Renin as a Biomarker to Guide Medical Treatment in Primary Aldosteronism Patients. Findings from the SPAIN-ALDO Registry.

INTRODUCTION: Primary aldosteronism (PA) is associated with several cardiometabolic comorbidities. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy has been reported to reduce the cardiometabolic risk. However, the cardiovascular benefit could depend on plasma renin levels in patients on MRA. AIM: To compare the development of cardiovascular, renal and metabolic complications between medically treated patients with PA and those who underwent adrenalectomy, taking the renin status during MRA treatment into account. METHODS: A multicenter retrospective study (SPAIN-ALDO Register) of patients with PA treated at 35 Spanish tertiary hospitals. Patients on MRA were divided into two groups based on renin suppression (n = 90) or non-suppression (n = 70). Both groups were also compared to unilateral PA patients (n = 275) who achieved biochemical cure with adrenalectomy. RESULTS: Adrenalectomized patients were younger, had higher plasma aldosterone concentration, and lower potassium levels than MRA group. Patients on MRA had similar baseline characteristics when stratified into treatment groups with suppressed and unsuppressed renin. 97 (55.1%) of 176 patients without comorbidities at diagnosis, developed at least one comorbidity during follow-up (median 12 months vs. 12.5 months' follow-up after starting MRA and surgery, respectively). Surgery group had a lower risk of developing new cardiovascular events (HR 0.40 [95% CI 0.18-0.90]) than MRA group. Surgical treatment improved glycemic and blood pressure control, increased serum potassium levels, and required fewer antihypertensive drugs than medical treatment. However, there were no differences in the cardiometabolic profile or the incidence of new comorbidities between the groups with suppressed and unsuppressed renin levels (HR 0.95 [95% CI 0.52-1.73]). CONCLUSION: Cardiovascular, renal, and metabolic events were comparable in MRA patients with unsuppressed and suppressed renin. Effective surgical treatment of PA was associated with a decreased incidence of new cardiovascular events when compared to MRA therapy.

Alemtuzumab induces severe orbitopathy in relapsing-remitting multiple sclerosis.

CONTEXT: Treatment with Alemtuzumab (ALZ) in patients with Relapsing-Remitting Multiple Sclerosis (RRMS) is associated with the development of ALZ-induced Graves' disease (GD-ALZ). Some cases may develop associated Graves´ Orbitopathy (GO-ALZ), with possible visual compromise. AIM: The aim of this study was to describe the main clinical and biochemical characteristics of GD-ALZ, as well as the clinical course of a case series of GO-ALZ METHODS: This study is a retrospective observational study, carried out in a reference hospital for the care of patients with RRMS in Spain. Cases treated with ALZ in the period 2014-2022 were included. GO-ALZ cases were identified among those with clinical symptoms compatible with thyroid eye disease after initiating ALZ treatment. RESULTS: A total of 135 cases, with a mean follow-up of 69.6 months after the first ALZ cycle, were included. The incidence of GD-ALZ was 32.6% (44/135), with a predominance of women (77.3%) and mean age of 41.9 years. The presence of first-degree relatives with hypothyroidism was identified as risk factor for the development of GD-ALZ (adjusted P-value: 0.02). GO-ALZ was diagnosed in 6 cases (incidence: 13.6%), of which 3 had severe clinical forms of GO, requiring anti-IL-6 treatment. A favorable response was reported in all of them, with a significant decrease in disease activity and improvement in proptosis. CONCLUSIONS: We report one of the largest cohorts of GD-ALZ and GO-ALZ cases. The diagnosis of these entities should be taken into account in patients treated with Alemtuzumab, given the risk of developing severe clinical forms. In moderate-severe forms of GO-ALZ, drugs with anti-IL-6 activity are a safe and effective option.

Is adrenal venous sampling always necessary to differentiate between unilateral and bilateral primary aldosteronism? Lesson from the SPAIN-ALDO register.

PURPOSE: To evaluate whether the clinical, biochemical and radiological features of patients with primary aldosteronism (PA) can predict both main subtypes of PA. METHODS: A retrospective multicenter study of PA patients followed in 27 Spanish tertiary hospitals (SPAIN-ALDO Register). Only patients with confirmed unilateral or bilateral PA based on adrenal venous sampling (AVS) and/or postsurgical biochemical cure after adrenalectomy were included. Supervised regression techniques were used for model development. RESULTS: 328 patients [270 unilateral PA (UPA), 58 bilateral PA (BPA)] were included. The area under the curve (AUC) for aldosterone/potassium ratio and aldosterone responses following saline infusion test were 0.602 [95%CI 0.520 to 0.684] and 0.574 [95% CI 0.446-0.701], respectively, to differentiate UPA from BPA. The AUC was 0.825 [95% 0.764-0.886] when the prediction model with seven parameters - comorbidities (dyslipidemia, cerebrovascular disease, sleep apnea syndrome [SAS]), systolic blood pressure (SBP), plasma aldosterone levels (PAC), hypokalemia and unilateral adrenal nodule >1 cm and normal contralateral adrenal gland on CT/MRI - was used. In patients without comorbidities, hypokalemia, SBP > 160 mmHg, PAC > 40 ng/dL, and unilateral adrenal lesions were associated with a likelihood of having a UPA of 98.5%. The chance of BPA was higher in individuals with comorbidities, SBP < 140 mmHg, normokalemia, low PAC levels, and no adrenal tumors on the CT/MRI (91.5%). CONCLUSION: A combination of high PAC, SBP > 160 mmHg, low serum potassium, a unilateral adrenal nodule>1 cm and no comorbidities could predict a UPA with a 98.5% accuracy.

Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes.

Purpose: The aim of this study was to evaluate the prevalence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) and its implications on cardiometabolic and surgical outcomes. Methods: This is a retrospective multicenter study of PA patients who underwent 1 mg dexamethasone-suppression test (DST) during diagnostic workup in 21 Spanish tertiary hospitals. ACS was defined as a cortisol post-DST >1.8 µg/dL (confirmed ACS if >5 µg/dL and possible ACS if 1.8-5 µg/dL) in the absence of specific clinical features of hypercortisolism. The cardiometabolic profile was compared with a control group with ACS without PA (ACS group) matched for age and DST levels. Results: The prevalence of ACS in the global cohort of patients with PA (n = 176) was 29% (ACS-PA; n = 51). Ten patients had confirmed ACS and 41 possible ACS. The cardiometabolic profile of ACS-PA and PA-only patients was similar, except for older age and larger tumor size of the adrenal lesion in the ACS-PA group. When comparing the ACS-PA group (n = 51) and the ACS group (n = 78), the prevalence of hypertension (OR 7.7 (2.64-22.32)) and cardiovascular events (OR 5.0 (2.29-11.07)) was higher in ACS-PA patients than in ACS patients. The coexistence of ACS in patients with PA did not affect the surgical outcomes, the proportion of biochemical cure and clinical cure being similar between ACS-PA and PA-only groups. Conclusion: Co-secretion of cortisol and aldosterone affects almost one-third of patients with PA. Its occurrence is more frequent in patients with larger tumors and advanced age. However, the cardiometabolic and surgical outcomes of patients with ACS-PA and PA-only are similar.

Diagnostic Accuracy of Adrenal Iodine-131 6-Beta-Iodomethyl-19-Norcholesterol Scintigraphy for the Subtyping of Primary Aldosteronism.

PURPOSE: To evaluate the diagnostic accuracy of the 131I-6ß-iodomethyl-19-norcholesterol (NP-59) adrenal scintigraphy for the subtyping diagnosis of primary aldosteronism (PA), considering as gold standard for the diagnosis of unilateral PA (UPA), either the results of the adrenal venous sampling (AVS) or the outcome after adrenalectomy. METHODS: A retrospective multicenter study was performed on PA patients from 14 Spanish tertiary hospitals who underwent NP-59 scintigraphy with an available subtyping diagnosis. Patients were classified as UPA if biochemical cure was achieved after adrenalectomy or/and if an AVS lateralization index > 4 with ACTH stimulation or >2 without ACTH stimulation was observed. Patients were classified as having bilateral PA (BPA) if the AVS lateralization index was ≤4 with ACTH or ≤2 without ACTH stimulation or if there was evidence of bilateral adrenal nodules >1 cm in each adrenal gland detected by CT/MRI. RESULTS: A total of 86 patients with PA were included (70.9% (n = 61) with UPA and 29.1% (n = 25) with BPA). Based on the NP-59 scintigraphy results, 16 patients showed normal suppressed adrenal gland uptake, and in the other 70 cases, PA was considered unilateral in 49 patients (70%) and bilateral in 21 (30%). Based on 59-scintigraphy results, 10.4% of the patients with unilateral uptake had BPA, and 27.3% of the cases with bilateral uptake had UPA. The AUC of the ROC curve of the NP-59 scintigraphy for PA subtyping was 0.812 [0.707-0.916]. Based on the results of the CT/MRI and NP-59 scintigraphy, only 6.7% of the patients with unilateral uptake had BPA, and 24% of the cases with bilateral uptake had UPA. The AUC of the ROC curve of the model combining CT/MRI and 59-scintigraphy results for subtyping PA was 0.869 [0.782-0.957]. CONCLUSION: The results of NP-59 scintigraphy in association with the information provided by the CT/MRI may be useful for PA subtyping. However, their diagnostic accuracy is only moderate. Therefore, it should be considered a second-line diagnostic tool when AVS is not an option.

Outcomes of a multidisciplinary Diabetic Foot Day Unit.

OBJECTIVE: To analyse the main characteristics of patients and the health outcomes obtained and to evaluate the impact of peripheral artery disease (PAD) in patients treated in our multidisciplinary Diabetic Foot Unit. RESEARCH DESIGN AND METHODS: Observational prospective study. 273 patients from two different populations (with and without PAD - classified according to the presence of distal pulses) treated over a 14-month period in the multidisciplinary Diabetic Foot Unit were included. The data on patient characteristics and outcomes were analysed for the purpose of comparison. For the inference study, a comparison of medians with the non-parametric test for independent samples for the quantitative variables and a χ2 test for the comparison of proportions in qualitative variables were performed. RESULTS: Patients with PAD ulcers were older (60 (54-67) vs. 64 (75-81), p=0.000) and had a higher macrovascular burden (8.1% vs. 29% for ischaemic heart disease history, p=0.000; 6.7% vs. 18.1% for cerebrovascular disease history, p=0.004). Their Texas Score was higher (p=0.000) and their major amputation rate was higher (1.4% vs. 12.3%, p=0.001). They had less background of previous ulcers (52.6% vs. 26.8%, p=0.000), their episode duration was shorter (4 (0-10) vs. 0 (0-3) weeks, p=0.000), and their proportional need for antibiotic therapy was lower (64.4% vs. 51.4%, p=0.03). CONCLUSIONS: The differences found between ulcers with and without vascular involvement support the need for a different approach and for the inclusion of vascular surgeons on the team. The multidisciplinary care model for diabetic foot patients could be effective and improve health outcomes.

Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice.

Objectives: The aim of this study is to investigate in depth diabetes mellitus associated with immune checkpoint inhibitors (DM-ICIs) by analysing a case series. We also evaluated the clinical impact of flash glucose monitoring (FGM) systems in the management of this entity. Methods: We conducted an observational cohort study of DM-ICIs diagnosed in two hospitals in Seville (Spain). Patients with a new diagnosis of diabetes mellitus (DM) or with sudden worsening of preexisting DM after starting treatment with ICIs, with a random 5 hour-postprandial C-peptide value of <0.6 nmol/L and without possibility of subsequent withdrawal of insulin treatment, were included. Results: A total of 7 cases were identified, mostly males (n = 6; 85.7%), with a mean age of 64.9 years. The mean glycated hemoglobin (HbA1c) upon diagnosis was 8.1%, with diabetic ketoacidosis (DKA) observed in 6 cases (85.7%). Subcutaneous flash glucose monitoring (FGM) systems were used in six cases, with a mean follow-up period of 42.7 weeks. During the first 90 days of use, mean average glucose was 167.5 mg/dL, with a coefficient of variation (CV) of 34.6%. The mean time in the range 70-180 mg/dL (TIR) was 59.7%, with a mean time above range (TAR) 181-250 mg/dL of 27.8% and a mean TAR > 250 mg/dL of 10.2%. The mean time below range (TBR) 54-69 mg/dL was 2%, while the mean TBR < 54 mg/dL was 0.3%. The mean glucose management indicator (GMI) was 7.3%. No significant differences were observed in FGM values for the following 90 days of follow-up. A progressive improvement in all parameters of glycaemic control was observed between the first month of FGM use and the sixth month of FGM use. Of note, there was a decrease in mean CV (40.6% to 34.1%, p = 0.25), mean TAR 181-250 (30.3% to 26%, p = 0.49), mean TAR > 250 mg/dL (16.3% to 7.7%, p = 0.09), mean TBR 54-69 mg/dL (5.2% to 2%, p = 0.16), and mean TBR < 54 mg/dL (1.8% to 0.2%, p = 0.31), along with an increase in mean values of TIR 70-180 mg/dL (46.5% to 60.5%, p = 0.09). The lack of statistical significance in the differences observed in the mean FGM values over the follow-up period may be related to the small sample size. Conclusion: DM-ICI is recognised by a state of sudden-onset insulinopenia, often associated with DKA. The use of FGM systems may be a valid option for the effective management of DM-ICIs and for the prevention of severe hyperglycaemic and hypoglycaemic episodes in this condition.

A national survey on the efficacy and safety of continuous subcutaneous insulin infusion in patients with type 1 diabetes in Spain.

AIMS: To assess safety and benefits of continuous subcutaneous insulin infusion (CSII) therapy in a cohort of type 1 diabetes patients in Spain. METHODS: A web-based national registry was created by the Working Group of the Spanish Diabetes Association. All patients on CSII being followed at selected referral centers were included. A cross-sectional analysis was performed. RESULTS: A total of 1275 patients were included. Data completion for patients on CSII was 67 ±â€¯32%. Indications for treatment were suboptimal glycemic control (32%), high glucose variability (24%), preconception care (14%) and hypoglycemia (11%). In the patients on CSII for ≥1 year (n = 843, mean CSII duration of 5 years), HbA1c decreased by 5 mmol/mol (0.5%) in the whole population and by 8 mmol/mol (0.7%) in subjects with suboptimal glycemic control as CSII indication. Percentage of patients achieving HbA1c ≤ 53 mmol/mol (7%) increased from 20% before CSII to 34% at the end of follow-up. Severe hypoglycemia decreased from 29% to 5%. The rate of discontinuation was 9.5%. HbA1c was lower in patients using bolus advisor and temporary basal rates. CONCLUSIONS: CSII was associated with a sustained improvement in glycemic control and a reduction in severe hypoglycemia. The use of advanced CSII settings was related to better glycemic control.

Diagnostic utility of PET/CT with 18F-DOPA and 18F-FDG in persistent or recurrent medullary thyroid carcinoma: the importance of calcitonin and carcinoembryonic antigen cutoff.

PURPOSE: This study sought to evaluate and compare the utility of 18-F-fluorodihydroxyphenylalanine (18F-DOPA) and 18-F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for identification of lesions in patients with recurrent medullary thyroid carcinoma (MTC). In addition, we analyzed the correlation between the calcitonin (Ct), carcinoembryonic antigen (CEA) levels, each doubling time (DT), and PET positivity. We evaluated the reliability of the 150 pg/mL Ct cutoff set by the American Thyroid Association guidelines for further imaging (including 18F-DOPA PET/CT). METHODS: We prospectively recruited 18 patients with recurrent MTC, identified by elevation of Ct or CEA. Each patient underwent a 18F-FDG PET/CT and a 18F-DOPA PET/CT. RESULTS: Abnormal uptakes were detected with 18F-DOPA (n=12) and 18F-FDG (n=9), (sensitivity of 66.7% vs. 50%; p<0.01). Twenty-eight lesions were detected with 18F-DOPA vs. 16 lesions with 18F-FDG (1.56±1.5 vs. 0.89±1.18 lesions per patient; p=0.01). None of our patients showed additional lesions with 18F-FDG in comparison to 18F-DOPA. Patient-based detection rate increased significantly with Ct levels ≥150 pg/mL vs. Ct<150 pg/mL for both 18F-DOPA (sensitivity 90.9% vs. 28.6%; p=0.013) and 18F-FDG PET/CT (sensitivity 72.7% vs. 14.3%; p=0.025). Using a CEA cutoff of ≥5 ng/mL, detection rates of 18F-DOPA and 18F-FDG PET/CT were 81.1% and 72.7%, respectively. No correlation between Ct-DT or CEA-DT and PET positivity was found. Histological confirmation was obtained in eight patients. CONCLUSIONS: 18F-DOPA PET/CT appears to be superior to 18F-FDG PET/CT in detecting and locating lesions in patients with recurrent MTC. This technique tends to be especially useful in patients with negative results in other imaging modalities and Ct≥150 pg/mL or CEA≥5 ng/mL.

Pheochromocytoma in neurofibromatosis type 1 during pregnancy.

Pregnant women with neurofibromatosis type 1 (NF-1) have increased complications during gestation, including hypertensive disorders that are sometimes caused by pheochromocytoma. Pheochromocytoma is an extremely rare condition during pregnancy, and the main clinical manifestation is hypertension. If not properly treated, pheochromocytoma has high maternal and fetal mortality rates. Early recognition and adequate clinical management before delivery have led to better outcomes in the last few decades. Despite the association of NF-1 and pheochromocytoma, there are few clinical reports of these two conditions in pregnant patients. We present a rare case of pheochromocytoma diagnosed during pregnancy in a patient with NF-1, and we describe the treatment and the obstetric and fetal outcomes. We also review other medical conditions related to NF-1 that complicated this patient's pregnancy.

Advanced thyroid carcinoma in pregnancy: case report of two pregnancies.

Differentiated thyroid carcinoma is one of the most frequently diagnosed cancers during pregnancy, second only to breast cancer. Therefore, it would be of value to determine if there are pregnancy-related physiological effects that impact long-term prognosis for patients with this disease. Hormone effects attributable to ß-human chorionic gonadotropin and estrogens seem particularly likely. We present a case of a 40-year-old woman with thyroid follicular carcinoma with accompanying bone metastases. The cancer was discovered immediately after childbirth and the woman became pregnant again when the disease was in an advanced stage. We describe the cancer evolution and present the maternal and fetal results. Pregnancy in women with advanced thyroid carcinoma could affect long-term prognosis. However, more studies are needed to evaluate this hypothesis. In this unique case, there were two pregnancies and the second occurred in an advanced state of the disease. We evaluated how these pregnancies could affect short-term prognosis of the disease.

The lack of consensus in management of malignant struma ovarii.

Struma ovarii is a rare variant of teratoma characterized by the presence of thyroid tissue in more than 50%. Malignant transformation is rare (less than 5%) and the criteria to classify this condition have changed over time. Nowadays it must fulfill the histological categories of differentiated thyroid carcinoma. Its treatment is controversial and there is no unanimous management. We present three cases of women with malignant struma ovarii, diagnosed by the surgical specimen.