Acetaminophen-induced Hepatitis Research Articles

Chemical characterization, in vitro and in vivo evaluation of chitosan-Aloe marlothii gel loaded nanoparticles on acetaminophen-induced hepatitis in mice

Chemical characterization, in vitro and in vivo evaluation of chitosan-Aloe marlothii gel loaded nanoparticles on acetaminophen-induced hepatitis in mice

S2688 COVID-19-Induced Acute Hepatitis Treated Successfully With N-Acetylcysteine: Case Report

INTRODUCTION: Mild liver impairment is widely reported in patients with COVID19. However, Acute hepatitis (AH) was reported in only one case found in a 99-case series published in China.N- acetylcysteine (NAC) is a known medication used in acetaminophen-induced hepatitis, works as a hepatoprotective agent via multiple mechanisms, including restoring hepatic glutathione as well as an antioxidant. It seems that its therapeutic use could be extended to manage cases of AH induced by other medical conditions like COVID 19 as in our case. CASE DESCRIPTION/METHODS: 64 years old male presented with progressive dyspnea, fever, and myalgia. He was diagnosed with COVID19 at a different facility two days prior to the current presentation and was sent home to self-quarantine. On presentation, the patient was mildly hypoxia that responded to nasal oxygen, but never hypotensive. Laboratory results were significant for elevated aspartate transaminase (AST) and alanine transaminase (ALT) at 1,264, 767 Units/L respectively. Alkaline phosphates showed a 1.5-fold increase from his baseline. Total bilirubin, Albumin, prothrombin time, partial thromboplastin time, international normalized ratio (INR) were all normal throughout hospitalization. Viral hepatitis panel and autoimmune hepatitis panel (including anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, and immunoglobulin G level were also negative. Serum salicylate and acetaminophen levels, urine toxicology screening test, and respiratory viral panel (novel Coronavirus not included) were all negative. Serum ferritin was elevated at 20,325 ng/mL, while serum iron was 40 mcg/dL and total iron-binding capacity was 282 mcg/dL. Upon admission, the patient was given a loading dose of NAC followed by maintenance doses. Two days later, AST and ALT started to trend down. Two days later, alkaline phosphatase followed suit. The patient was also placed on the COVID19 treatment regimen used in our facility, including Azithromycin, Hydroxychloroquine, and Zinc sulfate. Systemic corticosteroids were initiated on day 6 due to worsening hypoxia. Eventually, the patient’s inflammatory markers normalized on day 9. Hypoxia improved and he was successfully discharged home. DISCUSSION: We reported a rare case of COVID19 induced AH along with our observation of possible benefit from using NAC in treating this condition. NAC is known for its safety profile. Hence, we believe that more studies need to investigate the role of NAC in treating cases of AH.Figure 1.: Liver enzymes trending over time. ALT( alanine transaminase), AST Aspartate transferase, ALk Pho (alkaline phosphatase).Figure 2.: Patient vital signs during admission.

Activity of enzymes of tyrosine metabolism in the rat liver under the conditions of acetaminophen-induced hepatitis on the background of protein deficiency

The contribution of the mis-metabolism of individual amino acids to the development of drug-induced damage to liver cells remains unexplored. The aim of the present study was to investigate the changes in liver tyrosine level and activity of the enzymes of its metabolism: tyrosine aminotransferase, 4-hydroxyphenylpyruvate dioxygenase, aldehyde dehydrogenase ALDH3A1 under the conditions of acetaminophen-induced hepatitis on the background of protein deficiency. Determination of tyrosine in deproteinized with 6% sulfosalicylic acid extracts of the liver tissue was performed using the automatic analyzer of amino acids T-339 (“Microtechnology”, Czech Republic). The enzyme activity was determined by spectrophotometric method – tyrosine aminotransferase by the amount of 4-hydroxybenzaldehyde, which has a maximum absorption at 330 nm, 4-hydroxyphenylpyruvate dioxygenase – by the colored product intensity at λ 336 nm, aldehyde dehydrogenase ALDH3A1 activity was measured at 340 nm wavelength. Results have shown that in animals with toxic liver injury which were maintained in conditions of alimentary protein deficiency, a 5-fold decrease in tyrosine level in the liver was observed. At the same time in animals of this group there was a decrease in TAT activity by 1.6 times, a 4-fold decrease in activity of aldehyde dehydrogenase ALDH3A1 and increase in the activity of 4-hydroxyphenylpyruvate dioxygenase by 2.5 time comparing to control parameters. Conclusion was made, that alimentary protein deficiency is a factor leading to an intensification of tyrosine metabolism disturbances in animals with toxic liver injury. The pronounced exhaustion of the tyrosine pool is accompanied by the activation of the homogentisate pathway of its metabolism, as evidenced by the increase in the activity of 4-hydroxyphenylpyruvate dioxygenase and simultaneous reduction in the aldehyde dehydrogenase ALDH3A1activity. The established changes open prospects to study the possible targets for the exogenous correction of metabolic disorders under the conditions of intoxication with acetaminophen, especially in people with protein deficiency.

Activity of the mitochondrial isoenzymes of endogenous aldehydes catabolism under the conditions of acetaminophen-induced hepatitis

Activity of the mitochondrial isoenzymes of endogenous aldehydes catabolism under the conditions of acetaminophen-induced hepatitis

The State of the Adenyl Nucleotide System in the Liver of Rats with Toxic Hepatitis under Conditions of Protein Deficiency

Adenyl nucleotide levels and activity of AMP catabolism enzymes in the cytosolic liver fraction of rats with acetaminophen-induced hepatitis have been studied under different dietary protein regimens. It was found that in animals with toxic hepatitis maintained on a diet rich in protein the ATP and ADP levels decreased, while AMP levels were similar to those in control animals. At the same time, in the cytosolic liver fraction of rats with acetaminophen-induced hepatitis kept under conditions of protein deficiency, ATP and AMP pools were depleted. Changes in the adenyl nucleotides content were accompanied by altered activity of AMP catabolism enzymes, such as 5′-nucleotidase and AMP deaminase. It was found that in rats with toxic hepatitis that were fed a complete diet, AMP deaminase activity increased in comparison to the control level along with 5′-nucleotidase stimulation. At the same time, in protein-restricted rats with toxic liver damage, AMP deaminase activity decreased, while 5′-nucleotidase activity was elevated in comparison to control values. These results indicate depletion of energy sources in the liver cells of rats with acetaminophen-induced hepatitis that were fed a low-protein diet. The observed changes in the activity of AMP catabolism enzymes may be considered as one of the mechanisms that regulate the cellular energy function.

Activity of cytosolic isoenzymes of endogenous aldehydes catabolism under the conditions of acetaminophen-induced hepatitis on the background of protein deficiency

Activity of cytosolic isoenzymes of endogenous aldehydes catabolism under the conditions of acetaminophen-induced hepatitis on the background of protein deficiency

Activity of liver mitochondrial Krebs cycle NAD+-dependent dehydrogenases in rats with hepatitis induced by acetaminophen under conditions of alimentary protein deficiency

Activity of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and the NAD+/NADН ratio were studied in the liver mitochondrial fraction of rats with toxic hepatitis induced by acetaminophen under conditions of alimentary protein deficiency. Acetaminophen-induced hepatitis was characterized by a decrease of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase activities, while the mitochondrial NAD+/NADН ratio remained at the control level. Modeling of acetaminophen-induced hepatitis in rats with alimentary protein deficiency caused a more pronounced decrease in the activity of studied Krebs cycle NAD+-dependent dehydrogenases and a 2.2-fold increase of the mitochondrial NAD+/NADН ratio.

Вміст аденілових нуклеотидів у мітохондріях печінки за умов ацетамінофен-індукованого гепатиту та аліментарної депривації протеїну

Вміст аденілових нуклеотидів у мітохондріях печінки за умов ацетамінофен-індукованого гепатиту та аліментарної депривації протеїну

Activity of liver mitochondrial NAD+-dependent dehydrogenases of the krebs cycle in rats with acetaminophen-induced hepatitis developed under conditions of alimentary protein deficiency

Activity of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and the NAD(+)/NADН ratio were studied in the liver mitochondrial fraction of rats with toxic hepatitis induced by acetaminophen under conditions of alimentary protein deprivation. Acetaminophen-induced hepatitis was characterized by a decrease of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase activities, while the mitochondrial NAD(+)/NADН ratio remained at the control level. Modeling of acetaminophen-induced hepatitis in rats with alimentary protein caused a more pronounced decrease in the activity of NAD(+)-dependent dehydrogenases studied and a 2.2-fold increase of the mitochondrial NAD(+)/NADН ratio. This suggests that alimentary protein deprivation potentiated drug-induced liver damage.

The peculiarities of the structural and functional state of the cytochrome component of the liver mitochondrial respiratory chain under conditions of acetaminophen-induced hepatitis on the background of alimentary protein deprivation

The activity of a key enzyme of the cytochrome component of the respiratory chain (cytochrome oxidase), the quantitative redistribution of mitochondrial cytochromes b, c1, c, and aa3, as well as the activities of the key enzymes of cytochrome heme metabolism (δ-aminolevulinate synthase and heme oxygenase) under conditions of acetaminophen-induced liver injury were studied on the background of dietary protein deprivation. Under conditions of acetaminophen-induced hepatitis that developed on the background of alimentary protein deprivation, an inhibition of cytochrome oxidase activity and a decrease in the contents of mitochondrial cytochromes on the background of an increase in the δ-aminolevulinate synthase and heme oxygenase activity were observed. In animals with a toxic liver injury that were kept under conditions of dietary protein deprivation, the contents of mitochondrial cytochromes b, c1, c, and aa3 progressively decreased, which was accompanied by an increase in heme oxygenase activity, whereas δ-aminolevulinate synthase activity remained at the control level. It was concluded that dietary protein deprivation is a critical factor for the development of disturbances in the structural-functional integrity of the cytochrome component of the respiratory chain. The identified changes can be considered as a possible mechanism that underlies the disturbance in the function of the energy biotransformation system under conditions of dietary protein deprivation.

Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

BackgroundAn overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis.MethodsMale mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT).ResultsIn APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology.ConclusionsAPAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP-induced hepatitis through the improvement of liver histopathology by decreased oxidative stress, reduced liver injury, and restored hepatic GSH.

Albumin Fusion Prolongs the Antioxidant and Anti-Inflammatory Activities of Thioredoxin in Mice with Acetaminophen-Induced Hepatitis

Overdoses of acetaminophen (APAP) are a major cause of acute liver failure. N-Acetylcysteine (NAC) is the standard therapy for patients with such an overdose because oxidative stress plays an important role in the pathogenesis of APAP-induced hepatitis. However, NAC is not sufficiently efficacious. We previously developed a recombinant human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx), designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an endogenous protein with antioxidative and anti-inflammatory properties. In this study, we investigated the therapeutic impact of HSA-Trx in mice with APAP-induced hepatitis. The systemic administration of HSA-Trx significantly improved the survival rate of mice treated with a lethal dose of APAP compared with saline. HSA-Trx strongly attenuated plasma transaminases in APAP-induced hepatitis mice compared with HSA or Trx, components of the fusion protein. HSA-Trx also markedly caused a diminution in the histopathological features of hepatic injuries and the number of apoptosis-positive hepatic cells. In addition, an evaluation of oxidative stress markers and plasma cytokine and chemokine levels clearly showed that HSA-Trx significantly improved the breakdown of hepatic redox conditions and inflammation caused by the APAP treatment. HSA-Trx also significantly decreased oxidative and nitrosative/nitrative stress induced by SIN-1 in vitro. Finally, HSA-Trx, but not the NAC treatment at 4 h after APAP injection, significantly inhibited the elevation in plasma transaminase levels. In conclusion, the findings suggest that HSA-Trx has considerable potential for use as a novel therapeutic agent for APAP-induced hepatitis, due to its long-lasting antioxidative and anti-inflammatory effects.

Evaluation of efficacious activities of aqueous extract of <em>Phyllanthus niruri</em> against acetaminophen-induced hepatitis in rats

The efficacy of aqueous extract of Phyllanthus niruri against acetaminophen-induced hepatitis in rats was evaluated. The hepatic injury was induced with 200 mg/kg, p.o. of acetaminophen, which led to rise in serum levels of the biochemical parameters observed. These are the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) which were elevated by 22% compared to respective negative control. Treatment with the plant extract (500, 1000 and 2000 mg/kg, p.o.) lowered the biochemical parameters of the respective serum AST 31 to 38%, ALT 20 to 31%, Bilirubin -2 to 4%, protein 5 to 15%, cholesterol 0.2 to 0.5%, and albumin 5 to 12%. The histopathological results indicated that, the effect of the extracts on the condition of the liver as compared to the normal control ranges from mild to moderate. The biochemical variations were as a result of the different treatment involved in the study. The result therefore, shows lowering of the elevated parameters in the serum and possible reversal of hepatic cell damage with aqueous extract of Phyllanthus niruri. The trend of the study shows that, the longer the period of treatment at lower doses, the better the efficacy of the plant extract.Keywords: Phyllanthus niruri, hepatitis, acetaminophen, biochemical, histopathology, rats

Treatment of acetaminophen-induced hepatitis and fulminant hepatic failure with extracorporeal sorbent-based devices.

When a patient with acetaminophen overdose arrives in the emergency room more than 14 hours after ingestion, the value of N-acetylcysteine is unproven and patient mortality is at least 10%. Anecdotal case reports have indicated benefit of extracorporeal detoxification of these late-arriving patients with acetaminophen overdose. We identified 10 patients with serious acetaminophen overdose, 8 that arrived in the emergency room 16 to 44 hours after acetaminophen overdose with plasma levels predicting severe hepatic toxicity, and 2 that arrived in the emergency room 8 to 12 hours after overdose but with exceedingly high levels. All patients developed severe hepatitis (mean peak alanine aminotransferase, 4,052; mean peak protime, 25 seconds). At 16 to 68 hours after overdose, the patients were treated for 4 to 6 hours with the Liver Dialysis System (Hemocleanse Inc, W. Lafayette, IN), a single-access hemodiabsorption system indicated for treatment of serious drug overdose and for treatment of hepatic encephalopathy. Acetaminophen levels fell an average of 73% during treatment. Treatment was repeated 24 or 48 hours later if acetaminophen was still measurable in plasma. All 10 patients recovered intrinsic liver function and general health, with liver enzymes starting to normalize 24 hours after treatment, and were discharged 3 to 7 days after overdose. No patient required liver transplant. Because market introduction of Liver Dialysis, there have been 40 more patients with acetaminophen-induced hepatotoxicity treated with Liver Dialysis. All have recovered liver function without long-term sequelae. Though most of these patients with already established hepatic toxicity from acetaminophen would recover without extracorporeal blood therapy, treatment with the Liver Dialysis System should assure recovery from acute hepatic failure, and may shorten the clinical course of the illness.

Transcriptional activation of heme oxygenase-1 and its functional significance in acetaminophen-induced hepatitis and hepatocellular injury in the rat

Background/Aim: Glutathione depletion contributes to acetaminophen hepatotoxicity and is known to induce the oxidative stress reactant heme oxygenase-1. The metabolites of the heme oxygenase pathway, biliverdin, carbon monoxide, and iron may modulate acetaminophen toxicity. The aim of this study was to assess cell-type specific expression of heme oxygenase-1 and its impact on liver injury and microcirculatory disturbances in a model of acetaminophen-induced hepatitis. Methods: Gene expression of heme oxygenase-1 was studied by Northern- and Western analysis as well as immunohistochemistry. The time course of heme oxygenase-1 and -2, cytokine-induced neutrophil chemoattractant-1, and intercellular adhesion molecule-1 was studied by Northern analysis. DNA-binding activity of nuclear factor-κB was determined by electrophoretic mobility shift assay. Sinusoidal perfusion and leukocyte-endothelial interactions were assessed by intravital microscopy. Results: Acetaminophen caused a moderate sinusoidal perfusion failure (−15%) and infiltration of neutrophils along with activation of nuclear factor-κB and intercellular adhesion molecule-1 and cytokine-induced neutrophil chemoattractant-1 mRNAs. Induction of heme oxygenase-1 mRNA and protein (∼30-fold) in hepatocytes and non-parenchymal cells paralleled the inflammatory response. Blockade of heme oxygenase activity with tin-protoporphyrin-IX abrogated acetaminophen-induced hepatic neutrophil accumulation and nuclear factor-κB activation, but failed to affect sinusoidal perfusion and liver injury. Conclusions: The inflammatory response associated with acetaminophen hepatotoxicity is modulated by the parallel induction of the heme oxygenase-1 gene. However, heme oxygenase-1 has no permissive effect on sinusoidal perfusion and does not affect liver injury in this model. These data argue against a central role of nuclear factor-κB activation and neutrophil infiltration as perpetuating factors of liver injury in acetaminophen toxicity.

Gastric emptying in rats with acetaminophen-induced hepatitis.

The objective of this work was to study the gastric emptying (GE) of liquids in fasted and sucrose-fed rats with toxic hepatitis induced by acetaminophen. The GE of three test meals (saline, glucose and mayonnaise) was evaluated in Wistar rats. For each meal, the animals were divided into two groups (N = 24 each). Group I was fed a sucrose diet throughout the experiment (66 h) while group II was fasted. Forty-two hours after the start of the experiment, each group was divided into two subgroups (N = 12 each). Subgroup A received a placebo and subgroup B was given acetaminophen (1 g/kg). Twenty-four hours later, the GE of the three test meals was assessed and blood samples were collected to measure the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and acetaminophen. In group IB, the mean AST and ALT values were 515 and 263 IU/l, respectively, while for group IIB they were 4014 and 2472 IU/l, respectively. The mean serum acetaminophen levels were higher in group IIB (120 micrograms/ml) than in group IB (87 micrograms/ml). The gastric retention values were significantly higher in group IIB than in group IIA for all three test meals: saline, 51 vs 35%; glucose, 52 vs 38% and mayonnaise, 51 vs 29% (median values). The correlation between gastric retention and AST levels was significant (P < 0.05) for group IIB for the three test meals: r = 0.73, 0.67 and 0.68 for saline, glucose and mayonnaise, respectively. We conclude that GE is altered in rats with hepatic lesions induced by acetaminophen, and that these alterations may be related to the liver cell necrosis caused by the drug.