Hypothyroidism and Hypertension

Stella Stabouli; Sofia Papakatsika; Vasilios Kotsis


Expert Rev Cardiovasc Ther. 2010;8(11):1559-1565. 

In This Article

Mechanisms of Hypothyroidism-related Hypertension

Increase in Peripheral Vascular Resistance

To exert its cellular activity, T4 is converted to T3 via the enzymatic action of iodothyronine deiodinase. The two types of iodothyronine deiodinase, type I (DI) and II (DII), are expressed in different tissues. DI has been found in the thyroid gland, liver, kidneys and other tissues and DII in a limited number of tissues, such as the CNS, anterior pituitary tissue, human skeletal muscle and brown fat in the rat.[14,15] DI activity is known to be decreased in the hypothyroid state and may play a primary role in regulating circulating T3 levels, while DII activity is increased in hypothyroidism and probably regulates intracellular T3 concentrations.

3,5,3'-triiodothyronine represents the metabolically active thyroid agent that possibly has a vasodilatory effect on the vascular muscle cells.[16] Hypothyroidism and T3 deficiency are associated with peripheral vasoconstriction.[17] DII was identified in cultured human coronary and aortic arterial smooth muscle cells. DII is believed to be responsible for the local conversion of T4 to T3 in these vessels. It has been demonstrated that the expression of DII in vascular smooth muscle cells is dependent on a cAMP-mediated mechanism.[18] T3 inhibits DII activity at the pretranslational level (inhibition of DII mRNA expression). DII expression has been reported to be increased in hypothyroidism and to have a protective action on human vessels. Local production of T3 by DII is another vasolidating mechanism mediated by cAMP.[18] In normal thyroid function there is a balance between these vasoconstrictor and vasodilator mechanisms.

Hypothyroidism has been associated with increased arterial stiffness.[19,20] Arterial stiffness is an important determinant of arteriosclerosis and changes in arterial wall elasticity, and may occur before or during the early stages of atherosclerosis. Early systolic arrival of the reflected waves – from the peripheral arteries to the heart – increases central aortic BP and augments systolic BP. Pulse wave velocity (PWV) is the gold standard of arterial stiffness. Increased PWV is an index of early vascular ageing and is present even in subclinical forms of hypothyroidism.[19,21] In elderly hypertensive patients the increased arterial stiffness of central arteries, such as the aorta, leads to an increased systolic BP and a decreased diastolic BP, leading to increases in pulse pressure and isolated systolic hypertension. This mechanism is probably not responsible for the increase in diastolic BP in hypothyroidism but may increase systolic BP. On the other hand, the increased systolic and diastolic BP could induce changes in the arterial wall, reducing elasticity and increasing stiffness. Adequate thyroid hormone replacement therapy successfully reduced BP, supporting the secondary cause of hypertension in patients with hypothyroidism.[22] Increased central aortic pressures and arterial stiffness were also reversed after adequate hormone replacement therapy.[23] Patients with hypothyroidism have been reported to have greater radial wall thickness and compliance than euthyroid healthy age- and sex-matched controls.[24] Intima–media thickness (IMT) of the common carotid arteries of hypothyroid patients was decreased after normalization of thyroid function by hormone replacement for 1 year.[25] This finding was associated with reduced levels of LDL-cholesterol and improvement in the total/HDL-cholesterol ratio.

Renal Dysfunction

Thyroid and renal function are interrelated. Thyroid hormone insufficiency has been associated with deterioration of renal function. The renal disorders that follow hypothyroidism are attributed to the cardiovascular consequences of T3 deficiency rather than autoimmune mechanisms. Excess thyroid hormonal secretion leads to increased kidney mass owing to hypertrophy of the renal compartments. Conversely, hypothyroidism presents reduced kidney-to-body weight ratio.[26] Free water clearance is lowered and glomerular filtration rate (GFR) is reduced owing to lowered cardiac output, leading to dilution hyponatremia.[27,28] Hyponatremia is the most common electrolyte derangement in hypothyroid patients and is associated with the inability of the hypothyroid kidney to excrete water overload. The action of T3 on sodium reabsorption is Na+/K+ ATPase dependent.[28] However, sodium excretion was restored in rats treated with methimazole to become hypothyroid.[29] The prevalence of hyponatremia was more common in patients with decreased GFR, especially in subjects with increased age.[30] Despite the low creatinine clearance in patients with hypothyroidism, plasma creatinine concentration is not a valuable index of renal failure, as the production of creatinine also decreases during hypothyroidism.[31] All the aforementioned changes are reversible with hormonal substitution. Therapy with thyroid hormone can lead to amelioration of chronic renal failure and improvement of prognostic indices in patients with undiagnosed severe hypothyroidism.[32]

Proteinuria has also been described as a complication of hypothyroidism, with nephrotic syndrome already developed at presentation. Renal biopsies indicated minimal change nephrotic syndrome[33] or evident glomeruloplathy, most often membranous or membranoproliferative.[34] Glomerular and tubular damage could be attributed to the autoimmune processes in Hashimoto's or autoimmune thyroiditis disease.

Volume Changes

The renin–angiotensin–aldosterone system is important for medium- and long-term BP regulation. Plasma renin increases during sodium deprivation and hypotension, while b-blockade has been reported to lower active renin.[35] Hypothyroidism is a low-renin hypertensive state.[36] Renin release is minimal in the hypothyroid state, in part owing to decreased renal β-adrenergic activity.[37,38] Kobori et al. reported that thyroid hormone stimulates renin gene expression in Calu-6 cells, an experimental cell line derived from human lung cancer used as a model of renin synthesis.[39]

Water and sodium retention during severe hypothyroidism create a state of volume depletion, low extracellular fluid osmolality and increased water retention. The hypothyroid population is characterized by significant volume changes, initiating a volume-dependent, low plasma renin activity (PRA) mechanism of BP elevation. The incidence of salt sensitivity was found to be increased in untreated hypothyroid patients. A low-sodium diet induced small increases in plasma renin activity in hypothyroid patients with salt-sensitive BP compared with individuals 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 β-adrenergic response by increasing the number of β-adrenoreceptors with an opposite action on α-adrenergic receptors.[41] In the hypothyroid state, the density of α1-adrenoreceptors is increased while β-adrenoreceptors are reduced in vascular beds. Actions of α1-adrenoreceptors mainly involve smooth muscle cell contraction, causing vasoconstriction in the blood vessels, while reduced β-adrenoreceptors can induce low cardiac output, renin secretion from the kidneys, low lipolysis and anabolism in skeletal muscle. Several clinical features of hypothyroidism, 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 sympathiticoexcitatory and tachycardiac response to decreased BP among the hypothyroid population. Hypothyroid rats had depressed arterial baroreflex function and elevated dependence on the resting sympathetic 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 stimulation may contribute to sustained BP elevation in acute hypothyroidism, 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 retention.[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 substances are released, such as nitric oxide (NO) and endothelium-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 receptors. 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/protein kinase Akt pathway. In vascular endothelial cells, increased T3 activates the Akt pathway and increases endothelial NO synthase, contributing to the rapid vasodilatory effects of thyroid hormone.[26,48] Downregulation of vasodilatory NO production 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 vasodilatory action of NO synthesis.[51] In subclinical hypothyroid patients, vasodilatation to acetylcholine was reduced compared with euthyroid subjects and L-NAME was ineffective, suggesting reduced NO availability.[50] Reduced availability of NO was fully reversible with L-thyroxine treatment 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 peptide 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 contributed 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 Ca2+ 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 compared 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 hypothyroid 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 hypothyroidism compared with those with mild thyroid dysfunction.[57] In severe hypothyroidism, mechanisms reducing BP, such as 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 demonstrated 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 detection 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 associated 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 restoration of normal thyroid function has been found to decrease arterial 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 aforementioned 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 subclinical hypothyroidism represents an independent risk factor for coronary heart disease.[71–73]