**1. Introduction**

Subclinical hypothyroidism (sHT) is defined as serum thyrotropin-stimulating hormone (TSH) concentration above the statistically defined upper limit of the reference range in the face of serum free T4 (FT4) and free T3 (FT3) concentrations within the normal range (Ross, 2004). sHT is a frequent condition among the general population, especially middle-aged and elderly women (Canaris et al., 2000). Depending on the degree of TSH elevation, sHT has been associated with hyperlipidemia, intermediary metabolism alterations, arterial hypertension and cardiovascular disease (CVD) as well as neuropsychiatric features, including cognitive impairment (Ashizawa et al., 2010; Biondi & Cooper., 2008; Cappola et al., 2006; Ceresini et al., 2010; Mitrou et al., 2011; Monzani et al., 2006; Rodondi et al., 2010; Tan et al., 2008; Tappy, 1987). Interestingly, the analysis of variation in thyroid function tests in healthy volunteers has shown that the physiological individual reference ranges for test results are narrow compared with laboratory references (Andersen et al., 2002). This finding suggests that a test result within laboratory reference limits is not necessarily normal for an individual. Giving that serum TSH responds with logarithmically amplified degree to minor changes in serum T4 and T3, abnormal serum TSH may indicate that T4 and T3 are not normal for an individual although still within the laboratory references. These data point out that the distinction between subclinical and overt thyroid failure (elevated serum TSH and low T4 and/or T3) is somewhat arbitrary. Indeed, for the same degree of thyroid function abnormality, the diagnosis depends to a considerable extent on the position of the patient's normal set point for T4 and T3 within the laboratory reference range.

Because sHT is mainly detected as a biochemical TSH abnormality, the definition of the TSH reference range represents a critical point, especially in the elderly (Baloch et al., 2003; Olsen, 1978; Dayan et al., 2001). In the past, the upper normal limit of TSH was considered about 10 mIU/L with the first-generation TSH RIA assay while, the current normal reference range of serum TSH concentration is around 0.45 to 4.5 mIU/L (Biondi & Cooper, 2008; Surks et al.,

© 2012 Monzani et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Mild Thyroid Deficiency in the Elderly 185

micrograms/g creatinine), 10.4% in region of obligatory iodinated salt prophylaxis (urinary iodine 100 micrograms/g creatinine) and 23.9% in an abundant iodine intake area (urinary

Overall, these data show that sHT is a very frequent condition and raise the question of the opportunity for general population screening programs, although a consensus is still lacking on this topic (Biondi & Cooper, 2012). The above notwithstanding, screening older people for thyroid disorders is still suggested by some authorities, aiming at the discovery of previously undiagnosed cases of overt hypothyroidism and the monitoring of cases with

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

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).

iodine 513 micrograms/g creatinine) (Szabolcs et al., 1997).

subclinical dysfunction (Ladenson et al., 2000; Surks et al., 2004).

(Basaria & Cooper, 2004; Caraccio et al., 2005).

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