Impact of endometrial preparation on early pregnancy loss and live birth rate after frozen embryo transfer: a large multicenter cohort study (14 421 frozen cycles).

STUDY QUESTION: Does the endometrial preparation protocol (artificial cycle (AC) vs natural cycle (NC) vs stimulated cycle (SC)) impact the risk of early pregnancy loss and live birth rate after frozen/thawed embryo transfer (FET)? SUMMARY ANSWER: In FET, ACs were significantly associated with a higher pregnancy loss rate and a lower live birth rate compared with SC or NC. WHAT IS KNOWN ALREADY: To date, there is no consensus on the optimal endometrial preparation in terms of outcomes. Although some studies have reported a higher pregnancy loss rate using AC compared with NC or SC, no significant difference was found concerning the pregnancy rate or live birth rate. Furthermore, no study has compared the three protocols in a large population. STUDY DESIGN SIZE DURATION: A multicenter retrospective cohort study was conducted in nine reproductive health units in France using the same software to record medical files between 1 January 2012 and 31 December 2016. FET using endometrial preparation by AC, modified NC or SC were included. The primary outcome was the pregnancy loss rate at 10 weeks of gestation. The sample size required was calculated to detect an increase of 5% in the pregnancy loss rate (21-26%), with an alpha risk of 0.5 and a power of 0.8. We calculated that 1126 pregnancies were needed in each group, i.e. 3378 in total. PARTICIPANTS/MATERIALS SETTING METHODS: Data were collected by automatic extraction using the same protocol. All consecutive autologous FET cycles were included: 14 421 cycles (AC: n = 8139; NC: n = 3126; SC: n = 3156) corresponding to 3844 pregnancies (hCG > 100 IU/l) (AC: n = 2214; NC: n = 812; SC: n = 818). Each center completed an online questionnaire describing its routine practice for FET, particularly the reason for choosing one protocol over another. MAIN RESULTS AND THE ROLE OF CHANCE: AC represented 56.5% of FET cycles. Mean age of women was 33.5 (SD ± 4.3) years. The mean number of embryos transferred was 1.5 (±0.5). Groups were comparable, except for history of ovulation disorders (P = 0.01) and prior delivery (P = 0.03), which were significantly higher with AC. Overall, the early pregnancy loss rate was 31.5% (AC: 36.5%; NC: 25.6%; SC: 23.6%). Univariable analysis showed a significant association between early pregnancy loss rate and age >38 years, history of early pregnancy loss, ovulation disorders and duration of cryopreservation >6 months. After adjustment (multivariable regression), the early pregnancy loss rate remained significantly higher in AC vs NC (odds ratio (OR) 1.63 (95% CI) [1.35-1.97]; P < 0.0001) and in AC vs SC (OR 1.87 [1.55-2.26]; P < 0.0001). The biochemical pregnancy rate (hCG > 10 and lower than 100 IU/l) was comparable between the three protocols: 10.7% per transfer. LIMITATIONS REASONS FOR CAUTION: This study is limited by its retrospective design that generates missing data. Routine practice within centers was heterogeneous. However, luteal phase support and timing of embryo transfer were similar in AC. Univariable analysis showed no difference between centers. Moreover, a large number of parameters were included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: Our study shows a significant increase in early pregnancy loss when using AC for endometrial preparation before FET. These results suggest either a larger use of NC or SC, or an improvement of AC by individualizing hormone replacement therapy for patients in order to avoid an excess of pregnancy losses. STUDY FUNDING/COMPETING INTERESTS: The authors declare no conflicts of interest in relation to this work. G.P.-B. declares consulting fees from Ferring, Gedeon-Richter, Merck KGaA, Theramex, Teva; Speaker's fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter, Theramex, Teva. N.C. declares consulting fees from Ferring, Merck KGaA, Theramex, Teva; Speaker's fees or equivalent from Merck KGaA, Ferring. C.R. declares a research grant from Ferring, Gedeon-Richter; consulting fees from Gedeon-Richter, Merck KGaA; Speaker's fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter; E.M.d'A. declares Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Theramex, Teva. I.C-D. declares Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, IBSA. N.M. declares a research grant from Merck KGaA, MSD, IBSA; consulting fees from MSD, Ferring, Gedeon-Richter, Merck KGaA; Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Teva, Goodlife, General Electrics. TRIAL REGISTRATION NUMBER: N/A.

[Adverse obstetric and perinatal outcome with in vitro fertilization technology: A French nationwide population-based study]. / Risques de morbidité maternelle et périnatale en fécondation in vitro : une étude nationale de cohorte française.

OBJECTIVES: The objective of this study was to quantify the risk of maternal and perinatal morbidity with in vitro fertilization (IVF) technology compared to non-IVF pregnancies in a recent French national cohort. METHOD: The data was extracted from the hospital information data system, including all pregnancies with a delivery from 2013 to 2016. The risks of preterm birth, maternal morbidity (venous and arterial thrombosis, gestational diabetes, vascular disorders, placenta previa, placenta abruption), hypotrophy and congenital malformation were compared in both groups in univariate and multivariate analysis after adjustment on the characteristics of women (age, parity, obesity, tobacco dependence, history of diabetes or high blood pressure), multiple deliveries and sex of children. RESULTS: In all, 2,875,662 pregnancies and 2,922,712 births were analyzed, of which 49,224 were derived from IVF (1.7%). In multivariate analysis, all risks were significantly higher in IVF: premature deliveries (ORajusted=1.28; CI95%=1.24-1.32), maternal morbidity (ORajusted=1.24; CI95%=1.21-2.28), (mainly for thrombosis venous, placenta previa and placenta abruption). The risks of hypotrophy (ORajusted=1.13; CI95%=1.10-1.16) and congenital malformations (ORajusted=1.11; CI95%=1.05-1.17) were slightly increased. CONCLUSION: The results of this study on a large cohort of recent births in France confirm that there was an increased risk of maternal and perinatal morbidities in IVF. These risks were similar to those published in the international literature. This study is the starting point for a forthcoming surveillance.

[Analysis of prenatal follow-up strategies for trisomy 21 affected pregnancies in France]. / Analyse du parcours de dépistage prénatal des femmes ayant donné naissance en France à un enfant atteint de trisomie 21.

OBJECTIVE: The main objective of this study was to screen the prenatal follow-up of women with live birth trisomy 21 child in order to evaluate the proportion of prenatal screening failure versus cases where the women refused either the screening or the prenatal diagnosis of Down syndrome. This study covers the period of time from 2009 to 2012 when the national prenatal screening policy changed from second to first trimester and allows for a comparative assessment of the nationwide efficiency of the various maternal serum marker based strategies. METHOD: All authorized cytogenetic laboratories sent required data for all cases of trisomy 21 diagnosed in FRANCE in new-borns (less than 1-year-old) from January 2010 to July 2013. RESULTS: A total of 1253 cases of trisomy 21 were diagnosed before 1 year of age whose mother did not had prenatal diagnosis. For 861 of them, information on the prenatal follow-up was available, with 72% of cases where a prenatal screening was organized either by maternal serum marker or by ultrasound. Results of the screening strategy was positive with maternal serum marker in 28% of cases (calculated risk≥1/250), positive because of abnormal ultrasound in 5% and negative with maternal marker screening (whatever the strategy used) in 67% of cases. Detection rate over the period of the study was 82%, with similar efficiency of first and second trimester strategies (83%) but significantly lower with sequential association of first trimester Nuchal translucency measurement and second trimester serum screening (70%). CONCLUSION: Switching from second trimester to first trimester screening strategy, with as many trisomy 21 foetuses diagnosed with half invasive procedures fulfilled national health policy objectives. Analysis of these data gives useful insights to elaborate a future screening policy involving cell-free foetal DNA sequencing.

[Evolution of the access to the kidney transplantation in France of foreign patients and French patients living in overseas territories]. / Évolution de l'accès à la greffe rénale en France des patients étrangers ou résidant outre-mer.

In France, foreign patients, whether resident or not in France, can register on the national waiting list under administrative and financial conditions. We performed a retrospective analysis to evaluate the access to kidney transplantation on a cohort 2004-2008, using the national registry. Among the 14,732 patients registered during this period, 15.3% are of non-French nationality (3.4% other European, 5.9% North African, 3.9% sub-Saharan African, 2.9% other). Among the 84.6% of French nationality, 3.3% are living in French overseas territories. Compared to the 17.6-month median waiting time of the cohort, median waiting time differs significantly between groups, from 15.7 months for mainland French patients to 36 months for sub-Saharan African patients. Despite the regular development of the allocation rules, these disparities in access to transplantation are mainly, but not completely, explained by blood group or HLA matching difficulties. After adjustment for the other factors known to be significantly linked to a difficult access to transplantation, North and sub-Saharan African patients have the worst difficulties. Future research should consider nonmedical factors, such as socio-economic or socio-cultural factors, potentially relevant to avoid disparities in access to transplantation and should aim at developing specific interventions.

A simple clinico-histopathological composite scoring system is highly predictive of graft outcomes in marginal donors.

The predictive value of pre-implantation biopsies versus clinical scores has not been studied extensively in marginal donors. Pre-implantation biopsies were performed in 313 kidneys from donors that were > or = 50 years of age (training set, n = 191; validation set, n = 122). The value of the donor clinical parameters and histological results in predicting 1-year estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m(2) was retrospectively evaluated. In multivariate analysis, the only clinical parameters associated with low eGFR were donor hypertension and a serum creatinine level > or =150 micromol/L before organ recovery. Clinical scores (Nyberg and Pessione) were not significantly associated with graft function. Regarding histological parameters, univariate analysis showed that glomerulosclerosis (GS) (p = 0.02), arteriolar hyalinosis (p = 0.03) and the Pirani (p = 0.02) and chronic allograft damage index (CADI) (p = 0.04) histological scores were associated with low eGFR. The highest performance in predicting low eGFR was achieved using a composite score that included donor serum creatinine (> or =150 micromol/L or <150 micromol/L), donor hypertension and GS (> or =10% or <10%). The validation set confirmed the critical importance of taking into account biopsy and clinical parameters during marginal donor evaluation. In conclusion, clinical scores are weak predictors of graft outcomes with marginal donors. Instead, a simple and convenient composite score strongly predicts graft function and survival and may facilitate optimal allocation of marginal donors.

Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry.

Post-transplant lymphoproliferative disorders (PTLD) are a rare but serious complication after organ transplantation. A French Registry of PTLD was set up in a nationwide population of kidney transplant recipients. We prospectively enrolled all adult kidney recipients developing PTLD between January 1, 1998, and December 31, 2003. We analyzed the incidence, risk and prognostic factors of PTLD by Kaplan-Meier and Cox analyses. Totally 230 cases of PTLD were referred to the French Registry. Cumulative incidence was 1.18% after 5 years. Older age (per year, AHR = 2.19, CI = 1.22-3.94) and recipient Epstein-Barr virus seronegativity (AHR = 3.01, CI = 1.57-5.08) were associated with an increased risk of PTLD. Patients with PTLD had a reduced survival rate (61% at 5 years). Graft PTLD had the best prognosis with an 81% survival rate after 5 years. Infection with hepatitis C or B virus (HCV or HBV), late-onset PTLD, multiple sites involvement and high Ann Arbor staging were risk factors for patient death. Use of azathioprine was associated with a poorer survival rate. PTLD incidence and risk factors in French recipients are in line with the international or American PTLD series. We highlighted the role of HBV or HCV in patient mortality and described the relevant prognosis factors for patients with post-transplant lymphoproliferations.

Retrospective follow-up of transplantation of kidneys from 'marginal' donors.

The organ shortage has led to extend the procurement to kidneys from 'marginal' donors. As a result, an increasing number of kidneys are discarded, but an extended analysis of the validity of the clinical decision to accept or decline a marginal graft remains to be determined. We have retrospectively analyzed the outcome of 170 kidney transplantations, performed in eight renal transplantation centers between 1992 and 1998. Study group included transplantation from donors accepted after refusal for poor donor or graft quality by at least two centers. Control group included 170 paired recipients from kidneys unanimously accepted by all centers. Main causes of kidney refusal included impaired donor hemodynamics (28%), abnormal pre-harvesting serum creatinine (22%), advanced age in donors (15%), and donor atheroma (14%). The 5-year patient survival (88.2% in the study group and 88.9% in controls) and graft survival (70.4% in the study group and 76.7% in controls, P=0.129) were not significantly different. Delayed graft function occurred significantly more often in the study group patients than in controls patients (63 vs 32%, P<0.0001). Primary non-functioning kidneys were significantly more frequently observed in study patients than in controls (7.7 vs 1.8%, P=0.01). Mean creatinine clearance was significantly lower in the study group patients compared with controls during the post-transplant course. Our results suggest that these initially discarded kidneys provide satisfactory survival rates despite their impaired early functional recovery and poorer long-term renal function, and therefore might be considered acceptable for transplantation in the context of organ shortage.

Preemptive renal transplantation in adults.

Recent studies have clearly demonstrated that preemptive renal transplantation is associated with better graft and patient survival. It improves the quality of life and is a cost-effective option compared to conventional transplantation. We report our experience with this concept and review the literature. We retrospectively analyzed all adult kidney transplantations performed in our center between March 1986 and May 2004: among 463 renal transplantations 44 were preemptive (9.5%). Mean follow-up was 45.7 +/- 6 months in preemptive versus 62.3 +/- 2.6 months in the other group. At the end of the study, graft survivals were 93.2% and 77.1%, respectively (P = .02). Patient survival rates were similar in both groups. In the preemptive group, grafts were more likely to come from living donors (P < .001) and cold ischemia time was shorter (P = .02). A subgroup case-control study showed that cost saving for dialysis in the preemptive group was about 119,000 Euros per patient. More preemptive patients had professional activity before (P = .0002) and after transplantation (P = .02). Our results and data from the literature support the place of preemptive transplantation as the optimal mode of renal replacement therapy for medical and socioeconomic reasons.

Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence.

AIM: To evaluate 5-year survival predictive factors in hospitalised patients with excessive alcohol intake and cirrhosis, including in a multivariate analysis the severity of the liver disease, gastrointestinal bleeding, concomitant viral B or C infection, smoking status, presence of alcoholic hepatitis at inclusion and abstinence from alcohol during follow-up. METHODS: In a non-concurrent cohort study, 122 patients with excessive alcohol intake and cirrhosis were followed up at least five years or till death. Two patients were lost to follow-up. RESULTS: The 5-year survival rates were 43% in the 122 patients and 66%, 50% and 25% in Child-Pugh class A, B and C patients, respectively. In multivariate analysis, age (P = 0.01), Child-Pugh score (P = 0.0001), gastrointestinal bleeding (P = 0.01), presence of HBs Ag and/or anti-HCV (P = 0.03), smoking (P = 0.01), absence of histologically proven alcoholic hepatitis (P = 0.05) and persistent alcohol intake (P = 0.002) were associated with significantly increased risk ratios of death. CONCLUSIONS: In hospitalised patients with excessive alcohol intake and cirrhosis: (1) age, liver failure, gastrointestinal bleeding, concomitant viral B or C infection and persistent alcohol intake are independent poor prognostic markers, (2) smoking may contribute to the aggravation of cirrhosis, and (3) alcoholic hepatitis, being a potentially reversible cause of liver failure, has a favourable prognostic significance.

Risk of pancreatic adenocarcinoma in chronic pancreatitis.

BACKGROUND: The risk of pancreatic cancer in patients with chronic pancreatitis (CP) is difficult to assess. Previous studies, mostly case control studies or studies relying on data case registers, reported relative risks varying from 2.3 to 18.5. METHODS: We studied a prospective, single centre, medical-surgical cohort of 373 consecutive patients (322 (86%) men, median age 40 years) with proven CP (alcoholic origin 85%) and a follow up of at least two years (median follow up 9.2 years; range 2.0-34.8) in order to exclude pancreatitis revealing pancreatic cancer. We calculated the age and sex standardised incidence ratio (SIR) as the ratio of the number of observed cases of pancreatic cancer in this cohort to the number of expected cases, as provided by the French National Cancer Register. RESULTS: Four cases of pancreatic adenocarcinoma (1.1% of patients) were observed in 3437 patient years (expected number of cases 0.15; SIR 26.7, 95% confidence interval (CI) 7.3-68.3; p=0.00002). In a second analysis in which patients lost to follow up were considered to be followed up until the end point without having developed pancreatic adenocarcinoma (4762 patient years), SIR was 19.0 (CI 5.2-48.8; p=0.00007). CONCLUSION: Patients with CP have a markedly increased risk of pancreatic cancer compared with the general population.

Comparison of the effect of terlipressin and albumin on arterial blood volume in patients with cirrhosis and tense ascites treated by paracentesis: a randomised pilot study.

BACKGROUND: Patients with cirrhosis and tense ascites treated by paracentesis alone have a decrease in effective arterial blood volume after ascites removal. Although intravenous albumin is effective in preventing paracentesis induced decreased arterial blood volume, its clinical use is controversial. As paracentesis induces arteriolar vasodilation which plays a role in the development of decreased effective arterial blood volume, administration of a vasoconstrictor (terlipressin) could prevent circulatory alterations due to paracentesis. AIMS: To perform a pilot study comparing the effects of terlipressin and albumin on effective arterial blood volume in patients with cirrhosis treated by paracentesis for tense ascites. METHODS: Twenty patients with cirrhosis and tense ascites were randomly assigned to be treated by either paracentesis and terlipressin or paracentesis and albumin. Terlipressin (3 mg) or albumin (8 g/l of removed ascites) were administered on the day of paracentesis. Effective arterial blood volume was assessed by measuring plasma renin concentrations at baseline and on the day of hospital discharge (4-6 days after treatment). Decreased effective arterial blood volume was defined as an increase in plasma renin concentrations on the day of hospital discharge of more than 50% of baseline values. RESULTS: Irrespective of the treatment group, mean values for plasma renin concentrations at hospital discharge did not differ from their respective baseline values (p=0.10). Baseline plasma levels of renin concentrations did not differ between the terlipressin and albumin groups (p=0.61). Changes from baseline in plasma renin concentrations did not differ between groups (p=0.39). Three patients in the terlipressin group and three in the albumin group developed decreased arterial blood volume. CONCLUSIONS: This randomised pilot study suggests that terlipressin may be as effective as intravenous albumin in preventing a decrease in effective arterial blood volume in patients with cirrhosis treated by paracentesis for tense ascites.

Role of small-conductance Ca2+-dependent K+ channels in in vitro nitric oxide-mediated aortic hyporeactivity to alpha-adrenergic vasoconstriction in rats with cirrhosis.

BACKGROUND/AIMS: In vitro studies have shown that cirrhotic aortas are hyporeactive to the contractile effect of vasoconstrictors because upregulated endothelial nitric oxide-synthase (NOS) overproduces nitric oxide (NO). Although stimulation of endothelial small-conductance Ca2+-dependent K+ (SK(Ca)) channels may elicit vasorelaxation in normal arteries, the role of these channels in cirrhosis-induced hyporeactivity is unknown. Thus, the aim of the present study was to investigate the role of endothelial SK(Ca) channels in cirrhosis-induced, NO-mediated, in vitro aortic hyporeactivity to alpha1-adrenergic vasoconstrictors. METHODS: Isolated thoracic aortas from cirrhotic and normal rats were used. The effects of apamin, a selective SK(Ca) channel blocker, were measured on the vascular reactivity to phenylephrine. In addition, SK(Ca) channel protein expression was studied. The effects of iberiotoxin and charybdotoxin, blockers of other K(Ca) channels, were also studied in cirrhotic aortas. RESULTS: Apamin suppressed cirrhosis-induced aortic hyporeactivity to phenylephrine in an endothelium-dependent, NOS-inhibitor-sensitive manner. SK(Ca) channel protein was overexpressed in cirrhotic aortic walls. Iberiotoxin abolished cirrhosis-induced aortic hyporeactivity to phenylephrine in an endothelium-dependent but NOS-inhibitor-resistant manner. Charybdotoxin did not induce any significant increase in phenylephrine-elicited contraction. CONCLUSIONS: In cirrhotic aortas, the overexpression and overactivity of endothelial SK(Ca) channels contributes to in vitro NO-mediated hyporeactivity to the contractile action of alpha1-adrenergic agonists.

Cigarette smoking and hepatic lesions in patients with chronic hepatitis C.

A possible hepatotoxicity of cigarette smoke has been recently suggested by epidemiological and experimental studies. Our aim was to study the possible relationships between smoking and liver fibrosis and activity in patients with chronic hepatitis C. A cross-sectional study was performed in a group of 310 patients with chronic hepatitis C consecutively hospitalized for their first liver biopsy. The relationships between age, gender, alcohol consumption, route of contamination, tobacco consumption, and Knodell fibrosis and activity scores were examined in univariate, age-adjusted, and multivariate analyses. One hundred and seventy-six patients (57%) were current smokers. Smokers were younger (P <.001), more often of male gender (P =.001), more often alcohol consumers (P =.001), and more often had a history of intravenous drug use (P =.0001) than never smokers. Smoking was related to increased fibrosis and activity scores in age-adjusted (P =.009 and P =.005, respectively) and multivariate analyses (P =.03 and P =.04, respectively). Smoking increases the severity of hepatic lesions in patients with chronic hepatitis C.

Relationships between haemodynamic alterations and the development of ascites or refractory ascites in patients with cirrhosis.

OBJECTIVE: In patients with cirrhosis, the relationships between haemodynamic alterations and the development of ascites or the occurrence of refractory ascites are unknown. The aim of the present study was to compare haemodynamic measurements obtained in patients with non-refractory ascites to haemodynamic measurements obtained in patients without ascites and in patients with refractory ascites. METHODS: A cohort of 121 patients was prospectively studied, of whom 29 patients did not have ascites, 45 had non-refractory ascites and 47 had refractory ascites. Splanchnic, renal and systemic haemodynamics were measured in all patients. RESULTS: The hepatic venous pressure gradient was significantly higher in patients with non-refractory ascites than in patients without ascites (18.5 +/- 0.8 mmHg versus 15.8 +/- 0.7 mmHg). Renal and systemic haemodynamics did not significantly differ between patients with non-refractory ascites and patients without ascites. The glomerular filtration rate and renal blood flow were significantly lower in patients with refractory ascites than in patients with non-refractory ascites (77 +/- 4 versus 107 +/- 5 ml/min and 867 +/- 62 versus 1,008 +/- 68 ml/min, respectively). Splanchnic and systemic haemodynamics did not significantly differ between patients with refractory ascites and patients with non-refractory ascites. CONCLUSIONS: In patients with cirrhosis, an increase in portal hypertension was the sole haemodynamic alteration related to the development of ascites. Renal vasoconstriction (and subsequent renal hypoperfusion and hypofiltration) was the only haemodynamic alteration related to the occurrence of refractory ascites. The development of ascites or refractory ascites was not associated with any alteration in systemic haemodynamics.

[Patients with alcoholic liver disease hospitalized in gastroenterology. A national multicenter study]. / Maladies alcooliques du foie hospitalisées en Hépato-Gastroentérologie. Enquête multicentrique nationale.

OBJECTIVES: To describe the characteristics of in-patients with alcoholic liver disease in Hepatogastroenterology and to evaluate whether geographic location was a risk factor for cirrhosis. METHODS: A French, national, multicenter, prospective investigation was performed in the last quarter of 1997. To be included in the study, patients had to have drunk at least 50 g of alcohol per day for the past year or to have cirrhosis. RESULTS: Seventeen centers included 802 patients, 20% had histologically proven cirrhosis or probable cirrhosis. Thirty-five percent had undergone liver biopsy. Twenty five percent of these patients had cirrhosis without acute alcoholic hepatitis and 37% had cirrhosis with acute alcoholic hepatitis. After dividing France along a Bordeaux-Strasbourg axis, there was more histologically proven or probable cirrhosis in the North (46%) than in the South (36%) (P<0.005) while daily alcohol intake was greater the South (150 +/- 6 g) than in the North (129 +/- 4 g) (P<0.0001). When the six variables (age, sex, daily consumption of alcohol over the past 5 years, presence of hepatitis B surface antigen and antibodies to hepatitis C virus, total duration of alcohol abuse) were considered together in stepwise logistic regression analysis, geographic location changed the prediction of cirrhosis. The odds ratio for cirrhosis in patients living to the North of the Bordeaux-Strasbourg axis was 1.9 (95% confidence interval range 1.1-3.2) (P<0.02), suggesting the role of nutritional factors.

Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.

BACKGROUND & AIMS: The outcome of portal vein thrombosis in relation to associated prothrombotic states has not been evaluated. We assessed current outcome and predictors of bleeding and thrombotic events in a cohort of 136 adults with nonmalignant, noncirrhotic portal vein thrombosis, of whom 84 received anticoagulant therapy. METHODS: Multivariate Cox model analysis for event-free survival and analysis taking into account multiple events were used. RESULTS: Median follow-up was 46 months. The incidence rate of gastrointestinal bleeding was 12.5 (95% confidence interval [CI], 10-15) per 100 patient-years. Large varices were an independent predictor for bleeding. Anticoagulant therapy did not increase the risk or the severity of bleeding. The incidence rate of thrombotic events was 5.5 (95% CI, 3.8-7.2) per 100 patient-years. Underlying prothrombotic state and absence of anticoagulant therapy were independent predictors for thrombosis. In patients with underlying prothrombotic state, the incidence rates of splanchnic venous infarction were 0.82 and 5.2 per 100 patient-years in periods with and without anticoagulant therapy, respectively (P = 0.01). Two nonanticoagulated patients died of bleeding and thrombosis, respectively. CONCLUSIONS: In patients with portal vein thrombosis, the risk of thrombosis is currently as clinically significant as the risk of bleeding. The benefit-risk ratio favors anticoagulant therapy.

Evidence for an endothelium-derived hyperpolarizing factor in the superior mesenteric artery from rats with cirrhosis.

In cirrhosis, in splanchnic arteries, endothelium-dependent relaxation may persist even if overactive nitric oxide synthase (NOS) and cyclooxygenase (COX) are inhibited. In normal arteries, a significant endothelium-dependent relaxation to acetylcholine persists after NOS/COX inhibition. This relaxation is caused by smooth muscle cell (SMC) membrane hyperpolarization, which is sensitive to a combination of the potassium channel blockers apamin and charybdotoxin, and is mediated by an endothelium-derived hyperpolarizing factor (EDHF). The aim of this study was to detect EDHF and evaluate its pathophysiologic role in isolated superior mesenteric arteries from cirrhotic rats. Arterial rings were obtained and exposed to N(w)-nitro-L-arginine (L-NNA, a NOS inhibitor) and indomethacin (a COX inhibitor). Acetylcholine-induced membrane potential responses and concentration-response curves to the relaxant of acetylcholine were obtained with and without apamin plus charybdotoxin. Acetylcholine-induced responses were measured in certain rings from endothelium-denuded arteries. Contractions caused by the alpha(1)-adrenoceptor agonist phenylephrine were obtained in cirrhotic and normal rings with and without apamin and charybdotoxin. Significant acetylcholine-induced, endothelium-dependent, apamin- and charybdotoxin-sensitive, SMC membrane hyperpolarization and relaxation were found. An apamin- and charybdotoxin-sensitive hyporesponsiveness to the contractile action of phenylephrine was found in cirrhotic rings. In conclusion, in cirrhotic rats, in the superior mesenteric artery exposed to NOS/COX-inhibitors, an EDHF exists that may replace NOS/COX products to induce endothelium-dependent arterial relaxation.

Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy.

Characteristics and outcomes of recent portal or mesenteric venous thrombosis are ill-known. We intended to compare these features with those of patients with portal cavernoma, and also to assess the incidence of recanalization of recent thrombosis on anticoagulation therapy. All patients seen between 1983 and 1999 were enrolled into this retrospective study if recent portal or mesenteric venous thrombosis or portal cavernoma had been documented, and if cancer of the liver, pancreas, or bile duct, intrahepatic block including cirrhosis, and obstruction of the hepatic veins had been ruled out. The proportion of recent thrombosis was 7% in patients seen before 1990 and 56% after 1994 (P <.05). Patients with recent thrombosis (n = 33) or cavernoma (n = 108) did not differ with regard to age, sex ratio, or prevalence of prothrombotic states and of previous thrombotic events. In patients with recent thrombosis, septic pylephlebitis was more common and the incidence of gastrointestinal bleeding was lower (2.4 vs. 12.7/100 patient-years). Recanalization occurred in 25 of 27 patients given anticoagulation and 0 of 2 patients not given anticoagulation. The probability of recanalization was related to the extent of thrombosis (P =.003). In conclusion, mesenteric or portal venous thrombosis is increasingly recognized at an early stage. The features differentiating recent thrombosis and cavernoma are related to silent onset precluding early recognition and therapy in the latter. Frequent association with prothrombotic states and frequent recanalization on anticoagulation support the recommendation of early anticoagulation therapy in all patients with recent portal vein thrombosis.

Aquaretic effects of niravoline, a kappa-opioid agonist, in patients with cirrhosis.

BACKGROUND/AIMS: In patients with cirrhosis, decreased renal water excretion is a common complication. Niravoline (RU51599), a kappa-opioid receptor agonist, has been shown to induce an aquaretic response. The aim of this study was to evaluate the aquaretic effect and tolerance of niravoline in patients with cirrhosis. METHODS: Biochemical tests and hemodynamic values were determined before and 1, 2, 3 and 24 h after niravoline administration at doses ranging from 0.5 to 2 mg iv in 18 patients with cirrhosis. RESULTS: Diuresis significantly increased in the first hour from 64+/-9 to 146+/-31 ml/h, and returned to basal values after 3 h. Free water clearance also significantly increased, reaching the positive range at 1 h. Plasma osmolality significantly decreased at 2 h (from 290+/-4 to 286+/-4 mOsm/kg). Plasma sodium concentrations increased significantly at 3 h (from 133+/-1 to 134+/-1 mEq/l). Heart rate and arterial pressure did not change. The highest doses (1.5 mg or 2 mg) induced personality disorders and mild confusion within 2 h. These effects reversed completely within 8 h. CONCLUSION: This study shows that niravoline administration induces an aquaretic response and is well tolerated, at moderate doses, in patients with cirrhosis. Thus, moderate doses of niravoline may be useful for treating patients with cirrhosis and water retention.