Assessing Lateralization Index of Adrenal Venous Sampling for Surgical Indication in Primary Aldosteronism.

BACKGROUND: Clinical practice guidelines recommend the Lateralization Index (LI) as the standard for determining surgical eligibility in primary aldosteronism (PA). Our goal was to identify the optimal LI cut-offs in adrenal venous sampling (AVS) for diagnosing PA that is amenable to surgical cure. METHODS: We conducted a retrospective international cohort study across 16 institutions in 11 countries, including 1,550 patients with PA who underwent AVS, with and/or without ACTH stimulation. The establishment of optimal cut-offs was informed by a survey of 82 PA patients in Japan, aimed at determining the LI cut-off aligned with patient expectations for a surgical cure rate. RESULTS: The survey revealed that a median cure rate expectation of 80% would motivate PA patients towards undergoing adrenalectomy. The optimal LI cut-offs achieving an adjusted positive predictive value (PPV) of 80% were identified as 3.8 for unstimulated AVS and 3.4 for ACTH-stimulated AVS. Furthermore, a contralateral ratio of less than 0.4 and the detection of an adrenal nodule on CT imaging were identified as independent predictors of surgically curable PA. Incorporating these factors with the optimal LI cut-offs, the adjusted PPV increased to 96.6% for unstimulated AVS and 89.6% for ACTH-stimulated AVS. No clear differences in predictive ability between unstimulated and ACTH-stimulated LI were found. CONCLUSIONS AND RELEVANCE: The present study clarified the optimal LI cut-offs for without and with ACTH stimulation. The presence of contralateral suppression and adrenal nodule on CT imaging seems to provide additional available information besides LI for surgical indication.

Long-term hypothyroidism in patients started on levothyroxine during pregnancy.

Background: Current guidelines recommend different postpartum approaches for patients started on levothyroxine (LT4) during pregnancy. Objective: We studied the postpartum management of these patients and determined factors associated with long-term hypothyroidism. Methods: A retrospective study was conducted at a tertiary center between 2014 and 2020, with LT4 initiation according to 2014 ETA recommendations. We performed multivariate logistic regression (MVR) and a receiver operating characteristic curve analysis to determine variables associated with long-term hypothyroidism and their optimal cutoffs. Results: LT4 was initiated in 177 pregnant women, and 106/177 (60%) were followed at long-term (at least 6 months post partum) (28.5 (9.0-81.9) months). LT4 could have been stopped in 45% of patients who continued it immediately after delivery. Thirty-six out of 106 (34%) patients were long-term hypothyroid. In them, LT4 was initiated earlier during pregnancy than in euthyroid women (11.7 ± 4.7 vs 13.7 ± 6.5 weeks, P = 0.077), at a higher thyroid-stimulating hormone (TSH) level (4.1 (2.2-10.1) vs 3.5 (0.9-6.9) mU/L, P = 0.005), and reached a higher dose during pregnancy (62.8 ± 22.2 vs 50.7 ± 13.9 µg/day, P = 0.005). In the MVR, only the maximal LT4 dose during pregnancy was associated with long-term hypothyroidism (odds ratio (OR) = 1.03, 95% CI: 1.00-1.05, P = 0.003). The optimal cutoffs for predicting long-term hypothyroidism were an LT4 dose of 68.75 µg/day (87% specificity, 42% sensitivity; P = 0.013) and a TSH level ≥ 3.8 mU/L (68.5% specificity, 77% sensitivity; P = 0.019). Conclusion: One-third of the patients who started on LT4 during pregnancy had long-term hypothyroidism. The TSH level at treatment initiation and the LT4 dose during pregnancy could guide the decision for continuing long-term LT4.

Personalized non-invasive diagnostic algorithms based on urinary free cortisol in ACTH-dependant Cushing's syndrome.

CONTEXT: Current guidelines for distinguishing Cushing's disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary MRI as first-line investigation for all patients, CRH testing is no longer available and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients. OBJECTIVE: To establish non-invasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters. DESIGN: Retrospective study. SETTING: University hospitals. PATIENTS: 247 CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served for external validation. RESULTS: 24h-urinary free cortisol (UFC) had the highest area under ROC curve for discrimination of CD from EAS (0·96 [95% CI, 0·92-0·99] in the primary study and 0·99 [95% CI, 0·98-1·00] in the validation cohort). The addition of clinical, imaging and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (c-statistic index 0·99 [95% CI, 0·97-1·00]). 3 groups were defined based on baseline UFC: < 3 (group one), 3-10 (group 2) and > 10 x the upper limit of normal (group 3), and were associated with 0%, 6·1% and 66·7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group one, MRI first followed by neck-to-pelvis CT-scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value. CONCLUSION: UFC accurately predicts EAS and can serve to define personalized and non-invasive diagnostic algorithms.

International multicenter survey on screening and confirmatory testing in primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. DESIGN: In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. RESULTS: We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers. CONCLUSIONS: Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.

Influence of secretory phenotype and preoperative preparation on surgical outcome in pheochromocytoma.

OBJECTIVES: Surgery of pheochromocytomas (PCs) still carries a high risk of haemodynamic complications during the perioperative period. We aimed to evaluate the influence of their secretory phenotype and preoperative alpha-blocker treatment on surgical outcome. DESIGN: A retrospective monocentric study at a tertiary medical centre. PATIENTS: In this study, 80 consecutive patients operated by the same team for a PC between 1988 and 2018. RESULTS: Diagnosis was based on typical symptoms and signs in 58 patients, genetic testing in 12 and work-up of an adrenal incidentaloma in 9. It was made during surgery in one patient. A genetic predisposition was found in one-third of index cases (21/62). The majority of the patients (73/79) had a secreting PC; more than 2/3 had an adrenergic phenotype and less than 1/3 a noradrenergic phenotype. The rate of perioperative haemodynamic complications was not influenced by the secretory phenotype, but persistent hypertension after surgery, recurrence and malignancy were more frequently observed in patients with a noradrenergic tumour. Preoperative alpha-blocker treatment was given for ≥ 14 days in 29 patients and, although being more symptomatic at diagnosis, these patients had less haemodynamic complications (3/29 vs 12/51 non-treated patients, P = 0.05). CONCLUSIONS: The occurrence of haemodynamic complications during surgery was not significantly affected by the secretory phenotype in our study, but noradrenergic tumours show a worse post-surgical outcome. Our data also provide additional support in favour of a sufficient preoperative alpha-blockade in patients with pheochromocytoma.

Endoscopic ultrasound-guided radiofrequency ablation: An effective and safe alternative for the treatment of benign insulinoma.

BACKGROUND: Insulinomas are usually benign, small-sized, well-encapsulated and often solitary pancreatic tumors. Currently, enucleation is the treatment of choice for sporadic solitary insulinoma if diameter is less than 2cm and the structural integrity of the pancreatic duct can be maintained. However, the procedure has a risk of postoperative complications, and especially of pancreatic fistula. There is growing interest in endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) as an effective and less invasive alternative treatment for benign sporadic insulinoma. METHOD: We retrospectively analyzed the efficacy and safety of EUS-RFA in four patients with benign localized insulinoma treated in our tertiary care center between June 2018 and November 2019. EUS-RFA was performed with a EUS-guided RFA 19-gauge needle electrode (Starmed; Taewoong Medical, Seoul, South Korea) that released energy at 50W up to 100 Ohms impedance. RESULTS: The series comprised three women and one man, with a median age of 58 years (range 52-82 years). Mean tumor size was 12mm. Although three of the four patients would have been eligible for surgery, EUS-RFA was proposed to them. Symptomatic and biological improvement occurred immediately, generally straight after the procedure, in all patients, and no serious complications were observed. During the mean follow-up period of 22 months, no symptom recurrence was observed. CONCLUSIONS: This preliminary report in 4 patients showed that EUS-RFA was an effective and relatively safe alternative treatment, devoid of major complications, for benign sporadic insulinoma. Larger-scale prospective multicenter studies are, however, needed to confirm the long-term effectiveness and safety of this novel technique.

A sarcoidosis-lymphoma syndrome revealed by hypopituitarism.

SUMMARY: A 26-year-old woman presented with persistent headache and tiredness. Biological investigations disclosed a moderate inflammatory syndrome, low PTH-hypercalcemia and complete anterior hypopituitarism. A magnetic resonance imaging (MRI) of the pituitary gland was performed and revealed a symmetric enlargement with a heterogeneous signal. Ophthalmological examination showed an asymptomatic bilateral anterior and posterior uveitis, and a diagnosis of pituitary sarcoidosis was suspected. As the localization of lymphadenopathies on the fused whole-body FDG-PET/computerized tomography (CT) was not evoking a sarcoidosis in first instance, an excisional biopsy of a left supraclavicular adenopathy was performed showing classic nodular sclerosis Hodgkin's lymphoma (HL). A diagnostic transsphenoidal biopsy of the pituitary gland was proposed for accurate staging of the HL and surprisingly revealed typical granulomatous inflammation secondary to sarcoidosis, leading to the diagnosis of a sarcoidosis-lymphoma syndrome. The co-existence of these diseases constitutes a diagnostic challenge and we emphasize the necessity of exact staging of disease in order to prescribe adequate treatment. LEARNING POINTS: The possibility of a sarcoidosis-lymphoma syndrome, although rare, should be kept in mind during evaluation for lymphadenopathies. In the case of such association, lymphoma usually occurs after sarcoidosis. However, sarcoidosis and lymphoma can be detected simultaneously and development of sarcoidosis in a patient with previous lymphoma has also been reported. An accurate diagnosis of the disease and the respective organ involvements, including biopsy, is necessary in order to prescribe adequate treatment.

[Factitious hypoglycemia : "a never-ending story"?] / Hypoglycémie factice : quand l'histoire se répète.

Our team of diabetologist is challenged by the case of a 41 year-old woman with recurrent hypoglycaemic episodes. Her clinical background was complex with, among others, a neuroendocrine tumor, a nonalcoholic steatohepatitis and an adrenal insufficiency; these conditions require the exploration of several potential causes. After excluding an endogenous etiology, a factitious hypoglycemia was quicky suspected by clinicians. However, several venous samples showed normal insulinemia and a moderately decreased C-peptide. After multidisciplinary team discussion and facing a strong clinical suspicion, samples were sent to another laboratory to confirm the insulin results. Substantially supratherapeutics insulin concentrations were highlighted. This confirms the previous suspicion of surreptitious insulin administration with a recombinant form unrecognized by our routinely used analyzer. This observation leads us to briefly discuss the lack of cross-reactivities observed with many different insulin assays.

Recurrent pituitary abscess: case report and review of the literature.

A 26-year-old woman presented with severe postpartum headaches. Magnetic resonance imaging (MRI) revealed a symmetric, heterogeneous enlargement of the pituitary gland. Three months later, she developed central diabetes insipidus. A diagnosis of postpartum hypophysitis was suspected and corticosteroids were prescribed. Six months later, the pituitary mass showed further enlargement and characteristics of a necrotic abscess with a peripheral shell and infiltration of the hypothalamus. Transsphenoidal surgery was performed, disclosing a pus-filled cavity which was drained. No bacterial growth was observed, except a single positive blood culture for Staphylococcus aureus, considered at that time as a potential contaminant. A short antibiotic course was, however, administered together with hormonal substitution for panhypopituitarism. Four months after her discharge, severe headaches recurred. Pituitary MRI was suggestive of a persistent inflammatory mass of the sellar region. She underwent a new transsphenoidal resection of a residual abscess. At that time, the sellar aspiration fluid was positive for Staphylococcus aureus and she was treated with antibiotics for 6 weeks, after which she had complete resolution of her infection. The possibility of a pituitary abscess, although rare, should be kept in mind during evaluation for a necrotic inflammatory pituitary mass with severe headaches and hormonal deficiencies. LEARNING POINTS: The possibility of a pituitary abscess, although rare, should be kept in mind during evaluation for a necrotic inflammatory pituitary mass with severe headaches and hormonal deficiencies.In a significant proportion of cases no pathogenic organism can be isolated.A close follow-up is necessary given the risk of recurrence and the high rate of postoperative pituitary deficiencies.

A severe but reversible reduction in insulin sensitivity is observed in patients with insulinoma.

BACKGROUND: Hypoglycemic manifestations are highly variable in patients with an insulinoma and largely independent of tumour size and severity of insulin hypersecretion. OBJECTIVES: We investigated the clinical, biological and tumoral characteristics of insulinomas in a large monocentric series of patients and we evaluated their insulin sensitivity before and after successful pancreatic surgery. PATIENTS AND METHODS: This was a retrospective analysis of 40 patients treated for an insulinoma between 1982 and 2012 in our academic hospital. Insulin sensitivity and beta cell function were evaluated by a HOMA test outside hypoglycaemic episodes in a large subset of these patients. RESULTS: The mean age at onset of symptoms was 48.8±20.1 years and the mean age at diagnosis was 50.7±19.9 years. Neuroglycopenic symptoms were observed in 90% of patients. The most effective preoperative imaging technique to localize the tumour was endoscopic ultrasound. Insulin sensitivity was greatly reduced in patients with insulinoma (38.9%±22.3%), while beta cells function was increased (359.0±171.5%), but to a variable extent (range: 110.6-678.6%). After complete resection of the tumour and remission of hypoglycemic episodes, insulin sensitivity increased in all evaluated subjects (72.8±36.7%) and normalized in the majority. CONCLUSION: Although neuroglycopenic symptoms are present in most patients, diagnosis of insulinoma is often delayed. Endoscopic ultrasound remains the most sensitive preoperative technique to localize the tumour. We also show that in response to chronic hyperinsulinemia, patients with insulinoma develop protective mechanisms responsible for a marked insulin resistance, which is reversible after complete resection of the tumour.