Histomorphometric study of rat liver during the treatment of the acute toxic injury

Introduction. There are a few effective therapies are available for acute liver injury at present. The aim of the study was to investigate histological and morphometric changes in the liver using models of toxic damage caused by carbon tetrachloride (CCl4 ) and acetaminophen during correction with Oxymethyluracil (OMU). Material and methods. A total of ninety rats were divided into 18 groups. The treatment of acute liver damage models caused by a single injection of CCl4 or acetaminophen was carried out using “Heptor”, “Mexidol”, and OMU. The correction was carried out twice (sacrificed 24 hours after intoxication) and four times (sacrificed 72 hours after intoxication). Liver tissues were processed using standard histological techniques (H&E). A semi-quantitative assessment was performed using a scale based on the severity of liver cell deaths. Results. Twenty-four hours after administration of CCl4 or 72 hours after administration of acetaminophen, the treatment with OMU led to a decrease in liver cell death compared to the group with administration of only CCl4 or acetaminophen. Seventy-two hours after CCl4 and 24 hours after acetaminophen intoxication, these groups with the OMU treatment did not differ from those of the carbon tetrachloride- or acetaminophen-induced liver injury groups, respectively. Conclusion. Thus, on the model of CCl4 liver injury, the treatment with OMU is more effective for 24 hours. In the case of acetaminophen intoxication, the effectiveness of treatment with OMU is better for 72 hours. The results obtained are possibly associated with a different mechanism of the damaging effect of the studied toxicants.

Acetaminophen Intoxication with Fulminant Hepatic Failure Salvaged by Plasmapheresis

Introduction Acetaminophen-induced liver injury is the most common cause of acute liver failure, where multiple ingestions or a delay in the presentation may lead to a poor prognosis. N-acetylcysteine (NAC) is the conventional antidote used to treat acute acetaminophen toxicity, and plasmapheresis can be used as an adjunct, though there are no systematic studies to prove its effectivity. Case Presentation An 18-year-old girl was admitted with reduced responsiveness for one day with a few episodes of diarrhea. On admission, she was febrile and had a GCS of 10/15, otherwise normal neurology. She had marked right hypochodrial tenderness, deep icterus, and a pulse of 120 beats per minute, with a blood pressure of 80/50 mmHg; fluid resuscitation with inotropic support was done. Initial investigations revealed severe metabolic acidosis, hemoglobin of 9.5 g/dL, white blood cell count 13,500/mm3, and platelet 119,000 per µL. The prothrombin time (PT) international normalized ratio (INR) was 4.7, and the activated partial thromboplastin time (APTT) was 38.6. The alanine aminotransferase (ALT) level was 8118 U/L, and aspartate aminotransferase (AST) was 3883 U/L with a total bilirubin of 107 µmol/L. The diagnosis of acute liver failure following acetaminophen intoxication was made and managed with intravenous NAC, pantoprazole cover, intravenous ceftriaxone, metronidazole, thiamine, and vitamin K. Fresh frozen plasma and platelets were given for severe coagulopathy. She was started with plasmapheresis at the intensive care unit (ICU), where she had a significant improvement, though she developed hospital-acquired pneumonia, which was successfully managed. Subsequently, her liver functions returned to the baseline, and she was discharged after a psychiatric assessment. Conclusion A high degree of suspicion needs to be adopted to diagnose acetaminophen-induced acute liver failure when a patient presents with hepatic encephalopathy, and plasmapheresis can be considered a life-saving measure adjunct to the NAC.

Mass Spectrometry-Based Proteomics Reveal Alcohol Dehydrogenase 1B as a Blood Biomarker Candidate to Monitor Acetaminophen-Induced Liver Injury

Acute liver injury (ALI) is a severe disorder resulting from excessive hepatocyte cell death, and frequently caused by acetaminophen intoxication. Clinical management of ALI progression is hampered by the dearth of blood biomarkers available. In this study, a bioinformatics workflow was developed to screen omics databases and identify potential biomarkers for hepatocyte cell death. Then, discovery proteomics was harnessed to select from among these candidates those that were specifically detected in the blood of acetaminophen-induced ALI patients. Among these candidates, the isoenzyme alcohol dehydrogenase 1B (ADH1B) was massively leaked into the blood. To evaluate ADH1B, we developed a targeted proteomics assay and quantified ADH1B in serum samples collected at different times from 17 patients admitted for acetaminophen-induced ALI. Serum ADH1B concentrations increased markedly during the acute phase of the disease, and dropped to undetectable levels during recovery. In contrast to alanine aminotransferase activity, the rapid drop in circulating ADH1B concentrations was followed by an improvement in the international normalized ratio (INR) within 10–48 h, and was associated with favorable outcomes. In conclusion, the combination of omics data exploration and proteomics revealed ADH1B as a new blood biomarker candidate that could be useful for the monitoring of acetaminophen-induced ALI.

Acetaminophen Oxidation and Inflammatory Markers – A Review of Hepatic Molecular Mechanisms and Preclinical Studies

Acetaminophen is a widely used analgesic for pain management, especially useful in chronic diseases, such as rheumatoid arthritis. However, easy access to this medicine has increased the occurrence of episodes of poisoning. Patients often develop severe liver damage, which may quickly lead to death. Consequently, numerous studies have been conducted to identify new biomarkers that allow the prediction of the degree of acetaminophen intoxication and thus intervene in a timely manner to save patients’ lives. This review highlights the main mechanisms of the induction and progression of liver damage arising from acetaminophen poisoning. In addition, we have discussed the possibility of using new clinical biomarkers for detecting acetaminophen poisoning.

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.

Differential TAM receptor regulation of hepatic physiology and injury

The TAM receptor tyrosine kinases (RTK) Mer and Axl have been implicated in liver disease, yet our understanding of their roles in liver homeostasis and injury is limited. We therefore examined the performance of Mer and Axl mutant mice during aging, and in four models of liver injury. We find that Mer and Axl are most prominently expressed in Kupffer and hepatic endothelial cells, and that as Axl-/-Mertk-/- mice normally age, they develop profound liver disease. We further find that Mer signaling is critical to the phagocytosis of apoptotic hepatocytes that are generated during acute hepatic injury, and that Mer and Axl act in concert to inhibit injury-triggered cytokine production. TAM expression in Kupffer cells is crucial for these effects. In contrast, we show that Axl is uniquely important in mitigating liver damage during acute acetaminophen intoxication. Finally, we demonstrate that Axl exacerbates the fibrosis that develops in a model of chronic hepatic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that target these RTKs in the liver.