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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Meta Analysis
Hepatitis A virus vaccination in persons with hepatitis C virus infection: consequences of quality measure implementation.
Hepatitis A virus (HAV) superinfection in persons with hepatitis C virus (HCV) infection has been associated with a high mortality rate, and vaccination is recommended. The incidence of HAV is low, and the aim of this study was to determine the mortality risk of HAV superinfection and the consequences of routine vaccination in persons with HCV infection. To determine the mortality risk of HAV superinfection, a meta-analysis including studies reporting mortality in HCV-infected persons was performed. Data were extracted independently by two investigators and recorded on a standardized spreadsheet. The pooled mortality estimate was used to determine the number needed to vaccinate (NNV) to prevent mortality from HAV superinfection. The total vaccine cost was also calculated. A total of 239 studies were identified using a defined search strategy. Of these, 11 appeared to be relevant, and of these, 10 were suitable for inclusion in the meta-analysis. The pooled odds ratio (OR) for mortality risk in HAV superinfection of HCV-infected persons was 7.23 (95% confidence interval: 1.24-42.12) with significant heterogeneity (I(2) = 56%; P = 0.03) between studies. Using the pooled OR for mortality, this translates to 1.4 deaths per 1,000,000 susceptible persons with HCV per year. The NNV to prevent one death per year is therefore 814,849, assuming 90% vaccine uptake and 94.3% vaccine efficiency. The vaccine cost for this totals $162 million, or $80.1 million per death prevented per year. ⋯ These data challenge the use of routine HAV vaccination in HCV-infected persons and its incorporation into clinical practice guidelines. HAV vaccination of all HCV-infected persons is costly and likely to expose many individuals to an intervention that is of no direct benefit.
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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.