Damiano Gullo

Levothyroxine and Potassium Iodide Are Both Effective in Treating Benign Solitary Solid Cold Nodules of the Thyroid

The prevalence of thyroid nodules in the general population has been estimated to be approximately 5% by neck palpation and as much as 30% to 50% by ultrasonography [1, 2]. Because most nodules are cold at scintigraphy, the management of cold thyroid nodules is a common presenting problem both to endocrinologists and general internists. Evaluation by fine-needle aspiration biopsy indicates surgical removal only for approximately 5% of cases because of malignancy and in 10% to 20% of cases (those with follicular lesions) because malignancy cannot be excluded [1-5]. Clinical evaluation may suggest the need for surgery in an additional 5% of patients [6, 7]. Thus, most cold thyroid nodules (70% to 80%) are managed medically. Until recently, most clinicians would have treated these patients with levothyroxine at thyroid-stimulating hormone (TSH)suppressing doses because TSH is the major thyroid stimulator for both function and growth [8, 9]. Thus, TSH suppression would be expected to cause either nodule reduction or growth inhibition [10, 11]. In the last 5 years, however, study findings have challenged this policy: Two randomized, controlled studies in which ultrasonography was used to evaluate nodule volume changes failed to prove the efficacy of levothyroxine [12, 13]; and recent reports of bone mineral density decreases in patients treated with levothyroxine have raised concern about the riskbenefit ratio of levothyroxine administration [14-16]. General clinical experience, however, and previous open, noncontrolled studies [10, 11] indicate that at least some cold nodules decrease in size when treated with levothyroxine. This controversy suggests the need for further randomized clinical trials of levothyroxine treatment. Because potassium iodide, either alone or in combination with levothyroxine, is used outside the United States for treating diffuse and nodular goiter caused by iodine deficiency [17-19] and for treating sporadic goiter [20], we tested iodide treatment in patients with solitary cold thyroid nodules. Methods Patients and Study Design We enrolled euthyroid patients with benign solitary solid cold nodules of the thyroid who were referred to our thyroid clinic. We first selected patients who had a solitary thyroid nodule and no major concomitant disease at clinical examination. Radioiodine scanning and ultrasound examination of the thyroid (Diasonics DRF 250 ultrasound scanner equipped with a linear 10-MHz probe; Sonotron SA, Les Ulis Cedex, France) and fine-needle aspiration biopsy of the nodule were then done. Because of the probe used, the accuracy of measures by ultrasonography could be obtained only for nodules with a diameter of 3.5 cm or less; we therefore excluded patients with larger nodules. We also measured the following in all patients: levels of serum thyroxine, total triiodothyronine, free triiodothyronine, and free thyroxine sub (commercial radioimmunoassay methods); TSH and thyroglobulin levels (immunoradiometric methods); antithyroglobulin and antimicrosomal antibodies (hemoagglutination method); and urinary iodine levels (colorimetric method). We included only newly diagnosed nodules (recognized less than 1 year before the study began). Using ultrasonography, we measured nodule size in three planes and recorded it on film. Nodule volume was calculated according to the following formula for a spherical ellipsoid: volume = (/6) x AP x width x length, where AP is the anteroposterior diameter [21]. For each patient, ultrasound measurements were done by the same operator, who had no access to the patients clinical and laboratory data or group assignment. Intraobserver variation of nodule measurement was assessed before the study began by a pilot investigation of 25 patients with a thyroid nodule. In these patients, nodules were measured twice at baseline and after 20 to 30 days, resulting in a weighted statistic of 99.9% [22]. We selected only solid nodules, including nodules with absent or minimal (<10%) cystic component. In addition, we carefully examined both thyroid lobes for the presence of additional nodules. Patients with a second thyroid nodule not evident at physical examination were included if the maximum diameter of the second nodule did not exceed 50% of the maximum diameter of the main nodule. We also measured contralateral thyroid lobe diameters and recorded the data [23]. A radioiodine scan (25 microcuries) was done in all patients to exclude all hot nodules, which are usually autonomous and unresponsive to medical treatment [24]. A fine-needle aspiration biopsy examination was then done as previously described [3]. Patients with a cytologic diagnosis of malignancy, follicular lesion, cyst-hemorrhagic lesion, or thyroiditis were excluded; we selected only colloid-parenchymatous nodules that showed colloid and benign follicular cells in variable proportion. In addition, we excluded patients with abnormal thyroid hormone or TSH serum levels, circulating thyroid antibodies, or concomitant cardiovascular or liver diseases, osteoporosis, or pregnancy. All patients lived in an area with a sufficient iodine supply and a goiter prevalence in schoolchildren of less than 1%. Urinary iodine excretion in this area ranges from 80 to 300 g/d. However, because iodine intake may affect nodule growth and response to therapy, the urinary iodine concentration of our patients was measured in a urine sample taken in the morning. Urinary iodine excretion less than 8.0 g/dL or exceeding 27.0 g/dL was a criterion for exclusion. Patients selected by these procedures gave informed consent and entered the study. We then randomly assigned patients to receive one of three treatments [using randomized blocks with a coin slightly biased in favor of treatment groups and with allocation blinded only to the ultrasonography operator]: 1) no treatment; 2) oral levothyroxine at an initial dose of 1.0 g/kg body weight per day to be taken in one single dose in the morning; and 3) oral iodine supplementation at 1.5 mg every 2 weeks, provided as potassium iodide tablets. For patients in the second group, the dose was increased to 1.8 g/kg per day after 15 days and then individually adjusted after the first 4 months to allow a serum TSH level less than normal values (<0.3 mU/L). At that point, the average levothyroxine dosage was 1.94 0.16 g/kg per day. Each treatment was continued for 12 months. Patients were evaluated at 4-month intervals by clinical and ultrasound examination. Levels of free triiodothyronine, free thyroxine, TSH, thyroglobulin, urinary iodine excretion, and antithyroid antibodies were also measured every 4 months. Compliance with therapy was individually controlled in patients receiving levothyroxine by carefully asking the patient and by measuring TSH serum levels at 4-month intervals. Urinary iodine was also measured in all patients at 4-month intervals to check both treatment compliance (in patients receiving potassium iodide) and the absence of iodine contamination in patients receiving no treatment and in those receiving levothyroxine. End Points We considered two end points: 1) the type of nodule volume variation from 0 to 12 months and 2) a nodule reduction of 50% of the initial volume after the 12-month observation period. Sample Size According to a previous report [12], a spontaneous decrease of 50% or more of the initial volume could be assumed to occur in 20% of patients. We therefore considered therapy successful when it caused a similar ( 50%) volume reduction at least 2.5 times more frequently than occurred with no treatment. Given a type I error of 0.05 (two-sided) and a power of 0.9 and considering that approximately 10% of patients might be lost to follow-up, we estimated the necessary total sample size to be 160 patients. Statistical Analysis We planned an interim analysis of the results after 12 months of observation for the first half of the patients who entered the study. Because nodule volumes were distributed in a skewed manner, appropriate transformation such as logarithms were applied to these data for statistical inference, and proper means (that is, geometric means) were used to describe results. We evaluated the statistical significance of nodule size variation in the three groups by repeated-measures analysis [25] and considered data obtained at months 0, 4, 8, and 12 from patients who completed 1 year of follow-up. We then fitted a linear random-effects model with a structured variance-covariance matrix to each loge-volume profile at 0, 4, 8, and 12 months of observation and considered such covariates as group assignment (no treatment, levothyroxine, or potassium iodide), patient age (in years), cytologic findings (colloid or parenchymatous nodular hyperplasia), and echographic patterns (hypoechogenic, isoechogenic, hyperechogenic, or mixed nodules). We subsequently fitted a second model to the same data, also taking into account the nodule volume class ( 5 mL, 5.1 to 10 mL, or >10 mL). We used the BMDP statistical package (Statistical Software, Inc., Los Angeles, California). We used a log-linear model [26] to test differences in the proportion of volume reduction by the GLIM statistical package (Royal Statistical Society, London, United Kingdom). A paired t-test was used for comparisons between values before and after 12 months of therapy. Every test of hypothesis was done at a 0.05 level of significance (two-sided). Results The study was stopped because at the interim analysis, we obtained clinically important results for the first 80 patients who entered the study; we did not include 18 patients who were still being studied at the time of interim analysis. After randomization, the characteristics of these 80 patients and their nodules were homogeneous in the three groups, and we saw no statistical differences (Table 1). Twelve nodules evenly distributed among the three groups had a cystic component of less than 10%. Of the 80 patients, 70 (87.5%) complete

Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients

Context Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients. Objective To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback. Design Retrospective study. Setting Academic hospital. Patients 1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls. Measurements TSH, FT4 and FT3 concentrations by immunoassays. Results FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients. Conclusions Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.

Effects of High Glucose on Insulin Secretion by Isolated Rat Islets and Purified β-Cells and Possible Role of Glycosylation

We investigated the effect of 24 h of exposure to various glucose concentrations on insulin secretion by isolated rat pancreatic islets and purified rat β-cells. Compared with islets cultured with standard medium (5.5 mM glucose), islets cultured with 16.7 mM glucose showed a higher basal insulin release (means ± SE, 3.0 ± 0.5 vs. 0.7 ± 0.2%, n = 8, P < .005) and reduced glucose-stimulated insulin secretion (2.4 ± 0.3 vs. 5.8 ± 0.4%, n = 8, P < .005). Similar results were also obtained with purified β-cells. The effect of high glucose was time dependent (present after 12 h, maximal after 24 h) and reversible: when islets cultured with high glucose were transferred to standard medium, normal responsiveness to glucose was restored within 8 h and normal basal release within 24 h. Mannitol, 3-O-methylglucose, and 2-deoxyglucose were not able to mimic the effects of glucose. Islets or purified β-cells cultured in the presence of high glucose had a normal response when stimulated with glyburide, dibutyryl cyclic AMP, and isobutylmethylxanthine. Tunicamycin, an inhibitor of N-terminal glycosylation, prevented glucose-induced desensitization when added during 24 h of islet culture with 16.7 mM glucose. Swainsonine, another agent that influences glycosylation, had a similar effect. Our study indicates 1) that 24 h of exposure to high glucose induces a specific and reversible impairment of insulin secretion in response to glucose, 2) that this is a direct effect of glucose on β-cells, and 3) that islet glucose metabolism and glycosylation processes may play a critical role in determining glucose desensitization.

Maternal hypothyroxinaemia during the first half of gestation in an iodine deficient area with endemic cretinism and related disorders

OBJECTIVE Iodine deficiency is well known as the cause of several disorders such as endemic goitre and cretinism, along with a wide spectrum of psychoneurological development disorders including endemic mental deficiency and endemic cognitive deficiency, which are generally correlated to damage to the fetus. Such damage Is, by Inference, deemed a consequence either directly of iodine deficiency or of insufficient availability of thyroxine at the feto‐placental unit level. Early pregnancy represents the crucial period for neurogenesis in the embryo. Several experimental studies have emphasized the direct role of maternal T4 in neurological embryo‐genesis, before the onset of fetal thyroid function and, therefore, Its protective role In fetal thyroid failure. The objective of this study was to evaluate whether Iodine deficiency may Influence thyroid status of pregnant women throughout the first half of pregnancy.

Direct effects of biguanides on glucose utilization in vitro

The effect of the biguanides metformin and phenformin on glucose utilization in isolated cells was studied with IM-9 human lymphocytes. Both agents stimulated glucose consumption from the incubation media. Detectable effects of metformin were seen at 33 mumol/L and detectable effects of phenformin were seen at 1.7 mumol/L. Both agents, at similar concentrations, also stimulated [3H] 2-deoxy-D-glucose uptake. Studies with phenformin indicated that biguanides increase the Vmax of uptake without changing the Km. In contrast to the biguanides, IM-9 cells insulin did not influence either glucose consumption or [3H] 2-deoxy-D-glucose uptake. These data provide evidence, therefore, that biguanides may directly influence the cellular utilization of glucose.

Hashimoto's Thyroiditis: Similar and Dissimilar Characteristics in Neighboring Areas. Possible Implications for the Epidemiology of Thyroid Cancer

Context Medical centers worldwide report an increased frequency of Hashimotos thyroiditis (HT) and thyroid cancer (TC), two environmentally influenced diseases. In Sicily, data on HT are available for the province of Messina (1975–2005); data on TC are available for the whole island (2002–2004), with the volcanic province of Catania having the highest incidence. Objective To replicate in Catania, on comparable years, the HT data of Messina. Design, Methods, Setting Review of the clinical records of patients in years 1995–2005 to compare presentation and yearly changes of HT. During 1995–2005, records were computer stored in the Endocrine Divisions of the University Hospitals of Catania and Messina, two tertiary referral centers. Results Catania is outnumbered by Messina (742 vs. 3,409 HT patients). Similar were the linear increase in the yearly number of HT patients, rates of thyroid dysfunctions though with different proportions of subclinical and overt hypothyroidism, and rates of positiveness for TgAb or TPOAb. Different were age and its yearly trend; gender distribution and rates of the sonography variants, though yearly trends were similar. Conclusion The HT epidemics is smaller in Catania, with changes in presentation overlapping partially those in Messina. Whatever environmental factors might be involved, they (and/or their intensity) were not necessarily the same in these provinces. Intriguingly, the expected number of TC in HT patients with thyroid nodules in Catania is congruent with that of the general population of this province, but it is far less than in the Messina province. Thus, TC and HT incidences could be influenced by distinct environmental factors.

Metformin enhances certain insulin actions in cultured rat hepatoma cells

SummaryThe effect of the oral antidiabetic agent metformin on insulin regulation of glycogen metabolism, tyrosine-aminotransferase activity, and [1-14C]aminoisobutyric acid uptake was studied in H4IIE cultured rat hepatoma cells. Metformin enhanced both basal (from 0.213±0.016 to 0.262±0.024 nmol/mg protein,p<0.01) and insulin stimulated [3H] glucose incorporation into glycogen in a time-dependent and dose-dependent manner. A small effect of metformin was seen at 1 μmol/l, and its greatest effects were obtained at 10 μmol/l. At the same concentrations, metformin did not influence basal tyrosine-aminotransferase activity but it potentiated insulin stimulated tyrosine-aminotransferase activity (+ 29.2±1.4%,p<0.01) and prevented the loss of tyrosine-aminotransferase responsiveness to insulin in H4IIE cells desensitised by a previous exposure to insulin. In contrast, metformin had no effect on basal or insulin-stimulated [1-14C]aminoisobutyric acid uptake. Over the concentrations of metformin that enhanced insulin action in H4IIE cells, the drug had no significant effect on insulin binding to its receptor. These studies suggest, therefore, that metformin may influence cellular metabolism by potentiating certain insulin actions through mechanisms that may be beyond insulin receptor binding.

Chronic exposure to glibenclamide impairs insulin secretion in isolated rat pancreatic islets

We investigated the effect of 24 h exposure to 100 nmol/l glibenclamide on insulin secretion in isolated rat pancreatic islets. The insulin content was similar in control islets and in islets preincubated with 100 nmol/l glibenclamide for 24 h. In islets preexposed to glibenclamide: 1) the subsequent response to a maximal glibenclamide stimulatory concentration (10 µmol/l, 1 h at 37 C) was greatly reduced in comparison to control islets (0.69 ± 0.20 % vs 2.16 ± 0.41%; mean ± SE; n=14; p < 0.001); 2) the response to 100 µmol/l tolbutamide stimulation was also reduced (0.55 ± 0.15% vs 2.38 ± 0.44 %; n=8; p < 0.001); 3) the response to 16.7 mmo/l glucose, both in the presence or in the absence of 1 mmol/l IBMX, a phosphodiesterase inhibitor, was also diminished by about 50% (1.79 ± 0.39% vs. 3.22 ± 0.42%; n= 14, p < 0.001). In glibenclamide pretreated islets, blunted responses to stimuli were confirmed also by dynamic studies using a perifusion system. The effect of glibenclamide preincubation was fully reversible: when islets cultured in the presence of glibenclamide were transferred to a glibenclamide-free medium for further 24 h, insulin release in response to glibenclamide stimulation returned to control values. We conclude that prolonged exposure of rat pancreatic islets to glibenclamide induces a reversible desensitization to a variety of metabolic stimuli. The inhibition by prolonged glibenclamide exposure of a common pathway in the mechanism of insulin release is one possible explanation for these results.

Insulin autoimmune syndrome (Hirata Disease) in European Caucasians taking α-lipoic acid

Lipoic acid (LA) is a widely used nutritional supplement and is sometimes used as an adjuvant treatment for diabetic neuropathy and other conditions. Insulin autoimmune syndrome (IAS, Hirata disease) is a rare cause of spontaneous hypoglycaemia, extremely high serum insulin levels and high titres of autoantibodies against endogenous insulin despite no prior exposure to exogenous insulin. In Japanese individuals, IAS is associated with the human leucocyte antigen (HLA) HLA‐DRB1*04:06 allele and often occurs upon exposure to sulphhydryl‐containing compounds including LA. Only one case has been reported in Caucasians. We now report six Caucasian patients taking LA with IAS and describe a unique HLA subtype in these patients.

Healing of chronic necrobiosis lipoidica lesions in a Type 1 diabetic patient after pancreas-kidney transplantation : A case report

Necrobiosis lipoidica (NL) is a degenerative disease of dermal connective tissue of unknown etiology characterized by erythematous plaques preferentially localized to distal extremities. Skin lesions show a chronic relapsing nature. NL is often associated with diabetes mellitus and satisfactory treatment options are lacking. We describe the spontaneous healing of NL lesions after pancreas and kidney transplantation in a Type 1 diabetic patient with chronic NL recalcitrant to a variety of standard treatments. The 31-yr-old male patient had experienced NL lesions for more than 15 yr; despite various systemic and topical treatments, the skin lesions had pregressively enlarged. Because of end-stage renal disease, a simultaneous pancreas and kidney transplantation was performed and immunosuppressive therapy with tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisone was started. Pancreatic transplantation maintained satisfactory metabolic control with no need of exogenous insulin. After transplantation, skin lesions slowly healed without any specific treatment, leaving residual areas of fibrotic scars. A skin biopsy confirmed the absence of typical NL lymphocytic and histiocytic inflammatory response. Clinical remission of NL lesions may probably be explained by the concomitant effect of multiple-drug regimen for immunosuppression (TAC, MMF, and prednisone) and improved skin microcirculation secondary to the good metabolic control provided by pancreas transplantation.