Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and Acute Liver Failure
TL;DR: N-acetylcysteine is recommended for all patients with APAP-induced ALF and it reduces mortality and Liver transplantation should be offered early to those who are unlikely to survive based on described prognostic criteria.
About: This article is published in Clinics in Liver Disease.The article was published on 2018-05-01. It has received 105 citations till now. The article focuses on the topics: Acetaminophen & Liver transplantation.
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TL;DR: In this article, metabolic and transcriptional profiling of germ-free and conventionalized mouse liver revealed an upregulation of the Nrf2 antioxidant and xenobiotic response in microbiome-replete animals.
120 citations
TL;DR: Detailed and updated evidence regarding Nrf2 and its involvement in the development of the main liver diseases such as alcoholic liver damage, viral hepatitis, steatosis, steatohepatitis, cholestatic damage, and liver cancer is provided.
Abstract: Liver diseases represent a critical health problem with 2 million deaths worldwide per year, mainly due to cirrhosis and its complications. Oxidative stress plays an important role in the development of liver diseases. In order to maintain an adequate homeostasis, there must be a balance between free radicals and antioxidant mediators. Nuclear factor erythroid 2-related factor (Nrf2) and its negative regulator Kelch-like ECH-associated protein 1 (Keap1) comprise a defense mechanism against oxidative stress damage, and growing evidence considers this signaling pathway as a key pharmacological target for the treatment of liver diseases. In this review, we provide detailed and updated evidence regarding Nrf2 and its involvement in the development of the main liver diseases such as alcoholic liver damage, viral hepatitis, steatosis, steatohepatitis, cholestatic damage, and liver cancer. The molecular and cellular mechanisms of Nrf2 cellular signaling are elaborated, along with key and relevant antioxidant drugs, and mechanisms on how Keap1/Nrf2 modulation can positively affect the therapeutic response are described. Finally, exciting recent findings about epigenetic modifications and their link with regulation of Keap1/Nrf2 signaling are outlined.
47 citations
TL;DR: MSCs and their derivatives will effectively promote liver regeneration and liver injury repair in APAP overdose-treated animals and patients and may serve as an effective strategy for patients waiting for liver transplantation during the early and late stages of APAP-induced ALF in the near future.
Abstract: Acetaminophen (APAP)-induced injury is a common clinical phenomenon that not only occurs in a dose-dependent manner but also occurs in some idiosyncratic individuals in a dose-independent manner. APAP overdose generally results in acute liver injury via the initiation of oxidative stress, endoplasmic reticulum (ER) stress, autophagy, liver inflammation, and microcirculatory dysfunction. Liver transplantation is the only effective strategy for treating APAP-induced liver failure, but liver transplantation is inhibited by scarce availability of donor liver grafts, acute graft rejection, lifelong immunosuppression, and unbearable costs. Currently, N-acetylcysteine (NAC) effectively restores liver functions early after APAP intake, but it does not protect against APAP-induced injury at the late stage. An increasing number of animal studies have demonstrated that mesenchymal stem cells (MSCs) significantly attenuate acute liver injury through their migratory capacity, hepatogenic differentiation, immunoregulatory capacity, and paracrine effects in acute liver failure (ALF). In this review, we comprehensively discuss the mechanisms of APAP overdose-induced liver injury and current therapies for treating APAP-induced liver injury. We then comprehensively summarize recent studies about transplantation of MSC and MSC derivatives for treating APAP-induced liver injury. We firmly believe that MSCs and their derivatives will effectively promote liver regeneration and liver injury repair in APAP overdose-treated animals and patients. To this end, MSC-based therapies may serve as an effective strategy for patients who are waiting for liver transplantation during the early and late stages of APAP-induced ALF in the near future.
35 citations
Cites background from "Acetaminophen (APAP or N-Acetyl-p-A..."
...In general, doses of APAP ranging from 1 to 4 g/day are considered to be clinically safe, while a single overdose ingestion due to suicide or unintentional overdose exceeding 15 to 25 g may cause severe and lethal liver injury [1, 2]....
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TL;DR: Most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.
Abstract: Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.
31 citations
TL;DR: Recommendations for non-invasive pharmacological management of NSLBP from recent clinical practice guidelines were compared with each other and with the best available evidence on drug efficacy to improve the quality of N SLBP care.
Abstract: Introduction: Analgesic drugs are often prescribed to patients with non-specific low back pain (NSLBP). Recommendations for non-invasive pharmacological management of NSLBP from recent clinical pra...
31 citations
Cites background from "Acetaminophen (APAP or N-Acetyl-p-A..."
...Although severe AEs of paracetamol are relatively rare, paracetamol remains the leading cause of acute liver failure worldwide and overdosing may lead to severe liver damage and even death [37,45]....
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References
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University of Texas Southwestern Medical Center1, University of Michigan2, University of Washington3, University of California, San Francisco4, University of California, Los Angeles5, University of Nebraska Omaha6, University of Pittsburgh7, Mayo Clinic8, Baylor University Medical Center9, Northwestern University10, Washington University in St. Louis11, Icahn School of Medicine at Mount Sinai12, Oregon Health & Science University13, University of Miami14, Yale University15, University of Alabama at Birmingham16, Harvard University17
TL;DR: The primary aim was to compare presenting clinical features and liver transplantation in patients with acute liver failure related to acetaminophen hepatotoxicity, other drugs, indeterminate factors, and other causes.
Abstract: Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent causes of acute liver failure. The cause of liver failure and coma grade at admission were...
1,988 citations
TL;DR: The successful use of orthotopic liver transplants in fulminant hepatic failure has created a need for early prognostic indicators to select the patients most likely to benefit at a time when liver transplantation is still feasible.
1,839 citations
TL;DR: In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States, and education of patients, physicians, and pharmacies to limit high‐risk use settings is recommended.
1,705 citations
Journal Article•
TL;DR: A fundamental role of glutathione in the body may be to protect tissues against electrophilic attack by drug metabolites and other alkylating agents.
Abstract: The possibility that glutathione may protect against acetaminophen-induced hepatic necrosis was examined. Pretreatment of mice with diethyl maleate, which depletes hepatic glutathione, potentiated acetaminophen-induced hepatic necrosis, whereas pretreatment with cysteine, a glutathione precursor, prevented hepatic damage. Administration of acetaminophen caused a dose-dependent depletion of hepatic glutathione. Glutathione depletion by acetaminophen was enhanced by treatments that potentiate the hepatic necrosis and covalent binding produced by the toxic metabolite of acetaminophen. Conversely, glutathione depletion was inhibited by treatments that protect against these toxic effects. Moreover, covalent binding of this metabolite to hepatic macromolecules did not occur until the availability of glutathione was exhausted through conjugation with the metabolite. Similarly, alteration of glutathione availability by pretreatment with diethyl maleate or cysteine, respectively, increased or decreased covalent binding of the toxic metabolite. We propose that. a fundamental role of glutathione in the body may be to protect tissues against electrophilic attack by drug metabolites and other alkylating agents.
1,666 citations
1,564 citations