Guillaume Lefevre

Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan

BACKGROUND/AIMS Bosentan, a dual endothelin ET(A/B) receptor antagonist, may cause dose-dependent reversible cholestatic liver injury. We herein tested whether bosentan or metabolites, both eliminated in bile, induce alterations in bile secretion. METHODS Bile flow and output of bile constituents were monitored in pentobarbital-anesthetized rats with biliary fistulas. Normal and TR(-) rats with a genetic defect in mrp2, received bosentan intravenous injections. RESULTS Bosentan bolus intravenous injections of 0.1-10mg/kg triggered a dose-dependent increase in biliary bilirubin excretion. In addition, doses (> or =10mg/kg) caused a sustained increase in canalicular bile salt-independent bile flow, combined with significant increases in the concentration and output of glutathione and of bicarbonate in bile. In rats receiving bosentan (> or =10mg/kg), both under basal conditions and under intravenous taurocholate perfusion (2micromol/min/kg), phospholipid and cholesterol secretions were profoundly inhibited and uncoupled from bile salt secretion. In TR(-) rats, the choleretic effect of bosentan was reduced to non-significant levels. The stimulation of bilirubin secretion and the uncoupling of phospholipid from bile salt secretion were absent, whereas that of cholesterol was maintained. CONCLUSIONS Bosentan alters canalicular bile formation in major part via mrp2-mediated mechanisms. Intermittent uncoupling of lipid from bile salt secretion may contribute to bosentan hepatic adverse reaction.

European multicenter analytical evaluation of the Abbott ARCHITECT STAT high sensitive troponin I immunoassay.

Abstract Background: International recommendations highlight the superior value of cardiac troponins (cTns) for early diagnosis of myocardial infarction along with analytical requirements of improved precision and detectability. In this multicenter study, we investigated the analytical performance of a new high sensitive cardiac troponin I (hs-cTnI) assay and its 99th percentile upper reference limit (URL). Methods: Laboratories from nine European countries evaluated the ARCHITECT STAT high sensitive troponin I (hs-TnI) immunoassay on the ARCHITECT i2000SR/i1000SR immunoanalyzers. Imprecision, limit of blank (LoB), limit of detection (LoD), limit of quantitation (LoQ) linearity of dilution, interferences, sample type, method comparisons, and 99th percentile URLs were evaluated in this study. Results: Total imprecision of 3.3%–8.9%, 2.0%–3.5% and 1.5%–5.2% was determined for the low, medium and high controls, respectively. The lowest cTnI concentration corresponding to a total CV of 10% was 5.6 ng/L. Common interferences, sample dilution and carryover did not affect the hs-cTnI results. Slight, but statistically significant, differences with sample type were found. Concordance between the investigated hs-cTnI assay and contemporary cTnI assay at 99th percentile cut-off was found to be 95%. TnI was detectable in 75% and 57% of the apparently healthy population using the lower (1.1 ng/L) and upper (1.9 ng/L) limit of the LoD range provided by the ARCHITECT STAT hs-TnI package insert, respectively. The 99th percentile values were gender dependent. Conclusions: The new ARCHITECT STAT hs-TnI assay with improved analytical features meets the criteria of high sensitive Tn test and will be a valuable diagnostic tool.

Steroid profiling in preeclamptic women: evidence for aromatase deficiency

OBJECTIVE Experimental data have revealed the critical role played by 2-methoxy-estradiol, a metabolite of 17β-estradiol, in the pathophysiology of preeclampsia. We used gas chromatography/mass spectrometry to measure a whole panel of hormonal steroids in the plasma from women during the third trimester of their pregnancy. STUDY DESIGN The population study consists of 24 pregnant patients with different outcomes: normal, or complicated by isolated preeclampsia or by severe preeclampsia with Hemolysis Enzyme Liver Low Platelets (HELLP) syndrome. RESULTS 17β-estradiol was reduced by 50% in isolated preeclampsia, and by 70% in severe preeclampsia with HELLP syndrome (normal: 8.54 ± 0.9 ng/mL; isolated preeclampsia: 4.65 ± 1.0 ng/mL; severe preeclampsia with HELLP syndrome: 2.64 ± 0.4 ng/mL), as is estrone. Downstream, 2-methoxy-estradiol was decreased only in severe preeclampsia with HELLP syndrome. The concentrations of estrone and 17β-estradiol precursors were comparable between groups, suggesting that placental aromatase is deficient in preeclampsia. CONCLUSION The gradual decrease of estrogen levels with increasing severity of preeclampsia suggests an impairment of placental steroidogenesis.

Diagnostic value of procalcitonin in acutely hospitalized elderly patients

The aim of this study was to evaluate procalcitonin as an adjunct to diagnose bacterial infections in older patients. One hundred seventy-two patients admitted to an acute-care geriatric unit during a 6-month period were prospectively included, 39 of them with an invasive bacterial infection. The best cut-off value to rule in a bacterial infection was 0.51 µg/l with sensitivity 64% and specificity 94%. The best cut-off value to rule out a bacterial infection was 0.08 µg/l with sensitivity 97% and specificity 20%. Procalcitonin was inconclusive (between 0.08 and 0.51 µg/l) for 112 admissions. Procalcitonin over 0.51 µg/l was useless 22 times out of 33 (infection already ruled in on clinical grounds) and misleading in eight of the 11 remaining cases (no infection). Procalcitonin below 0.08 µg/l was useless 23 times out of 27 (infection already ruled out on clinical grounds) and misleading in one of the four remaining cases (infection). Despite a good overall diagnostic accuracy, the clinical usefulness of PCT to diagnose invasive bacterial infections in elderly patients hospitalized in an acute geriatric ward appears to be very limited.

Defining normality in a European multinational cohort: Critical factors influencing the 99th percentile upper reference limit for high sensitivity cardiac troponin I

OBJECTIVE To establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria. METHODS 1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c] < 48 mmol/mol), myocardial (B-type natriuretic peptide [BNP] < 35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m(2)), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods. RESULTS The use of biomarker selection criteria resulted in a decrease of the 99th percentile URL for hs-cTnI from 23.7 to 14.1 ng/L and from 11.2 to 7.1 ng/L, when using the non-parametric percentile and robust methods, respectively; a further reduction after exclusion of individuals with dyslipidemia was noted. Male gender, BNP, HbA1c and smoking status were independently associated with hs-cTnI concentration in the presumably healthy population, while the impact of age, present in the univariate analysis, decreased after adjustments for gender and surrogate biomarkers. The BNP-based inclusion criterion had the most pronounced effect on the 99th percentile URL, excluding 21% of the study participants and decreasing its value to 11.0 (7.1) ng/L according to the non-parametric (robust) method. Gender, but not age-specific, differences at 99th percentile URL have been identified. CONCLUSION The selection of a reference population has a critical impact on the 99th percentile value for hs-cTnI. A uniform protocol for the selection of the healthy reference population is needed.

Soluble endoglin in preeclamptic patients with or without HELLP syndrome

OBJECTIVE The pathogenesis of the HELLP (hemolysis, enzyme liver, low platelets) syndrome is unknown. Recently soluble endoglin (sEng) was identified as a cause of the appearance of schistocytes and liver pathology in an animal model of preeclampsia (PE). STUDY DESIGN We explored the value of sEng in 82 women who delivered in a context of normal pregnancy (NP, n = 10), PE (n = 49), or HELLP (n = 23). RESULTS sEng was elevated in pathological pregnancies (66.7 +/- 62 and 75.7 +/- 48 pg/mL in PE and HELLP, respectively, vs 5.29 +/- 1.25 in NP, P < .001 for both comparisons) and was correlated with an increase in transaminases (r(2) = 0.17; P = .05), but it was not statistically different between PE and HELLP. CONCLUSION Although recent literature findings demonstrated a role of sEng in the pathophysiology of HELLP syndrome in animal models, we found that, at the time of delivery, sEng was not specifically elevated in preeclamptic patients with HELLP.

High lactate dehydrogenase levels at admission for painful vaso-occlusive crisis is associated with severe outcome in adult SCD patients

OBJECTIVES The aim of this study is to assess biological prognostic factors at the onset of vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD). METHODS A monocentric prospective study including all patients admitted for VOC in a reference center for SCD was utilized. We used multivariate logistic regression to find independent predictors of severe evolution, defined by death or a worsening clinical state indicating transfusion or transfer to the intensive care unit. RESULTS Eighty eight patients were included, 63% were women, median age of 23 years, and 90% of patients were homozygous SCD, 10% compound heterozygous. VOC became severe in 17 patients. Patients with severe VOC were more frequently males, who also had higher white blood cell (WBC) count, procalcitonin (PCT), and lactate dehydrogenase (LDH) levels. LDH level was the best predictor of the outcome; WBC and PCT had no significant added predictive values when coupled with LDH in multivariable models, even in patients with fever or acute chest syndrome. Severe evolution always occurred when LDH levels were over 4 times the upper limit of the normal range at admission and never occurred when LDH levels were within the normal range. CONCLUSION Further studies should confirm the predictive value of LDH before its widespread use as a prognostic factor. If it is confirmed, the benefit of preemptive transfusion when LDH levels at admission are very high could be investigated.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy. A retrospective study of 19 cases.

OBJECTIVE We studied the clinical and biological effects and safety of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy (ICP). METHODS All cases of ICP treated with ursodeoxycholic acid in our department from January 1st, 1991 to May 31st, 1997 were reviewed. RESULTS Forty-three patients had ICP, of whom 19 received ursodeoxycholic acid. The first symptoms appeared after a mean of 29.7 weeks of pregnancy (WP). Treatment was started after a mean of 32 WP, and lasted a mean of 28.5 days. Fourteen patients showed a clinical improvement on UDCA, and 11 showed a biological improvement. Two had a biological deterioration with increased liver enzyme concentrations. CONCLUSIONS Ursodeoxycholic acid appears to be an effective treatment for ICP, but further studies are needed to confirm its safety in pregnancy.

From Pregnancy to Preeclampsia: A Key Role for Estrogens

Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, estrogen is produced primarily in the placenta by conversion of androgen precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in estradiol levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy

Objective. We studied the clinical and biological effects and safety of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy (ICP).