**5.1. Pathophysiology**

The most characteristic and common symptoms and signs, experienced by patients with thyroid disease, are those related to the cardiovascular (CV) system (Klein & Ojamaa, 2001). Both hyperthyroidism and hypothyroidism produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistances (SVR) (Dillmann, 2002). Indeed, either hyper or hypothyroidism can produce heart arrhythmias, although it is less well recognized that hypothyroidism may predispose to specific dysrhythmias (Klein & Danzi., 2007). Cardiovascular signs and symptoms of hypothyroidism include bradycardia, mild (diastolic) hypertension, narrowed pulse pressure, cold intolerance, and fatigue (Klein & Ojamaa, 2001).

Subclinical hypothyroidism might be interpreted as an intermediate alteration between overt dysfunction and euthyroidism, consequently, the modifications of CV system observed in sHT qualitatively resemble those produced by overt hypothyroidism even if less evident. Accordingly, several evidences indicated that there is a direct association between serum TSH value and CV alterations as well as blood pressure, cholesterol level etc. (Biondi & Cooper, 2008; Asvold et al., 2007). There are many evidences that, in major part of the cases of thyroid patients, cardiovascular changes are reversible when the underlying thyroid disorder is recognized and treated (Kahaly et al., 2005). Moreover, there is substantial evidence that overt hypothyroidism and also sHT, although to a lesser extent, may alter several of the traditional risk factors for ischemic CVD.

The effects of thyroid hormone deficiency on the cardiovascular system have been evaluated from many points of view as heart diastolic and systolic dysfunction, endothelial dysfunction, hypertension, metabolic alterations and impaired exercise performance (Biondi & Cooper, 2008). To understand well the impact of sHT on CV system and the consequent increased risk of cardiovascular events, it is necessary to review the molecular effects of T3 and T4, and the modifications that they exert in myocytes, endothelium, vascular muscle cells, intermediate metabolism etc. The decrease of cardiac output associated with hypothyroidism results, in part, from changes in cardiac gene expression, specifically reduced expression of the sarcoplasmic reticulum Ca2-ATPase, and increased expression of its inhibitor, phospholamban (Belke et al., 2007). In addition, these molecular changes explain the prolonged isovolumic relaxation phase of the hypothyroid myocardium and early reversible diastolic impairment (Klein & Danzi, 2007). Interestingly, this mechanism functionally resembles the progressive age related myocardium modification, in which increased fibrosis, myocyte hypertrophy and myocyte loss result in increased myocardial stiffness leading to diastolic heart failure (Biondi & Cooper, 2008).

188 Thyroid Hormone

as cognitive impairment (Mariotti et al., 2005).

**5.1. Pathophysiology** 

**5. Subclinical hypothyroidism and cardiovascular diseases** 

pressure, cold intolerance, and fatigue (Klein & Ojamaa, 2001).

may alter several of the traditional risk factors for ischemic CVD.

The most characteristic and common symptoms and signs, experienced by patients with thyroid disease, are those related to the cardiovascular (CV) system (Klein & Ojamaa, 2001). Both hyperthyroidism and hypothyroidism produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistances (SVR) (Dillmann, 2002). Indeed, either hyper or hypothyroidism can produce heart arrhythmias, although it is less well recognized that hypothyroidism may predispose to specific dysrhythmias (Klein & Danzi., 2007). Cardiovascular signs and symptoms of hypothyroidism include bradycardia, mild (diastolic) hypertension, narrowed pulse

Subclinical hypothyroidism might be interpreted as an intermediate alteration between overt dysfunction and euthyroidism, consequently, the modifications of CV system observed in sHT qualitatively resemble those produced by overt hypothyroidism even if less evident. Accordingly, several evidences indicated that there is a direct association between serum TSH value and CV alterations as well as blood pressure, cholesterol level etc. (Biondi & Cooper, 2008; Asvold et al., 2007). There are many evidences that, in major part of the cases of thyroid patients, cardiovascular changes are reversible when the underlying thyroid disorder is recognized and treated (Kahaly et al., 2005). Moreover, there is substantial evidence that overt hypothyroidism and also sHT, although to a lesser extent,

The effects of thyroid hormone deficiency on the cardiovascular system have been evaluated from many points of view as heart diastolic and systolic dysfunction, endothelial dysfunction, hypertension, metabolic alterations and impaired exercise performance (Biondi & Cooper, 2008). To understand well the impact of sHT on CV system and the consequent

All together, these findings might support the idea that mild physiologically decline of thyroid activity at the tissue level might have favorable effects in the oldest-old subjects. However, the interpretation of the predictive value of thyroid failure in old subjects has to be considered with caution, carefully defining the context and the criteria of analyzed populations. In this setting, the comparison of observational trials is not so easy and the different population analyzed should be taken into account. Indeed, there is not a unique definition of TSH limits for patient classification in the clinical studies or statistical analysis, and the population of published trials is very heterogeneous differing for the age of enrolled patients, life styles, comorbidities, treatments, ethnics etc. Although in some selected elderly subjects (specific ethnic population or very old subjects) (subtle) thyroid failure might be a beneficial factor or a longevity associated character, one of the most debated issues regarding the health consequences of (subclinical) hypothyroidism in the elderly is represented by the potential increase of ischemic heart disease (IHD) or other CVDs as well

Triiodothyronine produces a decrease in systemic vascular resistance enhancing arteriole dilatation of the peripheral circulation (Klein & Ojamaa, 2001). The endothelium and smooth muscle cells are biological targets of action of T3 with a vasodilatation effect, also in coronary arteries (Ojamaa et al., 1996). As stated by Klein & Ojamaa (2001), T3 induces in vitro relaxation of smooth muscle cells with a non-genomic effect and independently of nitric oxide production (Klein & Ojamaa, 2001). Indeed, Ojamaa et al. (1996) found that the exposure of primary cultures vascular smooth muscle cells to T3 resulted in cellular relaxation within 10 min while, the exposure of primary cultures of vascular endothelial cells to the same hormone did not induce nitric oxide production, suggesting a direct effect of T3 on vascular smooth muscle cells. By contrast, Colantuoni et al. (2005) showed that *in vivo* thyroid hormone induced vasodilatation is delayed and mainly dependent to nitric oxide. The aim of their study was to assess the effects of topically applied T3 and T4 on the arterioles of hamster cheek pouch microcirculation *in vivo* by visualizing microvessels through a fluorescent microscopy technique. Topical application of both T3 and T4 consistently induced a dose-dependent dilation of arterioles within few minutes. However, T3-induced dilation was countered by the inhibition of nitric oxide synthase with specific *i*Nos inhibitors. These discrepancies between *in vitro* and *in vivo* findings might be related to differences in experimental procedures and to the fact that *in vivo* conditions are more complex than *in vitro* insolated cell cultures (Galli et al., 2010). The vascular action of T3 and T4 has been also reported to be associated with the modulation of gene expression related to endothelial homeostasis like angiotensin receptors (Fukuyama et al., 2003), reinforcing the hypothesis that thyroid hormones mainly target the vasculature. Accordingly, a cross-sectional study on 30728 patients without previous known thyroid diseases revealed a linear positive association between TSH level and systolic and diastolic blood pressure (Asvold et al., 2007). In this setting, Fommei et al. (2002) reported the physiological relationships between blood pressure and neuro-humoral modifications induced by acute hypothyroidism [levothyroxine (LT4) withdrawal] in normotensive subjects. During the hypothyroid state daytime arterial blood pressure (mainly diastolic) significantly increased along with noradrenaline and adrenaline levels. By contrast, plasma renin activity remained unchanged. These data, besides confirming the role of thyroid hormones in systemic arterial blood pressure homeostasis, suggest that sympathetic and adrenal reversible activation may contribute to the development of arterial hypertension in human hypothyroidism (Fommei et al., 2002).

Arterial hypertension related to thyroid hormone deficiency may result in aortic stiffness and early atherosclerosis. In this setting, aortic stiffness was studied in 30 patients who never received treatment for hypertension or hypothyroidism, 15 patients with normal blood pressure and hypothyroidism, and 15 patients with hypertension and normal thyroid function. Aortic diameter, evaluated by M-mode echocardiography and blood pressure measured by sphygmomanometer, were assessed to calculate the aortic stiffness index. Patients with hypertension and hypothyroidism have increased aortic stiffness, which was decreased in all patients by hormone replacement therapy, although hypertension resulted completely reversible in 50% of the patients (Dernellis et al., 2002). In addition, it has been hypothesized that thyroid hormone deficiency might be related to endothelial dysfunction. In this area, Lekakis et al. (1997) enrolled 35 subjects with various serum TSH levels to assess endothelial and smooth muscle responses of the brachial artery by high-resolution ultrasound imaging. Results of this study showed that flow-mediated, endotheliumdependent (FMD) vasodilatation progressively impaired with increasing serum TSH value; the phenomenon appearing still in patients with TSH value within the normal reference range (2.01-4.00 microIU/mL) (Lekakis et al., 1997). Furthermore, in order to assess vascular reactivity and NO availability in patients with sHT and its relation to the serum lipid profile, Taddei et al. (2003) evaluated, by strain-gauge plethysmography, the forearm blood flow response to intrabrachial acetylcoline, an endothelium-dependent vasodilator, at baseline and during infusion of the *e*NO synthase inhibitor Ng-monomethyl-L-arginine (L-NMMA). Results from sHT patients were compared with two groups of euthyroid control subjects, one with normal lipid profile and one with mildly elevated serum TC levels, comparable to those of sHT patients. They found that vasodilation in response to acetylcholine of patients affected by sHT was reduced as compared to that of both groups of euthyroid control subjects. Similarly, L-NMMA blunted the vasodilation in response to acetylcholine either in normolipemic or in mildly hypercholesterolemic controls, whereas it was ineffective in sHT patients, thus suggesting a reduced NO availability due to impaired NO synthase induced by sHT *per se*. Interestingly, six months of euthyroidism induced by LT4 replacement increased acetylcholine vasodilation and restored L-NMMA inhibition. Subsequently, the same group (Taddei et al. 2006) demonstrated that endothelial dysfunction of a cohort of sHT patients with autoimmune thyroiditis was, at least partially, related to oxidative stress and low-grade systemic inflammation. Indeed, sHT patients had higher plasma C-reactive protein (CRP) levels as compared to euthyroid controls, and endothelium dysfunction was significantly improved after either local infusion of vitamin C or systemic administration of indomethacin, a non-selective cyclo-oxygenase (COX) inhibitor. Comparable results were obtained after administration of celecoxib, a selective COX-2 inhibitor, thus suggesting that an association between thyroid function and lowgrade systemic inflammation could be postulated. Accordingly, several studies (Kvetny et al., 2004; Luboshitzky et al., 2004; Christ-crain et al., 2003; Lee et al., 2004) investigated the possible relationship between TH deficiency and serum CRP level, that was mostly found higher in hypothyroid patients, although unaffected by LT4 therapy (Christ-crain, 2003).

Mild Thyroid Deficiency in the Elderly 191

characterized by hypercholesterolaemia with elevation of low-density lipoprotein cholesterol (LDLc) levels because of decreased fractional clearance of LDLc by a reduced number of the receptors in the liver (Duntas et al., 2002; Staub et al., 1992). Early studies in hypothyroid humans, using isotopically labeled LDLc, demonstrated a prolonged half-life of LDLc due to a decreased catabolism; this effect was reversible with LT4 therapy (Walton et al., 1965). Accordingly, the addition of T3 to human fibroblast cultures induced a higher LDLc degradation, through an increase in LDLc receptor number, without any receptor affinity change (Chait et al., 1979). Molecular mapping has revealed functional thyroid response elements in the promoter region of the LDLc receptor. Indeed, specific stimulation by T3 of a chimeric gene resulting from the LDLc receptor promoter linked to a reporter gene, cotransfected with the isoform of the thyroid hormone receptor into a hepatic cell line, has been reported (Bakker et al., 2001). Moreover, the deletion of the upstream thyroid response elements in the LDLc receptor promoter inhibited T3-mediated reporter gene activity (Cappola et al., 2003). Although the relationship between thyroid function and altered lipid profile is well documented in overt hypothyroidism it is still controversial in sHT (Biondi & Cooper, 2012). The conflicting results about lipid profile and sHT might reflect differences in study design as well as in age, gender, and ethnicity of the study cohorts (Palmieri et al., 2002).

Various changes in the coagulation-fibrinolytic system have been described in patients with thyroid dysfunction although, data regarding the association between thyroid failure and modifications of the coagulation-fibrinolytic system are still controversial (Chadarevian et al., 2001; Canturk et al., 2003; Muller et al., 2001). The influence of thyroid hormone on the coagulation fibrinolytic system is mainly mediated by the interaction between the hormone and its receptors (Shih et al., 2004). Various abnormalities have been described, ranging from subclinical laboratory abnormalities to major hemorrhages or fatal thromboembolic events (Squizzato et al. 2007). The relationship between thyroid hormones and the coagulation system is, however, often ignored. One of the reasons could be that, although several in vivo abnormalities have been reported in patients with hypothyroidism and hyperthyroidism, most published studies focus on laboratory measurements, and good studies on the relationship between thyroid dysfunction and clinically manifest bleeding or thrombosis are lacking. However, most studies confirm that both overt hyper- and hypothyroidism modify the coagulation-fibrinolytic balance. Thyroid hormone excess or deficit is the probable main pathophysiological mechanism and, patients with overt hypoand hyperthyroidism appear to have an increased risk of bleeding and of thrombosis,

Overall, these findings support a biologically plausible role for hypothyroidism in increasing the risk of atherosclerotic CV disease, via the increase in circulating levels of LDLc, systemic (diastolic) hypertension, diastolic dysfunction and heart failure as well as an imbalance of the coagulation system and direct effects on vascular smooth muscle (Cappola et al., 2003). However, the actual relationship between sHT and increased cardiovascular risk is still unresolved and represents one of the most common topics in endocrinology, leading to several controversies concerning the clinical management of sHT patients

respectively (Squizzato et al. 2007).

(Turemen et al., 2011).

Another concurring factor for developing early atherosclerosis in hypothyroidism is represented by the metabolic alterations induced by hormone deficiency. Hypothyroidism is characterized by hypercholesterolaemia with elevation of low-density lipoprotein cholesterol (LDLc) levels because of decreased fractional clearance of LDLc by a reduced number of the receptors in the liver (Duntas et al., 2002; Staub et al., 1992). Early studies in hypothyroid humans, using isotopically labeled LDLc, demonstrated a prolonged half-life of LDLc due to a decreased catabolism; this effect was reversible with LT4 therapy (Walton et al., 1965). Accordingly, the addition of T3 to human fibroblast cultures induced a higher LDLc degradation, through an increase in LDLc receptor number, without any receptor affinity change (Chait et al., 1979). Molecular mapping has revealed functional thyroid response elements in the promoter region of the LDLc receptor. Indeed, specific stimulation by T3 of a chimeric gene resulting from the LDLc receptor promoter linked to a reporter gene, cotransfected with the isoform of the thyroid hormone receptor into a hepatic cell line, has been reported (Bakker et al., 2001). Moreover, the deletion of the upstream thyroid response elements in the LDLc receptor promoter inhibited T3-mediated reporter gene activity (Cappola et al., 2003). Although the relationship between thyroid function and altered lipid profile is well documented in overt hypothyroidism it is still controversial in sHT (Biondi & Cooper, 2012). The conflicting results about lipid profile and sHT might reflect differences in study design as well as in age, gender, and ethnicity of the study cohorts (Palmieri et al., 2002).

190 Thyroid Hormone

Arterial hypertension related to thyroid hormone deficiency may result in aortic stiffness and early atherosclerosis. In this setting, aortic stiffness was studied in 30 patients who never received treatment for hypertension or hypothyroidism, 15 patients with normal blood pressure and hypothyroidism, and 15 patients with hypertension and normal thyroid function. Aortic diameter, evaluated by M-mode echocardiography and blood pressure measured by sphygmomanometer, were assessed to calculate the aortic stiffness index. Patients with hypertension and hypothyroidism have increased aortic stiffness, which was decreased in all patients by hormone replacement therapy, although hypertension resulted completely reversible in 50% of the patients (Dernellis et al., 2002). In addition, it has been hypothesized that thyroid hormone deficiency might be related to endothelial dysfunction. In this area, Lekakis et al. (1997) enrolled 35 subjects with various serum TSH levels to assess endothelial and smooth muscle responses of the brachial artery by high-resolution ultrasound imaging. Results of this study showed that flow-mediated, endotheliumdependent (FMD) vasodilatation progressively impaired with increasing serum TSH value; the phenomenon appearing still in patients with TSH value within the normal reference range (2.01-4.00 microIU/mL) (Lekakis et al., 1997). Furthermore, in order to assess vascular reactivity and NO availability in patients with sHT and its relation to the serum lipid profile, Taddei et al. (2003) evaluated, by strain-gauge plethysmography, the forearm blood flow response to intrabrachial acetylcoline, an endothelium-dependent vasodilator, at baseline and during infusion of the *e*NO synthase inhibitor Ng-monomethyl-L-arginine (L-NMMA). Results from sHT patients were compared with two groups of euthyroid control subjects, one with normal lipid profile and one with mildly elevated serum TC levels, comparable to those of sHT patients. They found that vasodilation in response to acetylcholine of patients affected by sHT was reduced as compared to that of both groups of euthyroid control subjects. Similarly, L-NMMA blunted the vasodilation in response to acetylcholine either in normolipemic or in mildly hypercholesterolemic controls, whereas it was ineffective in sHT patients, thus suggesting a reduced NO availability due to impaired NO synthase induced by sHT *per se*. Interestingly, six months of euthyroidism induced by LT4 replacement increased acetylcholine vasodilation and restored L-NMMA inhibition. Subsequently, the same group (Taddei et al. 2006) demonstrated that endothelial dysfunction of a cohort of sHT patients with autoimmune thyroiditis was, at least partially, related to oxidative stress and low-grade systemic inflammation. Indeed, sHT patients had higher plasma C-reactive protein (CRP) levels as compared to euthyroid controls, and endothelium dysfunction was significantly improved after either local infusion of vitamin C or systemic administration of indomethacin, a non-selective cyclo-oxygenase (COX) inhibitor. Comparable results were obtained after administration of celecoxib, a selective COX-2 inhibitor, thus suggesting that an association between thyroid function and lowgrade systemic inflammation could be postulated. Accordingly, several studies (Kvetny et al., 2004; Luboshitzky et al., 2004; Christ-crain et al., 2003; Lee et al., 2004) investigated the possible relationship between TH deficiency and serum CRP level, that was mostly found higher in hypothyroid patients, although unaffected by LT4 therapy (Christ-crain, 2003).

Another concurring factor for developing early atherosclerosis in hypothyroidism is represented by the metabolic alterations induced by hormone deficiency. Hypothyroidism is Various changes in the coagulation-fibrinolytic system have been described in patients with thyroid dysfunction although, data regarding the association between thyroid failure and modifications of the coagulation-fibrinolytic system are still controversial (Chadarevian et al., 2001; Canturk et al., 2003; Muller et al., 2001). The influence of thyroid hormone on the coagulation fibrinolytic system is mainly mediated by the interaction between the hormone and its receptors (Shih et al., 2004). Various abnormalities have been described, ranging from subclinical laboratory abnormalities to major hemorrhages or fatal thromboembolic events (Squizzato et al. 2007). The relationship between thyroid hormones and the coagulation system is, however, often ignored. One of the reasons could be that, although several in vivo abnormalities have been reported in patients with hypothyroidism and hyperthyroidism, most published studies focus on laboratory measurements, and good studies on the relationship between thyroid dysfunction and clinically manifest bleeding or thrombosis are lacking. However, most studies confirm that both overt hyper- and hypothyroidism modify the coagulation-fibrinolytic balance. Thyroid hormone excess or deficit is the probable main pathophysiological mechanism and, patients with overt hypoand hyperthyroidism appear to have an increased risk of bleeding and of thrombosis, respectively (Squizzato et al. 2007).

Overall, these findings support a biologically plausible role for hypothyroidism in increasing the risk of atherosclerotic CV disease, via the increase in circulating levels of LDLc, systemic (diastolic) hypertension, diastolic dysfunction and heart failure as well as an imbalance of the coagulation system and direct effects on vascular smooth muscle (Cappola et al., 2003). However, the actual relationship between sHT and increased cardiovascular risk is still unresolved and represents one of the most common topics in endocrinology, leading to several controversies concerning the clinical management of sHT patients (Turemen et al., 2011).

### **5.2. Clinical evidences**

As above described, thyroid hormone deficiency is associated to several cardiovascular and metabolic abnormalities (Biondi & Cooper, 2008; Caraccio et al., 2003; Dardano & Monzani, 2008). Indeed, thyroid failure may favour the onset of several CV risks like diastolic hypertension, hyperlipidemia, vascular stiffness, heart failure etc. However, although the relationship between overt hypothyroidism and coronary heart disease (CHD) as well as increased CHD mortality is widely recognized (Klein, 2004), the clinical significance of sHT is still controversial and conflicting opinions remain on the association between sHT and CVD or mortality, especially in older people (Biondi & Cooper, 2008; Monzani et al., 2006). Indeed, data regarding the association between sHT and CHD or total mortality are contradictory among various population based, observational studies (Aho et al., 1984; Cappola et al., 2004; Hak et al., 2000; Walsh et al., 2005).

Mild Thyroid Deficiency in the Elderly 193

These studies, however, did not accurately explore potential differences related to participant characteristics like age, even if older people represented large a share of the population. In this setting, the pooled analysis of large cohort of patients may be affected by hypothetical bias and may not investigate specific classes of patients like very old people versus moderate elderly patients or other specific conditions affecting the clinical outcome. Ochs et al. (2008) analysed in a meta-analysis the effect of ageing on sHT associated CV events and total mortality. Similar to previous meta-analysis, they found a pattern of modestly increased risk for CHD and mortality associated with sHT. A weak evidence for statistical heterogeneity among individual study findings was found, and age explained part of the heterogeneity for the association between sHT and CHD, with an increased risk for CHD only in cohorts with a younger mean age. Accordingly, Cappola et al. (2006), in a large population-based, longitudinal study of coronary heart disease and stroke in adults aged 65 years and older, concluded that the results did not support the hypothesis of an association between unrecognized sHT and increased CV events or mortality. On the other hand, one cross-sectional study with subgroup analyses by age found that increased risk for CHD was present in younger sHT participants only (<50 years old) (Kvetny et al. 2004). In this regard, a prospective, observational, population-based follow-up study carried out on 599 participants followed up from age 85 years through age 89 years showed no association between serum TSH and FT4 levels and disability in daily life, depressive symptoms, and cognitive impairment at baseline or during follow-up. Moreover, increasing serum TSH levels were associated with a lower mortality rate that remained after adjustments for baseline disability and health status (Gusseklo et al. 2004). Overall, these data support the hypothesis that in the oldest old population, individuals with abnormally high levels of TSH do not experience adverse effects and may have a prolonged life span. The study focused on a specific class of patients (very older people), for this reason, the results should be rigorously interpreted, also considering the weakness of observational studies. However, these data together with the results obtained by Rozing et al., (2010) that demonstrated a possible genetic predisposition of nonagenarians to a decrease function of hypothalamus-pituitary-thyroid axis, suggest that the oldest old may represent a different population respect to moderate old people or young adults. Potential explanations for these age differences might be competing mortality among older adults (for example, due to cancer) or more competing risk factors for CHD among older adults (for example, age or sex). However, the above reported substantial age differences should be interpreted with caution, given the possibility of ecological fallacy without individual patient data and, should be confirmed by stratified analyses in future

prospective cohort studies with a wide age range (Egger et al., 2001).

There are few clinical studies evaluating the effects of hormone replacement in sHT subjects and none aimed to determine the impact of therapy on total mortality especially in older people. Previous research in this area has shown contradictory results, with some randomized, controlled trials (number of patients ranging from 45 to 63) showing an improvement in the atherogenic lipid profile as well as surrogate endpoints of atherosclerosis (Meier et al., 2001; Caraccio et al., 2002; Monzani et al., 2004) but others (number of patients ranging from 17 to 35) showing no difference (Cooper et al., 1984; Jaeschke et al., 1996; Kong et al., 2002; Nystrom et al., 1988). Recently, Razvi et al. (2007)

One of the first large study (Whickham Survey) that evaluated vascular events over 20 years in community-dwelling subjects stratified by thyroid function and thyroid autoantibody status did not show any association between CHD and sHT (Vanderpump et al., 1995). This result appeared at odds with the findings of other subsequent cohort studies (Hak et al., 2000; Imaizumi et al., 2004; Walsh et al., 2005). However, while reanalyzing incident CHD events and mortality in Whickham participants including LT4 replacement during follow-up as covariate, a significant increment of incident CHD events and mortality was found in individuals with baseline sHT (Razvi et al., 2010). Based on the results of this analysis, it would appear that treatment of sHT might be associated with reduced mortality as well as CHD events. However, besides the small total number of events in each group of sHT participants, there is a potential for bias in this retrospective observational analysis (i.e. sHT patients who were treated may have been more health conscious leading to a healthy user bias). Therefore, these results need to be interpreted with caution until a large prospective, randomized controlled trial will be available. The inconsistency in results among several studies (Aho et al., 1984; Hak et al., 2000; Cappola et al., 2004; Razvi et al., 2010; Walsh et al., 2005) may be due to differences in the enrolled populations as well as the duration either of tissues exposure to sHT or of follow-up of the various studies. Nonetheless, meta-analyses of CHD events and sHT have shown that such an association probably exists (Razvi et al., 2008; Rodondi et al., 2006), especially in younger cohorts. In this regard, to assess the risks of CHD and total mortality for adults with sHT, Rodondi et al. (2010) carried out a large metaanalysis on 11 prospective cohorts, enrolling a total of 55,287 participants. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Among 55,287 adults, 3450 had sHT (6.2%) and 51,837 were euthyroid. The Authors found that the risk of CHD events and mortality increased with higher TSH concentrations. Results were similar after adjustment for traditional cardiovascular risk factors. Moreover, this pooled analysis showed a higher rate of CHD events in sHT patients with higher TSH levels (>10 mIU/L). These data are consistent with most previous meta-analysis and several naturalistic studies, showing an increased risk of CHD events associated with sHT (Hak et al., 2000; Singh et al., 2007; Walsh et al., 2005).

These studies, however, did not accurately explore potential differences related to participant characteristics like age, even if older people represented large a share of the population. In this setting, the pooled analysis of large cohort of patients may be affected by hypothetical bias and may not investigate specific classes of patients like very old people versus moderate elderly patients or other specific conditions affecting the clinical outcome. Ochs et al. (2008) analysed in a meta-analysis the effect of ageing on sHT associated CV events and total mortality. Similar to previous meta-analysis, they found a pattern of modestly increased risk for CHD and mortality associated with sHT. A weak evidence for statistical heterogeneity among individual study findings was found, and age explained part of the heterogeneity for the association between sHT and CHD, with an increased risk for CHD only in cohorts with a younger mean age. Accordingly, Cappola et al. (2006), in a large population-based, longitudinal study of coronary heart disease and stroke in adults aged 65 years and older, concluded that the results did not support the hypothesis of an association between unrecognized sHT and increased CV events or mortality. On the other hand, one cross-sectional study with subgroup analyses by age found that increased risk for CHD was present in younger sHT participants only (<50 years old) (Kvetny et al. 2004). In this regard, a prospective, observational, population-based follow-up study carried out on 599 participants followed up from age 85 years through age 89 years showed no association between serum TSH and FT4 levels and disability in daily life, depressive symptoms, and cognitive impairment at baseline or during follow-up. Moreover, increasing serum TSH levels were associated with a lower mortality rate that remained after adjustments for baseline disability and health status (Gusseklo et al. 2004). Overall, these data support the hypothesis that in the oldest old population, individuals with abnormally high levels of TSH do not experience adverse effects and may have a prolonged life span. The study focused on a specific class of patients (very older people), for this reason, the results should be rigorously interpreted, also considering the weakness of observational studies. However, these data together with the results obtained by Rozing et al., (2010) that demonstrated a possible genetic predisposition of nonagenarians to a decrease function of hypothalamus-pituitary-thyroid axis, suggest that the oldest old may represent a different population respect to moderate old people or young adults. Potential explanations for these age differences might be competing mortality among older adults (for example, due to cancer) or more competing risk factors for CHD among older adults (for example, age or sex). However, the above reported substantial age differences should be interpreted with caution, given the possibility of ecological fallacy without individual patient data and, should be confirmed by stratified analyses in future prospective cohort studies with a wide age range (Egger et al., 2001).

192 Thyroid Hormone

**5.2. Clinical evidences** 

Cappola et al., 2004; Hak et al., 2000; Walsh et al., 2005).

Singh et al., 2007; Walsh et al., 2005).

As above described, thyroid hormone deficiency is associated to several cardiovascular and metabolic abnormalities (Biondi & Cooper, 2008; Caraccio et al., 2003; Dardano & Monzani, 2008). Indeed, thyroid failure may favour the onset of several CV risks like diastolic hypertension, hyperlipidemia, vascular stiffness, heart failure etc. However, although the relationship between overt hypothyroidism and coronary heart disease (CHD) as well as increased CHD mortality is widely recognized (Klein, 2004), the clinical significance of sHT is still controversial and conflicting opinions remain on the association between sHT and CVD or mortality, especially in older people (Biondi & Cooper, 2008; Monzani et al., 2006). Indeed, data regarding the association between sHT and CHD or total mortality are contradictory among various population based, observational studies (Aho et al., 1984;

One of the first large study (Whickham Survey) that evaluated vascular events over 20 years in community-dwelling subjects stratified by thyroid function and thyroid autoantibody status did not show any association between CHD and sHT (Vanderpump et al., 1995). This result appeared at odds with the findings of other subsequent cohort studies (Hak et al., 2000; Imaizumi et al., 2004; Walsh et al., 2005). However, while reanalyzing incident CHD events and mortality in Whickham participants including LT4 replacement during follow-up as covariate, a significant increment of incident CHD events and mortality was found in individuals with baseline sHT (Razvi et al., 2010). Based on the results of this analysis, it would appear that treatment of sHT might be associated with reduced mortality as well as CHD events. However, besides the small total number of events in each group of sHT participants, there is a potential for bias in this retrospective observational analysis (i.e. sHT patients who were treated may have been more health conscious leading to a healthy user bias). Therefore, these results need to be interpreted with caution until a large prospective, randomized controlled trial will be available. The inconsistency in results among several studies (Aho et al., 1984; Hak et al., 2000; Cappola et al., 2004; Razvi et al., 2010; Walsh et al., 2005) may be due to differences in the enrolled populations as well as the duration either of tissues exposure to sHT or of follow-up of the various studies. Nonetheless, meta-analyses of CHD events and sHT have shown that such an association probably exists (Razvi et al., 2008; Rodondi et al., 2006), especially in younger cohorts. In this regard, to assess the risks of CHD and total mortality for adults with sHT, Rodondi et al. (2010) carried out a large metaanalysis on 11 prospective cohorts, enrolling a total of 55,287 participants. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Among 55,287 adults, 3450 had sHT (6.2%) and 51,837 were euthyroid. The Authors found that the risk of CHD events and mortality increased with higher TSH concentrations. Results were similar after adjustment for traditional cardiovascular risk factors. Moreover, this pooled analysis showed a higher rate of CHD events in sHT patients with higher TSH levels (>10 mIU/L). These data are consistent with most previous meta-analysis and several naturalistic studies, showing an increased risk of CHD events associated with sHT (Hak et al., 2000;

There are few clinical studies evaluating the effects of hormone replacement in sHT subjects and none aimed to determine the impact of therapy on total mortality especially in older people. Previous research in this area has shown contradictory results, with some randomized, controlled trials (number of patients ranging from 45 to 63) showing an improvement in the atherogenic lipid profile as well as surrogate endpoints of atherosclerosis (Meier et al., 2001; Caraccio et al., 2002; Monzani et al., 2004) but others (number of patients ranging from 17 to 35) showing no difference (Cooper et al., 1984; Jaeschke et al., 1996; Kong et al., 2002; Nystrom et al., 1988). Recently, Razvi et al. (2007) conducted a randomized, double-blind, crossover study to determine the short-term (12 weeks) effect of LT4 replacement therapy in 100 sHT patients (age range 18-80 yrs, mean 53.8) with serum TSH level>4.0 mIU/L. Primary end points included: serum cholesterol level variations along with improvement in flow-mediated dilation (FMD) as a marker of vascular endothelial function. LT4 treatment significantly reduced either TC or LDLc concentrations, and improved FMD, as compared to placebo group. Moreover, multivariate analysis showed that increased serum FT4 level was the most significant variable predicting reduction in TC or FMD improvement. The Authors hypothesized that if the reduction of LDLc level would be long term sustained, this would result in a relative reduction in 10-yr CV mortality of about 10%, thus supporting the use of LT4 replacement therapy also in patients with slightly elevated TSH value. Long-term studies are nonetheless required to confirm whether these apparent short-term benefits will translate into reduction in CV mortality and morbidity. Moreover, notwithstanding the wide age range of the studied patients, these results cannot directly transfer to the elderly, especially the oldest old population.

Mild Thyroid Deficiency in the Elderly 195

2002). It should be underlined, however, that different cognitive deficits possibly related to thyroid failure do not necessarily follow a consistent pattern, and LT4 treatment may not always completely restore normal functioning in patients with hypothyroidism. Giving these premises, we summarize here the growing, conflicting literature on the relationship

**Figure 1.** Hypothetical relationship between risk of total mortality and age in patients with subclinical

Subclinical hypothyroidism and cognitive function have been investigated in several preclinical experiments and clinical trials. To date, the actual relationship between mild thyroid hormone deficiency and cognitive impairment in the elderly is not well understood. In fact, there are several contrasting data resulting from cross-sectional and clinical experiments (Gussekloo et al., 2004; Roberts et al., 2006; Tan et al., 2008; Ceresini et al., 2009). Moreover, the available published data, in many cases, are not easily comparable considering the differences in inclusion criteria of each clinical study. Several small observational and interventional studies have reported an association, although not homogeneously, between cognitive impairment and sHT and, in some cases, it was described a cognitive performance improvement after LT4 replacement (Etgen et al., 2011; Monzani et al., 1993; Osterweil et al., 1992; St. John et al., 2009; Volpato et al., 2002). Moreover, Hogervost et al. (2008) studied the association between TSH and FT4 levels and cognition at baseline and after 2 years of follow-up in 1047 participants over 64 years of age, without physical frailty or severe cognitive impairment. The study showed that elevated TSH levels were associated with lower MMSE performance at baseline, independently of

hypothyroidism (sHT) (Modified from Mariotti, 2005).

between cognitive performance and thyroid function from an ageing perspective.

In summary, conflicting results among large prospective cohort studies regarding the relationship between sHT and cardiovascular disease might reflect differences in participants such as age, gender, TSH value, or pre-existing cardiovascular disease. However, as demonstrated by some meta-analyses, the negative effect of sHT on cardiovascular risk is well established in younger people while in moderately old population (>65 and <85 years) it appears no longer evident. Moreover, in the oldest old people (>85 years) one study suggested that high levels of TSH not only do not exert adverse effects but also may favor a prolonged life span (Fig. 1). In this regard, elderly population can be interpreted as a heterogeneous group, nonagenarians representing a genetically selected cluster. Indeed, these subjects may have a genetic background that protects from CVD and/or thyroid hormone deficiency, thus suggesting an intriguing link between gene, thyroid status and longevity.
