Journal Article Studies on the in vitro cytotoxic effect of amiodarone Get access L Chiovato, L Chiovato 1Istituto di Endocrinologia, University of Pisa, Italy. Search for other works by this author on: Oxford Academic Google Scholar E Martino, E Martino 1Istituto di Endocrinologia, University of Pisa, Italy. Search for other works by this author on: Oxford Academic Google Scholar M Tonacchera, M Tonacchera 1Istituto di Endocrinologia, University of Pisa, Italy. Search for other works by this author on: Oxford Academic Google Scholar F Santini, F Santini 1Istituto di Endocrinologia, University of Pisa, Italy. Search for other works by this author on: Oxford Academic Google Scholar P Lapi, P Lapi 1Istituto di Endocrinologia, University of Pisa, Italy. Search for other works by this author on: Oxford Academic Google Scholar C Mammoli, C Mammoli 1Istituto di Endocrinologia, University of Pisa, Italy. Search for other works by this author on: Oxford Academic Google Scholar L E Braverman, L E Braverman 1Istituto di Endocrinologia, University of Pisa, Italy. Search for other works by this author on: Oxford Academic Google Scholar A Pinchera A Pinchera 1Istituto di Endocrinologia, University of Pisa, Italy. Search for other works by this author on: Oxford Academic Google Scholar Endocrinology, Volume 134, Issue 5, 1 May 1994, Pages 2277–2282, https://doi.org/10.1210/endo.134.5.8156930 Published: 01 May 1994
Major histocompatibility class II molecules human leukocyte antigen-DR (HLA-DR) are abnormally expressed by human thyroid cells (HTC) in autoimmune thyroid glands. The simultaneous expression of HLA-DR and organ-specific autoantigens such as thyroid peroxidase (TPO) by HTC might enable these cells to function as antigen-presenting cells, thus perpetuating the autoimmune process. The aim of the present study was to clarify the interplay of endocrine (TSH) and immune [TSab or interferon-gamma (IFN gamma)] factors on the expression of HLA-DR and TPO in HTC. Thyrocytes were cultured with supernatants of T-cells cloned from the infiltrate of Hashimoto's glands, human recombinant IFN gamma, TSab, or TSH. These factors were added either alone or in different combinations and sequences. HLA-DR and TPO were identified in HTC by a double indirect immunofluorescence technique, using a monoclonal anti-HLA-DR antibody and human serum containing anti-TPO antibody, respectively. IFN gamma, either recombinant or produced by T-cell clones, induced HLA-DR appearance in thyrocytes, whereas TSH or TSab stimulated TPO expression. The appearance of HLA-DR induced by IFN gamma was accompanied by a progressive reduction of TPO despite stimulation by TSH or TSab. This decline reached a nadir after 9-10 days in different primary cultures. During this period, a percentage of cells ranging from 10-40% simultaneously expressed HLA-DR and TPO on their surface and in the cytoplasm. The inhibition of TPO expression and the appearance of HLA-DR induced by IFN gamma were rapidly reverted when TSH or TSab was substituted for interleukin in the culture medium and vice versa. We conclude that 1) the expression of TPO or HLA-DR in thyroid cells is a dynamic phenomenon that is differently influenced by TSH, TSab, and IFN gamma. It is the interplay of these factors in different follicles and during different periods of time that determines the expression of TPO alone, HLA-DR alone, or both molecules together in the same thyroid cell; 2) during exposure to TSH (or TSab) and IFN gamma, TPO and HLA-DR can be expressed simultaneously by thyroid cells for up to 7 days; and 3) the modulation of HLA-DR and TPO by supernatants of T-cells cloned from Hashimoto's glands is reproduced by IFN gamma alone.
The main steps in the management of differentiated thyroid cancer are thyroidectomy, treatment with iodine-131 (131I), and follow-up with whole-body scanning (WBS) and serum thyroglobulin (Tg) determination. Both 131I treatment and follow-up require maximum stimulation of normal or pathological thyroid remnants by TSH. The use of recombinant human TSH (rhTSH) has been shown to be useful for follow-up, whereas previous reports are not univocal regarding the use of 131I postsurgical ablation of thyroid remnants, at least when low doses (30 mCi) of 131I are administered. A possible explanation for the diminished effectiveness of 131I treatment after rhTSH may be the interference of iodine content of l-thyroxine (l-T4) therapy during the protocol of administration of rhTSH. We have evaluated the effectiveness of stimulation by rhTSH for radioiodine ablation of postsurgical remnants, stopping l-T4 the day before the first injection of rhTSH and restarting l-T4 the day after 131I. The study included two groups of patients: group 1 included 16 patients with differentiated thyroid cancer (15 papillary cancers and 1 follicular cancer, stages I and II), who were treated with 30 mCi 131I with the aid of rhTSH, using the standard protocol but stopping l-T4 as stated previously; and group 2 included 24 patients with the same features (histology and stage) of disease treated with 30 mCi in the hypothyroid state after l-T4 withdrawal. In both groups, serum TSH reached a very good stimulation level [76–210 U/liter (mean, 112 ± 11 se) and 38–82 U/liter (mean, 51 ± 3 se), respectively]. At the first WBS (after 131I treatment), all patients showed thyroid remnants. Furthermore, two patients of the first group and three patients of the second group showed lymph node metastases. After 1 yr, all patients were studied again and underwent WBS with a tracer dose of 131I and serum Tg measurement using rhTSH with the same protocol in both groups. The percentage of ablation (undetectable Tg and a negative WBS) was higher, although not reaching statistical significance, in patients treated with rhTSH: 81.2% in patients treated by rhTSH withdrawal and 75.0% in patients treated by l-T4 withdrawal, respectively. No patient experienced symptoms of hypothyroidism during the 4 d of l-T4 interruption, and serum T4 remained in the normal range. Urinary iodine was analyzed in both groups and compared with a control group of patients who received, for diagnostic purposes, rhTSH without stopping l-T4. In the first group, urinary iodine was 47.2 ± 4.0 μg/liter (mean ± se; P = 0.21 vs. the second group, P = 0.019 vs. control group). In the second group, urinary iodine was 38.6 ± 4.0 μg/liter (mean ± se; P < 0.001 vs. control group); urinary iodine in the control group was 76.4 ± 9.3 μg/liter (mean ± se). Our data show that rhTSH, as administered in the protocol stated previously, allows at least the same rate of ablation of thyroid remnants when low doses (30 mCi) of 131I are used. The possible role of interference of iodine content in l-T4 is not surprising if we consider that the amount of iodine in 30 mCi is negligible (5 μg) compared with the amount of iodine content in a daily dose of T4 (∼50 μg). The cost of rhTSH seems modest compared with the high cost of complex therapeutic regimens in other areas of oncology and in consideration of the well-being of patients and of the high level of effectiveness of the treatment.
We report two cases of anaplastic thyroid cancer (ATC) which had a very good response to a treatment with lenvatinib at 14 mg. A 73-year-old man with ATC stage IVB was operated on, undergoing a near-total thyroidectomy, and the pathological remnant tissue showed a quick and partial response to treatment with the drug. The patient had a single metastasis in the brain after 9 months, but then died due to bronchopneumonia after undergoing a neurosurgical intervention for the complete removal of the lesion. A 74-year-old woman with ATC stage IV was operated on, undergoing a near-total thyroidectomy after a neoadjuvant treatment with the drug, that was continued after surgical treatment. She had a partial remission of the local disease and of distant metastasis, which lasted for 14 months. She then died 4 months later due to cancer progression. Lenvatinib at 14 mg appears to be effective, fast and well tolerated.
Thyroid-cytotoxic antibodies (thyroid-cytotoxic Abs) have been described in patients with autoimmune thyroiditis, but their role in the development of hypothyroidism remains to be clarified. In this study, we evaluated the pathogenetic role of thyroid-cytotoxic Abs in 20 patients with atrophic thyroiditis (idiopathic myxedema; AT) and 94 patients with goitrous Hashimoto's thyroiditis (HT). Among patients with HT, 27 were euthyroid (HT-E), 27 had subclinical hypothyroidism (HT-SH), and 40 had overt hypothyroidism (HT-H). Seventeen normal subjects and 8 patients with nonthyroidal illnesses were used as controls (C). To detect thyroid-cytotoxic Abs, human thyroid cells expressing thyroid peroxidase (TPO) were labeled with 51Cr and challenged with the immunoglobulin G (IgG) fraction of serum plus rabbit complement. The cytotoxic effect of IgGs was calculated as the percent specific lysis (% SL), taking into account the lytic effect of complement alone and the maximal lysis produced by a detergent. Most C-IgGs decreased the cytotoxic effect of complement (median % SL, -3.3). IgGs from hypothyroid patients with thyroiditis had a greater cytotoxic effect than C-IgGs, either as a whole group (P < 0.001), or when subdivided according to clinical diagnosis: HT-SH (median % SL, 4.8; P < 0.005), HT-H (%SL, 2.2; P < 0.0001), or AT (%SL, 0.9; P < 0.01). Among patients with HT, the lytic activity of IgGs from patients with subclinical and overt hypothyroidism was higher than that of IgGs from euthyroid patients (P < 0.05). The results of IgGs from euthyroid patients with HT (median % SL, -0.9) did not significantly differ from those of C-IgGs. By taking a cut-off over the upper range of % SL produced by C-IgGs (> 2), the prevalence of thyroid-cytotoxic Abs was 30% in AT, 59% in HT-SH, and 55% in HT-H. However, 37% of euthyroid patients with HT also had thyroid-cytotoxic Abs. No IgG containing TPO antibodies (TPOAb) at low titer (< 40(2)) was cytotoxic. However, the levels of thyroid-cytotoxic Abs did not correlate with TPOAb titers, and preabsorption with TPO only partially abolished the lytic effect of some HT-IgG. These findings suggest that TPO is a target of thyroid-cytotoxic Abs, but other thyroid antigens are also involved in the cytotoxic reaction.(ABSTRACT TRUNCATED AT 400 WORDS)
Santini F, Chiovato L, Bartalena L, Lapi P, Palla R. Panichi V, Velluzzi F, Grasso L, Chopra IJ, Martino E. Pinchera A. Study of serum 3,5,3′-triiodothyronine sulfate concentration in patients with systemic non-thyroidal illness. Eur J Endocrinol 1996;134:45–9. ISSN 0804–4643 Sulfation is an important pathway of triiodothyronine (T 3 ) metabolism. Increased serum T 3 sulfate (T 3 S) values have been observed during fetal life and in pathological conditions such as hyperthyroidism and selenium deficiency. Similar variations have also been reported in a small number of patients with systemic non-thyroidal illness, but the underlying mechanisms have not been elucidated. In this study, serum T 3 S concentrations have been measured by a specific radioimmunoassay in 28 patients with end-stage neoplastic disease (ESND) and in 44 patients with chronic renal failure (CRF); 41 normal subjects served as controls. Both ESND and CRF patients had lower serum total T 4 (TT 4 ) and total T 3 (TT 3 ) than normal controls, while serum reverse T 3 (rT 3 ) was increased significantly in ESND (0.7 ±0.5 nmol/l; p < 0.001 vs. controls) but not in CRF (0.3 ± 0.1 nmol/l). The TT 3 /rT 3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T 4 -binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T 3 S was significantly higher both in ESND (71 ± 32 pmol/l) and CRF 100 ± 24 pmol/l) than in controls (50 ± 16 pmol/l, p < 0.001). Serum T 3 S values showed a positive correlation with rT 3 values and a negative correlation with both TT 3 and FT 3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T 3 S and TBG values. The T 3 S/FT 3 ratio was higher both in CRF (18 ± 5) and in ESND (23 ± 18) as compared to controls (10 ± 4). Serum inorganic sulfate was increased and correlated positively with T 3 S values in CRF patients. In conclusion, the results of this study in a large series of patients confirm that patients with systemic non-thyroidal illness have increased serum T 3 S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T 3 S levels is mainly related to reduced degradation of the hormone by type I MD, whereas in CRF it might be driven by the enhanced sulfate ion concentration, and could be partially dependent on the impaired renal excretion of T 3 S Because T 3 S can be reconverted to T 3 . it is possible that increased T 3 S concentrations contribute to maintenance of the euthyroid state in systemic non-thyroidal disease. Ferruccio Santini, Institute of Endocrinology, University of Pisa. Viale del Tirreno 64. 56018 Tirrenia, Pisa, Italy
Permanent congenital hypothyroidism (CH) has an incidence of 1/3000-4000 newborns and is among the most frequent cause of mental retardation and neurological alterations in children. In 80% to 85% of cases CH is associated with thyroid dysgenesis. A group of 61 patients with CH (22 with agenesis, 18 with ectopy, 1 with hypoplasia, and 20 cases with CH without thyroid enlargement but not further characterized) and 30 normal subjects were examined for the presence of mutations in the gene encoding the thyroid transcription factor 1 (TTF-1). The coding-region of the TTF-1 gene was analyzed in all cases by the single stranded conformational polymorphism (SSCP) and no mutations were detected. Direct sequencing also carried out in patients with thyroid agenesis confirmed the absence of mutations or polymorphisms in the TTF-1 gene. The absence of mutations in the TTF-1 gene in our samples indicates that the mutations in the TTF-1 gene are not a frequent cause of CH.
