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.
RAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves' disease.
Serum thyroid hormone concentrations increase after radioiodine (RAI) therapy for Graves' disease. This phenomenon has been ascribed to either antithyroid drug withdrawal before RAI therapy or release of preformed thyroid hormones into the bloodstream from the RAI-damaged thyroid. Lithium blocks the release of iodine and thyroid hormones from the thyroid, thus enhancing the effectiveness of RAI therapy. Changes in serum-free thyroxine (FT4) and triiodothyronine (FT3) levels after methimazole (MMI) discontinuation and RAI therapy were evaluated in a prospective, randomized, control study of 36 patients with Graves' disease. After a 3- to 4-month course of MMI, patients were assigned to one of three groups: G1 (RAI alone); G2 (RAI plus lithium for 6 d starting on the day of RAI therapy); or G3 (RAI plus lithium for 19 d starting on the day of MMI withdrawal). G1-G2 patients had an increase in serum FT4 and FT3 levels from 13.5 +/- 6.5 to 19.8 +/- 9.2 pmol/liter and 5.0 +/- 2.0 to 8.0 +/- 4.8 pmol/liter, respectively (P < 0.0001), 2-5 d after MMI withdrawal, but G3 patients showed no changes. In the 30 d after RAI therapy, mean serum FT4 values increased in G1 patients (P = 0.02), peaking at 3-7 d (P < 0.05) but not in G2 and G3 patients. Serum FT3 levels decreased in G1, G2, and G3 (P = 0.03, P = 0.001, P = 0.02, respectively). Hyperthyroidism was cured in 8 of 12 G1 patients, 11 of 12 G2 patients, and 11 of 12 G3 patients (P = 0.31). Control of hyperthyroidism was prompter in G2 (P = 0.08) and G3 (P < 0.05) than in G1 patients. Patients in the three groups received a similar dose of RAI, but the committed radiation to the thyroid was higher in G3 (563 +/- 174 Gray) and G2 (588 +/- 347 Gray) than in G1 (429 +/- 204 Gray) (P < 0.03). In conclusion, the results of the present study demonstrate that: 1) MMI withdrawal is associated with a slight rise in serum thyroid hormone levels; 2) a further increase occurs after RAI therapy; 3) changes in serum thyroid hormone concentrations are prevented by lithium; and 4) the increased effectiveness of RAI therapy in lithium-treated patients is related to the increased RAI retention in the thyroid gland. Accordingly, a short course of lithium therapy can be considered a useful adjunct to RAI therapy to obtain a prompter control of thyrotoxicosis and avoid its transient exacerbation because of MMI withdrawal and RAI administration.
Parathyroid carcinoma (PC) is a rare endocrine malignancy. The tumor is mostly functioning, causing severe primary hyperparathyroidism, with high serum calcium and parathyroid hormone (PTH) levels. Nonfunctioning PC is extremely rare. We report a 50-year-old male patient who was referred to our Department for a right thyroid nodule, incidentally detected on carotid Doppler ultrasound scan, with a fine-needle aspiration cytology showing a follicular lesion. At the time of our evaluation, neck ultrasound showed a 1.3 cm right hypoechoic thyroid nodule with irregular margins and the absence of enlarged bilateral cervical lymph nodes. Thyroid function tests were normal. Serum calcium was normal and plasma PTH slightly above the upper limit of the normal range. The patients underwent right lobectomy. The intraoperative frozen-section pathological examination raised the suspicion of a PC. Definitive histology showed a markedly irregular infiltrative growth of the tumor with invasion of the thyroid tissue and cervical soft tissues. Immunostaining for thyroglobulin was negative, whereas staining for chromogranin A and PTH showed a strong reactivity. Based on the microscopic findings and the immunohistochemical profile, the tumor was diagnosed as a PC. Postoperative serum calcium and phosphate levels were in the normal range. One month after surgery, serum calcium and PTH were normal. Neck ultrasound and total body computed tomography scan were negative for local and metastatic disease. Eight months later, serum calcium was normal and plasma PTH level remained around the upper limit of normal range. Neck ultrasound did not show any pathological lesions. This is the first case of a nonfunctioning sporadic PC misdiagnosed prior of surgery as a follicular thyroid nodule. The parathyroid nature of the neck lesion could not be suspected before surgery. Fine-needle aspiration cytology (FNAC) may fail to distinguish a parathyroid tumor from a benign thyroid nodule because at FNAC, parathyroid and thyroid lesions have some morphological similarities. Histological criteria are not always sufficient for the differential diagnosis, which can definitely be established using immunohistochemistry.
Polychlorinated biphenyls (PCBs) are environmental contaminants which may affect thyroid function. PCBs may reduce serum thyroid hormone (TH) concentrations by either displacing T4 from TH transport proteins or increasing its hepatic metabolism. The reduced serum T4 causes neurological and growth defects in animals exposed to PCBs during the perinatal period, which can partially be reverted by T4 administration. In addition to a hypothyroid-like syndrome, a direct action of PCBs on TH-sensitive genes has been postulated. In the present study the effects of Aroclor 1254 (ARO), a mixture of PCBs, on transcription of TH-dependent genes were investigated. A reporter plasmid containing the TH-responsive element (TRE) of malic enzyme (ME) gene was used in transient transfections to assess the responsiveness to ARO. ARO (10 microM) reduced the CAT activity by about 50% and competed with T3 to reduce the induction of transcription. Cotransfection of TH receptor (TR) and a wild type TRE was required to reveal ARO inhibitiry effect, which was abolished by a mock reaction not containing TR or by a mutated TRE. ARO reduced the 125I-T3 binding to TR by 30%, but did not affect the interaction of TR with a 32P-labeled TRE in gel shift assay. ARO is likely to produce a conformational change in in vitro translated TR, leading to its increased proteolysis by trypsin. These results demonstrate that ARO interacts with TR, thereby affecting the transcription of TH-sensitive genes, and provide a molecular basis to further explain the complex effects of PCBs on TH disruption.
We have identified a novel mutation in the pendrin gene causing Pendred's syndrome, and confirm that molecular analysis is a useful tool for a definitive diagnosis. This is particularly relevant in cases such as in the subjects of our family in which the clinical features might be misleading and other genetics factors might be responsible for deafness.
Effectiveness of radioiodine for Graves' hyperthyroidism depends also on its intrathyroidal persistence. The latter is enhanced by lithium by blocking iodine release from the thyroid. One hundred ten patients with Graves' hyperthyroidism were randomly assigned to treatment with radioiodine or radioiodine plus lithium, stratified according to goiter size (< or =40 or >40 mL) and evaluated for changes in thyroid function and goiter size, at monthly intervals, for 12 months. Cure of hyperthyroidism occurred in 33 of 46 patients (72%) treated with radioiodine and in 45 of 54 patients (83%) treated with radioiodine plus lithium. The probability of curing hyperthyroidism was higher and its control prompter (P = 0.02) in the radioiodine-plus-lithium group. Patients with < or =40-mL goiters had similar persistence of hyperthyroidism (13%), but lithium-treated patients had hyperthyroidism controlled earlier (P = 0.04). Among patients with >40-mL goiters, hyperthyroidism was cured in 6 of 15 patients (40%) treated with radioiodine alone and in 12 of 16 patients (75%) treated with radioiodine plus lithium (P = 0.07), and cure occurred earlier in the latter (P = 0.05). Goiters shrank in both groups (P < 0.0001), more effectively and promptly (P < 0.0005) in the radioiodine-plus-lithium group. Serum free T4 and T3 levels increased shortly after therapy only in the radioiodine group (P < 0.01). Lithium carbonate enhances the effectiveness of radioiodine therapy, in terms of prompter control of hyperthyroidism, in patients with small or large goiters. In the latter group, lithium also increases the rate of permanent control of hyperthyroidism.
Patients with untreated active acromegaly had low-pitched voice characterized by lowering F0 and increased values related to noise, micro perturbation of frequency, and amplitude.
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