Rosaria Santi

Intraprocedural cortisol measurement increases adrenal vein sampling success rate in primary aldosteronism.

BACKGROUND Adrenal venous sampling (AVS) is the gold standard for the identification of unilateral primary aldosteronism (PA), but is technically difficult. The aim of our study was to assess whether intraprocedural cortisol measurement (IPCM) increases AVS success rate. METHODS Twenty-five consecutive PA patients underwent cosyntropin-stimulated AVS. Cortisol was measured immediately in a first set of samples drawn from adrenal veins and inferior vena cava. The selectivity criterion was an adrenal vein-to-inferior vena cava cortisol ratio ≥5. If bilateral selectivity was not achieved in a first set of samples, a second set was obtained during the same radiological session. PA was judged as unilateral if the gradient of cortisol-corrected aldosterone between dominant and nondominant side was >3.5. Twenty-five consecutive PA patients who had previously been submitted to AVS without IPCM served as historical controls. Lateralizing patients who underwent unilateral adrenalectomy were followed for 2 years after surgery. RESULTS Bilateral selectivity using IPCM was achieved in 19/25 patients in the first set of samples, and in an additional four cases in the second set (92% vs. 76%; P = 0.06). The final rate of bilateral selectivity was higher than that obtained in the historical series (23/25 vs. 16/25, P = 0.04), whereas bilateral selectivity in the first set of samples was not different from that achieved in the historical series. Nineteen lateralizing patients (13 of the present series, six of the historical series) were submitted to adrenalectomy, resulting in reversal of PA. CONCLUSIONS IPCM increases the success rate of AVS.

A Clinical phenotype mimicking essential hypertension in a newly discovered family with liddle's syndrome

BACKGROUND Liddles syndrome (LS) is a monogenic form of hypertension simulating a mineralocorticoid excess, and is currently suspected in young hypokalemic hypertensives. The aims of the study were: (i) to evaluate the clinical phenotype of LS in a newly identified Italian family of Sicilian origin carrying a gain-of-function mutation of the β subunit of the epithelial sodium channel (ENaC) (P617L) previously reported by our group in an apparently unrelated Sicilian patient presenting the typical phenotype of LS including hypokalemia; (ii) to determine whether an unknown biological relationship exists between the newly identified family and the family of the proband previously reported. METHODS Genetic analysis was performed in the present family, in the individual in which the βP617L mutation was first observed, and in his relatives. RESULTS βP617L mutation was identified in the proband and in three maternal relatives. None of them showed hypokalemia. Mild to severe early onset hypertension and left ventricular hypertrophy were present in all of them. Analysis of mitochondrial DNA (mtDNA) and Y chromosome profiles in the present family and in the probands family previously reported showed the absence of a relationship between them. The availability of only one carrier of the mutation in one of the two families meant that a genetic analysis able to assess a founder effect was not feasible. CONCLUSIONS LS should be considered in all cases of early onset hypertension, independently of the plasma potassium concentration. The incidence of LS may be greater than is currently thought, because hypokalemia is not invariably present.

Letter: sprue‐like enteropathy associated with angiotensin II receptor blockers other than olmesartan

1. Kawaguchi-Suzuki M, Bril F, Kalavalapalli S, Cusi K, Frye RF. Concentration-dependent response to pioglitazone in nonalcoholic steato hepatitis. Aliment Pharmacol Ther. 2017;46:56-61. 2. Kalliokoski A, Neuvonen M, Neuvonen PJ, Niemi M. No significant effect of SLCO1B1 polymorphism on the pharmacokinetics of rosiglitazone and pioglitazone. Br J Clin Pharmacol. 2008;65:78-86. 3. Chang KL, Pee HN, Yang S, Ho PC. Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer’s disease. Sci Rep. 2015;5:9000. 4. Itkonen MK, Tornio A, Neuvonen M, Neuvonen PJ, Niemi M, Backman JT. Clopidogrel markedly increases plasma concentrations of CYP2C8 substrate pioglitazone. Drug Metab Dispos. 2016;44:1364-1371. 5. Kawaguchi-Suzuki M, Frye RF. Current clinical evidence on pioglitazone pharmacogenomics. Front Pharmacol. 2013;4:147.

Methotrexate versus cyclophosphamide for remission maintenance in ANCA-associated vasculitis: A randomised trial

Objectives The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. Methods In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. Results Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. Conclusions MTX may be effective and safe for remission-maintenance in AAV. Trial registration clinicaltrials.gov NCT00751517

A Rare Case of Carney-Stratakis Syndrome in a Patient With SDHA Mutation

Paragangliomas (PGLs) and pheochromocytomas (PCCs) are rare tumors that originate from the neuroendocrine tissue along the paravertebral axis. Up to 35% of these tumors may be hereditary either alone or as a component of a multiple tumor syndrome. The gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Most GISTs are driven by gain-of-function mutations in KIT (75-80%) or platelet-derived growth factor receptor-alpha (PDGFRA) (10%). Approximately 15% of GISTs occurring in adults with no KIT or PDGFRA mutations are thermed “wild-type” GISTs. Succinate dehydrogenase (SDH) mutations may contribute to occurrence of wild-type tumors. In 2002, Carney and Stratakis described a new familiar syndrome (CSS) of PGLs/PCCs and GIST caused by germline mutations in SDH. SDH may act as a tumor suppressor gene, and its defects may be oncogenic. In most of CSS cases, the mutations involve the SDHB/C/D subunits; SDHA mutations are reported but extremely rare. We report a case of CSS with a solitary GIST and an incidentally discovered silent PCC harboring an SDHA mutation. J Med Cases. 2017;8(6):191-195 doi: https://doi.org/10.14740/jmc2831w

Peptide Receptor Radionuclide Therapy–Induced Gitelman-like Syndrome

Peptide receptor radionuclide therapy (PRRT) is a molecular-targeted therapy in which a somatostatin analogue (a small peptide) is coupled with a radioligand so that the radiation dose is selectively administered to somatostatin receptor-expressing metastasized neuroendocrine tumors, particularly gastroenteropancreatic. Reported toxicities include myelotoxicity and nephrotoxicity, the latter manifesting as decreased kidney function, often developing months to years after treatment completion. We present a case of PRRT-induced kidney toxicity manifesting as a severe Gitelman-like tubulopathy with preserved kidney function. Because profound hypokalemia and hypocalcemia can lead to life-threatening arrhythmias, we highlight the necessity for careful monitoring of serum and urine electrolytes in patients receiving PRRT.

Total gastrectomy for rare refractory gastroparesis in patient with syringomyelia: A good impact on quality of life

Syringomyelia is a chronic progressive disease of the spinal cord. In symptomatic patients, bilateral sensory motor signs and symptoms prevail, moreover they can develop gastrointestinal disorders, although few studies have succeeded in explaining this correlation so far. We report a case of a 67-year-old woman with a history of pain in the back-lumbar spine and lower limbs, paresthesia and urinary incontinence. MRI revealed syringomyelia, extended from T3 to the medullary cone. Neurological picture was worsened by progressive and increasingly debilitating gastrointestinal symptoms refractory to dietary changes and medical treatment. Blood tests, gastrointestinal investigations and imaging were all normal apart from scintigraphy which confirmed delayed gastric emptying. The neurological symptoms disappeared after removal of an hemangioblastoma of the medullary cone. The persistent gastroparesis was treated by total gastrectomy with complete resolution of the patients gastrointestinal symptoms.

Hypertension-induced posterior reversible encephalopathy syndrome as the presentation of progressive bilateral renal artery stenosis

Posterior reversible encephalopathy syndrome (PRES) is characterized clinically by headache, altered mental status, visual loss, and seizures. PRES is associated with neuroradiological findings characterized by white matter abnormalities, predominantly in the parieto-occipital regions of the brain. PRES is most often described in cases of hypertensive encephalopathy, eclampsia, renal failure, and immunosuppressive or anticancer therapy. We report a case of PRES associated with severe hypertension in the setting of a progressive renovascular hypertension from bilateral atherosclerotic renal artery stenosis. The pathogenesis of PRES is discussed and the importance of a prompt diagnosis and treatment is emphasized.

LIDDLEʼS SYNDROME WITH A CLINICAL PHENOTYPE MIMICKING ESSENTIAL HYPERTENSION: PP.37.496

Objective: Liddles syndrome (LS) is a monogenic form of hypertension due to mutations of either β or γ subunits of the epithelial sodium channel (ENaC). We have previously reported a novel mutation (βP617L) of ENaC, resulting in the typical phenotype of LS, which includes hypokalemic alkalosis. Functional expression of this mutant ENaC showed a three-fold increase in the amiloride-sensitive Na+ current. Aim of this study was to analyze the clinical and biochemical phenotype of a second family carrying the βP617L mutation. Subjects and Methods: Both direct sequencing and restriction enzyme digestion of the C-terminal exon of the SCNN1B gene were performed in the proband, in the probands parents and in the members of the maternal line who consented to the analysis. Results: The proband, a 21 year-old male, had been hypertensive since the age of 17 ys. Early onset hypertension characterized 7 members of the maternal line across 3 generations. βP617L mutation was detected in all available members with juvenile hypertension. Probands maternal kindred was of Sicilian origin, as was the family carrying the same mutation previously reported by our group, despite no apparent relationship between them. Pretreatment clinical findings in the proband and the other analyzed carriers of the mutation are shown in the Table. Figure 1. No caption available. Conclusion: Measurement of both renin and aldosterone is worth performing in all patients with early onset hypertension, independently of serum potassium level, in order to exclude monogenic forms of low-renin hypertension. The incidence of LS may be greater than is currently thought.

INTRA-OPERATIVE CORTISOL ASSAY IMPROVES THE SUCCESS RATE OF ADRENAL VENOUS SAMPLING FOR PRIMARY ALDOSTERONISM: PP.18.198

Objective: Adrenal venous sampling (AVS) is the most accurate way for identification of unilateral subtypes of primary aldosteronism (PA). However, AVS is technically challenging, since the right adrenal vein is difficult to catheterize. Aim of this study was to measure the contribution of intra-operative cortisol assay in increasing the bilateral selectivity of AVS. Design and Methods: We performed AVS in 25 consecutive PA patients (age 49.3 ± 12.5, 7F/18 M). Diagnosis of PA was based on both plasma aldosterone (pg/ml)/renin (ng/ml/h) ratio >300 and plasma aldosterone >75 pg/ml at the end of i.v. saline load. Sequential AVS was performed during continuous cosyntropin infusion. In each patient, a first set of samples were drawn, and cortisol was measured on all specimens. The procedure was ended if bilateral selectivity was shown by the cortisol assay. If AVS did not turn out to be bilaterally selective, the patient was submitted to a second set of samples. Each adrenal venous sample was considered selective if adrenal vein to inferior vena cava (IVC) cortisol ratio (selectivity index) was >5. Among bilaterally selective AVSs, unilateral PA was considered if the gradient of cortisol-corrected-aldosterone (aldosterone/cortisol) between dominant and non-dominant adrenal veins (aldosterone lateralization ratio) was higher than 3.5. All patients who showed unilateral PA were subsequently submitted to unilateral laparoscopic adrenalectomy. Results: All samples drawn from left adrenal vein were selective. Bilateral selectivity was found in 19/25 (76%) in the first set of samples. Among the 6 patients with unsuccessful AVS in the first set, the second set of samples turned out to be bilaterally selective in four. Eventually, bilateral selectivity was achieved in 23/25 (92%) vs 19/25 (76%) in the first set of AVS (P = 0.06). Eleven out of the 23 subjects with successful AVSs showed lateralization and were submitted to unilateral adrenalectomy, resulting in both reversal of PA and cure or improvement of hypertension. Conclusion: Intra-procedure cortisol assay is useful in increasing the success rate of AVS for primary aldosteronism.