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Default Subclinical Thyroid Disease: Consensus or Conundrum? (hypothyroidism cardiology antibodies cardiac heart)

From Clinical Endocrinology
Subclinical Thyroid Disease: Consensus or Conundrum?
Posted 04/20/2004
David S. Cooper
'Subclinical hypothyroidism is an example of the impact of technology
on the concept of a disease' (Nilsson et al., 1976).

The term 'subclinical hypothyroidism' was probably first used by
Evered and colleagues to describe a group of individuals in whom
'conventional tests of thyroid function showed nothing abnormal ...
but they were all found to have a raised serum TSH concentration'
(Evered et al., 1973). Today, subclinical hypothyroidism is similarly
defined by normal serum free T4 levels and serum TSH levels above the
upper limit of the reference range (Cooper, 2001). At least 75% of
patients have TSH serum levels < 10 mU/l (Canaris et al., 2000).
Although some studies have suggested that mild hypothyroid symptoms
may be more frequent in this population (Canaris et al., 2000), most
authorities agree that individual patients cannot be distinguished
from euthyroid controls on the basis of symptoms; hence the term
'subclinical'. The prevalence of subclinical hypothyroidism in the
United States is 4-85% (Canaris et al., 2000; Hollowell et al.,
2002), increases with age, and may differ among ethnic groups
(Hollowell et al., 2002).

It was not until the advent of sensitive TSH assays in the mid-1980s
that the term 'subclinical hyperthyroidism' became part of the
thyroidologist's lexicon. Subclinical hyperthyroidism also has a
laboratory-based definition: normal serum free T4 (and free T3) levels
and a serum TSH level that is below normal, after excluding other
causes of low serum TSH (Toft, 2001). Whether the definition requires
the serum TSH to be < 01 mU/l, or simply below the lower limit of the
reference range, has not been formally agreed upon. As in subclinical
hypothyroidism, patients with subclinical hyperthyroidism as a group
may have more hyperthyroid symptoms than controls (Biondi et al.,
2000), but on an individual basis the diagnosis is clinically elusive
unless the patient presents with a goitre, thyroid nodule(s) or atrial
fibrillation. Subclinical hyperthyroidism is less frequent than
subclinical hypothyroidism. If the definition includes only those
patients with TSH levels < 01 mU/l, the prevalence in the United
States is approximately 02% (Hollowell et al., 2002).

From the beginning, the clinical implications of subclinical thyroid
disease have provoked controversy. Because of the high prevalence of
subclinical hypothyroidism and its possible associations with
cardiovascular disease, dyslipidaemia and a host of other problems, as
well as progression to overt hypothyroidism, some experts and
professional organizations have called for screening of the general
population, and treatment of all diagnosed patients. This is a
particularly emotional subject when dealing with pregnant women
because mild hypothyroidism might effect the intellectual potential of
the unborn child (Haddow et al., 1999). Similarly, some groups have
recommended population screening and possible treatment of subclinical
hyperthyroidism because of the potential serious complications of this
disorder in older populations (osteoporosis, atrial fibrillation).

In an attempt to address these contentious issues in a nonbiased and
systematic way, The (American) Endocrine Society, the American Thyroid
Association (ATA) and the American Association of Clinical
Endocrinologists (AACE) cosponsored a Consensus Development Conference
modelled on similar conferences convened by the National Institutes of
Health (NIH). To quote the NIH (2004) consensus conference guidelines:
'Consensus Development Conferences are particularly useful for
providing guidance when a controversy exists over preventive,
the****utic, or diagnostic options, or when the issue is of public as
well as professional interest. The timing of the conference should
neither be so early in the development of a new consensus that the
data are insufficient nor so late that the conference merely
reiterates a consensus already reached by the profession.... the
statement reflects the views of a panel of thoughtful people who
understand the issue before them and who carefully examine and discuss
the scientific data available on the issue. The creative work of the
panel is to synthesize this information, along with sometimes
conflicting interpretations of the data, into clear and accurate
answers to the questions posed to the panel.'

In the spirit of the NIH guidelines, a panel was selected to represent
multiple disciplines (thyroidology, women's health, nutrition,
clinical epidemiology, decision ****ysis and cardiology), and the
process was designed to be evidence-based. To achieve these ends, the
conference planning committee contracted an independent consulting
firm to review, categorize and summarize the existing published
evidence (195 articles in total). The conference was held on September
21-32, 2002, and consisted of a day and a half of oral presentations
on a wide range of topics by authorities in the field, followed by an
additional day and a half of closed deliberation. The panel was
charged with answering five questions: 1) What is the definition of
subclinical thyroid disease? 2) What is the epidemiology of
subclinical thyroid disease? 3) What are the consequences of untreated
subclinical thyroid disease, and how should it be evaluated? 4) What
are the risks and benefits of treatment for subclinical thyroid
disease? 5) Is screening for subclinical thyroid disease warranted?
The panel used evidence levels and recommendation categories
promulgated by the United States Preventative Services Task Force
(USPSTF), an expert committee convened by the US government Agency for
Healthcare Research and Quality (AHRQ).

Highlights of the panel's conclusions (Surks et al., 2004) are
summarized below.
Subclinical Hypothyroidism

With regard to the definition of subclinical hypothyroidism, the panel
concluded that the upper limit of normal for serum TSH should remain
at 45 or 5 mU/l, and not be lowered to 3 or 35 mU/l as had been
advocated by some professional organizations (Baloch et al., 2003).
The panel also concluded that there was either insufficient or no
evidence for a clinically significant relationship between subclinical
hypothyroidism and cardiac dysfunction, or systemic hypothyroid or
neuropsychiatric symptoms. The evidence for an association with
dyslipidaemia was rated as 'fair', and only in individuals with serum
TSH levels > 10 mU/l. The panel concluded that thyroxine therapy is
'reasonable' for patients with serum TSH levels > 10 mU/l because of
their high rate of progression to overt hypothyroidism over time. The
panel did not recommend routine thyroxine treatment for patients with
TSH levels 45-10 mU/l but did admit that a trial of thyroxine in
symptomatic patients 'might be reasonable'. In the panel's judgement,
however, 'the likelihood of improvement (was) small and must be
balanced against the inconvenience, expense, and potential risks of
therapy.' The panel did not advise the use of antiTPO antibodies in
the decision-making process. This differs from recommendations
published by the Royal College of Physicians (Vanderpump et al.,
1996), the AACE (AACE, 2002) and the ATA (Singer et al., 1995), all of
which were favourably disposed to treatment of antibody positive
Subclinical Hyperthyroidism

In defining subclinical hyperthyroidism the panel took the broadest
view, including anyone with a serum TSH concentration below the lower
limit of the reference range, rather than only those with TSH < 01
mU/l. The panel concluded that the evidence for adverse effects on the
skeleton and the heart was 'fair' to 'good', but only in patients with
serum TSH levels < 01 mU/l. For that reason it recommended that
treatment 'be considered' even though there is a 'paucity of
intervention trials' showing benefit. For patients with serum TSH
levels between 01 and 045 mU/l, the evidence for adverse health
consequences was considered insufficient or absent, and therefore
therapy was not recommended. Other groups have not been able to reach
consensus on the treatment of subclinical hyperthyroidism (Vanderpump
et al., 1996; AACE, 2002).
Screening for Subclinical Thyroid Disease

A number of professional societies have recommended population
screening for subclinical thyroid disease either in all adults or in
older women (e.g. the ATA; Ladenson et al., 2000), but the panel
specifically recommended against mass screening. Rather, 'case
ascertainment' in certain high-risk groups was recommended. This
finding is similar to the recommendations of the Royal College of
Physicians (Vanderpump et al., 1996), a 2003 report on population
screening of older individuals issued by the Institute of Medicine (a
branch of the US National Academy of Sciences) (Stone & Wallace,
2003), and the most recent 2004 recommendations of the USPSTF (US
Preventative Services Task Force, 2004).

The panel recommended treatment of subclinical hypothyroidism in
pregnant women who are 'found' to have an elevated serum TSH level,
basing this conclusion primarily on possible cognitive deficits in the
offspring of women with subclinical hypothyroidism (Haddow et al.,
1999). With regard to screening of pregnant women, the panel concluded
that a TSH 'might be obtained' in pregnant women and in women
considering pregnancy who have a family or personal history of thyroid
disease, signs and symptoms suggesting thyroid disease, or underlying
autoimmune conditions. However, the panel did not go so far as to
recommend routine TSH screening of all pregnant women or women
considering pregnancy. This differs from an AACE position paper that
states that routine screening in pregnancy is 'reasonable' but should
be 'left to the judgement of the physician in consultation with the
patient' (Gharib et al., 1999).

Are the recommendations of the consensus conference panel any more
'valid' that any of the other recommendations or guidelines published
by other professional groups? As summarized by Arbel and Porath
(1999), differences in practice guidelines can be due to differences
in the composition of expert panels (e.g. practitioners vs a more
diverse group), the basis of the recommendations (expert opinion vs
evidence-based literature reviews), and varying efforts of groups to
take into account the risks, benefits and costs of various
interventions. Thus, like all of its predecessors, this panel's
recommendations can be defended or refuted, depending on one's point
of view. However, there is no question that the panel's conclusions
are based on an examination of all the available evidence, that it is
carefully reasoned, appropriately critical of the existing literature,
and patient-centred. Unfortunately, until there are large randomized
treatment trials that address the important clinical questions
involved in the diagnosis and management of subclinical thyroid
disease, we will have to continue to rely on imperfect and necessarily
vague recommendations. However, in my opinion this is the most

David S. Cooper, Sinai Hospital of Baltimore, The Johns Hopkins
University School of Medicine, 2401 Belvedere Ave, Baltimore, MD
21204, USA. Tel.: 410 601 5961; Fax: 410 601 9390;
David S. Cooper, Sinai Hospital of Baltimore, The Johns Hopkins
University School of Medicine, Baltimore, MD, USA
Clin Endocrinol 60(4):410-412, 2004. 2004 Blackwell Publishing
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