Hidden hypercortisolism: a too frequently neglected clinical condition.

PURPOSE: Classic Cushing's syndrome (CS) is a severe disease characterized by central obesity, hypertension, easy bruising, striae rubrae, buffalo hump, proximal myopathy and hypertricosis. However, several CS cases have also been reported with unusual or camouflaged manifestations. In recent years, several authors investigated the prevalence of "hidden hypercortisolism" (HidHyCo) among subjects affected with bone fragility, hypertension and type 2 diabetes mellitus (DM2). The prevalence of the HidHyCo is estimated to be much higher than that of classic CS. However, similarly to classic CS, HidHyCo is known to increase the risk of fractures, cardiovascular disease and mortality. METHODS: We reviewed all published cases of unusual presentations of hypercortisolism and studies specifically assessing the HidHyCo prevalence in diabetic, osteoporotic and hypertensive patients. RESULTS: We found 49 HidHyCo cases, in whom bone fragility, hypertension and diabetes were the presenting manifestations of an otherwise silent hypercortisolism. Amongst these cases, 34.7%, 32.7%, 6.1% and 19.0%, respectively, had bone fragility, hypertension, DM2 or hypertension plus DM2 as the sole clinical manifestations of HidHyCo. Overall, 25% of HidHyCo cases were of pituitary origin, and bone fragility was the very prevalent first manifestation among them. In population studies, it is possible to estimate that 1-4% of patients with apparent primary osteoporosis has a HidHyCo and the prevalence of this condition among diabetics ranges between 3.4 and 10%. CONCLUSION: These data indicate that patients with resistant or suddenly worsening hypertension or DM2 or unexplainable bone fragility should be screened for HidHyCo using the most recently approved sensitive cut-offs.

The cytoskeleton actin binding protein filamin A impairs both IGF2 mitogenic effects and the efficacy of IGF1R inhibitors in adrenocortical cancer cells.

Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells. Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC. In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation. In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R. Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only. In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.

Minding the gap between cortisol levels measured with second-generation assays and current diagnostic thresholds for the diagnosis of adrenal insufficiency: a single-center experience.

PURPOSE: The current cut-offs for the diagnosis of adrenal insufficiency (AI) have been established using outdated immunoassays. We compared the cortisol concentrations measured with Roche Cortisol I (R1), the newly available Roche Cortisol II (R2), and liquid chromatography tandem mass spectrometry (LC-MS/MS), the gold standard procedure to measure steroids in patients undergoing the corticotropin (ACTH) test. METHODS: We enrolled 30 patients (age 47 ± 21 years) referred to undergo the ACTH test (1 or 250 µg). Cortisol was measured at 0, 30, and 60 min after stimulation with R1, R2, and LC-MS/MS. AI was diagnosed for R1-stimulated peak cortisol concentrations < 500 nmol/L. RESULTS: Mean cortisol concentrations measured with R2 and LC-MS/MS were comparable, while mean cortisol concentrations measured by R1 were higher than those of both R2 and LC-MS/MS (respectively, basal 411 ± 177, 287 ± 119, and 295 ± 119 nmol/L; at 30 min, 704 ± 204, 480 ± 132, and 500 ± 132 nmol/L; at 60 min, 737 ± 301, 502 ± 196, and 519 ± 201 nmol/L, p ≤ 0.01 for R1 vs. both R2 and LC-MS/MS at each point). Considering the 500 nmol/L cortisol peak cut-off, AI was diagnosed in 5/30 patients using R1 and in 12/30 using R2 (+ 140%). Based on the correlation between R1 and R2, the threshold of 500 nmol/L became 351 nmol/L (12.7 µg/dL) when cortisol was measured with R2, and 368 nmol/L (13.3 µg/dL) with LC-MS/MS. CONCLUSIONS: The use of more specific cortisol assays results in lower cortisol concentrations. This could lead to misdiagnosis and overtreatment when assessing AI with the ACTH test if a different cut-off for cortisol peak is not adopted.

Mood symptoms and suicidality across the autism spectrum.

BACKGROUND: Autism spectrum is a psychopathological dimension which encompasses a wide range of clinical presentations: from subthreshold forms and autistic traits (AT), that can be found in the general population, to full-blown autism spectrum disorder (ASD). Many studies reported high rates of comorbidity between both ASD and AT and mood disorders, as well as a high prevalence of suicidal ideation among patients with ASD/AT. The aim of this study was to investigate the presence of mood symptoms and suicidal ideation and behaviors in patients with full-blown ASD and in subjects with AT, as well in a healthy control (HC) group, with a specific focus on which of the autistic features may be predictive of suicidal ideation and behaviors. METHODS: We recruited 262 adult subjects: 34 with ASD without intellectual impairment or language disability (ASD group), 68 fulfilling only one symptom criterion for ASD according to DSM-5 but who do not meet criteria for a full-blown diagnosis of ASD (AT group), and 160 HC. All subjects were assessed with the Structured Clinical Interview for DSM-5 (SCID-5); in addition, they were asked to fill two questionnaires: The Mood Spectrum, Self-report (MOODS-SR) and the Adult Autism Subthreshold Spectrum (AdAS Spectrum). RESULTS: ASD subjects reported significantly higher AdAS Spectrum and MOODS-SR total scores, as well as higher MOODS-SR depressive component total scores, when compared with AT and HC subjects. AT subjects scored significantly higher than the HC group. No significant differences were reported between ASD and AT subjects for the suicidality score according to MOODS-SR, despite both groups scored significantly higher than the HC group. The strongest predictor of suicidality score were MOODS-SR depressive component score and AdAS Spectrum Restricted interests and rumination domain score. CONCLUSIONS: Our results highlight a correlation between autism and mood spectrum, as well as between suicidality and both ASD and AT. Subthreshold forms of ASD should be accurately investigated due to their relationship with suicidal thoughts and behaviors.

Bone involvement and mineral metabolism in Williams' syndrome.

CONTEXT: The previous studies suggested a possible increased risk of hypercalcaemia and reduced bone mineral density (BMD) in Williams' syndrome (WS). However, an extensive study regarding bone metabolism has never been performed. OBJECTIVE: To investigate bone health in young adults with WS. DESIGN: Cross-sectional study. SETTINGS: Endocrinology and Metabolic Diseases and Medical Genetic Units. PATIENTS: 29 WS young adults and 29 age- and sex-matched controls. MAIN OUTCOME MEASURES: In all subjects, calcium, phosphorus, bone alkaline phosphatase (bALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHVitD), osteocalcin (OC), carboxyterminal cross-linking telopeptide of type I collagen (CTX), 24-h urinary calcium and phosphorus, femoral-neck (FN) and lumbar-spine (LS) BMD and vertebral fractures (VFx) were assessed. In 19 patients, serum fibroblast growth factor-23 (FGF23) levels were measured. RESULTS: WS patients showed lower phosphorus (3.1 ± 0.7 vs 3.8 ± 0.5 mg/dL, p = 0.0001) and TmP/GFR (0.81 ± 0.32 vs 1.06 ± 0.25 mmol/L, p = 0.001), and an increased prevalence (p = 0.005) of hypophosphoremia (34.5 vs 3.4%) and reduced TmP/GFR (37.9 vs 3.4%). Moreover, bALP (26.3 ± 8.5 vs 35.0 ± 8.0 U/L), PTH (24.5 ± 12.6 vs 33.7 ± 10.8 pg/mL), OC (19.4 ± 5.3 vs 24.5 ± 8.7 ng/mL), and FN-BMD (- 0.51 ± 0.32 vs 0.36 ± 0.32) were significantly lower (p < 0.05), while CTX significantly higher (401.2 ± 169.3 vs 322.3 ± 122.4 pg/mL, p < 0.05). Serum and urinary calcium and 25OHVitD levels, LS-BMD and VFx prevalence were comparable. No cases of hypercalcemia and suppressed FGF23 were documented. Patients with low vs normal phosphorus and low vs normal TmP/GFR showed comparable FGF23 levels. FGF23 did not correlate with phosphorus and TmP/GFR values. CONCLUSIONS: Adult WS patients have reduced TmP/GFR, inappropriately normal FGF23 levels and an uncoupled bone turnover with low femoral BMD.

Predictability of hypoadrenalism occurrence and duration after adrenalectomy for ACTH-independent hypercortisolism.

OBJECTIVE: To evaluate if the parameters of hypothalamic-pituitary-adrenal (HPA) axis activity could predict the occurrence and duration of post-surgical hypocortisolism (PSH) in patients with Cushing's syndrome (CS) and with adrenal incidentaloma (AI). METHODS: We studied 80 patients (54 females, age 53.3 ± 11 years), who underwent adrenalectomy for CS (17 patients) or for AI (53 patients). Before surgery, we measured adrenocorticotroph hormone (ACTH), urinary free cortisol (UFC) and serum cortisol after 1 mg dexamethasone suppression test (1 mg-DST) levels. After surgery, all patients were given a steroid replacement therapy, and PSH was searched after 2 months by a low-dose (1 µg, iv) corticotropin stimulation test, that was repeated every 6 months in PSH patients for at least 4 years. RESULTS: The PSH occurred in 82.4 and 46% of CS and AI patients, respectively. In the whole sample and in AI patients separately considered, the PSH was independently predicted by the preoperative cortisol levels after 1 mg-DST, however, with a low (< 70%) accuracy. In AI patients the PSH occurrence was not ruled out even by the cortisol levels after 1 mg-DST lower than 1.8 µg/dL (50 nmol/L). In the 50% of CS patients and in 31% of AI patients the PSH lasted more than 18 months and in 35.7% of CS patients it persisted for more than 36 months. In AI patients, the PSH duration was not predictable by any parameter. However, a PSH duration of at least 12 months was significantly predicted before adrenalectomy (sensitivity 91.7%, specificity 41.2%, positive predictive value 52.4%, negative predictive value 87.5%, p = 0.05) by the presence of at least 2 out of low ACTH levels, increased UFC levels and cortisol levels after 1 mg-DST ≥ 3.0 µg/dL (83 nmol/L). CONCLUSION: The PSH occurrence and its duration are hardly predictable before surgery. All patients undergoing unilateral adrenalectomy should receive a steroid substitutive therapy.

Cofilin is a cAMP effector in mediating actin cytoskeleton reorganization and steroidogenesis in mouse and human adrenocortical tumor cells.

cAMP pathway plays a major role in the pathogenesis of cortisol-producing adrenocortical adenomas (CPA). cAMP-induced steroidogenesis is preceded by actin cytoskeleton reorganization, a process regulated by cofilin activity. In this study we investigated cofilin role in mediating cAMP effects on cell morphology and steroidogenesis in adrenocortical tumor cells. We demonstrated that forskolin induced cell rounding and strongly reduced phosphorylated (P)-cofilin/total cofilin ratio in Y1 (-52 ± 16%, p < 0.001) and human CPA cells (-53 ± 18%, p < 0.05). Cofilin silencing significantly reduced both forskolin-induced morphological changes and progesterone production (1.3-fold vs 1.8-fold in controls, p < 0.05), whereas transfection of wild-type or S3A (active), but not S3D (inactive) cofilin, potentiated forskolin effects on cell rounding and increased 3-fold progesterone synthesis with respect to control (p < 0.05). Furthermore, cofilin dephosphorylation by a ROCK inhibitor potentiated forskolin-induced cell rounding and steroidogenesis (2-fold increase vs forskolin alone). Finally, we found a reduced P-cofilin/total cofilin ratio and increased cofilin expression in CPA vs endocrine inactive adenomas by western blot and immunohistochemistry. Overall, these results identified cofilin as a mediator of cAMP effects on both morphological changes and steroidogenesis in mouse and human adrenocortical tumor cells.

Lipid levels and risk of recurrent venous thrombosis: results from the MEGA follow-up study.

Essentials The role of lipid levels in the risk of recurrent venous thrombosis is unclear. Lipids were assessed in patients with a first venous thrombosis (n = 2106) followed for 6.9 years. Lipids were not associated with recurrence, overall or in patients with unprovoked first events. Testing lipid levels is not useful to identify patients at an increased risk of recurrence. SUMMARY: Background Knowledge of risk factors for recurrent venous thrombosis may guide decisions on duration of anticoagulation. The association between lipid levels and first venous thrombosis has been studied extensively. However, data on the role of lipids in the risk of recurrence are scarce. Objective To assess the association between lipid levels and recurrent venous thrombosis. Patients/Methods Patients with a first venous thrombosis from the MEGA study were included. Follow-up started at the date of end of anticoagulant treatment. Percentile categories of total/low-density lipoprotein/high-density lipoprotein cholesterol, triglycerides and apolipoproteins B and A1 were established (< 10th, 10th-25th, 25th-75th [reference], 75th-90th, > 90th percentile). Lipids were measured at least 3 months after discontinuing anticoagulation. Results Of 2106 patients followed for a median of 6.9 years, 326 developed recurrence (incidence rate, 2.7/100 patient-years; 95% confidence interval [CI], 2.5-3.1). With hazard ratios ranging from 0.88 (95% CI, 0.55-1.42) to 1.33 (95% CI, 0.86-2.04) in the highest percentile category vs. the reference, we found no association across percentile categories between recurrence and lipid levels in age- and sex-adjusted models, nor after further adjustments for body mass index, diabetes, estrogen and statin use, and duration of anticoagulation. Subgroup analyses stratified by unprovoked or provoked first events, location (deep vein thrombosis or pulmonary embolism) and sex also did not reveal an association with any of the lipid levels studied. Conclusions Testing lipid levels did not identify patients at an increased risk of recurrent venous thrombosis in this study, including those with unprovoked first events, and these should not influence decisions on duration of anticoagulation.

Follow-up of patients with adrenal incidentaloma, in accordance with the European society of endocrinology guidelines: Could we be safe?

Recently, the European Society of Endocrinology (ESE) published new guidelines on the management of adrenal incidentalomas. At the same time Lopez and coworkers published on the Annals of Internal Medicine an important study showing that even patients with non-functioning adrenal tumors have an increased risk of incident diabetes. In consideration of previous data and of the results of the study of Lopez and coworkers, some points emerge from the ESE Guidelines that deserve attention. Firstly, it must be observed that the term "autonomous cortisol secretion," introduced by the ESE Panel in the place of the commonly used "subclinical hypercortisolism," seems questionable, since the guidelines do not suggest determining the adrenocorticotroph hormone levels that could give the certain proof of a truly autonomous cortisol secretion. Secondly, the ESE Guidelines suggest against repeated hormonal workup in AI patients with a normal hormonal secretion at initial evaluation, but also in those with a "possible autonomous cortisol secretion," if in the absence of comorbidities potentially related to hypercortisolism. Thirdly, the ESE Guidelines suggest against further imaging during follow-up in patients with an adrenal mass below 4 cm in size with clear benign features on imaging studies. Considering the available literature data that are briefly summarized in this comment, we believe that no sufficient evidence is available to date for giving sharp-cutting recommendations about the uselessness of a biochemical and morphological follow-up in AI patients, even in those with initially benign and not hypersecreting adrenal adenomas. However, if a recommendation has to be given on the basis of the present evidences, we should suggest to biochemically and morphologically follow-up AI patients for at least 5 years.

MECHANISMS IN ENDOCRINOLOGY: Endogenous subclinical hypercortisolism and bone: a clinical review.

In recent years, the condition of subclinical hypercortisolism (SH) has become a topic of growing interest. This is due to the fact that SH prevalence is not negligible (0.8-2% in the general population) and that, although asymptomatic, this subtle cortisol excess is not harmless, being associated with an increased risk of complications, in particular of osteoporosis and fragility fractures. As specific symptoms of hypercortisolism are absent in SH, the SH diagnosis relies only on biochemical tests and it is a challenge for physicians. As a consequence, even the indications for the evaluation of bone involvement in SH patients are debatable and guidelines are not available. Finally, the relative importance of bone density, bone quality and glucocorticoid sensitivity in SH is a recent field of research. On the other hand, SH prevalence seems to be increased in osteoporotic patients, in whom a vertebral fracture may be the presenting symptom of an otherwise asymptomatic cortisol excess. Therefore, the issue of who and how to screen for SH among the osteoporotic patients is widely debated. The present review will summarize the available data regarding the bone turnover, bone mineral density, bone quality and risk of fracture in patients with endogenous SH. In addition, the role of the individual glucocorticoid sensitivity in SH-related bone damage and the problem of diagnosing and managing the bone consequences of SH will be reviewed. Finally, the issue of suspecting and screening for SH patients with apparent primary osteoporosis will be addressed.

The utility of lumbar spine trabecular bone score and femoral neck bone mineral density for identifying asymptomatic vertebral fractures in well-compensated type 2 diabetic patients.

UNLABELLED: The objective of the study was to evaluate the usefulness of trabecular bone score (TBS) and bone mineral density (BMD) for identifying vertebral fractures (VFx) in well-compensated type 2 diabetic (T2D) patients. TBS and femoral neck BMD below certain cutoffs may be useful for identifying VFx in well-compensated T2D patients. INTRODUCTION: In T2D, the prevalence of VFx is increased, especially in poorly compensated and complicated diabetic patients. The possibility of predicting the fracture risk in T2D patients by measuring BMD and TBS, an indirect parameter of bone quality, is under debate. Therefore, the objective was to evaluate the usefulness of TBS and BMD for identifying VFx in well-compensated T2D patients. METHODS: Ninety-nine T2D postmenopausal women in good metabolic control (glycosylated haemoglobin 6.8 ± 0.7 %) and 107 control subjects without T2D were evaluated. In all subjects, we evaluated the following: the BMD at the lumbar spine (LS) and the femoral neck (FN); the TBS by dual X-ray absorptiometry; and VFx by radiography. In T2D subjects, the presence of diabetic retinopathy, neuropathy, and nephropathy was evaluated. RESULTS: T2D subjects had increased VFx prevalence (34.3 %) as compared to controls (18.7 %) (p = 0.01). T2D subjects presented higher BMD (LS -0.8 ± 1.44, FN -1.06 ± 1.08), as compared to controls (LS -1.39 ± 1.28, p = 0.002; FN -1.45 ± 0.91, p = 0.006, respectively). TBS was not different between diabetics and controls. In fractured T2D patients, LS-BMD, FN-BMD, and TBS were reduced (-1.2 ± 1.44; -1.44 ± 1.04; 1.072 ± 0.15) and the prevalence of retinopathy (15.4 %) was increased than in nonfractured T2D subjects (-0.59 ± 1.4, p = 0.035; -0.87 ± 1.05, p = 0.005; 1.159 ± 0.15, p = 0.006; 1.8 %, p = 0.04, respectively). The combination of TBS ≤1.130 and FN-BMD less than -1.0 had the best diagnostic accuracy for detecting T2D fractured patients (SP 73.8 %, SN 63.6 %, NPV 78.9 %, PPV 56.8 %). CONCLUSIONS: TBS and FN-BMD below certain cutoffs may be useful for identifying VFx in well-compensated T2D patients.

Lipid abnormalities in patients with adrenal incidentalomas: role of subclinical hypercortisolism and impaired glucose metabolism.

BACKGROUND: Subclinical hypercortisolism (SH) has been associated with metabolic complications such as type 2 diabetes mellitus, obesity and dyslipidemia. Scarce data are available regarding the lipid pattern abnormalities in SH, in relation to insulin resistance and impaired glucose metabolism (IGM). We aimed to evaluate the possible influence of SH on lipid pattern in relation to the presence/absence of impaired glucose metabolism. METHODS: In 338 patients with adrenal incidentaloma, the presence of SH, hypertension, dyslipidemia and IGM was evaluated. According to the presence of SH and IGM the patients were divided into 4 groups (IGM+SH+, IGM+SH-, IGM-SH+, IGM-SH-). We recruited 98 subjects without IGM (IGM-) and 100 with IGM (IGM+) as control groups. RESULTS: The prevalence of dyslipidemia was comparable among Group IGM+SH+, Group IGM+SH- and IGM+ controls (57.9, 58.4, 56%, P = NS). No difference in dyslipidemia prevalence among IGM- patients and IGM- controls was observed. The IGM+SH+ patients had a higher prevalence of dyslipidemia (57.9%) than IGM-SH+ ones (29.1%, P < 0.01). The IGM+SH- patients showed an increased prevalence of hypertension (76.6 vs 54.8%, P < 0.01) and dyslipidemia (58.4 vs 23.8%, P < 0.0001) as compared with IGM-SH- patients. Logistic regression analysis showed that only IGM was associated to dyslipidemia (OR 4.31, 95% CI 2.61-7.12, P = 0.0001) regardless of age, SH and gender. CONCLUSIONS: In the absence of alterations of glucose metabolism the presence of a subtle cortisol excess has no effect on lipid pattern. IGM seems to influence the lipid metabolism regardless of the presence of SH.

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis.

UNLABELLED: Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8% of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure. INTRODUCTION: To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO). METHODS: We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥ 7.5%, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥ 2 incident fragility fractures and/or a BMD decrease greater than the least significant change. RESULTS: Bisphosphonate treatment failure was observed in 25.8% of patients. Age, body mass index, years since menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95% CI 1.10-9.50, P = 0.034) and baseline alkaline phosphatase total activity levels ≥ 66.5 U/L (OR 4.22, 95% CI 1.48-12.01, P = 0.007), regardless of age, number of falls, LS BMD, and baseline SDI. CONCLUSIONS: The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates.

The role of salivary cortisol measured by liquid chromatography-tandem mass spectrometry in the diagnosis of subclinical hypercortisolism.

OBJECTIVE: The use of late-night salivary cortisol (LNSalC) for diagnosing subclinical hypercortisolism (SH) is debated. No data are available regarding the role of LNSalC as measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in SH diagnosis. The aim of this study was to evaluate the diagnostic accuracy of LNSalC measured by LC-MS/MS in SH. DESIGN: Cross-sectional prospective study of outpatients. METHODS: In 70 consecutive patients with adrenal incidentalomas (AI), without signs and symptoms of hypercortisolism, we diagnosed SH in the presence of at least two of the following: cortisol after 1 mg overnight dexamethasone suppression test (1  mg DST) >83  nmol/l, 24-h urinary free cortisol (UFC) >193  nmol/24  h, and morning ACTH <2.2  pmol/l. The LNSalC levels by LC-MS/MS at 2300  h (normal values <2.8  nmol/l) and the presence of hypertension, type 2 diabetes mellitus (T2DM), and osteoporosis (OP) were assessed. RESULTS: The increased LNSalC levels (>2.8  nmol/l) had an 83.3% specificity (SP) and a 31.3% sensitivity (SN) for predicting the biochemical diagnosis of SH. The increased LNSalC had an 85.2% SP and a 55.6% SN for predicting the presence of hypertension, T2DM, and OP, while the combination of LNSalC >1.4  nmol/l (cutoff with 100% SN) plus 1 mg DST >50  nmol/l had an 88.9% SN and an 85.2% SP (similar to SH criterion at enrollment). CONCLUSIONS: In AI patients, LNSalC measured by LC-MS/MS appears to be useful in combination with 1 mg DST for diagnosing SH, while it is not useful as a single criterion.

Bilateral and unilateral adrenal incidentalomas: biochemical and clinical characteristics.

OBJECTIVE: The possible different prevalence of arterial hypertension (AH), type 2 diabetes mellitus (T2DM), dyslipidaemia (DL) and vertebral fractures (FX) between patients with bilateral and unilateral adrenal incidentalomas (BAI and UAI, respectively) with and without subclinical hypercortisolism (SH) is unknown. In this study we compared the prevalence of AH, T2DM, DL and FX in BAI and UAI patients in relation to SH. DESIGN: Prospective study. METHODS: In 175 UAI and 38 BAI patients, we evaluated BMI, spinal and femoral bone mineral density (LS and FN BMD, respectively) and the presence of AH, T2DM, DL and FX. SH was diagnosed in the presence of 2 of the following: urinary free cortisol levels >193 nmol/24 h, serum cortisol levels after 1 mg dexamethasone suppression test >83 nmol/l or ACTH levels <2.2 pmol/l. RESULTS: Age, BMI and cortisol secretion were comparable, while FN BMD was lower in BAI than in UAI patients (-0.45±0.86 vs 0.09±1.07, P=0.004). The prevalence of SH, AH, T2DM, and DL was comparable, while the prevalence of FX was higher in BAI than in UAI (52.6 vs 28%, P=0.007). The presence of FX was associated with BAI (odds ratio (OR) 2.6, 95% confidence interval (95% CI) 1.2-5.6, P=0.016), after adjusting for SH (OR 1.77, 95% CI 0.85-3.7, P=0.12), BMI (OR 1.06, 95% CI 0.98-1.13, P=0.1), age (OR 1.07, 95% CI 1.04-1.11, P=0.0001) and LS BMD (OR 1.31, 95% CI 1.03-1.67, P=0.03). CONCLUSION: BAI patients have an increased FX risk than UAI ones. Further studies should investigate the causes of bone involvement in BAI patients.

Evidence for vitamin D deficiency and increased prevalence of fractures in autoimmune bullous skin diseases.

BACKGROUND: Vitamin D deficiency plays a role in autoimmune diseases and risk of fractures. No data are available on vitamin D levels and vertebral fractures in autoimmune bullous skin diseases. OBJECTIVES: To assess serum vitamin D levels and the prevalence of vertebral fractures in patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP), potentially fatal autoimmune bullous disorders. METHODS: We studied 13 consecutive inpatients with untreated active PV (six men and seven women, mean ± SD age 53·5 ± 14·3 years), 15 with BP (seven men and eight women, mean ± SD age 76·9 ± 12·4 years) and 28 age-, body mass index- and sex-matched controls. The 25-hydroxyvitamin D (25-OHD) levels and presence of vertebral fractures on spinal X-ray were assessed in all subjects. RESULTS: In patients with PV, 25-OHD levels were lower (mean ± SD 12 ± 4·4 ng mL(-1) ) and prevalence of severe hypovitaminosis D higher (62%) than in controls (mean ± SD 22·2 ± 11·7 ng mL(-1) , P = 0·012; 23%, P = 0·0047, respectively). The prevalence of fractures was 54% and 31% in patients with PV and controls, respectively. Patients with BP showed lower 25-OHD levels (mean ± SD 9·6 ± 7·2 ng mL(-1) ) and higher prevalence of severe hypovitaminosis D (73%) than controls (mean ± SD 22·6 ± 18·7 ng mL(-1) , P = 0·022; 27%, P = 0·01, respectively). The prevalence of fractures tended to be higher in patients with BP than in controls (67% vs. 33%, respectively, P = 0·068). CONCLUSIONS: The low 25-OHD levels found in PV and BP may suggest a role for this agent in their pathogenesis. The increased prevalence of fractures should be taken into consideration in patients who must be given corticosteroids.

Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects.

OBJECTIVE: Subclinical hypercortisolism (SH) has been associated with increased prevalence of hypertension, type 2 diabetes mellitus, dyslipidaemia, central obesity, osteoporosis and vertebral fractures. We aimed to investigate the accuracy of different SH diagnostic criteria in predicting the presence of complications. DESIGN: This was a retrospective study. PATIENTS: We evaluated data from 231 patients (120 women and 111 men) affected with adrenal incidentalomas (AI). MEASUREMENTS: We studied the accuracy of different SH diagnostic criteria (cortisol after 1 mg overnight dexamethasone suppression test - 1mg-DST - at different cut-off such as 49.7, 82.8, 137.9 nmol/l, elevated urinary free cortisol, reduced adrenal corticotroph hormone (ACTH) levels alone or various combination of these parameters) in predicting the concomitant presence of the following three complications: hypertension, type 2 diabetes and vertebral fractures. RESULTS: The criterion characterized by the presence of two of 1mg-DST >82.8 nmol/l, elevated UFC and reduced ACTH struck the best balance between sensitivity and specificity, reaching a good accuracy in predicting the cluster of complications (61.9%; 77.1% and 75.8%, respectively). The presence of this cluster was associated with this criterion (OR 4.75, 95%CI 1.8-12.7, P = 0.002) regardless of gonadal status, body mass index (BMI) and age. CONCLUSIONS: The SH criterion characterized by the presence of two of 1mg-DST >82.8 nmol/l, elevated UFC and reduced ACTH seems the best in predicting the presence of chronic manifestations of subtle cortisol excess.

Role of adrenal gland scintigraphy in patients with subclinical hypercortisolism and incidentally discovered adrenal mass.

BACKGROUND: The role of adrenal scintigraphy (AS) in the diagnosis of subclinical hypercortisolism (SH) in adrenal incidentaloma (AI) is debated. AIM: To evaluate the possible role of AS in identifying SH in AI patients. SUBJECTS AND METHODS: In the retrospective phase (2000-2004), 102 AI patients [71 females (F)/31 males (M)] referred to our center were reevaluated for SH. In the prospective phase (2005-2006), 42 patients (32F/10M) with suspected SH were evaluated performing AS and biochemical assessment of cortisol secretion. We report data of the prospective phase of the study. In these patients AS was performed at baseline; the difference between the uptake of the affected and the controlateral gland [mean Delta uptake (MDeltau)] was calculated. Cortisol secretion was evaluated in 3 different occasions. Patients were considered affected with SH if they presented at least twice 2 of the following criteria: urinary free cortisol >193 nmol/l, cortisol after 1 mg dexamethasone suppression test >83 nmol/l, ACTH levels <2.2 pmol/l. RESULTS: MDeltau was higher in patients with SH (no.=27, 5/22 M/F) than in patients without SH (83.7+/-12.5 vs 54.7+/-24.1%, p<0.001), and directly correlated with UFC (beta=0.387, p=0.015) and was predictive of SH (odds ratio 1.12, 95% confidence interval 1.03-1.22, p=0.009) regardless of age, body mass index, and diameter of the mass. A 75% MDeltau cut-off has 86.7% specificity and 81.5% sensitivity in diagnosing SH. CONCLUSIONS: AS is not recommended as screening test in AI patients, but it can be useful to exclude the presence of a subtle cortisol excess in patients with unclear biochemical diagnosis of SH.