Lucia Grasso

Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens.

RiassuntoLe malattie autoimmuni della tiroide sono caratterizzate dalla presenza di anticorpi diretti contro la tireoperossidasi (TPO), la tireoglobulina (Tg) e il recettore per l’ormone tireotropo (TSH-R). Questo studio ha valutato se la rimozione completa degli antigeni tiroidei fosse in grado di indurre la scomparsa dei segni di autoimmunità tiroidea circolante. Lo studio è basato su una revisione retrospettiva delle cartelle cliniche di pazienti che erano stati seguiti e trattati secondo un protocollo standard. Sono stati studiati 182 pazienti affetti da tumore differenziato della tiroide i quali, per la coesistenza di una tiroidite cronica autoimmune, di un morbo di Basedow o di una tiroidite focale autoimmune, risultavano positivi per anticorpi anti-TPO (TPOAb), anti-Tg (TgAb) o anti-TSH-R (TRAb). Dei 182 soggetti, 151 erano di sesso femminile e 31 di sesso maschile; l’età media era di 39,7±13,7 anni, con un range da 6 a 81 anni. Tutti i pazienti sono stati sottoposti a tiroidectomia totale e a trattamento con iodio radioattivo allo scopo di ablare il tessuto tiroideo residuo o metastatico. Il follow-up è stato effettuato mediante scintigrafie corporee totali con radioiodio e dosaggio della Tg circolante. La media del follow-up era di 10,1±4,1 anni, con un range di 4–20 anni. A seguito del trattamento con tiroidectomia totale e iodio radioattivo, si è verificata la scomparsa dei TgAb, TPOAb e TRAb. La mediana di scomparsa è stata di 6,3 anni per iTPOAb e di 3,0 anni per i TgAb. La scomparsa del tessuto tiroideo e quella degli anticorpi antitiroide erano correlate in modo statisticamente significativo. La persistenza di TPOAb e TgAb non veniva influenzata dal sesso, dall’età e dalla concomitanza della tiroidite autoimmune o del morbo di Basedow.

Thyroid function differently affects serum cystatin C and creatinine concentrations.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p<0.05), and significantly decreased in short-term, long-term and mild hypothyroids (p<0.05, p<0.05, p<0.01, respectively). However, 36 (62%) hyperthyroid patients and 50 (76%) hypothyroid patients had normal serum Cys C values. In the prospective study, restoration of euthyroidism by either methimazole or L-T4 therapy was associated with normalization of mean serum Cys C concentrations. In conclusion, thyroid dysfunction affects serum Cys C concentration, possibly influencing the production rate of the protein. However, the observation that hyper- or hypothyroid patients have normal serum Cys C levels limits its use as a marker of peripheral thyroid hormone effect.

Are the Clinical and Pathological Features of Differentiated Thyroid Carcinoma Really Changed over the Last 35 Years? Study on 4187 Patients from a Single Italian Institution to Answer this Question

BACKGROUND In the last decades, a marked increased prevalence of differentiated thyroid cancer (DTC) has been observed worldwide. The aim of this study was to evaluate the changing features of DTC referred to our institution between 1969 and 2004. METHODS Clinical and pathological features and prognostic factors were analyzed in 4187 DTC patients, subdivided into two groups: group 1 (n = 1215) and group 2 (n = 2972) diagnosed before and after 1990, respectively. RESULTS Group 2 showed an increased proportion of micropapillary carcinoma and a concomitant decrease of follicular histotype. Male percentage was greater in group 2, whereas median age at diagnosis was unchanged. DTC of group 2 were more frequently associated with multinodular goiter or autoimmune thyroiditis, but many were unexpected findings. Features of aggressiveness were significantly less frequent in group 2, and the survival rate was greater (98.7 vs. 91.4%, P < 0.0001). Gender, age, histotype, tumor size, extrathyroidal macroinvasion, and lymph node and/or distant metastases were found to be poor prognostic factors in both groups using univariate analysis, but with multivariate analysis, only advanced age (odds ratio = 22.52 for older patients) and advanced stage (odds ratio = 53.54 for more advanced cases) were independently correlated with a lower survival. CONCLUSIONS DTC patients diagnosed after 1990 have smaller tumors with less advanced stage and a better prognosis. The question of whether this is related to the finding of tumors with a low clinical penetrance or to the anticipation of diagnosis remains to be clarified. Despite these significant differences, both advanced stage and older age still represent the most important poor prognostic factors for survival.

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 thyroglobulin in thyroid carcinoma and other thyroid disorders

Measurements of serum thyroglobulin (hTg) were performed using a specific radioimmunoassay. Sera with detectable anti-thyroglobulin (anti-Tg) antibody titers (>1∶10) as assessed by passive hemagglutination were discarded. Assays were carried out under conditions in which anti-Tg titers less than 1:10 produced no interference. The assay sensitivity was 1.25 ng/ml and the mean ± SE concentration of serum hTg in 58 control subjects was 9.5 ± 0.9 ng/ml (range< 1.25–27 ng/ml). A slight but significant (p<0.025) increase in the mean hTg level was observed in 12 pregnaint women at delivery (25.7 ± 5.2 ng/ml). Moderate to marked elevations of serum hTg were observed in patients with nontoxic goiter (61.4 ± 15 ng/ml; n = 23), subacute thyroiditis (138 ± 67 ng/ml; n =5), toxic adenoma (129 ±47 ng/ml; n =13), untreated (424 ± 101 ng/ml; n = 35) or treated (328 + 222 ng/ml; n =14) toxic diffuse goiter. 88 patients with thyroid carcinoma and 10 with nonthyroidal malignancies were studied. The mean level of serum hTg was increased in untreated differentiated thyroid carcinoma (89.5 ± 19 ng/ml; n = 13) but not in undifferentiated (10 ±2.9 ng/ml; n =6) or medullary (0.8 ±0.2 ng/ml; =3) carcinoma. In treated differentiated thyroid carcinoma the mean hTg levels were normal (8.2 ± 2.2 ng/ml) in patients (n = 24) with no evidence of either a thyroid residue or metastatic disease, moderately increased (56.6 ± 16 ng/ml) in patients (n =27) with residual thyroid tissue, markedly elevated in patients with lymph node metastases (199 ± 50 ng/ml; n = 15) and extremely elevated in those with bone (4004 ± 982 ng/ml; n = 8) or lung (2520 ± 620 ng/ml; n = 5) metastases. There was no significant difference in serum hTg between functioning (n =23) and nonfunctioning (n =5) metastases as assessed by 131| whole body scan. A slight but significant (p < 0.0005) increase in the mean concentration of hTg was observed in nonthyroidal malignancies (21.7 ±4.5 ng/ml; n = 10). Serial measurements showed a transient increase of serum hTg after131| therapy of differentiated thyroid carcinoma, toxic diffuse goiter or toxic adenoma, with peak values usually occurring within the first three days. A fall of serum hTg after administration of suppressive doses of thyroid hormone to patients with nontoxic goiter and a rise after discontinuation of thyroid suppressive therapy in patients with metastatic differentiated thyroid carcinoma was observed. The present data confirm and extend previous data indicating that serum hTg is frequently elevated in thyroid disease, and that the release of hTg from malignant and nonmalignant thyroid tissue is at least in part thyrotropin (TSH) dependent and it is enhanced by radioiodine therapy. Measurements of serum hTg do not differentiate from benign and malignant thyroid disease, but may be usefullly employed in the follow up of differentiated thyroid carcinoma. Of particular interest was the finding that nonfunctioning metastases may be detected by measurement of serum hTg and that bone or lung metastases are associated with much higher levels of serum hTg than lymph node metastases.

Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer

To assess the significance of a single serum thyroglobulin (Tg) determination on and off thyroid suppressive therapy, serum Tg measurements have been performed in 349 serum samples from 82 patients with differentiated thyroid cancer. All samples were collected after total thyroidectomy with or without subsequent ablation of residual thyroid tissue by radioiodine. One hundred and fifty‐three samples were obtained while the patients were on thyroid suppressive therapy and 196 after withdrawal of medication. The results of serum Tg assays were analysed in relation to the presence or absence of residual or metastatic thyroid tissue, as assessed by clinical and laboratory evaluation, including 131I whole body scan. In patients with thyroid residue but no metastases, undetectable serum Tg (false negative results) occurred in 45% of cases off therapy and in 92·9% of cases during therapy. In the presence of metastases no undetectable serum Tg result was found in patients off therapy, while four (6·9%) out of 58 samples from patients with bone and/or lung metastases and seven (31·8%) out of 22 samples from patients with lymph node metastases alone were undetectable (falsely negative) during suppressive therapy. Serum Tg was undetectable in sera from patients with no evidence of thyroid residue or metastatic disease in all but one (1·7%) of 59 samples on and three (5·4%) of 56 samples off suppressive therapy. These Tg results were confirmed to be truly rather than falsely positive, since evidence of metastatic disease was obtained by whole body scan after the administration of therapeutic doses of 131I. These data indicate that the finding of detectable serum Tg during suppressive therapy is a reliable indicator of metastatic disease, while a negative result does not exclude the presence of metastases especially in the case of lymph node involvement. In this regard assays performed off therapy have greater diagnostic value.

Thyroid ultrasonography as a tool for detecting thyroid autoimmune diseases and predicting thyroid dysfunction in apparently healthy subjects

In order to establish its usefulness for the diagnosis and follow-up of thyroid autoimmune diseases, thyroid ultrasonography together with free T4 (FT4), free T3 (FT3), TSH, antibodies (Tg Ab) and thyroperoxidase antibodies (TPO Ab) were performed and re-evaluated during a 3-yr follow-up in 482 apparently healthy subjects, living in a borderline iodine-sufficient urban area. Thyroid dysfunction was found in 7 out of 12 (58.3%) subjects with circulating thyroid autoantibodies, who also had thyroid hypoechogenicity (2 had overt and 3 subclinical hypothyroidism at booking; 2 developed subclinical hypothyroidism during the follow-up), and in none of the 12 subjects with normal thyroid echostructure (χ2=7.26, p=0.007). Thyroid dysfunction was found in 4 out of 29 (13.7%) subjects with negative Tg and/or TPO Ab who also had thyroid hypoechogenicity (1 had Graves’ disease at booking, 1 developed Graves’ disease and 2 subclinical hypothyroidism during the follow-up), and in none of the 429 with normal thyroid echostructure (χ2=82.03, p<0.0001). Although positive TPO and/or Tg Ab were more frequent (24/482, 5%) in subjects with thyroid dysfunction (7/11) than in those who remained euthyroid during the study (17/471, χ2=69.66, p<0.0001), thyroid hypoechogenicity had a higher sensitivity than the positivity of thyroid autoantibody tests (100 vs 63.3%) for diagnosing or predicting thyroid dysfunction. In conclusion: 1) thyroid ultrasonography is a useful tool to detect thyroid autoimmune disease in apparently healthy subjects; 2) present and future thyroid dysfunction is more readily predicted by a hypoechogenic pattern at thyroid ultrasound than by the occurrence of serum thyroid autoantibodies.

Serum thyroglobulin concentrations and 131I whole body scans in the diagnosis of metastases from differentiated thyroid carcinoma (after thyroidectomy)

SUMMARY. Measurements of circulating thyroglobulin (hTg) and 131I whole body scan were performed in 101 patients with differentiated thyroid carcinoma who had been subjected to surgical thyroidectomy and 131I ablation of remaining thyroid tissue. All 45 patients with positive scans (i.e. functioning metastases) had elevated hTg concentrations. Of fifty‐six patients with negative scans forty‐two had undetectable or very low hTg levels and were considered to be free of metastatic thyroid tissue, whereas fourteen showed the presence of non‐functioning metastases in the clinical and/or radiological examination. In this group of patients, eleven had elevated serum hTg levels while the other three patients had detectable hTg concentrations within the normal range. These results indicate that serum hTg measurements correlate very well with scan findings and have the added advantage of detecting non‐functioning metastases which would not be detected by scanning. We concluded that measurement of serum hTg may be used together with scanning, as the first step in the follow‐up of thyroidectomized patients with differentiated thyroid carcinoma.

Relationship of the increased serum interleukin-6 concentration to changes of thyroid function in nonthyroidal illness

Variations in the serum concentration of interleukin-6 (IL-6) have been reported concomitantly with thyroid dysfunction: increased serum IL-6 levels have been found in patients with thyroidal destructive processes, such as subacute thyroiditis, some forms of amiodarone-induced thyrotoxicosis, or after percutaneous ethanol injection into “hot” thyroid nodules, as a result of the cytokine release from the damaged thyrocyte. In addition, recent in vitro evidence suggests that IL-6 might account, at least in part, for changes of thyroid economy found in nonthyroidal illness (NTI). In this cross-sectional study we addressed this problem by measuring serum IL-6 levels in 71 patients with NTI, due to neoplasia(n=25), chronic liver disease (n=9), chronic renal failure (n=28), or other chronic nonthyroidal disorders (n=9). These patients had reduced mean serum total T3 (TT3) and free T3 (FT3) concentrations, normal total and free T4 levels, normal TSH values, and increased serum reverse T3 (rT3) concentration (with the exception of chronic renal failure patients, who had normal rT3 levels). Serum IL-6 concentration was increased above normal (i.e. >100 fmol/L) in almost all NTI patients, especially in those with low T3 values (median value: 258 fmol/L, range 73–3210, vs 152 fmol/L, range <12.5–460, in patients with normal TT3 values, p<0.001). Serum IL-6 values in NTI patients were negatively correlated with serum FT3 values (r=0.56, p<0.001), and positively correlated with serum rT3 values (r=0.78, p<0.001). The increased serum IL-6 levels might represent a systemic reaction to disease, possibly mediated by stimulation of IL-6 synthesis and release induced by other cytokines, such as IL-1 and tumor necrosis factor. Whether IL-6 is simply a marker of NTI or is responsible, at least in part, for abnormalities of thyroid function tests, as suggested by previous in vitro evidence, remains to be established.

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