DTC patients have a good prognosis and survival . While DTC can arise in young age, its incidence generally increases over time . Our DTC subjects ranged from young to elderly, with a median age of 57 years at the moment of the present study and a median age of 53 years on diagnosis. Thyroid carcinomas are 3 times as frequent in females as in males ; a similar ratio was also seen in our study population. On the basis of undetectable Tg levels and negative neck sonography, in our study a disease-free condition was observed in 81% of patients with DTC of follicular origin, which is in line with the reported good prognosis of this cancer.
The medical therapy of follicular-origin DTC focuses on TSH suppression by means of L-T4 administration. In a meta-analysis involving 4174 patients (69% of cases with TSH < 0.1 mU/L), McGriff et al.  found a lower risk of recurrence, progression and disease-related death among patients on TSH-suppressive therapy. TSH suppression therefore remains the gold standard and only in low-risk tumors with favorable disease evolution is a reduction in L-T4 dosage countenanced. In our subjects, the L-T4 dosage was significantly higher in DTC patients than in controls, and TSH levels were correspondingly lower. Indeed, suppressed TSH levels (< 0.1 mIU/L) were found in 38% of DTC patients and only in 3% of controls. In the Colorado study, in which 6% of subjects were on L-T4 treatment, about 40% of these latter presented an abnormal TSH level . In our study, too, both DTC and control subjects sometimes showed an abnormal TSH level (e.g. recent surgery, recent L-T4 withdrawal for radioiodine therapy, incorrect L-T4 administration, inadequate dosage, low compliance); we therefore feel that the efficacy of L-T4 therapy should be routinely checked to prevent under- or over-treatment. Exogenous hyperthyroxinemia accompanied by undetectable TSH levels and/or f-T4 above the therapeutic target has been found in 14% – 21% of patients under L-T4 [19, 20]; in this situation, the objective of treatment should be weighed, on account of its well-known, potentially dangerous effects .
As cardiovascular and metabolic complications may be induced by L-T4 treatment, our goal was to evaluate DTC patients with regard to such complications, which could affect prognosis and life expectancy. Recently, in patients with thyroid cancer, concomitant diseases were found in 32%, hypertension being the most frequent . In our study, the same prevalence of hypertension was noted in DTC and control subjects; hypertension seemed to be more closely linked to age, BMI and other independent cardiovascular risk factors, such as IMT and fibrinogen, than to L-T4 and thyroid hormones. Moreover, our data do not indicate a marked correlation between DTC and glucose control, in that the same percentage of subjects with impaired short- and medium-term glucose control and HOMA-IR levels was found among DTC and control subjects matched for BMI and age. Although higher insulin levels were found in DTC patients, the related exogenous hyperthyroxinemia did not induce the insulin resistance reported by some [22, 23] but not all [24, 25] authors with regard to overt endogenous hyperthyroxinemia. Moreover, the restoration of euthyroidism does not generally affect glucose metabolism in patients with DTC and long-term exogenous hyperthyroxinemia  and no correlation between current L-T4 dosage, TSH or free thyroid hormone levels and the evaluated parameters of glucose metabolism is reported [our data]. On the other hand, we observed a negative correlation between current L-T4 dosage and glucose levels, as well as a positive correlation between TSH and insulin levels in controls. This inter-group discrepancy could be due to the small number of subjects evaluated in our study and in similar studies [24, 26]. By contrast, several literature data are available on the relationship between glucose metabolism and sub-clinical [27, 28] or overt [26, 29] hyperthyroidism, which are functional thyroid conditions that can be encountered during L-T4 titration even in subjects who have undergone thyroidectomy for malignant or non-malignant disease. Moreover, it cannot be excluded that fluctuations in thyroid hormones and TSH might, over time, affect glyco-metabolic parameters .
It is well known that lipid metabolism can be deranged both in sub-clinical and overt hypothyroidism [31, 32]. While L-T4 treatment can improve dyslipidemia, the long-term effect of the L-T4 load on cardiovascular risk is unknown [33, 34]. Overt hyperthyroidism is associated with reduced total- and HDL-cholesterol concentrations [35, 36], which normalize after remission of hyperthyroidism . Several studies have found no difference in lipid profiles in sub-clinical hyperthyroidism [38, 39], though reduced cholesterol levels have sometimes been reported in subjects older than 55 years . In our control and DTC subjects, cholesterol and triglyceride levels were not significantly different. However, HDL-cholesterol levels were significantly lower in DTC patients than in controls, and correlated negatively with L-T4 dosage and positively with f-T4. A similar reduction in HDL-cholesterol has been observed in sub-clinical hyperthyroidism and in L-T4 treated patients . Recently, Regalbuto et al.  reported an increase in cholesterol levels in 45% of DTC patients before diagnostic L-T4 discontinuation. Other authors, however, have not found lipid profile changes in DTC patients before  and after [23, 24] L-T4 dosage reduction. Moreover, in an old study, exogenous hyperthyroxinemia was reported to be associated with low total- and LDL-cholesterol . In overt hyperthyroidism, triglyceride levels have been reported to be reduced , normal  or increased .
Non-invasive carotid artery IMT evaluation is an accepted index of cardiovascular risk and a pre-clinical marker of arteriosclerosis that is influenced by sex, age, smoking, lipid profile and hemodynamics [12, 13]. As changes in lipid profile and hemodynamics may occur in thyroid diseases, interest in IMT evaluation has grown. In one cohort study, increased IMT correlated negatively with f-T4 levels in euthyroid subjects even after adjustment for age, sex and lipid profile . However, IMT has been seen to be greater in both sub-clinical [14, 46] and overt hypothyroidism , and can be reduced by L-T4 treatment [46, 47]. In our study, no difference in IMT score or percentage of subjects with carotid stenosis was observed between the two cohorts of subjects. At present, it cannot be excluded that longitudinal studies or studies involving larger numbers of subjects might elucidate the direct effect of thyroid disease and treatment on IMT, over and above the effect exerted by age, BMI, glucose levels and hypertension. A linear relationship between thyroid function and IMT was found in a large cohort of at least 45-year-old subjects without known thyroid disorders, the highest IMT values being recorded in hyperthyroxinemia subjects and the lowest in subjects with elevated TSH levels . In that study, thyroid function was identified as an independent risk factor for increased IMT . The association between IMT and endogenous or exogenous thyroid hyperfunction is regarded as biologically plausible because there is a known link between hyperthyroidism and peripheral vasodilatation, which leads to a decrease in renal perfusion and activation of the renin-angiotensin system . Angiotensin II stimulates vascular smooth muscle cell growth  and matrix synthesis . Vascular hypertrophy is associated with increased vascular stiffness, a phenomenon reported in diffuse toxic goiter . Thus, increased IMT of the carotid artery may merely reflect an adaptive response to shear and tensile stress linked to the increase in heart rate and systolic blood pressure generally found in hyperthyroxinemia . Thus, in DTC, the permanent hyperthyroxinemia needed to maintain TSH suppression could increase the risk of both arrhythmias  and arteriosclerosis .
CRP levels are thought to be a widely fluctuating marker of inflammation, and moderate CRP elevation is linked to subsequent cardiovascular events [28, 54]. In subjects with sub-clinical hypothyroidism, CRP has been found to be positively related to insulin and higher than in control subjects with normal thyroid function . However, CRP levels are not normalized by L-T4 administration in sub-clinical hypothyroidism  and CRP is not related to TSH levels . On the other hand, in a small group of 15 mostly disease-free DTC patients, Horne et al.  reported higher CRP levels under exogenous hyperthyroxinemia than after diagnostic L-T4 withdrawal. According to these data, it could be hypothesized that a mild inflammatory state is present in DTC patients on LT4 therapy. Our data did not show any difference between subjects on L-T4 after thyroidectomy for malignant or non-malignant thyroid disease. However, in DTC subjects, CRP seems to be modulated by BMI and HOMA-IR, and CRP and fibrinogen are significantly related in both groups of subjects [our data, ].
Fibrinogen is another well-known independent risk factor for cardiovascular diseases . High fibrinogen levels are reported in sub-clinical  and overt [55, 57] hyperthyroidism, as well as in sub-clinical  and overt  hypothyroidism. About 50% of both our DTC and control subjects displayed an increase in fibrinogen levels, which was also positively related to age, BMI, IMT score, HbA1c and systolic blood pressure. However, only in DTC subjects did plasma fibrinogen levels correlate positively with HOMA-IR and total- and LDL-cholesterol, and negatively with TSH levels but not with L-T4 dosages, as also reported in L-T4 treated hypothyroid patients . Even in over-treated DTC patients Horne et al.  reported an increase in fibrinogen levels and several other coagulation factors. On the whole, these data seem to indicate that TSH-suppression in DTC patients could support an increased coagulation risk factor, which is probably independent of disease status and L-T4 dosage. Finally, another study has shown that high fibrinogen levels are linked in hyperthyroidism to an elevation of von Willebrand factor and to altered platelet plug formation as an direct index of endothelial dysfunction . However, further data need to be considered, including the direct endothelial effect of TSH  and the role of cytokines such as osteoprotegerin [62, 63] and interleukin-6 and tumor necrosis factor .