Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease.

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.

Acute lower limb ischemia as a triggering condition in hypoxic hepatitis: a study of five cases.

BACKGROUND/AIM: Acute centrilobular liver cell necrosis in hypoxic hepatitis (HH) occurs mainly in the setting of hemodynamic failure owing to cardiac failure, respiratory failure, and septic-toxic shock. Cases of HH were also reported under specific conditions such as heat stroke, grand mal seizure, obstructive sleep apnea, and complicated aortic aneurysm. In this study, we report 5 cases of HH occurring in the course of acute lower limb ischemia (ALLI). To the best of our knowledge, the association between HH and ALLI has not yet been reported. METHODS: In a prospective and consecutive series of 142 cases of HH, we identified 5 cases (3.5%) in which ALLI was the triggering condition. The clinical, hemodynamic, and liver laboratory data of these 5 cases are reported. A review of the literature on liver injury observed in the case of ALLI is also made. RESULTS: The 5 patients were 4 males and 1 female of mean age 63 years. All 5 had typical HH after ALLI. Four of them were in shock on admission. Arterial blood pH lower than 7.15 was observed upon admission in the 3 patients who died. Other potential causes of liver hypoxia were present in all patients. Urgent and efficient revascularization of the ischemic limb was a necessary condition for survival. CONCLUSIONS: Acute lower limb ischemia should be added to the list of conditions able to trigger HH. In this particular setting, urgent revascularization of the ischemic limb seems to be a prerequisite for survival.

Involuntary human exposure to carbamazepine: A cross-sectional study of correlates across the lifespan and dietary spectrum.

Treated wastewater (TWW) is increasingly used for agricultural irrigation, especially in arid and semi-arid regions. Carbamazepine is among the most frequently detected pharmaceuticals in TWW. Moreover, its uptake and accumulation have been demonstrated in crops irrigated with TWW. A previous controlled trial found that urine concentrations of carbamazepine were higher in healthy volunteers consuming TWW-irrigated produce as compared to freshwater-irrigated produce. The aim of the current study was to assess whether carbamazepine is quantifiable in urine of Israelis consuming their usual diets and whether concentrations vary according to age, personal characteristics and diet. In this cross-sectional study, we recruited 245 volunteers, including a reference group of omnivorous healthy adults aged 18-66; pregnant women; children aged 3-6 years; adults aged >75 years; and vegetarians/vegans. Participants provided spot urine samples and reported 24-hour and "usual" dietary consumption. Urinary carbamazepine levels were compared according to group, personal characteristics, health behaviors, and reported diet. Carbamazepine was detectable (≥1.66 ng/L) in urine of 84%, 76%, 75.5%, 66%, and 19.6% of the reference group, vegetarians, older adults, pregnant women, and children, respectively. Quantifiable concentrations (≥5.0 ng/L) of carbamazepine were found in 58%, 46%, 36.7%, 14%, and 0% of these groups, respectively (p = 0.001 for comparison of proportions across groups). In adults, higher carbamazepine concentrations were significantly associated (p < 0.05) with self-defined vegetarianism, usual consumption of dairy products and at least five vegetables/day, and no meat or fish consumption in the past 24-hours. This study demonstrates that people living in a water-scarce region with widespread TWW irrigation, are unknowingly exposed to carbamazepine. Individuals adhering to recommended guidelines for daily fresh produce consumption may be at higher risk of exposure to TWW-derived contaminants of emerging concern.

Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases.

The centrilobular liver cell necrosis observed in hypoxic hepatitis is generally attributed to failure of hepatic blood perfusion. Accordingly, this injury of the liver is commonly recognized under the terms "shock liver" or "ischemic hepatitis." During a 10-year period, 142 episodes of hypoxic hepatitis were consecutively identified in the intensive care unit of a general hospital, and the clinical, biological, and hemodynamic parameters were prospectively collected on individual files. We conducted the current study to assess retrospectively the role of the hemodynamic mechanisms of tissue hypoxia: ischemia, passive venous congestion, and hypoxemia. Among the 142 episodes of hypoxic hepatitis, 138 were separated in 4 main groups based on clinical features: decompensated congestive heart failure (80 cases), acute cardiac failure (20 cases), exacerbated chronic respiratory failure (19 cases), and toxic/septic shock (19 cases). An elementary hemodynamic evaluation, including blood pressure, central venous pressure, and arterial blood gas analysis, was carried out in every episode and a more complete hemodynamic assessment through pulmonary artery catheterization was performed in 61 episodes. The hemodynamic mechanisms responsible for hypoxic hepatitis were different in the 4 groups. In congestive heart failure and acute heart failure, the hypoxia of the liver resulted from decreased hepatic blood flow (ischemia) due to left-sided heart failure and from venous congestion secondary to right-sided heart failure. In chronic respiratory failure, liver hypoxia was mainly due to profound hypoxemia. In toxic/septic shock, oxygen delivery to the liver was not decreased but oxygen needs were increased, while the liver was unable to use oxygen properly. In all conditions underlying hypoxic hepatitis, except toxic/septic shock, a shock state was observed in only about 50% of the cases. Therefore, the expressions "shock liver" or "ischemic hepatitis" are misleading and should be replaced by the more general term "hypoxic hepatitis."

[Screening for hepatocarcinoma in a cohort with cirrhosis mainly of alcoholic origin]. / Dépistage du carcinome hépatocellulaire dans une cohorte de malades porteurs d'une cirrhose d'origine principalement alcoolique.

OBJECTIVES: To assess the feasibility and efficiency of the screening for hepatocarcinoma in a cohort of cirrhoseis mainly of alcoholic origin. PATIENTS AND METHODS: 293 patients with cirrhosis, among them 186 (63.5%) from alcoholic origin, were included in a surveillance programme for hepatocarcinoma by carrying out liver ultrasonography and alpha-foetoprotein dosage every 6 months. Results were analyzed with a mean follow-up of 60 months. Seventeen hepatocarcinoma discovered through the surveillance programme ("screened HCC") were compared with 40 hepatocarcinoma discovered outside the surveillance programme during the same period ("incidental HCC"). RESULTS: The alcoholic origin of the cirrhosis was a predictive factor of poor compliance to the surveillance programme. Among the 186 patients with alcoholic cirrhosis, 129 (69%) were lost during the surveillance programme due to lack of compliance (97 cases) or death (32 cases). By comparison, among the 65 patients with hepatitis C-related cirrhosis, 18 were lost by lack of compliance (11 cases) or death (7 cases) (P<0.001). Moreover, sustained or relapsing alcohol abuse after inclusion in the surveillance programme were also related to the quality of the compliance. Seventeen hepatocarcinoma were discovered through the surveillance giving an annual incidence of 2% for the emergence of hepatocarcinoma. The comparison between screened (n=17) and incidental (n=40) hepatocarcinoma showed that screened HCC were more often asymptomatic (P<0.01), were more often a solitary nodule less than 5 cms (P<0.001) and underwent more often curative treatment (P=0.02). However, the survival between screened and incidental hepatocarcinoma was not different. CONCLUSIONS: Screening for hepatocarcinoma in patients with alcoholic cirrhosis is a difficult task due to poor compliance and early death. According to our results, a surveillance every 6 months is sufficient to detect early lesions accessible to curative treatment by surgical resection or transcutaneous ablation.

Acute upper gastrointestinal bleeding in cirrhosis: changes and advances over the past two decades.

BACKGROUND AND AIMS: Few studies have compared two or more cohorts of cirrhotic patients admitted for upper gastrointestinal bleeding (UGIB) several decades apart. Our aim was to compare epidemiological, clinical, therapeutic and prognostic characteristics of UGIB (whatever the source) in two cohorts of cirrhotic patients admitted to the emergency room of the same general hospital 2 decades apart. METHODS: One-hundred cases of UGIB in cirrhotic patients consecutively admitted between 1984 and 1990 (cohort A) were compared with 100 similar cases admitted between 2004 and 2009 (cohort B). RESULTS: The sex ratio (M/F: 2/1), mean age (approximately 55Y) and the proportion of patients with alcoholic cirrhosis (approximately 80%) did not change. Mean Child-Pugh score and the proportion of patients in Child-Pugh stage C increased from 7.6 and 19% in cohort A to 8.8 and 35% in cohort B (p < 0.001). Therapeutic intervention was performed during initial endoscopy in 13 cases from cohort A and 50 from cohort B (p < 0.001), respectively. The number of transfused patients (85 in cohort A, 58 in cohort B) and the number of red blood cell units administered on the first day (median: 4 in cohort A, 2 in cohort B) were significantly decreased in cohort B (p < 0.001). The rate of rebleeding (45 in cohort A, 11 in cohort B), the need for rescue surgery (8 in cohort A, 0 in cohort B) and the in-hospital mortality (24 in cohort A, 9 in cohort B) significantly decreased in the more recent cohort (p < 0.005). CONCLUSION: This study demonstrated that several characteristics of cirrhotic patients admitted with UGIB have changed over the past 2 decades. Above all, outcome has improved despite an increase in the severity of cirrhosis.