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In the past, morphological evaluation of the thyroid gland relied primarily on the thyroid scan. In recent years high resolution sonography has became the first-line test in the assessment of thyroid morphology, due to its sensitivity, and easiness and because it avoids the use of radioactivity. Moreover, the ultrasonographic features of the gland may help to identify specific thyroid pathology as in the case of autoimmune thyroid disorders, characterized by diffuse hypoechogenicity (1,2).

We studied blood coagulation and fibrinolysis activities in hyperthyroidism before and after methimazole or 131I. Fibrinopeptide A and B beta 15-42, in vivo indicators of thrombin and plasmin activity, were measured by RIA, while fibrinogen by the Clauss method. We studied 50 patients, affected by toxic diffuse goiter. We evaluated 21 of them before and after treatment. Fibrinogen, fibrinopeptide A, and B beta 15-42 were higher in patients than in controls (p less than 0.0001). There was no difference in fibrinopeptide A nor in B beta 15-42 before or after treatment. In euthyroidism fibrinogen returned to normal values. Inflammation of the thyroid gland secondary to autoimmunity may activate blood coagulation by release of tissue factor. High fibrinogen before treatment may be explained as an aspecific response. Since it persists in euthyroidism, autoimmunity could account for high fibrinopeptide A and B beta 15-42 aftertreatment.

Amiodarone may induce hyper- or hypothyroidism. Patients with beta-Thalassemia Major (beta-Thal) have an increased prevalence of primary hypothyroidism and often require amiodarone for hemosyderotic cardiomyopathy. Aim of this study was to retrospectively evaluate thyroid function in beta-Thal adult patients on long-term amiodarone. The study group consisted of twenty-two (21 males, 1 female; age: 23-36 yr) beta-Thal patients submitted to long-term (3-48 months) amiodarone therapy from January 1991 to July 1996. Controls included 73 beta-Thal patients (23 males and 50 females aged 25-35 yr) not treated with amiodarone. In all cases serum free thyroid hormones, thyrotropin and thyroid autoantibodies were evaluated. A higher prevalence of overt hypothyroidism (5/22 [22.7%]) as compared to controls (3/73 [4.1%], p=0.02) was found in beta-Thal patientsor = 3 months after starting amiodarone, while the prevalence of subclinical hypothyroidism was similar in amiodarone-treated (18.2%) and untreated (15%) beta-Thal patients. Overt hypothyroidism resolved spontaneously after amiodarone withdrawal in 1 case, while the remaining patients were maintained euthyroid on amiodarone by L-thyroxine administration. After 21-47 months of amiodarone therapy, 3 patients (13.6%) developed thyrotoxicosis (2 overt and 1 subclinical), which remitted shortly after amiodarone withdrawal. No case of hyperthyroidism was observed in beta-Thal controls (p=0.012 vs amiodarone-treated patients). In conclusion, amiodarone administration is often associated in adult beta-Thal patients to a rapid progression of the pre-existing subclinical hypothyroidism, but transient thyrotoxicosis may also be observed after a longer period of therapy. These findings should be carefully considered in the management of these patients.

Thyrotoxicosis factitia, a syndrome due to the surreptitious ingestion of excess thyroid hormones, has generally been diagnosed in young or middle-aged women with psychopathological disturbances. We reviewed all the cases seen at our Institution over a 24-yr period, from 1973 to 1996. All 25 patients were women. Analysis was restricted to 17 patients who were born and lived in Tuscany (our region), since only these patients were distributed during the whole observation period. Diagnosis of thyrotoxicosis factitia was based on the following parameters: elevated serum total and/or free thyroid hormone levels, undetectable serum thyrotropin levels, low/undetectable serum thyroglobulin concentration, normal urinary iodine excretion, low/suppressed thyroidal radioactive iodine uptake (RAIU), absence of goiter, absence of circulating anti-thyroid antibodies. Surreptitious ingestion of thyroid hormone pill was eventually admitted by all patients. Age at diagnosis was >50 yr in 7/17 patients (41%): 6 of them were distributed in the period 1995-1996, and one in 1988. Patients older than 60 yr were 5/17 (29%), all in the last two years of the period under investigation. There was an increase in the age of patients with thyrotoxicosis factitia (p=0.02), which lost a statistical significance when the patients of the 1995-1996 period were excluded from analysis (p=0.88). This study provides evidence of an increased age of patients with thyrotoxicosis factitia in more recent years. From a practical standpoint, our study suggests that thyrotoxicosis factitia should be suspected and adequately looked for even in old patients with thyrotoxicosis of inexplicable origin, especially in the absence of goiter and thyroid autoimmune phenomena, and when common causes of low-RAIU hyperthyroidism, such as a load with iodine-containing drugs or subacute thyroiditis, have been excluded.

Nonthyroidal illness (NTI) is associated with complex changes in thyroid function tests and thyroid regulation known as the euthyroid sick syndrome (ESS) (1). The most common abnormality is a reduction in serum total triiodothyronine (TT3) and, to a lesser extent, free T3 (FT3) concentrations (2). Kinetic studies showed that the daily production rate (PR) of T3 is decreased, while its clearance is unchanged in NTI (3). The reduction in serum TT3 concentration is usually accompanied by an increase in serum reverse T3 (rT3) concentration (1), although the latter is normal in patients with chronic renal failure (4), AIDS (5), or traumatic brain injury (6). PR of rT3 is unchanged, but its clearance is reduced (3). These changes in serum TT3 and rT3 concentrations are related to inhibition of the activity of type I 5-deiodinase (5-DI), the enzyme catalyzing deiodination of thyroxine (T4) to T3 and of rT3 to 3,3 -diiodothyronine (7). Serum thyrotropin (TSH) concentration is usually normal, although suppressed values may be found in a minority of patients (1). In addition, a decrease in the nocturnal surge of TSH has been consistently reported in patients with NTI (8–12). Abnormalities of TSH glycosylation causing its decreased biological activity were also described (13). The decrease in serum TSH secretion is in some instances related to the use of dopamine and glucocorticoids in critically ill patients (14). The pathogenesis of changes in serum thyroid hormone and TSH concentrations leading to ESS is not completely understood. Reduced T3 generation in peripheral tissue may be related not only to a decreased 5-DI activity, but also to decreased T4 transport into tissues (15). Substances, such as 3-carboxy-4-methyl-5propyl-2-furanpropanoic acid (CMPF) and indoxylsulfate, which are increased in chronic renal failure, and bilirubin and free fatty acids (FFA), which are increased in other NTI, were reported to decrease T4 uptake in rat liver tissue (16, 17). Interestingly, CMPF and indoxyl-sulfate did not affect TSH secretion in cultured rat anterior pituitary cells (18). Recently, particular attention was focused on the role of cytokines in the pathogenesis of ESS. Cytokines are multifunctional molecules with different biological effects and target cells, which can exert autocrine (on the same cells that secrete them) and paracrine (on adjacent cells), but also endocrine (on distant cells) actions (19). They are usually produced in response to inflammation, infections and cellular injury, and their physiological role remains to be clarified (19). In general, cytokines act through binding to specific cellsurface receptors that were demonstrated also in thyrocytes (20, 21). In addition, thyrocytes synthesize and release cytokines, which might be involved in autocrine or paracrine regulation of thyroid function (22–32). The importance of cytokines in thyroid pathophysiology was recently underscored (Fig. 1). They participate in the pathogenesis of thyroid autoimmune disease by contributing to the growth and differentiation of B and T cells, by inducing expression of HLA class II antigens and adhesion molecules, by recruiting and activating immune cells and by modulating the course of the disease (33). Interleukin-6 (IL-6) and possibly other cytokines are useful markers of thyroid-destructive processes (34). Cytokines have a role in the pathogenesis of Graves’ ophthalmopathy, since they induce orbital fibroblast proliferation and glycosaminoglycan production, and expression of HLA class II antigens, adhesion molecules and heat shock proteins in orbital fibroblasts (35). Numerous studies in vitro and in vivo (both in animals and humans) were carried out in recent years on the effects of cytokines on thyroid function. Since the number of published papers on this issue is very large, in this review we analyzed the most crucial studies to discuss the role of cytokines in the pathogenesis of ESS.

It is unclear whether smoking affects the course of Graves ophthalmopathy and therapeutic outcomes.To observe smoking behavior in a randomized study of the effect of radioiodine therapy on ophthalmopathy and in a case series of patients with Graves ophthalmopathy receiving orbital radiation therapy and glucocorticoids.Randomized, single-blind study of smoking and mild ophthalmopathy after radioiodine therapy (study 1) and a retrospective cohort study of the association between smoking and response of severe ophthalmopathy to treatment (study 2).University medical center.300 patients with mild ophthalmopathy (study 1) and 150 patients with severe ophthalmopathy (study 2).In study 1, patients received radioiodine alone or radioiodine and a 3-month course of oral prednisone (initial dosage, 0.4 to 0.5 mg/kg of body weight per day). In study 2, patients received high-dose oral prednisone for 6 months (initial dosage, 80 to 100 mg/d) and underwent orbital radiation therapy by linear accelerator (cumulative dose, 20 Gy per eye over 2 weeks).Degree of ophthalmopathy was assessed by overall evaluation (inflammatory changes, proptosis, extraocular muscle dysfunction, corneal involvement, and optic neuropathy).In study 1, ophthalmopathy progressed in 4 of 68 nonsmokers (5.9% [95% CI, 3% to 9%]) and 19 of 82 smokers (23.2% [CI, 13% to 33%]) who received radioiodine alone (P = 0.007). Ophthalmopathy was alleviated in 37 of 58 nonsmokers (63.8% [CI, 51% to 78%]) and 13 of 87 smokers (14.9% [CI, 10% to 26%]) who received radioiodine plus prednisone (P0.001). In study 2, 61 of 65 nonsmokers (93.8% [CI, 90% to 98%]) and 58 of 85 smokers (68.2% [CI, 57% to 78%]) responded to treatment (P0.001).Cigarette smoking increases the risk for progression of ophthalmopathy after radioiodine therapy and decreases the efficacy of orbital radiation therapy and glucocorticoid therapy.

We have investigated an Italian family with generalized resistance to thyroid hormone (RTH), consisting of two individuals with elevated serum thyroid hormones (TH) and a non-suppressed TSH, together with unaffected family members, for a mutation in the thyroid hormone receptor beta gene (hTR beta). We have identified a single nucleotide substitution (1321 CTT to GTT) corresponding to a leucine to valine substitution at codon 346 (L346V) in the predicted protein. The index case and her affected child are heterozygous for the receptor defect, with normal sequence in unaffected family members. Furthermore, both parents of the index case were unaffected, suggesting that the mutation had arisen de novo. When expressed in vitro, the L346V mutant receptor showed a marked reduction in its affinity for tri-iodothyronine (T3), impaired ligand-dependent transactivation and potent dominant negative activity. Its functional impairment could not be alleviated, even at supraphysiological concentrations of T3, suggesting that the mutation might interfere with the intrinsic ligand-dependent transactivation function (AF-2) located in the hormone binding domain of hTR beta. Finally, the presence of the L346V mutation in the son of the propositus, who died from complications associated with congenital heart disease, raises the possibility that RTH might have contributed to the pathogenesis or severity of the latter.

A 38-year-old caucasian woman developed typical Graves' hyperthyroidism and ophthalmopathy while being chronically treated for pemphigus vulgaris with low doses of glucocorticoids capable of effectively controlling skin disease. HLA typing showed positivity for DR3 and DR4, suggesting a genetic susceptibility for both Graves' disease and pemphigus vulgaris. The apparent contradiction whereby thyroid autoimmune disease flared up during therapy with glucocorticoids, known for their immunosuppressive effects, may be related to the dose of steroids. It is possible that high doses of glucocorticoids, commonly employed in the treatment of severe Graves' ophthalmopathy, might indeed suppress the disease, whereas the low doses used in this patient might precipitate or aggravate it.

A 57-year-old woman with no previous personal or family history of thyroid disease developed typical subacute thyroiditis, with pain and tenderness in the anterior cervical region, fever, mild thyrotoxicosis; thyroid autoantibodies were negative, serum thyroglobulin (TG) levels were increased, radioactive iodine uptake (RAIU) values were decreased, urinary iodine excretion was normal, and erythrocyte sedimentation rate (ESR) elevated. Symptoms subsided with glucocorticoid treatment, with normalization of serum thyroid hormone and TG levels. Four months later, while still on a low dose of glucocorticoid, she had recurrence of hyperthyroidism, with no thyroid pain or tenderness, high RAIU values, positive thyroid-directed autoantibodies including TSH-receptor antibody. HLA typing showed positivity for B35 and DR3, suggesting a genetic susceptibility for both subacute thyroiditis and Graves' disease. The development of Graves' disease after subacute thyroiditis is extremely rare, suggesting that a genetic susceptibility to the disease must exist in such an instance.

The relationship between thyroid dysfunction and breast cancer (BC) is debated. To clarify this controversial issue, a prospective study on thyroid function in BC was performed. The prevalence of thyroid disease was examined in 102 consecutive BC patients with ductal infiltrating carcinoma after surgery and before starting any chemohormonal or x-ray therapy and in 100 age-matched control healthy women living in the same borderline iodine-sufficient geographic area. All subjects were submitted to clinical ultrasound thyroid evaluation and serum free T4, free T3, TSH, thyroperoxidase antibody, and thyroglobulin antibody determination. Fine needle aspiration was performed in all thyroid nodules. Estrogen and progesterone receptors (ER and PR, respectively) were assayed in 92 and 55 BC specimens, respectively. The overall prevalence of thyroid disease was 47 in 102 (46%) in BC patients and 14 in 100 (14%) in controls (P < 0.0001). The prevalence of nontoxic goiter was 27.4% in BC patients and 11% in controls (P = 0.003). Hashimoto's thyroiditis was found in 13.7% of BC patients and in only 2% of the controls (P < 0.005). Other thyroid disorders found in the BC group included 2 cases of Graves' disease, 2 of thyroid carcinoma, and 1 of subacute thyroiditis, whereas in the control group only 1 case of Graves' disease and none of the other disorders were found. Mean free T3, free T4, and TSH concentrations showed no difference between BC patients and controls. The prevalence of thyroperoxidase antibody was higher in BC patients than in controls (23.5% vs. 8%; P < 0.005), whereas the prevalence of thyroglobulin antibody was not different. In BC patients the presence of thyroid antibodies was more frequently associated with clinically detectable autoimmune thyroiditis (14 of 26, 51.8%; P = 0.03) and was more common in the younger group. The positivity of ER was found in 51 of 92 (55.43%) and that of PR was found in 26 of 55 (47.27%) BC specimens. No relationship was found among ER, PR status, and the presence of serum thyroid antibodies. In conclusion, 1) the present study provides evidence that the overall prevalence of thyroid disorders is increased in patients with breast cancer, and 2) thyroid autoimmune disorders, especially Hashimoto's thyroiditis, account to a large extent for the increased prevalence of thyroid disease in patients with breast cancer. This feature is independent from the ER and PR status of the primary tumor. The present findings call attention to the usefulness of screening for thyroid disease in any patient with breast cancer.

Free thyroid hormones (free thyroxine, FT4, and free triiodothyronine, FT3) represent a more useful index of thyroid status than total thyroid hormones, because the latter are influenced by variations of thyroid hormone-binding proteins, especially T4-binding globulin (TBG). Thus, increased serum total T4 (TT4) and, in many instances, T3 (TT3) concentrations are encountered in euthyroid subjects with TBG excess, familial dysalbuminemic hyperthyroxinemia and transthyretin-associated hyperthyroxinemia, while decreased serum TT4 and TT3 levels are associated with TBG deficiency: under these circumstances, measurement of serum FT4 and FT3 levels correctly establishes the diagnosis of euthyroidism. In cases of suspected hyperthyroidism, a diagnostic strategy can be suggested based on serum FT3 (and TSH) measurement, since FT4 may occasionally be elevated, also in euthyroid subjects, e.g., in patients under chronic amiodarone or L-T4 treatment. When hypothyroidism is suspected, the most reliable test appears to be FT4 (together with TSH), because FT3 may still be normal in patients with subclinical or mild thyroid failure. In any case, it is essential that reliable free thyroid hormone assays be used, which are devoid of methodological limitations responsible for artifactual results under particular circumstances, such as thyroid hormone-binding protein abnormalities, pregnancy and nonthyroidal illness.

The 3alpha-hydroxy metabolites of progesterone (P), 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, A-PREG) and 3alpha-hydroxy-5beta-pregnan-20-one (pregnanolone, PREG), have been found to be among the most potent ligands of gamma-aminobutyric (GABA)-A receptors; in experimental animals, they have been found to have anxiolytic, hypnotic and anticonvulsant effects. Similar to those of the benzodiazepines and barbiturates that interact with GABA-A receptors. The present study was undertaken to determine plasma A-PREG and PREG concentrations in the luteal phase in women with partial epilepsy, in order to determine if an impaired metabolism of P occurs in this convulsive disorder. We measured plasma P, A-PREG and PREG levels in 15 women with partial epilepsy in the intercritical phase, and in 15 age-matched healthy women, during the luteal phase of the ovarian cycle (22nd-24th day). The mean plasma +/- S.E. A-PREG levels (three blood samples) were 0.7 +/- 0.6 ng/ml in the epileptic women and 0.5 +/- 0.2 ng/ml in controls, with no significant difference between the two groups (p = NS); the PREG levels were also similar (1.4 +/- 1 ng/ml and 1 +/- 1.1 ng/ml, respectively: p = NS). A significant correlation was found between P levels and both A-PREG and PREG levels (r = 0.72, p0.001 and r = 0.79, p0.001, respectively). There were no significant differences between the two groups in terms of serum adrenocorticotropic hormone, cortisol, dihydroepiandrosterone-sulfate, follicle stimulating hormone, prolactin, luteinizing hormone or estradiol levels.

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 (T3) metabolism. Increased serum T3 sulfate (T3S) 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 T3S 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 T4 (TT4) and total T3 (TT3) than normal controls, while serum reverse T3 (rT3) 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 TT3/rT3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T4-binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T3S 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 T3S values showed a positive correlation with rT3 values and a negative correlation with both TT3 and FT3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T3S and TBG values. The T3S/FT3 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 T3S 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 T3S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T3S 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 T3S Because T3S can be reconverted to T3. it is possible that increased T3S 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

Germline point mutations in exons 10, 11, and 16 of the ret protooncogene have been identified as causative in multiple endocrine neoplasia type 2 and in familial medullary thyroid carcinoma (MTC). Somatic point mutations of the same gene, exclusively associated with codon 918 of exon 16, have also been reported in few cases of sporadic medullary thyroid carcinoma. We analyzed the blood and tumor DNA of 19 patients with sporadic MTC and 6 patients with primary parathyroid adenoma for point mutations at exons 10, 11, and 16 of the ret protooncogene by restriction analysis of the PCR-amplified product and by sequence analysis of exons 10 and 11. A Cys634-->Tyr mutation was found in both the tumoral and blood DNA of one patient, indicating that he was affected by an hereditary form of MTC, erroneously considered sporadic. In the other 18 patients with MTC, somatic point mutations of ret were found in 8 cases (44.4%). In 5 cases the mutation affected exon 16 (Met918-->Thr), and in 3 cases it affected exon 11 (Cys634-->Arg in 1 and Cys634-->Trp in 2); these 3 mutations were confirmed by sequence analysis. The remaining 10 patients had no mutation in exon 10 by either restriction analysis or sequence analysis. Clinical data showed that 75% of the patients whose tumor carried ret mutation had tumor recurrence and/or increased serum calcitonin concentrations during the postsurgical follow-up period as opposed to 10% of the patients without mutations (P < 0.02, by chi2 analysis). No ret mutation was found in the tumoral DNA from parathyroid adenomas. Our findings indicate that the somatic ret point mutation frequently found in sporadic MTC may affect not only exon 16 but also exon 11 and is associated with less favorable clinical outcome.

Roti E, Bartalena L, Minelli R, Salvi M, Gardini E, Pistolesi A, Martino E, Braverman LE. Circadian thyrotropin variations are preserved in normal pregnant women. Eur J Endocrinol 1995;133:71–4. ISSN 0804–4643 Serum thyrotropin (TSH) concentration circadian rhythm is abolished in many endocrine and nonendocrine diseases. In the present study we have measured serum TSH concentration over 24 h every 2 h in second and third trimester pregnant women. During the 24-h period, serum free thyroxine and free triiodothyronine concentrations did not change significantly. In contrast, serum TSH concentrations demonstrated significant circadian variations both in the second and third trimester pregnant women (p Elio Roti, Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, University of Parma, via Gramsci 14, 1-43100 Parma, Italy

Thyroid hypoechogenicity at ultrasound is a characteristic of autoimmune thyroid diseases, with an overlap of this echographic pattern in patients affected by Graves' disease or Hashimoto's thyroiditis. Aim of the present paper was to study the thyroid blood flow (TBF) by color-flow doppler (CFD) and peak systolic velocity (PSV) at the inferior thyroid artery in 37 Graves' and 45 goitrous Hashimoto's thyroiditis patients. CFD pattern was defined as normal (or type 0): TBF limited to peripheral thyroid arteries (PSV = 17.7 +/- 3 cm/sec, mean +/- SD); type I: TBF mildly increased; type II: TBF clearly increased; type III: TBF markedly increased. The CFD was in direct relationship to the PSV. Out of 18 patients with Graves' disease and untreated active hyperthyroidism CFD pattern was type III in 17 and type II in 1. The PSV was 42.1 +/- 15 cm/sec. In 17 patients euthyroid under methimazole, the CFD pattern was type 0 in 3 (17%) type I in 5 (30%), type II in 5 (30%), type III in 4 (23%). In this group of Graves' patients the PSV was 36 +/- 14 cm/sec. In two patients, hypothyroid after radioiodine treatment, the CFD pattern was type 0 in 1 and type I in 1. In the group of Hashimoto's patients TBF was in no relationship with thyroid status or treatment and was type 0 in 22 (49%), type I in 20 (44%), type II in 3 (7%), while none had type III CFD pattern. Thyroid hypoechogenicity at ultrasound was present in 32/37 (86%) Graves' and 41/45 (91%) Hashimoto's patients. All the four patients with Hashimoto's thyroiditis and normal thyroid ultrasound pattern had also a normal CFD pattern, while 4/5 patients with Graves' disease and normal echographic pattern had an increased TBF. In conclusion, a diffusely increased thyroid blood flow is pathognomonic of untreated Graves' disease and an abnormal CFD pattern identifies the majority of Graves' patients with a normal thyroid ultrasound pattern. Thus, CFD sonography may be useful in distinguishing patients with Graves' disease and Hashimoto's thyroiditis having a similar thyroid echographic pattern at ultrasound.

Background: The iodine-rich antiarrhythmic drug, amiodarone, can induce both thyrotoxicosis and hypothyroidism, the former being more frequent in iodine-deficient areas, the latter in iodine-sufficient areas. In this study we evaluated prospectively thyroid function in amiodarone-treated patients with positive or negative baseline thyroid autoantibody test results who resided in a moderately iodine-deficient area of Italy. Subjects: Two groups of patients received long-term amiodarone treatment: Group 1 included 13 patients with negative thyroid autoantibody test results. Group 2 consisted of seven patients with positive thyroid autoantibody test results and thyroid ultrasound patterns compatible with Hashimoto's thyroiditis. The control group (group 3) included 16 untreated euthyroid patients with Hashimoto's thyroiditis. All subjects resided in a mildly iodine-deficient area of Italy (Southern Sardinia) and had low urinary iodine values. Patients in groups 1 and 2 had markedly elevated urinary iodine excretion during treatment. The follow-up period ranged from 6 to 29 months in group 1, from 4 to 9 months in group 2, and from 12 to 55 months in group 3. Results: Two (15%) of 13 patients in group 1 with nodular goiter developed thyrotoxicosis. No patient in this group developed circulating thyroid autoantibodies. Five (71%) of seven patients in group 2 became hypothyroid after 4 to 9 months of amiodarone treatment associated with a rise in serum thyroid autoantibody levels. No patient in group 3 became hypothyroid. Conclusions: (1) Amiodarone administration can cause both thyrotoxicosis and hypothyroidism. (2) Hypothyroidism is far more frequent in patients with preexisting thyroid autoimmune disease. (3) Amiodarone can modify the natural history of Hashimoto's thyroiditis. (4) Circulating thyroid autoantibodies do not appear in amiodarone-treated patients who have negative test results prior to therapy. (Arch Intern Med. 1994;154:2722-2726)

Sperm morphology has been suggested to be one of the most reliable factor in predicting male fertility potential both in spontaneous cycles and in assisted reproduction. In this work the morphology of spermatozoa selected with three different techniques (layering, swimup from pellet and mini-percoll) has been assessed and compared in 20 infertile patients. All the techniques allowed the recovery of sperm populations of a better quality than in basal samples, with a higher percentage of normal forms (p

Although the existence of endemic goiter and cretinism in Sardinia is known since to ancient time, scanty information collected according to WHO criteria is available. In the present paper the results of an extensive epidemiological survey carried out in juvenile population living in some rural and/or hilly villages in the provinces of Nuoro and Oristano in Central-Southern Sardinia and in urban area of Cagliari, are reported. In the majority of the villages the mean urinary iodine excretion was lower than 60 μg/L; the goiter prevalence ranged between 39% and 61% in the district of Nuoro and between 21% and 56% in the district of Oristano. In the control area the urinary iodine excretion was 105 μg/L with a goiter prevalence of 12%. Goiter prevalence was not always inversely related to urinary iodine excretion. No relevant thyroid function alterations were found. In conclusion: 1) in extraurban areas of Central-Southern Sardinia mild to moderate iodine deficiency and endemic goiter are still a widespread problems; 2) also in urban area endemic goiter prevalence is still higher than 10%; 3) extemporary urinary samples are inadequate for assessing the severity of goiter endemia in mild to moderate iodine deficiency; 4) in mildly affected districts palpation is inaccurate for assessing the prevalence of goiter; 5) no relevant alterations of thyroid function were documented in juvenile population.

Bartalena L, Grasso L, Brogioni S, Martino E. Interleukin 6 effects on the pituitary–thyroid axis in the rat. Eur J Endocrinol 1994;131:302–6. ISSN 0804–4643 It has been postulated recently that cytokines, and in particular interleukin 1 (IL-1) and tumor necrosis factor-α TNF-α), may have a role in the pathogenesis of the changes of serum thyroid hormone concentrations that are encountered in patients with non-thyroidal illness (NTI). Many of the IL-1 and TNF-α effects are believed to be mediated by the induction of IL-6 synthesis, which might, therefore, represent an important mediator of thyroid hormone changes in NTI. To address this problem, male Wistar rats were injected subcutaneously with 2.5 μg of recombinant human IL-6 (rhIL-6, in 500 μl of saline solution), with 2.5 μg of rhIL-6 preincubated with 100 μl of anti-IL-6 neutralizing antibody or with saline solution alone (control group). Administration of rhIL-6 resulted in a significant decrease of thyroxine (T4) from 82 ± 4 nmol/l (mean± sem) to a nadir of 33 ± 3 nmol/l (p < 0.0001) after 48 h, and of triiodothyronine (T3) from 1.6 ± 0.1 to 0.8 ± 0.1 nmol/l after 48 h (p < 0.0001). A slight decrease in serum T4 and T3 concentrations also was observed in the control group, but the lowest values (T4, 66 ± 3 nmol/l; T3, 1.2 ± 0.1 nmol/l) were significantly higher (p < 0.0001) than in IL-6-treated rats. The IL-6-induced changes could be prevented by preincubation of rhIL-6 with its neutralizing antibody. Slight but not significant changes occurred in serum reverse T3 (rT3) concentration, so that the T4/rT3 ratio remained substantially unchanged after rhIL-6 injection, whereas the T4/T3 ratio decreased significantly from 53.6 to 39.9 (p < 0.02) in IL-6-treated rats. The effects of IL-6 on thyrotropin (TSH) were investigated after rendering the rats hypothyroid by methimazole administration for 3 weeks. Serum TSH decreased from 19.0 ± 6.8 to 13.3 ± 3.8 μg/l after 48 h (p < 0.01) in IL-6-treated rats, while it increased from 17.2 ± 2.8 to 25.8 ± 4.0 μg/l (p < 0.01) in the control group. These results show that a single injection of rhIL-6 causes a decrease in serum T4, T3 and TSH concentrations in the rat, without affecting serum rT3 levels. This is compatible with a predominantly central effect of the cytokine. The apparent lack of inhibition of 5′-deiodinating activity, a key feature of NTI, suggests that IL-6, if involved, is only one of the factors responsible for the changes of thyroid hormone secretion and metabolism observed in NTI. Luigi Bartalena, Istituto di Endocrinologia, University of Pisa, Viale del Tirreno 64, 56018 Tirrenia-Pisa, Italy

In this study, plasma samples from eight lithium-free patients with affective disorders starting on carbamazepine treatment were assayed for thyroid function with a special focus on free triiodothyronine

An abnormal thyroid echographic pattern, characterized by a diffuse low thyroid echogenicity associated with a reduced thyroid volume, was found in 53 of 55 (96%) patients with atrophic thyroiditis. In 10 of these patients, the ultrasound examination was diagnostic for thyroid atrophy, whereas the scintiscan had no abnormality. In only two cases was the reverse observed, ie, absent thyroid radioiodine uptake and no evidence of abnormality in the ultrasound examination. Six out of 24 (25%) patients with thyroperoxidase antibody titersor = 1:1600 and 4 of 31 (13%) patients with titersor = 1:6400 had a normal thyroid scintiscan in the presence of an abnormal thyroid echographic pattern. Thus, thyroid echography can be considered the first morphological procedure in patients with hypothyroidism due to atrophic thyroiditis, and thyroid scintiscan can be used to confirm the diagnosis when other results are not definitive.

From 1969 to 1990 there were 309 patients with differentiated thyroid carcinoma (241 papillary and 68 follicular) treated with radioactive iodine for functioning node metastases alone (n=191) or distant metastases (n=118) with or without node metastases. These patients represented 32.7% of 945 patients treated in our institution during the same period. Initial treatment included near-total thyroidectomy and 131I ablation of postsurgical thyroid residue, followed by L-thyroxine suppressive therapy. At the end of follow-up (mean 5.8 years), 146 patients (76.4%) in the group with nodal metastases were considered cured, as assessed by clinical and laboratory evaluation including whole body scan (WBS) and serum thyroglobulin (Tg) levels; 32 patients (16.7%) had persistent disease. Loss of 131I uptake in persistent metastatic lesions occurred in five patients (2.6%), and newly developed distant metastases occurred in eight patients (4.2%). Of the patients with distant metastases, 36.4% were cured by 131I. Distant metastases from papillary carcinomas had a higher cure rate than follicular carcinomas (p

The present report illustrates the clinical and biochemical outcome in two amiodarone iodine-induced thyrotoxicosis (AlIT) patients submitted to plasmapheresis. Amiodarone was discontinued, and treatment with MMI (40 mg/day) was started. In addition, patients were submitted to two sessions of plasma-exchange, with a one-day interval between the two session. In both patients serum total T3 (TT3) and free T3 (FT3) concentrations decreased promptly but in contrast to the serum TT3, FT3 levels remained steadily above the normal range. A similar behaviour was observed for total T4 and free T4 plasma concentrations. Interestingly, a clearcut clinical amelioration was observed in both patients even before a reduction of circulating free thyroid hormone concentrations could be documented. In conclusion, our experience indicates that plasmapheresis may be useful in order to obtain a rapid amelioration of severe clinical picture of thyrotoxicosis, but cannot be considered as a definite therapy in AIIT. It should be considered that plasmapheresis is not devoid of risks and is also a very expensive procedure.

The somatostatin analogue, octreotide (OC) has commonly been used in the management of growth hormone- and thyrotropin-secreting pituitary tumors, and shown to be effective both on hormone production and tumor size. Because OC receptors may be expressed also in some nonfunctioning pituitary adenomas, it has been postulated that OC might play a role in the treatment of these tumors as well. In the present study, the morphological effects of OC administration, as assessed by computer tomography (CT) scan, were evaluated in 8 patients (5 men, 3 women, age range 25-79 yr) affected by non-functioning pituitary tumors. The drug was given sc at the dose of 100 micrograms tid for 3-6 months. No significant change in visual field or tumor size occurred after OC treatment in 7 patients, whereas one showed a significant improvement of visual field associated with a decreased tumoral mass. These data suggest that OC is not an effective drug in the management of nonfunctioning pituitary adenomas.

Interleukin-6 (IL-6) is the main mediator of the acute phase response. Increased serum concentrations of the cytokine have been found in patients with nonthyroidal inflammatory disorders and infections. In 18 patients with subacute thyroiditis (SAT) evaluated within 1-2 weeks after the onset of the disease, serum IL-6 values, as assessed by an ELISA method having a limit of detection of 25 fmol/L, ranged 139.2-543.9 fmol/L (mean +/- SE, 287.2 +/- 28.2 fmol/L). These values were significantly higher than those of 25 normal healthy controls (mean +/- SE, 26.2 +/- 5.5 fmol/L, range < 25-99.4), 18 of whom had serum IL-6 values below the detection limit. The increase in serum IL-6 levels in SAT patients appeared to be related to the inflammatory disorder and not to thyrotoxicosis, because 18 Graves' disease patients and 13 patients with toxic adenoma or toxic multinodular goiter had significantly lower serum IL-6 concentrations (101.7 +/- 35.2 fmol/L, range < 25-251, for Graves' disease, 79.6 +/- 41.4 fmol/L, range < 25-168.5, for toxic adenoma, p < 0.001 vs SAT for both groups) despite the markedly higher levels of total and free thyroid hormones. Neither free T4 nor free T3 values were correlated with serum IL-6 levels both in SAT and Graves' patients. Twelve SAT patients were reevaluated 3-4 months later, after remission of the disease and at least one month after glucocorticoid withdrawal. At the final observation, all SAT patients showed a normalization of IL-6 concentration, which was undetectable in 8/12 (mean +/- SE, 22.8 +/- 5.4 fmol/L, p < 0.001 vs acute phase values).(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple endocrine neoplasia (MEN) 2A associated to cutaneous lichen amyloidosis is a variant of MEN 2A recently reported in few families. We describe an additional family with this syndrome. The skin lesion is a pruritic one, located over the upper back showing, at biopsy, cutaneous amyloid. The propositus of our family was a 35-year-old woman already treated with total thyroidectomy for medullary thyroid cancer and with bilateral adrenalectomy for pheochromocytoma. The patient referred that the skin lesion was present since childhood and increased with time. Skin biopsy showed negative staining for amyloid, for calcitonin and neuron-specific enolase. The paraspinal muscles corresponding to the area of affected skin showed slight neurogenic abnormalities. Ten other members of her family were affected by MEN 2A, three of whom (all females) had the same cutaneous alteration.