Etiologies of Acute Liver Failure

Lee, William M.

doi:10.1055/s-2008-1073114

Cited by 217 publications

(102 citation statements)

References 68 publications

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“…Acute liver failure (ALF) is mostly related to acetaminophen (paracetamol) overdoses [Lee, 2003, Verma et al , 2009], along with use of other drugs like halothane, isoniazid or rifampin [Lee, 2008, Kim et al , 2010]. Viral hepatitis, toxins including carbon tetrachloride and Amanita phalloides (death cap), vascular events like pulmonary embolism, myocardial infarction, and heat stroke, acute fatty liver of pregnancy or Wilson’s disease may also result in ALF [Lee, 1993; 2008, Lee et al , 2008]. In contrast, common causes of chronic liver failure (CLF) are alcohol abuse, chronic viral hepatitis, and nonalcoholic fatty liver disease [Adams et al , 2005, Heidelbaugh et al , 2006].…”

Section: Pathophysiologymentioning

confidence: 99%

Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

Büdingen

González

Tucker

et al. 2014

Therapeutic Advances in Infection

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The liver is a complex organ with great ability to influence drug pharmacokinetics. Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism, clearance, and biliary elimination. These alterations differ widely depending on the cause of the liver failure, if it is acute or chronic in nature, the extent of impairment, and comorbid conditions. In addition, effects on liver functions do not occur in a proportional or predictable manner for escalating degrees of liver impairment. The ability of hepatic alterations to influence PK is also dependent on drug characteristics, such as administration route, chemical properties, protein binding, and extraction ratio, among others. This complexity makes it difficult to predict what these effects have on drugs. Unlike certain classes of agents, efficacy of anti-infectives is most often dependent on fulfilling pharmacokinetic/pharmacodynamic targets, such as Cmax/MIC, AUC/MIC, T>MIC, IC50/EC50, or T>EC95. Loss of efficacy, or conversely, increased risk of toxicity may occur in certain circumstances of liver injury. Although important to consider these potential alterations and their effects on specific anti-infectives, many lack data to constitute specific dosing adjustments, making it important to monitor patients for effectiveness and toxicities of therapy.

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Section: Pathophysiologymentioning

confidence: 99%

Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

Büdingen

González

Tucker

et al. 2014

Therapeutic Advances in Infection

View full text Add to dashboard Cite

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“…A majority of the clinical cases of acute liver failure results from either accidental or intentional overdose of acetaminophen (APAP), a readily available analgesic and antipyretic drug (Ichai and Samuel, 2011; Lee, 2008). In case of an APAP overdose, a substantial amount of APAP is metabolized by cytochrome P450 2E1, yielding the reactive metabolite N -acetyl- p -benzoquinone imine (NAPQI), which depletes the glutathione (GSH) pool and that gives rise to deleterious APAP-protein adducts (Dahlin et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

et al. 2017

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Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficiency of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5 hour. Sampling was performed 3, 6, 24 and 48 hours following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.

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“…However, despite these significant differences, there are similarities. All together, DILI accounts for more cases of acute liver failure in the U.S. and several other Western countries than any other etiology [2]. Moreover, although not a single drug approved for sale in the U.S. since 1997 has been withdrawn for hepatotoxicity [3], DILI remains the most common cause for withdrawal of existing drugs from the market and for black box warnings, and is a major reason for the discontinuation of testing of new entities during pre-clinical studies [4].…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

McGill

Jaeschke

2015

JCM

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Drug-induced liver injury (DILI) is major problem for both the drug industry and for clinicians. There are two basic categories of DILI: intrinsic and idiosyncratic. The former is the chief cause of acute liver failure in several developed countries, while the latter is the most common reason for post-marketing drug withdrawal and a major reason for failure to approve new drugs in the U.S. Although considerably more progress has been made in the study of intrinsic DILI, our understanding of both forms of drug hepatotoxicity remains incomplete. Recent work involving microRNAs (miRNAs) has advanced our knowledge of DILI in two ways: 1) possible roles of miRNAs in the pathophysiological mechanisms of DILI have been identified and 2) circulating miRNA profiles have shown promise for the detection and diagnosis of DILI in clinical settings. The purpose of this review is to summarize major findings in these two areas of research. Taken together, exciting progress has been made in the study of miRNAs in DILI. Possible mechanisms through which miRNA species contribute to the basic mechanisms of DILI are beginning to emerge, and new miRNA-based biomarkers have the potential to greatly improve diagnosis of liver injury and prediction of patient outcomes.

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Etiologies of Acute Liver Failure

Cited by 217 publications

References 68 publications

Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

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