Assessment of Plasma-Free Cortisol Concentrations by LC-MS/MS in Patients with Autonomous Cortisol Secretion.

Autonomous cortisol secretion (ACS) of an adrenal incidentaloma (AI) is associated with mild cortisol excess that could result in poor metabolic and cardiovascular outcomes. The biological activity of glucocorticoids depends on the unbound, free fraction. We aimed to evaluate plasma free cortisol (FC) concentrations in patients with ACS in this cross-sectional study. One hundred and ten AI patients in 3 groups; non-functioning (NFA, n=33), possible ACS (n=65), ACS (n=12) were enrolled. Following measurements were conducted: Clinical data and total serum cortisol (TC), plasma corticotrophin (ACTH), serum dehydroepiandrosterone sulfate (DHEA-S), cortisol after 1 mg dexamethasone by both immunoassay and LC-MS/MS (DexF), serum corticosteroid binding globulin (CBG), plasma dexamethasone concentration [DEX] and plasma FC by LC-MS/MS. Patients with ACS featured an unfavorable metabolic profile. Plasma [DEX] and serum CBG levels were similar between groups. Plasma FC was significantly higher in ACS when compared to NFA and possible ACS groups p<0.05 and p<0.01, respectively. In multiple regression analysis DexF (beta=0.402, p<0.001) and CBG (beta=-0.257, p=0.03) remained as the independent predictors of plasma FC while age, sex, BMI, smoking habit, and existing cardiovascular disease did not make a significant contribution to the regression model. In conclusion, the magnitude of cortisol excess in ACS could lead to increased plasma FC concentrations. Further studies in AI patients are needed to demonstrate whether any alterations of cortisol affinity for CBG exist and to establish whether plasma FC concentrations predict the unfavorable metabolic profile in ACS.

Chemical shift magnetic resonance imaging could predict subclinical cortisol production from an incidentally discovered adrenal mass.

CONTEXT: To investigate whether any association between chemical shift magnetic resonance (MRI) findings, cortisol secretion and pathological findings exists that could predict subclinical hypercortisolism (SCH) in patients with adrenal incidentalomas (AI). DESIGN: Retrospective, cross-sectional study in a tertiary centre. PATIENTS: Sixty-eight subjects with AIs and 13 patients with Cushing's syndrome (CS). Patients with AIs were categorized according to cortisol levels post 1 mg dexamethasone (post-DST). MEASUREMENTS: Visual inspection of the lipid content of the adrenal tumour and calculation of adrenal-to-spleen ratio (ASR), the signal intensity index (SII), volume and the assessment of the association between pathological, radiological and hormonal findings in surgically treated patients. RESULTS: Percentage of clear cells was correlated with ASR (r = -.525, P = .01), SII (r = .465, P = .025), post-DST cortisol (r = -.711, P < .001) and ACTH (r = .475, P = .046). By ANOVA and post hoc analysis, patients with CS and five subjects with a post-DST cortisol greater than 137 nmol/L differed significantly in ASR and SII from those with a post-DST cortisol less than 50 nmol/L. An ASR level higher than 0.245 (OR 19.7, 95% CI 1.5-257.5; P = .023) and a SII level lower than 78.37 (OR 15.6, 95% CI 1.2-20; P = .034) remained as the independent predictors for SCH while age, presence of arterial hypertension or tumour volume did not make significant contribution to the models. CONCLUSIONS: Cortisol hypersecretion by adrenal adenomas is associated with distinctive MRI characteristics. The quantitative assessment of intracellular lipid in an AI could help distinguish patients with a clear phenotype of SCH.

Autonomous cortisol secretion in adrenal incidentalomas and increased visceral fat accumulation during follow-up.

OBJECTIVE: Autonomous cortisol secretion of adrenal incidentalomas (AIs) is associated with poor cardiovascular outcome. Because centripetal obesity is a cardiovascular risk factor, we aimed to investigate whether autonomous cortisol secretion is associated with increased visceral fat accumulation. DESIGN: Retrospective cohort study. PATIENTS: Patients with AIs who attended for follow-up between January 2014 and December 2016 were evaluated. Autonomous cortisol secretion was diagnosed when 1 mg overnight dexamethasone (post-DST) cortisol was >50 nmol/L at baseline and follow-up. Follow-up duration was 34 (12-105) months. Thirty patients with nonfunctioning AIs and 44 patients with autonomous cortisol secretion were included. Adrenalectomy was performed in five patients. Six patients with Cushing's syndrome were also recruited. MEASUREMENTS: Hormonal evaluation and assessment of total (T), visceral (V) and subcutaneous (S) fat area by computed tomography and calculation of V:S and V:T ratios at baseline and follow-up. RESULTS: V, V:S and V:T increased (P<.001 for each comparison, Wilcoxon signed rank test for repeated measures) in patients with autonomous cortisol secretion while did not change significantly in patients with nonfunctioning adenomas. Linear regression models including post-DST cortisol, gender, concomitant treatments and follow-up duration showed that both baseline and follow-up DST significantly predicted Δ(V:S) and Δ(V:T) (P<.01 for all models). CONCLUSIONS: In patients with AIs, a post-DST cortisol >50 nmol/L at both baseline and follow-up, was associated with a significant increase in visceral fat after a follow-up duration of ~3 years. This may be of importance to explain the link between autonomous cortisol secretion and poor cardiovascular outcome.

Multiple immunoassay interference in a patient with falsely elevated calcitonin.

Calcitonin (CT) is a diagnostic and follow-up marker of medullary thyroid carcinoma. Heterophile antibodies (HAbs) may interfere during immunometric assay measurements and result in falsely high CT levels and different markers. A 50-year-old female patient was referred to our institution for elevated CT levels (3,199 pg/mL [0-11,5]). Physical examination and thyroid ultrasonography show no thyroid nodules. Because of the discrepancy between the clinical picture and the laboratory results, various markers and hormones were examined to determine whether there was any interference in the immunometric assay. Thyroglobulin (Tg) and Adrenocorticotropic hormone (ACTH) levels were also found inaccurately elevated. After precipitation with polyethylene glycol, CT, Tg, and ACTH levels markedly decreased, showing macro-aggregates. Also, serial dilutions showed non-linearity in plasma concentrations. Additionally, CT samples were pretreated with a heterophilic blocking tube before measuring, and the CT level decreased to < 0.1 pg/mL, suggesting a HAb presence. Immunoassay interference should be considered when conflicting laboratory data are observed. This may help reduce the amount of unnecessary laboratory and imaging studies and prevent patients from complex diagnostic procedures.

Many Faces of Adrenal Lesions in a Large Patient Cohort: What Has Changed Over the Last Two Decades?

OBJECTIVE: To review the presentation characteristics, clinical and hormonal evaluations, and histopathological results of patients with adrenal lesions over a 21-year period and evaluate the changes across the two decades. METHODS: This single-center, retrospective study included 1003 patients with adrenal lesions who presented to our department between 2000 and 2021. Clinical, metabolic, hormonal, radiological, and pathological data of the patients were collected. RESULTS: Forty-seven percent of the lesions were non-functioning adrenal adenomas. Possible autonomous and autonomous cortisol secretion were detected in 22.2% of the patients. The percentages of the patients diagnosed with pheochromocytoma, primary hyperaldosteronism, adrenal Cushing syndrome, adrenocortical carcinoma, and adrenal metastasis were 7.4%, 4.8%, 4.7%, 0.9%, and 5.6%, respectively. Adrenalectomy was performed in 31.3% of the patients. Functional adrenal lesions were the leading cause of surgery (46.5%), followed by large size and/or suspicious imaging features (38.6%). Among the patients referred to surgery due to large size (≥6 cm), the diagnosis in 19% was metastasis, and in 12.1%, it was primary adrenocortical carcinoma. In patients with adrenal lesions with a size of 4-6 cm and suspicious imaging properties, the rates of metastasis and primary adrenocortical carcinoma were 44.4% and 4.8%, respectively. From the first to the second decade, major differences in presentation characteristics were increased detection of bilateral lesions and increased prevalence of possible autonomous and autonomous cortisol secretion. CONCLUSIONS: Adrenal lesions are common in the adult population, and while it is important to avoid overtreatment, hormone secretion, and malignancy should not be overlooked.

Evaluation of the Transcatheter Aortic Valve Replacement Results in Patients with Borderline Aortic Annulus and the Impact of Under- or Oversizing the Valve.

BACKGROUND: Optimal valve sizing provides improved results in transcatheter aortic valve replacement. Operators hesitate about the valve size when the annulus measurements fall into borderline area. Our purpose was to compare the results of borderline versus non-borderline annulus and to understand the impact of valve type and under or oversizing. METHODS: Data from 338 consecutive transcatheter aortic valve replacement procedures were analyzed. The study population was divided into 2 groups as 'borderline annulus' and 'non-borderline annulus.' Balloon expandable valves already have a grey zone definition. Similar to balloon expandable valves, annulus sizes that are within 15% above or below the upper or lower limit of a particular self-expandable valve size are defined as the 'borderline annulus' for self-expandable valves. The borderline annulus group was also divided into 2 subgroups according to the smaller or larger valve selection as 'undersizing' and 'oversizing.' Comparisons were made regarding the paravalvular leakage and residual transvalvular gradient. RESULTS: Of these 338 patients, 102 (30.1%) had a borderline and 226 (69.9%) had a non-borderline annulus. Both the transvalvular gradient (17.81 ± 7.15 vs. 14.44 ± 6.27) and the frequency of paravalvular leakage (for mild, mild to moderate, and moderate, 40.2%, 11.8%, and 2.9% vs., 18.8%, 6.7%, and 0.4%, respectively) were significantly higher in the borderline annulus than the non-borderline annulus group (P <.001). There were no significant differences between the groups balloon expandable versus self-expandable valves and oversizing versus undersizing regarding the transvalvular gradient and paravalvular leakage in patients with borderline annulus (P >.05). CONCLUSION: Regardless of the valve type and oversizing or undersizing, borderline annulus is related to significantly higher transvalvular gradient and paravalvular leakage when compared to the non-borderline annulus in transcatheter aortic valve replacement.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.

Evaluation of postpartum carbohydrate intolerance and cardiovascular risk factors in women with gestational diabetes.

We aimed to evaluate the predictors of subsequent development of postpartum carbohydrate intolerance, metabolic syndrome and cardiovascular risk factors in women with previous GDM. Two hundred fifty-two consecutive women with GDM were enrolled. After exclusion of women who did not attend to the hospital for follow-up visits for minimum 1 year, data of 195 patients were evaluated. Seventy-one lean women with negative screening for GDM were included as a control group. The prevalence of diabetes, impaired glucose tolerance and impaired fasting glucose and metabolic syndrome was significantly higher in women with previous GDM than healthy controls. Women with previous GDM were more insulin resistant, had an atherogenic lipid profile and increased carotid IMT. The most important predictors of postpartum diabetes were the need for insulin treatment during index pregnancy and glucose values on antepartum OGTT. Among women with previous GDM, the development of postpartum diabetes and metabolic syndrome was associated with increased carotid IMT. Our data show that women with previous GDM are at high risk for developing carbohydrate intolerance, metabolic syndrome and atherosclerosis. Antepartum prediction of high risk subjects for the subsequent development of postpartum carbohydrate intolerance and metabolic syndrome seems to be vital to prevent cardiovascular outcomes.

Effect of levothyroxine suppression therapy on plasma thrombin activatable fibrinolysis inhibitor antigen levels in benign thyroid nodules.

OBJECTIVE: The aim of this prospective study was to investigate the effect of LT4 suppression therapy on plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen and plasminogen activator inhibitor-1 (PAI-1) levels in benign thyroid nodules. We also compared hyperthyroid patients and healthy controls. SUBJECTS AND METHODS: Twenty premenopausal women with benign thyroid nodules were given LT4 suppression therapy for 1 year. Plasma TAFI and PAI-1 antigen levels were measured at baseline and after LT4 suppression treatment. The endogenous hyperthyroid group was composed of 19 premenopausal females with newly diagnosed endogenous hyperthyroidism. Eighteen age-matched euthyroid healthy premenopausal women were enrolled as the control group. RESULTS: TAFI antigen levels decreased after LT4 suppression treatment; however, the difference was not statistically significant (p = 0.057). LT4 treatment resulted in a nonsignificant increase in PAI-1 levels. Patients with endogenous hyperthyroidism had decreased levels of TAFI antigen and increased levels of PAI-1 antigen (p < 0.05). There was a negative correlation between the FT(4) and TAFI antigen levels. Serum TSH was positively correlated with the plasma levels of TAFI antigen. CONCLUSION: LT4 suppression therapy for benign thyroid nodules did not result in a significant decrease in TAFI antigen levels in premenopausal women, but endogenous hyperthyroidism was associated with significantly decreased levels of TAFI antigen.

Levothyroxine (LT4) suppression treatment for benign thyroid nodules alters coagulation.

OBJECTIVE: Endogenous hyperthyroidism is associated with altered coagulation. The aim of the present study is to investigate the effect of levothyroxine (LT(4)) suppression treatment for benign thyroid nodules on coagulation system. DESIGN: Prospective case-control study. Patients Thirty consecutive euthyroid pre-menopausal women with nodular goitre disease and 28 healthy controls were included in the study. MEASUREMENTS: Plasma fibrinogen, d-dimer, von Willebrand factor (vWF), tissue factor (TF), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1) and tissue factor pathway inhibitor (TFPI) levels were measured at baseline and after LT(4) suppression therapy. RESULTS: Plasma levels of fibrinogen, d-dimer, vWF, TF and PAI-1 increased significantly after treatment with LT(4) for 1 year. Serum FT(4) was a significant predictor of increased fibrinogen, vWF and PAI-1 levels, when the data was controlled for age and BMI. CONCLUSIONS: Our results suggest that LT(4) suppression therapy for benign thyroid nodules is associated with enhanced coagulation.

Soluble CD40 ligand, plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor-1-antigen in normotensive type 2 diabetic subjects without diabetic complications. Effects of metformin and rosiglitazone.

OBJECTIVE: To evaluate subclinical inflammation and fibrinolysis in low-risk type 2 diabetic subjects and to assess the efficacy of metformin and rosiglitazone in this group. SUBJECTS AND METHODS: Sixty-one normotensive, normoalbuminuric type 2 diabetic subjects without diabetes-related complications were included in a 4-week standardization period with glimepiride. After the standardization period, 21 subjects were excluded and the remaining 40 were randomly divided into two groups matched for age, gender, body mass index and disease duration. The first group (n = 20) received metformin (1,700 mg/day), the second group (n = 20) rosiglitazone (4 mg/day) for 12 weeks. Patients with low-density lipoprotein-cholesterol higher than 130 mg/dl at the beginning of the randomization period were treated with simvastatin (maximum dose 20 mg/day). Twenty-three healthy controls were also recruited. Cytokine measurements were performed with ELISA kits. RESULTS: Baseline plasma plasminogen activator inhibitor-1 (PAI-1) level of type 2 diabetic subjects was significantly elevated (p = 0.038), but baseline levels of soluble CD40 ligand (sCD40L) and thrombin-activatable fibrinolysis inhibitor-1 (TAFI) antigen did not differ from healthy controls. Twelve weeks of metformin or rosiglitazone therapy did not cause significant changes in sCD40L, PAI-1 and TAFI antigen levels. In simvastatin-treated subjects (n = 9) significant reductions of PAI-1 were achieved (p = 0.028), while sCD40L and TAFI-Ag did not differ from baseline values. CONCLUSION: Our results showed that nonobese diabetic patients at low cardiovascular risk had similar levels of subclinical markers of inflammation and fibrinolysis as matched healthy controls. Neither metformin nor rosiglitazone caused marked changes in sCD40L, PAI-1 and TAFI antigen levels. A subset of patients who received simvastatin showed a modest decrease in PAI-1 level and could contribute to beneficial vasculoprotective effect of the drug in type 2 diabetics.

Predictors of amputation in diabetics with foot ulcer: single center experience in a large Turkish cohort.

OBJECTIVE: Prediction of diabetic foot ulcer outcome may be helpful for clinicians in optimizing and individualizing management strategy. The aim of the present study was to examine the possibility of predicting the outcome of patients with diabetic foot ulcers by using easily assessed clinical and laboratory parameters at baseline. DESIGN: In this observational study, data were collected prospectively in 670 consecutive diabetic foot ulcer episodes in 510 patients examined between January 1999 and June 2008 and were used to evaluate potential predictors of amputation retrospectively. After exclusion of patients who did not come to the hospital for follow-up for a minimum of six months, data of 574 foot ulcer episodes were evaluated. RESULTS: Limb ischemia, osteomyelitis and presence of gangrene and ulcer depth, determined by the Wagner classification system, were the major independent predictors of overall and major amputations. Older age, presence of coronary artery disease, smoking and ulcer size were found to be associated with either overall or major amputations. Baseline levels of acute phase reactants (white blood cell count, polymorphonuclear leukocyte count, platelet count, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) and albumin) and decreased hemoglobin levels were associated with amputation risk. Multivariate analysis showed that one standard deviation increase in baseline CRP and ESR levels were independent predictors of overall and major amputations, respectively. CONCLUSIONS: The presence of limb ischemia, osteomyelitis, local and diffuse gangrene and ulcer depth were independent predictors of amputation. Baseline levels of ESR and CRP appeared to be helpful for clinicians in predicting amputation.

Multiple immunoassay interference in a patient with falsely elevated calcitonin

SUMMARY Calcitonin (CT) is a diagnostic and follow-up marker of medullary thyroid carcinoma. Heterophile antibodies (HAbs) may interfere during immunometric assay measurements and result in falsely high CT levels and different markers. A 50-year-old female patient was referred to our institution for elevated CT levels (3,199 pg/mL [0-11,5]). Physical examination and thyroid ultrasonography show no thyroid nodules. Because of the discrepancy between the clinical picture and the laboratory results, various markers and hormones were examined to determine whether there was any interference in the immunometric assay. Thyroglobulin (Tg) and Adrenocorticotropic hormone (ACTH) levels were also found inaccurately elevated. After precipitation with polyethylene glycol, CT, Tg, and ACTH levels markedly decreased, showing macro-aggregates. Also, serial dilutions showed non-linearity in plasma concentrations. Additionally, CT samples were pretreated with a heterophilic blocking tube before measuring, and the CT level decreased to < 0.1 pg/mL, suggesting a HAb presence. Immunoassay interference should be considered when conflicting laboratory data are observed. This may help reduce the amount of unnecessary laboratory and imaging studies and prevent patients from complex diagnostic procedures.

Evaluation of the Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Inadequately Controlled With First-Generation Somatostatin Analogs.

Introduction: Acromegaly is a rare, serious endocrine disorder characterized by excess growth hormone (GH) secretion by a pituitary adenoma and overproduction of insulin-like growth factor I (IGF-I). Transsphenoidal surgery is the treatment of choice, although many patients require additional interventions. First-generation somatostatin analogs (SSAs) are the current standard of medical therapy; however, not all patients achieve control of GH and IGF-I. Outcomes from a Phase IIIb open-label study of patients with uncontrolled acromegaly on first-generation SSAs switching to pasireotide are reported. Methods: Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 µg/L from a five-point profile over 2 h, and IGF-I >1.3× upper limit of normal [ULN]) despite ≥3 months' treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be increased (maximum: 60 mg/28 days) after week 12 if biochemical control was not achieved, or decreased (minimum: 10 mg/28 days) for tolerability. Patients who completed 36 weeks' treatment could continue receiving pasireotide during an extension (weeks 36-72) when concomitant medication for acromegaly was permitted. Primary endpoint was proportion of patients with mGH <1 µg/L and IGF-I 2.5 µg/L. For patients who entered the extension, 14.8% (95% CI: 8.1-23.9), 12.5% (95% CI: 6.4-21.3), 14.8% (95% CI: 8.1-23.9) and 11.4% (95% CI: 5.6-19.9) had mGH <1 µg/L and IGF-I

Hashimoto's thyroiditis, but not treatment of hypothyroidism, is associated with altered TGF-beta1 levels.

BACKGROUND: Although the role of cytokines in the development of Hashimoto's thyroiditis has already been established, its pathogenesis has not yet been clearly elucidated. The aim of our study was to investigate serum transforming growth factor-beta1 (TGF-beta1) levels in patients with Hashimoto's thyroiditis as well as the effect of achieving euthyroidism by levothyroxine replacement on TGF-beta1 levels. METHODS: Twenty nine female, newly diagnosed hypothyroid Hashimoto's thyroiditis patients (16 overt, 13 subclinical hypothyroid) and 25 age- and sex-matched healthy controls were enrolled in the study. RESULTS: Serum TGF-beta1 levels were lower in the Hashimoto's thyroiditis group when compared with control cases. Although significant differences were noted in lipid levels and in anthropometric measurements following levothyroxine replacement, serum TGF-beta1 levels remained unchanged. CONCLUSIONS: Our data suggest that altered TGF-beta1 levels are associated with the presence of Hashimoto's thyroiditis, not with the treatment of thyroid dysfunction. Autoimmunity may have been triggered as a result of decreased immunosuppressive effect induced by depressed TGF-beta1 levels in patients with Hashimoto's thyroiditis.

Misdiagnosis due to the hook effect in prolactin assay.

OBJECTIVES: To describe a patient who was misdiagnosed as having a nonfunctional pituitary tumor due to the hook effect on prolactin measurements. CLINICAL PRESENTATION AND INTERVENTION: A 45-year-old female was admitted with visual disturbances, panhypopituitarism and central diabetes insipidus due to pituitary tumor recurrence. She had been operated 4 times earlier and received cranial irradiation for a suspected nonfunctional pituitary adenoma. Serum prolactin was moderately elevated (164.5 ng/ml), but increased markedly after 1:100 dilution to 14,640 ng/ml. Diagnosis of a giant macroprolactinoma was made and cabergoline was started. Prolactin level normalized and a mild shrinkage of the tumor was achieved after 12 months of therapy. CONCLUSION: The hook effect must be kept in mind while evaluating a giant pituitary adenoma with moderately elevated prolactin levels. This way unnecessary surgical procedures or irradiation may be avoided.

Alterations of coagulation in metformin intoxication.

It is widely known that metformin reduces the levels of circulating pro-coagulant factors and improve fibrinolytic activity in type 2 diabetes when used in therapeutic doses. Potential alterations of coagulation have not been reported in patients with metformin intoxication. We evaluated certain components of the coagulation system in a patient with metformin intoxication upon admission and after recovery. Our results indicate that both the levels of coagulation proteins synthesized by the liver and the anti-coagulant activity decrease temporarily in metformin intoxication. Nevertheless, no change in the coagulation factors secreted by the endothelium were observed.

Serum transforming growth factor-beta 1 levels in normoalbuminuric and normotensive patients with type 2 diabetes. Effect of metformin and rosiglitazone.

OBJECTIVE: a)To determine serum Transforming Growth Factor-beta 1 (TGF-beta 1) levels in patients with type 2 diabetes who do not have diabetes related complications and in healthy controls, b) to evaluate the effects of metformin and rosiglitazone on TGF-beta 1 levels. DESIGN: In the washout period, 61 patients with Fasting Plasma Glucose levels (FPG) higher than 140 mg/dl, Postprandial Glucose (PPG) levels higher than 180 mg/dl and A1c levels exceeding 6.5% were treated with glimperide. After 4 weeks, 39 of these patients were randomised to receive either metformin or rosiglitazone for 12 weeks. Thirty healthy controls were also studied. RESULTS: There were no significant differences with regard to age, gender, body weight and BMI between patients and healthy controls. Type 2 diabetics had higher waist circumference, FPG, total cholesterol, LDL-cholesterol and triglyceride levels. Baseline TGF-beta 1 levels in diabetics were higher than in controls (29.84+/-7.04 ng/ml vs 11.37+/-4.06 ng/ml, p<0.001). Metformin or rosiglitazone did not significantly modify the TGF-beta 1 levels. In a multiple regression analysis FPG was the only variable that was significantly associated with plasma TGF-beta 1 levels. CONCLUSION: The elevated levels of TGF-beta 1 in subjects with type 2 diabetes possibly indicate a tendency for renal and endothelial damage in such patients. The association of TGF-beta 1 with FPG possibly links poor diabetic control to vascular damage, leading to diabetic complications. Lack of changes in the levels of TGF-beta 1 after therapy may reflect inadequate therapy duration.

Airway and sleep disorders in patients with acromegaly.

OBJECTIVE: Acromegaly is a multisystemic disorder caused by excessive secretion of growth hormone (GH). Sleep-disordered breathing (SDB) such as sleep apnea syndrome (SAS) may occur in acromegaly. The aim of study was to assess the presence of sleep disorders and evaluate the systemic complications on respiratory, cardiovascular, and upper airway systems in acromegalic patients. METHODS: The study group consisted of 30 acromegaly outpatients. GH and insulin-like growth factor 1 (IGF-1) measurements were obtained; body pletysmography, arterial blood gas analysis, tissue-doppler imaging, echocardiography, polysomnography, otorhinolaryngologic examination, and head-neck computed tomography were performed. RESULTS: Sixteen female (53.3%) and 14 male (46.7%) acromegalic patients had a mean age of 51.1 ± 13.2. GH was supressed in 19 patients (63.3%) when 11 had active acromegaly (36.7%). There were 17 patients with SAS (62.9%) (7: mild, 3:intermediate, 7:severe SAS) and average AHI was 16/h. Sixteen patients had predominantly obstructive SAS while one patient had predominantly central SAS. SAS was statistically more frequent in males than females (P = .015). The mean neck circumference was significantly longer in patients with SAS (P = .048). In SAS patients,the soft palate was elongated and thickened,which was statistically significant (P = .014 and P = .05).Vallecula-to-tongue distance was statistically longer in acromegalic patients with SAS (P = .007).There was a positive correlation between tonsil size,vallecula-to-tongue distance and AHI (r = 0.432, P = .045 and r = 0.512, P = .021, respectively). CONCLUSION: SDB seems to be common and clinically important in patients with acromegaly, particularly in men. The most frequent type of apnea in acromegalics is obstructive. Hormonal activity of acromegaly does not seem to have an effect on the development of SAS. Despite its high prevalence, SAS is frequently under-assessed in patients with acromegaly. Systemic complications and SDB should be researched in acromegalics.

Plasma thiobarbituric acid-reactive substance levels in subclinical hypothyroidism.

OBJECTIVE: The purpose of this study was to determine thiobarbituric acid-reactive substance (TBARS) levels in subclinical hypothyroidism and to examine the effect of levothyroxine replacement on TBARS levels. SUBJECTS AND METHODS: A cohort of 28 female patients with subclinical hypothyroidism and 24 healthy controls were enrolled in this study. The levels of plasma TBARS, serum lipids, and high-sensitive C-reactive protein (CRP) in patients with subclinical hypothyroidism at baseline and after achieving euthyroid state by levothyroxine were assessed. RESULTS: TBARS levels of the patients were similar to those of the control group in the subclinical hypothyroid state and after restoration of euthyroidism by levothyroxine replacement. TBARS levels decreased after levothyroxine treatment, but did not reach statistical significance. There was no significant correlation between TBARS, lipid and CRP levels. Serum CRP levels were higher in subclinical hypothyroidism (4.28 +/- 0.9 mg/l) than in the control group (1.95 +/- 0.34 mg/l) and the difference was statistically significant (p = 0.03). After achieving euthyroid state, CRP levels decreased significantly in patients with subclinical hypothyroidism from 4.28 +/- 0.9 to 2.32 +/- 0.6 mg/l (p = 0.006). CONCLUSION: Our findings suggest that there is no significant alteration of plasma TBARS levels neither in subclinical hypothyroid state nor after achieving euthyroid state. Serum CRP level is higher in patients with subclinical hypothyroidism than in the control group. Normalization of thyroid state seems to effectively reduce serum CRP levels in subclinical hypothyroidism without any correlation with TBARS activity.