Gabriele Parenti

Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis.

Background Hyponatremia is the most common electrolyte disorder in clinical practice, and evidence to date indicates that severe hyponatremia is associated with increased morbidity and mortality. The aim of our study was to perform a meta-analysis that included the published studies that compared mortality rates in subjects with or without hyponatremia of any degree. Methods and Findings An extensive Medline, Embase and Cochrane search was performed to retrieve the studies published up to October 1st 2012, using the following words: “hyponatremia” and “mortality”. Eighty-one studies satisfied inclusion criteria encompassing a total of 850222 patients, of whom 17.4% were hyponatremic. The identification of relevant abstracts, the selection of studies and the subsequent data extraction were performed independently by two of the authors, and conflicts resolved by a third investigator. Across all 81 studies, hyponatremia was significantly associated with an increased risk of overall mortality (RR = 2.60[2.31–2.93]). Hyponatremia was also associated with an increased risk of mortality in patients with myocardial infarction (RR = 2.83[2.23–3.58]), heart failure (RR = 2.47[2.09–2.92]), cirrhosis (RR = 3.34[1.91–5.83]), pulmonary infections (RR = 2.49[1.44–4.30]), mixed diseases (RR = 2.59[1.97–3.40]), and in hospitalized patients (RR = 2.48[2.09–2.95]). A mean difference of serum [Na+] of 4.8 mmol/L was found in subjects who died compared to survivors (130.1±5.6 vs 134.9±5.1 mmol/L). A meta-regression analysis showed that the hyponatremia-related risk of overall mortality was inversely correlated with serum [Na+]. This association was confirmed in a multiple regression model after adjusting for age, gender, and diabetes mellitus as an associated morbidity. Conclusions This meta-analysis shows for the first time that even a moderate serum [Na+] decrease is associated with an increased risk of mortality in commonly observed clinical conditions across large numbers of patients.

Genetic screening for pheochromocytoma: should SDHC gene analysis be included?

PGL3 syndrome is caused by mutations in the SDHC gene. At present, only a few families affected by SDHC mutations have been reported in the literature and in each of them the clinical presentation was characterised by paragangliomas located only in the head and neck regions. No evidence of thoracic or abdominal catecholamine-secreting chromaffin tumours has been reported to date. We report the case of a 15-year-old girl with hypertension and a norepinephrine-secreting abdominal paraganglioma who was found to harbour a novel nonsense SDHC mutation, demonstrating that the clinical presentation of PGL3 syndrome can be more diverse than expected.

Updated and New Perspectives on Diagnosis, Prognosis, and Therapy of Malignant Pheochromocytoma/Paraganglioma

Malignant pheochromocytomas/paragangliomas are rare tumors with a poor prognosis. Malignancy is diagnosed by the development of metastases as evidenced by recurrences in sites normally devoid of chromaffin tissue. Histopathological, biochemical, molecular and genetic markers offer only information on potential risk of metastatic spread. Large size, extraadrenal location, dopamine secretion, SDHB mutations, a PASS score higher than 6, a high Ki-67 index are indexes for potential malignancy. Metastases can be present at first diagnosis or occur years after primary surgery. Measurement of plasma and/or urinary metanephrine, normetanephrine and metoxytyramine are recommended for biochemical diagnosis. Anatomical and functional imaging using different radionuclides are necessary for localization of tumor and metastases. Metastatic pheochromocytomas/paragangliomas is incurable. When possible, surgical debulking of primary tumor is recommended as well as surgical or radiosurgical removal of metastases. I-131-MIBG radiotherapy is the treatment of choice although results are limited. Chemotherapy is reserved to more advanced disease stages. Recent genetic studies have highlighted the main pathways involved in pheochromocytomas/paragangliomas pathogenesis thus suggesting the use of targeted therapy which, nevertheless, has still to be validated. Large cooperative studies on tissue specimens and clinical trials in large cohorts of patients are necessary to achieve better therapeutic tools and improve patient prognosis.

Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients

Head and neck paragangliomas (HNPGLs) are neural crest-derived tumors. In comparison with paragangliomas located in the abdomen and the chest, which are generally catecholamine secreting (sPGLs) and sympathetic in origin, HNPGLs are, in fact, parasympathetic in origin and are generally nonsecreting. Overall, 79 consecutive patients with HNPGL were examined for mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX, and TMEM127 genes by PCR/sequencing. According to a detailed family history (FH) and clinical, laboratory (including metanephrines), and instrumental examinations, patients were divided into three groups: a) patients with a positive FH for HNPGL (index cases only), b) patients with a negative FH and multiple HNPGLs (synchronous or metachronous) or HNPGL associated with an sPGL, and c) patients with negative FH and single HNPGL. The ten patients in group a) proved to be SDHD mutation carriers. The 16 patients in group b) proved to be SDHD mutation carriers. Among the 53 patients in group c), ten presented with germ-line mutations (three SDHB, three SDHD, two VHL, and two SDHAF2). An sPGL was found at diagnosis or followed up in five patients (6.3%), all were SDHD mutation carriers. No SDHC, SDHA, MAX, and TMEM127 mutations were found. In SDHD mutation carriers, none of the patients affected by HNPGL associated with sPGL presented missense mutations. In conclusion, a positive FH or the presence of multiple HNPGLs is a strong predictor for germ-line mutations, which are also present in 18.8% of patients carefully classified as sporadic. The most frequently mutated gene so far is SDHD but others, including SDHB, SDHAF2, and VHL, may also be affected.

Evaluation of the anterior pituitary function in the acute phase after spontaneous subarachnoid hemorrhage

Background: Subarachnoid hemorrhage (SAH) is a potential cause of hypopituitarism. Most of the studies regarding the relationship between SAH and anterior pituitary function were retrospective and hormonal assessment was performed several months after SAH. Aim: To prospectively evaluate the prevalence of anterior pituitary hormone deficiencies in the acute phase after spontaneous SAH and their possible correlation with clinical and radiological parameters. Methods: Pituitary function was tested in 60 patients within 72 h after spontaneous SAH. Results: 56.9% of the patients showed at least one anterior pituitary hormone deficiency: gonadotropin and GH secretion failure represented the most prevalent hormonal deficiencies (33.3 and 22.0%, respectively), whereas ACTH and TSH deficiency was less frequent (7.1 and 1.8%, respectively). With the exception of secondary hypogonadism, the prevalence of other pituitary hormone deficiencies is in agreement with previous studies, which evaluated pituitary function on long-term follow up after SAH. No correlation was found between hypopituitarism and clinical status, as assessed with Hunt-Hess and Glascow Coma Scales. Moreover, no correlation was found between hypopituitarism and bleeding severity evaluated with Fisher’s scale. Conclusions: We demonstrated a high prevalence of anterior pituitary hormone deficiencies acutely after SAH. Although part of GH and gonadotropin deficiencies might be a consequence of functional alteration due to SAH itself, the finding of low cortisol levels in this stressful condition strongly suggests the presence of true hypocortisolism. Therefore, an evaluation of pituitary function shortly after SAH might be useful to identify a subset of patients who deserve a more accurate follow-up.

Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

The syndrome of inappropriate ADH secretion (SIADH), also recently referred to as the “syndrome of inappropriate antidiuresis”, is an often underdiagnosed cause of hypotonic hyponatremia, resulting for instance from ectopic release of ADH in lung cancer or as a side-effect of various drugs. In SIADH, hyponatremia results from a pure disorder of water handling by the kidney, whereas external Na+ balance is usually well regulated. Despite increased total body water, only minor changes of urine output and modest edema are usually seen. Renal function and acid-base balance are often preserved, while neurological impairment may range from subclinical to life-threatening. Hypouricemia is a distinguishing feature. The major causes and clinical variants of SIADH are reviewed, with particular emphasis on iatrogenic complications and hospital-acquired hyponatremia. Effective treatment of SIADH with water restriction, aquaretics, or hypertonic saline + loop diuretics, as opposed to worsening of hyponatremia during parenteral isotonic fluid administration, underscores the importance of an early accurate diagnosis and careful follow-up of these patients.

Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline mutations

Context  The von Hippel‐Lindau (VHL) syndrome is an inherited multitumour disorder characterized by clinical heterogeneity and high penetrance. Pheochromocytoma (Pheo) is present in 10%–15% of cases and can be isolated or associated with other lesions such as haemangioblastomas, kidney cysts or cancer and pancreatic lesions. In VHL patients, Pheos generally secrete norepinephrine and are located in the adrenals. Extra‐adrenal Pheos (paragangliomas, PGLs) are rare.

Incidental and Metastatic Adrenal Masses

In the last decades discoveries of adrenal masses incidentally during the course of diagnostic procedures for unrelated disorders (incidentalomas) have become progressively more frequent. The clinician in this position must answer two main questions: Is the mass benign or malignant?, and To what extent is the adrenal secretion altered? To come to a clinical decision, several diagnostic tools need to be engaged, starting with an accurate and correct radiological evaluation and a hormonal assessment of the adrenal function. When necessary, other diagnostic procedures such as functional imaging and fine-needle biopsy (FNB) can be considered in selected cases. Surgical removal is recommended for clinically relevant hypersecretory masses, as well as for masses suspected to be malignant. Most frequently, adrenal incidentalomas (AIs) are represented by benign cortical adenomas, a subset of which causes a mild hypercortisolism, known as subclinical Cushings syndrome (SCS). The criteria to define this syndrome, as well as its treatment, are still debated and controversial. AIs that are not surgically removed should be re-examined in time to exclude a supervening increase in size or function. Follow-up criteria have not been established. Laparoscopic surgery is the recommended procedure to remove benign masses. The surgical procedure for adrenal malignancies is still debated.

A case of hyponatremia caused by central hypocortisolism

Background A 43-year-old woman was referred to the Psychiatric Unit of the University of Florence Hospital, 1 year after the development of a clinical picture characterized by nausea, hyporexia, muscle weakness, insomnia, weight loss, amenorrhea and severe depression. These clinical manifestations had started 2 months after delivery of her first child. Initial laboratory investigations revealed hypoglycemia and hyponatremia. The patient was, therefore, transferred to the Endocrine Unit of the same hospital for further evaluation of the case.Investigations Physical examination to evaluate extracellular volume status, standard laboratory investigations, and evaluation of plasma and urinary osmolality and urinary sodium excretion. Basal and dynamic evaluation of anterior pituitary function and a pituitary MRI were also performed.Diagnosis Hyponatremia caused by central hypocortisolism (isolated adrenocorticotropic hormone deficit).Management Glucocorticoid therapy (25 mg cortisone acetate tablets, 1.5 tablets per day).

Pitfalls in Genetic Analysis of Pheochromocytomas/Paragangliomas—Case Report

CONTEXT About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism. OBJECTIVE We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation. METHODS We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry. RESULTS Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism. CONCLUSIONS Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay.