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Department of Clinical and Molecular Endocrinology and Oncology (B.B.), University of Naples Federico II, 80131 Naples, Italy; and Sinai Hospital of Baltimore (D.S.C.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21215
Correspondence: Address all correspondence and requests for reprints to: Bernadette Biondi, Department of Clinical and Molecular Endocrinology and Oncology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy. E-mail: bebiondi{at}unina.it or bebiondi{at}libero.it
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Abstract |
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 Top Abstract I. IntroductionII. MethodsIII. Normal Thyrotropin...IV. Set-Point of the...V. Subclinical HypothyroidismVI. Subclinical HyperthyroidismReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. MethodsIII. Normal Thyrotropin...IV. Set-Point of the...V. Subclinical HypothyroidismVI. Subclinical HyperthyroidismReferences |
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At present, there is no consensus about the TSH concentration at which treatment should be contemplated (5, 6), except for elderly individuals with serum TSH values less than 0.1 mIU/liter (6). Moreover, because the definition of SCTD is based on abnormal TSH levels, the normal TSH range must be established, and it is proving to be a difficult task to define the upper limit of normal (10, 11). To compound the issue further, it has been difficult to correlate possible adverse effects at the tissue level with a TSH cut-off point, because of the individual set-point of the hypothalamic pituitary-thyroid axis (12).
Here we review clinical and epidemiological data to determine the: 1) prevalence and progression of SCTD; 2) global clinical risk (cardiovascular, bone, muscle, lipid, and hemostatic profile, etc.) associated with SCTD and its prognostic implications; 3) risks of untreated SCTD in relation to the patient’s age; 4) benefits of correcting SCTD; 5) optimal treatment; and 6) benefits of a screening program. Lastly, an algorithm for the practical evaluation and treatment of SCTD examined from a global viewpoint is provided.
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II. Methods |
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TopAbstractI. IntroductionII. MethodsIII. Normal Thyrotropin...IV. Set-Point of the...V. Subclinical HypothyroidismVI. Subclinical HyperthyroidismReferences |
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B. Methods of evaluation to assess study quality
The two authors agreed on the inclusion/exclusion status of the studies reviewed after assessing the quality of studies. Although this review is not a meta-analysis, we critically assessed the literature and tried to identify high-quality studies. The TSH range at baseline evaluation was recorded to determine the degree of thyroid hormone deficiency or excess that was considered in each study. In the evaluation of treatment for SCTD, wherever possible, preference was given to randomized controlled trials and longitudinal studies; however, very few reports had these characteristics. Therefore, we included other types of clinical trials. Moreover, we examined whether the control group was appropriate, whether euthyroidism was completely obtained after treatment of SCTD, and whether over- or undertreatment was avoided. Furthermore, we evaluated whether the methods used to evaluate the effects of SCTD at tissue level were correct. Lastly, we evaluated whether a correct statistical analysis was applied in the studies. Previously published review articles evaluating the effects of SCTD are discussed.
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III. Normal Thyrotropin-Stimulating Hormone Range |
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TopAbstractI. IntroductionII. MethodsIII. Normal Thyrotropin...IV. Set-Point of the...V. Subclinical HypothyroidismVI. Subclinical HyperthyroidismReferences |
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TSH in the circulation is heterogeneous with respect to both glycosylation and biological activity. Assays vary widely because current TSH immunometric assays involve the use of monoclonal antibodies that differ in specificity and may measure different TSH isoforms. Thus, the variation in the reference intervals obtained with different methods reflects differences in epitope recognition of different TSH isoforms. These differences make it difficult to establish a universal upper TSH reference limit. Lymphocytic infiltration of the thyroid gland is present in up to 40% of healthy women. Moreover, the National Health and Nutritional Examination Survey (NHANES) III survey, which used a competitive immunoassay procedure, reported an antithyroglobulin antibody (TgAb) prevalence of 10% and detectable thyroid peroxidase (TPO) levels in 12% of the general population (16). Furthermore, a hypoechoic ultrasound pattern or an irregular echo pattern may precede antithyroid peroxidase antibody (TPOAb) positivity in autoimmune thyroid disease, and TPO may not be detected in more than 20% of individuals with ultrasound evidence of thyroid autoimmunity (TA) (17, 18). For this reason, it is recommended that the serum TSH reference interval be established using blood sampled in the morning from fasting euthyroid subjects who have no family history of thyroid disease, are not taking medication, have no visible or palpable goiter or pathological thyroid ultrasonography findings, and are not positive for TPOAb or TgAb (19). For example, in the NHANES III study, in subjects without reported thyroid disease, TPOAb frequency increased as TSH levels increased in the study population (being 5.5% at TSH 0.4–1.0 mIU/liter, 30.6% at TSH 3.5–4.0 mIU/liter, and 80–90% in subjects with a TSH concentration over 10 mIU/liter (20). Further evidence of a relationship between TPOAb and serum TSH comes from a Norwegian study (21). In this health survey, all inhabitants 20 yr and older (n = 94,009) in Nord-Trøndelag were evaluated by a questionnaire and blood samples. In individuals without a history of thyroid disease, the median and the 2.5th and 97.5th percentiles for TSH were 1.80 and 0.49–5.70 mIU/liter for females and 1.50 and 0.56–4.60 mIU/liter for males. However, when individuals with positive TPOAb were excluded, the 97.5th percentiles dropped to 3.60 and 3.40 mIU/liter for females and males, respectively. Moreover, the percent of TPO-positive subjects was lowest in the TSH range between 0.2 and 1.9 mIU/liter and increased with both lower and higher levels of TSH (21).
In the NHANES III study, a separate population of 13,344 subjects without a history of thyroid disease, goiter, pregnancy, or biochemical hypo- or hyperthyroidism; not taking thyroid medication, androgens, or estrogens; and free of anti-TPO and TgAb (the so-called "reference population") was examined separately from the entire cohort of 17,353 persons. In this group without thyroid disease or risk factors, the median TSH level was 1.39 mIU/liter and the 2.5th and 97.5th percentiles were 0.45 and 4.12 mIU/liter, respectively (16). However, TSH values did not have a Gaussian distribution, and about 9% of the subjects in this reference population had TSH levels above 2.5 mIU/liter. Although it may be conjectured that this "upper tail" was observed because the group included people with occult TA and negative anti-TPO antibodies, other recent data argue against this explanation.
Evidence against occult autoimmunity being responsible for the "tail" in the TSH distribution comes from a recent German study that established reference intervals for TSH based on National Academy of Clinical Biochemistry criteria as well as sonographic confirmation of a normal thyroid gland (19). Of the 870 apparently healthy persons investigated, only 453 were included in the study; 47.9% of healthy blood donors did not meet all criteria for normal thyroid function and morphology by sonography. In this reference group, the lower limit of reference range for TSH increased from 0.3 to 0.4 mIU/liter, and the upper reference limit decreased from 4.1 to 3.7 mIU/liter compared with the NHANES III study. However, serum TSH levels were not Gaussian in this study either, which suggests that the upper tail may be a biological phenomenon, possibly related to TSH receptor gene polymorphisms or TSH microheterogeneity. Of course, occult thyroid disease that cannot be detected by antibody testing and thyroid sonography can never be completely ruled out. Moreover, iodine intake may affect the reference interval for thyroid function tests. The differences between the German and U.S. data could be related to the higher incidence of Hashimoto disease in the United States or because of higher iodine intake or increased thyroidal autonomy in the possibly mildly iodine-deficient German population. Despite iodine supplementation programs, iodine deficiency persists in some European countries. In a cross-sectional epidemiological survey in a previously iodine-deficient area (western Pomerania, northeast Germany), the reference interval for serum TSH was 0.25–2.12 mIU/liter, and the reference intervals for serum TSH and free thyroid hormones were narrower and moved to the left when compared with the NHANES study (22). In an iodine-deficient village of southern Italy, the entire resident population underwent thyroid function tests, thyroid ultrasound examination, and measurement of urinary iodine concentration (23). The mean serum TSH concentration in the adult population was 1.4 ± 1.1 mIU/liter in goitrous subjects and 2.0 ± 2.4 mIU/liter in nongoitrous subjects (23).
Evidence in support of a narrower normal TSH range comes from the Whickham survey (24). This 20-yr follow-up study of hypothyroidism in 1700 subjects demonstrated a higher prevalence of progression to overt disease in patients with TSH levels above 2 mIU/liter. However, the risk was far higher in those subjects who had positive antithyroid antibodies at baseline.
Conflicting results have been reported about the association between TSH at the upper limit of the considered normal range and cardiovascular risk factors (25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38). Subjects with high-normal serum TSH (2.0–4.0 mIU/liter) and positive thyroid autoantibodies had higher mean serum cholesterol levels than those with TSH values in the lower half of the normal range (0.40–1.99 mIU/liter) (25). Moreover, administration of T4 to the subjects with high-normal serum TSH was accompanied by a significant lowering of cholesterol and low-density lipoprotein cholesterol (LDL-C), but only in antibody-positive subjects (25). In the fifth Tromso study (a cross-sectional epidemiological study of 5143 subjects), there was a significant, positive correlation between serum TSH levels and serum total cholesterol (TC) and LDL-C levels in men and women (26). However, this did not reach statistical significance in women after adjusting for age and body mass index (BMI). In an interventional study, which included subjects with SHypo receiving T4 supplementation for 1 yr (32 subjects given placebo and 32 subjects given T4), serum TC and LDL-C levels were significantly reduced after T4 therapy in subjects with SHypo, including those who at the end of the study had serum TSH levels between 0.2 and 2.0 mIU/liter (26).
The association between TSH within the reference range and serum lipid concentration was evaluated in a large cross-sectional population-based study of 30,656 individuals without known thyroid disease (27). Total serum cholesterol, LDL-C, non-high-density lipoprotein cholesterol (HDL-C), and triglycerides increased consistently with increasing TSH (P for trend < 0.001), whereas HDL-C decreased consistently (P for trend < 0.001). The association with serum lipids was linear across the entire reference range, with no indication of any threshold effect. Moreover, the associations with triglycerides and HDL-C were stronger among overweight than among normal-weight individuals (27).
Studies evaluating whether thyroid function within the euthyroid TSH range can affect blood pressure have produced conflicting results (28, 29, 30, 31, 32, 33). The relation between thyroid function and blood pressure was assessed in 284 subjects (68% hypertensive) who consumed high- and low-sodium diets. The serum FT4 index was lower (P < 0.0001) and the TSH concentration higher (P = 0.046) in hypertensive than in normotensive subjects, irrespective of other baseline characteristics, and the FT4 index independently predicted salt sensitivity of blood pressure (28). Similarly, a population-based study showed that small differences in serum TSH (within and above the reference range) were associated with significant differences in diastolic blood pressure (29). The relation between serum TSH and blood pressure was also assessed in the recent Tromso study, a population-based health survey, which included 5872 subjects not using blood pressure or T4 medication (30). In this study, there was a modest but significant positive correlation between serum TSH within the normal range (0.2–4.0 mIU/liter) and both systolic and diastolic blood pressure (30).
However, in a cross-sectional study of 2033 individuals in the Busselton thyroid study, mean systolic blood pressure, diastolic blood pressure and the prevalence of hypertension did not differ between subjects with SHypo and euthyroid subjects, nor did they differ between subjects with serum TSH concentrations in the upper reference range (2.0–4.0 mIU/liter) and those with TSH concentration in the lower reference range (0.4–2.0 mIU/liter) (31). On the other hand, a linear and positive association between TSH and systolic and diastolic blood pressure was found in a recent cross-sectional, population-based study on 30,728 individuals without previously known thyroid disease (32). Comparing TSH of 3.0–3.5 mIU/liter (upper part of the reference) with TSH of 0.50–0.99 mIU/liter (lower part of the reference), the odds ratio (OR) for hypertension was 1.98 [95% confidence interval (CI), 1.56 to 2.53] in men, and 1.23 (95% CI, 1.04 to 1.46) in women (32). In addition, a measure of endothelial function, flow-mediated endothelium-dependent vasodilatation of the brachial artery, was lower in healthy individuals with a serum TSH concentration between 2.0 and 4.0 mIU/liter than in those with TSH values between 0.4 and 2.0 mIU/liter (33).
Conflicting results have also been reported about the association between thyroid function and the BMI in individuals with TSH and FT4 within normal range (34, 35, 36, 37). A cross-sectional population study examined the association between the category of serum TSH or serum thyroid hormones and BMI or obesity (34). There was a positive association between obesity (BMI > 30 kg/m2) and serum TSH levels (P = 0.001). Moreover, there was a negative association between BMI and serum FT4 (P < 0.001) and no association between BMI and serum FT3 levels. The difference in BMI between the groups with the highest and lowest serum TSH levels was 1.9 kg/m2, which corresponds to a difference in body weight of 5.5 kg among women. The results of this study suggest that even slightly elevated serum TSH levels are important in determining body weight in the population (34). Among 87 obese women (BMI > 30 kg/m2), serum TSH concentrations were positively associated with increasing BMI, but there was no relationship between serum FT4 and BMI (35). Furthermore, in 6164 subjects living in Tromso, TSH concentrations were positively associated with BMI in women and men who did not smoke (36). However, in 401 euthyroid subjects there was no association between thyroid status within the normal range and BMI and no difference in BMI when subjects were stratified according to serum TSH or FT4 (37). Lastly, there was no difference in serum TSH or FT4 between lean and obese euthyroid subjects (37).
There are no prospective long-term studies to suggest increased risks of cardiovascular morbidity or mortality in patients with TSH levels at the upper limit of the considered normal range. A recent community-based study carried out in Busselton, Western Australia, examined whether serum TSH in the upper reference range (2.0–4.0 mIU/liter) was associated with cardiovascular end-points (38). The prevalence of coronary heart disease was not higher in subjects with a serum TSH level in the upper normal range (>2.0 mIU/liter) than in euthyroid controls (0.4–2.0 mIU/liter). Similarly, it did not differ between subjects with and those without thyroid antibodies (38).
In summary, the strongest epidemiological evidence for lowering the TSH normal range is the higher rate of antithyroid autoimmunity in subjects with TSH between 3 and 4.5 mIU/liter and the higher rate of progression to overt thyroid disease in this subgroup. Arguments in favor of lowering the upper limit of the TSH normal range are the cost of monitoring patients with thyroid autoantibodies and a TSH concentration between 3.0 and 4.5 mIU/liter, the risk of progression to overt disease, and the potential morbidity in subjects lost to follow-up.
Arguments against lowering the upper limit of normal include the fact that mild elevations in serum TSH are sometimes reversible (39), the expense of therapy without proven benefit, and the possibility of overtreatment leading to iatrogenic hyperthyroidism. In fact, links between TSH at the upper limit of normal range and some important cardiovascular risk factors are either conflicting or inconclusive (25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38). Moreover, the evidence in support of lowering the upper limit of the TSH normal range should be weighed against the health and economic impact that a reduced TSH range would have (11). About 10% of the 25,862 individuals screened in the Colorado study had mild thyroid failure, namely a TSH level above the laboratory upper limit of 5.1 mIU/liter (40). About 74% of those subjects had TSH levels between 5.0 and 10.0 mIU/liter. Given these figures, about 13 million people in the United States may have undiagnosed SHypo. A decrease in the upper limit of the TSH reference range from 5 to 3 mIU/liter would result in an increase of more than 3.0- to 5.0-fold in the percentage of patients classified as having mild thyroid disease (41).
A more convincing demonstration of the positive impact on patient outcome in identifying and treating persons with TSH levels in the upper normal range is necessary before lowering the upper limit of normal for serum TSH. In addition, it must be recognized that a normal range upper or lower limit, based on a reference population, does not of necessity mean that any person who falls outside that limit requires treatment or has an illness. In the meantime, careful follow-up should be considered for asymptomatic patients with serum TSH levels between 3 and 4.5 mIU/liter, especially if they have positive anti-TPO antibodies.
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IV. Set-Point of the Hypothalamic-Pituitary-Thyroid Axis and Individual TSH Range |
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TopAbstractI. IntroductionII. MethodsIII. Normal Thyrotropin...IV. Set-Point of the...V. Subclinical HypothyroidismVI. Subclinical HyperthyroidismReferences |
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Interindividual differences in the hypothalamic-pituitary-thyroid axis set-point are genetically determined (42, 43). Moreover, genetic variants have been found to affect both blood pressure and serum TSH levels (44). Consequently, interindividual differences in the hypothalamic pituitary-thyroid axis set-point might explain the different symptoms, signs, and peripheral thyroid hormone effects in subjects with exactly the same hormonal pattern. Furthermore, the biological activity of thyroid hormone, in terms of T3 availability, is regulated by type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) (45). The efficiency of conversion of T4 to T3 by D2 increases as the serum T4 decreases (45). Consequently, in the presence of a low level of T4 or in case of a hypothyroid state, D2 is increased and can generate a significant quantity of plasma T3. Moreover, polymorphisms in genes involved in thyroid hormone metabolism may affect thyroid hormone bioactivity (46). Deiodinases are tissue specifically regulated, and this may have consequences for the peripheral effects of thyroid hormone and for set points of endocrine feedback regulation (47).
In conclusion, a serum TSH level within the normal range, even if it is below 2.5 mIU/liter, may not be as sensitive a parameter of thyroid dysfunction for individual subjects as had previously been thought. Therefore, it is important to evaluate and integrate the laboratory results in relation to the clinical assessment, e.g., the patient’s symptoms, physiological status (e.g., age, pregnancy, etc.), and underlying health status (other comorbidities and drug intake).
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V. Subclinical Hypothyroidism |
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TopAbstractI. IntroductionII. MethodsIII. Normal Thyrotropin...IV. Set-Point of the...V. Subclinical HypothyroidismVI. Subclinical HyperthyroidismReferences |
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B. Etiology of subclinical hypothyroidism
The etiology of SHypo is the same as the etiology of overt hypothyroidism (1, 2)(Table 1
). It is most often caused by chronic lymphocytic thyroiditis (goitrous Hashimoto’s thyroiditis and atrophic thyroiditis), an autoimmune disorder of the thyroid gland that is the most common cause of decreased thyroid hormone production in patients with acquired mild, subclinical, or overt hypothyroidism (2, 48, 49, 50). Other causes of primary hypothyroidism may result from therapies that destroy thyroid tissue such as radioactive iodine treatment or external radiation therapy. Mild and overt hypothyroidism are common after external radiotherapy of the head and neck area and develops gradually within the first year with a risk that appears to be dose-dependent (51). It is frequent after external radiation therapy in patients with Hodgkin’s lymphoma, leukemia, aplastic anemia, brain tumors, or bone marrow transplantation. Chemotherapy also may induce hypothyroidism in patients with lymphoma (52). Women with breast cancer may have an increased risk of autoimmune thyroid disease after adjuvant chemotherapy and tamoxifen (53, 54). Transient or persistent increases in serum TSH may occur after subacute, postpartum, or painless thyroiditis and after partial thyroidectomy.
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Interferon-
, used for the treatment of hepatitis or certain tumors, alone or in combination with IL-2, may induce thyroid dysfunction due to the activation or enhancement of the autoimmune process (51, 59). Risk factors associated with the possible development of hypothyroidism include female sex, longer duration of interferon- treatment, presence of chronic hepatitis C virus, older age, and preexisting presence of anti-TPO antibodies. The prevalence of interferon--associated hypothyroidism in patients with chronic hepatitis C virus is reported to be between 7 and 39%, and the presence TPO antibodies may be an important risk factor (51) that predicts persistent hypothyroidism at the end of interferon- treatment. TA and dysfunction frequently occur in multiple sclerosis patients during interferon-β therapy, particularly within the first year of treatment; thyroid dysfunction is generally subclinical and transient in over half of the cases (60).
Hypothyroidism may develop during treatment with aminoglutethimide, ethionamide, sulfonamides, and sulfonylureas, which interfere with thyroid hormone synthesis (51). Persistent primary hypothyroidism and transient, mild TSH elevation are frequent complications of sunitinib therapy, an oral tyrosine kinase inhibitor recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma (61). Toxic injury to the thyroid gland was reported after exposure to various pesticides, herbicides, industrial chemicals, and naturally occurring environmental chemicals (51). Infiltrative disease (Riedel’s thyroiditis, amyloidosis, hemochromatosis, and cystinosis) or infectious disorders of the thyroid gland (Pneumocystis carini infection and Kaposi’s sarcoma in patients with AIDS) may induce thyroid hormone deficiency; however these diseases rarely cause hypothyroidism (51).
The postpartum period is associated with an increased risk of developing subclinical or overt hypothyroidism. Similarly, subjects with a family history of autoimmune thyroid disorders, autoimmune endocrine diseases, and nonendocrine autoimmune disorders (vitiligo, pernicious anemia, celiac disease, atrophic gastritis, multiple sclerosis, etc.) have an increased risk of hypothyroidism (62, 63, 64). Autoimmune thyroiditis can be associated with other endocrine deficiency syndromes: polyendocrine failure syndrome type 1, which includes hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis; and polyendocrine failure type 2, which includes adrenal insufficiency, type 1 diabetes mellitus, and primary ovarian failure.
SHypo is frequently observed in patients with overt hypothyroidism receiving inadequate replacement therapy due to poor compliance, drug interactions, or inadequate monitoring of therapy. In fact, between 17.6 and 30% of patients with overt thyroid failure were reported to have SHypo due to inadequate thyroid hormone supplementation (40, 65).
Germline loss-of-function mutations in one or both alleles of the TSH-receptor gene can cause SHypo (66, 67). TSH was slightly (6.6–14.9 mIU/liter) to moderately (24–46 mIU/liter) increased in these patients and was associated with normal free thyroid hormone concentrations, normal thyroid size, and normal biochemical parameters of TA (67). Recently, a low prevalence of TSH receptor mutations was reported in a large series of subjects with sporadic and familial nonautoimmune SHypo (68). However, TSH receptor mutations should be considered in subjects with a familial TSH increase associated with normal thyroid ultrasound and without markers of TA.
C. Differential diagnosis of serum TSH elevation
Only persistent or progressive SHypo should be considered an early stage of thyroid disease. It may be difficult to distinguish between transient disturbances of thyroid gland function and mild thyroid failure (Table 2). Transient hypothyroidism, followed by a euthyroid state, may be due to thyroiditis caused by viral infection (subacute thyroiditis) or autoimmunity (postpartum, painless, or silent thyroiditis). In the early phase of the disease, a mild TSH increase with absent or mild symptoms of hypothyroidism may make it difficult to distinguish who will recover from those destined to be permanently hypothyroid. Moreover, evidence from a long-term follow-up of patients with subacute thyroiditis suggests that viral infection can precipitate an autoimmune thyroid disease in susceptible individuals, thereby resulting in the development of permanent hypothyroidism (51). A diagnosis of persistent SHypo can be verified by reevaluating TSH concentration after 6 or 12 months. This will ensure that only persistent or progressive disease is treated, and will also rule out the possibility that abnormal values were due to a laboratory error. A high thyroid autoantibody titer associated with an increased persistent serum TSH concentration may be useful to identify individuals with autoimmune thyroid disease who are at increased risk of developing permanent hypothyroidism.
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Central hypothyroidism can present with mild TSH elevation (5–10 mIU/liter) in approximately 25% of cases that may represent bioinactive TSH (2). The association of low serum thyroid hormone levels with normal or slightly high serum TSH has often been observed in patients with pituitary or hypothalamic disorders.
D. Prevalence of subclinical hypothyroidism
The prevalence of SHypo has been reported to be between 4 and 10% of adult population samples (16, 40, 65, 75, 76, 77, 78, 79). Two large population-based screening studies have provided important epidemiological data about SHypo: the Whickham Survey (75), and NHANES III (16). A third important large study, the Colorado Thyroid Prevalence Study (40), was not truly population-based. In the Whickham Survey (2779 subjects), SHypo, defined by serum TSH levels above 6 mIU/liter, was identified in 7.5% of females and 2.8% of males (75). TSH levels did not vary with age in males but increased markedly in females after the age of 45 yr. Serum TSH concentration was not age-related in women without antithyroid antibodies.
The sample examined in NHANES III (16,353 people aged 
12 yr) represented the geographic and ethnic distribution of the U.S. population (16). SHypo was found in 4.3% of this population (normal TSH range, 0.39–4.6 mIU/liter). TPOAb were significantly associated with thyroid failure, were more prevalent in women than in men, increased with age, and were more prevalent in whites than in blacks.
In the Colorado study (over 25,000 state residents attending a series of statewide health fairs), 9.5% of all subjects had an elevated serum TSH concentration (normal range, 0.3–5.1 mIU/liter), and 89% of these were not on thyroid hormone therapy (40). Seventy-five percent of these individuals had serum TSH levels in the 5–10 mIU/liter range. In each age decade, a higher percentage of women than men had an elevated serum TSH concentration; the difference was significant after age 34 yr (P > 0.01). In the ninth decade of life, the prevalence of elevated TSH was as high as 15–20%.
The prevalence of mild thyroid dysfunction was higher in older populations in all epidemiological surveys conducted so far (16, 40, 65, 75, 76, 77, 78, 79, 80). Elevated values of serum TSH (>6 mIU/liter) were found in 6.73% of subjects in a healthy urban population over the age of 55 yr in which a highly sensitive serum TSH assay was used to screen 968 subjects (79). Using a very sensitive assay, Parle et al. (76) measured serum TSH concentrations in 1210 patients aged over 60 yr registered with a single general practice. High TSH values occurred more frequently in females (11.6%) than in males (2.9%), and antithyroid antibodies were identified in 60% of patients with high TSH concentrations (76). In a study of 370 patients (287 women, 83 men) between 60 and 97 yr of age, after excluding patients with a history of thyroid disease, 14.6% of the women and 15.4% of the men had SHypo (78).
SHypo is more frequent in areas of iodine sufficiency, i.e., 4.2% in iodine-deficient areas compared with 23.9% in areas of abundant iodine intake (80). This finding was confirmed by a high prevalence of SHypo in Iceland (18%) and Hungary (24%), which have a high iodine intake (81). Similarly, the incidence rate of overt hypothyroidism was lower than that of hyperthyroidism in an area with moderately low iodine intake (82). Iodine supplementation of a population may increase the incidence of thyroid hormone deficiency (83, 84).
In conclusion, SHypo represents a common disorder. The wide range (4–10%) of its prevalence might be due to the TSH cutoff used to define SHypo and differences in age, gender, and dietary iodine intake in the populations studied.
E. Natural history of subclinical hypothyroidism
In the 20-yr follow-up of the Whickham cohort, an increased serum TSH level was predictive of progression to overt hypothyroidism (24). Old age, female sex, and TPO antibodies were also associated with an increased risk of progression to overt hypothyroidism. The annual rate of progression to overt hypothyroidism was 4.3% in women with both raised serum TSH and antithyroid antibodies, 3% if only serum TSH was raised, and 2% if only antithyroid antibodies were present. A serum TSH level above 2 mIU/liter was associated with an increased probability of overt hypothyroidism (24). Thyroid autoantibodies were found to have prognostic relevance in other studies carried out in elderly subjects (76, 85, 86, 87, 88, 89, 90). Rosenthal et al. (89) reported that one third of geriatric patients developed overt hypothyroidism during 4 yr of follow-up. Among these, overt hypothyroidism developed in all subjects with initial TSH levels above 20 mIU/liter, and 80% of those with high-titer thyroid antimicrosomal antibodies (regardless of initial TSH level) became overtly hypothyroid (89).
Several possible prognostic factors for overt hypothyroidism were analyzed in a prospective study of 82 women with increased TSH concentrations due to autoimmune thyroiditis, radioiodine treatment, or thyroidectomy, over a mean observation period of 9.2 yr with annual follow-up (90). After 10 yr, 28% of the women had developed overt hypothyroidism, and 68% remained in the subclinical stage. TSH value became normal in 4% (all from the group with TSH between 4–6 mIU/liter). According to the initial serum TSH concentrations (TSH 4–6, >6–12, and >12 mIU/liter), Kaplan-Meier estimates of the incidence of overt hypothyroidism were 0, 42.8, and 76.9%, respectively, after 10 yr (P > 0.0001). In the entire population, the risk of hypothyroidism was higher in patients with TSH levels above 6 mIU/liter and positive antimicrosomal antibodies (90).
In another prospective study, serum TSH was the most powerful predictor of the outcome of spontaneous SHypo in 107 subjects over the age of 55 yr with SHypo and no history of thyroid disease (91). Twenty-eight patients (26.8%) developed overt hypothyroidism, and 40 (37.4%) normalized their TSH values. The incidence rate of overt hypothyroidism was 9.91 cases per 100 patient-years in the whole population, and 1.76, 19.67, and 73.47 cases per 100 patient-years in subjects with initial TSH values between 5.0–9.9, 10.0–14.9, and 15.0–19.9 mIU/liter, respectively. A stepwise multivariate Cox regression analysis showed that the only significant factor for progression to overt hypothyroidism was serum TSH concentration (P < 0.0001). The same authors analyzed the time course of normalization of TSH levels in 40 patients (32 women, mean age 62.8 ± 8.2 yr) with spontaneous SHypo (TSH > 5 mIU/liter and normal FT4) during a mean (±SD) observation period of 38.3 ± 17.0 months (range, 12–72 months) (39). The rate of normalization was greater in patients who had lesser degrees of serum TSH elevations and negative antithyroid antibody titers. Thus, the rate of normalization was 52% for those with serum TSH values between 5.0 and 9.9 mIU/liter and only 13% for those with TSH values between 10 and 14.9 mIU/liter. Fifteen patients (37.5%) normalized their TSH levels during the first year of follow-up and 27 (67.5%) during the first 2 yr. Ten patients (25%) had decreased TSH values at the fourth or fifth years of follow-up. However, the final spontaneous TSH normalization was in the range of 3 to 5 mIU/liter. Most subjects (65%) ended with TSH values higher than 3 mIU/liter, and 12 patients (30%) had values above 4.12 mIU/liter; only a minority of patients (10%) showed a reversion to TSH less than 2 mIU/liter (39). Finally, in another study, 11 of 21 octogenarians with SHypo and a TSH value greater than 4.7 mIU/liter had normal thyroid function after 3 yr (92).
A high risk of disease progression was observed in pregnant women with asymptomatic autoimmune thyroiditis (93). Women with autoimmune thyroiditis had basal TSH values significantly higher, albeit still normal, in the first trimester (1.6 vs. 0.9 mIU/liter; P < 0.001) than did women with healthy pregnancies used as controls. Despite a 60% average reduction in TPOAb titers during gestation, serum TSH remained higher in women with autoimmune thyroiditis than in controls throughout gestation: at delivery, 40% of cases had serum TSH levels above 3 mIU/liter, and 16% had serum TSH levels above 4 mIU/liter. A TRH test carried out in the days after parturition showed an exaggerated response in 50% of the cases.
The risk of progression from subclinical to overt hypothyroidism is less common in children and adolescents, and the recovery of thyroid function is more frequent. In 18 children and adolescents with autoimmune thyroiditis and elevated TSH, seven patients were euthyroid, 10 continued to have SHypo, and one became hypothyroid after a follow-up period of 5.8 yr (94). In another study, about 25% of adolescents affected by goitrous thyroiditis had spontaneous resolution of the disease over 20 yr, and about 33% developed overt hypothyroidism (95).
In conclusion, progression from mild to overt hypothyroidism may be related to the cause of thyroid hormone deficiency, the basal TSH value, and the patient’s age. Moreover, SHypo may be a persistent or transient disease (96). Transient expression of TSH-receptor blocking antibodies may explain the recovery of thyroid function in some cases (2). On this basis, it may be reasonable to reevaluate patients with previously diagnosed SHypo to assess whether it is persistent. This may be accomplished by progressive reduction in L-T4 dosage followed by serial TSH testing.
F. Symptoms, quality of life, and cognitive function in subclinical hypothyroidism
The decision to treat patients with SHypo is often based on the assessment of the clinical symptoms and signs of mild disease. A number of validated instruments are available to evaluate the presence or absence of various symptoms and signs of thyroid hormone deficiency (which are less sensitive in mild disease than in overt disease) or to evaluate mood, cognition, or quality of life. Moreover, the clinical picture of hypothyroidism has changed in recent years because of an earlier diagnosis. Formerly, the classical clinical picture of hypothyroidism focused on severe, long-standing disease. Thus, old clinical scoring systems may not identify symptoms and signs of very early disease, even if present. To complicate the issue further, nonspecific symptoms that occur in hypothyroidism are present commonly in persons with normal thyroid function or TA (97, 98, 99). Another obscure issue is the possible link between depression and impaired thyroid function (100, 101). This association is further complicated by evidence that autoimmune thyroiditis is more frequent in depressed patients than in healthy euthyroid individuals (20 vs. 5%) (102)
The groups of Billewicz (103) and Seshadri (104) have developed symptom scores to investigate the value of symptoms in discriminating overt hypothyroidism from euthyroidism, and these systems have also been applied to investigate the potential clinical significance of SHypo. In the Colorado study, a questionnaire that included 17 thyroid symptoms revealed a clear correlation between the type of symptom (dry skin, poor memory, slow thinking, muscle weakness, fatigue, muscle cramp, cold intolerance, puffy eyes, constipation, and hoarseness), the number of symptoms, and elevated TSH (40, 105). A small increase in total symptoms was observed with progressive deterioration of thyroid function. In fact, whereas euthyroid subjects reported a mean of 12.1% of all listed symptoms, overtly hypothyroid subjects had 16.6% of these symptoms (P < 0.05 vs. euthyroid group), and subjects with mild hypothyroidism had 13.8% (P < 0.05 vs. euthyroid group). Moreover, reporting more symptoms, in particular recently "changed symptoms" increased the likelihood of disease.
Using a new clinical score constituted by 14 symptoms and signs of hypothyroidism to assess the severity of thyroid failure, Zulewski et al. (106) found a good correlation between this score, FT4, and TSH in patients with SHypo. However, thyroid status was not predicted from clinical signs and symptoms in a retrospective study conducted in a primary care geriatrics clinic (107). There was no significant relationship between TSH levels and the total number of hypothyroid symptoms experienced by all patients (P = 0.99), and logistic regression analyses showed that clinical signs and symptoms were poor predictors of SHypo in these elderly patients (107).
A community-based cross-sectional study was recently performed on a total of 1423 non-healthcare-seeking women, aged 18–75 yr randomly recruited. Short-Form 36 (SF-36) and the Psychological General Well-being Index (PGWI) were used to evaluate health-related quality of life in subjects with SHypo defined as serum TSH above 4.0 mIU/liter. In this study, SHypo was not associated with lower well-being or impaired health-related quality of life (108).
The presence of symptoms in patients with SHypo was evaluated in two studies. In a study by Cooper et al. (109), patients with SHypo had a higher prevalence of hypothyroid symptoms than age- and sex-matched euthyroid controls. However, in a study by Kong et al. (110) of women with SHypo, the most common hypothyroid symptoms were fatigue (83%) and weight gain (80%). At presentation, 20 women (50%) had elevated anxiety scores, and 22 (56%) had elevated scores on the General Health Questionnaire (110).
Results obtained with anxiety scores and cognitive deficiency scores in SHypo subjects are controversial (77, 92, 111, 112, 113, 114, 115, 116, 117). Impaired memory function has been reported in SHypo in small numbers of patients (111, 113), but more recent larger studies have not corroborated this observation (77, 92, 112, 114, 115, 116, 117). For example, an interview survey of 825 Medicare subjects in New Mexico (mean age, 74.1 yr) did not reveal any differences in the age-adjusted frequency of self-reported symptoms, cognitive tests, or depression between subjects with elevated serum TSH (from 4.7 to 10 mIU/liter) and those with normal TSH concentrations (77). Also, in a prospective observational population study of 559 individuals monitored from ages 85 through 89 yr, plasma TSH levels and FT4 were not associated with disability in daily life, depressive symptoms, or cognitive function (92). The relation between neuropsychological function and SHypo (defined as serum TSH between 3.5 and 10 mIU/liter) was recently studied in 89 subjects with SHypo older than 29 yr and 154 control subjects recruited from a general health survey (115). No significant differences in cognitive function or hypothyroid symptoms were observed between patients and controls, whereas patients scored better than controls on the General Health Questionnaire (GHQ-30) for emotional function. In a survey carried out in Pomerania, which included 3790 participants with known thyroid disease, 27 subjects with SHypo did not differ from controls in their mental and physical complaints (116). However, autoimmune thyroiditis in 47 patients was associated with negative effects on health also in euthyroid subjects (116). A recent cross-sectional study of 5865 patients at least 65 yr of age with known thyroid disease (168 with SHypo defined by TSH > 5.5 mIU/liter) was carried out in primary care practices in England to assess the association with cognitive function, depression, and anxiety. This study provides good evidence that SCTD is not associated with depression, anxiety, or cognition (117). In contrast, in a recent study, functional magnetic resonance imaging (MRI) was used to evaluate brain function in overt and SHypo patients in comparison with euthyroid subjects (118). This study suggested that working memory (but not other memory functions) is impaired by SHypo, and impairment is more severe in overt hypothyroidism (118).
In conclusion, the presence of symptoms in patients with SHypo remains controversial. It is difficult to distinguish euthyroid subjects from patients with SHypo using clinical symptoms. Moreover, many symptoms are nonspecific. In our opinion, symptoms of hypothyroidism are probably related to disease severity, disease duration, and individual sensitivity to thyroid hormone deficiency, which in turn depend on the sensitivity of the peripheral target organs. Age may also affect the identification of symptoms of hypothyroidism. The typical findings of hypothyroidism are less common in the elderly and, when present, are often attributed to chronic illnesses, drugs, depression, or age (119, 120). Similarly, clinical signs and symptoms are poor predictors of SHypo in the elderly; this may explain why the diagnosis of SHypo, like overt disease, may be delayed in elderly patients (Fig. 1). Symptoms and signs can also be minimal or nonspecific in young and middle-aged patients with SHypo. Furthermore, patients with SHypo identified by population screening may be more likely to be asymptomatic than those identified in clinical trials. In fact, patients with persistent SHypo or with a poor quality of life are more likely to present to a physician for thyroid function testing. The presence of specific symptoms may suggest thyroid hormone deficiency and may serve to identify patients who need thyroid function tests and to select SHypo patients who can benefit from replacement therapy. Patients who report more symptoms and more recently developed symptoms may be more likely to have overt thyroid hormone deficiency (105).
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1. Cardiac function in SHypo.
The impact of SHypo on the cardiovascular system has been evaluated by looking at diastolic function, systolic function, and exercise performance (127, 128). Left ventricular diastolic function was evaluated in seven studies by Doppler echocardiography and radionuclide ventriculography at rest and during exercise, in young and middle-aged patients with Hashimoto thyroiditis and mild but persistent TSH increases compared with euthyroid controls (129, 130, 131, 132, 133, 134, 135) (Table 3). Subclinically hypothyroid patients had a more prolonged isovolumetric relaxation time and an impaired time-to-peak filling rate (which are parameters of altered left ventricular diastolic function) than controls (129, 130, 131, 132, 133, 134, 135). As shown in Fig. 2, overt hypothyroidism can affect left ventricular diastolic function (136, 137, 138, 139) by causing decreased expression of sarcoplasmic reticulum calcium ATPase (121, 123, 136). This leads to reduced calcium reuptake into the sarcoplasmic reticulum during diastole, resulting in impaired diastolic relaxation. A similar mechanism could impair diastolic function in patients with SHypo (129, 130, 131, 132, 133, 134, 135). This cardiac finding may be an important negative prognostic factor, because isolated left ventricular diastolic dysfunction has been associated with increased morbidity and mortality in the general population (140). Moreover, impaired left ventricular diastolic function at rest may be an important cause of exercise intolerance and may lead to diastolic heart failure in the elderly (141).
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) (131, 132, 133, 134, 135, 142, 143, 144, 145). Cardiac systolic function was normal in patients with SHypo in three studies in which Weissler’s method (simultaneous recording electrocardiography, carotid tracing, and phonocardiogram) was used to assess systolic function (142, 143, 145). However, impaired at-rest left ventricular function, as defined by an increased preejection period (PEP)/left ventricular ejection time (LVET) ratio, was reported in five studies using the more sensitive echocardiographic technique in SHypo patients compared with control subjects (131, 132, 133, 134, 135). Only Tseng et al. (144) did not find a significant variation in PEP and PEP/LVET by means of concurrent aortic and mitral valve echocardiography. The systolic time interval alterations reported in SHypo patients resemble those found in patients with overt disease (138, 146), although they are of a lesser magnitude. Impaired left ventricular systolic (147) and diastolic (130) function on effort were also documented by Doppler echocardiography and cardiopulmonary exercise testing in SHypo patients in comparison with euthyroid controls.
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More sophisticated techniques have recently been used to assess systolic and diastolic function and myocardial texture in patients with SHypo. Cardiac MRI (CMR), which gives high resolution, three-dimensional reconstructions, is at present the most accurate procedure with which to evaluate cardiac volumes and function. Indeed, it resolved conflicting data about systolic function in mild SHypo (149). Thirty women with SHypo (TSH range, 8.7 ± 3.7 mIU/liter) due to Hashimoto thyroiditis and 20 matched control subjects were evaluated by MRI in comparison with normal subjects. Cardiac volumes and systolic performance were significantly altered in the SHypo patients. In particular, the preload (end-diastolic volume) was significantly decreased and the afterload (SVR) was significantly increased, thereby leading to impaired cardiac performance (149).
Tissue Doppler imaging is an emerging noninvasive ultrasound tool that makes it possible to measure velocities at any point of the ventricular wall during the cardiac cycle. It is minimally affected by alterations in afterload and changes in heart rate (150). Tissue Doppler imaging revealed changes in myocardial time intervals in several segments in 20 healthy women with SHypo (TSH, 10.5 ± 4.05 mIU/liter) (132). Myocardial time intervals, evaluated as precontraction time, the precontraction time/myocardial contraction time ratio, and myocardial relaxation time, were prolonged at the level of both the posterior septum and the mitral annulus in patients with autoimmune SHypo in comparison with controls (132). These alterations were similar to those identified in patients with overt hypothyroidism (138).
Finally, ultrasonic myocardial textural analysis was used in two studies to characterize myocardial tissue in patients with SHypo (131, 133). The cyclic variation index, which is a percentage of systolic/diastolic change in mean gray levels of the interventricular septum and the left ventricular posterior wall, was lower in patients than in normal subjects. These findings are indicative of alterations in myocardial composition, which may represent early myocardial structural changes in mild thyroid deficiency.
In conclusion, the most consistent cardiac abnormality reported in patients with SHypo is impaired left ventricular diastolic function, which is characterized by slowed myocardial relaxation and impaired ventricular filling (129, 130, 131, 132, 133, 134, 135). Results concerning systolic function at rest are not consistent (131, 132, 133, 134, 135 ,142, 143, 144, 145); however impaired systolic function has been identified with new, more sensitive techniques (Doppler echocardiography and CMR) (131, 132, 133, 134, 135, 149). Only two studies have assessed systolic function and diastolic function during exercise and documented impaired cardiac performance on effort (130, 147). All the cardiovascular alterations that have been reported in patients with SHypo are similar to those observed in overt hypothyroidism. This suggests that there is a continuum in the cardiac changes that occur through mild, subclinical disease into overt hypothyroidism.
2. Vascular system and SHypo.
T3 directly affects the vascular smooth-muscle cells that promote relaxation. It also decreases SVR by increasing tissue thermogenesis and metabolic activity (151, 152, 153, 154). Overt hypothyroidism may be a risk factor for hypertension, and reversible diastolic hypertension has been reported in 20–40% of patients with overt disease (121, 123, 151, 152, 153, 154). An increased risk of hypertension has also been reported in some studies of patients with SHypo (155, 156). As in overt disease, three factors can contribute to systemic hypertension in SHypo: increased peripheral vascular resistance, increased arterial stiffness, and endothelial dysfunction. An increase in SVR and in mean arterial pressure was reported in some studies of normotensive patients with SHypo compared with euthyroid subjects (129, 157) but not in all (133, 135). Recently, a significant increase in SVR was reported using CMR in 30 patients with SHypo (TSH, 8.7 ± 3.7 mIU/liter) compared with 20 euthyroid controls (149). These data suggest that mild thyroid hormone deficiency might also affect vascular tone (123).
Increased central arterial stiffness appears to be an important risk factor for cardiovascular disease. Changes in arterial wall elasticity may occur before and during the early stages of atherosclerosis and may have detrimental effects on left ventricular function and coronary perfusion. Increased arterial stiffness may contribute to the development of hypertension and has been reported to be an independent risk factor for cardiovascular morbidity and mortality (158, 159).
Increased arterial stiffness can be identified from an increased augmentation of central aortic pressure and central arterial stiffness in untreated patients with overt hypothyroidism compared with age-, sex-, and BMI-matched controls (160, 161). Pulse wave analysis has also revealed increased arterial stiffness in patients with SHypo (156). Increased arterial stiffness has also been identified from increased augmentation gradient, augmentation index, and corrected augmentation index in patients with SHypo compared with controls (162). Pulse wave velocity is a direct parameter of arterial stiffness and a marker of cardiovascular risk (163, 164). The brachial-ankle pulse wave velocity is a parameter of arterial stiffening and is a good independent predictor for coronary artery disease. It has been used to investigate the risk of ischemic heart disease in overt hypothyroidism and SHypo. Both groups of subjects tended to have increased arterial wall stiffness (160, 161). Diastolic blood pressure and brachial-ankle pulse wave velocity were significantly increased in patients with SHypo (TSH, 6.9 ± 0.82 mIU/liter) compared with normal subjects (156, 165). Moreover, central and peripheral pulse wave velocities were significantly higher in SHypo patients than in normal subjects (156, 165).
The vascular endothelium is a regulator of vascular smooth-muscle cell function and helps to maintain homeostasis and blood fluidity. Nitric oxide in the endothelium diffuses to the vascular smooth muscle and induces relaxation. Similar to what is observed in hypothyroidism, SHypo has been found to be associated with endothelial dysfunction (33, 166). High-resolution ultrasound imaging of the brachial artery showed that, compared with a control group, flow-mediated endothelium-dependent vasodilatation was significantly impaired in hypothyroid subjects with TSH levels between 4.01 and 10 mIU/liter, and greater than 10 mIU/liter (33). Taddei et al. (166) used the perfused forearm technique to measure the forearm blood flow response to intrabrachial acetylcholine, which is an endothelium-dependent vasodilator, at baseline and during infusion of the NO inhibitor, NG-monomethyl-L-arginine, in SHypo patients (TSH, 7.68 ± 3.21 mIU/liter) before and after L-T4 therapy (166). The vasodilating effect of acetylcholine was significantly reduced in patients vs. healthy subjects and was not affected by NG-monomethyl-L-arginine. Endothelial dysfunction was attributed to the reduced NO availability. Recent data suggest that low-grade chronic inflammation could be responsible for endothelial dysfunction and impaired NO availability by a cyclooxygenase (COX-2)-dependent pathway, increasing oxidative stress in patients with SHypo due to Hashimoto’s thyroiditis (167).
Carotid artery intima-media thickness (CIMT) can be a useful parameter in the early diagnosis of atherosclerosis and coronary heart disease. Increased CIMT has been documented in SHypo (168, 169). Patients with SHypo had higher TC, LDL-C, and apolipoprotein (Apo) B levels and higher mean intima-media thickness (IMT) values compared with age- and sex-matched controls. Moreover, mean IMT was positively related to age, TSH, and LDL-C (168).
Myocardial functional reserve, assessed by iv dobutamine, did not differ between subjects with SHypo and controls and remained unaltered after treatment (162). There were no differences in resting global, regional left ventricular function, or regional myocardial velocities during maximal dobutamine stress between SHypo patients and controls, or in patients treated with replacement therapy compared with baseline values (162). However, in a recent study, coronary flow reserve was lower in subclinical and overt hypothyroidism than in euthyroid subjects (170).
In conclusion, on the basis of the data available, SHypo could impair vascular function by inducing an increase in SVR and arterial stiffness and by altering endothelial function, thereby potentially increasing the risk of atherosclerosis and coronary artery disease.
3. SHypo and lipid profile.
The relationship between SHypo and serum lipids remains controversial (126, 171). In several cross-sectional studies, SHypo was found to be associated with a variable and somewhat inconsistent increase in TC and in LDL-C (40, 77, 172, 173, 174, 175, 176), higher plasma oxidized LDL-C levels (177), and inconsistent changes in serum levels of HDL-C (145, 155, 168, 172, 173, 175, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190). Not unexpectedly, the lipid pattern is more abnormal in SHypo individuals with serum TSH greater than 10 mIU/liter (77, 145, 173, 178, 181, 182, 183), and it is also more deranged in those who smoke (177, 183, 191). Moreover, in a group of healthy euthyroid subjects, Bakker et al. (191) found a strong, positive relationship between TSH and LDL-C in insulin-resistant subjects, but not in insulin-sensitive subjects.
The association between SHypo and serum TC and LDL-C has been investigated in several large population-based studies. In the Whickham Survey, SHypo was not related to hyperlipidemia (174). In the NHANES III, mean cholesterol levels and rates of elevated cholesterol levels were higher in people with SHypo (TSH, 6.7–14.9 mIU/liter) than in euthyroid controls (TSH, 0.36–6.7 mIU/liter); there were no differences in LDL or HDL levels (192). However, when adjusted for age, race, sex, and the use of lipid-lowering drugs, SHypo was not related to increased cholesterol levels (192). In another study, there was no apparent relationship in subjects with SHypo between serum concentrations of TSH ranging from 4.0 to 49.0 mIU/ml and concentrations of LDL-C (186). In the Rotterdam Study, TC was lower in women with SHypo than in euthyroid women (193). Similar data were reported in the Nagasaki study (194). In the New Mexico Elder Health survey, there were no differences in TC, HDL-C, or triglycerides between patients with a serum TSH level below 4.6 mIU/liter and those with a serum TSH level between 4.7 and 10 mIU/liter (77). The levels of LDL-C and HDL-C were higher among women with serum TSH greater than 10 mIU/liter than in euthyroid women, although the difference was not significant (77). In the Busselton study, serum TC was significantly higher in subjects with SHypo than in euthyroid subjects, but the difference was barely significant after adjustment for age and sex (195). Moreover, LDL-C was significantly increased in subjects with mild SHypo and TSH levels of at least 10 mIU/liter. In a Danish study, SHypo (TSH, 3.70 mIU/liter) was associated with a higher concentration of triglycerides and CRP (196).
In a large population-based study (2799 adults aged 70–79 yr), TSH levels were stratified to establish a cutoff for the relationship between TSH and serum lipids (197). A serum TSH level above 5.5 mIU/liter was associated with a cholesterol increase of 0.23 mmol/liter (10 mg/dl). In a cross-sectional study of middle-aged patients, Bindels et al. (198) estimated that, after correction for age, an increase of 1 mIU/liter in serum TSH was associated with a rise in serum TC of 0.09 mmol/liter (3.5 mg/dl) in women and 0.16 mmol/liter (6.2 mg/dl) in men. They estimated that approximately 0.5 mmol/liter (
20 mg/dl) of serum TC could be attributed to SHypo. Bauer et al. (172) evaluated the association of TSH with serum lipids in an unselected population of older women. After multiple adjustment, LDL-C was 13% higher and HDL-C was 12% higher in women with elevated TSH (TSH > 5.5 mIU/liter) vs. women with normal TSH. The LDL-C to HDL-C ratio was 29% greater among women with elevated TSH. Women with multiple lipid abnormalities were twice as likely to have increased TSH levels.
In conclusion, there are conflicting results about lipid pattern and SHypo. This might reflect differences in the population studied (e.g., cause of SHypo, duration of thyroid dysfunction, TSH levels), as well as differences in age, gender, and ethnicity of the subjects tested (199). In addition, smoking and insulin resistance may play a role in mediating the effects of mild hypothyroidi
