Anna Pia

AME Position Statement on Adrenal Incidentaloma.

OBJECTIVE To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushings syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma

The use of either mitotane or chemotherapy in the treatment of advanced adrenocortical carcinoma (ACC) has led to scanty and controversial results. The recent finding that mitotane is able to reverse in vitro multidrug resistance has provided a rational basis for combining this agent with cytotoxic drugs. The association of mitotane with etoposide, doxorubicin, and cisplatin (EDP) in the treatment of patients with advanced, inoperable ACC was tested in an Italian multicenter Phase II trial.

Twenty-four hour profile of blood pressure in patients with acromegaly. Correlation with demographic, clinical and hormonal features

Cardiovascular events are frequently reported in patients with acromegaly and they are usually related to arterial hypertension. Aim of the present study was to assess the 24-hour profile of blood pressure (BP) and heart rate (HR) in patients with active acromegaly and to correlate them with clinical and hormonal data. Sixteen patients and 16 healthy, age and sex matched subjects underwent ambulatory blood pressure monitoring by means of a portable automatic device (SpaceLabs monitor 90207, Kontron) with measurements every 20 minutes for 24 hours. The presence of the nocturnal fall was assessed by the calculation of the night-day systolic and diastolic ratio. The mean 24-hour diastolic BP was significantly higher in acromegalic patients than in controls (79.1±11.5 mmHg vs 70.8±5.3 mmHg, p<0.05) and the circadian diastolic profile was flatten. In fact, 10/16 patients were defined as nondippers while this figure was 2/16 in the control group (62% vs 12%, p<0.01). Also the mean 24-hour systolic BP was higher in acromegalic patients than in controls (124.8±17.2 mmHg vs 114.1±8.6 mmHg, p<0.05). The circadian systolic profile paralleled that of diastolic and was flatten, without a significant nocturnal fall. Ten out of 16 patients were nondippers compared to 2/16 controls (62 vs 12%, p<0.01). No significant correlation was found between mean 24-hour BP, either diastolic or systolic, and demographic or hormonal characteristics of the patients. HR patterns did not differ between patients and controls and were characterized by a prominent nocturnal fall.

The oral glucose tolerance test reveals a high frequency of both impaired glucose tolerance and undiagnosed Type 2 diabetes mellitus in primary hyperparathyroidism

Aims To evaluate the frequency of impaired glucose tolerance (IGT)and undiagnosed diabetes mellitus together with the indices of insulinresistance (IR) in primary hyperparathyroidism (pHPT).

Management of adrenal incidentaloma

Clinically inapparent adrenal masses, or adrenal incidentalomas, are discovered inadvertently in the course of work-up or treatment of unrelated disorders. Cortical adenoma is the most frequent tumour detected incidentally, but adrenocortical cancer, phaeochromocytoma and metastasis are not rare. Two critical questions should be answered before trying to outline the management of adrenal incidentaloma: (1) which tumours may cause harm to the patient, and (2) can we recognize and effectively treat such tumours? Based on the available scientific evidence, two major recommendations should be made: (1) identify either primary (adrenocortical cancer) or secondary (adrenal metastasis) malignancy; (2) identify phaeochromocytoma. Radiological evaluation is the key to the differential diagnosis of benign and malignant tumours. Endocrine testing is necessary to exclude phaeochromocytoma in all patients with an adrenal incidentaloma because this tumour may remain undiagnosed after imaging studies. The management of clinically inapparent adrenal adenomas may vary depending whether or not they are functioning. It is reasonable to screen for primary aldosteronism all hypertensive patients and recommend adrenalectomy when an aldosterone-producing adenoma is confirmed. A subset of adenomas secretes cortisol autonomously and may lead to mild hypercortisolism, a condition defined as subclinical Cushings syndrome. The criteria for defining subclinical Cushings syndrome are controversial, and we currently do not have sufficient evidence to define a gold standard for screening. Also the management of this condition is largely empirical, and data are insufficient to indicate the superiority of a surgical or non-surgical approach to managing patients with subclinical Cushings syndrome.

Subclinical Cushing’s syndrome: definition and management

Subclinical Cushing’s syndrome is an ill‐defined endocrine disorder that may be observed in patients bearing an incidentally found adrenal adenoma. The concept of subclinical Cushing’s syndrome stands on the presence of ACTH‐independent cortisol secretion by an adrenal adenoma, that is not fully restrained by pituitary feed‐back. A hypercortisolemic state of usually minimal intensity may ensue and eventually cause harm to the patients in terms of metabolic and vascular diseases, and bone fractures. However, the natural history of subclinical Cushing’s syndrome remains largely unknown. The present review illustrates the currently used methods to ascertain the presence of subclinical Cushing’s syndrome and the surrounding controversy. The management of subclinical Cushing’s syndrome, that remains a highly debated issue, is also addressed and discussed. Most of the recommendations made in this chapter reflects the view and the clinical experience of the Authors and are not based on solid evidence.

Screening of Cushing's syndrome in adult patients with newly diagnosed diabetes mellitus

Objective  Recent studies have shown that a relatively high number of diabetic patients may have unsuspected Cushings syndrome (CS). The aim of the present study was to screen for CS in adult patients with newly diagnosed diabetes mellitus who were not selected for clinical characteristics, such as poor control and obesity, which may increase the pre‐test probability of CS.

Screening of Cushing's Syndrome in Outpatients with Type 2 Diabetes: Results of a Prospective Multicentric Study in Italy

CONTEXT Cushings syndrome may remain unrecognized among patients referred for metabolic syndrome; thus, a proactive screening has been suggested in certain patient populations with features of the disorder. However, conflicting data have been reported on the prevalence of Cushings syndrome in patients with type 2 diabetes. OBJECTIVE Our aim was to evaluate the prevalence of unsuspected Cushings syndrome among outpatients with type 2 diabetes. DESIGN AND SETTING This was a cross-sectional prospective study in 24 diabetes clinics across Italy. PATIENTS Between June 2006 and April 2008, 813 patients with known type 2 diabetes without clinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September 2010. Patients were not selected for characteristics conferring a higher pretest probability of hypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexamethasone suppression test. RESULTS Forty patients failed to suppress serum cortisol less than 5.0 μg/dl (138 nmol/liter) and underwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6% of the overall series) failed to suppress cortisol less than 1.8 μg/dl (50 nmol/liter), receiving a definitive diagnosis of Cushings syndrome that was adrenal dependent in five patients. Four patients were cured, being able to discontinue, or reduce, the glucose-lowering agents. CONCLUSIONS The present data do not support widespread screening of patients with type 2 diabetes for Cushings syndrome; however, the disorder is less rare than previously thought when considering epidemiology of type 2 diabetes. Our results support a case-finding approach in patients with uncontrolled diabetes and hypertension despite appropriate treatment.

Cyclic Cushing’s syndrome due to ectopic ACTH secretion by an adrenal pheochromocytoma

Pheochromocytoma is a rare cause of ectopic Cushing’s syndrome. We report on such a patient in whom ectopic ACTH secretion displayed a cyclic pattern. A 35-year-old woman was referred to us with a diagnosis of ACTH-dependent Cushing’s syndrome. A 3.3 cm left-sided adrenal mass was noted at abdominal computerized tomography. At admission, clinical and hormonal data were unrewarding, so it was decided to continue to observe the patient. Four months later, she became symptomatic with hypertensive and psychotic crises and glycemic decompensation. By that time, a full-blown Cushing picture was evident. Severe hypercortisolism was documented with urinary free Cortisol ranging 1500–2200 μg/24 h, serum Cortisol 143–160 μg/dl and plasma ACTH 167–218 pg/ml. Neither ACTH nor Cortisol values were significantly modified after high-dose dexamethasone, oCRH or metyrapone. Urinary catecholamine and vanilyl mandelic acid excretion were moderately elevated. Chest CT and total body MIBG scan were negative and magnetic resonance of the sella region was inconclusive. No center to periphery ACTH gradient was observed by inferior petrosal sinus catheterization, whereas a significant left to right gradient was found on selective adrenal vein catheterization. A left adrenalectomy was performed and a 4 cm medullary neoplasia was removed. The cells were immunostained for ACTH, neuron-specific enolase and A chromogranin. Signs and symptoms of Cushing’s syndrome resolved with normalization of basal and dynamic endocrine evaluations. The patient is considered cured 10 months after surgery.

The limited value of the desmopressin test in the diagnostic approach to Cushing's syndrome.

OBJECTIVE The desmopressin test is generally regarded as an alternative to the CRH test but it is unclear whether desmopressin is as effective as CRH in the differential diagnosis of ACTH‐dependent Cushings syndrome. However, a precise assessment of the operating characteristics of the desmopressin test in comparison with the CRH test has not been reported. The aim of the present study was to make a comparative evaluation of desmopressin and CRH tests in a consecutive cohort of patients with ACTH‐dependent Cushings syndrome and in a group of healthy subjects.