In conclusion, we found that individual reference ranges for
serum
T3 and T4 are about half the width of population-based reference
ranges.
Hence, a test result within the laboratory reference limits is not
necessarily normal for the individual.
>> What Does it Mean for You? What Should You Do?
And What Does It All Mean For You and Your Health?
What this all means for you is that--
1. Your doctor probably is still using the old reference range of 0.5
to 5.0
for diagnosis and management of your thyroid disease
2. You should not accept the answers "normal," "high" or "low" as a
report
of your blood tests. Instead, ask for the actual numbers and ask for
the lab
s normal range. Better yet, ask that a copy of your blood test report
be
faxed or mailed or given to you.
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.
4. If your doctor refuses to consider your results according to the
new
range, you may want to look for a new doctor who is more accepting of
change
and new evidence, and who will in fact be practicing according to the
American Association of Clinical Endocrinologists new guidelines.
Mary Shomon, About.com's Thyroid Guide since 1997, is a nationally-
known
patient advocate and best-selling author of 10 books on health,
including
The Thyroid Diet: Manage Your Metabolism for Lasting Weight
Loss," "Living
Well With Hypothyroidism: What Your Doctor Doesn't Tell You...That
You Need
to Know," "Living Well With Graves' Disease and
Hyperthyroidism," "Living
Well With Autoimmune Disease," "Living Well With Chronic Fatigue
Syndrome
and Fibromyalgia," and the "Thyroid Guide to Fertility, Pregnancy and
Breastfeeding Success." Click here for more information on Mary
Shomon.
References
American Association of Clinical Endocrinologists. "January is Thyroid
Awareness Month~ 2003 Campaign Encourages Awareness of Mild Thyroid
Failure,
Importance of Routine Testing." January 2003. Web
Anderson et. al., "Narrow Individual Variations in the Serum T4 and
T3 in
Normal Subjects: A Clue to the Understanding of Subclinical Thyroid
Disease,
Journal of Clinical Endocrinology and Metabolism, 87(3): 1068-1072
Casey et. al. "Subclinical hypothyroidism and pregnancy outcomes."
Obstetrics & Gynecology. 2005 Feb 105(2):239-45.
Fatourechi V, Klee GG, Grebe SK, et al. Effects of reducing the upper
limit
of normal TSH values. Journal of the American Medical Association.
2003
290:3195-3196.
NACB Laboratory Medicine Practice Guidelines, Laboratory Support for
the
Diagnosis and Monitoring of Thyroid Disease, 2002. Web
Nyrnes et. al. "Serum TSH is positively associated with BMI."
International
Journal of Obesity. 2005 Sep 27
Surks, et. al. "Controversy in Clinical Endocrinology: The Thyrotropin
Reference Range Should Remain Unchanged," Journal of Clinical
Endocrinology
and Metabolism 90(9)/5489-5496
Wartofsky & Dickey, "Controversy in Clinical Endocrinology: The
Evidence for a Narrower Thyrotropin Reference Range is Compelling,"
Journal of Clinical Endocrinology and Metabolism 90(9)/5483-5488