THEMED ARTICLE I Hypertension
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Stella Stabouli1,2,
Sofia Papakatsika2
and Vasilios Kotsis†2
1
Pediatric Intensive Care Unit,
Hippokration Hospital,
Thessaloniki, Greece
2
Hypertension Center, 3rd Department
of Medicine, Papageorgiou Hospital,
Aristotle University of Thessaloniki,
3 Filippoupoleos, Thessaloniki 55132,
Greece
†
Author for correspondence:
Tel.: +30 697 474 8860
Fax: +30 231 045 2429
bkotsis@med.uoa.gr
www.expert-reviews.com
Review
Hypothyroidism
and hypertension
Expert Rev. Cardiovasc. Ther. 8(11), 1559–1565 (2010)
Hypothyroidism has been recognized as a cause of secondary hypertension. Previous studies
on the prevalence of hypertension in subjects with hypothyroidism have demonstrated elevated
blood pressure values. Increased peripheral vascular resistance and low cardiac output has
been suggested to be the possible link between hypothyroidism and diastolic hypertension.
The hypothyroid population is characterized by significant volume changes, initiating a
volume‑dependent, low plasma renin activity mechanism of blood pressure elevation. This
article summarizes previous studies on the impact of hypothyroidism on blood pressure and
early atherosclerotic process.
Keywords : ambulatory blood pressure monitoring • blood pressure • hypothyroidism
Hypothyroidism has been recognized as a cause found in the thyroid gland, liver, kidneys and
of secondary hypertension [1,2] . The most com- other tissues and DII in a limited number of
mon type of hypothyroidism is that caused tissues, such as the CNS, anterior pituitary
by primary thyroid gland failure. Basic causes tissue, human skeletal muscle and brown fat
of primary hypothyroidism are autoimmune, in the rat [14,15] . DI activity is known to be
silent, postablative, goitrous, athyreotic and decreased in the hypothyroid state and may
nonautoimmune (e.g., Riedel’s), and subacute play a primary role in regulating circulating T3
thyroiditis [3] . Chronic autoimmune lympho­ levels, while DII activity is increased in hypo-
cytic thyroiditis (Hashimoto’s disease) is the thyroidism and probably regulates intracellular
most common cause of thyroid gland dysfunc- T3 concentrations.
tion. Replacement of lacking thyroid hormones 3,5,3´-triiodothyronine represents the meta-
reduces high blood pressure (BP) and total bolically active thyroid agent that possibly has
cardio­vascular risk [4] . Similar effects have also a vasodilatory effect on the vascular muscle
been described in ­subclinical ­hypothyroidism [5] . cells [16] . Hypothyroidism and T3 deficiency
are associated with peripheral vasoconstric-
Systolic or diastolic hypertension? tion [17] . DII was identified in cultured human
Previous studies on the prevalence of hyper­ coronary and aortic arterial smooth muscle cells.
tension in subjects with hypothyroidism have DII is believed to be responsible for the local
demonstrated elevated systolic or diastolic BP conversion of T4 to T3 in these vessels. It has
values, whereas one study has reported no asso- been demonstrated that the expression of DII
ciation between hypertension and hypothyroid- in vascular smooth muscle cells is dependent on
ism (Table 1) [2,6–13] . Saito et al. found that dia- a cAMP-mediated mechanism [18] . T3 inhibits
stolic BP correlated significantly with thyroxine DII activity at the pretranslational level (inhi-
(T4) and 3,5,3´-triiodothyronine (T3) in slightly bition of DII mRNA expression). DII expres-
hypothyroid females over 50 years of age [2] . sion has been reported to be increased in hypo-
thyroidism and to have a protective action on
Mechanisms of human vessels. Local production of T3 by DII
hypothyroidism-related hypertension is another vasolidating mechanism mediated by
Increase in peripheral vascular resistance cAMP [18] . In normal thyroid function there
To exert its cellular activity, T4 is converted is a balance between these vasoconstrictor and
to T3 via the enzymatic action of iodothyro- ­vasodilator mechanisms.
nine deiodinase. The two types of iodothy- Hypothyroidism has been associated with
ronine deiodinase, type I (DI) and II (DII), increased arterial stiffness [19,20] . Arterial stiffness
are expressed in different tissues. DI has been is an important determinant of arterio­sclerosis
10.1586/ERC.10.141 © 2010 Expert Reviews Ltd ISSN 1477-9072 1559
 Review Stabouli, Papakatsika & Kotsis

of the renal compartments. Conversely,

Table 1. Studies on hypertension and hypothyroidism.
hypothyroidism presents reduced kidney-
Authors (year) Results Ref. to-body weight ratio [26] . Free water clear-
Saito et al. (1983) Diastolic hypertension [2] ance is lowered and glomerular filtration
Endo et al. (1979) Hypertension only in the slightly hypothyroid patients [6] rate (GFR) is reduced owing to lowered
cardiac output, leading to dilution hypo-
Streeten et al. Diastolic hypertension >90 mmHg in 40% of patients [7]
natremia [27,28] . Hyponatremia is the
(1988)
most common electrolyte derangement
Bergus et al. No significant association between hypothyroidism [8]
in hypothyroid patients and is associated
(1997) and hypertension with the inability of the hypothyroid kid-
Bergus et al. No difference in diastolic blood pressure compared with [9] ney to excrete water overload. The action
(1999) control subjects of T3 on sodium reabsorption is Na +/K+
Iqbal et al. (2006) Systolic and diastolic hypertension [10] ATPase dependent [28] . However, sodium
Saltiki et al. (2008) Systolic and diastolic hypertension [11] excretion was restored in rats treated with
methimazole to become hypothyroid [29] .
Kanbay et al. Nondipping status in lower levels of free [12]
The prevalence of hyponatremia was
(2007) 3,5,3´-triiodothyronine
more common in patients with decreased
Liu et al. (2010) Higher risk of hypertension in subclinical hypothyroidism [13]
GFR, especially in subjects with increased
Stronger association in females
age [30] . Despite the low creatinine clear-
ance in patients with hypothyroidism,
and changes in arterial wall elasticity, and may occur before or plasma creatinine concentration is not a valuable index of renal
during the early stages of atherosclerosis. Early systolic arrival failure, as the production of creatinine also decreases during
of the reflected waves – from the peripheral arteries to the heart hypothyroidism [31] . All the aforementioned changes are revers-
– increases central aortic BP and augments systolic BP. Pulse ible with hormonal substitution. Therapy with thyroid hormone
wave velocity (PWV) is the gold standard of arterial stiffness. can lead to amelioration of chronic renal failure and improve-
Increased PWV is an index of early vascular ageing and is pres- ment of prognostic indices in patients with undiagnosed severe
ent even in subclinical forms of hypothyroidism [19,21] . In elderly hypothyroidism [32] .
hypertensive patients the increased arterial stiffness of central Proteinuria has also been described as a complication of hypo-
arteries, such as the aorta, leads to an increased systolic BP and a thyroidism, with nephrotic syndrome already developed at presen-
decreased diastolic BP, leading to increases in pulse pressure and tation. Renal biopsies indicated minimal change nephrotic syn-
isolated systolic hypertension. This mechanism is probably not drome [33] or evident glomeruloplathy, most often membranous
responsible for the increase in diastolic BP in hypothyroidism or membranoproliferative [34] . Glomerular and tubular damage
but may increase systolic BP. On the other hand, the increased could be attributed to the autoimmune processes in Hashimoto’s
systolic and diastolic BP could induce changes in the arterial or autoimmune thyroiditis disease.
wall, reducing elasticity and increasing stiffness. Adequate thyroid
hormone replacement therapy successfully reduced BP, support- Volume changes
ing the secondary cause of hypertension in patients with hypo- The renin–angiotensin–aldosterone system is important for
thyroidism [22] . Increased central aortic pressures and arterial medium- and long-term BP regulation. Plasma renin increases
stiffness were also reversed after adequate hormone replacement during sodium deprivation and hypotension, while b‑blockade
therapy [23] . Patients with hypothyroidism have been reported to has been reported to lower active renin [35] . Hypothyroidism is a
have greater radial wall thickness and compliance than eu­thyroid low-renin hypertensive state [36] . Renin release is minimal in the
healthy age- and sex-matched controls [24] . Intima–media thick- hypothyroid state, in part owing to decreased renal b-adrenergic
ness (IMT) of the common carotid arteries of hypothyroid activity [37,38] . Kobori et al. reported that thyroid hormone stimu-
patients was decreased after normalization of thyroid function lates renin gene expression in Calu‑6 cells, an experimental cell
by hormone replacement for 1 year [25] . This finding was associ- line derived from human lung cancer used as a model of renin
ated with reduced levels of LDL‑cholesterol and improvement in synthesis [39] .
the total/HDL‑cholesterol ratio. Water and sodium retention during severe hypothyroidism
create a state of volume depletion, low extracellular fluid osmo-
Renal dysfunction lality and increased water retention. The hypothyroid popula-
Thyroid and renal function are interrelated. Thyroid hormone tion is characterized by significant volume changes, initiating a
insufficiency has been associated with deterioration of renal volume-dependent, low plasma renin activity (PRA) mechanism
function. The renal disorders that follow hypothyroidism are of BP elevation. The incidence of salt sensitivity was found to
attributed to the cardiovascular consequences of T3 deficiency be increased in untreated hypothyroid patients. A low-sodium
rather than autoimmune mechanisms. Excess thyroid hormonal diet induced small increases in plasma renin activity in hypo-
secretion leads to increased kidney mass owing to hypertrophy thyroid patients with salt-sensitive BP compared with individuals

1560 Expert Rev. Cardiovasc. Ther. 8(11), (2010)


with salt-resistant BP [40] . Furthermore, oral sodium overload in
­hypothyroid subjects is followed by a volume-dependent increase
in BP.
Hormonal changes
Thyroid hormones potentiate the b‑adrenergic response by increas-
ing the number of b‑adrenoreceptors with an opposite action on
a-adrenergic receptors [41] . In the hypothyroid state, the density
of a1‑adrenoreceptors is increased while b‑adrenoreceptors are
reduced in vascular beds. Actions of a1‑adrenoreceptors mainly
involve smooth muscle cell contraction, causing vasoconstriction
in the blood vessels, while reduced b-adrenoreceptors can induce
low cardiac output, renin secretion from the kidneys, low lipolysis
and anabolism in skeletal muscle. Several clinical features of hypo-
thyroidism, such as low heart rate, suggest a reduced sympathetic
activity but indirect measurements of sympathetic activity showed
that it is elevated. There is evidence of blunted sympathitico­
excitatory and tachycardiac response to decreased BP among the
hypothyroid population. Hypothyroid rats had depressed arterial
baroreflex function and elevated dependence on the resting sym-
pathetic tone [42] . Data on normotensive patients with previous
thyroidectoctomy after withdrawal of oral levothyroxine (L‑T4)
showed increased daytime systolic and diastolic BP levels, and
increased levels of noradrenaline, adrenaline, aldosterone and
cotrizol with no increase in plasma renin activity. Adrenal stimu-
lation may contribute to sustained BP elevation in acute hypo-
thyroidism, since the adrenal cortex can release adrenaline and
glucocorticoid hormones [4] .
Plasma vasopressin levels have been found to be increased in
hypothyroidism, suggesting a possible role in total water reten-
tion [43] . The discrepancy between vasopressin levels, serum
sodium and osmolality may be the result of the lowered threshold
of the hypothalamic osmoreceptors or a renal insensitivity to the
hormone. Low atrial natriuretic peptide (ANP) release may also
cause impaired natriuresis in hypothyroidism, as T3 acts directly
to ­accelerate ANP mRNA synthesis and consequently ANP
release [44] .
Endothelial dysfunction
The endothelium serves as a site where several vasoactive sub-
stances are released, such as nitric oxide (NO) and endothe-
lium-derived hyperpolarizing factor (EDHF) [45] . The effects
of thyroid hormones in the vasculature are mediated through
the vascular renin–angiotensin system, which represents a local
system that can produce angiotensin II [46] . Angiotensin II
presents its biological actions by binding AT1 and AT2 recep-
tors. Normally, T3 exerts its vasodilatory local action through
reduced mRNA expression of the AT1 receptor. Downregulation
of AT1 receptor occurred several hours after T3 stimulation in
rat vascular smooth muscle cells, indicating that the suppression
is a genomic effect of T3 (mediated by nuclear receptors) [47] .
Thyroid hormone receptor may also initiate rapid effects in the
cardiovascular system through cross-coupling to the PI3K/pro-
tein kinase Akt pathway. In vascular endothelial cells, increased
T3 activates the Akt pathway and increases endothelial NO
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Hypothyroidism & hypertension Review
synthase, contributing to the rapid vasodilatory effects of thy-
roid hormone [26,48] . Downregulation of vasodilatory NO pro-
duction in clinical and subclinical forms of hypothyroidism
has been related to endothelial dysfunction [49,50] . Nw -nitro-l-
arginine methyl ester (l‑NAME) is an inhibitor of the vasodi-
latory action of NO synthesis [51] . In subclinical hypothyroid
patients, vasodilatation to acetylcholine was reduced compared
with euthyroid subjects and l‑NAME was ineffective, suggest-
ing reduced NO availability [50] . Reduced availability of NO
was fully reversible with l‑thyroxine ­t reatment in subclinical
hypothyroid subjects [50] .
3,5,3´-triiodothyronine modestly induced adrenomedullin
mRNA expression in both endothelial and vascular cultured rat
smooth muscle cells [52] . Adrenomedullin is a vasodilatory pep-
tide originally isolated from human pheochromocytoma. Despite
these in vitro findings, in vivo human studies in hypothyroid and
hyperthyroid subjects reported that changes in total peripheral
resistance from the hypo- or hyperthyroid state to euthyroid state
were not associated with plasma levels of adrenomedullin. Altered
atrial natriuretic peptide and noradrenaline probably contrib-
uted to the T3-induced changes in total peripheral resistance [53] .
It has also been reported that T3 may induce the activation of
ADP-ribosyl cyclase, which promotes Ca 2+ release and therefore
contractility of vascular smooth muscle cells [54] .
Evidence from ambulatory BP monitoring
Ambulatory BP monitoring (ABPM) is used for assessment of
the 24‑h BP profile. It represents a more useful clinical tool com-
pared with clinic BP measurements in terms of reproducibility
of the readings [55] , clinical evaluation and prognosis. It has been
demonstrated that ambulatory BP values are predictive of the risk
of cardiovascular events, even after adjustment for classical risk
factors and office BP values [56] .
Fommei et al. studied 12 normotensive subjects with previous
total thyroidectomy after 6 weeks of L‑T4 withdrawal and 2 months
after resumption of treatment [4] . ABPM revealed significantly
higher systolic and diastolic daytime BP levels in the hypothyroid
compared with the euthyroid state. L‑T4 treatment resulted in a
significant decrease in daytime systolic and diastolic BP values.
Kotsis et al. examined the differences in ABPM parameters
between hypothyroid and euthyroid healthy volunteers [57] .
Mean 24‑h systolic BP, 24‑h pulse pressure and 24-h systolic
BP variability were significantly higher among the hypothy-
roid population compared with subjects with normal thyroid
function. 24‑h diastolic BP values did not differ significantly,
whereas 24‑h daytime and night-time heart rate variabilities
were significantly lower, despite the similar 24‑h heart rate levels.
24‑h systolic BP, 24‑h pulse pressure [58] and BP variability [59,60]
have been reported to independently associate with end-organ
damage and total cardio­vascular morbidity and mortality. The
findings of this study suggested an increased total cardiovascular
risk among the hypothyroid population. However, lower 24‑h
BP parameters were found in patients with severe hypothyroid-
ism compared with those with mild thyroid dysfunction [57] .
In severe hypothyroidism, mechanisms reducing BP, such as
1561
 Review Stabouli, Papakatsika & Kotsis

reduced cardiac output [61] , GFR, lower sympathetic nervous
system activity (as reflected by lower heart rates) and decreased
sodium reabsorption, probably have a stronger effect than the
mechanisms that increase BP, such as vasoconstriction and
increased total peripheral resistance.
Nocturnal BP fall below 10% compared with daytime BP has
been defined as a nondipping pattern. ABPM studies also demon-
strated that the proportion of nondippers is significantly increased
in overt hypothyroidism (50%) compared with 17% in the control
group [57,62] . Regarding the clinical and prognostic significance
of the nondipping pattern, acceleration of target organ damage
has previously been described in the nondippers and the risk for
cardiovascular events was reportedly higher in the nondipping
state [63,64] .
Subclinical hypothyroidism
Subclinical hypothyroidism is defined as a state of relative
thyroid dysfunction, characterized by normal serum levels of
thyroid hormones and increased serum thyroid-stimulating
hormone (TSH) levels [65] . It concerns 4–10% of the general
population, with greater prevalence among the elderly. High
sensitivity of the modern assay methods has facilitated its detec-
tion and clinical evaluation. Its etiology is common with that of
clinical hypothyroidism; clinical symptoms most often include
weight gain and fatigue. Subclinical forms of hypothyroidism
are of increasing interest, as they exhibit the same consequences
as clinical hypothyroidism, although to a lesser extent.
Hemodynamic changes include lowered cardiac output and
increased peripheral resistance. Mild thyroid dysfunction is asso-
ciated with impaired left ventricular function and left ventricular
systolic dysfunction [66] . Endothelial dysfunction is prominent in
subclinical hypothyroidism and is attributed to a reversible defect
in the production of NO [50] . Acceleration of arterial stiffness has
also been reported in subclinical hypothyroidism [21] , while resto-
ration of normal thyroid function has been found to decrease arte-
rial stiffness and improve prognosis [67] . In the Colorado study,
total cholesterol levels were higher in subjects with subclinical
hypo­thyroidism [68] . Danese et al. found that lipid profile was
improved with L‑T4 treatment [69] . Increased carotid artery IMT
has also been reported in subclinical hypothyroidism, which was
reversible after normalization of TSH levels [70] . The aforemen-
tioned data suggest that subclinical hypothyroidism may have a
critical role on deterioration of the atherogenic profile and total
cardiovascular risk. Other studies have demonstrated that sub-
clinical hypothyroidism represents an independent risk factor for
coronary heart disease [71–73] .
Expert commentary
The majority of the studies in the literature reported a high
prevalence of hypertension in hypothyroidism. Mechanisms
for the pathogenesis of hypertension in hypothyroidism include
increases in peripheral vascular resistance and arterial stiff-
ness. Vasoconstriction may reflect the absence of demonstrated
vasodilatory T3 effects on vascular smooth muscle cells or may
be the result of a higher circulating noradrenaline level and
increased AT1 with decreased number of vascular AT2 recep-
tors. Hypothyroid hypertensive patients display low plasma renin
activity, low angiotensin levels and increased vasopressin plasma
levels. On the other hand, thyroid hormone deficiency is associ-
ated with a reduction of the GFR and renal blood flow, inducing
lower BP values.
Patients visiting a hypertension clinic for evaluation of high BP
may benefit from the diagnosis of hypothyroidism as the majority
of them would avoid antihypertensive treatment. Replacement of
thyroid hormones would also reduce high cholesterol levels and
consequently their total cardiovascular risk. BP-lowering treat-
ment is usually ineffective in noneuthyroid patients. Therefore,
thyroid hormone screening is suggested regularly in patients with
hypothyroidism. It is also essential to reduce high cardiovascular
risk in younger ages. An adolescent with high BP, obesity and
high cholesterol levels may also be a candidate for TSH screening.
Timely diagnosis and treatment could lead to early reduction in
cardiovascular risk.
Five-year view
Epidemiological community studies using out of office BP mea-
surements are needed to investigate the prevalence of thyroid
disorders in large samples of hypertensive individuals. This is
best accomplished with a single measure of TSH. Such studies
will also answer the question of whether screening for thyroid
disorders in a population is cost effective. These studies should
focus on the identification of hypothyroidism-induced hyper­
tension in subjects with different age, race and gender. Long-term
follow-up of patients receiving adequate replacement of thyroid
hormones would reveal the impact of therapeutic strategies on
future cardiovascular morbidity and mortality.

Key issues
• Hypothyroidism has been recognized as a cause of secondary hypertension.
• Previous studies have demonstrated elevated blood pressure values in hypothyroid patients.
• 3,5,3´-triiodothyronine deficiency is associated with peripheral vasoconstriction.
• In severe hypothyroidism, free-water clearance is reduced, leading to dilution hyponatremia.
• Renin is reduced in the hypothyroid state.
• Oral sodium overload in hypothyroid subjects is followed by a volume-dependent increase in blood pressure.
• Reduced nitric oxide availability has been found in hypothyroidism.
• Adequate thyroid hormone replacement therapy successfully reduced blood pressure.

1562 Expert Rev. Cardiovasc. Ther. 8(11), (2010)


Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
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