Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

AIMS: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist. MATERIALS AND METHODS: PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration. RESULTS: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. CONCLUSIONS: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

Evaluation of left ventricular diastolic function according to new criteria and determinants in acromegaly.

Left ventricular diastolic dysfunction (LVDD) develops in the early stages of acromegaly. The purpose of this study was to identify LVDD analyzing by new echocardiograpic criteria as well as to evaluate determinants of the LVDD in acromegaly. This cross-sectional study examined 42 patients with acromegaly; 16 in active disease (AA) and 26 cured/ well controlled (CA), and compared them with 30 healthy controls (CG). Ventricular systolic and diastolic functions were studied by conventional and tissue Doppler imaging based on the E/Em ratio and myocardial performance index (MPI). Other clinical parameters possibly contributing to LVDD in acromegaly were also investigated. The prevalence of LV hypertrophy (33%) and LVDD (35.7%) were increased in acromegaly, however, there were no differences between the AA and CA groups. Acromegalic patients had higher LV volumes and LV mass, and septal E/Em ratio compared to CG, whereas LV ejection fraction and MPI were not different. The presence of acromegaly (r = 0.29, P = 0.013), diabetes mellitus (DM) (r = 0.41, P < 0.001), hypertension (r = 0.35, P = 0.002), and sleep apnea (r = 0.56, P = 0.003) were found to be correlated with LVDD, whereas duration and activity of acromegaly were not. In regression analysis, advanced age (OR: 8.53, P = 0.006) and DM (OR: 25.9, P = 0.007) were found to be independent risk factors for LVDD. The risk of LVDD according to new criteria increases in acromegaly. However, it seems to be related to the presence of DM and advanced age and is independent of disease duration and activity.

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.

Effect of levothyroxine replacement therapy on paraoxonase-1 and carotid intima-media thickness in subclinical hypothyroidism.

BACKGROUND: Paraoxonase-1 (PON-1) may play an important role in atherosclerosis. Atherosclerosis is an inflammatory disease and C-reactive protein is a marker for inflammation. The aim of this study was to determine serum PON-1 activity and high-sensitivity C-reactive protein (hs-CRP) levels and assess carotid intima-media thickness, a marker of early atherosclerotic changes, in patients with subclinical hypothyroidism. MATERIAL/METHODS: hs-CRP concentrations and PON-1 activity with respect to carotid intima-media thickness were evaluated in 38 subclinical hypothyroidism patients (normolipidemic, mean age: 49.79+/-10.04 years) before and after 3 months of stable euthyroidism and compared with those of 19 euthyroid normolipidemic healthy individuals (mean age: 49.95+/-8.12 years). RESULTS: At baseline, the patients with subclinical hypothyroidism had similar levels of PON-1 activity and hs-CRP and a similar lipid profile as the controls; however, the carotid intima-media thickness was greater than in the controls. Levothyroxine treatment had no effect on serum PON-1 activity and hs-CRP level, but it resulted in a significant reduction in carotid intima-media thickness in the subclinical hypothyroidism patients. CONCLUSIONS: PON-1 activity and hs-CRP levels did not significantly differ between subclinical hypothyroid patients and controls. Although levothyroxine treatment might have the potential to reverse the progression of atherosclerosis in subclinical hypothyroid patients, PON-1 activity and hs-CRP levels were not affected by this treatment. The reduction in carotid intima-media thickness was independent of the decrease in serum lipid profile or other variables.

The prevalence of non-classic adrenal hyperplasia among Turkish women with hyperandrogenism.

The prevalence of non-classic adrenal hyperplasia (NCAH) among Turkish women with hirsutism has not been established so far. Thus, we aimed to evaluate the prevalence of 21-hydroxylase (21-OH) deficiency by ACTH stimulation test among hirsute women. The study population consisted of 285 premenopousal women, aged 16-46 years (mean: 23.2 ± 0.3). All were hirsute and hyperandrogenic. Androgen secreting tumors of the ovaries and the adrenal glands were excluded as well as thyroid dysfunction and hyperprolactinemia. All the patients were evaluated by 0.25 mg (i.v.) ACTH stimulation test and 17-OHP responses were obtained at 30 and 60 min. The diagnosis of NCAH due to 21-OH deficiency was considered in patients with the poststimulation 17-OHP level exceed 10 ng/ml. Six (2.1%) of the patients had NCAH due to 21-OH deficiency confirmed by genotyping. The rest of the patients were polycystic ovary syndrome (n = 166, 58.2%) and idiopathic hyperandrogenemia (n = 113, 39.7%). There were no patients with idiopathic hirsutism because patients with normal serum androgen levels were excluded. This first and most extensive national study investigating NCAH prevalence among Turkish population showed that NCAH is not prevalent in this population.

The relationship between premature ejaculation and hyperthyroidism.

PURPOSE: We determine the prevalence of premature ejaculation in patients with hyperthyroidism and observed intravaginal ejaculation latency time alterations before and after hyperthyroidism treatment. MATERIALS AND METHODS: Between January 2004 and June 2007, 49 patients with hyperthyroidism and no history of hyperthyroidism treatment were enrolled in the study. After obtaining a detailed sexual anamnesis an erectile function questionnaire was completed and a patient self-reported outcome measure of difficult control over ejaculation was examined. We assessed stopwatch measurements of intravaginal ejaculation latency time performed by the patient or partner. Patient anxiety status was also evaluated. Changes in the mentioned measurements induced by hyperthyroidism treatment were examined 8 weeks after the achievement of euthyroidism. RESULTS: In the 43 eligible patients mean +/- SD age was 48.0 +/- 8.8 years. Premature ejaculation was observed in 31 of the 43 patients (72.1%). Mean intravaginal ejaculation latency time in patients with hyperthyroidism was 72.8 +/- 83.3 seconds. Of the 43 patients 30 (69.8%) were considered to have definite premature ejaculation according to stopwatch measurements. In patients with hyperthyroidism who had definite premature ejaculation anxiety scores were determined to be higher. A positive correlation was noted between serum thyroid stimulating hormone and intravaginal ejaculation latency time in the patients. In 24 patients who completed the followup visits we noted statistically significant improvement in intravaginal ejaculation latency time after the achievement of euthyroidism. CONCLUSIONS: Excess thyroid hormone and premature ejaculation are clinically interrelated conditions. Hyperthyroidism should be considered a novel and reversible etiological risk factor for premature ejaculation.

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.

Penile vascular impairment in erectile dysfunction patients with metabolic syndrome: penile Doppler ultrasound findings.

BACKGROUND: The constellation of truncal obesity, glucose intolerance, dyslipidemia (high triglycerides, low HDL cholesterol), and hypertension has been recognized as metabolic syndrome. However, the pathophysiological association between metabolic syndrome and erectile dysfunction (ED) has not yet been clearly determined. This study aimed to evaluate the penile Doppler ultrasound (PDU) findings of ED patients with metabolic syndrome. PATIENTS AND METHODS: Sixty-one age-matched ED patients with or without metabolic syndrome were included in the study. Patients were investigated by grouping according to risk factors of metabolic syndrome with PDU parameters (5th, 10th and 20th minute peak systolic velocity and end-diastolic velocity). PDU parameters of patients with and without metabolic syndrome were compared. RESULTS: The mean age of the patients were 54.9 +/- 8.3 and 54.9 +/- 7.6 years for the groups of with (n = 27) and without (n = 34) metabolic syndrome, respectively. When the mean peak flow velocities were compared with presence of metabolic syndrome, we observed differences between at the 5th, 10th and 20th minute peak systolic velocities (p = 0.083, p = 0.022 and p = 0.080, respectively). CONCLUSION: Metabolic syndrome seems to be the potential risk factor for ED, which may exert its effect by decreased arterial inflow due to endothelial dysfunction.

The effects of body fat distribution on pulmonary function tests in the overweight and obese.

OBJECTIVES: To determine the predominant pulmonary function abnormality in overweight and moderately obese subjects and to evaluate the correlation between the severity of lung function impairment and the degree of obesity. METHODS: Fifty-three volunteers underwent physical examination, skin fold measurements, and standardized pulmonary function tests. Thirty-one women and 22 men with a mean age of 40.2 (18-66) years were studied. RESULTS: The reduction in functional residual capacity (FRC) and expiratory reserve volume (ERV) were the most common abnormalities in overweight and obese subjects. The reduction in static lung volume was correlated with the degree of obesity in women and men. Stepwise multiple regression coefficients were obtained separately for women and men. Subscapular skinfold was the best predictor in women for FRC and waist-to-hip ratio (WHR) and BMI were found the best for ERV. WHR was found predictive for forced vital capacity, total lung capacity, and FRC in men. CONCLUSIONS: The lung volumes are substantially affected in our overweight and obese subjects. This influence is focused on different parameters of respiratory functions in men and women in relation to body fat distribution.

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.

Familial hypobetalipoproteinemia in a Turkish family with hereditary spastic paraplegia.

A 24-year-old male presented with progressive gait disturbance and was diagnosed with hereditary spastic paraplegia. His brother and possibly one uncle also had the condition. Routine biochemical testing found that the patient had unusually low plasma concentrations of low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B, the hallmark of familial hypobetalipoproteinemia. DNA sequencing showed that he, along with other family members (n=5; mean LDL cholesterol 0.8 mmol/L, apoB 0.31 g/L), were heterozygous for a single nucleotide deletion in exon 26 of the APOB gene. This mutation is predicted to form a truncated apoB species of 3545 amino acids, which we have designated apoB-78.2.

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.

[The effect of levothyroxine suppression therapy for benign thyroid nodules on bone metabolism in premenopausal women]. / Menopoz öncesinde selim tiroid nodülleri için uygulanan levotiroksin supresyon tedavisinin kemik metabolizmasina etkisi.

OBJECTIVES: This prospective study was designed to investigate the effect of levothyroxine suppression therapy for benign thyroid nodules on markers of bone turnover in premenopausal women. PATIENTS AND METHODS: The study included 28 premenopausal women who received levothyroxine suppression therapy for benign thyroid nodules for one year. The size of the thyroid gland and nodules, biochemical markers of bone turnover and urinary calcium excretion were measured before and after levothyroxine suppression therapy. RESULTS: No significant adverse effects were seen during levothyroxine treatment. Decreases in total thyroid volume and the size of the nodules were not significant at the end of treatment. Although levothyroxine suppression therapy did not result in changes in serum levels of calcium and phosphor, and urinary calcium excretion, bone turnover markers, namely serum osteocalcin and urinary deoxypyridinoline levels, increased significantly. Serum intact parathyroid hormone levels showed a minimal decrease, which was not statistically significant. CONCLUSION: Data from our study suggest that levothyroxine suppression therapy is associated with increased osteoblastic and osteoclastic activity in premenopausal women with benign thyroid nodules.

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.

The alteration of serum soluble CD40 ligand levels in overt and subclinical hypothyroidism.

OBJECTIVE: There is controversy as to whether hypothyroidism increases cardiovascular risk. The effect of levothyroxine on the cardiovascular risk profile is also unclear. Recent studies suggest that there is evidence of inflammation and endothelial dysfunction in hypothyroidism. Soluble CD40 ligand (sCD40L) is a protein expressed mainly by activated platelets which have been found to be associated with cardiovascular events. The aim of our study was to investigate serum sCD40L levels and the effect of levothyroxine replacement on sCD40L levels in overt and subclinical hypothyroidism. DESIGN: We assessed lipid profile, serum sCD40L and hsCRP levels in 21 overt and 22 subclinical hypothyroid age-matched female patients with chronic autoimmune thyroiditis at baseline and one month after achieving euthyroidism by levothyroxine replacement, and compared them with the data from 22, age-matched, healthy controls. RESULTS: Overt and subclinical hypothyroid patients had decreased sCD40L levels compared to age-matched controls. The patients with subclinical hypothyroidism had slightly increased hsCRP levels, but the result was not statistically significant. In multiple regression analysis, FT3 and FT4 were found to be independent predictors of sCD40L levels. After levothyroxine replacement, serum sCD40L levels increased significantly in the patients with overt hypothyroidism. Although an increase was also observed in the subclinical hypothyroid group, it was not statistically significant. Levothyroxine replacement had no significant effect on hsCRP levels in the patients with overt hypothyroidism. However, the subjects with subclinical hypothyroidism showed a significant reduction in hsCRP levels after levothyroxine. CONCLUSION: The values of sCD40L and hsCRP in our study suggest that inflammatory pathways are complex and may be affected by different factors in hypothyroidism.

Interference in ACTH immunoassay negatively impacts the management of subclinical hypercortisolism.

PURPOSE: Low plasma corticotropin is considered a useful parameter for the diagnosis of subclinical hypercortisolism in patients with an adrenal incidentaloma. However, immunoassays are vulnerable to interference from endogenous antibodies. In this study, subjects who underwent Hypothalamus-pituitary-adrenal axis evaluation for the assessment of subclinical hypercortisolism were evaluated. The objective of the study was to ascertain whether antibody interference in corticotropin immunoassay affected the diagnostic work-up and clinical decisions. METHODS: The 437 consecutive patients with incidentally discovered adrenal adenomas were included in this single centre study. Patients who had a combination of a nonsuppressed corticotropin concentration (>4.4 pmol/L) and a non-suppressed cortisol concentration after 1 mg overnight dexamethasone suppression test (>50 nmol/L) were selected. Eight eligible subjects without specific features of Cushing's syndrome were identified and recruited for interference studies and follow-up. Nine controls including one patient with unilateral adrenalectomy and one patient with Cushing's disease were recruited as well. MEASUREMENTS: Eligible subjects and controls were subjected to hormonal tests and investigations for suspected interference. Interference studies included measurement of corticotropin on a different analytical platform, serial dilutions, polyethylene glycol precipitation and heterophilic antibody analysis. Patients were followed with clinical and laboratory parameters for a median duration of 30 (12-90) months. RESULTS: Antibody interference was identified in four patients. Rheumatoid factor was responsible for the interference in one patient. Clinical management of the patients was affected by the erroneous results. Interference tests were negative in control subjects. CONCLUSIONS: Erroneous results associated with analytical interference negatively impacted on clinical decision making in this patient group. This should be considered particularly in conditions such as subclinical hypercortisolism which decisions depend on laboratory investigations mainly. Analytical interference could explain the high variability observed both in field measurements from patients who were expected to have lower corticotropin concentrations and in subclinical hypercortisolism prevalence reported by different studies. Many problems can be resolved by ensuring good communication between clinical and laboratory staff.