Download Subclinical Hypothyroidism: When to Treat, When to

DOUGLAS S. ROSS, MD
Harvard University
Subclinical Hypothyroidism:
When to Treat, When to Watch
Dr Ross is professor of medicine at
Harvard Medical
School in Boston
and a physician at
Massachusetts
General Hospital,
also in Boston. He
is co-editor of the
thyroid disease section of UpToDate.
ABSTRACT: Subclinical hypothyroidism
is associated with elevated low-density
lipoprotein (LDL) cholesterol levels and
several factors related to atherosclerosis,
including increased C-reactive protein levels and impaired endothelium-dependent
vasodilatation. However, considerable
controversy exists about screening for
and treating this thyroid disorder. Thyroxine therapy lowers elevated LDL cholesterol levels in patients whose serum
thyroid-stimulating hormone (TSH) concentrations are higher than 10 mIU/L;
thus, most experts recommend treatment
for such patients. However, there is no
consensus regarding the management of
patients with TSH levels of less than
10 mIU/L. Offering treatment to younger symptomatic patients is reasonable;
however, the benefit of treating elderly
patients whose TSH levels are less than
10 mIU/L is uncertain, and unintentional
over-treatment may be associated with
cardiovascular and skeletal morbidity.
Key words: subclinical hypothyroidism,
thyroid-stimulating hormone, thyroxine
Dr Ross reports that he
has no financial relationships relevant to the
content of this article
to disclose.
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A 76-year-old woman complains of
impaired memory, and excessive
fatigue (she usually falls asleep
after dinner while watching television). Thyroid tests reveal the following values:
• Thyroid-stimulating hormone
(TSH), 6.2 mIU/L.
•Free thyroxine (T4 ), 1.2 ng/dL
(normal 0.8 to 1.8 ng/dL).
Would you of fer this patient
treatment?
Subclinical hypothyroidism is defined as an elevated serum TSH level
with a normal serum free T4 concentration. It is a laboratory diagnosis;
hypothyroid symptoms—such as fatigue, inability to lose weight, memory impairment, hair loss, and depression—are nonspecific and are not included in the definition. If a patient’s
serum TSH level is elevated and the
serum T4 concentration is low, he or
she has overt hypothyroidism.
The optimal approach to subclinical hypothyroidism continues to
be debated. Experts disagree over
screening for thyroid dysfunction,
the threshold TSH level for treatment, and the upper limit of normal
of the TSH reference range. Here I
examine the often conflicting data—
and I offer a practical strategy for
patients you are likely to see in your
practice (Table).
PREVALENCE AND
NATURAL HISTORY
Subclinical hypothyroidism is
common, with a prevalence of 4.3%
in the National Health and Examination Survey (NHANES III).1 In population-based studies, the condition
affects 7.5% to 8.5% of women and
2.8% to 4.4% of men.2,3 In women
older than 60 years, the prevalence
is as high as 15%.2 The prevalence is
lower in African Americans and
higher in patients with type 1 diabetes mellitus.
In patients with no history of thyroid surgery or radioiodine treatment,
hypothyroidism almost always results
from Hashimoto thyroiditis. The titer
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Subclinical
Hypothyroidism:
When to Treat,
When to Watch
of anti-thyroid peroxidase (TPO) antibodies is proportional to the degree of
lymphocytic infiltration and inflammation within the gland. Thus, hypothyroidism in patients with high titers of
anti-TPO antibodies is more likely to
progress from subclinical to overt disease. In one population-based survey
with a 20-year follow-up, the progression to overt hypothyroidism was 2.6%
per year among patients with an elevated TSH concentration and negative
results on anti-TPO antibody testing
and 4.3% per year among those with
an elevated TSH concentration and
positive results on anti-TPO antibody
testing.4
SCREENING AND
TREATMENT CONTROVERSIES
Controversy persists about
screening for subclinical hypothyroidism and the TSH level at which treatment should be initiated. A 1998 position paper from the American College
of Physicians questioned whether
there were sufficient data to recommend treatment of patients with subclinical hypothyroidism.5 A 2004 publication from the US Preventive Ser-
vices Task Force found that the data
were insufficient to recommend for
or against screening in adults.6
In 2002, a consensus development panel sponsored by the American Thyroid Association, the American Association of Clinical Endocrinologists, and the Endocrine Society
found insufficient evidence to support
screening and recommended against
treating patients with a TSH concentration between 4.5 and 10 mIU/L.7
The conclusions of this panel were so
controversial that the organizations
involved formed a second panel of ex-
Table – Possible indications for treatment of subclinical hypothyroidism
Indication
Comments
Hypothyroid symptoms
Placebo effect is 40%
No improvement in symptoms seen in RCTs if TSH < 15 mIU/L
Overtreatment may result
Elevated lipid levels
Improvement seen only when TSH > 10 mIU/L
At risk for atherosclerosisData suggest an association between subclinical hypothyroidism and markers
for atherosclerosis
Studies do not consistently show a reduction in cardiovascular disease or mortality;
in a meta-analysis cardiovascular mortality, but not all-cause mortality was
increased if TSH > 7.0 mIU/L
No trials assess whether the benefits of treatment outweigh the risks of treatment
in the elderly
Neuropsychiatric symptomsMany studies testing the association with subclinical hypothyroidism have been
poorly designed
Depression in patients with subclinical hypothyroidism may be the result of a
genetic predisposition
Overweight
Modest increased BMI associated with TSH > 3.6 mIU/L
No therapeutic trial shows weight loss
Pregnancy
Reduced IQ in offspring of women with subclinical hypothyroidism
TPO antibodies and TSH > 2.5 mIU/L during pregnancy is associated with
a poor pregnancy outcome
Treatment is recommended in pregnant women for TSH > 4.5 mIU/L,
or TSH > 2.5 mIU/L if she has positive TPO antibodies
High anti-TPO antibody titer
Without treatment, progression to overt hypothyroidism is likely
Goiter
Reduction of TSH may limit growth
RCT, randomized controlled trial; TSH, thyroid-stimulating hormone; BMI, body mass index; TPO, thyroid peroxidase.
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perts. These experts disagreed with
the findings of the first panel and recommended screening for thyroid dysfunction, especially among pregnant
women; they also recommended
treatment of “most patients” with subclinical hypothyroidism.8
In 2007 the Cochrane Collaboration assessed 12 randomized controlled trials and concluded that
treatment did not result in improved
survival or reduced cardiovascular
mortality, or improvement in symptoms, but noted improvement in lipid
profiles and left ventricular function
in some studies.9
Since these repor ts were issued, there has been considerable
controversy regarding the upper
limit of normal for ser um TSH.
While most clinical laboratories use
values between 4.2 and 5.0 mIU/L,
data from NHANES III demonstrate
an age-related shift toward higher
TSH values in TPO antibody-negative subjects: the 97.5 centile for TSH
was 3.56 mIU/L for subjects aged 20
to 29 years, but increased to 4.33,
5.90, and 7.49 mIU/L for those aged
60 to 69, 70 to 79, and over 80 years,
respectively.10
CLINICAL AND
METABOLIC CONSEQUENCES
OF SUBCLINICAL
HYPOTHYROIDISM
Elevated cholesterol levels. A
large cross-sectional study of 25,862
persons found that those with serum
TSH concentrations of 5.1 to 10
mIU/L had higher serum cholesterol levels than those who were euthyroid (223 mg/dL vs 216 mg/dL).11
The extensive literature on the
effect of thyroxine treatment on lipid
concentrations includes many conflicting results. A meta-analysis of
several therapeutic trials revealed a
10-mg/dL reduction in low-density
lipoprotein (LDL) cholesterol levels,
but this occurred only in patients
with total cholesterol levels of greatwww.Consultant360.com
er than 240 mg/dL at baseline.12 The
recommendation of the 2002 consensus panel7 that only patients with
TSH concentrations of greater than
10 mIU/L be treated is based on several studies that showed that treatment reduced serum total and LDL
cholesterol levels in patients whose
initial serum TSH concentrations
were greater than 10 mIU/L. Nonrandomized trials have shown that
thyroxine therapy lowers serum lipoprotein (a) concentrations.13,14
Atherosclerosis. Patients with
subclinical hypothyroidism have abnormalities in parameters that are
associated with atherosclerosis. Of
note, all of these studies were published after the recommendations of
the 2002 consensus panel were released. Moreover, all of these studies
are of patients who have minimal elevations in serum TSH levels, with
values generally less than 15 mIU/L.
Impaired endothelium-dependent vasodilatation is an early marker for atherosclerosis. This abnormality has been found in patients
with subclinical hypothyroidism and
was reversed by thyroxine treatment. 15 Platelet-activating factor
(PAF) is a proinflammatory lipid mediator that has been implicated in
atherogenesis. PAF-acetylhydrolase
inactivates PAF; levels of PAF-acetylhydrolase have been found to be low
in patients with subclinical hypothyroidism and increased to normal
with treatment.16 Elevated C-reactive
protein levels also became normal
with treatment in one study,17 but not
in another study.18 Increased concentrations of osteoprotegerin, involved
in the regulation of endothelium-dependent vasodilatation, have been
noted in patients with subclinical hypothyroidism; the values normalized
after treatment.19 Finally, thyroxine
therapy in patients with subclinical
hypothyroidism resulted in an 11%
reduction in carotid arter y intimamedia thickness.20
Cardiovascular disease and
mortality. The evidence is conflicting
about whether subclinical hypothyroidism results in an increase in cardiovascular disease or cardiovascular
mortality. In the Rotterdam Study of
women older than 55 years, the risk
of aortic atherosclerosis and myocardial infarction (MI) was increased by
about 2-fold in participants who had
subclinical hypothyroidism.21 The
Nagasaki study found a 2-fold elevation in the risk of angina and MI in
men but not in women with subclinical hypothyroidism.22 A study of patients with subclinical hypothyroidism who were between the ages of 70
and 79 years showed a 2.5- to 3-fold
increased risk of congestive heart
failure (for serum TSH higher than
7.0 mIU/L), but no increased risk of
coronary or cerebrovascular disease
or cardiovascular mortality.23 The
Busselton Health Study (Australia)
revealed a 2- to 3-fold increase in the
risk of coronary artery disease and a
1.5-fold increase in the risk of cardiovascular mortality in patients with
subclinical hypothyroidism.24
In contrast, the Cardiovascular
Health Study—a prospective study
of 3233 patients older than 65 years
who were monitored for 12 to 13
years—found no differences in incidence of coronar y arter y disease,
cerebrovascular disease, or cardiovascular mortality between euthyroid participants and those with subclinical hypothyroidism,25 although
there was an increase in heart failure
if the TSH exceeded 10 mIU/L.26 An
analysis of the individual data from
these and other studies found significant hazard ratios for coronar y
events to be 1.89 (CI, 1.28 to 2.80)
for serum TSH levels from 10 to 19.9
mIU/L, and for cardiovascular mortality to be 1.42 (CI, 1.03 to 1.95) for
serum TSH from 7.0 to 9.9 mIU/L
and 1.58 (CI, 1.10 to 1.27) for serum
TSH from 10 to 19.9 mIU/L; however, total mortality was not increased
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Hypothyroidism:
When to Treat,
When to Watch
for TSH lower than 20 mIU/L. 27 A
study of patients aged 85 to 89 years
showed lower cardiovascular mortality (hazard ratio, 0.77) in patients
with subclinical hypothyroidism than
in those who were euthyroid.28
Neuropsychiatric disease. Studies of neuropsychiatric disease and
subclinical hypothyroidism are difficult to interpret because of such confounding variables as inadequate control groups and the inclusion of patients taking lithium, those with
normal TSH levels and positive results on anti-TPO antibody tests, and
those with normal TSH levels but abnormal responses to thyrotropin-releasing hormone. On the whole, these
studies suggest an increased risk of
depression and panic disorder and a
poorer response to antidepressant
treatment in patients with subclinical
hypothyroidism.29,30 One study found
an increased risk of depression in patients with positive titers of anti-TPO
antibodies, but not in patients with elevated serum TSH concentrations
and negative antibody titers.31 These
results suggest a possible genetic
basis for the association of hypothyroidism and depression. In the Framingham study, Alzheimer disease was
more common in women, but not in
men, with subclinical hypothyroidism.32 However cognitive function was
unchanged by thyroxine treatment in
a randomized 1-year placebo-controlled trial of elderly patients with
TSH between 6.0 and 8.5 mIU/L.33
Weight gain. In the Framingham trial, the 3.5-year weight gain
among women with TSH values between 0.5 and 10 mIU/L was 2.3 kg
for those in the highest quintile and
0.5 kg for those in the lowest quintile.34 No study has demonstrated
weight loss with treatment of subclinical hypothyroidism.
Neuromuscular disease. A survey showed that 64% of patients with
subclinical hypothyroidism had 2 or
more symptoms of neuromuscular
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disease, compared with 14% of euthyroid controls; treatment with thyroxine ameliorated these symptoms.35
However, the patients in this survey
knew their diagnosis, and treatment
was not blinded or placebo-controlled. In another study older patients with TSH levels from 4.5 to 6.9
mIU/L had improved mobility (faster
usual and rapid gait speed) and cardiorespiratory fitness.36
Poor pregnancy outcomes.
Children born to mothers who had
elevated serum TSH concentrations
during the second trimester of pregnancy had a slightly lower IQ score
at age 7 to 9 years than did children
born to mothers with normal serum
TSH concentrations (103 vs 107).37
THE ARGUMENT FOR
THERAPY: A CRITICAL LOOK
AT THE EVIDENCE
Those who favor treating most
patients with subclinical hypothyroidism commonly cite 1 or more of
the several randomized clinical trials. Among 8 trials38-45:
•Four of the seven that assessed for
hypothyroid symptoms showed improvement with treatment.
•Two of the three that used psychometric testing results as an outcome
measure found an improvement with
treatment.
•Three of the seven that measured
serum total and LDL cholesterol levels found lower levels with treatment.
However, 3 of these studies included patients who met the strict
biochemical criteria for subclinical
hypothyroidism but had serum TSH
concentrations as high as 30 to 55
mIU/L,38,40,41 and 2 studies used a
fixed dose of thyroxine for treatment,39,45 which resulted in over-treatment in some patients. In 3 randomized controlled trials that included
only patients whose TSH values were
less than 15 mIU/L,42-44 there was no
improvement in any parameter studied except for a reduction in total and
LDL cholesterol levels in 1 study,42
while a fourth study that included patients with TSH up to 15.8 mIU/L, in
which 10% of patients were given excessive doses of thyroxine, found improvement in lipids, fatigue, and endothelial function.45
Problems in interpretation of
trial results. Other studies point to
the difficulty of interpreting many of
these results, especially those whose
end points are symptom scores. In a
population-based study of almost 400
patients who had normal serum TSH
concentrations while taking levothyroxine, participants had significantly
distressed scores on both general
health and thyroid-specific symptom
questionnaires.46 One explanation for
these findings may be a possible genetic predisposition to depression
among patients with autoimmune
thyroid disease.
It is also possible that levothyroxine therapy is suboptimal treatment for hypothyroidism in a subset
of patients. While twelve randomized
trials have compared combined
treatment (triiodothyronine [T3] and
T4 therapy) to therapy with T4 alone,
only 1 of these studies found that
symptoms (as assessed by standardized questionnaires) abated with
combined therapy. However, in another study, patients preferred combined therapy despite negative results on standardized symptom assessments.47 And a recent study from
the United Kingdom suggests that
16% of patients have a polymorphism
in the type 2 deiodinase that converts T4 into T3; those patients had
improved symptoms (by standardized questionnaires) when treated
with both T4 and T3.48
In one study that is commonly
cited to suppor t the treatment of
subclinical hypothyroidism, patients
were given doses of levothyroxine
that were slightly lower or slightly
higher than optimal doses (based on
TSH levels). The investigators found
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Subclinical
Hypothyroidism:
When to Treat,
When to Watch
CLINICAL HIGHLIGHTS
q Considerable controversy persists regarding screening for thyroid
dysfunction and treatment of subclinical hypothyroidism. Statements
from the American College of Physicians, the US Preventive Services
Task Force, the American Thyroid Association, the Endocrine Society,
and the American Association of Clinical Endocrinologists have failed to
reach a consensus.
q The upper limit of normal for serum TSH is age-related, with a value
of 3.56 mIU/L for patients aged 20 to 29 years, increasing to 7.49 for
patients over 80 years old.
q Subclinical hypothyroidism may be associated with modest weight
increases; however, no study has demonstrated weight loss with treatment of the condition.
q When serum TSH concentrations are greater than 10 mIU/L, subclinical hypothyroidism is associated with increases in serum low-density
lipoprotein cholesterol levels. In a meta-analysis, cardiovascular mortality,
but not all-cause mortality was increased when serum TSH was greater
than 7 mIU/L. Thus, thyroxine therapy should be considered if the
serum TSH level is 7 to 10 mIU/L or higher.
q Consider a trial of thyroxine for symptomatic patients whose serum
TSH level is below 10 mIU/L. If the patient perceives no benefit, therapy
can be discontinued.
that patients preferred slightly higher doses of thyroid hormone.49 However, this study was not blinded. A
double-blinded, randomized crossover trial assessed 3 different levels
of thyroxine treatment, which resulted in mean serum TSH concentrations of 2.8, 1.0, and 0.3 mIU/L, respectively. There were no differences in hypothyroid symptoms among
the groups, and patients could not
distinguish among the 3 levels of
thyroid hormone replacement.50
Placebos have a significant effect
on hypothyroid symptoms. In one of
the trials of combined T3 and T4 therapy, symptoms abated in 39% of patients who received placebo.51 In another study of patients with hypothyroid symptoms, 52 thyroxine and
placebo produced equal benefit despite the fact that the average serum
TSH concentrations in the thyroxinetreated group were at the lower limit
of the normal reference range. Because hypothyroid symptoms are
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readily amenable to the placebo effect, a large, double-blind, randomized, placebo-controlled trial is needed
to accurately assess the efficacy of levothyroxine therapy on hypothyroid
symptoms, cognitive function, and
psychological well-being in patients
with subclinical hypothyroidism.
RECOMMENDATIONS FOR
SYMPTOMATIC PATIENTS
Let us return to the 76-year-old
woman in the opening clinical scenario. Her TSH level is within the ageadjusted normal range for TSH.
There is no evidence that treating her
will improve her cognitive function or
fatigue. I would not treat her with levothyroxine. Patients taking levothyroxine are commonly unintentionally
over-treated; in one study 41% of patients over age 65 had subnormal
serum TSH levels.53 Only one trial
has assessed the risks of treatment;
while that trial found a 10% mortality
rate among treated patients and a 31%
mortality rate among untreated patients, the study is hardly robust with
only 20 patients treated, and only 2
deaths in the treatment group.54
Measurement of TPO antibodies might be useful. If they are high,
the patient should be more closely
monitored, and if her TSH increased
to values above 7.5 mIU/L, I would
then consider treatment. If the TSH
increased to values above 10 mIU/L,
treatment is indicated.
If the patient was younger and
had symptoms possibly related to
subclinical hypothyroidism, I would
offer a trial of levothyroxine, since in
younger patients—eg, a premenopausal woman—the risks of overtreatment (atrial fibrillation, reduced
bone density) are minimal.
RECOMMENDATIONS FOR
ASYMPTOMATIC PATIENTS
The evidence for treating patients with TSH values of less than
10 mIU/L is not compelling—except
in women who are pregnant.37,55 At
present, a TSH value of 7 to 10
mIU/L appears to be a reasonable
threshold for routinely recommending treatment (based on the favorable response of LDL cholesterol
levels to levothyroxine, and the higher risk of cardiovascular, but not allcause mortality). Thus, I would not
advise treating a patient whose TSH
concentration is elevated—but below
7 to 10 mIU/L—if he or she exhibits
no hypothyroid symptoms.
n
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