New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH).

BACKGROUND: To perform genetic screening for ARMC5 gene germline pathogenic variants in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). SUBJECTS AND METHODS: In a group of 10 PBMAH patients, we performed complete sequencing of the coding region of the ARMC5 gene and MLPA analysis for large deletion detection. In subjects with the ARMC5 variant, we searched ARMC5 gene somatic variants on tumor samples. RESULTS: Among 10 PBMAH patients, we identified four ARMC5 germline variants (40%). One variant, c:174dupC p.Glu59Argfs*44, was already known; one variant p.Gly323Asp, was already reported and classified as likely disease-causing VUS (class 3-4); two variants p.Leu596Arg and p.Arg811Pro, were never reported before. For p.Gly323Asp and p.Arg811Pro, we identified second deleterious variants at the somatic level, enforcing the possible pathogenic effect of germline variants. CONCLUSIONS: Our results underscore the importance of performing genetic testing also in sporadic PBMAH patients and broaden the spectrum of molecular variants involved in PBMAH syndrome.

When and why patients drop out from benign thyroid nodules follow-up: a single centre experience.

PURPOSE: Drop-out in clinical long-term follow-up is a general problem that is potentially harmful to patients. No data about patients that drop out from thyroid ultrasound follow-up is available literature. The aim of the present retrospective study was to evaluate the characteristics of patients that dropped out from ultrasound thyroid nodule follow-up. PATIENTS AND METHODS: We reviewed medical records of all consecutive patients who underwent a fine needle aspiration from January 2007 to March 2009 in our department. All the patients with benign nodule(s) were recommended annual ultrasounds; patients who had dropped out from follow-up were included and a telephone interview was obtained to evaluate the reasons for dropping out. RESULTS: 289/966 (30%) of patients with benign nodules dropped out during follow-up; 94% of them within the first 5 years. Phone interviews were obtained from 201/289 (70%) of the patients. In the 57% of cases, the main declared reason for dropping out was nodular dimension stability during the first 2-3 years; 8.7% of them had forgotten about the appointment; 6.4% of subjects claimed to check only serum TSH, and 3.2% stated that they would undergo an ultrasound only if the nodule(s) were symptomatic. Finally, 10.7% patients continued follow-up in other centres. CONCLUSION: we showed that a third of patients miss their thyroid ultrasound follow-ups, and that the major cause is the low perceived threat coming from the disease. As a certain amount of drop-out is inevitable, attempting to reinforce our patients' awareness regarding their own health state is mandatory. TRIAL REGISTRATION: Trial registration: no. 4084.

Incidence of De Quervain's thyroiditis during the COVID-19 pandemic in an area heavily affected by Sars-CoV-2 infection.

PURPOSE: To evaluate the possible association between Covid-19 infection and subacute thyroiditis. METHODS: We reviewed the medical and imaging records of patients referred to our Department's outpatient setting dedicated to 'thyroid emergency' (records with a 'bollino verde'-green sticker, classifed as urgent) from April 2020 to October 2020. This outpatient clinic is devoted to patients requiring evaluation for severe hypothyroidism, thyrotoxicosis and neck discomfort or pain. All patients with a newly-diagnosed subacute thyroiditis were selected. The data of all patients receiving a diagnosis of subacute thyroiditis was collected retrospectively, taking into account the same period of time (April-October) and starting from 2016. RESULTS: During the COVID-19 outbreak in our region (April 2020 to October 2020) 396 patients attended the outpatient emergency clinic. Among them, 10 (2.5%) patients received a diagnosis of subacute thyroiditis. In a single patient, a 44-year-old man, a COVID-19 pulmonary infection had been diagnosed 7 weeks before the diagnosis of subacute thyroiditis. All of the remaining patients were and remain COVID-19 free as confirmed by telephone interview. The percentage of patients who received a diagnosis of subacute thyroiditis in the same period starting from 2016 was very similar (2.9%, 2.9%, 2.6% and 3.0% in 2016, 2017, 2018 and 2019, respectively). CONCLUSIONS: Our data do not show an increase in the incidence of subacute thyroiditis in the Brescia area, a region with the highest prevalence of COVID-19 in Italy during the period of the pandemic outbreak.

Ultrasound of benign thyroid nodules: A 120 months follow-up study.

OBJECTIVE: Some evidence suggests that most benign nodules exhibit no significant size increase during 5 years of follow-up, although conflicting results have emerged. The aim of the present study is to evaluate the frequency and the magnitude of growth in benign nodules during 120 months of follow-up. DESIGN: We reviewed the medical and imaging records of patients who were submitted to ultrasound-guided FNA of thyroid nodules at our hospital from January 2007 to March 2009. We selected only patients with benign nodules who underwent annual ultrasound evaluation in our Department. RESULTS: Among 966 selected patients, 289 were lost during follow-up, meaning that the total number of patients analysed was 677 (474 women and 203 men), with a mean age of 45.6 (16-71) years. In 559/677 patients (82.7%), the size of the nodule remained stable during follow-up; 42 (6.2%) patients experienced spontaneous nodule shrinkage, and 75 (11.1%) patients showed nodule growth. Patients with or without nodule growth during follow-up were superimposable at baseline for age, gender, TSH values, number of patients on levothyroxine treatment and nodule characteristics. All baseline variables in predicting nodular growth were entered to an adjusted multivariate logistic regression model. None of the parameters taken into account was associated with nodular growth. CONCLUSIONS: In conclusion, the majority of benign nodules remained stable over the period of monitoring. On the basis of our experience, we recommend ultrasound examination at a distance of 2 and 5 years following cytological evaluation, then every 4-5 years from then on.

A new self-administered semi-quantitative food frequency questionnaire to estimate nutrient intake among Italian adults: development design and validation process.

Food Frequency Questionnaires (FFQs) are valuable research tools in nutritional epidemiology. This study aimed to develop and validate a new semi-quantitative FFQ, specifically designed for the Italian population and best fitted for self-administration. During the development process, we adapted to Italian needs the validated FFQ proposed by the Fred Hutchinson Cancer Research Center, revising food items, food frequency scale, portion sizes, and time frame. To assess the validity of the proposed FFQ, we compared the estimated daily intake using FFQ with the mean of 3-day food diaries and one 24-hour recall (considered as reference method). The validation process was conducted among a cohort of 51 healthy subjects enrolled in a clinical trial. Four statistical tests were applied on 23 estimated nutrient intakes. Spearman's coefficients ranged from 0.223 (sodium) to 0.748 (alcohol) and were good (≥0.50) and acceptable (0.20-0.49) for 7 and 16 nutrients, respectively. Cross classification showed a good agreement (≥50% in the same tertile or ≤10% in the opposite tertile) for 7 nutrients. The weighted Cohen's kappa values indicated an acceptable outcome (0.20-0.60) for 13 nutrients. Bland Altman plots did not show heteroscedasticity in the error terms, despite the presence of a bias. Our study provided a new Italian semi-quantitative FFQ for self-administration with an acceptable validation level. Its definitive release requires additional refinements and efforts.

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy.

A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24-72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0-2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10. In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.

Could Serum TSH Levels Predict Malignancy in Euthyroid Patients Affected by Thyroid Nodules with Indeterminate Cytology?

BACKGROUND: Serum TSH levels in the upper-normal range were reported to be associated with increased risk of thyroid malignancy. However, measurement of TSH levels is currently not recommended for assessing the risk of malignancy in patients with newly diagnosed thyroid nodules. OBJECTIVE: To evaluate a possible relationship between the serum levels of TSH and the histological outcome of patients undergoing thyroidectomy for thyroid nodules with indeterminate cytology. MATERIALS AND METHODS: We collected the clinical data of all patients who had performed ultrasound-guided FNA of thyroid nodules with cytological diagnosis of indeterminate lesions (TIR3A and TIR3B) and serum TSH levels within the normal range. All patients had been submitted to thyroid surgery (hemi or thyroidectomy, as appropriate), and histological diagnosis had been performed. RESULTS: A histological diagnosis of thyroid malignancy was rendered in 74/378 (19.6%) nodules. Patients with histologically proven thyroid malignancy were characterized by higher serum levels of TSH as compared to patients with histologically proven benign nodules (3.03 ± 1.16 vs. 2.37 ± 1.19 mIU/L, p < 0.001). To further analyze the role of serum TSH in predicting thyroid cancer, patients were stratified in 4 groups according to quartiles of TSH concentrations. The prevalence of malignancy was 12.2% for the first quartile and 50.0% for the last quartile. ROC curve analysis identified that a serum TSH level of ≥2.7 mIU/L predicted thyroid malignancy with a sensitivity of 61% and a specificity of 65%. CONCLUSIONS: TSH levels in the upper-normal range are associated with an increased risk of thyroid malignancy in patients affected by thyroid nodules with indeterminate cytology at FNA. The measurement of serum TSH levels represents an easily performed additional tool for decision-making in patients with indeterminate cytological findings.

Ultrasound Microvascular Blood Flow Evaluation: A New Tool for the Management of Thyroid Nodule?

BACKGROUND: Toshiba Medical System has developed a new Doppler technique [Superb Microvascular Imaging (SMI)] that has improved microvascular flow imaging. SMI depicts perinodular and intranodular thyroid microvascular flow in higher detail compared to standard colour Doppler (CD) and power Doppler (PD) imaging. OBJECTIVE: Assess the nodular microvascular architecture by SMI compared to CD and PD features in a series of thyroid nodules submitted to fine needle aspiration cytology, in order to evaluate the potential of SMI in detecting thyroid cancer. MATERIALS AND METHODS: From April 2016 to July 2017, 254 patients with thyroid nodules, evaluated as at high risk for malignancy in agreement with AACE/ACE/AME guidelines, were submitted to cytology. All nodules were previously submitted to ultrasound grayscale, CD, PD, and SMI evaluation. Benign and malignant nodules were stratified in accordance to the number of vessels visualised by SMI: score 1 with a maximum of two blood vessels and score 2 with three or more vessels. RESULTS: Score 1 was found in 59.6% of benign nodules and in 17.9% of malignant nodules, whereas score 2 was found in 40.4% and in 82.1%, respectively (sensitivity 81.7%; specificity 60.5%, p < 0.001). Variables significantly associated with malignancy in the univariate analysis were gender (OR, 0.18; 95% CI, 0.08-0.37; p < 0.001), vascularity (OR, 1.91; 95% CI, 1.65-3.89; p < 0.001), and SMI (OR, 6.72; 95% CI, 3.89-11.59; p < 0.001); multivariate logistic model confirmed SMI score 2 as an independent risk factor for malignancy (OR, 6.99; 95% CI, 3.46-12.09; p < 0.001). CONCLUSIONS: This prospective pilot study showed that SMI can depict intranodular flow in higher detail compared to CDI and PDI, thus improving thyroid cancer detection.

p.Ser891Ala RET gene mutations in medullary thyroid cancer: Phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy.

Applying genetic screening in medullary thyroid cancer (MTC) patients we identified an unexpectedly high frequency of c.2671T>G, p.Ser891Ala RET mutation carriers. Our aim was to: (a) deeply characterize the clinical expression of this mutation, (b) identify the presence of a founder effect in our region. Genetic analysis was performed in 251 relatives from 28 Ser891Ala kindreds, among 108 p.Ser891Ala asymptomatic carriers, 64 were submitted to thyroidectomy: mean age for 10 subjects presenting C-cells hyperplasia was 30.2 ± 13.7 years, raising to 37.9 ± 10.3 in 14 subjects with micro-MTC and to 55.0 ± 14.7 years in 39 subjects with MTC. Age-related progression across histopathological groups CCH/microMTC and MTC were statistically significant: genetic screening in Ser891Ala families could be safely postponed at the age of 14. To investigate the hypothesis of a common ancestor for Ser891Ala mutation we genotyped for 18 polymorphic microsatellite markers encompassing RET locus all subjects belonging to Ser891Ala families and we identified a founder effect, estimating the age of a common ancestor, dating back to 1493 AD. Ethnographic data collected in historical archives support laboratory results; the high prevalence of this mutation in our region could suggest the hypothesis of a population study to realize a preventive intervention in a rare neoplastic disease.

TSH Variability of Patients Affected by Differentiated Thyroid Cancer Treated with Levothyroxine Liquid Solution or Tablet Form.

BACKGROUND: Recent guidelines from the American Thyroid Association (ATA) indicate that, in many patients affected by differentiated thyroid cancer (DTC), the serum TSH should be maintained between 0.1 and 0.5 mU/L. The purpose of this study was to evaluate the TSH variability of patients affected by DTC treated with liquid L-T4 formulation or in tablet form. PATIENTS AND METHODS: Patients were eligible if (a) they were submitted to a total thyroidectomy and 131I remnant ablation for DTC in our institution and (b) they were classified low-risk patients according to ATA guidelines 2009. Patients were randomized (1 : 1) to receive treatment of hypothyroidism with liquid L-T4 or tablet form. The first check-up evaluation was made from 8 to 12 months after 131I remnant ablation. TSH values were established again after further 12 months. RESULTS: A significant increase in TSH values (median) was observed in patients taking tablets [TSH (min-max): 0.28 (0.1-0.45) versus 0.34 (0.01-0.78) mIU/L, p = 0.041] as compared to those taking liquid formulation [TSH (min-max): 0.28 (0.1-0.47) versus 0.30 (0.1-0.55) mIU/L, p = 0.345]. CONCLUSIONS: The use of L-T4 liquid formulation, as compared to that of tablets, resulted in a significantly higher number of DTC patients maintaining TSH values in range for the ATA risk score, reducing TSH variability over the time.

Relationship between different subpopulations of circulating CD4+ T lymphocytes and microvascular or systemic oxidative stress in humans.

BACKGROUND AND OBJECTIVE: Different components of the immune system, including innate and adaptive immunity (T effector lymphocytes and T regulatory lymphocytes - TREGs) may be involved in the development of hypertension, vascular injury and inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular oxidative stress. Our objective was to investigate possible relationships between T-lymphocyte subtypes and systemic and microvascular oxidative stress in a population of normotensive subjects and hypertensive patients. PATIENTS AND METHODS: In the present study we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. A peripheral blood sample was obtained before surgery for assessment of T lymphocyte subpopulations by flow cytometry and circulating indices of oxidative stress. RESULTS: A significant direct correlation was observed between Th1 lymphocytes and reactive oxygen species (ROS) production (mainly in microvessels). Additionally, significant inverse correlations were observed between ROS and total TREGs, or TREGs subtypes. Significant correlations were detected between circulating indices of oxidative stress/inflammation and indices of microvascular morphology/Th1 and Th17 lymphocytes. In addition, a significant inverse correlation was detected between TREGs in subcutaneous small vessels and C reactive protein. CONCLUSIONS: Our data suggest that TREG lymphocytes may be protective against microvascular damage, probably because of their anti-oxidant properties, while Th1-Th17 lymphocytes seem to exert an opposite effect, confirming an involvement of adaptive immune system in microvascular damage.

Relationship Between Different Subpopulations of Circulating CD4+ T-lymphocytes and Microvascular Structural Alterations in Humans.

BACKGROUND: Different components of the immune system, including innate and adaptive immunity (T-effector lymphocytes and T-regulatory lymphocytes-TREGs) may be involved in the development of hypertension. In addition, it was demonstrated in animal models that TREGs may prevent angiotensin II-induced hypertension and vascular injury/inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular structural alterations. METHODS: For this purpose, in the present study, we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph and the media to lumen ratio (M/L) was calculated. In addition, retinal arteriolar structure was evaluated noninvasively by scanning laser Doppler flowmetry. Capillary density in the nailfold, dorsum of the finger, and forearm were evaluated by videomicroscopy. A peripheral blood sample was obtained before surgery for assessment of T-lymphocyte subpopulations by flow cytometry. RESULTS: Significant negative correlations were observed between indices of microvascular structure (M/L of subcutaneous small arteries and wall to lumen ratio of retinal arterioles) and circulating TREG lymphocytes. A direct correlation was observed between M/L of subcutaneous small arteries and circulating Th17 lymphocytes. In addition, total capillary density was correlated with a TREG effector memory subpopulation. CONCLUSION: Our data suggest that some lymphocyte subpopulations may be related to microvascular remodeling, confirming previous animal data, and opening therapeutic possibilities.

Elastography Evaluation of Benign Thyroid Nodules in Patients Affected by Hashimoto's Thyroiditis.

The aim of the present prospective study was to evaluate the predictive value of elastography in benign thyroid nodules of patients affected by Hashimoto's thyroiditis (HT). From January 2011 to January 2012, 242 nodules in patients affected by HT were submitted to fine needle aspiration cytology (FNAC). All of the patients underwent sonography and elastography performed before FNAC. 230 (95%) nodules were benign, 8 papillary cancers, and 4 follicular lesions. Score 1 was found in 79.1% of benign lesions (sensitivity 79.1%; specificity 66.7%; PPV 97.8%; NPV 14.3%; accuracy 78.5%; p < 0.05). In order to evaluate the outcome of thyroid ultrasound echogenicity in relation to elastography features of nodule(s), all the patients with benign nodules were stratified according to their hypoechoic pattern of thyroid (mild-moderate and severe). Following stratification score 1 was found in 84.2% of benign nodules (sensitivity 75.0%; specificity 88.9%; PPV 27.3%; NPV 98.4%; accuracy 88.2%; p < 0.0001) of patients with a mild-moderate ultrasound thyroid hypoechogenicity, whereas it was found in 60% of benign nodules (p = 0.715) of patients with a marked thyroid hypoechogenicity. Elastography appears to have limited value in detecting thyroid cancer in patients affected by Hashimoto's thyroiditis with severe hypoechoic thyroid tissue.

Thyroglobulin measurement in fine-needle aspiration biopsy of metastatic lymph nodes after rhTSH stimulation.

BACKGROUND: Thyroglobulin measurement in the washout of the needle used in fine-needle aspiration cytology (FNAC) has been proposed for the early detection of lymph node metastasis both in patients with or without serum thyroglobulin antibodies; however, up to now, there have been no reports that recombinant human thyrotropin (rhTSH) stimulation modifies thyroglobulin measurement in lymph node aspirates. METHODS: We described, after rhTSH stimulation, the switching from undetectable to detectable levels of thyroglobulin in fine-needle aspiration fluid from a suspected metastatic lymph node in 2 patients. RESULTS: We hypothesized that thyroglobulin levels in the lymph node increased after rhTSH stimulation. The excess thyroglobulin saturates all thyroglobulin antibody binding sites and becomes detectable, explaining why it was undetectable when TSH was suppressed. CONCLUSION: On the basis of our experience, we suggest submitting to thyroglobulin measurement in the washout of the needle used in FNAC all patients with detectable serum thyroglobulin antibody after rhTSH stimulation.

Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome.

SDH genes, encoding succinate dehydrogenase, act as tumour suppressor genes, linking mitochondrial dysfunction with tumourigenesis. Heterozygous germline mutations in SDHA, SDHB, SDHC, SDHD and in the assembly factor encoding gene SDHAF2 have all been shown to predispose to heritable endocrine neoplasias such as pheochromocytomas (PHEO) and paragangliomas (PGLs) called 'PHEO-PGL syndrome'. SDH genes mutations, in addition to deletions or truncations which are most likely pathogenic, often include missense substitutions which can be of uncertain significance. Unclassified missense substitutions may be difficult to interpret unless the cause-effect link between mutation and the disease is established by functional and in silico studies or by the familial segregation with the phenotype. Using the yeast model, here, we report functional investigations on several missense SDH mutations found in patients affected by pheochromocytomas or paragangliomas. The aim of this study was to evaluate whether and to which extent the yeast model may be useful for establishing the pathological significance of missense SDH mutations in humans. The results of our study demonstrate that the yeast is a good functional model to validate the pathogenic significance of SDHB missense mutations while, for missense mutations in SDHC and SDHD genes, the model can be informative only when the variation involves a conserved residue in a conserved domain.

Real-time elastography: a useful tool for predicting malignancy in thyroid nodules with nondiagnostic cytologic findings.

OBJECTIVES: The aim of this study was to evaluate the predictive value of sonography and sonographic elastography in thyroid nodules with nondiagnostic cytologic findings. METHODS: The study included 101 patients (74 female, mean age ± SD, 55 ± 11 years [range, 27-70 years]; and 27 male, mean age, 62 ± 9 years [range, 42-72 years]) who had at least 1 nodule with nondiagnostic cytologic findings at two different fine-needle aspiration cytologic evaluations and with an indication for hemi or total thyroidectomy for clinical suspicion of malignancy, nodule size, or the occurrence of a coexisting nodule with cytologic findings suspicious for malignancy. All of the patients underwent sonography and elastography 2 months after the second fine-needle aspiration and before surgery. The elastogram was matched with an elasticity color scale and classified as follows: score 1, nodules with high elasticity (soft); score 2, nodules with indeterminate elasticity; and score 3, nodules with low elasticity (hard). RESULTS: A total of 135 nodules (93.7%) were hyperplastic; 15 (9.4%) were papillary carcinomas; and 9 (6.3%) were follicular adenomas. The association of scores 2 and 3 identified 12 of 15 thyroid cancers (sensitivity, 80.0%; specificity, 93.7%; positive predictive value, 57.1%; negative predictive value, 97.8%; and accuracy, 92.4%), whereas the association of conventional sonographic features plus scores 2 and 3 identified all of the cancers (specificity, 70.8%; positive predictive value, 26.3%; negative predictive value, 100%; and accuracy, 73.6%). CONCLUSIONS: Our data suggest that elastography could be a promising tool in the management of nodules that are nondiagnostic at cytologic evaluation, reducing unnecessary surgery.

Thyreotropin levels in diabetic patients on metformin treatment.

OBJECTIVE: A retrospective study to evaluate the changes in TSH concentrations in diabetic patients treated or not treated with metformin and/or L-thyroxine (L-T(4)). METHODS: Three hundred and ninety three euthyroid diabetic patients were divided into three groups on the basis of metformin and/or L-T(4) treatment: Group (M-/L-), 119 subjects never treated with metformin and L-T(4); Group (M+/L-), 203 subjects who started metformin treatment at recruitment; and Group (M+/L+), 71 patients on L-T(4) who started metformin recruitment. RESULTS: The effect of metformin on serum TSH concentrations was analyzed in relation to the basal value of TSH (below 2.5 mIU/L (Q1) or between 2.51 and 4.5 mIU/L (Q2)). In patients of group M+/L+, TSH significantly decreased independently from the basal level (Q1, from 1.450.53 to 1.011.12 mU/L (P=0.037); Q2, from 3.600.53 to 1.910.89 mU/L (P<0.0001)). In M+/L group, the decrease in TSH was significant only in those patients with a basal high-normal serum TSH (Q2: from 3.24±0.51 to 2.27±1.28 mU/l (P=0.004)); in M-/L- patients, no significant changes in TSH levels were observed. In patients of group M+/L showing high-normal basal TSH levels, a significant decrease in TSH was observed independently from the presence or absence of thyroid peroxidase antibodies (ABTPO; Q2 ABTPO +: from 3.38±0.48 to 1.87±1.08 mU/l (P<0.001); Q2 AbTPO -: from 3.21±0.52 to 2.34±1.31 mU/l (P<0.001)). CONCLUSIONS: These data strengthen the known TSH-lowering effect of metformin in diabetic patients on L-T(4) treatment and shows a significant reduction of TSH also in euthyroid patients with higher baseline TSH levels independently from the presence of AbTPO.

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. DESIGN: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Morbid obesity in women is associated to a lower prevalence of thyroid nodules.

BACKGROUND: Few studies have recently showed functional and morphological changes of the thyroid gland in relation to obesity. To our knowledge, no data are available about the prevalence of thyroid nodules in female obese patients. The aim of this study was to investigate the prevalence of thyroid nodules in morbidly obese women. METHODS: One hundred eight consecutive female obese patients were selected from those referred to our medical and surgery outpatients providing that following criteria were satisfied: (1) affected by morbid obesity (body mass index (BMI) >40 kg/m(2)); (2) no previous diagnosis of thyroid disease; (3) biochemically proven euthyroid state at the time of recruitment. Ninety-seven control subjects, constituted by normo-weight and/or slightly overweight (BMI ≤ 30 kg/m(2)) women, should satisfy the above criteria 2 and 3. All the subjects were submitted to ultrasound investigation. RESULTS: The two groups of patients displayed no differences for age and fT4 levels. Obese patients clearly showed a lower prevalence of thyroid nodules [odds ratio 0.294, 95% confidence interval 0.206-0.382]. A single nodule was found in 23% of obese patients as compared to 65% of control subjects (p < 0.0001). No difference for age (year) was found between obese and non-obese subjects with nodules (40.5 ± 8.2 vs. 44.2 ± 8.9, respectively, p = 0.07). CONCLUSIONS: Our data clearly show a significantly lower prevalence of thyroid nodules in morbidly obese patients. Further studies are needed to confirm and to understand this first observation.

Thyroidal effect of metformin treatment in patients with polycystic ovary syndrome.

OBJECTIVE: Metformin is widely used for the treatment of type 2 diabetes. Growing evidence supports the beneficial effects of metformin also in patients with polycystic ovary syndrome (PCOS). It was recently reported that metformin has a TSH-lowering effect in hypothyroid patients with diabetes being treated with metformin. DESIGN: Aim of this study was to evaluate the effect of metformin treatment on the thyroid hormone profile in patients with PCOS. PATIENTS AND MEASUREMENTS: Thirty-three patients with PCOS were specifically selected for being either treated with levothyroxine for a previous diagnosis of hypothyroidism (n = 7), untreated subclinically hypothyroid (n = 2) or euthyroid without levothyroxine treatment (n = 24) before the starting of metformin. The serum levels of TSH and FT(4) were measured before and after a 4-month period of metformin therapy. RESULTS: Thyroid function parameters did not change after starting metformin therapy in euthyroid patients with PCOS. In the 9 hypothyroid patients with PCOS, the basal median serum levels of TSH (3·2 mIU/l, range = 0·4-7·1 mIU/l) significantly (P < 0·05) decreased after a 4-month course of metformin treatment (1·7 mIU/l, range = 0·5-5·2 mIU/l). No significant change in the serum levels of FT4 was observed in these patients. The TSH-lowering effect of metformin was not related to the administered dose of the drug, which was similar in euthyroid as compared with hypothyroid patients with PCOS (1406 ± 589 vs 1322 ± 402 mg/day, respectively; NS). CONCLUSIONS: These results indicate that metformin treatment has a TSH-lowering effect in hypothyroid patients with PCOS, both treated with l-thyroxine and untreated.