CARDIOVASCULAR CONSEQUENCES OF SUBCLINICAL HYPER- AND HYPOTHYROIDISM
Department of Clinical and Molecular Endocrinology and Oncology, University of Naples Federico II School of Medicine, Via S. Pansini 5, 80131, Naples.;
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Subclinical thyroid dysfunctions are defined by normal free-triiodothyronine
(FT3) and free-thyroxine (FT4) concentrations in the presence of abnormal
TSH, which is low-undetectable in subclinical hyperthyroidism (SH) and
increased in subclinical hypothyroidism (Sh).
The clinical significance of subclinical thyroid dysfunction is much
debated (1-3). The presence of tissue effects, symptoms and signs of
mild thyroid hormone excess or deficiency and the management and treatment
of these conditions are controversial issues. Similarly, the TSH cut-off
point that determines the effects of subclinical thyroid dysfunction
remains to be established.
The cardiovascular system, which is a major target of thyroid hormone,
is sensitive to the effects of thyroid hormone excess or deficiency
at the tissue level. Many symptoms and signs in patients with overt
hypo- or hyperthyroidism are related to the reduced or increased action
of thyroid hormone on cardiac function. Triiodothyronine (T3) affects
the heart and vascular system through genomic and non-genomic mechanisms;
it influences heart rate, systolic and diastolic function and systemic
vascular resistance, and hence cardiac performance (4,5).
In human overt hyperthyroidism, the increase in left ventricular performance
is predominantly sustained by the increased preload that results in
enhanced left ventricular diastolic function (6,7). The reduced systemic
vascular resistance, coupled with increased venous return and preload,
enhances cardiac output (6,7). The decreased cardiac output in hypothyroid
patients at rest depends largely on altered diastolic relaxation and
hemodynamic loading (5,8). The reduced cardiac preload, combined with
bradycardia and slightly depressed myocardial contractility, accounts
for a subnormal cardiac output in overt hypothyroidism, whereas peripheral
vascular resistance is remarkably increased (4,5,8). Moreover, cardiovascular
alterations have been found in individuals with subclinical thyroid
disease (9). This review covers the data about the progression of subclinical
thyroid dysfunctions and cardiovascular risk. It also deals with the
cardiovascular risk and the need for treatment as estimated from epidemiological
data on cardiovascular morbidity and mortality.
Causes, prevalence and progression
The reported overall prevalence of SH ranges between 0.5 and 6.3%, the
prevalence being higher in patients over 65 years. The prevalence can
differ in relation to iodine intake and the TSH cut-off point used for
Subclinical hyperthyroidism may be caused by exogenous or endogenous
factors. The exogenous form is usually related to TSH-suppressive therapy
with L-thyroxine for the treatment of benign thyroid disease and differentiated
thyroid carcinoma. The endogenous form is usually related to the same
causes as overt thyrotoxicosis subsequent to autonomously functioning
thyroid adenomas, and multinodular goitre. TSH suppressive or unintentional
over-replacement L-thyroxine therapy was the most common form of SH
(20.7%) among subjects taking L-thyroxine in the Colorado study (11),
whereas endogenous factors accounted for a minority of cases and prevailed
in areas of iodine insufficiency (12). Endogenous SH is usually a slowly
progressive disorder and may last several years before developing into
overt thyrotoxicosis. The risk of SH progressing to overt hyperthyroidism
varies between 2% and 7% per year in patients with undetectable TSH
(12). Unfortunately, there are no data on the progression of SH in patients
with TSH between 0.1-0.5 mU/L.
Exogenous and endogenous SH may lead to signs and symptoms of thyroid
hormone excess thereby mimicking adrenergic overactivity and impairing
quality of life (12, 13). Subclinical hyperthyroidism affects the cardiovascular
system in various ways, and its increased cardiovascular risk is well
documented in the elderly (14,15). The cardiovascular abnormalities
are similar in stable endogenous and exogenous SH (12)
The major cardiovascular findings in patients with SH coupled with undetectable
TSH are a higher heart rate and a higher risk of supraventricular arrhythmias
(15-17). The most consistent cardiac abnormality is a significant increase
in left ventricular mass with unchanged or increased at-rest systolic
function and, usually, impaired diastolic function (16,18-20). Moreover,
reduced systolic performance on effort and decreased exercise tolerance
has been reported in patients with SH who had a greater increase in
left ventricular mass (21). Thyroid hormone-induced hypertrophy in SH
is due primarily to the cardiac response induced by the increased cardiac
workload. This is accordance with cardiac hypertrophy induced in rats
by thyroid hormone excess (22). Moreover, the significant increase in
left ventricular mass with a tendency towards LV concentric remodelling
reported in patients with long-standing SH (16,18,19) may counteract
the favourable effect acutely exerted by thyroid hormone on diastolic
performance, and so lead to impaired ventricular relaxation and systolic
dysfunction during effort (20,21). The altered passive elasticity of
the ventricle (chamber stiffness) determined by the presence of myocardial
hypertrophy is the major determinant of diastolic dysfunction in patients
The prognostic significance of these cardiovascular alterations in patients
with SH remains to be clarified especially in young and middle-aged
patients with low TSH. Unfortunately, there is no study of the effects
on cardiovascular system of minimally suppressed TSH (i.e., TSH between
0.1-0-4 mU/L). However, the increase in heart rate and in left ventricular
mass usually precedes the onset of more severe cardiovascular disease,
and is an independent risk factor for increased cardiovascular morbidity
and mortality in the general population (23).
The detrimental effects of SH are well documented in the elderly and
atrial fibrillation represents an important cardiovascular risk. The
Framingham study evaluated the risk of atrial fibrillation during the
10-year follow-up in 2007 people aged 60 years or older with endogenous
or exogenous SH (15). The adjusted relative risk for atrial fibrillation
was 3.1 times higher in the group with serum TSH ?0.1 mU/L compared
with those with normal TSH concentrations (>0.4-5.0mU/L). The relative
risk of atrial fibrillation was 1.6 times higher in the group with slightly
low TSH concentrations (0.1-0.4 mU/L) (p=0.04) with an an incidence
of atrial fibrillation in 16/1000 patients person-years) (p=0.11) (15).
Similarly, in a large retrospective study on hospitalized consecutive
older subjects, the relative risk of atrial fibrillation was 5.2 (p<0.01)
in patients affected by SH with TSH <0.4 mU/L. (17). The combination
of subclinical hyperthyroidism and age may have deleterious effects
on the heart (12,23). Furthermore, the possible onset of overt hyperthyroidism
in hearts previously exposed to longstanding untreated SH may further
increase the cardiovascular risk (9). This body of data is in agreement
with the increased cardiovascular mortality reported in a community-based
review of subjects aged 60 years or older with endogenous SH and TSH
values <0.5 mU/L monitored for 10 years (14).
In patients with benign thyroid disease and in low-risk patients with
differentiated thyroid cancer, cardiovascular parameters and quality
of life can be improved by reducing L-T4 dosage to keep TSH at the lower
limit of normal range (24). A cardioselective b-blocking drug, in addition
to L-thyroxine, can be used in high-risk thyroid cancer patients to
attenuate symptoms caused by mild thyroid hormone excess, and to reduce
the risk of atrial arrhythmias and an increase in left ventricular mass
(12). Methimazole administration and radioiodine therapy may restore
euthyroidism and so improve the cardiovascular risk in patients with
endogenous SH (25,26).
A panel of experts recently recommended that treatment of endogenous
SH should be considered in case of TSH <0.1 mU/L especially when
patients are older than 60 years, and if there are symptoms or risk
of heart disease (3). The routine treatment of SH if TSH is between
0.1 and 0.4 mU/L is not recommended (3). In fact, despite increased
mortality in the elderly, it remains to be established if a subnormal
TSH concentration induces the same adverse effects as suppressed TSH
on the heart of young and middle-aged patients. However, it is important
to stress that the clinical manifestations of ‘subclinical’
hyperthyroidism may be related to an individual's sensitivity to thyroid
hormone excess, which depends on the patient’s thyroid function
set-point (12), and may be triggered by individual predisposing conditions
Causes, prevalence and progression
Subclinical hypothyroidism reflects an early and mild form of thyroid
failure. Most patients with Sh have chronic autoimmune thyroiditis and
test positive for serum antithyroid peroxidase (anti-TPO) antibodies;
in these patients, the risk of progression to overt disease is particularly
increased. Poor compliance with L-T4 therapy or suboptimal treatment,
may also result in Sh. Medications (e.g., lithium, iodine, interferon,
etc.), 131I therapy or thyroidectomy and external irradiation of the
neck can also cause Sh. The epidemiologic data from three large population-based
screening studies (the Whickham Survey, the Colorado Thyroid Disease
Prevalence Study and the National Health and Nutrition Examination Survey
III) (10,11,28) show that the prevalence of Sh is 4-10% and that this
condition increases significantly with age, so that by the ninth decade
of life the prevalence is 15%-20%.
A mild TSH increase (between 4-10 mU/L) is present in about 74% of Sh
patients, and whether to treat Sh associated with this TSH range is
hotly debated. The progression to overt hypothyroidism occurs at a rate
of 2-5% per year and it is increased in patients with TSH >6 mU/L
and positive thyroid antibodies.
The reasons for treating Sh are: to prevent progression to overt disease,
to attenuate symptoms, and to correct lipid profile and cardiovascular
abnormalities and so reduce the cardiovascular risk. However, the TSH
cut-off at which to start replacement therapy with L-thyroxine is still
The cardiovascular risk in patients with Sh results from changes in
cardiovascular function and from accelerated atherosclerosis (8,9)
The most consistent cardiac abnormality in patients with Sh is impaired
left ventricular diastolic function, which is characterized by slowed
myocardial relaxation and impaired early ventricular filling (9,29).
Impaired left ventricular relaxation was identified in patients with
Sh by echocardiography and radionuclide ventriculography (30-33). All
studies of young and middle-aged patients with a mild and persistent
TSH increase (4-10 mU/L) due to Hashimoto thyroiditis show that diastolic
dysfunction of the left ventricle is a common finding in patients with
persistent Sh (30-33). Diastolic function is impaired both at rest and
during exercise (33). Slowed left ventricle relaxation is in accordance
with the finding that thyroid hormone affects the calcium-regulating
proteins SERCA and PLB thereby slowing down calcium re-uptake into the
sarcoplasmic reticulum during diastole (29). Altered diastolic function
can be reversed by L-thyroxine replacement therapy (8,9,29-33).
Conflicting results on systolic function are reported in patients with
overt and Sh (8). Impaired left ventricular systolic function on effort
was documented in patients with Sh by using radionuclide ventriculography,
Doppler echocardiography and cardiopulmonary exercise testing (29, 34).
The negative effect induced by Sh on systolic function at rest and during
effort is reverted by restoring euthyroidism with L-T4 therapy (29-34).
Ultrasonic myocardial textural analysis indicates that myocardial composition
is altered in patients with Sh (35). Many Sh patients are elderly and
the onset or progression of the disease in these vulnerable subjects
may precipitate cardiac decompensation and promote congestive diastolic
heart failure (5,8).
Overt hypothyroidism is associated with premature atherosclerosis and
coronary artery disease. Epidemiological studies of the link between
Sh and atherosclerosis have yielded conflicting results (36,37). Compelling
evidence of a higher prevalence of atherosclerotic cardiovascular disease
in patients with Sh (defined as TSH >4.0 mU/L) emerges from a recent
large cross-sectional survey of 1,149 women aged 55 years or more, living
in Rotterdam (37). It was shown that Sh patients had a significantly
increased age-adjusted prevalence of aortic atherosclerosis on chest
radiographs and myocardial infarction compared with controls. The attributable
risk percentage for Sh associated with myocardial infarction was within
the range of the traditionally recognized risk factors for coronary
artery disease, including hypercholesterolemia, hypertension, smoking
and diabetes mellitus. Moreover, in a cross-sectional analysis, Sh was
associated with ischemic heart disease independent of age, systolic
blood pressure, body mass index, cholesterol, smoking, or presence of
diabetes mellitus (38).
The mechanisms responsible for atherosclerosis and coronary artery disease
in patients with Sh are controversial (8,39). Diastolic hypertension
(40,41), dyslipidemia (42-45), endothelial dysfunction (46), elevated
C reactive protein levels (47) and coagulation abnormalities (48) are
atherosclerotic risk factors associated with Sh and may be reversed
after L-T4-induced euthyroidism.
In a recent review of guidelines, treatment of Sh was recommended when
serum TSH is >10 mU/L so as to prevent progression to overt disease
(3). Treatment of subclinical hypothyroidism based on cardiovascular
risk was not recommended because the data available were considered
insufficient and unconvincing (3). Furthermore, routine levo-thyroxine
treatment was not recommended when TSH is between 4.5 and 10 mU/L (3).
However, mild hypothyroidism (TSH <10 mU/L) can negatively affect
the cardiovascular system, especially diastolic function, endothelial
function and systemic vascular resistance. Treatment of this mild form
of hypothyroidism may improve cardiovascular function (8, 49) and it
may prevent atherosclerosis and coronary artery disease (50) thereby
reducing the cardiovascular risk.
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Cardiovascular consequences of subclinical hyper- and hypothyroidism
Title: Hot Thyroidology; Abbreviated key title: Hot Thyroidol.; Online ISSN: 2075-2202
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