Hepatology : official journal of the American Association for the Study of Liver Diseases
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Acetaminophen (APAP) is the leading cause of acute liver injury in the developed world. Timely administration of N-acetylcysteine (N-Ac) prevents the progression of serious liver injury and disease, whereas failure to administer N-Ac within a critical time frame allows disease progression and in the most severe cases may result in liver failure or death. In this situation, liver transplantation may be the only life-saving measure. Thus, the outcome of an APAP overdose depends on the size of the overdose and the time to first administration of N-Ac. We developed a system of differential equations to describe acute liver injury due to APAP overdose. The Model for Acetaminophen-induced Liver Damage (MALD) uses a patient's aspartate aminotransferase (AST), alanine aminotransferase (ALT), and international normalized ratio (INR) measurements on admission to estimate overdose amount, time elapsed since overdose, and outcome. The mathematical model was then tested on 53 patients from the University of Utah. With the addition of serum creatinine, eventual death was predicted with 100% sensitivity, 91% specificity, 67% positive predictive value (PPV), and 100% negative predictive value (NPV) in this retrospective study. Using only initial AST, ALT, and INR measurements, the model accurately predicted subsequent laboratory values for the majority of individual patients. This is the first dynamical rather than statistical approach to determine poor prognosis in patients with life-threatening liver disease due to APAP overdose. ⋯ MALD provides a method to estimate overdose amount, time elapsed since overdose, and outcome from patient laboratory values commonly available on admission in cases of acute liver failure due to APAP overdose and should be validated in multicenter prospective evaluation.
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Mutations in hemochromatosis protein (HFE) or transferrin receptor 2 (TFR2) cause hereditary hemochromatosis (HH) by impeding production of the liver iron-regulatory hormone, hepcidin (HAMP). This study examined the effects of disruption of Hfe or Tfr2, either alone or together, on liver iron loading and injury in mouse models of HH. Iron status was determined in Hfe knockout (Hfe(-/-)), Tfr2 Y245X mutant (Tfr2(mut)), and double-mutant (Hfe(-/-) ×Tfr2(mut) ) mice by measuring plasma and liver iron levels. Plasma alanine transaminase (ALT) activity, liver histology, and collagen deposition were evaluated to assess liver injury. Hepatic oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and F(2)-isoprostane levels. Gene expression was measured by real-time polymerase chain reaction. Hfe(-/-) ×Tfr2(mut) mice had elevated hepatic iron with a periportal distribution and increased plasma iron, transferrin saturation, and non-transferrin-bound iron, compared with Hfe(-/-), Tfr2(mut), and wild-type (WT) mice. Hamp1 expression was reduced to 40% (Hfe(-/-) and Tfr2(mut) ) and 1% (Hfe(-/-) ×Tfr2(mut)) of WT values. Hfe(-/-) ×Tfr2(mut) mice had elevated plasma ALT activity and mild hepatic inflammation with scattered aggregates of infiltrating inflammatory cluster of differentiation 45 (CD45)-positive cells. Increased hepatic hydoxyproline levels as well as Sirius red and Masson's Trichrome staining demonstrated advanced portal collagen deposition. Hfe(-/-) and Tfr2(mut) mice had less hepatic inflammation and collagen deposition. Liver F(2) -isoprostane levels were elevated, and copper/zinc and manganese SOD activities decreased in Hfe(-/-) ×Tfr2(mut), Tfr2(mut), and Hfe(-/-) mice, compared with WT mice. ⋯ Disruption of both Hfe and Tfr2 caused more severe hepatic iron overload with more advanced lipid peroxidation, inflammation, and portal fibrosis than was observed with the disruption of either gene alone. The Hfe(-/-) ×Tfr2(mut) mouse model of iron-induced liver injury reflects the liver injury phenotype observed in human HH.
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Comparative Study
Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study.
Epidemiology, risk factors, and clinical effect of infections by multiresistant bacteria in cirrhosis are poorly known. This work was a prospective evaluation in two series of cirrhotic patients admitted with infection or developing infection during hospitalization. The first series was studied between 2005 and 2007 (507 bacterial infections in 223 patients) and the second between 2010 and 2011 (162 bacterial infections in 110 patients). In the first series, 32% of infections were community acquired (CA), 32% healthcare associated (HCA), and 36% nosocomial. Multiresistant bacteria (92 infections; 18%) were isolated in 4%, 14%, and 35% of these infections, respectively (P < 0.001). Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E; n = 43) was the main multiresistant organism identified, followed by Pseudomonas aeruginosa (n = 17), methicillin-resistant Staphylococcus aureus (n = 14), and Enterococcus faecium (n = 14). The efficacy of currently recommended empirical antibiotic therapy was very low in nosocomial infections (40%), compared to HCA and CA episodes (73% and 83%, respectively; P < 0.0001), particularly in spontaneous bacterial peritonitis, urinary tract infection, and pneumonia (26%, 29%, and 44%, respectively). Septic shock (26% versus 10%; P < 0.0001) and mortality rate (25% versus 12%; P = 0.001) were significantly higher in infections caused by multiresistant strains. Nosocomial origin of infection (hazard ratio [HR], 4.43), long-term norfloxacin prophylaxis (HR, 2.69), recent infection by multiresistant bacteria (HR, 2.45), and recent use of β-lactams (HR, 2.39) were independently associated with the development of multiresistant infections. Results in the second series were similar to those observed in the first series. ⋯ Multiresistant bacteria, especially ESBL-producing Enterobacteriaceae, are frequently isolated in nosocomial and, to a lesser extent, HCA infections in cirrhosis, rendering third-generation cephalosporins clinically ineffective. New antibiotic strategies tailored according to the local epidemiological patterns are needed for the empirical treatment of nosocomial infections in cirrhosis.
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Comparative Study
Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis and inflammation in murine models of nonalcoholic fatty liver disease.
Hepatic fat accumulation and changes in lipid composition are hallmarks of nonalcoholic fatty liver disease (NAFLD). As an experimental approach for treatment of NAFLD, we synthesized the bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). Previous work demonstrated profound hepatoprotective properties of the conjugate in vitro and in vivo. Here we investigated the effects of UDCA-LPE in two nutritional mouse models of NAFLD. C57BL/6 mice were fed a high-fat diet (HFD) for 28 weeks, resulting in steatosis with hyperlipidemia. In a second model, mice received a methionin-choline-deficient (MCD) diet for up to 11 weeks, which induced advanced nonalcoholic steatohepatitis (NASH). Establishment of liver injury was followed by intraperitoneal injections of 30 mg/kg UDCA-LPE three times a week for different time periods. UDCA-LPE ameliorated both HFD- and MCD-induced increases in alanine aminotransferase (ALT) values near to normalization. As for metabolic parameters, UDCA-LPE reduced elevated serum triglyceride and cholesterol values in HFD mice. Liver histology showed improvement of steatosis in HFD and MCD mice concomitant with reductions in hepatic triglyceride and cholesterol levels. Additionally, the conjugate lowered serum caspase-8 activity in both models and decreased lipid hydroperoxides in MCD mice. Abundance of proinflammatory lysophosphatidylcholine (LPC), which was detectable in both HFD and MCD mice, was reduced by UDCA-LPE. Quantitative reverse transcriptase-polymerase chain reaction qRT-PCR of liver specimens revealed that UDCA-LPE strongly down-regulated inflammatory genes and modified the expression of genes involved in lipid metabolism. ⋯ The current study demonstrates that UDCA-LPE improves hepatic injury at different stages of NAFLD. By concurrently lowering hepatic lipid overloading as well as susceptibility of hepatocytes toward inflammatory stimuli, the conjugate may be able to ameliorate disease progression. Thus, UDCA-LPE represents a promising compound suitable for the treatment of NAFLD.