Fibroblast Growth Factor 23-Producing Phosphaturic Mesenchymal Tumor with Extraordinary Morphology Causing Oncogenic Osteomalacia.

A possible cause of hypophosphatemia is paraneoplastic secretion of fibroblast growth factor 23 (FGF-23). Tumors secreting FGF-23 are rare, mostly of mesenchymal origin, usually benign, and may be located anywhere in the body, including hands and feet, which are often not represented in conventional imaging. A 50-year-old woman presented with diffuse musculoskeletal pain and several fractures. Secondary causes of osteoporosis were excluded. Laboratory analysis revealed hypophosphatemia and elevated alkaline phosphatase, parathyroid hormone, and FGF-23. Thus, oncogenic osteomalacia due to neoplastic FGF-23 secretion was suspected. FDG-PET-CT and DOTATATE-PET-CT imaging demonstrated no tumor. Cranial MRI revealed a tumorous mass in the left cellulae ethmoidales. The tumor was resected and histopathological examination showed a cell-rich tumor with round to ovoid nuclei, sparse cytoplasm, and sparse matrix, resembling an olfactory neuroblastoma. Immunohistochemical analysis first led to diagnosis of olfactory neuroblastoma, which was later revised to phosphaturic mesenchymal tumor. Following the resection, FGF-23 and phosphate levels normalized. In conclusion, we here describe a patient with an FGF-23-secreting phosphaturic mesenchymal tumor with an unusual morphology. Furthermore, we emphasize diagnostic pitfalls when dealing with FGF-23-induced hypophosphatemia.

The SPARTACUS Trial: Controversies and Unresolved Issues.

Adrenal vein sampling (AVS) is considered the gold standard for the differential diagnosis in patients with primary aldosteronism (PA). The distinction between unilateral and bilateral disease dictates the targeted therapeutic approach with surgery for aldosterone producing adenomas and medical therapy for patients with bilateral hyperplasia. Thereby, this diagnostic step is crucial in clinical care. As AVS is an invasive, not well standardized procedure that is restricted to few specialized centers, several attempts have been made to simplify diagnostic algorithms. In this clinical scenario, the recently published SPARTACUS trial aimed at answering the question whether AVS in fact is superior for differential diagnosis in comparison to imaging of the adrenal glands. In this multicenter study, patients were randomized to be treated according to AVS results or based on abdominal imaging only. Clinical outcome in both patient groups after one year was reported as not different. While the study results found broad interest, it also stirred considerable controversies. This review provides an overview on the different views regarding the outline of the SPARTACUS trial and the interpretation of its results.

[Diagnosis and therapy of primary aldosteronism: new aspects]. / Diagnostik und Therapie des Conn-Syndroms: neue Aspekte.

Primary aldosteronism represents the most frequent cause of endocrine hypertension. It is associated with a higher morbidity and mortality compared to essential hypertension. Early identification of the affected patients is crucial, as the adequate therapy leads to an excellent long-term prognosis, especially after unilateral adrenalectomy. Diagnosis consists of three steps: diagnosis, confirmation test and subtype differentiation. The 2 most frequent causes of primary aldosteronism are aldosterone producing adenoma, which can be cured by surgery, and idiopathic bilateral adrenal hyperplasia, which is treated with mineralocorticoid receptor antagonists.Screening by aldosterone-to-renin ratio is recommended in designed risk populations. As the aldosterone-to-renin ratio displays a limited sensitivity and specificity, confirmatory testing is recommended in most patients with positive screening test. Prediction scores allow to skip confirmatory testing under certain circumstances. Adrenal vein sampling still represents the gold standard in subtype differentiation of primary aldosteronism. Steroid profiling could possibly make dispensable adrenal vein sampling in patients with bilateral hyperplasia. Different studies investigate the potential of functional imaging for differential diagnosis of primary aldosteronism.

Prevalence of Primary Aldosteronism in Newly Diagnosed Hypertensive Patients in Primary Care.

CONTEXT: Primary aldosteronism (PA) represents the most frequent cause of endocrine arterial hypertension. PA is also common in patients with mild forms of hypertension and normokalemia. OBJECTIVE: To identify the prevalence of PA in newly diagnosed hypertensive patients in primary care in Southern Germany. PATIENTS AND METHODS: Newly diagnosed hypertensive patients in 27 primary care centers in Munich agreed to participate in the study. Patients were screened for PA using the aldosterone-to-renin ratio (ARR). In case of elevated ARR, confirmation testing was performed. After the diagnosis of PA, subtype differentiation and subsequent therapy of PA were initiated. RESULTS: A total of 235 patients with newly discovered arterial hypertension were initially screened for PA. Among these, 35 were excluded because the medication indicated pre-existing treated arterial hypertension or they were on interfering antihypertensive medication. At the first screening, 2.0% of the patients had hypokalemia. Of the 200 patients with newly discovered arterial hypertension, 42 had an elevated ARR. The incidence of the presence of hypokalemia did not differ according to normal or pathological ARR. Nine patients (21%) did not show up for further testing and were lost to follow-up, and 33 patients underwent a saline infusion test. Of these, 11 patients were diagnosed with PA, leading to at least 5.5% prevalence of PA in the collective. None of the diagnosed PA patients was hypokalemic at screening. CONCLUSION: A 5.5% prevalence of PA was observed in our data of untreated newly diagnosed patients with hypertension.

Primary and Secondary Hyperparathyroidism in Patients with Primary Aldosteronism - Findings From the German Conn's Registry.

CONTEXT: Recent studies support a bidirectional interaction between aldosterone and parathyroid hormone (PTH), possibly increasing the individual cardiovascular risk. Primary aldosteronism (PA) and primary hyperparathyroidism can occur simultaneously. OBJECTIVE: Our aim was to investigate the prevalence of hyperparathyroidism in PA. PATIENTS: We performed a case finding of primary hyperparathyroidism in a retrospective series of 503 patients with PA (cohort 1). We analysed primary and secondary hyperparathyroidism in 141 prospective PA patients who underwent PTH, serum calcium and phosphate measurements at time of diagnosis of PA (cohort 2). RESULTS: The prevalence for primary hyperparathyroidism was 1.2% in cohort 1, and 2.1% in cohort 2. Secondary hyperparathyroidism was found in 54.6% of the patients. Patients with secondary hyperparathyroidism had significantly higher aldosterone and lower potassium levels and took more antihypertensive medications compared to those with normal PTH levels. In multivariate analysis, aldosterone and 25-hydroxyvitamin D levels were significantly correlated with serum PTH levels. There was a nonsignificant trend to a higher cardiovascular morbidity in patients with secondary hyperparathyroidism. Patients with aldosterone producing adenoma had significantly higher PTH levels compared to patients with bilateral adrenal hyperplasia. After treatment, there was a significant decrease of PTH levels in both groups. CONCLUSION: Patients with PA frequently have primary or secondary hyperparathyroidism, which is alleviated by correction of PA by surgical or medical means. Patients affected by secondary hyperparathyroidism seem to have a more severe phenotype of PA and have a trend towards more cardiovascular co-morbidities.

Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism.

BACKGROUND: Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS: We performed mass spectrometry-based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS: Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION: Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING: Medical Research Council UK, Wellcome Trust, European Commission.

Worsening of lipid metabolism after successful treatment of primary aldosteronism.

Primary aldosteronism (PA) describes the most frequent cause of secondary arterial hypertension. Recently, deterioration of lipid metabolism after adrenalectomy (ADX) for aldosterone-producing adenoma (APA) has been described. We analysed longitudinal changes in lipid profiles in a large prospective cohort of PA patients. Data of 215 consecutive PA patients with APA (n = 144) or bilateral idiopathic adrenal hyperplasia (IHA, n = 71) were extracted from the database of the German Conn's Registry. Patients were investigated before and 1 year after successful treatment by ADX or by mineralocorticoid receptor antagonists (MRA). Glomerular filtration rate (GFR), fasting plasma glucose and components of lipid metabolism including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined at 8.00 after a 12-h fasting period. One year after initiation of treatment mean serum potassium levels and blood pressure normalized in the patients. HDL-C and TG developed inversely with decreasing HDL-C levels in patients with APA (p = .046) and IHA (p = .004) and increasing TG levels (APA p = .000; IHA p = .020). BMI remained unchanged and fasting plasma glucose improved in patients with APA (p = .004). Furthermore, there was a significant decrease of GFR in both subgroups at follow-up (p = .000). Changes in HDL-C and TG correlated with decrease in GFR in multivariate analysis (p = .024). Treatment of PA is associated with a deterioration of lipid parameters despite stable BMI and improved fasting plasma glucose and blood pressure. This effect can be explained by renal dysfunction following ADX or MRA therapy.