Emilio Fiore

Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: thyroid autonomy may play a protective role.

Higher TSH values, even within normal ranges, have been associated with a greater risk of thyroid malignancy. The relationship between TSH and papillary thyroid cancer (PTC) has been analyzed in 10 178 patients submitted to fine needle aspiration of thyroid nodules with a cytology of PTC (n=497) or benign thyroid nodular disease (BTND, n=9681). In 942 patients, submitted to surgery (521 from BTND and 421 from PTC), the histological diagnosis confirmed an elevated specificity (99.6%) and sensitivity (98.1%) of cytology. TSH levels were significantly higher in PTC than in BTND both in the cytological and histological series and also in patients with a clinical diagnosis of multinodular goiter (MNG) and single/isolate nodule (S/I). A significant age-dependent development of thyroid autonomy (TSH <0.4 microU/ml) was observed in patients with benign thyroid disease, but not in those with PTC, diagnosed both on cytology and histology. In patients with MNG, the frequency of thyroid autonomy was higher and the risk of PTC was lower compared to those with S/I. In all patients, the presence of thyroid auto-antibodies (TAb) was associated with a significant increase of TSH. However, both in TAb positive and TAb negative patients TSH levels were significantly higher in PTC than in BTND. Our data confirm a direct relationship between TSH levels and risk of PTC in patients with nodular thyroid diseases. Thyroid autonomy conceivably protects against the risk of PTC, while thyroid autoimmunity does not play a significant role.

Serum TSH and Risk of Papillary Thyroid Cancer in Nodular Thyroid Disease

CONTEXT TSH is the main factor involved in the control of proliferation of thyrocytes. Recently, a strong relationship between serum TSH and risk of thyroid malignancy has been reported. OBJECTIVES The aim was to review published papers about the relationship between serum TSH and frequency of differentiated thyroid cancer. EVIDENCE ACQUISITION PubMed was used to identify studies focused on the relationship between TSH and differentiated thyroid cancer. EVIDENCE SYNTHESIS In patients with nodular thyroid disease, the risk of thyroid malignancy increases with serum TSH, and even within normal ranges, higher TSH values are associated with a higher frequency and more advanced stage of thyroid cancer. The likelihood of papillary thyroid carcinoma is reduced when TSH is lower, as in thyroid autonomy, and increased when TSH is higher, as in thyroid autoimmunity. Treatment with l-thyroxine (LT4), which reduces serum TSH, is associated with significantly lower risk of developing clinically detectable thyroid cancer. CONCLUSIONS TSH plays a key role in the development of clinically detectable thyroid cancer, and LT4 treatment reduces the risk of thyroid malignancy in patients with nodular thyroid disease. According to the guidelines of the main scientific societies, LT4 therapy is not currently recommended for the treatment of patients with nodular goiter. Even if the available data are not sufficient to advise LT4 treatment in all patients with nodular goiter with the aim of reducing the risk of papillary thyroid carcinoma, we propose that this indication should be reconsidered, taking into account recent evidence reported in the literature.

Hashimoto's thyroiditis is associated with papillary thyroid carcinoma: role of TSH and of treatment with l-thyroxine

The possible association between Hashimoto’s thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a still debated issue. We analyzed the frequency of PTC, TSH levels and thyroid autoantibodies (TAb) in 13 738 patients (9824 untreated and 3914 under L-thyroxine, L-T4). Patients with nodular-HT (nZ1593) had high titer of TAb and/or hypothyroidism. Patients with nodular goiter (NG) were subdivided in TAbKNG (nZ8812) with undetectable TAb and TAbCNG (nZ3395) with positive TAb. Among untreated patients, those with nodular-HT showed higher frequency of PTC (9.4%) compared with both TAbKNG (6.4%; PZ0.002) and TAbCNG (6.5%; PZ0.009) and presented also higher serum TSH (median 1.30 vs 0.71 mU/ml, P!0.001 and 0.70 mU/ml, P!0.001 respectively). Independently of clinical diagnosis, patients with high titer of TAb showed a higher frequency of PTC (9.3%) compared to patients with low titer (6.8%, P!0.001) or negative TAb (6.3%, P!0.001) and presented also higher serum TSH (median 1.16 vs 0.75 mU/ml, P!0.001 and 0.72 mU/ml, P!0.001 respectively). PTC frequency was strongly related with serum TSH (odds ratio (OR)Z1.111), slightly related with anti-thyroglobulin antibodies (ORZ1.001), and unrelated with anti-thyroperoxidase antibodies. In the L-T4-treated group, when only patients with serum TSH levels below the median value (0.90 mU/ml) were considered, no significant difference in PTC frequency was found between nodular-HT, TAbKNG and TAbCNG. In conclusion, the frequency of PTC is significantly higher in nodular-HT than in NG and is associated with increased levels of serum TSH. Treatment with L-T4reduces TSH levels and decreases the occurrence of clinically detectable PTC. Endocrine-Related Cancer (2011) 18 429‐437

Thyroid autoimmunity and female gender

Sexual dimorphism exists in regard to the immune response between women and men, and it accounts for the greater prevalence of thyroid autoimmunity in women. Similarly to the human situation a sex-related susceptibility to autoimmune thyroiditis is evident in animal models. A direct influence of genes on sex chromosomes (X or Y) on the immune response has been postulated in some models of autoimmune thyroiditis in rats. On the other hand sex hormones have been implicated to explain the majority of sex differences in the autoimmune response against the thyroid. A state of immune suppression during pregnancy influences the clinical course of autoimmune thyroid diseases, in that a typical amelioration during pregnancy is accompanied by aggravation following delivery. This immmunologic rebound phenomenon may also underly the post partum thyroid dysfunction in otherwise healthy women with a genetic predisposition to autoimmune thyroid disease. Thyroid autoimmunity also interferes with the female reproductive function. Hypothyroidism and less frequently hyperthyroidism due to thyroid autoimmune disorders may produce menstrual dysfunction, anovulation and eventually infertility. Maternal hyper-or hypothyroidism can affect the outcome of pregnancy, producing a higher incidence of miscarriages, maternal complications, and congenital malformations. Untreated maternal hypothyroidism produced by Hashimoto’s disease during pregnancy can impair the neurological development of the fetus due to a reduced availability of maternal thyroxine during early gestation. More specifically, fetal and/or neonatal hypo- or hyperthyroidism produced by the transplacental passage of maternal thyroid autoantibodies can impair growth and neuropsychological development of affected children.

The Effect of Voluntary Iodine Prophylaxis in a Small Rural Community: The Pescopagano Survey 15 Years Later

CONTEXT Iodine deficiency disorders are a major public health problem, and programs have been implemented to improve iodine nutrition. OBJECTIVE The objective of the study was to verify the effects of voluntary iodine prophylaxis in a small rural community (Pescopagano, Italy). DESIGN The design of the study was the evaluation of the prevalence of thyroid disorders 15 years after a previous survey conducted before iodine prophylaxis. SETTING The setting for this study was a general community survey. PARTICIPANTS One thousand one hundred forty-eight residents were examined in 2010 and 1411 in 1995. RESULTS In 2010, 757 of 1148 subjects (65.9%) routinely used iodized salt, urinary iodine excretion being significantly higher than in 1955 (median 98.0 μg/L, vs 55.0 μg/L, P < .0001). The prevalence of goiter was lower in 2010 than in 1995 (25.8% vs 46.1%, P < .0001), mainly due to the reduction of diffuse goiter (10.3% vs 34.0%, P < .0001). In 2010 vs 1995, thyroid autonomy in subjects younger than 45 years old (3 of 579, 0.5% vs 25 of 1010, 2.5% P = .004) and nonautoimmune hyperthyroidism in subjects older than 45 years old (8 of 569, 1.4% vs 18 of 401, 4.5%, P = .03) were less frequent. The prevalence of hypothyroidism was higher in 2010 vs 1995 (5.0% vs 2.8%, P = .005), mainly because of an increased frequency of subclinical hypothyroidism in subjects younger than 15 years old (7 of 83, 8.4% vs 0 of 419, 0.0%, P < .0001). Accordingly, serum thyroid autoantibodies (19.5% vs 12.6%; P < .0001) and Hashimotos thyroiditis (14.5% vs 3.5%; P < .0001) were more frequent in 2010 than in 1995. CONCLUSIONS In the present work, the role of voluntary iodine prophylaxis was assessed in a small rural community relatively segregated, in which genetic and other environmental factors have not substantially changed between the 2 surveys. Iodine intake strongly affected the pattern of thyroid diseases, but the benefits of correcting iodine deficiency (decreased prevalence of goiter and thyroid autonomy in younger subjects and reduced frequency of nonautoimmune hyperthyroidism in older subjects) far outweighs the risk of development of thyroid autoimmunity and mild hypothyroidism in youngsters.

L-thyroxine-treated patients with nodular goiter have lower serum TSH and lower frequency of papillary thyroid cancer: results of a cross-sectional study on 27 914 patients

The risk of papillary thyroid cancer (PTC) is related to serum TSH, and the development of thyroid autonomy by reducing TSH levels decreases the frequency of PTC in patients with nodular goiter. Our aim was to investigate the effect of L-thyroxine (LT(4)) on the frequency of PTC diagnosed by cytology in a large series of patients with nodular goiter untreated (n=20 055) or treated with L-T(4) (n=7859). L-T(4)-treated patients with respect to untreated patients presented significantly lower serum TSH (median, interquartile range: 0.30 muU/ml, 0.08-0.62 microU/ml versus 0.70 muU/ml, 0.38-1.14 muU/ml; P<0.0001) and prevalence of PTC (3.2 vs 5.1%; P<0.0001). The frequency of PTC was closely related to serum TSH, with it being lowest in patients with TSH below the normal range (<0.4 muU/ml; 189/10 059, 1.9%) and highest in patients with TSH above the normal range (>3.4 muU/ml; 21/127, 16.5%), also showing a progressive increase from the lower to the upper quartile of normal range. A significantly higher proportion of L-T(4)-treated patients (6650/7859, 84.6%) had serum TSH below the median (0.90 muU/ml) with respect to untreated patients (12,599/20,055, 62.8%; chi(2) P value <0.0001), with it being included in the range of TSH associated with a lower frequency of PTC. The relationship between serum TSH and frequency of PTC was unrelated to the type of nodularity (solitary versus multinodular) and was not age dependent. In conclusion, patients with nodular goiter, treatment with L-T(4) is responsible for the reduction of serum TSH and is associated with a decreased frequency of PTC.

Papillary thyroid cancer, although strongly associated with lymphocitic infiltration on histology, is only weakly predicted by serum thyroid auto-antibodies in patients with nodular thyroid diseases

Objective: We evaluated the association between thyroid autoimmunity and thyroid cancer in a retrospective series of unselected thyroid nodules submitted to fine-needle aspiration (FNA) cytology. Design: Anti-thyroid antibodies (TAb) were measured in patients with multinodular goiter (MNG) and single/isolated thyroid nodule (S/I) submitted to FNA. Thyroid lymphocytic infiltration (LI) on histology was studied in a subgroup of patients submitted to thyroidectomy; 13,021 patients were included: on cytology 622 had papillary thyroid cancer (c-PTC) and 12,399 benign thyroid nodular diseases (c-BTN). LI was evaluated in histological samples of 688 patients: 304 with PTC (h-PTC) and 384 with BTN (h-BTN). Results: TAb prevalence was not different in c-BTN and c-PTC (38.7% vs 35.6%). TAb were more frequent in c-BTN than c-PTC in females with MNG (40.1% vs 32.5%, p=0.02), and in c-PTC than in c-BTN in males with S/I (31.2% vs 20.4%, p=0.02) and, although not significantly, in females younger than 30 yr (35.1% vs 30.7%). The frequency and severity of LI was significantly higher in h-PTC than h-BTN, both in MNG (82.5% vs 45.0%, p<0.001) and S/I (85.6% vs 71.0%, p<0.001), but a higher number of patients with h-PTC had negative circulating TAb, despite the presence of moderate/severe LI. Conclusions: TAb are weakly associated to PTC in males and young females, while they are more frequent in older females with BTN. The frequency and severity of LI is significantly higher in PTC than in BTN, but in cancer patients TAb are frequently negative, despite the evidence of histological thyroiditis. These data suggest that different kinds of immune response may be involved in PTC and BTN.

Detection of antibodies blocking thyrotropin effect using Chinese hamster ovary cells transfected with the cloned human TSH receptor

Chinese hamster ovary (CHO) cells transfected with the cloned human TSH receptor (CHO-R) were used to develop an assay to detect thyroid autoantibodies blocking the TSH-dependent cAMP production (TSHBAb). The study group included 38 patients with goitrous Hashimoto’s thyroiditis (HT) and 47 subjects with atrophic thyroiditis (AT). In the HT group, 8 patients had subclinical hypothyroidism (HT-SH) and 30 had overt hypothyroidism (HT-H). Thirty normal subjects served as controls. Immunoglobulin G (IgG) was prepared from serum by double chromatography on DEAE-Sephadex. CHO-R cells were seeded in 96-well plates and were cultured for 48 h before the assay in RPMI-1640 medium plus 1 mmol/L glutamine, 10% fetal calf serum, and 0.4 g/L geneticin. In the assay for TSHBAb, CHO-R cells were incubated with IgG alone (0.5–2 mg/ml), TSH alone (0.2–625 mU/L), or IgG plus TSH; all samples were diluted in hypotonic medium containing 0.5 mmol/L isobutylmethylxanthine (IBMX). After 2 h of incubation at 37°C in 5% CO2 −95% air atmosphere, TSH-stimulation was quantified by measuring extracellular cAMP by a RIA. IgGs from normal subjects did not significantly modify the stimulation of adenylate cyclase produced by TSH, the results obtained ranging between −30% and +18% (mean±SD=−3±14%). All IgGs producing an inhibition greater than 2SD from the mean of controls (>25%) were considered positive for blocking antibodies. TSHBAb were detected in 1/8 (12.5%) patients with HT-SH, in 7/30 (23.3%) with HT-H and in 16/47 (34.0%) patients with AT. When the same IgGs were tested in FRTL-5 cells, TSHBAb were detected in 1/8 (12.5%) patients with HT-SH, in 5/30 (16.6%) with HT-H and in 15/47 (31.9%) with AT. TSHBAb results in CHO-R cells showed a good correlation with those in FRTL-5 cells (r=0.74, p<0.0001), but 3/24 IgGs were positive for TSHBAb in CHO-R cells and negative in FRTL-5 cells. Using the radioreceptor assay, TSH-binding inhibiting antibodies were detected in 17/24 (70.8%) sera that contained TSHBAb when tested in the CHO-R cell system. Thyroid stimulating antibody (TSAb) and TSHBAb, that coexisted in 5 IgGs, were simultaneously detected using CHO-R cells. These IgGs belonged to patients in whom spontaneous hypothyroidism developed after hyperthyroidism, or viceversa. In conclusion a new in vitro assay for the detection of TSHBAb was developed using CHO-R cells. The sensitivity of this assay is slightly greater than that obtained in FRTL-5 cells and definitely greater than that of the radioreceptor assay. CHO-R cells have the advantages of expressing the human TSH receptor and of requiring less cumbersome procedures for cell culture than FRTL-5 cells.

Iodine Contributes to Thyroid Autoimmunity in Humans by Unmasking a Cryptic Epitope on Thyroglobulin

CONTEXT The mechanisms linking thyroid autoimmunity and iodine use in humans are unknown. OBJECTIVE Our aim was to correlate iodine intake, thyroid autoimmunity, and recognition of thyroglobulin (Tg) epitopes after implementation of iodine prophylaxis. SETTING The general community living in an Italian village was evaluated. MAIN OUTCOME MEASURES Thyroglobulin autoantibodies (TgAb), thyroperoxidase autoantibodies (TPOAb), and urinary iodine excretion were assessed in 906 iodized salt users (IS-users) and 389 nonusers (IS-nonusers). Ultrasound (US) was performed to identify thyroid hypoechogenicity, suggestive of Hashimoto thyroiditis (HT). TgAb epitope pattern in 16 IS-users and 17 IS-nonusers was evaluated by an inhibition binding assay to Tg, using human monoclonal TgAb-Fab directed to A, B, C, and D epitopes on Tg. RESULTS Median urinary iodine excretion was slightly higher in IS-users than in IS-nonusers (112.0 μg/L vs 86.5 μg/L; P < .01). TgAb, and not TPOAb, was more frequent in IS-users (18.9% vs 13.6%, P = .02). HT-US was found in 87 subjects, among whom both positive TgAb (58.4% vs 31.8%, P = .03) and TPOAb (61.5% vs 45.4%. P = .04) were more frequent in IS-users. In this group significantly higher serum levels of TgAb (median 108 U/mL vs 30 U/mL; P = .02), but not of TPOAb, were present. Iodized salt use had no effect on the 1208 non HT-US subjects. TgAb directed to the epitope B of Tg were more frequent in IS-users than in IS-nonusers (27.5% vs 3.0%, P = .047). CONCLUSIONS Iodine-induced thyroid autoimmunity is related to TgAb and the unmasking of a cryptic epitope on Tg contributes to this relationship in humans.

Favorable predictive value of thyroid autoimmunity in high aggressive breast cancer

A high incidence of anti-thyroid antibodies (TAb) has been found in patients with breast cancer (BC). The aim of this study was to evaluate the prognostic value of TAb in a group of 47 women submitted to mastectomy for high malignancy degree BC. All patients were evaluated for thyroid disorders after breast surgery and before any anti-tumoral adjuvant therapy. Five yr after BC diagnosis 31/47 (65.9%) patients were alive (survivors group: SG) and 16/47 (34.1%) were dead (deaths group: DG). The overall prevalence of TAb was 15/47 (31.9%): 14/31 (45.1%) in SG and 1/16 (6.2%) in DG (p=0.008). Five-yr mortality was 15/32 (46.9%) in TAb- and 1/15 (6.7%) in TAb+ patients (p=0.01). Eight out of 47 (17.0%) patients had Hashimoto’s thyroiditis and 7 of them (87.5%) were in SG. Estrogen receptor (ER) was measured in 43/47 (91.5%) BC specimens. ER was detected in 19/30 (63.0%) patients in SG and 3/13 (23.1%) in DG (p=0.01). Five-yr mortality was 10/21 (47.6%) in ER- and 3/22 (13.6%) in ER+ patients (p=0.008). Absence of ER expression [odds ratio (OR) 6.54; p=0.006] and absence of TAb (OR 9.37; p=0.03) were related to a higher mortality rate. TAb were detected in 8/21 (38.1%) ER- and in 7/22 (31.8%) ER+ patients; no relation was found between ER expression and TAb positivity (p=ns). Patients with ER+ and TAb+ have a better prognosis and the absence of a significant relationship between these two parameters suggests an independent prognostic role in high malignancy degree BC women.