Giovanni Di Cairano

Management of thyroid nodules: a clinicopathological, evidence-based approach

Management of thyroid nodules is one of the most controversial issues in thyroidology. Different approaches derive from geographical variation in presentation, inadequate or incomplete clinical diagnosis, lack of prospective controlled studies and, frequently, the different cultural backgrounds of physicians. This review aims to offer a practical approach to the management of nodular thyroid disorders, considering the way in which the pathophysiology of the disease provides clues to the correct clinical diagnosis and therapy.

Main endocrine modulators of vitamin D hydroxylases in human pathophysiology

Vitamin D is considered to be devoid of direct biological activity. It must be first hydroxylated in the liver by a 25-hydroxylase (25OHase), then in the kidney by a 1 alpha-hydroxylase (1 alpha OHase) which is responsible for the synthesis of the active metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D). The activity of 1 alpha OHase is known to be under the control of a series of endocrine modulators, particularly parathyroid hormone (PTH) and estrogens. We report here our studies in humans concerning the behaviour of vitamin D hydroxylases in some pathological conditions. In chronic liver disease no severe impairment of vitamin D-25-hydroxylation has been observed, except in the latest stages: this is probably due to the great functional reserve of the liver, so that normal levels of serum 25OHD can be maintained on condition that the vitamin D supply is adequate. 1 alpha OHase is impaired in chronic renal failure due to the decrease in the number of functioning nephrons. It has been demonstrated that kidney transplantation restores normal 1,25(OH)2D levels. A decrease in 1,25(OH)2D production due to reduced PTH stimulation has been observed in hypoparathyroidism: in these patients a subcutaneous substitution therapy with synthetic human parathyroid hormone resulted in restoration of normal 1,25(OH)2D levels. A reduced activity of 1 alpha OHase due to reduced estrogen stimulation plays a key role in postmenopausal osteoporosis. In these patients estrogens increase 1,25(OH)2D levels, as it has been demonstrated directly and indirectly. In the aforementioned pathological conditions an impairment of calcium absorption has been observed; it was directly related to the reduced production of 1,25(OH)2D. Treatment with 1,25(OH)2D3 was effective in restoring normal calcium absorption. In postmenopausal osteoporosis the reduced levels of 1,25(OH)2D were accompanied by serum levels of 25-hydroxyvitamin D (25OHD) higher than in age-matched control women. In these cases long-term treatment with physiological doses of 1,25(OH)2D3 resulted in a progressive decrease in 25OHD serum levels which approached to the normal range. These findings are likely to be related one to another: the low 1,25(OH)2D levels are responsible for reduced product-inhibition of 25OHase, so that the synthesis of 25OHD increases. A similar mechanism occurs in renal failure and in hypoparathyroidism.

Prospective Validation of ATA and ETA Sonographic Pattern Risk of Thyroid Nodules Selected for FNAC

Context Recently, the American Thyroid Association (ATA) and the European Thyroid Association (ETA) have proposed that thyroid ultrasound (US) should be used to stratify the risk of malignancy in thyroid nodules and to aid decision-making about whether fine-needle aspiration cytology (FNAC) is indicated. Objective To validate and to compare the ATA and ETA US risk stratification systems of thyroid nodules in a prospective series of thyroid nodules submitted to FNAC. Setting We prospectively evaluated 432 thyroid nodules selected for FNAC from 340 patients. Cytology reports were based on the five categories according to the criteria of the British Thyroid Association. Results The proportion of Thy2 nodules decreased significantly, whereas the proportion of Thy4/Thy5 nodules significantly increased with increasing US risk class (P < 0.0001). The ability to identify benign and malignant nodules was similar between ATA and ETA systems. According to ATA and ETA US risk stratification systems, 23.7% and 56.0% nodules did not meet the criteria for FNAC, respectively. Considering only categories at lower risk of malignancy, the cumulative malignancy rate in these nodules was 1.2% for ATA and 1.7% for ETA US risk stratification systems. Conclusions ETA and ATA US risk stratification systems provide effective malignancy risk stratification for thyroid nodules. In clinical practice, using this approach, we should be able to reduce the number of unnecessary FNAC without losing clinically relevant thyroid cancer.