Safety and effectiveness of a somatropin biosimilar in children requiring growth hormone treatment: second analysis of the PATRO Children study Italian cohort.

PURPOSE: To investigate the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the somatropin biosimilar Omnitrope®. METHODS: PATRO Children is an ongoing, multicenter, observational, post-marketing surveillance study. Children who received Omnitrope® for any indication were included. Adverse events (AEs) were evaluated in all study participants. Auxological data, including height standard deviation scores (HSDS) and height velocity standard deviation scores (HVSDS), were used to assess effectiveness. In this snapshot analysis, data from the Italian subpopulation up to August 2017 were reported. RESULTS: A total of 291 patients (mean age 10.0 years, 56.0% male) were enrolled at 19 sites in Italy. The mean duration of Omnitrope® treatment was 33.1 ± 21.7 months. There were 48 AEs with a suspected relationship to the study drug (as reported by the investigator) that occurred in 35 (12.0%) patients, most commonly headache, pyrexia, arthralgia, insulin-like growth factor above normal range, abdominal pain, pain in extremity and acute gastroenteritis. There were no confirmed cases of type 1 or type 2 diabetes; however, two patients (0.7%) had impaired glucose tolerance that was considered Omnitrope® related. The mean HSDS increased from - 2.41 ± 0.73 at baseline (n = 238) to - 0.91 ± 0.68 at 6.5 years (n = 10). The mean HVSDS increased from - 1.77 ± 1.38 at baseline (n = 136) to 0.96 ± 1.13 at 6.5 years (n = 10). CONCLUSIONS: In this sub-analysis of PATRO Children, Omnitrope® appeared to have acceptable safety and effectiveness in the treatment of in Italian children, which was consistent with the earlier findings from controlled clinical trials.

Can misdiagnosis in pre-operative FNAC of thyroid nodule influence surgical treatment?

BACKGROUND: Pre-operative cytology in thyroid disease remains the most appropriate diagnostic test for defining the nature of a thyroid nodule before surgical excision. MATERIALS AND METHODS: We selected the most recent 825 surgical thyroid procedures performed in our institution from January 2004 to June 2007; 776 were total thyroidectomies, 23 were lobe-isthmectomies, and 26 were radical neck dissections. We distributed the data based on pre-operative cytology. Each cytological diagnosis was compared to results obtained by definitive histology. Tumors were called incidentalomas if they consisted of a neoplastic focus with a low grade of aggressiveness, as demonstrated by dimension <5 mm, non-aggressive histological subtype. RESULTS: Of the 541 cases of benign disease, 417 were confirmed as benign. The other 124 cases are listed as follows: 29 follicular adenoma; 76 papillary carcinoma (35 found as incidentalomas), and 19 follicular carcinoma (3 incidentalomas). Cytology suggestive of papillary carcinoma was correct in 95.2% of cases (119/125). The 135 tumors termed "follicular neoplasm" were staged on pathology thus: 56 adenoma (41.4%), 26 carcinoma (19.2%), 13 (9.6%) absence of follicular proliferation, 38 (28.1%) papillary follicular variant, 2 (1.4%) undifferentiated cells. Medullary carcinomas were both confirmed. The "suspicious group" exhibited no malignancy on fine needle aspiration cytology (12 of 21; 57%). CONCLUSIONS: Cytology has good reliability in malignant lesions. Incidental tumors occurring in benign disease have little impact on clinical and surgical management; "follicular neoplasm" posed two problems - the impossibility of identifying the nature of the tumor, as well as the newer difficulty in distinguishing papillary follicular subtype.

Inferior epigastric artery pseudoaneurysm secondary to port placement during a robot-assisted laparoscopic radical cystectomy.

Pseudoaneurysm occurs when the artery wall is damaged and the blood is contained by the surrounding tissues with the eventual formation of a fibrous sac communicating with the artery. We report a case of a 74-year-old man with inferior epigastric artery (IEA) pseudoaneurysm secondary to an 8-mm port placement during a robot-assisted laparoscopic radical cystectomy with ureteroileocutaneostomy. The pseudoaneurysm was initially diagnosed by contrast-enhanced ultrasound (CEUS); subsequently, a computed tomography (CT) scan and an angiography test were performed. The pseudoaneurysm was then treated successfully with embolization of the inferior epigastric artery. Awareness of this rare complication is of clinical importance to avoid excessive morbidity of affected individuals.

A rare case of renal tumor in children: clear cell sarcoma.

Clear cell sarcoma of the kidney is an uncommon renal neopla sm of childhood. It represents about 4% of childhood malignant neoplasms and is generally more common in children under 5 years of age. In the present article, we describe the case of a 12-year-old male patient who came to our observation with left renal mass and with a clinical-laboratory picture indicative of inflammatory pathology.

Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function.

Loss of von Hippel Lindau (VHL) protein function is a key driver of VHL diseases, including sporadic and inherited clear cell renal cell carcinoma. Modulation of the proteostasis of VHL, especially missense point-mutated VHL, is a promising approach to augmenting VHL levels and function. VHL proteostasis is regulated by multiple mechanisms including folding, chaperone binding, complex formation and phosphorylation. Nevertheless, many details underlying the regulations of VHL proteostasis are unknown. VHL is expressed as two variants, VHL30 and VHL19. Furthermore, the long-form variant of VHL was often detected as multiple bands by western blotting. However, how these multiple species of VHL are generated and whether the process regulates VHL proteostasis and function are unknown. We hypothesized that the two major species are generated by VHL protein cleavage, and the cleavage regulates VHL proteostasis and subsequent function. We characterized VHL species using genetical and pharmacological approaches and showed that VHL was first cleaved at the N-terminus by chymotrypsin C before being directed for proteasomal degradation. Casein kinase 2-mediated phosphorylation at VHL N-terminus was required for the cleavage. Furthermore, inhibition of cleavage stabilized VHL protein and thereby promoted HIF downregulation. Our study reveals a novel mechanism regulating VHL proteostasis and function, which is significant for identifying new drug targets and developing new therapeutic approaches targeting VHL deficiency in VHL diseases.

Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone. A possible consequence of a destructive process in the thyroid.

Amiodarone is an iodine-rich drug used in the treatment of resistant cardiac arrhythmias. Amiodarone-induced thyrotoxicosis (AIT) is well recognized and is generally believed to be due to the excess iodine released from the metabolism of the drug, although amiodarone-associated thyroiditis has occasionally been observed. We report the clinical, laboratory, and therapeutic course of nine patients with AIT. The thyrotoxic phase was often followed by mild hypothyroidism during and after antithyroid drug or corticosteroid therapy. The thyroid was tender to palpation in two patients and a fine-needle aspiration biopsy of the thyroid revealed changes consistent with thyroiditis in three patients who underwent biopsy. These findings strongly suggest that the etiology of AIT, at least in some patients, is due, in part, to drug-induced inflammatory changes in the thyroid, as has been reported to occur in lung, bone marrow, and testes. Thus, the AIT may be due to excess iodine, drug-induced thyroiditis, or a combination of the two. The favorable response of AIT to corticosteroids in occasional patients previously reported also suggests that acute thyroiditis was probably present.

Graves' disease and thyroxine-binding globulin deficiency.

Thyroxine-binding globulin (TBG) deficiency has been frequently described in single patients and in many families. Most people with abnormal TBG concentrations are euthyroid. Cases of Graves' disease and TBG deficit have rarely been reported. We describe the case of a person with Graves' disease and TBG deficiency. Because of this condition, the patient had a misdiagnosis during part of his clinical history, and therefore underwent unnecessary therapy.

The effect of diltiazem, a calcium channel-blocking drug, on cardiac rate and rhythm in hyperthyroid patients.

Tachycardia and tachyarrhythmias are frequent in patients with thyrotoxicosis, especially in the elderly. Since myocardial calcium uptake is increased in thyrotoxic rats, the efficacy of the calcium channel-blocking drug diltiazem in decreasing heart rate and the incidence of arrhythmias was evaluated in 11 hyperthyroid patients. All patients were studied with a 24-hour Holter monitor prior to the beginning of sole diltiazem therapy (120 mg given every eight hours), on the tenth day of therapy, and five days after therapy was discontinued. Heart rate significantly decreased by 17% during diltiazem treatment (96.5 +/- 3.7 systoles/min vs 79.9 +/- 3.2 systoles/min [mean +/- SE]) and returned to baseline values five days after the therapy was discontinued (100.7 +/- 3.4 systoles/min). Similarly, the number of premature ventricular extrasystoles per hour was significantly decreased (18 +/- 7 vs 2 +/- 1). In three patients, asymptomatic bouts of supraventricular tachycardia, paroxysmal atrial fibrillation, or ventricular tachycardia disappeared during diltiazem therapy. These findings suggest that calcium-blocking drugs may be extremely useful as adjunctive therapy for thyrotoxicosis in the presence of angina, congestive failure, and tachyarrhythmias.

Iodine-induced hypothyroidism in euthyroid subjects with a previous episode of subacute thyroiditis.

The effects of the administration of pharmacological quantities of iodide on thyroid function in 18 euthyroid patients with a previous history of painful subacute thyroiditis (SAT) were evaluated, and the results compared to those of iodide administration to 12 euthyroid patients with a previous history of thyroid surgery (TX) for benign nodular thyroid disease. After baseline thyroid function tests, saturated solution of potassium iodide (SSKI; 10 drops; 300 mg iodide) was administered daily for 120 days, and serum T4, T3, and TSH concentrations were assessed 15, 30, 60, 90, 120 days and 2-4 months after SSKI was discontinued. Iodide perchlorate discharge tests were carried out before SSKI administration, and TRH tests were performed on the last day of iodide administration. Two SAT subjects developed clinical evidence of hypothyroidism with markedly elevated serum TSH concentrations, and SSKI was discontinued on days 60 and 90, respectively. Thirteen of 18 SAT patients had at least 1 abnormal thyroid function test (iodide perchlorate discharge test, elevated serum TSH concentration, and abnormal TSH response to TRH) compared to 2 of 12 TX patients. These findings strongly suggest that euthyroid subjects with a previous history of SAT are prone to develop iodide-induced hypothyroidism, suggesting that subtle abnormalities in the thyroid organification of iodide and subsequent thyroid hormone synthesis persist years after the episode of SAT.

Effects of chronic iodine administration on thyroid status in euthyroid subjects previously treated with antithyroid drugs for Graves' hyperthyroidism.

In view of the adverse effects of the administration of pharmacological quantities of iodine to euthyroid patients with a history of a wide variety of thyroid disorders, it has been suggested that iodine-containing medications and radioopaque dyes containing iodine should be avoided, if possible, in patients with underlying thyroid disease. We have now prospectively studied the effects of pharmacological doses of a saturated solution of potassium iodide (SSKI) on thyroid function in euthyroid patients with a previous history of hyperthyroid Graves' disease successfully treated with antithyroid drugs. Ten euthyroid women (mean age, 56 yr) who had hyperthyroid Graves' disease successfully treated with methimazole 36.4 +/- 4.7 months earlier were evaluated before, during, and after the administration of 10 drops SSKI daily for 90 days. The following thyroid function tests were obtained: serum T4, T3, TSH, TSH receptor antibody (TSH-RAb), and antithyroid peroxidase antibody (AbTPO) concentrations; TRH tests; and iodine perchlorate discharge tests. Serum T4, T3, basal and TRH-stimulated TSH, and TSH-RAb values were normal before SSKI administration, but serum AbTPO levels were markedly positive in 7 and iodine perchlorate discharge tests were positive in 4 of these 10 women. During SSKI administration, basal and TRH-stimulated serum TSH values increased above normal in 2 women with normal serum T4 and T3 concentrations; thyroid hormone values and TRH tests were normal in the other 8 patients and similar to values observed in 4 euthyroid women without a history of thyroid disease given SSKI. Serum AbTPO increased slightly, but significantly, during SSKI administration in the 7 women with positive values at baseline (P < 0.05). TSH-RAb remained undetectable. After SSKI withdrawal, the 10 women were reevaluated 60 and 120 days later. Two women developed a blunted TSH response to TRH, but normal serum T4 and T3 concentrations, and 2 women developed overt hyperthyroidism, with undetectable basal and TRH-stimulated serum TSH and elevated serum T4 and T3 concentrations, requiring methimazole therapy. All values in the remaining 6 women were similar to those present before SSKI administration. These results suggest that some euthyroid patients with a history of antithyroid drug therapy for Graves' disease may develop thyroid dysfunction during and after excess iodine administration. The development of subclinical hypothyroidism during SSKI administration was not clinically important, but the occurrence of overt hyperthyroidism after SSKI was discontinued did require antithyroid drug therapy. It is advisable, therefore, to avoid iodine-containing substances in euthyroid patients with a history of antithyroid drug therapy for Graves' disease.

Impaired intrathyroidal iodine organification and iodine-induced hypothyroidism in euthyroid women with a previous episode of postpartum thyroiditis.

Postpartum thyroiditis (PPT) is common and occurs in 1.7 to 16.7% of pregnant women, depending upon the study population. Most of these women develop transient hypothyroidism and thyroid function usually returns to normal. We have studied 11 euthyroid women with a previous history of PPT to determine the incidence of subtle defects in thyroid function measured by iodide-perchlorate (I-ClO4) discharge tests and TRH tests and to determine whether these women would develop iodide-induced hypothyroidism. Seven (64%) had positive I-ClO4 discharge tests and 5 (46%) had an abnormally high TSH response to TRH. Thyroid antimicrosomal and antithyroid peroxidase were positive in 8 women (73%) with a previous episode of PPT. The administration of pharmacological amounts of iodide (10 drops of saturated solution of potassium iodide daily) for 90 days to these 11 women resulted in elevated basal and TRH stimulated serum TSH concentrations in 8 (72.7%) compared to TSH values during iodide administration to women who had never been pregnant. Antimicrosomal and antithyroid peroxidase concentrations did not change during iodide administration. These findings strongly suggest that euthyroid women with a previous episode of PPT have permanent subtle defects in thyroid hormone synthesis and are inordinately prone to develop iodide-induced hypothyroidism, similar to findings previously reported in euthyroid subjects with Hashimoto's thyroiditis, with a previous episode of painful subacute thyroiditis, or previously treated with radioactive iodine or surgery for Graves' disease.

Iodine-induced subclinical hypothyroidism in euthyroid subjects with a previous episode of amiodarone-induced thyrotoxicosis.

Amiodarone-induced thyrotoxicosis (AIT) occurs most frequently in patients with underlying thyroid disease and is generally believed to be due to the iodine contamination of amiodarone and iodine released by the metabolism of the drug. We and others have suggested that the thyrotoxicosis may also be secondary to amiodarone-induced thyroiditis. To further determine the etiology of AIT, we administered large doses of iodides [10 drops saturated solution of potassium iodide (SSKI) daily] to 10 euthyroid patients long after an episode of AIT believed to be due at least in part to amiodarone-induced thyroiditis. Six of these 10 patients had an abnormal iodide-perchlorate discharge test before SSKI administration, indicating a subtle defect in the thyroidal organification of iodide. During SSKI administration, 6 patients developed marked iodine-induced basal and/or TRH-stimulated serum TSH elevations, 2 had suppressed basal and TRH-stimulated TSH values, and 2 had normal TSH responses compared to SSKI-treated euthyroid subjects with no history of amiodarone ingestion or thyroid disease. Serum T4 and T3 concentrations remained normal and unchanged during SSKI administration in both the AIT patients and control subjects. These results strongly suggest that excess iodine may not be the cause of the hyperthyroidism associated with amiodarone therapy, especially in those patients with probable amiodarone-induced thyroiditis. Furthermore, like patients with a previous history of subacute thyroiditis and postpartum thyroiditis, the present results suggest that some patients with a previous history of AIT may be at risk to develop hypothyroidism when given excess iodine.

The study of visual evoked potentials in patients with thyroid-associated ophthalmopathy identifies asymptomatic optic nerve involvement.

In the present study we have recorded visual evoked cortical potentials (VECP) in 88 patients affected by autoimmune thyroid disease and thyroid-associated ophthalmopathy (TAO) without clinical signs of optic neuropathy. At the time of ophthalmological examination, 37 of these patients were hyperthyroid, 41 were euthyroid, and 8 were hypothyroid; 2 were not assessed. Twenty-nine normal subjects served as controls. We performed pattern reversal visual stimulation and recorded the amplitude and latency of the cortical electric response at 100 ms (P100 wave). There were no differences in the mean P100 amplitude of TAO patients and normal subjects. The mean P100 latency in patients was 105.6 +/- 0.5 ms, significantly higher than that in normal subjects (102.0 +/- 0.5 ms; P < 0.00003). Latency in euthyroid patients did not differ from that in either hypo- or hyperthyroid patients. The VECP test was positive (latency, > or = 110.0 ms) in 21 (23.8%) TAO patients. In patients with proptosis greater than 21 mm, latency was 106.7 +/- 0.7 ms, significantly higher than that in patients with normal Hertel measurements (104.3 +/- 0.6 ms; P < 0.01). Latency was not increased in patients with acute inflammatory signs compared to those with inactive eye disease and in patients with altered extrinsic motility. In patients with an abnormal visual field study, the mean latency was 110.3 +/- 1.5 ms, significantly higher than that in patients with a normal visual field (104.7 +/- 0.4; by t test, P < 0.000003). In conclusion, we observed a prolongation of the latency of the evoked cortical response in patients with TAO without subjective visual complaints and without optic nerve compression. We believe that the study of VECP in TAO is complementary to the study of the visual field in identifying early optic nerve dysfunction in the absence of decreased visual acuity.

The iodine perchlorate discharge test before and after one year of methimazole treatment of hyperthyroid Graves' disease.

We have recently reported that many euthyroid patients with a history of Graves' disease treated years earlier with methimazole (MMI) have a positive iodide (500 micrograms)-perchlorate discharge test (I-ClO4 test), suggesting a permanent thyroid iodide organification defect. We now report the results of the I-ClO4 test in patients with hyperthyroid Graves' disease before beginning a 1-yr course of MMI therapy and 40 days after MMI was discontinued. Twenty-nine patients (25 women and 4 men; mean age, 38 +/- 1.7 yr) with their first episode of hyperthyroid Graves' disease were studied. Before MMI therapy, I-ClO4 tests were carried out, and serum T4, T3, and TSH were measured to confirm the diagnosis of hyperthyroidism. A positive I-ClO4 test is defined as more than 15% 131I discharged from the thyroid 1 h after the administration of 1 g KClO4. Patients were then treated with 20 mg MMI for the first 2 months and variable doses thereafter for the next 10 months to maintain euthyroidism. Serum T4, T3, and TSH were measured monthly. Forty days after MMI was discontinued, I-ClO4 tests were repeated, and serum T4, T3, and TSH were measured every 2 months thereafter. Before MMI treatment, the I-ClO4 test was positive in 20 of 29 patients (69%) and negative in 9. The favorable responses (normal serum T4 and T3 values) to MMI therapy were similar in both groups. We have thus far studied 16 patients after MMI was discontinued and 9 of 12 patients (75%) with a negative I-ClO4 test after MMI therapy, and 1 of 4 patients (25%) with a positive test remained in remission for a mean of 7 months. We conclude that the I-ClO4 test is frequently positive in patients with untreated hyperthyroid Graves' disease, suggesting either an inability to organify the increased iodide concentrated by the hyperfunctioning gland or the concomitant presence of Hashimoto's thyroiditis, which almost always is associated with a positive I-ClO4 test. The former hypothesis is more likely, because many patients with a positive I-ClO4 test before MMI therapy had a negative test after MMI was discontinued.

Increased serum concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor in patients with Graves' disease.

Increased serum interleukin-6 (IL-6) concentrations have been reported in patients with thyroid destructive processes. In the present study we measured IL-6 and soluble IL-6 receptor (sIL-6R) concentrations in the serum of normal subjects and patients with Graves' disease using a high sensitivity sandwich enzyme-linked immunoassay. We found increased serum IL-6 and sIL-6R concentrations (69.3 fmol/L, and 964 pmol/L, respectively) in 49 hyperthyroid patients with Graves' disease (GD) compared to those in controls [55.8 fmol/L (P = 0.019) and 772 pmol/L (P = 0.007), respectively]. In 31 newly diagnosed GD patients, serum concentrations of IL-6 and sIL-6R during the hyperthyroid phase were elevated, and after therapy with methimazole only, serum sIL-6R concentrations returned to normal (940 vs. 726 pmol/L; P < 0.001) but serum IL-6 did not. Serum sIL-6R concentrations (mean +/- 2 SD) were higher in GD patients with active inflammatory thyroid-associated ophthalmopathy than those in patients with inactive or absent thyroid-associated ophthalmopathy (P < 0.05). In conclusion, we have demonstrated activation of the IL-6 system in GD and, for the first time, have measured and found increased serum sIL-6R concentrations in hyperthyroid GD patients.

Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha.

OBJECTIVE: Recombinant human interferon-alpha (r-IFN-alpha) is often successfully used in the treatment of patients with chronic viral hepatitis B and C. Thyroid dysfunction has been reported to occur with variable frequency during r-IFN-alpha therapy especially in patients with preexisting thyroid autoimmunity. We have prospectively evaluated the effect of r-IFN-alpha on various aspects of thyroid function in patients with HCV chronic hepatitis. DESIGN: Thirty-two patients with HCV chronic active hepatitis were studied prospectively before and during r-IFN-alpha therapy. Serum TSH, FT4, FT3, and thyroid receptor (TSR) and thyroid peroxidase (TPO) antibodies, and the iodide-perchlorate discharge test (I-C10(4)) to detect subtle defects in the thyroid organification of iodide were carried out during the study. Thyroid radioactive iodine uptakes (RAIU) were obtained in patients who developed thyrotoxicosis. RESULTS: All patients were clinically and biochemically euthyroid prior to r-IFN-alpha therapy with negative I-C10(4) discharge tests. Four patients became thyrotoxic, 3 secondary to destructive or inflammatory thyroiditis with a low thyroid RAIU, and 1 patient developed hypothyroidism. The I-C10(4) discharge test became positive in 7 of the 32 patients studied prospectively; 5 of these patients did not develop other evidence of thyroid dysfunction and did not have positive TPO antibodies. In these 5 patients the test became negative after r-IFN-alpha was discontinued. Appropriate therapy of the patients with thyrotoxicosis (methylprednisolone for 3 patients with destructive thyroiditis and methimazole for 1 patient with hyperthyroidism) or with hypothyroidism (L-thyroxine) was successful. CONCLUSIONS: Thyroid dysfunction, especially destructive or silent thyroiditis resulting in thyrotoxicosis, is not infrequently observed in patients receiving r-IFN-alpha therapy for chronic active hepatitis. Although underlying autoimmune thyroid disease appears to predispose patients to develop thyroid dysfunction, other patients become thyrotoxic or hypothyroid in the absence of baseline positive TPO-Ab. Subtle defects in the thyroidal organification of iodine as determined by the I-C10(4) discharge test, in the absence of autoimmune thyroid disease, was observed in 5 patients who remained euthyroid, suggesting that r-IFN-alpha directly reduces the intrathyroidal organification of iodine.

Serum concentrations of proinflammatory cytokines in Graves' disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking.

OBJECTIVE: In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) in the serum of patients with Graves' disease (GD). By multivariate analysis, we have evaluated the effect of antithyroid treatment, thyroid function, the presence or absence of active thyroid-associated ophthalmopathy (TAO), the patient's smoking habits and the relation to circulating anti-thyrotropin (TSH) receptor (TRAb) and anti-thyroperoxidase antibodies (TPOAb). SUBJECTS: We studied 84 GD patients, 51 untreated and 33 receiving methimazole (MMI) therapy. Twenty-three (45%) untreated patients and 18 (54%) patients on MMI had active TAO. We also studied 67 normal subjects as controls. Thirty-one GD patients (43%) and 16 controls (36%) were smokers. RESULTS: Serum IL-6 concentrations were significantly higher in both untreated patients (P<0.001) and treated patients (P<0.006), when compared with controls. Serum sIL-6R concentrations were significantly affected by treatment (P=0.001). Serum IL-1Ra concentrations were not different in GD patients, whether treated or untreated, compared with controls. Serum IL-6 concentrations were not influenced by thyroid function and there was a significant interaction between treatment and the presence of active TAO (P=0.003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were significantly higher than in those with inactive TAO (P=0.003). In untreated GD patients there was no significant effect of thyroid function and TAO activity on the serum concentrations of TNF-alpha and IL-1 beta. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-alpha, IL-1 beta and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-alpha and IL-1 beta and IL-1Ra were not different in patients with and without TRAb or TPOAb, in relation to either thyroid function, TAO activity or smoking. CONCLUSIONS: Our work shows that: (i) the proinflammatory cytokine pattern in GD is greatly influenced by antithyroid drug treatment; (ii) the increased circulating IL-6/sIL-6R concentrations observed in patients with active TAO may derive from the activation of humoral reactions in sites other than the thyroid; and, (iii) cigarette smoking has no effect on serum IL-1/IL-1Ra concentrations in TAO.

Echographic diagnosis of pretibial myxedema in patients with autoimmune thyroid disease.

In the present study we have evaluated the use of pretibial ultrasound for the diagnosis of pretibial myxedema (PTM). We studied 76 patients, 58 with Graves' disease, 13 with Hashimoto's thyroiditis and five with idiopathic hypothyroidism. Thirty-two normal subjects were also studied as controls. Sixty-four patients had associated ophthalmopathy. The ultrasound scanner was equipped with 10- and 13-MHz probes. Punch biopsies were carried out in 11 patients and tissue sections examined on a light microscope. On clinical examination 21 patients (28%) had suspected PTM. By ultrasound, we measured the thickness of dermis and subcutaneous tissue (D1) and that including only deeper dermis (D2) in normal subjects to define the echographic parameters of normal pretibial skin. We then found increased skin thickness in 25 patients (33%), with mean D1 and D2 values significantly higher than those measured in controls (p < 0.00001). The echographic study was positive in 20 patients with ophthalmopathy (31%). Ultrasound showed increased skin thickness in 16 of 21 patients (76%) with clinically suspected PTM. Histopathological findings confirmed the presence of PTM in all the patients who underwent pretibial skin biopsy. We believe that the measurement of pretibial skin thickness by ultrasound may be useful for revealing the presence of PTM.

Circadian thyrotropin variations are preserved in normal pregnant women.

Serum thyrotropin (TSH) concentration circadian rhythm is abolished in many endocrine and non-endocrine 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 < 0.02 and p < 0.005, respectively). In summary, second and third trimester pregnancy is associated with a normal circadian TSH rhythm.

Sodium ipodate and methimazole in the long-term treatment of hyperthyroid Graves' disease.

A prospective study was conducted to evaluate the effect of prolonged treatment of hyperthryoid Graves' disease with methimazole (MMI) for 12 months or Na ipodate for only 6.6 +/- 1.1 months, since the drug had to be discontinued because of persistent or recurrent hyperthyroidism during treatment. The eight patients who were treated with MMI alone for 12 months became euthyroid, and seven remained in remission for at least 6 months after MMI was discontinued. In contrast, only two of 10 patients treated with Na ipodate alone became euthyroid and remained so during therapy. No ipodate was discontinued in the eight patients who did not respond, and they were then treated with MMI. One patient had recurrent hyperthyrodism after NA ipodate was discontinued, and she was then treated with MMI. MMI was efficacious in treating these nine patients, and all patients were euthyroid by the third month of MMI administration. Five of these nine patients remained euthyroid for at least 6 months after MMI was discontinued, a remission rate that was not significantly different from that observed in the eight patients treated only and initially with MMI (Fisher's Exact Test). There was no significant change in serum thyroid peroxidase antibodies during treatment with MMI alone, Na ipodate alone, or Na ipodate followed by MMI.(ABSTRACT TRUNCATED AT 250 WORDS)