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Marine Ollivier, Magalie Haissaguerre, Amandine Ferriere, and Antoine Tabarin
Cédric Fagour, Stéphane Bardet, Vincent Rohmer, Yannick Arimone, Pierre Lecomte, Nathalie Valli, and Antoine Tabarin
Prognostic factors for progression of benign adrenocortical adenomas (AI) remain poorly known. We assessed the usefulness of 131I-6-β-iodomethylnorcholesterol scintigraphy (IMS) to predict the occurrence of adrenal hyperfunction or mass enlargement.
Fifty-one consecutive inpatients with unilateral AI and normal 24-h urinary free cortisol (UFC) were enrolled in a multicenter observational prospective study to investigate the relationship between the scintigraphic pattern and the progression of biological abnormalities of the hypothalamo-pituitary–adrenal axis or tumor size.
Biochemically defined ‘subclinical’ Cushing's syndrome (SCS) was found at baseline in 47% of patients. Unilateral uptake (UU) was significantly associated with SCS (P<0.05). During the follow-up (4.3±1.6-year): 53% of patients showed unchanged hormonal evaluation, 29% displayed intermittent SCS and 18% showed definitive hormonal progression of SCS but without overt biochemical hypercortisolism. UU was associated with persistence of SCS and hormonal progression (P<0.01). In multivariate analysis, UU and impaired 1 mg dexamethasone suppression were independently associated with hormonal progression. Three patients with UU developed clinical CS despite persistently normal UFC. Tumor size increased in 10% patients and was not associated with any scintigraphic pattern.
Evolution of SCS toward overt biochemical CS in patients with AI is a rare event during a 4-year follow-up. UU is predictive for the occurrence of SCS, its persistence and progression within the spectrum of SCS. Further studies aiming to establish the clinical consequences of SCS are needed to recommend IMS as a complementary evaluation in patients with AI and biochemical SCS.
Antoine Tabarin, Pierre Cassiède, Anne Perrot Minot, Jean Claude Cuber, Patrick Roger, and Dominique Ducassou
The nature of NPY-like immunoreactivity (NPY-LI) was investigated in plasma and tumour tissue of 1 7 pheochromocytoma patients by HPLC, gel filtration and isoelectric focusing using two radioimmunoassays (RIAs) directed against the C- and N-terminals of NPY respectively. The two RIAs gave similar results in pheochromocytomas: 86% of cases had higher NPY-LI concentrations than those found in normal adrenal glands and NPY-LI behaved like authentic human NPY during gel filtration and HPLC. Assessed by isoelectric focusing, NPY was found to be amidated in seven of nine tumours. Contrary to the findings obtained in tumours, the results of the two RIAs in plasma samples were not always concordant: compared to controls, elevated concentrations of NPY-LI were found in 86% of cases of pheochromocytomas using the C-terminally directed RIA and in 76% of cases using the N-terminally directed RIA. The results of HPLC and gel filtration of NPY-LI in plasma suggested that circulating Cand N-terminal NPY fragments account for the discrepancy between the results of the two RIAs. In conclusion, most pheochromocytomas contain large amounts of NPY-LI that behaved like authentic NPY by chromatographic analysis. On the contrary, circulating NPY-LI in some pheochromocytoma patients is heterogeneous with cleaved products which influence differently the power of the C- and N-terminally directed RIAs for the diagnosis of pheochromocytoma.
John Newell-Price, Lynnette K Nieman, Martin Reincke, and Antoine Tabarin
Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing’s syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2–3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.
Julie Brossaud, Philippe Gosse, Blandine Gatta, Antoine Tabarin, Guy Simonnet, and Jean-Benoît Corcuff
We set up plasma normetanephrine (pNMA) and metanephrine (pMA) assays as they demonstrated their usefulness for diagnosing phaeochromocytomas. Our scope is to describe some practical laboratory aspects and the clinical relevance of these assays in our endocrinological or cardiological departments.
We retrospectively reviewed the results of MA from a population of in- and outpatients over a 7-year period. Subjects (n=2536) from endocrinological or cardiological departments were investigated (66 phaeochromocytomas). Urinary NMA (uNMA) and pNMA, and urinary MA (uMA) and pMA were assayed by HPLC with electrochemical detection.
pNMA and pMA assays are now more frequently requested than uNMA and uMA. This changed our laboratory work load with improved delivery, sensitivity and reliability of plasma assays as well as reduced apparatus maintenance time.
The pNMA and pMA upper reference limits (URLs) of subjects with no phaeochromocytoma were 1040 and 430 pmol/l respectively. Sensitivity and specificity based on receiver operating characteristic curves optimal points were 83 and 93% for pNMA at 972 pmol/l and 67 and 98% for pMA at 638 pmol/l. Sensitivity and specificity of paired tests of pMA (positive test: at least one analyte above its URLs) were 100 and 91% respectively.
The very low concentration of analytes requires a sustained very good apparatus analytical sensitivity. This can be obtained in an up-to-date laboratory. In terms of clinical performances, assays in plasma or urine are equivalent. Depending on local preferences, populations, strategies or departments, requests for one or the other assay may sustain the need for specifically defined reference ranges.
Magalie Haissaguerre, Marie Puerto, Marie-Laure Nunes, and Antoine Tabarin
Jean-Benoît Corcuff, Jacques Young, Pauline Masquefa-Giraud, Philippe Chanson, Eric Baudin, and Antoine Tabarin
Severe Cushing's syndrome elicited by ectopic ACTH syndrome (EAS) or adrenal carcinoma (ACC) can threaten life in the short term. The effectiveness of oral administration of the inhibitors of steroidogenesis ketoconazole and metyrapone in this situation is poorly described.
To report the short-term effectiveness and tolerability of metyrapone and ketoconazole elicited either by EAS or by ACC in patients exhibiting severe hypercortisolism.
Retrospective analysis of data obtained for patients with urinary free cortisol (UFC) level estimated to be fivefold the upper limit of the normal range (ULN).
Patients and settings
A total of 14 patients with EAS and eight with ACC treated in two tertiary-care university hospitals.
Metyrapone and ketoconazole treatment in combination (along with symptomatic treatments for co-morbidities).
Evolution of clinically relevant endpoints (blood pressure, kalaemia and glycaemia) and biological intensity of hypercortisolism 1 week and 1 month after starting steroidogenesis inhibition.
After 1 week of treatment, median UFC fell from 40.0 to 3.2 ULN and from 16.0 to 1.0 ULN in patients with EAS and ACC respectively. Median UFC after 1 month of treatment was 0.5 and 1.0 ULN in patients with EAS and ACC respectively and UFC values were normal in 73 and 86% of patients respectively. Clinical status improved dramatically along with kalaemia, glycaemia and blood pressure, allowing a decrease in the relevant treatments.
Side effects were minimal and only two patients (one EAS and one ACC) experienced plasma transaminase elevations necessitating ketoconazole withdrawal.
Metyrapone–ketoconazole combination therapy is well tolerated and provides rapid control of endocrine cancer-related life-threatening hypercortisolism.
Antoine Tabarin, Jean-Benoît Corcuff, Michel Rashedi, Reine Angibeau, Jean-Marie Caille, Dominique Ducassou, Bernard Dufy, and Patrick Roger
A multihormonal response to CRH during inferior petrosal sinus sampling in patients with Cushing's disease has recently been described. Whether it reflects multihormonal secretion by the corticotropic adenoma, or secretion by non-tumorous adjacent cells via paracrine mechanisms remains debatable. We have compared the effect of CRH on ACTH, GH, PRL and TSH secretion during inferior petrosal sinus sampling with its effect on the in vitro secretion of the corticotropic adenoma after excision in one case of Cushing's disease. Before CRH injection in vivo results show significant central-peripheral gradients for all hormones but only ACTH lateralized to the side of the tumor. After CRH administration, the petrosal concentrations of all hormones increased preferentially on the side of the adenoma resulting in significant intersinus gradients: 8.1 for ACTH, 2.0 for GH, 1.8 for PRL and 1.5 for TSH. In vitro results: the adenoma cells were immunostainable for ACTH only. In culture, they secreted ACTH only. Addition of CRH to the culture induced a mean increase of 160% in ACTH secretion but GH, PRL and TSH remained undetectable. Our results favor the hypothesis that the multihormonal response to CRH seen during inferior petrosal sinus sampling in Cushing's disease reflects a paracrine stimulation of the adjacent non-tumorous pituitary cells by the corticotropic adenoma.
Jacques Young, Magalie Haissaguerre, Oceana Viera-Pinto, Olivier Chabre, Eric Baudin, and Antoine Tabarin
Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in terms of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced comorbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to (1.) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and (2.) the tumoral status, ranging from resectable ACTH secreting tumors to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and include variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasize on the operational effectiveness of care.