Subclinical Hypothyroidism

Subclinical Thyroid Dysfunction: A Joint Statement
on Management From the American Association of
Clinical Endocrinologists, the American Thyroid
Association, and the Endocrine Society

Hossein Gharib, MD, MACE; R. Michael Tuttle, MD; H. Jack Baskin, MD, MACE; Lisa H.
Fish, MD; Peter A. Singer, MD; Michael T. McDermott, MD

Endocr Pract. 2004; 10 (6): 497-501. ©2004 American Association of Clinical
Endocrinologists

Introduction
Subclinical thyroid dysfunction is a common clinical problem with many controversial
issues regarding screening, evaluation, and management. Subclinical hypothyroidism
is defined as high levels of serum thyrotropin (thyroid-stimulating hormone or TSH)
associated with normal levels of total or free thyroxine (T4) and triiodothyronine (T3).
The overall prevalence is 4% to 10% in the general population and up to 20% in
women older than 60 years.[1-3] Several alternative labels have been proposed to
describe this condition and include "compensated hypothyroidism," "preclinical
hypothyroidism," "mild thyroid failure," and "mild hypothyroidism." Although each term
has subtle implications that may be more or less appropriate in various
circumstances, we will use the term "subclinical hypothyroidism" in the interest of
consistency with a recent publication that is the topic of this discussion. Subclinical
hyperthyroidism is defined as low levels of serum TSH associated with normal levels
of free T4 and free T3. The prevalence of this condition is about 2%, being more
common in women, in blacks, and in the elderly population.[4,5]

To develop an evidence-based approach to the various unresolved clinical issues
regarding subclinical thyroid disease, the American Association of Clinical
Endocrinologists (AACE), the American Thyroid Association (ATA), and The Endocrine
Society (TES) jointly sponsored a Consensus Development Conference, which was
held in September 2002. Several questions were presented to a panel of 13 experts,
including 8 experts in thyroid disease; the other 5 panel members had expertise in
cardiology, epidemiology, biostatistics, evidence-based medicine (EBM),
health-services research, general internal medicine, and clinical nutrition. The
consensus panel report was the result of an extensive review of the published
literature on these topics available at the time. The conference participants
meticulously followed the principles of EBM to summarize all existing pertinent data
and to make EBM recommendations on the controversial issues of screening,
evaluation, and management of patients with subclinical thyroid disease. The recently
published consensus panel's conclusions and recommendations[6] were developed
independently and therefore did not necessitate official review or approval by the
three sponsoring organizations. Recognizing that EBM methodology cannot
thoroughly address gray areas where existing evidence is inadequate and that
EBM-derived guidelines cannot specifically address the multitude of variations
encountered by clinicians in their management of individual patients, the consensus
authors also published an accompanying case-based discussion to illustrate how the
guidelines could be applied in several patient scenarios.[7] The authors of these two
outstanding articles are to be congratulated for these excellent publications and
thanked for their service to the community of health-care providers who are
responsible for the management of patients with thyroid disorders.

Subsequently, having carefully studied the consensus conference data, summaries,
and recommendations, the leadership of AACE, ATA, and TES determined that it would
not be appropriate for practicing clinicians and the regulatory elements of the
health-care industry to be given the impression that the membership of these 3
organizations unanimously agreed with all consensus conference recommendations,
despite their sponsorship of the conference itself. They believed that the data in
several areas were inconclusive and that further alternative interpretations and
recommendations were not only reasonable but also warranted in the interest of
academic fairness. Therefore, two members from each of these respective
organizations were invited to form a panel to review the consensus conference
recommendations to determine whether there were areas of legitimate and
substantial disagreement. All members of this panel (the authors of the current
report) are regularly involved in the clinical care of patients with thyroid disease, and
all have previously published literature in the thyroid field, although not necessarily
on the topic of subclinical thyroid disease. The participants were not chosen
specifically for their views on subclinical thyroid disease but rather to represent the
membership of the 3 organizations.

Panel members were or became thoroughly familiar with the body of literature that
provided the data on which the consensus conference recommendations were based.
They did not conduct an independent data analysis. Instead, they relied on the
existing data presentation from the consensus conference and offered their own
alternative interpretations, conclusions, and recommendations that they believed
were warranted on the basis of the strength of the evidence presented by the
consensus conference and their own extensive clinical experience. The present
opinion paper was then submitted to the leadership of each of the 3 organizations
(AACE, ATA, and TES), who presented it to each of their governing bodies, which
made further recommendations and then endorsed it in its current form as a
reasonable alternative and an appropriate response, not to refute but to provide a
counterbalance to the recommendations made by the consensus conference.
Areas of Contention

Overall, our panel agrees with many of the recommendations made by our colleagues
who participated in the consensus conference.[6] Nevertheless, we have important
disagreements in 3 specific areas in which the consensus conference made
recommendations against the following: ( 1 ) routine screening for subclinical thyroid
disease in the general population, ( 2 ) routine screening for subclinical thyroid
disease in women who are pregnant or planning pregnancy, and ( 3 ) routine
treatment of patients with subclinical hypothyroidism who have serum TSH levels of
4.5 to 10 mU/L (or µIU/mL).

Our reasons for disagreement on these issues are centered on the heavy, if not
exclusive, reliance of the consensus conference participants on EBM methodology to
substantiate these negative recommendations. In our opinion, their negative
recommendations are inappropriate because they are based primarily on a lack of
evidence for benefit rather than evidence for a lack of benefit. The consensus authors
thought that there was insufficient "good strength" evidence to support testing or
treating in these circumstances (meaning that no large randomized controlled clinical
trials have documented unequivocal benefit); however, there is clearly also no good
strength evidence that testing or treating is not beneficial or may somehow be
harmful. Accordingly, rather than the evidence being deemed "insufficient to
recommend for" testing or treatment, such inconclusive evidence should, at the very
least, be termed "insufficient to recommend for or against" the testing or treatment in
question. There are subtle but important distinctions between these statements that
have clear, practical implications for physicians actively involved in the care of
patients. Whereas the former statement could be viewed as being restrictive, the
latter phrase more clearly allows for the flexibility that is critical to the physician's role
of melding the existing scientific data, the patient's input, and personal clinical
judgment to make the best decision for each patient.

Ellrodt et al,[8] reviewing evidence-based disease management, stated that "if
inadequate research evidence is available, the disease management team may
decide to make no specific recommendations, thus avoiding inappropriate
micromanagement and allowing clinical flexibility." We strongly support this position,
maintaining that if adequate trials are not available to assess outcomes for treatment
of a condition, it is not appropriate to offer guidelines stating that treatment is not
indicated. The precepts of EBM indicate that recommendations are based first on
good evidence, then on fair evidence, and finally on expert opinion. In the area of
subclinical thyroid dysfunction, even though good evidence is unavailable, a sizable
amount of fair evidence and an abundance of opinions by experts in the field are
available. In the opinion of our panel members, the consensus conference
recommendations in the aforementioned areas are contrary to the practice of many,
though not all, experts in the field of thyroid disorders.

EBM is usually rated against a standard of "significant health outcomes of morbidity
and mortality".[8] When any subclinical condition, such as subclinical hypothyroidism,
is being considered, this issue becomes a problem. We believe that the clinical entity
of hypothyroidism is a continuum from subclinical, to overt, to life-threatening
myxedema coma. By isolating the mildest disease for analysis (TSH levels of 5 to 10
mU/L), one raises the bar so high that an intervention becomes difficult to justify
because the events of morbidity and mortality are likely to be many years away.

Screening for Thyroid Disease in the General Population
The consensus conference found "insufficient evidence to support population-based
screening," using US Preventive Services Task Force criteria,[9,10] and therefore
recommended "against population-based screening for thyroid disease." A review of
the same data in the more recent of the 2 publications from the US Preventive
Services Task Force[10] concluded, however, that the available data are "insufficient
to recommend for or against routine screening for thyroid disease in adults." As
discussed in the foregoing material, these statements may seem similar, but they
have very different clinical implications. Because the available published data are
admittedly insufficient to allow a rigorous EBM recommendation with regard to
screening, it is appropriate to include for consideration the previously published
guidelines that were based predominantly on expert opinion. Although population
screening has not been supported unanimously, expert panels of most professional
societies have endorsed routine TSH screening. For example, the ATA[11]
recommends screening both men and women, beginning at age 35 years and every 5
years thereafter; AACE[12] recommends screening older patients, especially women;
the American Academy of Family Physicians[13] recommends routine screening for
patients older than age 60 years; and the American College of Physicians[14]
recommends case-finding in women older than age 50 years with one or more
symptoms possibly caused by thyroid disease.

The views of the consensus conference participants and our panel may not be as far
apart on this matter as it appears. The primary issue at variance concerns the
advisability of population screening for subclinical thyroid disease, which on a
practical basis means making a TSH measurement a part of the routine periodic
health examination in asymptomatic people. Such routine screening is supported by
our panel but is not endorsed by the consensus conference panel; until additional
information is available, we will have to agree to disagree on this matter.
Nonetheless, both the consensus conference participants and our panel agree on the
need for "aggressive case-finding." This may be an even more pertinent issue for
practicing clinicians than is "routine screening" because case-finding is the situation
that exists whenever a healthcare provider believes there is a reason to measure a
serum TSH level on the basis of a patient's symptoms, signs, personal history, or
family history. In such a situation, guidelines for routine screening should never be
used to discourage or preclude the exercise of clinical judgment on the part of the
provider.

A related issue was the consensus conference conclusion that "evidence was
insufficient to recommend either for or against routine measurement of anti-TPO
[thyroid peroxidase] antibodies in patients with subclinical hypothyroidism".[6] In
contrast, we believe that the measurement of anti-TPO antibodies is a valuable
adjunct in the assessment of patients with subclinical hypothyroidism because, as the
consensus conference concluded, it "predicts a higher risk of developing overt
hypothyroidism (4.3% per year versus 2.1% per year in antibody-negative
individuals)".[6] Furthermore, the presence of anti-TPO antibodies raises the concern
that such patients may be at increased risk of developing other autoimmune
diseases, such as adrenal insufficiency and type 1 diabetes mellitus. Even though the
consensus conference participants found insufficient evidence to address this issue,
many societies, including AACE,[12] the Royal College of Physicians,[15] and the
ATA,[16] endorse the use of anti-TPO antibody determinations in the management of
patients with thyroid dysfunction. In fact, many clinical endocrinologists use the TPO
antibody test as a diagnostic tool in deciding whether to treat a patient with
subclinical hypothyroidism,[17] and we endorse this practice.

Screening for Thyroid Disease During Pregnancy
The consensus panel also recommended against routine screening for thyroid
dysfunction during pregnancy. Nevertheless, because the association between
subclinical hypothyroidism and adverse outcomes of pregnancy for either the fetus or
the mother was rated as "fair," they indicated that "a TSH level might be obtained in
pregnant women and women who wish to become pregnant" if they are at risk for
thyroid disease on the basis of personal or family history, findings on physical
examination, symptoms, or other autoimmune disorders.[6] Although we agree with
aggressive case-finding in all women of childbearing age, we disagree strongly that
thyroid function testing should be limited to women thought to be at increased risk
for the development of thyroid disease on the basis of clinical factors. Because the
prevalence of subclinical hypothyroidism in women of childbearing age may be as high
as 5%[2,3] and because elevated serum TSH levels in pregnant women represent
sufficient thyroid hormone deficiency to endanger both the optimal brain
development[18] and the survival[19] of the fetus, we believe that TSH testing
(followed by measurement of free T4 when the TSH level is abnormal) should be
performed routinely during the prepregnancy evaluation or as soon as pregnancy is
confirmed. Although additional studies may be needed to implement universal
population screening during pregnancy, our position is in complete agreement with a
previous position statement from AACE, which supported thyroid testing during
pregnancy and left the specifics of management "to the judgment of the physician in
consultation with the patient".[20] The American College of Obstetricians and
Gynecologists, however, has stated that "there are insufficient data to warrant
routine screening of asymptomatic pregnant women for hypothyroidism".[21]

Treatment of Subclinical Hypothyroidism
The consensus conference panel recommended against routine treatment of patients
with subclinical hypothyroidism who had serum TSH levels of 4.5 to 10 mU/L, but they
indicated that treatment was "reasonable" for patients with TSH levels >10 mU/L.[6]
Again, these recommendations were based on the existing evidence being insufficient
to endorse therapeutic intervention in patients with TSH levels from 4.5 to 10 mU/L,
whereas the evidence, though still considered inconclusive, was more compelling for
patients with TSH values >10 mU/L. The reviewed evidence consisted of published
data regarding the projected rate of progression from subclinical to overt
hypothyroidism and the effects of levothyroxine treatment on symptoms, depression,
lipid profiles, and cardiac function. Although our panel agrees that the data for
treating patients with TSH levels >10 mU/L are more compelling, we also believe, on
the basis of the available data and our collective clinical experience, that most
patients with serum TSH levels of 4.5 to 10 mU/L should be considered for treatment,
with the key determinant being the clinical judgment of the health-care provider. This
belief is in agreement with a published opinion survey of thyroid specialists[17] and a
previously published recommendation by one of the current authors.[22] We consider
thyroid failure to be a continuum, with patients having TSH levels of 4.5 to 10 mU/L
(or possibly lower) on one end of the spectrum and patients with myxedema coma on
the other end. Milder disease, of course, would be expected to be associated with
milder adverse effects, and the demonstration of beneficial treatment effects would
accordingly necessitate the assessment of larger numbers of subjects and longer
treatment periods to be conclusive. We agree that adequate data are not yet
available in this category; however, as previously mentioned, the lack of definitive
evidence for a benefit does not equate to evidence for lack of benefit.

Interventions must also be evaluated for evidence of potential harm. A published
report indicated that up to 20% of patients receiving levothyroxine therapy are
overtreated.[2] As educators and health-care providers, however, we should not
view this finding as an immutable statistic that justifies an argument against a
potentially beneficial intervention but rather as an issue that can be addressed and
substantially improved through physician education programs.

The consensus conference recommendation that levothyroxine doses should be
increased in patients already receiving treatment for hypothyroidism if their serum
TSH values even minimally exceed the normal range is a tacit acknowledgment that
having TSH values within the normal range is preferable to having TSH levels that are
mildly increased. Our panel agrees completely. In contrast, the consensus conference
participants did not recommend initiation of levothyroxine therapy in patients whose
untreated serum TSH levels are 4.5 to 10 mU/L, whereas our panel does recommend
this early intervention. We believe that the risk-to-benefit ratio is the same in both
instances. The benefits of normalizing the serum TSH level must certainly be the same
in both situations, and the risks of overtreatment should also be similar regardless of
whether the TSH level is lowered by adjusting the preexisting dose or by initiating
levothyroxine therapy. Although investigators have reported that up to 20% of
levothyroxine-treated patients may be receiving excessive thyroid hormone doses,[2]
that study made no distinctions between patients in whom thyroid hormone therapy
had recently been started and those with long-term stable therapy.

We again believe that in this overall area, however, the views of our panel and those
of the consensus conference panel are not far apart in principle. The concept of
"routine treatment" is the central issue. Although reflex treatment of any increase in
serum TSH level without proper consideration of the context of the patient's clinical
features would be unwise, measurement of the serum TSH level for any reason
constitutes case-finding rather than screening. The rationale for measuring the TSH
level, in most cases, makes it no longer "routine" but rather a reasonable
intervention based on the clinical circumstances. Therefore, the critical issue is that
data-based treatment guidelines in areas in which data are insufficient should be
carefully worded to avoid perceived restrictions and to allow health-care providers
the flexibility to use their sound clinical judgment, based on knowledge of each
patient's individual circumstances. On the basis of our clinical experience, our panel
believes that many patients with persistently increased serum TSH levels of any
degree will benefit from therapy and that the physician's judgment, in conjunction
with patient input, should be paramount in this decision-making process.

Treatment of Subclinical Hyperthyroidism
Subclinical hyperthyroidism is much less common than subclinical
hypothyroidism.[10,23,24] The recommendations from the consensus conference
panel to observe and monitor patients with partial TSH suppression (0.1 to 0.4 mU/L)
but to treat patients with complete TSH suppression (<0.1 mU/L) were acceptable
and consistent with previously published guidelines.[12,16] Although we agree with
their recommendations in regard to subclinical hyperthyroidism, it is important to
point out that the strength of evidence is, in our opinion, as insufficient for making
definitive recommendations for this condition as it is for subclinical hypothyroidism.

Conclusion
In our view as both practicing and academic endocrinologists, the potential benefits
of early detection and treatment of subclinical thyroid dysfunction significantly
outweigh the potential side effects that could result from early diagnosis and
therapy. Because the potential harms of early detection and treatment appear to be
minor and preventable, it seems prudent to err on the side of early detection and
treatment until sufficient data are available to address these issues definitively.
Therefore, we favor routine screening for subclinical thyroid dysfunction in adults,
including pregnant women and those contemplating pregnancy. We also strongly
agree with an aggressive approach to case-finding in patients presenting with
symptoms or signs (or both) that suggest the possibility of thyroid dysfunction. Until
adequate data have been accumulated, we believe that it will be necessary for
clinicians to consider each patient's unique situation and input in determining the
need for testing and treatment.

The optimal approach to subclinical thyroid dysfunction remains unsettled. In the
absence of "good evidence," however, a strict evidence-based strategy does not
help clinicians attempting to manage this problem on a day-to-day basis. Large,
randomized, prospective, adequately powered trials are clearly needed to provide
answers for appropriate evaluation and treatment of subclinical thyroid disorders. In
2004, we believe that expert opinion, based on evidence from observational studies
and small randomized trials, and thorough assessment of available clinical information
remain essential for appropriate decision making in the management of subclinical
thyroid dysfunction. Thus, we advise that routine screening for thyroid disease is
warranted in the general population, especially in pregnant women, and that most
patients with subclinical hypothyroidism and some patients with subclinical
hyperthyroidism should be treated. It is also important to allow flexibility in the
decision-making process by physicians responsible for the care of such patients. It is
equally important to recognize that many primary-care physicians, physician
assistants, and nurse-practitioners may use clinical guidelines as a health-care tool,
under the assumption that they are the best distillation of advice from research
results and experts in the field. Furthermore, individual agencies, health maintenance
organizations, and the Center for Medicare and Medicaid Services often use published
guidelines to limit reimbursement for both testing and therapy. It is the position of
both the consensus conference panel and this task force that, until adequate data
are available, the best clinical practice continues to combine "clinical judgment and
patients' preferences"(6).

This report was prepared by a task force created by the American Association of
Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society
and is being published concurrently in the following journals: Endocrine Practice, ATA,
and TES.

Acknowledgements

We thank Michelle Papaconstandinou and Sarah Bradley for expert assistance in the
preparation of this document.

Abbreviation Notes
AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid
Association; EBM = evidence-based medicine; T3 = triiodothyronine; T4 = thyroxine;
TES = The Endocrine Society; TPO = thyroid peroxidase; TSH = thyroid-stimulating
hormone (thyrotropin)

Reprint Address
Dr. Hossein Gharib, Division of Endocrinology, Diabetes, Metabolism, Nutrition, and
Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905. Email:
Gharib.Hossein@mayo.edu

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