**3. Subclinical hypothyrodism: Clinical features and etiology**

184 Thyroid Hormone

**2. Epidemiology** 

2004). Considering that serum TSH concentrations in a healthy population have a skewed distribution with a "tail" toward higher TSH values, the use of age specific reference limits for TSH has been suggested (Surks et al., 2004). This is especially proper in the elderly, in whom normal TSH is often shifted to a higher level (Mariotti, 1995) and the clinical presentation may differ from that in their younger counterparts (Mohandas, 2003). These considerations outline how making a correct diagnosis of sHT is challenging in the elderly but crucial to avoid significant misclassification of patients with abnormal TSH, who may or may not have thyroid dysfunction and may receive unnecessary or even harmful therapy (Laurberg, 2011). Indeed, the clinical significance of sHT in the elderly should be ascertained also in relation to the physiological changes of thyroid function with ageing (Biondi & Cooper, 2008; Carlè, 2007; Ceresini, 2010; Helfand, 2004; Surks et al., 2004). Therefore, the fundamental clinical question regarding these patients is on the clinical significance of sHT

Several population-based studies have reported that sHT is common in the general population, with a prevalence that increases with increasing age (Gharib et al., 2005a,b; Hollowell et al., 2002; Samuels, 1998; Tunbridge et al., 1977). In interpreting epidemiologic data, it should be taken into account that the ability to identify people with sHT varies by TSH assay and cut-off value, which ranged from >3 to >7 mIU/L (Kanaya et al., 2002; Rivolta et al., 1999). In this setting, it is noteworthy that some investigators suggest that the upper limit of normal for serum TSH level should be 2.5 mIU/L (Spencer et al., 1993). In support of this position is a higher prevalence of anti-thyroid antibodies in subjects with serum TSH levels >2.5 mIU/L (Vanderpump et al., 1995). Reasoning about these considerations, it is not astonishing that the reported prevalence of sHT in the general population ranges widely from 1.3% to 21%, depending on age, gender, and iodine intake (Kanaya et al., 2002; Rivolta et al., 1999; Samuels, 1998; Sawin et al., 1985; Tunbridge et al., 1977; Wang et al., 1997).

In the Wickham survey, the prevalence of sHT (TSH > 6 mIU/L) was 7.5% in women and 2.8% in men (Wickham study). An age dependent increase in serum TSH concentrations was found only when women with high serum anti-thyroid antibody values were included in the analysis; with 17.4% prevalence of sHT in women older than 75 years (Wickham study). Accordingly, in a Dutch study the prevalence of sHT in a group of middle-aged women (mean age 55 years) was 4%, the rate rising to 7.3% 10 years later (Geul et al., 1993). The higher prevalence of sHT in older people was confirmed by data from the Framingham Study, which reported a prevalence of sHT of 8.2% in men and 16.9% in women, older than 60 years and, the Colorado study (16% in men and 21% in women older than 74 yrs) (Sawin et al., 1979, Canaris et al., 2000). Overall these findings demonstrate that ageing is associated with an increased prevalence of positive anti-thyroid antibody titers and mild hypothyroidism (Mariotti et al., 1995). The prevalence of sHT varies also according to iodine intake; being higher in areas with elevated intake with respect to areas with low-normal or deficient intake (Biondi & Cooper, 2012). In this setting, the occurrence of sHT among nursing home elderly residents was 4.2% in an iodine-deficient area (urinary iodine 72

and the actual need of hormone replacement therapy (Villar, 2007).

Hypothyroidism is a graded phenomenon that encompasses a wide variety of clinical conditions from full blown myxedema to sHT, which is characterized by elevated serum TSH concentrations in the face of normal free thyroid hormone levels (Cooper, 2001). Currently, the most widely accepted interpretation of these biochemical findings is that increased TSH is an indication of slightly reduced peripheral thyroid hormone effect, leading to mild hypothyroidism instead of a new steady state of euthyroidism (Karmisholt et al., 2011, Ross, 2004). In a consensus statement of the American Association of Clinical Endocrinologists, sHT was classified in two categories according to TSH level: mildly increased serum TSH levels (4.5–10 mIU/liter), and more severely increased serum TSH value (>10 mIU/liter) (Gharib et al., 2005a,b). However, this classification was not adopted in all clinical investigations, thus making the comparison of different trials quite difficult.

There is scientific consensus that sHT is caused by the same etiology of overt hypothyroidism (Biondi & Cooper, 2008), the most frequent one being Hashimoto's thyroiditis. This is an autoimmune, inflammatory disorder of the thyroid gland, whose prevalence increases with increasing age, being higher in women (Canaris et al., 2000; Surks et al., 1996). Other causes of primary hypothyroidism may result from therapies that destroy the thyroid tissue such as radioactive iodine treatment, external radiation therapy or partial thyroidectomy (Cooper, 2001). Chemotherapy also was associated to hypothyroidism in patients with cancer or lymphoma (Hancock et al., 2001; Kumar et al., 2004). Moreover, both subclinical and overt hypothyroidism could be induced by many drugs such as amiodarone, lithium carbonate, type I interferons, sulfonamides and several other toxic molecules (Basaria & Cooper, 2004; Caraccio et al., 2005).

Patients with sHT have a different rate of progression to clinically overt hypothyroidism in the presence or not of autoimmunity: 2.6% each year if thyroperoxidase (TPO) antibodies are absent and 4.3% if they are present (Vanderpump et al., 1995). However, a significant number of sHT subjects do not show progression and some experiences normalization. One of the most predictive markers of progression to overt hypothyroidism is serum TSH level higher than 10 mIU/L, by contrast a level less than 6 mIU/L depicts a lower likelihood of progression (Fatourechi, 2009). Accordingly, a clinical study, enrolling men and women older than 55 years with mean follow-up of 32 months, indicated that serum TSH levels normalized in 52% of those with serum TSH value less than 10 mIU/L (Díez & Iglesias, 2004).

The most common symptoms reported by sHT patients are the same although less evident than those observed in overt hypothyroidism: dry skin, poor memory, slow thinking, muscle weakness, fatigue, muscle cramp, cold intolerance, puffy eyes, constipation, and hoarseness (Canaris et al., 2000; Canaris et al., 1997). It is conceivable that clinical symptoms of hypothyroidism are related to the degree of thyroid failure, disease duration, and individual sensitivity to thyroid hormone deficiency (Biondi & Cooper, 2008). However, the presence of typical symptoms in patients with sHT remains controversial considering that many of them are non-specific and shared with many clinical conditions, especially in the elderly. Therefore, it is difficult to distinguish euthyroid subjects from sHT patients only by using clinical symptoms (Biondi & Cooper, 2008). Baseline data from a randomized clinical study confirmed a significant prevalence of hypothyroid symptoms among individuals with sHT (Cooper et al., 1984). Moreover, Canaris et al., (2000) reported fewer symptoms related to hypothyroidism in subclinical than in overt hypothyroid patients, but more frequently than in euthyroid controls. However, this study did not distinguish between treated or untreated subclinical and overt hypothyroid patients. By contrast, other crosssectional and case-control studies did not confirm these observations, but they were conducted among selected or referred populations often involving old hospitalized patients (Bemben et al., 1994; Zulewski et al., 1997). Age represents a confounding factor that may hinder the identification of symptoms of mild hypothyroidism: the typical findings of hypothyroidism are less common in the elderly and, if present, often either resemble or are attributed to chronic illnesses, drugs, depression or ageing *per se* (Billewitc et al., 1969; Samuels, 1998). Therefore, clinical signs and symptoms are poor predictors of sHT especially in the elderly; this fact may explain why the diagnosis of sHT, and sometime overt disease yet, may be delayed in older people (Biondi & Cooper, 2008).

Mild Thyroid Deficiency in the Elderly 187

population (>85 yr) (Helfand et al., 2004; Mariotti et al., 1993). An interesting study focused on thyroid function during physiological ageing was carried out by Mariotti et al. (1993). In this study thyroid status was assessed in 41 healthy centenarians and 33 healthy elderly subjects as compared to two control groups: 98 healthy normal adult subjects and 52 patients with miscellaneous non-thyroidal illness. Healthy centenarians showed a lower prevalence of positive anti-thyroid autoantibody titer than elderly controls with a relatively low (7%) prevalence of sHT although the median serum FT3 level was lower than in each other group. Interestingly, median serum TSH level of centenarians was lower than in healthy elderly subjects, in whom however, was significantly lower than in young controls (Mariotti et al., 1993). This study did not resolve the question whether the decreased FT3 and TSH value observed in healthy centenarians, represents an adaptive mechanism to reduced metabolic homeostasis or a protective condition in ageing. At partial odds with these data, a population based survey and one large cross-sectional study (Atzmon et al., 2009; Surks et al., 2007) showed a progressive shift of the normal serum TSH range towards higher values from healthy young individuals up to centenarians. Overall these data seem to suggest that ageing is associated with a certain degree of down regulation of the hypothalamuspituitary-thyroid-peripheral axis, although the clinical significance of such condition is far to be elucidated. To this regard, Rozing et al. (2010) reported that the offspring of nonagenarian siblings presented a lower thyroidal sensitivity to TSH and a paradoxical beneficial cardiometabolic profile as compared to their partners. The authors concluded that the favorable role of low thyroid hormone metabolism on health and longevity, already observed in animal models, might be applicable to humans as well. However, the study by Rozing et al. (2010) enrolled a specific population in order to identify familial determinants of healthy longevity in nonagenarian siblings. The results might, therefore, be affected by some bias and cannot be extended to the general population. On the other hand, a crosssectional study by Corsonello et al. (2010) carried out in 604 home-dwelling subjects born in Calabria (southern Italy), with ancestry in the region ascertained up to the grandparents, confirms a declining of serum thyroid hormone levels with ageing. Moreover, lower levels of FT3, FT4 and TSH were found in centenarians' children and nieces/nephews with respect to age-matched controls. Indeed, the authors conclude that an age-related subtle decline of thyroid function (either due to a familial component or due to a reset of the thyroid function occurring between the sixth and the eighth decade of life) seems to be related to longevity. Two other studies support the hypothesis that mild hypothyroidism in elderly might be associated to a better survival and performance status. In the first, Gussekloo et al. (2006) found lower all-cause and cardiovascular mortality in hypothyroid subjects aged more than 85 years followed for 4 years, when compared with euthyroid individuals. In the second, van den Beld et al. (2005) showed that low-serum T3 (with normal rT3) concentrations were associated with a better survival and physical performance, while subjects with low-serum T3 and high rT3 concentrations ("low T3 syndrome") did not show any survival advantage and had lower baseline physical activity. The authors suggested that higher serum rT3 concentrations may result from a decreased peripheral metabolism of thyroid hormones due to the ageing process itself and/or disease and may reflect a catabolic state although, a certain degree of lower activity of the thyroid hormone axis might be beneficial during the

aging process.
