Subclinical Hypothyroidism Is Mild Thyroid Failure and Should be Treated
Michael T. McDermott and
E. Chester Ridgway
Division of Endocrinology, Metabolism and Diabetes, University of
Colorado Health Sciences Center, Denver, Colorado 80262
Address all correspondence and requests for reprints to: Michael T. McDermott, M.D., Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box B-151, Denver, Colorado 80262. E-mail:
michael.mcdermott{at}uchsc.edu
Subclinical hypothyroidism is defined as an
elevated serum TSH level associated with normal total or free
T4 and T3 values. The
overall prevalence has been reported to range from 410% in large
general population screening surveys (1, 2, 3, 4, 5) and from
726% in studies of the elderly (1, 2, 3, 6, 7, 8, 9, 10, 11). Because
of the frequency with which this condition is encountered, important
questions have been raised regarding its clinical relevance and
appropriate management. One of the myths that surrounds subclinical
hypothyroidism is that the laboratory profile of an elevated serum TSH
and normal free thyroid hormone levels really represents "compensated
hypothyroidism." The reasoning behind this idea is that, since the
circulating levels of thyroid hormones are within the normal range with
only the serum TSH being elevated, the affected subject is really
euthyroid because the increased TSH is stimulating and driving the
thyroid gland to produce normal thyroid hormone levels. Certainly,
elevated serum TSH levels do stimulate even a diseased thyroid gland to
produce and release more thyroid hormone. However, as long as the serum
TSH level remains elevated, the thyroid hormone levels are not truly
normal for that individual. The clearance kinetics of thyroid hormones
and TSH from the circulation actually make such a conclusion
inescapable. Because the half-life of T4 is
7 d and that of T3 is 1 d, the serum
TSH, which has a half-life of less than 1 h, would certainly be
expected to return to normal if thyroid hormone levels were, indeed,
normal for that individual. An elevated TSH in an individual patient,
thus, means that the circulating thyroid hormone concentrations are
insufficient, with a few rare exceptions (TSH-secreting tumors, thyroid
hormone resistance syndromes). We, indeed, believe that subclinical
hypothyroidism represents mild thyroid failure and is a clinically
important disorder that has adverse clinical consequences and that
should be treated in most, if not all, cases. We will support this
position by reviewing the reported objective data regarding its natural
history, its clinical manifestations, and the benefits of
treatment.
Natural history
Mild thyroid failure represents an early stage of thyroid disease
that will commonly progress to overt hypothyroidism. Progression has,
in fact, been reported to occur in approximately 318% of affected
patients per year (10, 11, 12, 13, 14, 15, 16, 17). One study evaluated the
natural history of mild thyroid failure in 154 female patients over a
10-yr period; 57% of patients continued to have mild thyroid failure,
34% of patients progressed to overt hypothyroidism, and 9% of
patients reverted to a normal TSH level. How many of the 9% had a
transient form of thyroiditis such as silent, subacute, or postpartum
thyroiditis is unclear (17). The strongest predictors of
progression are the presence of antithyroid antibodies, serum TSH
values greater than 20 µU/ml, a history of radioiodine
ablation for Graves disease, a history of external radiation therapy
for nonthyroid malignancies, and chronic lithium treatment
(10, 11, 12, 13, 14, 15, 16).
Clinical manifestations
Symptoms. Mild thyroid failure is often asymptomatic; however,
nearly 30% of patients with this condition may have symptoms that are
suggestive of thyroid hormone deficiency (2, 18). The
Colorado Thyroid Disease Prevalence Study (2) measured
serum TSH levels and conducted symptom surveys in over 25,000 state
residents. Elevated serum TSH values were found in 9.5% of all
subjects and in 8.9% of those who were not already on thyroid hormone
therapy (Fig. 1
); 75% of these
individuals had serum TSH levels in the 510 µU/ml range. In
response to a validated survey regarding symptoms of thyroid hormone
deficiency, the 2,336 subjects who were identified as having mild
thyroid failure significantly more often reported having dry skin
(28%; P < 0.001), poor memory (24%;
P < 0.001), slow thinking (22%; P <
0.001), muscle weakness (22%; P < 0.001), fatigue
(18%; P < 0.01), muscle cramps (17%;
P < 0.001), cold intolerance (15%; P
< 0.001), puffy eyes (12%; P < 0.05), constipation
(8%; P < 0.05), and hoarseness (7%;
P < 0.05) than did euthyroid subjects. It is important
to note that, whereas euthyroid subjects experienced a mean of 12.1%
of all listed symptoms, overtly hypothyroid subjects had 16.6% of
these symptoms (P < 0.05 vs. euthyroid
group), and subjects with mild thyroid failure reported an intermediate
13.7% of the symptoms (P < 0.05 vs.
euthyroid group) (Fig. 2
). This suggests
a "dosage effect" between levels of thyroid hormones and symptoms.
Consistent with these findings, a Swiss study involving 332 women with
hypothyroidism reported that 24% of the 93 subjects with mild thyroid
failure exhibited typical symptoms of hypothyroidism (18).
These studies also emphasize the difficulty in making the diagnosis of
primary hypothyroidism using clinical symptoms alone; euthyroid
subjects and patients with mild or overt hypothyroidism all had similar
constellations of symptoms. Despite statistical significance in large
groups, it can be difficult in an individual patient to distinguish a
euthyroid subject from one with either mild or overt thyroid
disease.

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Figure 1. The Colorado Thyroid Disease Prevalence Study
(2 ). Shown are the age- and gender-specific prevalences of
high serum TSH levels found during the screening of 25,862 Colorado
state residents in 1995.
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Figure 2. The Colorado Thyroid Disease Prevalence Study
(2 ). Participants were given a validated survey containing
questions regarding symptoms of thyroid hormone deficiency. Of all the
symptoms listed, euthyroid subjects (n = 22,842) reported having
12.1%, mild thyroid failure patients (n = 2,336) had 13.7%, and
overtly hypothyroid patients (114) had 16.6%. Compared with the
euthyroid subjects, total symptoms reported were significantly higher
for both the mild thyroid failure patients (P <
0.05) and those with overt hypothyroidism (P <
0.05).
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Neurobehavioral abnormalities and neuromuscular function.
Other cross-sectional studies have demonstrated evidence of specific
neurobehavioral and neuromuscular dysfunction in mild thyroid failure
patients (19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31). Depression (19, 20, 21, 22, 23),
memory loss (2, 19, 24), cognitive impairment
(25) and a variety of neuromuscular complaints (26, 27) have all been reported to occur more frequently in patients
with this condition. Objective peripheral nerve dysfunction, manifested
by decreased conduction amplitude in peripheral nerves
(28), and an abnormal stapedial reflex (29)
have been demonstrated in these patients. Skeletal muscle
abnormalities, including elevated serum creatine phosphokinase levels
(30), increased circulating lactate levels during exercise
(26), and repetitive discharges on surface
electromyography (27), have also been reported. Finally,
there is intriguing evidence that mild thyroid failure in pregnant
women may result in reduced intellectual development of their euthyroid
offspring (31).
Cardiac-pulmonary function. Myocardial function has been
reported in multiple studies to be subtly impaired in patients with
mild thyroid failure (32, 33, 34, 35, 36, 37, 38, 39, 40, 41). Identified functional
abnormalities include impaired myocardial contractility
(32, 33, 34, 35, 36, 37, 38, 39, 40) and diastolic dysfunction (39, 40, 41),
at rest (32, 34, 37, 39, 40, 41) or with exercise
(35, 36, 37, 38, 39). Myocardial texture has also been shown to be
abnormal by videodensitometric analysis (40). In one
comprehensive study of exercise capacity (38), patients
with mild thyroid failure were shown to have significant impairment of
exercise-related stroke volume, cardiac index, and maximal aortic flow
velocity. Pulmonary testing in these same patients revealed decreased
vital capacity, reduced anaerobic thresholds, and decreased oxygen
uptake at the anaerobic threshold (38). These data clearly
demonstrate that cardiovascular function in mild thyroid failure is
slightly impaired and not identical to that in the euthyroid state. The
important question is whether these differences result in clinically
significant impairment of performance in affected patients.
Cardiovascular risk factor. Mild thyroid failure has been
extensively evaluated as a cardiovascular risk factor. The condition
has been shown to be associated with increased serum levels of total
cholesterol (Fig. 3
) and low-density
lipoprotein (LDL) cholesterol in most but not all studies (2, 38, 42, 43) and with reduced high-density lipoprotein cholesterol in
some studies (38). Some reports have suggested that even
high normal serum TSH values may adversely affect serum lipid and
lipoprotein levels (44, 45, 46). It has been estimated that an
increase in the serum TSH level of 1 µU/ml is associated with a rise
in the serum total cholesterol concentration of 0.09 mmol/liter (3.5
mg/dl) in women and 0.16 mmol/liter (6.2 mg/dl) in men
(45). The relationship between TSH and LDL cholesterol
seems to be most significant in individuals who have underlying insulin
resistance (46). One recent study reported that patients
with mild thyroid failure, and even subjects with high normal serum TSH
values, have evidence of endothelial dysfunction, manifested by
impaired flow-mediated, endothelial-dependent vasodilatation
(47). An association between mild thyroid failure and
peripheral vascular disease was suggested by an older case-control
study involving elderly women (48). A 20-yr follow-up
study of the original Whickham Survey found no association between
initial hypothyroidism, raised serum TSH levels, or antithyroid
antibodies and the development of coronary artery disease
(49). In contrast, a more recent report from the Rotterdam
Study (9) concluded that patients with mild thyroid
failure have a significantly increased prevalence of aortic
atherosclerosis and myocardial infarctions. After adjustment for
multiple known coronary artery disease risk factors, the authors found
mild thyroid failure to be an independent and equivalently important
risk factor for myocardial infarctions (Fig. 4
).

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Figure 3. The Colorado Thyroid Disease Prevalence Study
(2 ). Shown are the mean serum total cholesterol levels in
the 22,842 euthyroid subjects (216 mg/dl), the 2,336 mild thyroid
failure subjects (224 mg/dl), and the 114 subjects with overt
hypothyroidism (251 mg/dl); both thyroid disease groups had
statistically higher total cholesterol levels and LDL cholesterol
levels (data not shown) than did the euthyroid controls
(P < 0.001).
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Figure 4. The Rotterdam Study (9 ). Analysis of
the relationship between subclinical hypothyroidism (SCH) and
myocardial infarctions in this study revealed an attributable risk of
60% (SCH contributed to 60% of the myocardial infarctions in the 124
women who had SCH) and a population attributable risk of 14% (SCH was
involved in 14% of all myocardial infarctions in the entire group of
1149 women). These risks were similar to those associated with the
major recognized cardiovascular risk factorshypercholesterolemia,
hypertension (BP), smoking, and diabetes mellitus.
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Benefits of treatment
Having defined the scope, natural history, clinical features, and
potential morbidity of mild thyroid failure, one must next ask whether
treatment of the condition has demonstrable benefits. A number of
studies have addressed this issue.
Symptoms. There have been three randomized controlled trials
(RCT) examining the effects of L-thyroxine treatment on
general symptoms in subjects with mild thyroid failure (Table 1
). Two of these RCTs (33, 34) reported that mild thyroid failure subjects who were treated
with L-thyroxine had significantly greater improvement in
general hypothyroid symptom scores than did subjects who were treated
with placebo (Fig. 5
). A third RCT
(50) showed no symptomatic treatment benefit; in this
study, however, the mean serum TSH level on L-thyroxine
treatment was 4.6 µU/ml, which was at the high end of the normal
range. One uncontrolled study also reported a reduction of general
somatic complaints after L-thyroxine treatment was
instituted (19).
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Table 1. Randomized controlled trials investigating the
effects of L-thyroxine treatment on general symptoms in
patients with mild thyroid failure
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Figure 5. A RCT of L-thyroxine (L-T4) therapy in
subjects with mild thyroid failure (33 ). Subjects (n
= 33) were randomly assigned to received L-thyroxine
therapy or placebo for a period of 1 yr.
L-thyroxine-treated subjects had a significant
improvement in their mean symptom score compared with the
placebo-treated group (P < 0.05).
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Neurobehavioral abnormalities and neuromuscular function.
Memory has been shown to improve significantly in one RCT
(50) and in two uncontrolled studies in which mild thyroid
failure patients were given L-thyroxine therapy (19, 24). Other reported benefits from uncontrolled interventional
studies include reduction in neuromuscular complaints (19, 27) and normalization of initially abnormal electromyograms
(27).
Cardiac-pulmonary function. Studies that have examined the
effects of L-thyroxine treatment on cardiac function,
including one RCT (40), have reported modest but
relatively consistent beneficial results (Table 2
). Observed responses to treatment have
included enhanced cardiac contractility (32, 33, 34, 35, 36, 37, 38, 39, 40, 41),
improvement of diastolic function (40, 41), and
normalization of videodensitometric myocardial texture
(40). Increases in pulmonary vital capacity, the anaerobic
threshold and oxygen uptake at the anaerobic threshold have also been
demonstrated (38).
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Table 2. Studies that have investigated the effects of
L-thyroxine on cardiac function in patients with mild
thyroid failure
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Cardiovascular risk factor. The reported lipid and lipoprotein
responses to treatment of mild thyroid failure with thyroid hormone
have been somewhat inconsistent (38). A retrospective
evaluation suggested that thyroid hormone replacement had very little
lipid-lowering effect in patients whose initial TSH values were less
than 10 µU/ml (51). However, two quantitative literature
reviews (42, 43) of the prospective studies examining this
issue have concluded that L-thyroxine treatment of patients
with mild thyroid failure lowers serum total cholesterol by
approximately 0.20.4 mmol/liter (7.915.8 mg/dl) and LDL cholesterol
by about 0.26 mmol/liter (10 mg/dl). The observed cholesterol
reductions were greater in patients with inadequately treated overt
hypothyroidism (0.44 mmol/liter; 17.4 mg/dl) than in those with
untreated spontaneous mild thyroid failure (0.14 mmol/liter; 5.5 mg/dl)
and were also greater in patients with higher initial cholesterol
levels (43). There have been no reported beneficial
effects on high-density lipoprotein cholesterol or triglycerides
(42, 43). One intriguing, but uncontrolled, retrospective
analysis (52) showed progression of coronary
atherosclerosis in subjects on L-thyroxine therapy with
elevated serum TSH levels compared with those with normal TSH levels
(P < 0.02).
Treatment goals. Firm data-based guidelines for treatment
goals have not yet been established. The distribution of serum TSH
values in the normal population is skewed, with the majority of
individuals having TSH values at the lower end of the normal range
(53). Recent studies have reported that "high normal"
TSH values may be associated with modest increases in serum cholesterol
levels (44, 45, 46) and that serum cholesterol levels improve
when TSH values are reduced from the high end to the low end of the
normal range with L-thyroxine supplementation
(44). Furthermore, individuals with high normal serum TSH
levels may have endothelial dysfunction (47). Thus,
although not based on prospective outcomes data, these findings would
suggest to us that the optimal goal TSH range for
L-thyroxine-treated patients is 0.52.0 µU/ml.
Cost-effectiveness and consensus opinion. Additional support
for a decision to treat comes from a recent analysis, which concluded
that screening for and treating mild thyroid failure in all adults
greater than 35 yr old is as cost-effective as many other screening
procedures used in the United States today (54). Finally,
we have recently conducted a survey seeking opinions from both primary
care providers (PCPs) and members of the American Thyroid Association
(ATA) regarding the management of hypothyroidism (55).
When presented the case of a 26-yr-old woman with minimally symptomatic
mild thyroid failure, the majority of respondents (70% of PCPs and
65% of ATA members) indicated that they would treat the patient if
antithyroid antibodies were negative, whereas 95% of ATA members
recommended treatment if antibodies were positive. Responses were
similar when the case was a 71-yr-old woman with minimally symptomatic
mild thyroid failure; the majority (64% of PCPs and 61% of ATA
members) chose to treat if antithyroid antibodies were negative, and
92% of ATA members recommended treatment if antibodies were
positive.
Summary
We believe that mild thyroid failure is a common disorder that
frequently progresses to overt hypothyroidism. The condition may
clearly be associated with somatic symptoms, depression, memory and
cognitive impairment, subtle neuromuscular abnormalities, subtle
systolic and diastolic cardiac dysfunction, raised serum levels of
total and LDL cholesterol, and an increased risk for the development of
atherosclerosis. There is documented evidence that many, if not most,
of these adverse effects are improved or corrected when
L-thyroxine replacement is instituted. Furthermore,
treatment of mild thyroid failure has been reported to be
cost-effective. Early treatment may even be justified in asymptomatic
individuals to prevent the symptoms of more severe thyroid hormone
deficiency that eventually develop as the thyroid gland progressively
fails; this is particularly true of antithyroid antibody-positive
patients, who have the highest risk of disease progression. For these
reasons, we recommend L-thyroxine treatment for the
majority of patients with mild thyroid failure, particularly those who
have symptoms, other cardiovascular risk factors, goiters, or positive
antithyroid antibodies, and in those who are pregnant. However, despite
these positive indications that treatment with thyroid hormone carries
a benefit, there are many unanswered questions. There are few
prospective, randomized placebo-controlled studies that have been
performed, a shame when compared with other common disorders such as
hypercholesterolemia and osteoporosis. The potential consequences of
untreated mild thyroid failure on atherosclerosis in adults and on
intellectual potential in infants born to mothers with mild thyroid
failure begs for definitive answers about the therapeutic benefits of
thyroid hormone replacement. It is no longer scientifically or morally
justifiable to argue whether mild thyroid failure is "something" or
"nothing." What is clearly needed now are clean, randomized,
prospective, and adequately powered trials to provide unequivocal
answers to the lingering but critical questions regarding the effects
of mild thyroid failure and its treatment on important end points such
as intellectual function, ischemic heart disease, and quality of
life.
Acknowledgments
Footnotes
Abbreviations: ATA, American Thyroid Association; PCP, primary
care provider; RCT, randomized controlled trial.
Received April 19, 2001.
Accepted June 26, 2001.
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