[Thyroid nodules: benign or malignant?]. / Le nodule thyroïdien: bénin ou malin?

A thyroid nodule is a frequent occurrence. Its prevalence in a general adult population is about 50% and can even reach 67% when a cervical echography is performed. Only 5% of these nodules are cancers, and it is therefore important to avoid an useless and riskful surgery. We review the clinical factors and diagnostic tools available to reach the best options. The patient history and clinical signs give some informations about potential risks. Thyroid tests shall evaluate thyroid functional status and a thyroid scintigraphy shall detect hot thyroid nodules. The thyroid echography is a key element before fine needle aspiration cytology. Some echographic criteria in the TIRADS (Thyroid Imaging Reporting and Data System), classification can reach a 88% sensitivity, a 49% specificity, a 49% positive predictive value, a 88% negative predictive value and a 94% diagnostic accuracy. The fine needle aspiration cytology performed with echography will be crucial to decide if the patient is to be eligible for surgery. In 70 to 80% of the cases, nodules can be classified as benign or malignant with a 92% negative predictive value for a benign diagnosis and a 100% positive predictive value for a diagnosis of cancer. The discovery of a follicular proliferation (cancer incidence of 20-30%) is a grey zone. Follicular proliferation and definite cancer lead of course to a surgical option. A decisional tree summarizes the different steps leading to a therapeutic decision. The type of surgery and its complications are described at the end.

[New data about lipoprotein(a): a curious molecule or a causal cardiovascular risk factor?]. / Données nouvelles sur la lipoprotéine(a): une curiosité biochimique ou un facteur de risque cardiovasculaire important?

Lipoprotein(a) is of interest to both basic researchers as well as to clinicians who are involved in the contribution of Lp(a) to cardiovascular risk profiles. The Lp(a) particle is a hybrid molecule consisting of a half part indistinguable from circulating LDL linked to the unique glycoprotein component apolipoprotein(a). Many epidemiological data indicate that elevated Lp(a) levels are an independent risk factor for vascular disease. Apo(a) is highly homologous to the fibrinolytic plasminogen containing many repeated kringle motifs similar to several of those found in the plasminogen molecule. The size of the kringle domain in apo(a) gives rise to Lp(a) isoforms heterogeneity which is a hallmark of this lipoprotein. The similarity between Lp(a) and plasminogen led to speculation of a bridging role for Lp(a) in atherosclerosis and thrombosis mechanisms based on the double structure of this lipoprotein. Moreover, there are specific properties that apo(a) confers to Lp(a) : this include the ability of Lp(a) to affect platelet function and to contribute to endothelial dysfunction. Recently, new data have revealed a potential role for Lp(a) in the elimination of oxidized phospholipids. Future areas of development in this field include the role of apo(a) isoform size as a risk factor, the possible physiological roles of Lp(a), as well as recommendations for the best treatment of elevated Lp(a) in clinical practice.

[Place of fibrates for the treatment of patients with atherogenic dyslipidemia]. / Place des fibrates dans le traitement de patients avec une dyslipidémie athérogène.

The demography of dyslipidemia has changed towards a more complex atherogenic dyslipidemia involving increased levels of LDL cholesterol, in particular highly atherogenic small dense particles, hypertriglyceridemia and low HDL cholesterol, together with increased levels of markers of inflammation, thrombogenesis and endothelial dysfunction. Statins were shown to significantly lower cardiovascular morbidity and mortality, but treated patients are still left with a high residual risk, in particular for those with metabolic syndrome, type 2 diabetes, or low HDL cholesterol levels. Fibrates have been shown to reduce plasma triglycerides and increase HDL cholesterol, while improving inflammation, thrombogenesis and endothelial dysfunction. Clinical trials with fibrates have demonstrated their potential to reduce cardiovascular morbidity and mortality too, often through other mechanisms than those of statins. Combination trials of statins with fibrates have shown a more complete improvement of lipid profile and risk markers than each class separately. In contrast with gemfibrozil, fenofibrate does not interact significantly with the pharmacokinetics of statins, and its combination with statins has been shown to have a low risk of muscular side-effects or liver toxicity. The ACCORD outcome trial is exploring possible benefits of the combination of fenofibrate with statins on morbidity and mortality of patients with type 2 diabetes.

[Severe hypokalemia after holidays return]. / Hypokaliémie sévère au retour de vacances.

A 52-year old man is referred to our institution for hypertension (190/90 mmHg) and lower limb edema. An initial blood sample reveals severe hypokalemia (1.58 mEq/l) associated with metabolic alkalosis (pH: 7.63; total bicarbonates: 47.7 mEq/I), rhabdomyolysis (CPK: 1.776 UI/I) and ECG modifications. Primary aldosteronism is suspected and further diagnostic procedures are performed. A urine sample shows inappropriate potassium elimination associated with both low plasmatic renin and aldosterone levels, orienting the diagnosis toward a case of pseudohyperaldosteronism. A more detailed history reveals daily consumption of more than half a liter of licorice-based aperitif during the holiday period. This case illustrates the paramount importance of a detective-like questioning and reminds the physiopathologic role of glycyrrhetinic acid as a cause of hyperaldosteronism.

[Decrease ApoB/ApoA-1 ratio and cardiovascular risk improvement: a tadalafil pleiotropic effect? Preliminary study on healthy volunteers]. / Diminution du rapport ApoB/ApoA-1 et amélioration du risque cardiovasculaire : effet pleïotropique du tadalafil ? Etude préliminaire sur volontaires sains.

OBJECTIVES: Recognition of erectile dysfunction (ED) as an early sign of systemic cardiovascular disease offers an opportunity for prevention. Cardiac risk assessment may deserve measurement of Apolipoprotein B/Apolipoprotein A-1 ratio. An elevated ApoB/ApoA-1 ratio is a risk factor for future coronary artery disease. ApoA-1 production, which is recognized as a cardioprotective lipid fraction, is down regulated by NFkappaB activation in vitro. Because inhibition of phosphodiesterases (PDEs) 5, 6 and 9 negatively attenuates NFkappaB translocation/activation, tadalafil, a selective PDE 5 inhibitor used for treatment of ED could present some interesting pleiotropic effects. The objective of this open study is to test the hypothesis that tadalafil treatment could decrease serum ApoB/ApoA-1 ratio. MATERIAL AND METHODS: Ten healthy men without any complain of ED or known cardiovascular risk factors were administered tadalafil 10mg intake on alternate days for 4 weeks. Lipid profile with total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, ApoA-1 and ApoB, was assessed at baseline (T0), after 2weeks (T1), at the end of the treatment period (T2) and after 2weeks of wash-out follow-up (T3). RESULTS: ApoB/ApoA-1 ratio was significantly decreased during treatment (mean+/-SEM, T0: 0.80+/-0.11, T1: 0.64+/-0.06, T2: 0.65+/-0.06; p<0.05) and remained lower after wash-out (T3: 0.67+/-0.05; p=0.08). Serum ApoA-1 (mg/dl) increased but not significantly during the treatment period (15.2+/-8.8, 16.5+/-7.9, 16.9+/-6, 15.3+/-7, p=0.26) and ApoB (mg/dl) significantly decreased (11.7+/-10.8, 10.3+/-8.4, 10.6+/-9.9, 10.2+/-8.6, p=0.03). HDL and LDL cholesterol were unchanged. CONCLUSION: This preliminary study showed the interest of PDE 5 inhibitors to decrease the cardiac risk factor ApoB/ApoA-1 ratio. Randomised controlled studies with longer follow-up are needed to confirm those results.

[Recent treatment perspectives in lipidology]. / Actualités thérapeutiques en lipidologie.

Clinical lipidology has gained its recognition with the publication of numerous clinical trials since the 4S study in 1994. Since that time statins have fully confirmed their promises and play now a crucial role in the battle against cardiovascular diseases. The last decade has been dominated by two demonstrations that apparently are discordant: (1) the lower the cholesterol level with the pharmacological intervention, the lower the risk of cardiovascular complications, arguing for the use of very efficacious cholesterol-lowering therapies; and (2) the cardiovascular protection provided by statins is present whatever the baseline cholesterol level, supporting the concept of pleiotropic effects of statins. As a consequence, statin treatment should be prescribed and intensified according to the high individual cardiovascular risk rather than because of the cholesterol level stricto sensu. Statin therapy should be completed by the addition of ezetimibe when LDL cholesterol level remains above target values or by the addition of fenofibrate when triglyceride levels are high and/or HDL cholesterol level is low. New pharmacological approaches aiming at further improving lipid profile, especially by targeting low HDL cholesterol levels, are currently in clinical development.

Antigens and granularity of blood monocytes in relation to inflammatory markers and lipids in postmenopausal women.

OBJECTIVES: The menopause is associated with an increase of inflammatory markers (C-reactive protein, fibrinogen), cytokines (INFgamma, TNF, etc.) and blood lipoproteins. In vitro, CRP, LDL and fibrinogen can modulate or potentiate interleukines production by monocytes. The aim of this work was to study, the relationships in vivo between hs-CRP, fibrinogen, lipoproteins and the phenotype of circulating monocytes. METHODS: The monocytes phenotype, in postmenopausal women (n=26) without history of cardiovascular disease, was determined, by flow cytometry, measuring granularity and CD14, HLA-DR and CD62-L antigens expression. Blood monocytes were divided in CD14+dim monocytes (low CD14 expression) and CD14+bright monocytes (high CD14 expression). RESULTS: HLA-DR was negatively correlated with hs-CRP and fibrinogen. The relationships between ApoB, LDL/ApoB ratio and CD14 expression was restricted to the CD14+bright monocytes. Blood lipids, i.e. total cholesterol, LDL-c and ApoB were correlated with the granularity of both subsets. CD14+dim monocytes were characterized by a low granularity and CD62-L expression. CONCLUSIONS: Our data show that fibrinogen and hs-CRP are correlated with a reduced antigen-presenting capacity. Expression of CD14 on CD14+bright monocytes is negatively associated to atherogenic LDL. Blood monocytes granularity was positively correlated with serum lipids indicating that monocytes could uptake modified LDL in circulation and not restricted to subendothelial space.

Beneficial effects of atorvastatin on sd LDL and LDL phenotype B in statin-naive patients and patients previously treated with simvastatin or pravastatin.

BACKGROUND: The presence of increased levels of small dense (sd) LDL (phenotype B) is associated with a substantial increase of cardiovascular disease risk. Since lowering of plasma low-density lipoprotein-cholesterol (LDL-C) by statins involves an up-regulation of the LDL receptor, we questioned whether LDL lowering by atorvastatin affects different LDL subfractions equally. METHODS: Fifty-four hypercholesterolemic patients, requiring treatment for prevention of coronary heart disease received atorvastatin (10, 20 or 40 mg/day), either as initial therapy (n=33), or as replacement therapy (n=21) for pravastatin or simvastatin (both at 40 mg/day). In addition to plasma lipid measurements, cholesterol LDL subfractions were separated and analysed before and after 3 months of treatment. RESULTS: In addition to the expected LDL-C decrease (-34%; p<0.0001), a major reduction in sd LDL occurred after atorvastatin therapy (-38.2%; p<0.0001). Interestingly, sd LDL decreased as much in patients previously treated with other statins (-36%; p<0.002). A close correlation (r=0.89, p<0.001) was found between reduction of sd LDL and that of LDL-C, in patients with phenotype B. Although high-density lipoprotein-cholesterol (HDL-C) was not affected by atorvastatin treatment, plasma triglycerides decreased by 27.4% (p<0.0001). Only a weak correlation (r=0.35, p<0.01) was found between the reduction of plasma triglycerides and the decrease of sd LDL after atorvastatin treatment. CONCLUSION: These results show that the reduction of LDL-C by atorvastatin largely reflects a lowering of sd LDL. Our data also suggest that triglyceride lowering plays only a partial role in sd LDL reduction.

[Dyslipidaemia and diabetes mellitus]. / Dyslipidémie et diabète.

Cardiovascular diseases are the main complications in diabetes. The lipid pattern includes high triglycerides, low HDL and increased small dense LDL. The treatment strategy is based upon the European Guidelines which insist on global risk evaluation and recommend more severe lipid targets for diabetic than for non diabetic patients. After changes of lifestyle and control of risk factors, statins or fibrates are the drugs of choice, even if fibrates have specific impact on patients with diabetes or the metabolic syndrome.

[The endocannabinoid system and the regulation of the metabolism]. / Le système endocannabinoïde et la régulation du métabolisme.

The endocannabinoid system modulates many physiological functions by acting on receptors CB1 and CB2. The endocannabinoids are produced only when and where they are needed. They act locally and are immediately metabolised after their action. Overactivation of the endocannabinoid system is observed in obesity, with stimulation of the appetite in the hypothalamus and fat accumulation in the adipocytes with increase of insulin resistance and decrease of adiponectin. Nicotine use overactivates also the endocannabinoid system. CB1 blockade by a specific inhibitor (rimonabant) decreases food intake and weight in animal studies and increases adiponectin and insulin sensitivity. Moreover, rimonabant decreases tobacco dependence. Clinical studies with rimonabant are encouraging.

[Rimonabant (Acomplia), specific inhibitor of the endocannabinoid system]. / Le rimonabant (Acomplia), inhibiteur spécifique du système endocannabinoïde.

The endocannabinoid system plays a major role in the regulation of body energy by stimulation of the appetite in the hypothalamus and increase of fat accumulation in adipocytes. The blockade of the cannabinoid system (CB1) by the specific inhibitor (rimonabant) decreases food intake and adiposity in animals and in humans. Moreover rimonabant lowers tobacco addiction. Clinical studies (RIO-LIPIDS and RIO-EUROPE) have recently confirmed that rimonabant combined with a hypocaloric diet over 1 year, promoted significant decrease of body weight, waist circumference and improvement of dyslipidemia. Rimonabant was well tolerated with mild and transient side effects. The future place of rimonabant in the strategy of obesity is still to be clarified.

[The endocannabinoid system and the regulation of the metabolism]. / Le système endocannabinoïde et la régulation du métabolisme.

The endocannabinoid system modulates many physiological functions by acting on receptors CB1 and CB2. The endocannabinoids are produced only when and where they are needed. They act locally and are immediately metabolised after their action. Overactivation of the endocannabinoid system is observed in obesity, with stimulation of the appetite in the hypothalamus and fat accumulation in the adipocytes with increase of insulin resistance and decrease of adiponectin. Nicotine use overactivates also the endocannabinoid system. CB1 blockade by a specific inhibitor (rimonabant) decreases food intake and weight in animal studies and increases adiponectin and insulin sensitivity. Moreover, rimonabant decreases tobacco dependence. Clinical studies with rimonabant are encouraging.

[Multifactorial approach of the cardiovascular risks in case of diabetes]. / La prise en charge globale des facteurs de risque cardiovasculaire chez le diabétique.

All patients with type 2 diabetes are at increased risk of cardiovascular diseases. Diabetics have a greater burden of atherogenic risk factors than non diabetics including mainly arterial hypertension and dyslipidemia. If strict glycemic control is recommended because of proved benefit in terms of microvascular disease the protection against macrovascular disease is less established. Vigorous risk factors reduction (diminution of blood pressure, reduction of lipids, smoking cessation) should be a priority in a multifactorial approach of diabetes treatment, involving the patients and the doctors. In addition to lifestyle and behaviour counselling, polypharmacologic treatment is often needed.

[Innovative therapies in metabolic diseases: ezetimibe (Ezétrol), nicotinic acid (Niaspan), acids omega-3 (Omacor), rimonabant (Acomplia)]. / Les innovations thérapeutiques dans les pathologies métaboliques: l'ézetimibe (Ezétrol), l'acide nicotinique (Niaspan), les acides oméga-3 (Omacor), le rimonabant (Acomplia).

In the field of dyslipidemia and metabolic syndrome, four innovative therapies are reviewed: Ezetimibe (Ezétrol) is a selective cholesterol absorption inhibitor. Co-administration of ezetimibe with low dose of statins shows LDL lowering comparable to that of the highest dose of the respective statin alone. Combination therapy helps more patients in achieving target LDL-cholesterol. Nicotinic acid (Niacin) favourably modifies all lipoprotein level (including Lp(a)). Extended release niacin (Niaspanâ) is a new galenic form, with less side effects (flushing and hepatotoxicity) than the native nicotinic acid. This new preparation represents an effective option in the management of dyslipidemia. The polyunsatured fatty acids (PUFA) omega-3 (Omacor) decreases cardiovascular deaths and mainly fatal arrhythmias after myocardial infarction. Their favourable effects are linked mainly to their anti-inflammatory and antiarrhythmic properties. The PUFA omega-3 could be added to the secondary prevention after myocardial infarction. The blockade of the endocannabinoid system by a specific inhibitor of CB1 receptor (rimonabant or Acomplia) decreases food intake and weight and increases adiponectin and insulin sensitivity. Clinical studies on obesity and tobacco dependence are very encouraging.

[Rimonabant (Acomplia), specific inhibitor of the endocannabinoid system]. / Le rimonabant (Acomplia), inhibiteur spécifique du système endocannabinoïde.

The endocannabinoid system plays a major role in the regulation of body energy by stimulation of the appetite in the hypothalamus and increase of fat accumulation in adipocytes. The blockade of the cannabinoid system (CB1) by the specific inhibitor (rimonabant) decreases food intake and adiposity in animals and in humans. Moreover rimonabant lowers tobacco addiction. Clinical studies (RIO-LIPIDS and RIO-EUROPE) have recently confirmed that rimonabant combined with a hypocaloric diet over 1 year, promoted significant decrease of body weight, waist circumference and improvement of dyslipidemia. Rimonabant was well tolerated with mild and transient side effects. The future place of rimonabant in the strategy of obesity is still to be clarified.

Patient with monoclonal gammopathy, thyrotoxicosis, pretibial myxedema and thyroid-associated ophthalmopathy; demonstration of direct binding of autoantibodies to the thyrotropin receptor.

We describe a patient with monoclonal gammopathy who subsequently developed thyrotoxicosis, pretibial myxedema and thyroid-associated ophthalmopathy. The pathogenesis of thyrotoxicosis in Graves' disease is due to the presence of autoantibodies that mimic the action of thyrotropin (TSH), called thyroid-stimulating antibodies (TS-ab); these antibodies may or may not inhibit the binding of TSH to the receptor (thyroid-binding inhibiting immunoglobulin, TBII). The patient's immunoglobulins were TS-ab positive and TBII negative when measured on CHO cells expressing the human TSH receptor. The pathogenetic link between the thyroid, orbit and skin is yet to be established but several candidate shared antigens have been proposed, including the TSH receptor itself. The monoclonal immunoglobulins were in evidence before the symptoms of pretibial myxedema, thyrotoxicosis and ophthalmopathy. In addition, the patient had no autoantibodies to thyroglobulin or thyroperoxidase, which are classic markers of thyroid autoimmunity. This combination led us to postulate that the monoclonal gammopathy could be the cause of all the observed pathology. One method to test this hypothesis would be to show that the monoclonal immunoglobulin is a TS-ab. Various methods were used to separate the monoclonal from the polyclonal components of the patient's serum. Preparative isoelectric focusing enabled us to obtain fractions containing only the monoclonal (as revealed by polyacrylamide gel electrophoresis), which were devoid of TS-ab activity (measured as cAMP accumulation in CHO cells expressing the human TSH receptor in a hypotonic bioassay). Subsequently, different oligoclonal fractions were shown to have varying degrees of TS-ab activity, with one fraction having faint biological activity and able to recognize a recombinant TSH receptor preparation in a Western blot. In conclusion, the monoclonal antibody does not seem to be responsible for the thyrotoxicosis, pretibial myxedema and ophthalmopathy. We confirm previous data showing that TSH receptor antibodies in patients with Graves' disease are heterogeneous in nature and we present the first demonstration of autoantibodies capable of binding the TSH receptor but devoid of TBII activity.

Progression of a naproxen and amoxicillin induced acute interstitial nephritis with nephrotic syndrome: case report.

This article reports an unusual case of acute interstitial nephritis associated with nephrotic syndrome which appeared after oral intake of naproxen and amoxicillin and led to end-stage renal failure. In the light of recent literature on this clinical entity, the authors formulate hypotheses accounting for this outcome.

Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: a placebo-controlled study.

BACKGROUND: Patients with end-stage renal disease commonly present with an atherogenic lipid profile characterized by the accumulation of triglyceride-rich, apoprotein B-containing "remnant" lipoproteins, small dense low-density lipoprotein, and low levels of high-density lipoprotein. They are at increased cardiovascular risk and may benefit from drastic lipid-lowering treatment with atorvastatin, a potent, broadacting lipid regulator. This study aims to assess the effects of atorvastatin on the lipid profile in hemodialysis patients, to determine wether atorvastatin is also effective at lowering lipid levels in this particular high-risk subgroup. METHODS: In this randomized, placebo-controlled, double-blind study in hemodialysis patients with hypercholesterolemia (n = 42, mean total cholesterol 243 +/- 33 mg/dl (6.3 +/- 0.8 mmol/l)), the efficacy of 4-weekly increasing doses of atorvastatin (10 - 40 mg daily) was investigated. Lipids and apoproteins were measured in plasma and isolated lipoprotein fractions. RESULTS: Mean total cholesterol and low-density lipoprotein cholesterol progressively decreased with increasing doses of atorvastatin (total cholesterol -33%, low-density lipoprotein cholesterol -43% after 12 weeks), while high-density lipoprotein cholesterol remained unchanged. Plasma levels of apoprotein B and apoprotein E were also significantly reduced by atorvastatin 10 mg, while up-titration to 20 and 40 mg daily provided additional benefits by lowering triglycerides and apoprotein C-III. At week 12, the fraction of small dense low-density lipoprotein was significantly reduced from 23% - 18%, and apoprotein B-containing intermediate-density lipoproteins were no longer detectable. CONCLUSION: In conclusion, atorvastatin not only treated hypercholesterolemia but also favorably affected the uremic lipid profile in patients on hemodialysis. Atorvastatin 4-weekly dose escalation up to 40 mg daily was well-tolerated. Further prospective studies are needed to evaluate the impact of this improved lipid profile on morbidity and mortality.

[Chronic hypernatremia. A study of plasma neurophysins and action of morphine]. / Hypernatrémie chronique. Etude des neurophysines plasmatiques et effet de la morphine.

The hypothalamo-neurohypophyseal function was evaluated in a patient with the chronic hypernatremia syndrome. By dosing plasmatic neurophysins, a selective loss of the osmoreceptor function was demonstrated. Morphine administration was followed by a reduction of the diuresis and a slight elevation of plasmatic neurophysins. The mechanism of morphine action is discussed.