Acute liver injury after intravenous amiodarone: a case report.

Acute hepatotoxicity is a rare but potentially fatal complication of amiodarone use. Although oral long-term use of the drug is frequently complicated by an asymptomatic rise in serum aminotransferase concentrations, acute hepatotoxicity during intravenous loading is much less frequent and potentially fatal. We report a case of liver injury after intravenous administration in a patient with atrial fibrillation.

Differential diagnosis of primary aldosteronism subtypes.

Primary aldosteronism (PA) is the most frequent endocrine form of secondary hypertension. The recognition of this disease has dramatically increased with the widespread use of a screening test in most hypertensive patients, including those who are normokalemic. Interest in PA has grown since the demonstration that aldosterone has deleterious effects that are, at least in part, independent from its effects on blood pressure. The identification of the subtype of PA is fundamental to distinguish between subtypes that benefit from surgery and subtypes that should be treated pharmacologically with mineralocorticoid receptor antagonists. This article reviews the strategies to correctly identify PA subtypes, underlining the central role of adrenal vein sampling.

Roles of clinical criteria, computed tomography scan, and adrenal vein sampling in differential diagnosis of primary aldosteronism subtypes.

CONTEXT: In patients with primary aldosteronism (PA), it is fundamental to distinguish between subtypes that benefit from different therapies. Computed tomography (CT) scans lack sensitivity and specificity and must be followed by adrenal venous sampling (AVS). Because AVS is not widely available, a list of clinical criteria that indicate the presence of an aldosterone-producing adenoma (APA) has been suggested. OBJECTIVE AND DESIGN: The objective of the study was to test the sensitivity and specificity of the last generation CT scans, test prospectively the usefulness of clinical criteria in the diagnosis of APA, and develop a flow chart to be used when AVS is not easily available. SETTING: Hypertensive patients referred to our hypertension unit were included in our study. PATIENTS: Seventy-one patients with confirmed PA participated in our study. INTERVENTION: All patients had a CT scan and underwent AVS. MAIN OUTCOME MEASURE: Final diagnosis of APA was the main measure. RESULTS: A total of 44 and 56% of patients were diagnosed as having an APA and a bilateral adrenal hyperplasia (BAH), respectively. Twenty percent of patients with PA displayed hypokalemia. CT scans displayed a sensitivity of 0.87 and a specificity of 0.71. The posture test displayed a lower sensitivity and specificity (0.64 and 0.70, respectively). The distribution grades of hypertension were not significantly different between APA and BAH. Biochemical criteria of high probability of APA displayed a sensitivity of 0.32 and a specificity of 0.95. CONCLUSIONS: This study underlines the central role of AVS in the subtype diagnosis of PA. The use of the clinical criteria to distinguish between APA and BAH did not display a satisfactory diagnostic power.

Primary aldosteronism (PA) and endothelial progenitor cell (EPC) bioavailability.

OBJECTIVE: Patients with primary aldosteronism (PA) experience more cardiovascular events than patients with essential hypertension matched for risk factor profile. Endothelial progenitor cells (EPC) represent a bone marrow-derived cell population implicated in vascular healing whose number correlates to the cardiovascular risk factor profile. Aldosterone has been reported to decrease EPC proliferation in rats. DESIGN AND PATIENTS: We assessed (i) the growth characteristics of EPC from six PA patients and six matched normotensive controls; (ii) the growth characteristics of EPC treated with increasing doses of aldosterone. MEASUREMENTS: Senescence and cell-cycle analysis of EPC from PA patients and normotensive controls and of aldosterone-treated EPC from healthy volunteers. RESULTS: No difference was found in the senescence rate between EPC from PA patients (72.4% senescent cells) and controls (70.7%, P > 0.05). No difference was also found in the cell-cycle distribution determined by FACS (controls: 75.2% cells in G0/G1 phase; PA: 73.5%, P > 0.05). Incubation of EPC with aldosterone did not modify their senescence rate (controls: 72.4% senescent cells; aldosterone 10 nmol/l: 70.9%; aldosterone 100 nmol/l 71.6%, P > 0.05 for all comparisons) and cell-cycle distribution (controls: 73.3% cells in G0/G1 phase; aldosterone 10 nmol/l: 74.9%; aldosterone 100 nmol/l: 75.4%, P > 0.05 for all comparisons). No expression of the mineralocorticoid receptor (MR) transcript was found in EPC by RT-PCR analysis. CONCLUSIONS: High aldosterone levels, both in PA patients and in vitro, exert no direct or indirect effect on EPC growth characteristics.

Aldosterone as an independent factor in cerebrovascular damage.

Aldosterone is produced not only in the adrenal gland but also in other tissues, including the brain, where it plays an important role in the control of blood pressure and water and electrolyte homeostasis. Aldosterone has also been demonstrated to be a major factor in target organ damage independent of its effects on blood pressure. Herein we review the pathophysiology of aldosterone action in the brain and the clinical and experimental studies on the detrimental effects of aldosterone in the brain.

When a Diuretic Causes Pulmonary Oedema.

BACKGROUND: Hydrochlorothiazide (HCTZ) is one of the most popular drugs for the treatment of hypertension and heart failure. Most of its side effects are harmless and predictable, but some studies report a few life-threatening reactions to this drug, one of the most dangerous being acute pulmonary oedema. CASE REPORT: A 73-year-old woman was admitted to the Emergency Department with acute respiratory failure due to pulmonary oedema. Her past medical history included long-lasting hypertension with permanent atrial fibrillation and mitral stenosis. Her blood pressure control had been suboptimal, so her cardiologist had changed amlodipine to combination therapy with ramipril and HCTZ. However, 20 min after taking the new drug, the patient experienced fever, vomiting and diarrhoea immediately followed by acute onset of dyspnoea. CONCLUSION: Since HCTZ is one of the most popular drugs for hypertension treatment and millions of patients take it every day, it is important to keep in mind both the common adverse reactions as well as the dangerous, although rare, ones. LEARNING POINTS: Pulmonary oedema is a very unusual adverse reaction to hydrochlorothiazide, and a rare presentation of a common condition.Pulmonary oedema is not always due to heart problems.It is important to keep in mind that hypersensitivity reactions may have many different presentations.

Protective effect of spironolactone on endothelial cell apoptosis.

Human umbilical vein endothelial cells (HUVECs) undergo apoptosis in response to serum deprivation. We show that the nonspecific mineralocorticoid receptor antagonist, spironolactone, protects from caspase-3 activation induced by serum deprivation in contrast to the selective mineralocorticoid receptor antagonist, eplerenone, that is nonprotective. We also demonstrate that progesterone, hydrocortisone, and dexamethasone all protect HUVECs from serum-deprivation-induced caspase-3 activation, whereas aldosterone and dihydrotestosterone have no effect. Spironolactone has been demonstrated to display agonist activity only to the progesterone receptor (PR), and we additionally show that spironolactone and progesterone, but not eplerenone, inhibit mitochondrial cytochrome c release and cleavage of nuclear poly (ADP-ribose) polymerase (PARP) and increase cell viability. Additionally, the PR antagonist mifepristone (RU486) partially blocked the inhibitory effect of both spironolactone and progesterone on caspase-3 activation, cytochrome c release, and nuclear PARP cleavage. Nitric oxide (NO) protects HUVECs from apoptosis in response to various stimuli including serum-deprivation; however, the NO synthase inhibitor N-monomethyl-l-arginine, did not abolish inhibition of caspase-3 activation or PARP cleavage by spironolactone. Thus, we demonstrate that spironolactone protects HUVECs from serum-deprivation-induced apoptosis by inhibition of caspase-3 activity, cytochrome c release and PARP cleavage by a NO-independent mechanism; further, this effect is likely mediated by the agonist properties of spironolactone toward the PR.

"First, know thyself": cognition and error in medicine.

Although error is an integral part of the world of medicine, physicians have always been little inclined to take into account their own mistakes and the extraordinary technological progress observed in the last decades does not seem to have resulted in a significant reduction in the percentage of diagnostic errors. The failure in the reduction in diagnostic errors, notwithstanding the considerable investment in human and economic resources, has paved the way to new strategies which were made available by the development of cognitive psychology, the branch of psychology that aims at understanding the mechanisms of human reasoning. This new approach led us to realize that we are not fully rational agents able to take decisions on the basis of logical and probabilistically appropriate evaluations. In us, two different and mostly independent modes of reasoning coexist: a fast or non-analytical reasoning, which tends to be largely automatic and fast-reactive, and a slow or analytical reasoning, which permits to give rationally founded answers. One of the features of the fast mode of reasoning is the employment of standardized rules, termed "heuristics." Heuristics lead physicians to correct choices in a large percentage of cases. Unfortunately, cases exist wherein the heuristic triggered fails to fit the target problem, so that the fast mode of reasoning can lead us to unreflectively perform actions exposing us and others to variable degrees of risk. Cognitive errors arise as a result of these cases. Our review illustrates how cognitive errors can cause diagnostic problems in clinical practice.

LXR-activating oxysterols induce the expression of inflammatory markers in endothelial cells through LXR-independent mechanisms.

AIMS: Liver X receptors alpha and beta (LXRalpha, LXRbeta) are key regulators of cholesterol homeostasis. The effects of LXR ligands on endothelial cells are largely unknown. While oxysterol LXR agonists can increase the endothelial-leukocyte interaction, synthetic LXR agonists are anti-atherogenic and anti-inflammatory. Mechanistic differences may underlie such findings. METHODS AND RESULTS: LXRalpha and LXRbeta were found to be expressed in human endothelial cells. While synthetic LXR agonists could blunt the LPS-induced up-regulation of adhesion molecules (ICAM-1, VCAM-1, E-Selectin), 22-hydroxycholesterol and 24,25-epoxycholesterol enhanced such response. Microarray profiling further showed that the endothelial gene expression fingerprints of 22-hydroxycholesterol and T0901317 largely differed and unexpectedly shared only a restricted number of genes. Indeed, 22-hydroxycholesterol down-regulated eNOS and up-regulated a vast cohort of inflammatory mediators such as adhesion molecules, cytokines, enzymes and transcription factors. Other LXR-activating oxysterols such as 24,25-epoxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol could also stimulate the endothelial expression of inflammatory markers, although significant differences were observed. These effects persisted in LXR-silenced cells, confirming the mechanistic dissociation of oxysterol and LXR pathways. Furthermore, the oxysterol-induced expression of inflammatory markers was not secondary to cell apoptosis and may relate to oxidative stress. CONCLUSIONS: LXR-activating oxysterols comprehensively activate the expression of endothelial inflammation markers independently from LXRs. At proper dosage, synthetic LXR agonists are safe on endothelial cells and may even transrepress inflammatory reactions.

Diagnosis and treatment of low-renin hypertension.

Plasma renin levels can be used to classify hypertension. A significant proportion of hypertensive individuals display a low-renin profile and thus low-renin hypertension (LRH) requires appropriate diagnosis and treatment. LRH includes essential, secondary and genetic forms, the most common of which are low-renin essential hypertension and primary aldosteronism. Several studies have investigated the relationship between PRA status and clinical response to different antihypertensive therapies. The present review will discuss the differential diagnosis of LRH subtypes and the most appropriate treatment options based on the pathophysiological background of this condition.