Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Efficacy of liraglutide 3.0 mg treatment on weight loss in patients with weight regain after bariatric surgery.

PURPOSE: Bariatric surgery, as Roux-en-Y gastric bypass (RYGB), laparoscopic gastric banding (LGB), and laparoscopic sleeve gastrectomy (LSG), is considered the gold standard treatment to achieve long-term weight loss in severe obesity. In patients who fail to maintain the achieved weight, pharmacological treatment may be required. Here, we reported our real-life experience on the efficacy of liraglutide therapy in 62 patients who regained weight after bariatric surgery. METHODS: We retrospectively evaluated 62 (60 F-2 M; mean age: 43.6 ± 9.9 years) patients received liraglutide for weight loss after bariatric surgery (17 RYGB, 22 LGB, and 23 LSG). Body mass index (BMI) before and after surgery was, respectively, of 45.4 ± 5.5 kg/m2 and 29.5 ± 4.9 kg/m2. Patients were followed up from 2016 until 2021. Liraglutide was administered after weight regain once-daily subcutaneously at starting dose of 0.6 mg and with weekly increases up to 3.0 mg. Treatments were administered when a weight regain of 10-15% occurred after reaching a minimum weight loss from bariatric surgery or if weight loss after bariatric surgery was unsatisfactory. RESULTS: After a mean of 70.7 ± 43.7 months from any bariatric surgery, all patients started liraglutide therapy. At this time, mean BMI was 34.2 ± 4.8 kg/m2 (mean increased BMI: 4.7 ± 2.8 kg/m2). After a mean of 10.5 ± 4.4 months from the beginning of liraglutide, 9 patients achieved normal weight (BMI 24.1 ± 0.9 kg/m2), and 28 were overweight (BMI 26.9 ± 1.6 kg/m2). Twenty patients achieved grade I (BMI 32.1 ± 1.5 kg/m2), 5 grade II (BMI 37.3 ± 2.0 kg/m2) obesity, and none had grade III obesity (mean BMI change: - 5.1 ± 2.5 kg/m2). The treatment was well tolerated, and no serious adverse events were recorded. CONCLUSION: These data confirm the efficacy and safety of liraglutide in patients who experienced weight regain after bariatric surgery. Considering the long-term follow-up, patients should be followed up regularly and the pharmacological treatment should be adapted to the weight fluctuations observed during the clinical history. LEVEL OF EVIDENCE: V. Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

Effectiveness of platelet-rich plasma in healing necrobiosis lipoidica diabeticorum ulcers.

Necrobiosis lipoidica diabeticorum (NLD) is a chronic condition, which is characterized by single or multiple lesions on the legs, and occurs in 0.3% of patients with diabetes. Recently, platelet-rich plasma (PRP) has been used in several clinical settings to promote sustained healing and better outcome. We propose the use of PRP for the treatment of NLD-associated recalcitrant wounds. In this study, 15 patients were treated with homologous PRP; all showed marked enhancement in wound healing without any adverse effects. After PRP application, advanced dressings were used until closure of the lesion was obtained, which was complete for all our patients. We therefore propose the use of PRP for recalcitrant wounds in patients with NLD.

Use of radioguided surgery with [111In]-pentetreotide in the management of an ACTH-secreting bronchial carcinoid causing ectopic Cushing's syndrome.

Intraoperative [111In]-pentetreotide scintigraphy with a hand-held gamma detector probe has recently been proposed to increase the intraoperative detection rate of small neuroendocrine tumors and their metastases. We report a case of a 28-yr-old woman with ectopic Cushing's syndrome due to an ACTH-secreting bronchial carcinoid, in whom the use of radioguided surgery improved disease management. At presentation, radiolabeled pentetreotide scintigraphy was the only procedure able to detect the ectopic source of ACTH. After radiologic confirmation, the patient underwent removal of a bronchial carcinoid, with disease persistence. After surgery, pentetreotide scintigraphy showed pathologic uptake in the mediastinum not previously detected at surgery and only subsequently confirmed by radiologic studies. Despite a second thoracic exploration, hormonal, scintigraphic, and radiological evidence of residual disease persisted. Radioguided surgery was then performed using a hand-held gamma probe 48 h after iv administration of a tracer dose of radiolabeled [111In-DTPA-D-Phe1]-pentetreotide, which permitted detection and removal of multiple residual mediastinal lymph node metastases. Clinical and radiologic cure, with no evidence of tracer uptake at pentetreotide scintigraphy, was subsequently observed. The use of an intraoperative gamma counter appears a promising procedure in the management of metastatic ACTH-secreting bronchial carcinoids.

Management of occult adrenocorticotropin-secreting bronchial carcinoids: limits of endocrine testing and imaging techniques.

The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography scan revealed the presence of a bronchial lesion in all patients, and pentetreotide scintigraphy identified four of six lesions. In all patients a bronchial carcinoid was found and removed. In one patient with scintigraphic evidence of residual disease after two operations, radioguided surgery, using a hand-held gamma probe after iv administration of radiolabeled pentetreotide, was performed; this allowed detection and removal of residual multiple mediastinal lymph node metastases. In conclusion, our data show that there is not a single endocrine test or imaging procedure accurate enough to diagnose and localize occult ectopic ACTH-secreting bronchial carcinoids. Radioguided surgery appears to be promising in the presence of multiple tumor foci and previous incomplete removal of the tumor.

The natural history of incidentally discovered adrenocortical adenomas: a retrospective evaluation.

Adrenal adenoma is the most frequent lesion among adrenal incidentalomas. The present retrospective study was undertaken to investigate medium-term evolution of supposed or ascertained adrenocortical adenomas in a group of 53 subjects (16 males and 37 females, aged 31-83 yr), with bilateral (no.=8) or monolateral (no.=45) incidentally discovered adrenal masses (size 10-50 mm, median 25 mm), who were followed-up for 6-78 months (median 24 months). Diagnosis of adenoma was based on size and morphovolumetric aspect of the lesion at computed tomography (CT), scintigraphic pattern using NP59 as a tracer, and it was histologically confirmed in 7 patients. After an extensive hormonal investigation including morning (no.=53) and midnight (no.=28) serum cortisol, plasma ACTH (no.=50), serum DHEAS (no.=51), daily urinary free cortisol excretion (no.=52), post-dexamethasone (1 mg) cortisol (no.=42) and ACTH stimulation test for 17-hydroxyprogesterone (17-OHP) response (no.=48) at the time of diagnosis, patients were periodically re-evaluated for hormonal function and radiological aspect of the lesion(s) by CT. Seven patients underwent surgery 6-42 months after incidentaloma demonstration, with histological diagnosis of adrenal adenoma. During follow-up an increase in the size of the lesion was demonstrated in 22 patients (41.5%); the increase was greater than 10 mm in 8 cases. In 3 patients with unilateral mass, a contralateral lesion appeared 10-52 months after first demonstration. Six patients (11.3%) showed reduction or disappearance of the lesions. On the basis of the hormonal evaluation 3 patients were considered to have subclinical Cushing's syndrome and 10 patients exhibited 17-OHP hyperresponse to ACTH test consistent with partial 21 -hydroxylase deficiency. A significant difference in the size of the lesions was observed between patients with or without 17-OHP hyperresponse to ACTH test (31.1 1.9 vs 24.1 +/- 1.2 mm; p<0.01). No significant changes in the hormonal parameters were observed in the patients, when retested. In conclusion, although none of the patients of the present series exhibited evolution to hypersecretion or to aberrant growth, in more than 40% of patients an increase in the size of the mass was observed, even after a long period of "quiescence". This suggests that a radiological re-evaluation of lesions should be periodically undertaken.

Growth hormone and prolactin responses to corticotrophin-releasing-hormone in patients with Cushing's disease: a paracrine action of the adenomatous corticotrophic cells?

OBJECTIVE: In patients with Cushing's disease multihormonal responses to ovine corticotrophin releasing hormone (oCRH) have been detected in blood from inferior petrosal sinuses. This finding has been explained by co-secretion of other hormones, in addition to ACTH, by the pituitary adenoma itself or by paracrine effects exerted by the adenoma on normal periadenomatous pituitary cells. To assess these hypotheses we compared the presence of a CRH induced GH and/or PRL response during inferior petrosal sinus sampling to the immunohistochemical detection of PRL and GH in adenomatous tissue removed from patients with Cushing's disease. PATIENTS AND MEASUREMENTS: Twenty-two patients with Cushing's disease and two patients with ectopic ACTH syndrome due to a bronchial carcinoid were studied; each patient had undergone preoperative inferior petrosal sinus sampling for diagnostic purposes with determination of GH and PRL in addition to ACTH, before and after administration of oCRH. Immunohistochemical studies for ACTH, GH and PRL detection were carried out on adenomatous tissue removed at surgery in the patients with pituitary dependent Cushing's disease and on the carcinoid tumours from the two patients with ectopic ACTH syndrome. RESULTS: All pituitary adenomas immunostained for ACTH, and four adenomas immunostained for GH or PRL in addition to ACTH. A PRL increase in the inferior petrosal sinus after oCRH administration was found in 11 of 22 patients, but none of their tumours immunostained for PRL. Immunostaining for PRL was found in the pituitary tumours from two patients but in neither patient was there a PRL response after oCRH. A GH response was found in 13 of 20 patients in whom it was sought; no patient showed immunostaining in their tumour. GH immunostaining was found in two tumours but in neither patient was there a GH response after oCRH. The oCRH-induced increase of GH and PRL was always recorded in the dominant inferior petrosal sinus. The ACTH response to oCRH was significantly higher in patients who showed oCRH induced increases in GH and/or PRL than in patients who did not, both in terms of area under the response-curve (22,032 +/- 9876 vs. 4371 +/- 2870 ng/l/10 min; P < 0.05) or mean percentage increase above baseline (754 +/- 229% vs. 147.2 +/- 67%, P < 0.02). A significant correlation was observed between ACTH and GH responses to oCRH. The two patients with ectopic Cushing's syndrome did not show ACTH, GH or PRL increases after oCRH administration and did not show immunostaining for GH or PRL in their tumours. CONCLUSIONS: The present data do not support the hypothesis of co-secretion of hormones by the pituitary adenoma as the cause of the GH and PRL responses to ovine corticotrophin releasing hormone observed in patients with Cushing's disease; it is suggested that a different mechanism, possibly involving an interaction between the ACTH secreting adenoma and the normal periadenomatous GH and PRL secreting cells, may be responsible.

Additive effect of ketoconazole and octreotide in the treatment of severe adrenocorticotropin-dependent hypercortisolism.

Over the last few years ketoconazole and octreotide have been employed in the treatment of pituitary-dependent or ectopic Cushing's syndrome. In four patients (two men and two women, aged 25-64 yr) with severe ACTH-dependent hypercortisolism in whom medical treatment with ketoconazole showed limited effectiveness and/or tolerability, we tried the association with octreotide. In all patients ketoconazole (200-1000 mg) induced a marked decrease in urinary free cortisol (UFC) excretion, but normalization could not be achieved. After ketoconazole discontinuation, three patients received octreotide alone (300-1500 micrograms/day, sc). This drug caused a dramatic decrease in UFC excretion, although not normalization; in all patients, escape from treatment occurred. Combined treatment was carried out for 10-180 days. Urinary cortisol excretion normalized and remained steadily within normal limits in three of four patients in whom normal UFC excretion had never been attained with both single drug regimens; in the fourth patient, UFC excretion decreased to levels lower than those achieved with ketoconazole or octreotide alone. The association with octreotide allowed a reduction in the daily dose of ketoconazole in three patients. Consistent with the steady reduction of cortisol production, a striking clinical improvement occurred in all patients after starting combined treatment. The normalization of UFC in three of four patients treated with both agents suggests that this approach may be useful in the long term treatment of severe forms of hypercortisolism of both pituitary and ectopic origin. In contrast to the limited effectiveness of each drug taken singularly at the same or higher doses, the association of the two drugs had an additive effect in the attainment of normal urinary cortisol excretion.

MR of corticotropin-secreting pituitary microadenomas.

PURPOSE: To assess the accuracy of MR in the preoperative identification of corticotropin-secreting pituitary microadenomas. METHODS: Twenty-six patients with clinical and biochemical evidence of pituitary-driven Cushing disease in whom MR of the seller region was performed were selected for this study. The MR examinations were retrospectively evaluated by a neuroradiologist who was aware of the presence of an adenoma at surgery but not of location and size of the lesion. RESULTS: Considering the whole group of MR examinations performed either without (n = 26) or without and with intravenous injection of gadopentetate dimeglumine (n = 16), overall 20 MR studies were judged to show disease. Seventeen of 26 microadenomas were adequately shown and located by MR (true-positive, 65.4%). In three cases the sides of the microadenomas were misjudged (false-positive, 11.5%). Six patients had negative MR studies (false-negative, 23%). Twelve of the 16 patients studied after gadopentetate dimeglumine injection had true-positive MR findings (75%). CONCLUSIONS: In our experience the accuracy of MR in detecting corticotropin-secreting microadenomas as small as 2 to 3 mm is 65% to 75%. Although precontrast images provide diagnostic information, the microadenoma can be better seen with administration of contrast material.

Early postoperative evaluation in patients with Cushing's disease: usefulness of ovine corticotropin-releasing hormone test in the prediction of recurrence of disease.

In the attempt to identify parameters that might predict the risk of recurrence of Cushing's disease at an early stage after successful pituitary microsurgery, we evaluated retrospectively the usefulness of an early postoperative determination of morning plasma and urinary cortisol levels and of adrenocorticotropin (ACTH) and cortisol responses to ovine corticotropin-releasing hormone (oCRH) stimulation in 30 patients with pituitary-driven Cushing's disease followed up for 9 months to 10 years after pituitary surgery. At an early postoperative evaluation, while off substitutive therapy, 30 patients, out of 36 treated by pituitary microsurgery for Cushing's disease, were considered in remission on the basis of subnormal (21 patients), low-normal (eight patients) or normal (one patient) morning plasma and urinary cortisol levels, whereas six patients with supranormal urinary cortisol excretion were considered as surgical failures. The plasma ACTH response to oCRH was subnormal (17 patients) or normal (four patients) in 21 patients (Group 1) and supranormal in nine patients (Group 2). All of the six patients with persistence of Cushing's disease had supranormal ACTH response to oCRH. Basal and oCRH-stimulated cortisol levels were subnormal in 25 out of 30 patients considered in remission. During long-term evaluation, six patients had recurrence of Cushing's disease 9 months to 5 years after surgery; their early postoperative mean basal morning plasma and mean urinary cortisol were higher than those recorded in patients who did not relapse, although a wide overlap between subjects was evident. In five out of these six patients urinary cortisol excretion had decreased to almost undetectable values during low-dose dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)

Memory impairment in Cushing's disease.

In the present study the cognitive performance of 25 patients with Cushing's disease (CD) was extensively evaluated in comparison with normal control subjects, matched one by one. The results indicate a selective impairment of memory functions: the number of patients showing a significantly impaired mnesic performance increases with age. Moreover, the neuropsychological impairment tends to recover in those cases who underwent further controls after surgical treatment. The neuropsychological data are discussed in the light of recent evidence in the literature concerning the effects of adrenal steroids on the brain.

Stimulatory effect of oCRH on alpha-subunit secretion during petrosal sinus sampling in patients with Cushing's disease.

During bilateral and simultaneous venous sampling of the inferior petrosal sinuses for preoperative localization of ACTH secreting microadenomas, alpha-subunit levels, in addition to ACTH, were determined in 9 patients with Cushing's disease. The aim of the study was to evaluate the possible occurrence of unilateral increases of alpha-subunit in basal conditions and the alpha-subunit responsiveness to oCRH. All the patients examined showed a central to peripheral and an intersinus gradient of ACTH concentrations before and/or after oCRH stimulation. Seven patients showed a central to peripheral alpha-subunit gradient in basal conditions. Lateralization of alpha-subunit concentrations was recorded in 4 patients in basal conditions (intersinus gradient > or = 1.55) and paralleled the side with the highest ACTH concentrations. After oCRH stimulation all but one patient showed a unilateral alpha-subunit increase in blood from the inferior petrosal sinus with the highest oCRH stimulated ACTH increase. The present data confirm the occurrence of an increase of alpha-subunit concentration in response to nonspecific stimulation with exogenously administered oCRH, concurrent with an ipsilateral increase of ACTH levels. The mechanism underlying this finding is still unclear, although a paracrine effect from the corticotroph tumour on adjacent pituitary tissue seems so far the most likely explanation.

Inferior petrosal sinus sampling: evidence of a stimulatory effect of oCRH on GH secretion in Cushing's disease.

Preoperative localization of ACTH-secreting microadenomas has been performed in 9 patients with Cushing's disease by using bilateral and simultaneous venous sampling of the inferior petrosal sinuses. In addition to ACTH and PRL we determined GH levels after oCRH stimulation in order to confirm the possible occurrence of unilateral GH increases, as recently observed by us in one patient. A central-to-peripheral and an intersinus gradient of ACTH concentration was observed in all patients examined before and/or after oCRH stimulation. In 7 patients central-to-peripheral and side-to-side PRL gradients were recorded in basal conditions: in 5 of these patients a unilateral oCRH-induced PRL increase was observed. Six out of the 7 patients with unilateral PRL increases also showed an intersinus GH gradient in basal conditions (ratio greater than or equal to 1.5); in 5 of them a clearcut oCRH-induced GH increase was observed. A peripheral oCRH-induced GH and PRL increase was not observed in any of the patients. The observation of a paradoxical oCRH-induced GH increase in the inferior petrosal sinus with the higher ACTH concentration is of speculative and clinical interest; whether it reflects co-secretion of hormones by the tumour or hormone release by non-tumourous cells via paracrine mechanism is still to be clarified. The unilateral GH increase could represent an additional signal of the presence and localization of an ACTH-secreting tumour.

Bilateral and simultaneous venous sampling of inferior petrosal sinuses for ACTH and PRL determination: preoperative localization of ACTH-secreting microadenomas.

We report our experience on venous sampling of the inferior petrosal sinuses for basal and CRH-stimulated ACTH and PRL gradients in 8 patients with surgically proven Cushing's disease who had normal preoperative neuroradiological studies. In 7 patients basal plasma ACTH concentrations in the inferior petrosal sinus ipsilateral to the tumor were higher than in the contralateral sinus; the gradients were enhanced by oCRH administration. In one out of two patients who had previously undergone unsuccessful pituitary microsurgery, neither basal nor oCRH-induced ACTH increases led to correct localization of the microadenoma within the pituitary. In 4 out of 7 patients basal serum PRL concentrations in the inferior petrosal sinus ipsilateral to the tumor were higher than in the contralateral; only two out of 4 showed an increase in PRL levels after oCRH injection. Our study confirms that simultaneous and bilateral venous sampling of inferior petrosal sinuses is a valuable means to identify the site of microadenomas in patients with Cushing's disease without neuroradiological evidence of the tumor. This procedure may give misleading results in patients previously operated on. Unilateral or predominant increases of PRL concentration during catheterization of the inferior petrosal sinuses, when present, always lateralize to the side of the corticotroph adenoma, providing a possible additional signal of the presence of the tumor.

Brain cholecystokinin depletion in rats with acute liver failure.

A decrease of both hypothalamic and cortical CCK occurred in the brain of rats killed 8 hours after hepatic artery ligation following portocaval anastomosis. Brain CCK depletion was not reproduced by exogenously provoked hyperammonemia nor by insulin-induced hypoglycemia, thus suggesting a central mechanism for the derangement of the CCKergic system in the course of acute liver failure.

Size reduction of an ACTH-secreting pituitary macroadenoma in Nelson's syndrome by sodium valproate: effect of withdrawal and re-institution of treatment.

We describe herein the reduction in the size of an ACTH-secreting pituitary macroadenoma in a patient with Nelson's syndrome during chronic administration of sodium valproate, and the changes in tumour volume after withdrawal and re-institution of treatment. The patient had elevated plasma ACTH levels (1123-1255 pmol/l), which increased markedly after CRH stimulation. A first 4-month course of sodium valproate administration (600 mg/day, orally) was started. Plasma ACTH fell to 550-726 pmol/l with persistence of responsiveness to CRH; brain computed tomography showed a clearcut reduction of tumour size. One month after drug withdrawal, the tumour volume appeared unchanged and plasma ACTH values ranged between 374 and 440 pmol/l. One and a half year after drug withdrawal, a brain computed tomography showed re-expansion of the pituitary adenoma with evidence of suprasellar extension, which had never been seen previously. Plasma ACTH ranged between 113 and 199 pmol/l. A second course of sodium valproate was started; after three months, a brain computed tomography documented clearcut reduction of tumour volume from a suprasellar extension to a partially empty pituitary fossa. Plasma ACTH ranged from 396 to 542 pmol/l with persistence of responsiveness to CRH. The present report documents for the first time the reduction of tumour size in a patient with an ACTH-secreting macroadenoma by chronic administration of sodium valproate.