An early event in SCH-related cardiomyopathy, evaluated by Doppler echocardiography, is the impairment of diastolic function [73,74]. The diastolic dysfunction is caused by the reduced activity of sarcoplasmic reticulum Ca2+-ATPase which controls the efficient concentration of calcium in the cytoplasm within the sarcoplasmic reticulum during diastole [2,73–75]. Both diastolic and systolic function during exercise are also impaired in SCH [73–75]. Others have  similarly reported diminished diastolic function by echocardiographic parameters in patients with SCH [76,77]. Finally, Ripoli et al.  demonstrated decreased cardiac-pump performance by MRI in SCH patients.
High blood pressure, mainly diastolic hypertension, has been documented in 20% of SCH patients compared with 3.4% in healthy euthyroid controls . In SCH, endothelial dysfunction is present due to reduced NO availability and consequent arterial stiffness [82,83]. Patients with SCH have significantly higher carotid artery intima-media thickness values than age- and sex-matched controls. In contrast, Völzke et al.  reported diminished intima-media thickness in hypothyroid subjects and Cikim et al.  found no effect on intima-media thickness. Owen et al. [86•] documented increased arterial stiffness in women with SCH compared with controls, as did Hamano and Inoue , who measured brachial-ankle pulse wave velocity. These results have recently been confirmed by Nagasaki et al. [88•].
Coagulation parameters may be altered in SCH, contributing to increased cardiovascular risk. Gullu et al.  demonstrated that activities of factor VIII and von Willebrand factor were significantly lower in patients with SCH than in controls. Guldiken et al.  found that the global fibrinolytic capacity was significantly lower in patients with SCH than in controls, suggesting a relative hypercoagulable state in SCH.
Elevated C-reactive protein, L-arginine, asymmetric dimethylarginine concentrations, and insulin resistance, all risk factors for cardiovascular disease, may occur in patients with SCH [91,92].
Several studies have investigated the relationship between SCH, lipoprotein profile, and the risk of cardiovascular disease, with controversial results . Some [30,94–97] demonstrated an increase in total cholesterol and low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B, and lipoprotein (a) levels. SCH does not significantly affect high-density lipoprotein-cholesterol (HDL-C). Table 4 summarizes the changes of the lipid profile observed in patients with SCH.
LDL-C levels are markedly elevated in overt hypothyroidism. Pearce and colleagues  have recently completed a study of patients with severe hypothyroidism and following restoration of normal TSH values with L-thyroxine administration. Lipids were analyzed by nuclear magnetic resonance when the patients were hypothyroid and again when euthyroid. The increase in LDL-C during hypothyroidism was due to an increase in concentrations of less atherogenic large LDL-C particles with no change in the concentrations of more atherogenic small and medium LDL-C particles.
The increase in total and LDL-C in hypothyroidism is due to a decrease in LDL receptor number [99,100]. Molecular mapping has revealed functional thyroid response elements in the promoter region of the LDL receptor gene . Furthermore, several steps involved in lipid metabolism are impaired in SCH, and a direct influence of thyroid hormones on both cholesterol ester transfer protein and hepatic lipase, leading to a reduction of LDL clearance, has been reported .
The Whickam survey did not observe any association between SCH and coronary heart disease, dyslipidemia, or mortality over 20 years . In contrast, an increased prevalence rate of atherosclerosis in elderly women with SCH has been documented in the Rotterdam study . Among 1149 women aged 69±7.5 years in this population-based, cross-sectional study, women with SCH had a greater prevalence of aortic atherosclerosis (odds ratio, 1.7) and myocardial infarction (odds ratio, 2.3).
In a 10-year longitudinal study, SCH was associated in men, but not in women, with ischemic heart disease independent of age, systolic blood pressure, body mass index, cholesterol, smoking, erythrocyte sedimentation rate, or presence of diabetes . There was no association, however, with cerebrovascular disease. By contrast, data from 3678 men and women enrolled in a Cardiovascular Health Study showed no differences between individuals with SCH and euthyroid subjects in the prevalence of angina, myocardial infarction, transient ischemic attack, stroke, or peripheral arterial disease .
A recent meta-analysis of the effects of SCH on coronary heart risk reviewed 14 studies published up to 2004 and concluded that SCH increased the risk of coronary heart disease with an odds ratio of 1.65 .
Basal and TRH-stimulated TSH concentrations were measured in 834 infertile women, and 20% had abnormal results . Postcoital tests and spontaneous conception were significantly poorer in women with SCH than controls. Staub et al.  suggested that secondary hyperprolactinemia could be the cause of infertility in SCH women. In contrast, menstrual function in SCH patients and controls was similar in luteinizing hormone pulse patterns and 24-h mean serum luteinizing hormone, TSH, and prolactin concentrations .
The detection of TPO-Ab in pregnant women during early gestation predicts an increased incidence of SCH during pregnancy and postpartum thyroid dysfunction . Pregnant women with positive TPO-Ab and normal TSH values at the beginning of pregnancy developed a significant increase in serum TSH concentrations at term, reaching values of 3.5 mIU/l [127••]. Some studies have reported that SCH during pregnancy is associated with suboptimal intellectual performance and neurologic development in the offspring when tested during infancy and childhood [130–132]. It has been suggested that maternal serum free thyroxine concentrations are more sensitive than TSH values in predicting the likelihood of adverse intellectual outcomes in the offspring .
Thyroid hormone deficiency is deleterious in infants, children, and adolescents because it causes growth delay, mental retardation, and precocious puberty in both sexes, and hirsutism in females. Iodine deficiency is the most common cause of hypothyroidism in children worldwide. In children living in iodine-replete areas, chronic autoimmune thyroid disease, X-ray treatment to the head and neck for malignant diseases, and drugs – in particular, carbamazepine and valproic acid – may induce SCH [134,135].
An important challenge during childhood is to diagnose SCH early when it is asymptomatic because it may cause irreversible damage when L-thyroxine-replacement therapy is delayed. A recent study  reported a 2.9% prevalence of thyroid autoantibodies in 8040 Sardinian schoolchildren living in areas with borderline iodine sufficiency or mild to moderate iodine deficiency. Seventy-seven (0.96%) children had serum TSH concentrations ranging between 5.2 and 32 mIU/l. As noted above, autoimmune thyroiditis and SCH are more common in children with type 1 diabetes mellitus .
Finally, an increased prevalence of SCH and more overt hypothyroidism due to autoimmune thyroiditis has been observed in children with Down's and Turner's syndromes compared with age-matched subjects [137,138].
A controversial subject is whether a screening program to detect hypothyroidism should be carried out, and if so, who should be screened. The ATA recommended screening both men and women, beginning at age 35 years and every 5 years thereafter ; the AACE recommended that only elderly patients, especially women, be screened ; the American Academy of Family Physicians recommended routine screening for patients older than 60 years of age . The Endocrine Society, AACE and ATA jointly sponsored a consensus development conference , and found ‘insufficient evidence to support population-based screening’, using US Preventive Services Task Force criteria [144,145] and, therefore, recommended ‘against population-based screening for thyroid disease’. The same societies reviewed the above conclusions and officially favored routine screening for subclinical thyroid dysfunction in adults, including pregnant women and those contemplating pregnancy . This statement is reinforced by the fact that the costs of routine screening for SCH in subjects older than 35 years with a serum TSH measurement every 5 years are as favorable as other accepted preventive medical practices . However, the above consensus statement was not universally accepted .
Whether all patients with SCH should be treated is a matter of debate. The Consensus Development Conferences sponsored by the Endocrine Society, AACE and ATA [12,13] recommended beginning L-thyroxine substitutive therapy when TSH values exceed 10 mIU/l caused by adverse effects on serum lipids and the risk of progression to overt hypothyroidism. Therapy for milder forms of hypothyroidism (i.e. TSH levels <10 mIU/l) is controversial.
Several studies have been performed to evaluate the effects of L-thyroxine replacement therapy on SCH symptoms. Results have been conflicting, showing statistically significant improvement [58,61,151,152], marginal improvement [56–58,66], or no benefit [57,59,60]. Furthermore, potential side effects of L-thyroxine overtreatment should always be considered. Indeed, iatrogenic thyrotoxicosis occurs in up to 20% of patients treated with L-thyroxine for hypothyroidism , potentially leading to more serious abnormalities than leaving SCH untreated [4,8].
Hypothyroidism occurring during pregnancy is associated with impaired cognitive development in the offspring and increased fetal mortality. During pregnancy, especially in the first trimester when human chorionic gonadotropin, a weak TSH-receptor stimulator, is highest, maternal requirements of thyroid hormone increase. Pregnant women with SCH, therefore, should be promptly treated or the L-thyroxine dose should be increased if they are already taking L-thyroxine-substitution therapy for hypothyroidism prior to pregnancy .
Newborns with proven SCH should be treated with adequate doses of L-thyroxine within the first few weeks of life to prevent possible mental and growth retardation. Thyroid hormone can be withdrawn at approximately 1 year and thyroid function retested.
There is general agreement that children and adolescents with SCH should be adequately treated with L-thyroxine since significant improvement in height and development will occur . Cetinkaya et al.  enrolled 2067 children with short stature and found that 39 subjects (0.19%) had SCH. When the anthropometric data of both prepubertal and pubertal patients were analyzed before and after 6–12 months of L-thyroxine-replacement therapy, both groups showed significant increases in growth velocity following L-thyroxine treatment. Finally, it has also been reported that the introduction of L-thyroxine-substitution therapy reduces the frequency of symptomatic hypoglycemia in pediatric patients with SCH and type 1 diabetes mellitus .
The administration of L-tri-iodothyronine in combination with L-thyroxine for the treatment of hypothyroidism should be questioned, since the large majority of circulating and tissue tri-iodothyronine derives from the peripheral outer-ring 5′-monodeiodination of thyroxine. Compared with L-thyroxine monotherapy, the combination therapy appeared to have beneficial effects on the mood, quality of life and psychometric performance in one study . Escobar-Morreale et al. [167•] conducted a systematic review of nine controlled clinical trials, including , comparing treatment with L-thyroxine alone with a combination of L-thyroxine and L-tri-iodothyronine in hypothyroid patients. Eight of the nine studies failed to show any difference between the two treatment regimens. Thus, L-thyroxine remains the best therapy for all forms of hypothyroidism.
An underestimated cause of SCH is insufficient L-thyroxine doses to maintain euthyroidism; in these patients, the dose of L-thyroxine should be increased, and thereafter serum TSH concentrations should be monitored and the L-thyroxine dose tailored accordingly. Moreover, the problem of iodine deficiency, which may cause SCH, is still present in some countries, and it should be prevented and cured through adequate iodine prophylaxis.
References and recommended reading
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