Cristina Eller-Vainicher

Beneficial Metabolic Effects of Prompt Surgical Treatment in Patients with an Adrenal Incidentaloma Causing Biochemical Hypercortisolism

CONTEXT In patients with adrenal incidentalomas, subclinical hypercortisolism (SH) is associated with an increased prevalence of the metabolic syndrome. The effect of surgical/conservative approach is debated. OBJECTIVE The objective of the study was to determine the effect of the surgical and conservative approaches on the metabolic syndrome in patients with adrenal incidentalomas. DESIGN This was a retrospective longitudinal study (18-48 months follow-up). SETTING The study was conducted on an in- and outpatient basis. PATIENTS One hundred eight patients with adrenal incidentalomas were studied for the presence of SH, which was diagnosed in the presence of more than two of the following: urinary free cortisol greater than 70 microg per 24 h (193 nmol per 24 h), cortisol after 1 mg dexamethasone suppression test greater than 3.0 microg/dl (83 nmol/liter), ACTH less than 10 pg/ml (2.2 pmol/liter). INTERVENTIONS Surgery was performed in 25 patients with SH (group TrSH+) and 30 without SH (group TrSH-), whereas the conservative approach was chosen by 16 patients with SH (group UntrSH+) and 37 without SH (group UntrSH-). MAIN OUTCOME MEASURES During the follow-up, the improvement/worsening of body weight, blood pressure, or glucose and cholesterol levels was defined in the presence of a greater than 5% weight decrease/increase and following the European Society of Cardiology or the Adult Treatment Panel III criteria, respectively. RESULTS In group TrSH+, weight, blood pressure, and glucose levels improved (32, 56, and 48%, respectively) more frequently than in group UntrSH+ (12.5%, P = 0.05; 0.0%, P < 0.0001; 0.0%, P = 0.001; and 0.0%, P = 0.0014, respectively). In group UntrSH+, blood pressure, glucose, and low-density lipoprotein levels worsened more frequently (50.0, 37.5, and 50.0%, respectively) than in group TrSH+ (0.0%, P < 0.0001; 0.0%, P = 0.001; and 20.0%, P = 0.05, respectively). CONCLUSIONS Regarding the various components of the metabolic syndrome, in patients with adrenal incidentalomas and SH, surgery is beneficial.

Bone Mineral Density, Prevalence of Vertebral Fractures, and Bone Quality in Patients with Adrenal Incidentalomas with and without Subclinical Hypercortisolism: An Italian Multicenter Study

CONTEXT In patients with adrenal incidentalomas and subclinical hypercortisolism (SH), the factors influencing bone and the prevalence of vertebral fractures are debated. Spinal deformity index (SDI), which reflects bone quality, has never been evaluated. OBJECTIVE The objective of the study was to investigate in these patients SDI and factors influencing the prevalence of fractures. DESIGN This was a retrospective, multicenter study. SETTING The study was conducted on an in- and outpatient basis. PATIENTS Patients included 287 adrenal incidentaloma patients (111 eugonadal males, 31 premenopausal, 145 postmenopausal females) and 194 controls (90 eugonadal males, 29 premenopausal, 75 postmenopausal females). MAIN OUTCOME MEASURE Bone mineral density (BMD) was measured by dual X-ray absorptiometry at lumbar spine and femoral neck. By radiograph each vertebra was assessed as intact (grade 0) or grade 1 (20-25%), 2 (25-40%), or 3 (>40%) deformity; SDI was calculated by summing the grade of deformity for each vertebra. SH was diagnosed in the presence of at least two of the following: urinary free cortisol greater than 70 microg per 24 h (193.1 nmol/liter), cortisol after 1-mg dexamethasone test greater than 3.0 microg/dl (>82.8 nmol/liter), ACTH less than 10 pg/ml (<2.2 pmol/liter). RESULTS BMD was significantly lower in SH+ than SH- patients and controls (lumbar spine -0.73 +/- 1.43, 0.17 +/- 1.33, 0.12 +/- 1.21, respectively; femoral neck -0.37 +/- 1.06, 0.07 +/- 1.09, 0.17 +/- 1.02). Patients with SH had higher fracture prevalence and SDI than those without SH and controls (70.6, 22.2, 21.8%, respectively, P < 0.0001; 0.31 +/- 0.68, 0.39 +/- 0.93, 1.35 +/- 1.27, respectively, P < 0.0001). Fractures and SDI were associated with SH (odds ratio 7.27, 95% confidence interval 3.94-13.41, P = 0.0001; beta = 0.352, t = 6.241, P = 0.0001, respectively) regardless of age, BMD, menopause, and gender. CONCLUSION SH is associated with low BMD, high fracture prevalence, and reduced bone quality as measured by SDI.

The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma

OBJECTIVE The criteria for defining subclinical hypercortisolism (SH) are debated and a real gold standard test or combination of tests is lacking. Recently, late-night salivary cortisol (MSC) has been described as a sensitive and easy-to-perform marker for diagnosing overt hypercortisolism. No data are available on the role of MSC in the diagnosis of SH. The aim of this study was to evaluate the sensitivity and specificity of MSC levels in the diagnosis of SH in patients with adrenal incidentalomas (AI). METHODS In 103 (females/males, 69/34) patients with AI, MSC levels were studied. One milligram overnight dexamethasone suppression test (DST), urinary-free cortisol (UFC), and ACTH plasma levels were also evaluated. Patients were defined as affected by SH if they showed two of the following criteria: DST>83 nmol/l, ACTH <2.2 pmol/l, and UFC >193 nmol/24 h. RESULTS No difference in MSC levels in patients with SH (3.1+/-3.1 nmol/l) compared with patients without SH (2.2+/-2.8 nmol/l) was observed. In patients with SH, MSC levels were significantly correlated with DST (r=0.4, P<0.05). Using the cut-off of 5.1 nmol/l, the sensitivity and specificity of MSC levels for diagnosis of SH is 22.7 and 87.7% respectively. CONCLUSION In patients with AI, normal levels of MSC do not exclude SH, whereas high levels may suggest the presence of SH identified by conventional tests. Thus, MSC is not suitable as a screening test, although it may be used in conjunction with other tests as the confirming test in selected patients.

Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: a multicenter longitudinal study

In patients with adrenal incidentalomas (AIs), cross‐sectional studies suggested the presence of an association between subclinical hypercortisolism (SH) and an increased prevalence of vertebral fractures (VFx) and spinal deformity index (SDI), which is a clinical index of bone quality. No longitudinal studies investigated the incidence of VFx and SDI changes over time in SH. The aim of this study was to evaluate VFx risk and SDI changes in SH over time. One‐hundred‐three consecutive AI patients were studied at baseline and after 12 and 24 months. Patients were divided into SH+ (n = 27) and SH– (n = 76) groups on the basis of the presence of two or more among urinary free cortisol greater than 70 µg/24 hours, serum cortisol after 1‐mg dexamethasone suppression test greater than 3.0 µg/dL, and adrenocorticotropic hormone (ACTH) less than 10 pg/mL in 2 or more of the 3 evaluations. At baseline and after 24 months, bone mineral density (BMD) by dual‐energy X‐ray absorptiometry and the presence of VFx and SDI by summing the grade of deformity for each vertebra were evaluated. At the end of follow‐up, the SH+ group showed a higher prevalence of VFx (81.5%) as compared with baseline (55.6%, p = .04) and a worsening of SDI (2.11 ± 1.85 versus 1.11 ± 1.47, p = .032) associated with SH regardless of age, gender, body mass index , BMD, baseline SDI, menopause duration [odds ratio (OR) = 12.3, 95% confidence interval (CI) 4.1–36.5, p = .001]. The incidence of new vertebral fractures was higher in the SH+ group (48%) than in the SH– group (13%; p = .001). It is concluded that subclinical hypercortisolism is associated with an increased risk of VFx and a possible deterioration of bone quality.

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.

Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism

Patients with adrenal incidentalomas (AIs) and subclinical hypercortisolism (SH) have increased risk of fracture independent of bone mineral density (BMD) and possibly due to reduced bone quality. The trabecular bone score (TBS) has been proposed as a index of bone microarchitecture. The aim of the study was to investigate TBS in AI. In 102 AI patients, SH was diagnosed in the presence of at least two of the following: (1) urinary free cortisol >70 µg/24 h (193.1 nmol/L); (2) cortisol after 1‐mg dexamethasone suppression test (1‐mg DST) >3.0 µg/dL (82.8 nmol/L); or (3) adrenocorticotropic hormone (ACTH) <10 pg/mL (<2.2 pmol/L). In patients and in 70 matched controls, BMD was measured at lumbar spine (LS) and femur (neck [FN] and total [FT]) by dual X‐ray absorptiometry and TBS was assessed in the region of LS‐BMD; BMD and TBS data were reported as Z‐scores. In patients, vertebral deformities were assessed by radiograph. Patients with SH (n = 34) had lower LS‐BMD (−0.31 ± 1.17), FT‐BMD (−0.29 ± 0.91), and TBS (−3.18 ± 1.21) than patients without SH (n = 68, 0.31 ± 1.42, p = 0.03; 0.19 ± 0.97, p = 0.01; −1.70 ± 1.54, p < 0.0001, respectively) and controls (0.42 ± 1.52, p = 0.02; 0.14 ± 0.76, p = 0.02; −1.19 ± 0.99, p < 0.0001, respectively). TBS was inversely correlated with 1‐mg DST (β = −0.26, t = −2.79, p = 0.006) regardless of age, LS‐BMD, body mass index (BMI), and gender. The presence of fracture was associated with low TBS alone (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.85–12.42, p = 0.001) and with the cluster low TBS plus low LS‐BMD (OR, 4.37; 95% CI, 1.71–11.4, p = 0.002), after adjustment for age, BMI, and gender. Low TBS plus low LS‐BMD showed a good specificity (79%) for predicting fractures, whereas normal TBS (ie, > −1.5) plus normal LS‐BMD high specificity (88.1%) for excluding fractures. Finally, TBS predicted the occurrence of a new fracture in 40 patients followed for 24 months (OR, 11.2; 95%CI, 1.71–71.41, p = 0.012) regardless of LS‐BMD, BMI, and age. In SH, bone quality, as measured by TBS, is altered. TBS is useful in detecting AI patients at risk of fractures.

Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency: a prospective intervention study.

CONTEXT Effects of vitamin D repletion in young people with low vitamin D status have not been investigated so far. OBJECTIVE We evaluated the effect of a single massive dose of cholecalciferol on calcium metabolism at 3, 15, and 30 d, compared to baseline. DESIGN AND SETTING We conducted a prospective intervention study in an ambulatory care setting. PARTICIPANTS Forty-eight young subjects with vitamin D deficiency participated in the study. INTERVENTION A single oral dose of 600,000 IU of cholecalciferol was administered to each subject. MAIN OUTCOME MEASURES We evaluated serum changes of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, calcium, and PTH induced by a single load of cholecalciferol. RESULTS The 25(OH)D level was 15.8 ± 6.5 ng/ml at baseline and became 77.2 ± 30.5 ng/ml at 3 d (P < 0.001) and 62.4 ± 26.1 ng/ml at 30 d (P < 0.001). PTH levels concomitantly decreased from 53.0 ± 20.1 to 38.6 ± 17.2 pg/ml at 3 d and to 43.4 ± 14.0 pg/ml at 30 d (P < 0.001 for both). The trends were maintained in a subgroup followed up to 90 d (P < 0.001). Mean serum Ca and P significantly increased compared to baseline, whereas serum Mg decreased at 3 d. 1,25-Dihydroxyvitamin D significantly increased from 46.8 ± 18.9 to 97.8 ± 38.3 pg/ml at 3 d (P < 0.001) and to 59.5 ± 27.3 pg/ml at 60 d (P < 0.05). CONCLUSIONS A single oral dose of 600,000 IU of cholecalciferol rapidly enhances 25(OH)D and reduces PTH in young people with vitamin D deficiency.

Sporadic and MEN1-related primary hyperparathyroidism: differences in clinical expression and severity.

Primary hyperparathyroidism (PHPT) is a common endocrine disease that is associated with multiple endocrine neoplasia type 1 (MEN1) in ∼2% of PHPT cases. Lack of a family history and other specific expressions may lead to underestimated MEN1 prevalence in PHPT. The aim of this study was to identify clinical or biochemical features predictive of MEN1 and to compare the severity of the disease in MEN1‐related versus sporadic PHPT (sPHPT). We performed a 36‐mo cross‐sectional observational study in three tertiary referral centers on an outpatient basis on 469 consecutive patients with sporadic PHPT and 64 with MEN1‐related PHPT. Serum calcium, phosphate, PTH, 25(OH)D3, and creatinine clearance were measured, and ultrasound examination of the urinary tract/urography was performed in all patients. In 432 patients, BMD was measured at the lumbar spine (LS) and femoral neck (FN). MEN1 patients showed lower BMD Z‐scores at the LS (−1.33 ± 1.23 versus −0.74 ± 1.4, p = 0.008) and FN (−1.13 ± 0.96 versus −0.6 ± 1.07, p = 0.002) and lower phosphate (2.38 ± 0.52 versus 2.56 ± 0.45 mg/dl, p = 0.003) and PTH (113.8 ± 69.5 versus 173.7 ± 135 pg/ml, p = 0.001) levels than sPHPT patients. Considering probands only, the presence of MEN1 was more frequently associated with PTH values in the normal range (OR, 3.01; 95% CI, 1.07–8.50; p = 0.037) and younger age (OR, 1.61; 95% CI, 1.28–2.02; p = 0.0001). A combination of PTH values in the normal range plus age <50 yr was strongly associated with MEN1 presence (OR, 13.51; 95% CI, 3.62–50.00; p = 0.0001). In conclusion, MEN1‐related PHPT patients show more severe bone but similar kidney involvement despite a milder biochemical presentation compared with their sPHPT counterparts. Normal PTH levels and young age are associated with MEN1 presence.

Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?

OBJECTIVE Few data are available regarding the need of steroid substitutive therapy after unilateral adrenalectomy for adrenal incidentaloma (AI). It is unknown whether, before surgery, the hypothalamic-pituitary-adrenal (HPA) axis secretion parameters can predict post-surgical hypocortisolism. AIM This study aimed to evaluate whether, in AI patients undergoing unilateral adrenalectomy, post-surgical hypocortisolism could be predicted by the parameters of HPA axis function. DESIGN Prospective, multicenter. METHODS A total of 60 patients underwent surgical removal of AI (surgical indication: 29 subclinical hypercortisolism (SH); 31 AI dimension). Before surgery, SH was diagnosed in patients presenting at least three criteria out of urinary free cortisol (UFC) levels>60 microg/24 h, cortisol after 1-mg dexamethasone suppression test (1 mg-DST)>3.0 microg/dl, ACTH levels<10 pg/ml, midnight serum cortisol (MSC)>5.4 microg/dl. Two months after surgery, HPA axis function was assessed by low dose ACTH stimulation test or insulin tolerance test when needed: 39 patients were affected (Group B) and 21 were not affected (Group A) with hypocortisolism. The accuracy in predicting hypocortisolism of pre-surgical HPA axis parameters or their combinations was evaluated. RESULTS The presence of >2 alterations among 1 mg-DST>5.0 microg/dl, ACTH<10 pg/ml, elevated UFC and MSC has the highest odds ratio (OR) for predicting post-surgical hypocortisolism (OR 10.45, 95% confidence interval, CI 2.54-42.95, P=0.001). Post-surgical hypocortisolism was predicted with 100% probability by elevated UFC plus MSC levels, but not ruled out even in the presence of the normality of all HPA axis parameters. CONCLUSION Post-surgical hypocortisolism cannot be pre-surgically ruled out. A steroid substitutive therapy is indicated after unilateral adrenalectomy for SH or size of the adenoma.

Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism

BACKGROUND AND OBJECTIVE Single nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT). DESIGN A genotype-phenotype association study. METHODS In all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients. RESULTS The allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygous or heterozygous PHPT patients for the AA haplotype (n=174, AA/AA or AA/GG diplotype) had an increased stone risk (odds ratio 1.83, 95% confidence interval 1.2-2.9, P=0.008). Furthermore, these PHPT patients had higher serum concentrations of ionized calcium and parathyroid hormone (1.50 ± 0.015 mmol/l and 183 ± 12.2 pg/ml) than patients with the GG/GG diplotype (n=145, 1.47 ± 0.011 mmol/l (P=0.04) and 150 ± 11.4 pg/ml (P=0.049)). Using a logistic regression model, the increase in stone risk in PHPT patients was predicted by AA/AA or AA/GG diplotype, the highest tertile of serum ionized calcium values and the lowest tertile of age. CONCLUSIONS Polymorphisms located in the regulatory region of the CASR gene may increase susceptibility of the PHPT patients to kidney stone production.