SUBCLINICAL THYROID DISEASE
Subclinical thyroid dysfunction is defined as an abnormal serum
thyroid-stimulating hormone level (reference range: 0.45 to 4.50
[micro]U per mL) and free thyroxine and triiodothyronine levels
within their reference ranges. The management of subclinical
thyroid dysfunction is controversial. The prevalence of
subclinical hypothyroidism is about 4 to 8.5 percent, and may be
as high as 20 percent in women older than 60 years. Subclinical
hyperthyroidism is found in approximately 2 percent of the
population. Most national organizations recommend against routine
screening of asymptomatic patients, but screening is recommended
for high-risk populations. There is good evidence that subclinical
hypothyroidism is associated with progression to overt disease.
Patients with a serum thyroid-stimulating hormone level greater
than 10 [micro]U per mL have a higher incidence of elevated serum
low-density lipoprotein cholesterol concentrations; however,
evidence is lacking for other associations. There is insufficient
evidence that treatment of subclinical hypothyroidism is
beneficial. A serum thyroid-stimulating hormone level of less than
0.1 [micro]U per mL is associated with progression to overt
hyperthyroidism, atrial fibrillation, reduced bone mineral
density, and cardiac dysfunction. There is little evidence that
early treatment alters the clinical course.
Subclinical hyperthyroid and hypothyroid disease are
laboratory diagnoses. In 2002, a scientific review and consensus
committee, which included representatives from the American
Thyroid Association, the American Association of Clinical
Endocrinologists, and the Endocrine Society, convened a panel of
experts to define subclinical thyroid disease, review the
literature concerning risks and benefits of treatment, and make
recommendations about evaluation and population-based screening.
This committee defined subclinical hypothyroidism as "a serum TSH
[thyroid-stimulating hormone] concentration above the
statistically defined upper limit of the reference range when
serum free [thyroxine] concentration is within its reference
range." Subclinical hyperthyroidism was defined as "a serum TSH
concentration below the statistically defined lower limit of the
reference range when serum [triiodothyronine] concentrations are
within their reference ranges." Based on a series of studies, the
panel determined that the reference range for serum TSH is 0.45 to
4.50 [micro]U per mL (0.45 to 4.50 mU per L).
Despite a working definition of subclinical thyroid
disease, the panel found little evidence to guide physicians in
managing subclinical hyperthyroidism and hypothyroidism. Some
patients will progress to overt disease, and in some patients, the
serum TSH concentration will remain stable over time or will
spontaneously return to the reference range. There also is
controversy regarding what, if any, adverse outcomes occur from
subclinical thyroid disease, and whether benefit can be expected
from treatment. As a result, various organizations have adopted
diverse recommendations regarding screening for subclinical
thyroid disease.
Screening for Thyroid Disease
In January 2004, the U.S. Preventive Services Task Force
updated its 1996 recommendations regarding routine screening for
thyroid disease. The new recommendations state that "the evidence
is insufficient to recommend for or against routine screening for
thyroid disease in adults."
The most recent revision of the American Academy of Family
Physicians' policy recommendation for periodic health examinations
remains unchanged; it recommends against routine screening for
thyroid disease in patients younger than 60 years, based on a lack
of evidence to support "net benefit over harm." The 2002 consensus
group's expert panel recommended against population-based
screening but "encouraged" assessment in high-risk groups (defined
as women with a family history of thyroid disease, prior thyroid
dysfunction, symptoms suggestive of hyperthyroidism or
hypothyroidism, abnormal thyroid gland on examination, type 1
diabetes, or a personal history of autoimmune disorder). The panel
found insufficient evidence to recommend for or against screening
pregnant women or women planning a pregnancy.
The American College of Physicians (ACP) issued its most
recent policy statement on thyroid disease in 1998, in which it
recommends screening for women older than 50 years who have
symptoms consistent with thyroid disease. The ACP was not a member
of the consensus committee.
Evaluation of Subclinical Hyperthyroidism
ETIOLOGY
In many patients who have subclinical hyperthyroidism,
careful clinical evaluation will suggest an etiology. Early
Graves' disease accounts for the majority of cases, with the
remainder caused by toxic multinodular goiter, autonomous
functioning nodules, or exogenous levothyroxine (Synthroid). other
causes of low serum TSH concentration include delayed recovery of
the pituitary after treatment for hyperthyroidism; pregnancy;
euthyroid sick syndrome; or medications such as dopamine
(Intropin), glucocorticoids, and dobutamine (Dobutrex). Few
persons with subclinical hyperthyroidism progress to overt
disease.
ASSOCIATED CLINICAL CONDITIONS
Subclinical hyperthyroidism appears to be associated with
atrial fibrillation, reduced bone mineral density, cardiac
dysfunction, and progression to overt hyperthyroidism in patients
with known thyroid disease. In the Framingham Study, investigators
found that persons with subclinical hyperthyroidism had a relative
risk of three to one for developing atrial fibrillation when
compared with control patients over 10 years. In another study,
accelerated bone loss was documented in women who received
excessive levothyroxine replacement therapy when compared with
control patients over a period of more than eight years.
The authors of a 10-year, population-based cohort study
concluded that there was an "increase in mortality from all causes
and from circulatory diseases in individuals with subclinical
hyperthyroidism," and that patients with low levels of serum TSH
"were at a clear survival disadvantage during the first [five]
years of follow-up." However, these data were not adjusted for
comorbidity. The consensus committee found fair evidence that
treatment of subclinical hyperthyroidism is beneficial for slowing
the loss of bone mineral density. However, committee members found
no evidence or insufficient evidence that treatment benefits other
outcomes.
MANAGEMENT
The consensus guidelines recommend that patients with
abnormal levels of serum TSH be evaluated. Patients who are not
receiving levothyroxine and who have serum TSH levels between 0.10
and 0.45 [micro]U per mL (0.10 and 0.45 mU per L) should have a
repeat test of serum TSH levels for confirmation. If results of
the repeat test are still outside the reference range, testing of
and or free levels should be done in two weeks for patients with
atrial fibrillation, known cardiac disease, or other serious
medical conditions. Patients who are otherwise healthy can wait
three months before repeating these studies. If the patient's
serum TSH level remains between 0.10 and 0.45 [micro]U per mL at
follow-up, a radioactive iodine uptake and scan are required to
evaluate for endogenous subclinical hyperthyroid disease (i.e.,
destructive thyroiditis, Graves' disease, or nodular goiter). Once
endogenous disease is excluded, serum TSH measurement can be
repeated every three to 12 months.
Patients whose serum TSH levels remain stable can discuss
with their physician whether their condition requires further
evaluation. When the etiology of a low serum TSH level is
determined to be excessive levothyroxine replacement therapy, the
dosage should be lowered until the serum TSH level is within the
reference range, unless serum TSH suppression for thyroid cancer
or nodules is the goal. The consensus panel recommends against
routine treatment of patients with serum TSH levels between 0.10
and 0.45 [micro]U per mL. However, the panel suggests that
physicians might consider treatment in older persons because of
the possible association with increased cardiovascular mortality.
When the serum TSH concentration is less than 0.10 [micro]U
per mL, evaluation for signs and symptoms of cardiac disease or
other urgent medical problems should be performed promptly, repeat
serum TSH testing, along with and or free testing, should be
performed within four weeks. There is insufficient evidence to
guide treatment decisions when the serum TSH concentration is less
than 0.10 [micro]U per mL, although the panel does recommend that
treatment be considered when a low level of serum TSH is caused by
Graves' disease or nodular thyroid disease.
The two most common abnormalities encountered in patients
with subclinical hyperthyroidism are spontaneous atrial
fibrillation and osteoporosis. The Framingham data showed an
increased risk of spontaneous atrial fibrillation in persons older
than 60 years who had an undetectable serum TSH level. Using these
data, investigators determined that over 10 years the number
needed to treat to reduce the risk of spontaneous atrial
fibrillation to that of the general population would be 4.2.
However, data showing a decrease in the incidence of spontaneous
atrial fibrillation or osteoporosis as a direct result of shifting
serum TSH into the reference range are not available. There is
some evidence that treated patients may benefit from less bone
loss. When a low serum TSH concentration is caused by destructive
thyroiditis, symptomatic treatment with agents such as beta
blockers is sufficient because this condition resolves
spontaneously.
Evaluation of Subclinical Hypothyroidism
ETIOLOGY
Because there are no long-term outcome data for patients
with subclinical hypothyroidism, it is difficult to state
definitive etiologic abnormalities. With a progression rate of
only 5 percent per year, it is reasonable to assume that, in many
patients, subclinical hypothyroidism may not be caused by the
progression of any specific disease state. However, there is good
evidence that a significant number of patients with a history of
Hashimoto's thyroiditis progress to overt hypothyroidism.
Therefore, a finding of subclinical hypothyroidism may represent a
point on that continuum, although a causal relationship has not
been shown, other possible causes of subclinical hypothyroidism
include protracted recovery from acute thyroiditis, early primary
pituitary or hypothalamic disorder, and inadequate levothyroxine
replacement therapy in a patient with known hypothyroidism.
ASSOCIATED CONDITIONS
There is good evidence that subclinical hypothyroidism is
associated with progression to overt hypothyroidism, and there is
fair evidence that serum TSH levels greater than 10 [micro]U per
mL (10 mU per L) are associated with elevations in total and
low-density lipoprotein (LDL) cholesterol levels. There is
insufficient evidence regarding adverse cardiac events, cardiac
dysfunction, neuropsychiatric symptoms, or systemic symptoms of
hypothyroidism.
In one study, investigators compared 57 women with
subclinical hypothyroidism with 34 healthy control patients,
looking at blood pressure, body mass index, levels of fasting TSH,
F[T.sub.4], thyroid antibodies, total cholesterol, high-density
lipoprotein (HDL) cholesterol, LDL cholesterol, and triglycerides.
Women with subclinical hypothyroidism had a higher incidence of
diastolic hypertension, hypertriglyceridemia, elevated total
cholesterol/ HDL cholesterol, and elevated LDL cholesterol/ HDL
cholesterol. The authors of two studies reported increased
prevalence of dyslipidemia, coronary artery disease, and
peripheral arterial disease in older men and women with
subclinical hypothyroidism.
PREGNANCY
There is only fair evidence to support an association
between subclinical hypothyroidism and adverse outcomes in
pregnancy. However, the consensus panel recommends screening serum
TSH levels in patients who are pregnant or who are planning to
become pregnant when there is a family or personal history of
thyroid disease, evidence of goiter, symptoms of hypothyroidism,
type 1 diabetes, or a personal history of autoimmune disorder.
Although there are few data, the panel recommends treatment
with levothyroxine during pregnancy to maintain serum TSH levels
within the reference range, with repeat testing every six to eight
weeks. Physiologic requirements of levothyroxine often increase
during pregnancy; therefore, women who were receiving therapeutic
replacement dosages before becoming pregnant should have their
serum TSH level monitored every six to eight weeks during
pregnancy.
MANAGEMENT
The consensus panel recommends that patients with an
elevated serum TSH level have the test repeated, with a serum
measurement, in no sooner than two weeks but no later than three
months. When repeat studies confirm subclinical hypothyroidism,
further evaluation is required, including signs and symptoms of
hypothyroidism, previous treatment for hyperthyroidism (e.g.,
radiotherapy, partial thyroidectomy), thyromegaly, and family
history of thyroid disease. In addition, these patients should be
screened for hyperlipidemia. Although the presence of antithyroid
peroxidase antibodies increases the chance of progression to overt
hypothyroidism, the panel found insufficient evidence to recommend
for or against obtaining titers because determining the presence
of antibodies does not change management.
Asymptomatic patients with serum TSH levels between 4.5 and
10 [micro]U per mL should have a repeat test every six to 12
months. Available data do not support a benefit for early
treatment of subclinical hypothyroidism; therefore, the panel does
not recommend treatment with levothyroxine for these patients.
Also, there is insufficient evidence to support therapeutic
intervention in patients with symptoms of hypothyroidism whose
serum TSH concentration is between 4.5 and 10 [micro]U per mL.
However, the panel suggests that patients may try levothyroxine to
see if symptoms improve. In this instance, the panel advises that
treatment be continued only if there is "clear symptomatic
benefit" to the patient. Patients should be monitored to evaluate
improvement in symptoms.
The panel recommends treatment with levothyroxine for
patients with serum TSH levels greater than 10 [micro]U per mL.
There is no conclusive evidence that treatment will improve
symptoms or associated clinical conditions such as hyperlipidemia;
however, because the rate of progression to overt hypothyroidism
is 5 percent, treatment may prevent development of symptoms in
patients whose level becomes low.
OVERT HYPOTHYROIDISM
In patients who have overt hypothyroidism, who are
receiving levothyroxine replacement therapy, who have serum TSH
levels greater than 4.5 [micro]U per mL, and have an F[T.sub.4]
concentration in the reference range, the dosage of levothyroxine
should be increased to bring the serum TSH concentration into the
reference range. For patients on levothyroxine replacement therapy
who experience symptoms of hypothyroidism, and whose serum TSH
level is in the upper half of the reference range, it is
reasonable to adjust the dosage of levothyroxine until the serum
TSH level moves into the lower half of the range.
