The incidence of thyroid cancer has increased markedly over the past few decades in several countries, reaching about 3% of newly diagnosed malignancies 1. This increase can be ascribed to the widespread use of sonography techniques and of fine needle biopsy of thyroid nodules rather than to known environmental causes of thyroid cancers. In Italy, the surgical evaluation both of cold thyroid nodules 2 and of cytologically indeterminate or suspect nodules 34 indicates a 5–6% rate of malignancy. After total thyroidectomy and radioiodine ablation of thyroid remnants, all thyroid cancer patients require lifelong substitutive treatment to prevent hypothyroidism and thyrotropin (TSH)-related cell growth stimulation 5. While thyroid hormone treatment improves disease-free survival, TSH-suppressive treatment must take into account the risk of causing iatrogenic damage due to prolonged exogenous hyperthyroxinemia 5.

Obesity and metabolic diseases are serious health problems in modern society. Indeed, body mass index (BMI), the most widely used indicator of obesity, has been seen to be positively related to a greater risk of mortality and morbidity 6, particularly cardiovascular diseases, diabetes mellitus, stroke and cerebrovascular diseases, osteoarticular diseases and, in some studies, malignancy 7. Several studies have tried to evaluate the relationship between metabolic diseases and cancer; however, the data are conflicting 8910.

A crucial factor in the outcome of cancer patients is comorbidity. In some patients, comorbidity may affect the presentation and recognition of symptoms, have prognostic significance, and increase the complexity of care. In a study conducted in newly diagnosed patients with differentiated thyroid cancer (DTC), one or more concomitant diseases were recorded in 32% 11. The study showed that cardiovascular diseases and/or diabetes mellitus were present in 6% of DTC patients on diagnosis. Moreover, the finding that hypertension was the most frequent comorbidity (18%) followed by "other cancers" (7%), suggests that the concomitance of cardiovascular disease is probably underestimated 11.

Carotid artery intima-media thickness (IMT) is thought to predict coronary heart disease and stroke 12 and is an accepted marker of sub-clinical atherosclerosis 13. Recently, Franzoni et al. 14 reported that patients with sub-clinical hypothyroidism showed an increase in carotid IMT. To our knowledge, no data on carotid IMT in patients with DTC have been reported.

Our aim was to evaluate several metabolic and cardiovascular parameters, including carotid artery IMT, in a cohort of patients with DTC. This evaluation was carried out in addition to the assessment of clinical and biochemical parameters indispensable for judging the evolution of DTC. We used a cohort of well-matched subjects with a history of partial or total surgery for non-malignant thyroid pathology as a control group. In both groups of subjects, metabolic parameters and parameters linked to cardiovascular risk were correlated with thyroid hormones, TSH and levo-thyroxine (L-T4) treatment. Our data confirm that DTC has a generally favorable evaluation. In addition, the present study shows a high incidence of abnormal metabolic and cardiovascular data, which are, at least in part, related to L-T4 therapy. Such comorbidity constitutes an additional risk factor over time. In particular, low HDL-cholesterol and high insulin levels, and a significant correlation between fibrinogen and TSH levels, underline the need for adequate L-T4 titration.

DTC patients have a good prognosis and survival 5. While DTC can arise in young age, its incidence generally increases over time 1. 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 1; 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. 17 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 18. 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 1920; in this situation, the objective of treatment should be weighed, on account of its well-known, potentially dangerous effects 21.

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 11. 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 2223 but not all 2425 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 24 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 2426. By contrast, several literature data are available on the relationship between glucose metabolism and sub-clinical 2728 or overt 2629 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 30.

It is well known that lipid metabolism can be deranged both in sub-clinical and overt hypothyroidism 3132. While L-T4 treatment can improve dyslipidemia, the long-term effect of the L-T4 load on cardiovascular risk is unknown 3334. Overt hyperthyroidism is associated with reduced total- and HDL-cholesterol concentrations 3536, which normalize after remission of hyperthyroidism 37. Several studies have found no difference in lipid profiles in sub-clinical hyperthyroidism 3839, though reduced cholesterol levels have sometimes been reported in subjects older than 55 years 40. 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 31. Recently, Regalbuto et al. 41 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 24 and after 2324 L-T4 dosage reduction. Moreover, in an old study, exogenous hyperthyroxinemia was reported to be associated with low total- and LDL-cholesterol 40. In overt hyperthyroidism, triglyceride levels have been reported to be reduced 42, normal 43 or increased 44.

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 1213. 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 45. However, IMT has been seen to be greater in both sub-clinical 1446 and overt hypothyroidism 47, and can be reduced by L-T4 treatment 4647. 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 48. In that study, thyroid function was identified as an independent risk factor for increased IMT 48. 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 49. Angiotensin II stimulates vascular smooth muscle cell growth 50 and matrix synthesis 51. Vascular hypertrophy is associated with increased vascular stiffness, a phenomenon reported in diffuse toxic goiter 52. 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 52. Thus, in DTC, the permanent hyperthyroxinemia needed to maintain TSH suppression could increase the risk of both arrhythmias 21 and arteriosclerosis 53.

CRP levels are thought to be a widely fluctuating marker of inflammation, and moderate CRP elevation is linked to subsequent cardiovascular events 2854. 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 28. However, CRP levels are not normalized by L-T4 administration in sub-clinical hypothyroidism 54 and CRP is not related to TSH levels 27. On the other hand, in a small group of 15 mostly disease-free DTC patients, Horne et al. 55 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, 55].

Fibrinogen is another well-known independent risk factor for cardiovascular diseases 56. High fibrinogen levels are reported in sub-clinical 56 and overt 5557 hyperthyroidism, as well as in sub-clinical 58 and overt 57 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 59. Even in over-treated DTC patients Horne et al. 55 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 60. However, further data need to be considered, including the direct endothelial effect of TSH 61 and the role of cytokines such as osteoprotegerin 6263 and interleukin-6 and tumor necrosis factor 61.

In conclusion, our study aims to draw greater attention to metabolic and cardiovascular parameters in both DTC and control subjects, in whom exogenous hyperthyroxinemia could increase metabolic and cardiovascular risk. In DTC patients, life-long evaluation, as well as L-T4 therapy, is mandatory. Moreover, in medullary thyroid carcinoma and in low-risk disease-free patients suffering from DTC of follicular origin, exogenous hyperthyroxinemia must be avoided even though it does not seem to modify most hepatic, muscular, cardiac and neuropsychological parameters 41. In DTC, slightly increased fT4 levels can, in the long term, induce an increase in insulin and a decrease in HDL-cholesterol levels, which are unfavorable developments. In addition, the significant inverse correlation between fibrinogen and (suppressed) TSH levels, associated to increases in cytokines 62, fibrinogen 60 and the endothelial release of von Willebrand factor 55, seems to document a greater cardiovascular risk in DTC patients.

The authors declare that they have no competing interests.

MG conceive the study, performed the statistical analysis and drafted the manuscript. LM participated in the design of the study. RD carried out the assays. FC participated in the design of the study. MM participated in the coordination of the laboratory data. GR carried out the instrumental evaluations. DF participated in the sequence alignment. FM participated in the conceive of the study. All authors read and approved the final manuscript.