Long-term outcome of interferon-alpha-induced thyroid autoimmunity and prognostic influence of thyroid autoantibody pattern at the end of treatment.

Thyroid autoimmunity and dysfunction have been widely reported as side effects of interferon-alpha (IFN-alpha) treatment, but the literature lacks data regarding the long-term course of these complications, clinical observation being limited to 6-12 months off therapy. Our study is the first that has aimed to evaluate the natural history of IFN-related thyroid autoimmunity during a 6.2-yr follow-up after the IFN-alpha withdrawal as well as to investigate the potential role of the autoantibody pattern at the end of treatment to predict the long-term outcome. Our study group included 114 patients (79 males, 35 females), mean age 48 yr (range 23-67 yr) with no preexisting thyroid disease, undergoing a 12-month treatment with recombinant IFN-alpha for C virus-related chronic active hepatitis. Thyroid autoimmunity (serum TgAb and TPOAb) and function (serum FT(4), FT(3), TSH) were retrospectively evaluated at the end of IFN therapy, 6 months after IFN withdrawal and after a median period of 6.2 yr (range 5.5-8.4 yr). At the end of treatment, 78 patients were negative for thyroid autoantibodies (Abs-) and all but one of them remained so for the following evaluations. The remaining 36 patients had thyroid autoantibodies (Abs+) at the end of treatment, and they subsequently showed a heterogeneous behavior: 16 patients remained Abs+ for the whole length of the study (persistent thyroiditis); 10 patients became Abs- 6 months off therapy but were again Abs+ 6.2 yr later (remitting/relapsing thyroiditis); 10 patients reverted to autoantibody negativity at different observation times (transient thyroiditis). The absence of thyroid autoantibodies at the end of treatment was a protective factor for the successive development of thyroiditis (odds ratio: 0.02, confidence interval (CI) 95%: 0-0.1). On the contrary, the positivity for TgAb and/or TPOAb at high titers at the end of IFN treatment was significantly related to the highest risk of having chronic thyroiditis (odds ratio: 17.3, CI 95%: 3.2-91.7 for TgAb levels > 50 degree percentile; odds ratio: 7.3, CI 95%: 1.5-35.2 for TPOAb levels > 50 degree percentile). None of the patients showed overt thyroid dysfunction throughout the study, whereas a subclinical hypothyroidism was found in 12 patients. In all 12 cases, the functional abnormality was accompanied by the presence of thyroid autoantibodies. Eight of these 12 patients belonged to the group with persistent thyroiditis (P < 0.05). The absence of thyroid autoantibodies at the end of treatment was a protective factor for the successive development of thyroid dysfunction (odds ratio: 0.06, CI 95%: 0.01-0.56). On the contrary, the positivity for both TgAb and TPOAb at the end of IFN therapy was significantly correlated with the highest risk of having subclinical hypothyroidism 6.2 yr. later (odds ratio: 38.7; CI 95%: 6.2-242). Our study demonstrates that in patients undergoing an IFN-alpha therapy for chronic hepatitis C and with no evidence of preexisting thyroid disease: 1) the negativity for thyroid autoantibodies after IFN treatment is a protective factor for the developing thyroid autoimmunity and/or dysfunction in following years; 2) the IFN-alpha-related thyroid autoimmunity is not a complete reversible phenomenon because some patients can develop chronic thyroiditis; 3) high autoantibody levels at the end of IFN therapy are related to the risk of having chronic thyroid autoimmunity; and 4) the coexistence of TgAb and TPOAb at the end of treatment is a predictive factor for the presence of thyroid dysfunction, even if subclinical, many years after IFN withdrawal.

Medullary thyroid cancer, papillary thyroid microcarcinoma and Graves' disease: an unusual clinical coexistence.

We describe the unusual case of a Caucasian woman who had a diagnosis of medullary thyroid cancer and papillary microcarcinoma 5 years after a diagnosis of Graves' disease. The patient came to our observation for recurrence of hyperthyroidism. An ultrasound scan revealed diffuse thyroid enlargement with a nodule, recently increased in size. The serum CT and carcinoembrional antigen were elevated, and the fine-needle aspiration cytology with immunocytochemical analysis for CT was suggestive for medullary thyroid carcinoma. The nodular lesion showed intense 111In-pentetreotide uptake, whereas total body scintigraphy with the same tracer and with Thallium-201, 99mTc (V) dimercaptosuccinic acid was negative for lymph node and distant metastasis. The histological examination of thyroidectomy specimens confirmed the diagnosis of medullary thyroid cancer, showing a lymphocytic intratumoral infiltration. The histological analysis of the controlateral lobe showed an occult papillary microcarcinoma. Medullary thyroid carcinoma and papillary microcarcinoma showed intense staining with policlonal anti-RET antibodies, although genetic analysis was negative for RET mutations most frequently involved in familial and sporadic medullary thyroid carcinomas. Possible implications about the coexistence of the 3 thyroid diseases are discussed.

Long-term treatment with interferon-beta therapy for multiple sclerosis and occurrence of Graves' disease.

Interferon (IFN)-beta has become a widespread therapy for multiple sclerosis. As already reported for IFN-alpha, thyroid autoimmunity and dysfunctions have been observed also in course of IFN-beta therapy. Nevertheless, very few cases of Graves' disease, occurred in such condition, have been reported in literature. We here describe the case of a 40-year-old female affected by multiple sclerosis, who received IFN-beta-1b, 8 million IU s.c. every other day for her condition. After 22 months of cytokine administration, she developed a severe Graves' disease with persistently positive TR-Ab which suggested the withdrawal of the treatment. Our patient had performed a complete thyroid evaluation with normal findings, before and during the first 6 months of therapy. This case suggests that patients undergoing long-term IFN-beta therapy should be monitored for thyroid hormones and antibodies throughout the treatment as thyroidal side effect can be a late event.

Postintervention serum TSH levels may be useful to differentiate patients who should undergo levothyroxine suppressive therapy after thyroid surgery for multinodular goiter in a region with moderate iodine deficiency.

Recent studies have raised doubts about the efficacy of the postoperative use of levothyroxine (LT4) suppressive doses in patients who underwent thyroid surgery for multinodular goiter. The purpose of this retrospective study was to examine the efficacy of different doses of LT4 in preventing postsurgical recurrences of simple multinodular goiter and to identify a marker that could be useful in discriminating patients with a higher risk of developing recurrence. Two hundred thirty-two patients (57 male, 175 female) operated for nontoxic multinodular goiter were divided into two groups: (I) patients with normal postsurgery thyrotropin (TSH) levels (0.25 to 4.5 mU/L) and (II) patients with elevated postsurgery TSH levels (>4.5 mU/L). All patients were subjected to replacement (1.3 microg LT4/kg/day) or suppressive (1.7 microg LT4/kg/day) doses of LT4, and they were followed for a median period of 6 years (range 2 to 12). No statistical difference was found for sex, age, and postsurgery serum TSH between patients submitted to suppressive and replacement therapy. The ultrasound (US) detection of new postsurgery nodules of at least 0.5 cm maximum diameter was considered a recurrence of disease and was found in 10% of the cases studied. Patients with normal postsurgery serum TSH showed a high recurrence rate (30.4%) when submitted to lower daily doses of LT4. In patients with elevated postsurgery serum TSH, the rate of nodular goiter recurrence did not vary with different types of LT4 therapy. In conclusion, our results suggest that the postsurgical serum TSH is useful for prediction of nodular goiter recurrence, as it reflects the amount of residual functioning thyroid tissue in the cervical area. It may also be indicative of patients who might benefit from LT4 suppressive therapy.

Bioactive parathyroid hormone in pregnant rats and fetuses.

Parathyroid function at the end of gestation (day 21) was investigated by measuring plasma calcium (PCa), immunoreactive parathyroid hormone (iPTH), bioactive parathyroid hormone (bioPTH; cytochemical bioassay), and bone histology in intact and thyroparathyroidectomized (TPTX; day 12, ether anesthesia) rats and their fetuses. In pregnant intact rats, PCa was significantly lower, and iPTH, bioPTH, and osteoclast number were higher than in nonpregnant rats. In fetuses, PCa was higher than maternal PCa and correlated with fetal bioPTH. TPTX suppressed maternal bioPTH and decreased iPTH and osteoclast number, whereas fetal iPTH and bioPTH were decreased with no change in osteoclast number. Fetal PCa was near normal and was correlated with maternal PCa but not with fetal bioPTH. The fetomaternal calcium gradient was maintained and even increased. This study shows that there is maternal physiological hyperparathyroidism and functional fetal parathyroid glands at the end of gestation in the rat. Parathyroid hormone does not seem to be responsible for maintaining the high fetomaternal calcium gradient in TPTX animals.

Differential diagnosis between undifferentiated tumor and thymoma by electron microscopy and immunohistochemical labelling.

This study of a particular case of tumor posed and resolved problems of differential diagnosis between an undifferentiated tumor and a thymoma by using electron microscopy in association with immunocytochemical methods. The first step was the distinction between an epithelial and a mesenchymal tumor, which was done by electron microscopy and immunofluorescence observation with anti-keratin antibody. The second step, a new approach to this problem, was the distinction between an epithelial tumor of thymic origin and another tumor located in the mediastinal lodge. A clear distinction was made by observation in immunofluorescence using anti-thymulin monoclonal antibody. This double approach permits differential diagnosis, excludes neoplasms of germ-cell origin, malignant lymphomas and leukemias, as well as mesenchymal tumors, and affirms the thymic origin of the tumor observed. A second type of cell observed in this tumor with a peculiar aspect, different from all types of epithelial cells observed in normal thymus, is discussed.

Hypocalcaemic effect of WR-2721, S-2 (3-aminopropylamino) ethyl-phosphorothioic acid in an anuric haemodialysis patient.

The radio- and chemoprotective agent, S-2 (3-aminopropylamino) ethyl-phosphorothioic acid (WR-2721) has been reported to lower hypercalcaemia in patients with cancer, probably by increased renal calcium excretion and decreased parathyroid hormone (PTH) secretion and bone calcium resorption. The present study reports the first clinical use of WR-2721 in an anuric haemodialysis patient with severe secondary hyperparathyroidism. The drug was administered intravenously at different doses, i.e. 150, 300, and 500 mg/m2. The infusion was followed by a striking decrease of plasma immunoreactive (i) PTH within 30 min. The nadir of the iPTH decrease was reached at 60 min and was followed by a steady return to previous values. Serum ionised calcium decreased more progressively from 1.55 mmol/l initially to 1.30 mmol/l at 4 h after the 300-mg dose, remained at that level at 24 h, but rose again to pre-infusion values after 48 h. The extent and duration of the decrease in plasma iPTH and ionised calcium were dose-dependent. The circulating iPTH at 24 h was inversely related to the corresponding plasma ionised calcium concentration and had risen above preinfusion values at that time. Plasma concentrations of three other hormones, i.e. renin, insulin, and prolactin, were not affected by the administration of WR-2721. In conclusion, WR-2721 can induce a decrease in serum ionised calcium in the absence of any excretory kidney function. The rapid effect of the drug on circulating iPTH supports the notion of an interference with PTH secretion or catabolism.

[Tubal sterilization: psychological and endocrinological aspects]. / La sterilizzazione tubarica; aspetti endocrini e psicologici.

PIP: Sterilization today represents the ultimate contraceptive method and requires the consent of both marriage partners. The method consists of blocking the fallopian tubes by either fulguration, application of clips, tying the fallopian tubes, or by using laparotomy with certain techniques. This type of contraception presents not only technical and gynecological problems; it is often accompanied by a series of psychological reactions not always foreseen before the operation. The impossibility of being able to conceive is sometimes perceived, especially by adolescents, women in premenopause, and sterilized women, as a lack of femininity. A study of 211 sterilized women between the ages of 22-34, parity 2-5, was conducted. They each answered a questionnaire intended to measure the effect of sterilization on their psychological lives and whether it entailed any possible modifications in their sexual lives. 77.7% answered that they had the operation because of repeated past Cesarean sections. Before the operation, 61.2% used coitus interruptus as a means of birth control. 38.9% couples reported increased pleasure in their sexual life; decrease of libido was reported for 22.2%, and no change of libido for 38.9%. 55.6% were generally pleased with the operation, especially those who were sufficiently informed about the irreversibility of it, and those who had a stable emotional psyche. The multiparous women or those with impending pregnancies had had no 2nd thoughts. 27.8% evaluated the operation negatively and 16.6% were indifferent. Longterm effects included spotting 38.9%, pelvic infection 33.3%, premenstrual tensions 27.8%, and dysmenorrhea 22.2%. Menstrual irregularities are related to a condition of insufficiency of the corpus luteum due to altered vascularization.^ieng

Thymoma epithelial cells secrete thymic hormone but do not express class II antigens of the major histocompatibility complex.

17 thymomas were studied by indirect immunofluorescence for the presence of thymic hormones and antigens of the major histocompatibility complex (MHC). The thymoma epithelial cells (specifically identified by their keratin content) contained thymic hormones (thymulin and thymosin alpha 1), a finding corroborated by the observation of elevated thymulin serum levels. In contrast with normal or hyperplastic thymuses, thymoma epithelial cells did not express HLA-DR and HLA-DC antigens as assessed by immunofluorescence as well as immunoblot analyses. Conversely, MHC class I antigens (HLA-ABC) were normally expressed. Thus, we conclude that thymoma epithelial cells are endocrinologically active but are defective for the expression of some MHC products (class II molecules) known to play an essential role in intrathymic T cell differentiation.