Subclinical
hypothyroidism (SHypo) is characterized by elevated serum TSH and thyroid
hormone levels at the lower limit but within their respective reference range.
It is
necessary to distinguish between patients with mildly increased serum TSH
levels (5–9 mU/L) and patients with more severely increased serum TSH levels
(10 mU/l or higher). About 75% of all SHypo patients have mild disease.
The
high prevalence (between 4 and 20% of the adult population) and the various
implications of SHypo require the need to establish a correct diagnosis,
clinical assessment and treatment of this disorder.
The
evaluation of transient and false causes of mild increases in TSH should be
excluded before treating SHypo.
Subclinical
hypothyroidism may be progressive or reversible. The annual rate of progression
to overt disease is particularly increased (4.3%) in women with elevated serum TSH
and anti-thyroid antibodies.
Important
cardiovascular and metabolic effects may develop in long-term untreated SHypo.
Elderly
Subjects with a TSH level of 7 mU/L or greater have a higher risk of heart
failure events than euthyroid subjects.
Initiating
levothyroxine replacement therapy is recommended for all
patients with a TSH greater than 10 mIU/L, even if the free thyroxine
concentration is within normal laboratory range. However, treatment of
patients with a serum TSH level between 5 and 10 mIU/L remains controversial.Initiating
levothyroxine replacement therapy is recommended for all
patients with a TSH greater than 10 mIU/L, even if the free thyroxine
concentration is within normal laboratory range. However, treatment of
patients with a serum TSH level between 5 and 10 mIU/L remains controversial.Subclinical hypothyroidism is an early, mild form of hypothyroidism, a condition
in which the body doesn't produce enough thyroid hormones.
It's called subclinical because only the serum level of thyroid stimulating
hormone from the front of the pituitary gland is a little bit above normalPu
Subclinical hypothyroidism is
defined by an elevated serum thyroid-stimulating hormone (TSH)
level along with a normal free thyroxine (T4) level. Whether it
should be treated remains controversial ch The typical range of
reference for TSH levels is anywhere between 0.4 and 4.9
milliunits per liter (mU/L) . ... Abnormally high TSH levels
mean that your thyroid is underperforming. Your pituitary gland reacts to a
lack of thyroid hormones by producing extra TSH to make up the
difference. This is called hypothyroidism.Aug 27, 2018as Subclinical
hypothyroidism may
be progressive or reversible. The annual rate of progression to
overt disease is particularly increased (4.3%) in women with elevated serum TSH
and anti-thyroid antibodies. ... No consensus exists on the
clinical significance and treatment of the mild form of thyroid failure.e
\
search
input
Subclinical
Hypothyroidism Is Mild Thyroid Failure and Should be Treated
The Journal of
Clinical Endocrinology & Metabolism, Volume 86, Issue 10,
1 October 2001, Pages 4585–4590, https://doi.org/10.1210/jcem.86.10.7959
Published:
Issue Section:
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
4–10% in large general population screening surveys (1–5) and from 7–26% in
studies of the elderly (1–3, 6–11). 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 3–18% of affected patients per
year (10–17). 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
(10–16).
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 5–10 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.
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.
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).
Neurobehavioral abnormalities and neuromuscular function. Other
cross-sectional studies have demonstrated evidence of specific neurobehavioral
and neuromuscular dysfunction in mild thyroid failure patients (19–31).
Depression (19–23), 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 (32–41). Identified functional abnormalities include impaired
myocardial contractility (32–40) and diastolic dysfunction (39–41), at rest
(32, 34, 37, 39–41) or with exercise (35–39). 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 (44–46). 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).
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).
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
factors—hypercholesterolemia, hypertension (BP), smoking, and diabetes
mellitus.
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).
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).
Table 1.
Randomized controlled
trials investigating the effects of L-thyroxine treatment on general symptoms in
patients with mild thyroid failure
|
Author (Ref.)
|
n
|
Design
|
TSH (uU/ml)
|
Results
|
|
|
Pre-L-thyroxine
|
On L-thyroxine
|
||||
|
Cooper (33 )
|
33
|
Randomized, double-blind,
placebo-controlled (1 yr)
|
10.8
|
2.6
|
Symptom score improvement in L-thyroxine group
(P < 0.05)
|
|
Nystrom (34 )
|
17
|
Randomized, double-blind,
placebo-controlled crossover (6 months)
|
7.7
|
1.9
|
Symptom score improvement in L-thyroxine group
(P < 0.01)
|
|
Jaeschke (50 )
|
32
|
Randomized, double-blind,
placebo-controlled (11 months)
|
12.3
|
4.6
|
Symptom score not improved
in L-thyroxine
group (P = ns); memory improved (P < 0.01)
|
ns, Not statistically
significant.
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
(32–41), 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).
Table 2.
Studies that have
investigated the effects of L-thyroxine on cardiac function in patients with
mild thyroid failure
|
Author (Ref.)
|
n
|
TSH (uU/ml)
|
Untreated
|
L-thyroxine
Therapy
|
Methodsa
|
|||
|
Pre-L-thyroxine
|
On L-thyroxine
|
Rest
|
Exercise
|
Rest
|
Exercise
|
|||
|
Ridgway (32 )
|
20
|
28
|
1.9
|
↓MC
|
|
↑MC
|
|
1
|
|
Cooper (33 )
|
33
|
10.8
|
2.6
|
Normal
|
|
↑MCb
|
|
1
|
|
Nystrom (34 )
|
17
|
7.7
|
1.9
|
↓MC
|
|
↑MC
|
|
1
|
|
Bell (35 )
|
18
|
17.9
|
3.2
|
Normal
|
↓MC
|
|
↑MC
|
2
|
|
Forfar (36 )
|
10
|
18.2
|
3.5
|
Normal
|
↓MC
|
|
↑MC
|
2
|
|
Foldes (37 )
|
17
|
10.3
|
|
↓MC
|
↓MC
|
↑MC
|
|
1,2
|
|
Kahaly (38 )
|
20
|
11.2
|
|
Normal
|
↓MC
|
|
↑MC
|
1,3
|
|
Arem (39 )
|
8
|
14.8
|
3.0
|
↓DF
|
↓MC
|
|
↑MC
|
1,3
|
|
Monzani (40 )
|
20
|
5.4
|
1.2
|
↓MC, DF
|
|
↑MC, DF
|
|
1,3,4
|
|
Biondi (41 )
|
10
|
8.6
|
1.7
|
↓DF
|
|
↑MC, DF
|
|
3
|
MC, Myocardial
contractility; DF, diastolic function.
a
1, Systolic time
intervals; 2, ventriculography; 3, Doppler echocardiography; 4,
videodensitometry.
b
In 5 subjects with
initially impaired MC.
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 0.2–0.4
mmol/liter (7.9–15.8 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 (44–46) 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 0.5–2.0
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.
No comments:
Post a Comment