Acetaminophen (APAP) overdose is the predominant cause of acute liver failure in the United States. Toxicity begins with a reactive metabolite that binds to proteins. In rodents, this leads to mitochondrial dysfunction and nuclear DNA fragmentation, resulting in necrotic cell death. While APAP metabolism is similar in humans, the later events resulting in toxicity have not been investigated in patients. In this study, levels of biomarkers of mitochondrial damage (glutamate dehydrogenase [GDH] and mitochondrial DNA [mtDNA]) and nuclear DNA fragments were measured in plasma from APAP-overdose patients. Overdose patients with no or minimal hepatic injury who had normal liver function tests (LTs) (referred to herein as the normal LT group) and healthy volunteers served as controls. Peak GDH activity and mtDNA concentration were increased in plasma from patients with abnormal LT. Peak nuclear DNA fragmentation in the abnormal LT cohort was also increased over that of controls. Parallel studies in mice revealed that these plasma biomarkers correlated well with tissue injury. Caspase-3 activity and cleaved caspase-3 were not detectable in plasma from overdose patients or mice, but were elevated after TNF-induced apoptosis, indicating that APAP overdose does not cause apoptosis. Thus, our results suggest that mitochondrial damage and nuclear DNA fragmentation are likely to be critical events in APAP hepatotoxicity in humans, resulting in necrotic cell death.

In the first randomized trial of antivenom in the United States, Fab AV effectively terminated venom effects. Since the unplanned use of Fab AV in the PRN group was common, the treatment regimen may require more than 1 initial dose.

We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.hsa-miR-122-5p | hsa-miR-3646-3p | hsa-miR-412 A cetaminophen (APAP) overdose (OD) is the major cause of acute liver failure and death due to analgesics in the developed world (1-3), with over 500 deaths per year in the United States (3, 4). APAP misuse results in over 78,000 emergency department (ED) visits annually, at a cost of more than $86 million/ year (5).Patients who present with a report of APAP ingestion are assessed for treatment with N-acetyl cysteine (NAC) by measuring serum APAP concentrations and liver function tests, including alanine aminotransferase (ALT) activity (4). There are limits to the utility of the current biomarker, ALT, in assessing the status of potentially APAP-poisoned patients. For example, ALT may take greater than 72 h to reach peak activity in blood (6), and elevated ALT activity is not specific for APAP hepatotoxicity. New biomarkers could serve as more sensitive and specific signatures to predict hepatotoxicity following APAP overdose and to distinguish APAP hepatotoxicity from other causes of liver disease. Ideal biomarkers should identify liver damage at an early stage, accelerating appropriate treatment.MicroRNAs (miRNAs) are short (∼22 nt in length) regulatory RNAs that control gene expression posttranscriptionally (7,8). The human genome contains more than 1,000 genes encoding distinct miRNAs whose levels in a biological sample can be quantified with great sensitivity and precision using quantitative real-time PCR (qRT-PCR) (9). Many miRNAs are expressed tissue-specifically or enriched in certain cell types, with the expression pattern providing signatures for the physiological or pathological status of specific cells and tissues (10, 11). Importantly, miRNAs can be exported from cells and are detectable in stable complexes extracellularly, in blood, serum, or plasma (12).There is ample evidence that circulating extracellular miRNAs in blood can serve as biomarkers for internal organ physiology and pathology (11,13,14). Increased levels of miR-122 and miR-192 were found in the plasma of APAP-overdosed (300 mg/kg) mice (15). A number of additional miRNAs (miR-135a, miR-466g, miR-574-5p, and miR-1196) were elevated in the plasma of mice with hi...

Methemoglobinemia must be considered in the differential diagnosis of the cyanotic patient. Methemoglobin cannot carry oxygen or carbon dioxide. Methemoglobinemia can result from exposure to a wide variety of chemicals, including many commonly prescribed drugs, usually in an overdose situation. Most cases require only supportive therapy and assessment for other toxic complications. Severe cases may result in hypoxia and require treatment with methylene blue. Not all cases respond to methylene blue, and methylene blue itself may produce serious side effects.

This cohort study characterizes the accuracy of the Sequential Organ Failure Assessment (SOFA) score to discriminate death from survival in patients with COVID-19 pneumonia receiving oxygen therapy for 4 hours or longer before undergoing endotracheal intubation.

Acetaminophen (APAP) is a widely used analgesic. However, APAP overdose is hepatotoxic and is the primary cause of acute liver failure in the developed world. The mechanism of APAP-induced liver injury begins with protein binding and involves mitochondrial dysfunction and oxidative stress. Recent efforts to discover blood biomarkers of mitochondrial damage have identified increased plasma glutamate dehydrogenase activity and mitochondrial DNA concentration in APAP overdose patients. However, a problem with these markers is that they are too large to be released from cells without cell death or loss of membrane integrity. Metabolomic studies are more likely to reveal biomarkers that are useful at early time points, before injury begins. Similar to earlier work, our metabolomic studies revealed that acylcarnitines are elevated in serum from mice after treatment with toxic doses of APAP. Importantly, a comparison with furosemide demonstrated that increased serum acylcarnitines are specific for mitochondrial dysfunction. However, when we measured these compounds in plasma from humans with liver injury after APAP overdose, we could not detect any significant differences from control groups. Further experiments with mice showed that N-acetylcysteine, the antidote for APAP overdose in humans, can reduce acylcarnitine levels in serum. Altogether, our data do not support the clinical measurement of acylcarnitines in blood after APAP overdose due to the standard N-acetylcysteine treatment in patients, but strongly suggest that acylcarnitines would be useful mechanistic biomarkers in other forms of liver injury involving mitochondrial dysfunction.

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