Cause Of Acute Liver Failure Research Articles

S3158 Supplement Gone Wrong: Drug-Induced Liver Injury Caused by Artemisinin

Introduction: Drug-induced liver injury (DILI) is defined as hepatic dysfunction caused by prescription medications, supplements, or xenobiotics after alternative causes have been excluded. As one of the leading causes of acute liver failure, DILI should be considered when patients present with hepatic dysfunction. We present a case of symptomatic DILI secondary to artemisinin use. Case Description/Methods: A 78-year-old Chinese man with no medical history presented to the hepatology clinic with 10 weeks of jaundice, weakness, and pruritis. He started taking Artemisinin/ Bioperine 12 weeks ago to prevent COVID-19 but stopped 3 weeks ago. He denied abdominal pain, a family history of liver disease, substance/alcohol use, and taking other concomitant drugs. Physical examination revealed scleral icterus and no other signs of chronic liver disease. Laboratory studies showed total bilirubin 11 mg/dL, alkaline phosphatase 293 U/L, aspartate transaminase 170 U/L, and alanine transaminase 196 U/L with negative workup for hepatitis A, B, and C. CT abdomen and MRCP were unremarkable for liver or biliary pathology. Further serological workup was negative and follow-up labs revealed normalization of liver enzymes and bilirubin. Given the patient’s improvement, liver biopsy was not pursued. The patient was instructed to avoid supplements unless prescribed by a physician. Discussion: DILI is a global issue with an estimated annual incidence rate of 13.9 to 24.0 per 100,000 persons. Diagnosing DILI is important as it can cause acute liver injury and liver failure in certain cases. Since COVID-19 emerged, supplement use has increased given claims of boosting the immune system. Artemisinin is an herb used in traditional Chinese medicine with antimalarial activity investigated to be a possible COVID-19 treatment, but no current evidence exists to support it being effective against COVID-193. Our patient’s supplement also contained Bioperine, a black pepper extract, which is likely benign. Contrarily, artemisinin is a well-described cause of idiosyncratic acute liver injury and hepatotoxicity, causing self-limited mild to moderate transaminitis but also severe cases requiring emergent liver transplantation. Our patient’s unrevealing workup, his spontaneous improvement correlating with supplement discontinuation, and RUCAM score of 7 led to high suspicion of DILI secondary to artemisinin. Providers should always ask patients about supplement use and consider DILI when patients present with liver injury. Table 1. - The patient’s laboratory values, including total bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT) improved after stopping Artemisinin/Bioperine Total bilirubin (mg/dL) ALP (U/L) AST (U/L) ALT (U/L) Initial labs with PCP 11 293 170 196 Repeat labs with PCP 5.6 143 75 98 3 weeks after stopping supplement 2.4 85 34 41

S3085 Molecular Adsorbent Recirculating System in Acute Liver Injury

Introduction: Acetaminophen (APAP) toxicity is common and has been known as a cause of acute liver failure (ALF). ALF has high mortality rate, and in many cases, liver transplantation (LT) is the only lifesaving treatment. Unfortunately, many ALF patients are not candidates for transplant due to many factors. In addition, Hemodialysis have minimal to no effect on liver detoxification. Alternative approach could be albumin dialysis using Molecular Adsorbent Recirculation System (MARS). The evidence of effectiveness of MARS is limited with very few clinical studies. Here we report a case of ALF in an adult due to APAP toxicity who was not a candidate for LT, and treatment therefore included the use of MARS. Case Description/Methods: A 44 y/o M with hx of heavy alcohol use presented with altered mental status. It was reported that he may have taken 40 APAP tablets over the last 1-2 days. Physical exam was significant for confusion, tachycardia and scleral icterus. CMP: total bilirubin of 10.6 mg/dL, alkaline phosphatase 195 U/L, AST 5605 U/L, ALT 7000 U/L, albumin of 2.6 g/L and INR of 3.9. Ammonia was 215 umol/L and Tylenol of 75 ug/ml. Autoimmune workup, viral hepatitis panel and a broad infectious workup were negative. Alpha 1 antitrypsin and ceruloplasmin were normal. US of the liver was normal. Etiology of ALF believed to be due to APAP toxicity. He was admitted to the ICU and started on N-acetylcysteine infusion. He was evaluated for LT and deemed to be not a candidate given psychosocial concerns. After multidisciplinary discussion, MARS was initiated and planned for 5 days. The patient was monitored with serial CMP and coagulation studies. Mental status, INR, bilirubin and hepatic transaminases rapidly improved while on MARS. Patient ultimately became clinically stable to be transferred to a regular medical floor and continued to show improvement in his liver functions. (Figure) Discussion: In USA, ALF due to APAP toxicity is very common. LT is the only intervention with known survival benefits in ALF, but many factors can play a rule in LT evaluation and can lead to delay or might exclude patients from being candidates for LT, as seen in our patient. MARS, works on the concept of removal of albumin-bound substances accumulating in ALF, may be an ideal bridge to spontaneous recovery during liver regeneration. MARS could be a promising treatment with improvement of clinical response, laboratory parameters and liver function. Further studies are needed to better understand the efficacy of MARS on ALF outcomes.Figure 1.: Total Bilirubin and INR levels before, during and after MARS treatment in a patient with Acute Liver Failure. The arrows indicate the first treatment session.

S3281 A Rare Case of Drug-Induced Liver Injury (DILI) Due to Valproate Hepatocellular Injury

Introduction: Valproate is a widely-used antiepileptic drug which works by increasing gamma-aminobutyric acid (GABA) levels in the brain. We present a unique form of drug-induced liver injury (DILI) in a patient prescribed valproate for trigeminal neuralgia pain. Case Description/Methods: A 45-year old African American female with a history of hypertension and trigeminal neuralgia was prescribed divalproex for trigeminal neuralgia pain after trials of duloxetine, gabapentin, baclofen, oxcarbazepine, carbamazepine, topiramate, amitriptyline, and tizanidine failed to provide relief. Six weeks later she presented with a two week history of worsening nausea, diarrhea, fever, facial rash, production of dark phlegm, and grade 1 encephalopathy. Lab results showed acute liver failure (ALF) with total bilirubin 15.6 mg/dL, ALP 180 U/L, AST 937 U/L, ALT 943 U/L, and INR 2.8. Exam findings included scleral icterus, hepatomegaly, small volume ascites, and some small liver cysts. A diagnosis of DILI was made, with likely drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Divalproex was discontinued and the patient was admitted for two weeks of stabilizing treatment including N-acetylcysteine, lactulose, rifaximin, Vitamin K, and L-carnitine transfusion (Figure 1). The patient was evaluated for liver transplant, but it was ultimately not indicated given her subsequent improvement in liver function. An acute kidney injury developed but was resolved before patient discharge. Two weeks later the patient presented with signs of acute kidney injury. Upon readmission, complications including hepatic encephalopathy, macrocytic anemia, spontaneous bacterial peritonitis, and acute respiratory failure developed over the course of several weeks. All stabilizing treatment efforts were made but the patient ultimately developed septic shock and died. Discussion: DILI is the most common cause of ALF in the United States. Valproate-induced hepatotoxicity as a result of mitochondrial injury from impaired beta-oxidation and decreased tissue carnitine levels is one rare effect of use. Such hepatocellular injury typically shows very elevated AST and ALT levels with a smaller elevation in ALP. Early diagnosis of DILI is crucial to promptly discontinue use of the causative agent and begin optimal treatment. In the case of valproate, it is recommended that patients receive intravenous (IV) carnitine until symptoms improve. Liver transplant evaluation is crucial for ALF patients given the high morality risk.Figure 1.: 1A. Patient’s AST and ALT values over the course of her hospital admission. Figure 1B. Patient’s INR values over the course of her hospital admission.

S3188 The Tale of an Ancient Herb: A Stress Reliever or a Liver Stressor

Introduction: Ashwagandha is found in several herbal products today. However, there is a paucity of literature regarding its safety. Our case serves to remind physicians about the potential liver toxicity of Ashwagandha and to illustrate how early recognition of drug-induced liver injury (DILI) and discontinuation of the offending substance can be lifesaving. Case Description/Methods: A 58-year-old man with a remote history of hepatitis B and C presented with nausea, vomiting, and right upper quadrant abdominal pain of one day duration. He reported using an herbal supplement called “Primal Male,” which contained Ashwagandha as a main ingredient, over the past two weeks. He was normotensive, tachycardic up to 120 beats per minute (bpm), and febrile. The initial laboratory studies were notable for elevated AST level of 954 U/L, ALT level of 860 U/L, and a normal alkaline phosphatase level of 101 U/L. He had a normal total bilirubin level and an international normalized ratio of 1.3. His complete blood count and renal function were unremarkable. His creatinine kinase (CK) level was also within the normal range. His drug test, alcohol level, and acetaminophen level were unremarkable. The viral panel did not suggest active viral infections. His autoimmune panel was negative. An abdominal CT scan did not reveal any acute abnormality. In the following days, his symptoms worsened, and he became more encephalopathic. His AST, ALT, total bilirubin, and INR levels continued to rise. He developed hypotension and received intravenous fluids and midodrine. He also completed a course of N-acetylcysteine treatment. On the fifth day of admission, he underwent a transjugular liver biopsy. Liver histology showed active lymphocytic hepatitis with moderate inflammation (primarily lymphocytes, abundant neutrophils, and occasionally eosinophils) around the portal tract. On the sixth day of hospitalization, he reported decreasing pain and was more hemodynamically stable. His liver enzymes also showed improvement. The cause of acute liver injury was suspected to be drug-induced liver injury from Ashwagandha use. He was counseled to avoid the use of the herbal supplement and other hepatotoxic products. One month later, his liver enzymes were in normal range. Discussion: DILI is a less common form of liver injury but is a leading cause of acute liver failure in the United States. Ashwagandha has been reported in a few cases of DILI. It is important to have an early suspicion of the offending agent and avoid further substance exposure.

S3259 A Case of Propofol-Induced Acute Liver Failure

Introduction: Propofol is a parenteral anesthetic routinely used for procedures given its beneficial pharmacokinetic profile of rapid onset of action and reversal. Propofol drug toxicity is rare but has been associated with idiosyncratic acute liver injury in a small number of cases. To the best of our knowledge, we present the second case of propofol-induced acute liver failure (ALF) reported in literature. Case Description/Methods: An 88-year-old male with concern for gastrointestinal bleed underwent an upper endoscopy with propofol used as the anesthetic agent. The patient tolerated the endoscopy well with no hemodynamic compromise during or afterwards. No source of bleeding was identified so the plan was to proceed with a colonoscopy the next day. Shortly after the procedure, he was noted to have altered mental status. Evaluation with routine laboratory testing revealed elevated AST of 3248 IU/L and ALT of 2411 IU/L, both increased from 35 IU/L and 24 IU/L, respectively. He was also found to have high anion gap metabolic acidosis and bicarbonate level less than 9 mEq/L. His altered mentation continued to worsen, and he became hemodynamically unstable requiring transfer to the intensive care unit. He had no history of liver disease or excessive alcohol use, no risk factors for viral hepatitis, and took no medications known to cause liver injury. Work-up was unremarkable for acute and chronic liver disease. Propofol was ultimately surmised as the cause of ALF. Unfortunately, the patient’s mental status progressively worsened despite hemodynamic stabilization and normalization of liver enzymes. His family ultimately chose to transition to comfort measures and the patient passed soon after. Discussion: The incidence of drug-induced liver injury is increasing in developed countries and is a major etiology of ALF, accounting for greater than 50% of cases. Drug toxicity secondary to an idiosyncratic reaction is unpredictable and occurs infrequently in certain individuals. While propofol is generally considered a safe agent widely used for sedation, propofol-induced acute liver injury is a rare outcome. To the best of our knowledge, it is reported to have caused five cases of acute hepatitis and one other case of ALF. We report the second case of ALF due to propofol with a lethal outcome. We recommend close monitoring of patients treated with propofol for signs of hepatitis and that ALF due to a drug insult should be considered after common causes have been excluded.

Screening for Wilson's disease in acute liver failure: A new scoring system in children.

BackgroundWilson’s disease (WD) is a rare cause of acute liver failure (ALF) and has a high fatality rate. Rapid and accurate diagnosis is important for ALF because of WD (ALF-WD). Our objective was to establish a simple, rapid, and accurate diagnostic test to distinguish ALF-WD from non-WD ALF (NWDALF) in children.Materials and methodsThe data from all cases with pediatric ALF were retrospectively collected and analyzed. We performed receiver operator characteristics curve (ROC) analysis and confirmed the optimum cut-off points.ResultsFifty-eight patients with pediatric ALF (12 with WD, 46 with other etiologies) were included. Older age was observed in ALF-WD compared to NWDALF (11.16 ± 2.51 years vs. 3.34 ± 3.81 years, p < 0.001). An analysis based on routine biochemical testings revealed that total bilirubin (TBil), direct bilirubin, indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST:ALT ratio, alkaline phosphatase (ALP), ALP:TBil ratio, serum albumin, gamma-glutamyl transferase, cholinesterase, hemoglobin, and platelet were statistically significant between the ALF-WD and NWDALF groups. The optimum cut-off points were obtained through ROC analysis. A scoring system was formed by assigning a score of 1 or 0 to patients who met the 13 cut-off points. Using ROC analysis, we determined a cut-off point of ≥ 6.5 for ALF-WD with 91.7% sensitivity and 97.8% specificity (p < 0.0001). In addition, a best cut-off point of ≥ 1.5 based on only five variables (ALT, AST, AST:ALT ratio, ALP, and ALP:TBil ratio), had 100% sensitivity and 91.3% specificity for ALF-WD (p < 0.0001). Based on this, when age was calculated as the sixth indicator, the best cut-off value of ≥ 2.5 had 100% sensitivity and 97.8% specificity (p < 00.0001).ConclusionOur study developed a new scoring system that consists of simple laboratory tests with good sensitivity and specificity and can be used by clinicians to quickly distinguish ALF-WD from NWDALF in children.

Drug-Induced Liver Injury: A Literature Review

Drug-Induced liver injury (DILI) is a common harmful drug reaction of some medication which can cause the damage to liver cells, or might be a chance of death. In the western countries DILI is the main cause for acute liver failure. These reactions are very common because almost all drug regimens can cause injury to liver. Most of DILI cases are harmless and they get better after stopping the offending drug. These reactions are mainly due to some pharmacological remedies, traditional medications, herbal and nutritional supplements. Due to these harmful reactions, elevation is noticed in the liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphate, total bilirubin) 2N from its normal value. Drug-induced liver injury includes 1,000 of pharmacological remedies or more. Here, we review the maximum current literature, so the treatment includes timely diagnosis and removal of the doubtable medication is the key. This paper explains the different causes, pharmacological medications responsible for drug-induced liver injury, effect of covid-19 on liver injury and future perspective. It is important to be aware of and remove the suspected agent as soon as possible. There are no specific risk factors for DILI, but existing liver disease and genetic factors may be a priority for some people. Treatment of liver damage caused by drugs and herbs includes immediate drug withdrawal and supportive care aimed at alleviating unwanted symptoms. Main purpose of this paper is to deliver the info about the DILI, which are dose related, identification and consideration of disease.&#x0D; Keywords: Drug-Induced liver injury (DILI), Pathophysiology, Diagnosis, Treatment, Risk factors and effect of covid-19 on liver injury.

On the Treatment of Acute Poisoning With Paracetamol

BACKGROUND Currently, despite the optimization of diagnostic methods in order to predict the development of liver damage, improvement of treatment protocols, paracetamol poisoning is a serious problem in medicine, being the most common cause of acute liver failure worldwide.AIM OF STUDY To determine the indications for the use of acetylcysteine in paracetamol poisoning and evaluate the effectiveness of the 21-hour protocol for its administration.MATERIAL AND METHODS We examined 20 patients with acute paracetamol poisoning (15 women and 5 men), the median age was 21.5 (19.8–32.3) years. ALT and AST were assessed during the entire period of stay in the hospital, the time period from the moment of taking paracetamol to hospitalization and the beginning of the administration of ACC, the concentration of paracetamol in the blood, and mortality. According to the level of ALT and AST in the blood, the patients were divided into 2 groups: Group I consisted of 14 patients, in whom the concentration of ALT and AST during the entire observation period did not exceed 50 U/L; in Group II (6 patients), an increase in the level of ALT and AST in the blood of more than 50 U/L was observed. To assess the risk of liver lesion, the Rumack-Matthew nomogram was used. To compare the concentrations of paracetamol in the blood of patients, the paracetamol index was used.RESULTS It was found that in 10 patients with a high risk of liver damage, who were treated with a 21-hour regimen of ACC administration, no hepatotoxic effect was found. The use of ACC according to a 21-hour protocol in patients with initially elevated ALT and AST levels of more than 50 U/L (n = 4) (25%) led to a rapid positive dynamics of laboratory and clinical parameters. It was found that in 2 patients, despite the introduction of ACC, the development of liver damage was observed. At the same time, the level of paracetamol in their blood was 6.6 and 10.6 fold higher than the “therapeutic” line of the nomogram, and the time from the moment of taking the drug to the beginning of the administration of ACC was 8 and 20 hours. High risk factors for the development of hepatotoxic effect in case of paracetamol poisoning are the time range from the moment of taking the drug to the beginning of the administration of ACC and the value of the paracetamol index.CONCLUSION Indications for the use of acetylcysteine in acute poisoning with paracetamol is a high risk of liver damage. Its criteria are high doses, increased concentrations of ALT and AST when patients are admitted to the hospital; if it is possible to determine the concentration of paracetamol in the blood, an increase in the value of the paracetamol index is more than 1. The use of a 21-hour protocol of intravenous administration of acetylcysteine is effective in case of paracetamol poisoning and its early use in the complex of treatment almost always prevents the development of acute liver failure.

Thiol “click” chromene mediated cascade reaction forming coumarin for in-situ imaging of thiol flux in drug-induced liver injury

Drug-induced organ damage has long been considered as a serious public health concern. Drug-induced liver injury (DILI) is one of the common clinical side effects of drugs and the main cause of acute liver failure. Previous evidence showed that there is a potential relationship between thiols and DILI. Many studies have reported that oxidative stress is involved in many drug-induced liver injury mechanisms. APAP, as the most representative drug for clinical DILI, is considered to cause large amounts of intracellular reactive oxygen species. However, thiols as the effective antioxidant maintain the normal redox balance of organisms and play a vital role in the liver injury and other diseases. Therefore, a new NIR fluorescent probe DCI-Ac-HMPC was developed based on thiol-chromene “click” reaction, which triggered the intramolecular cascade reaction to in-situ generate NIR coumarin fluorophore. In addition, we found that thiols levels in the liver of mice with DILI were significantly reduced, revealing a negative correlation between thiols and DILI. Furthermore, the therapeutic effects of three kinds of liver-protecting drugs on hepatotoxicity induced by acetaminophen (APAP) in vivo based on thiols fluctuations. This work provides a new idea for the in-situ synthesis strategy of NIR coumarin dyes, which is helpful for the diagnosis of DILI and the further study of the role of thiols in related diseases.

Human Wharton's Jelly-derived mesenchymal stem cells prevent acetaminophen-induced liver injury in a mouse model unlike human dermal fibroblasts.

The persistence of hepatotoxicity induced by N-acetyl-para-aminophenol (Acetaminophen or Paracetamol, abbreviated as APAP) as the most common cause of acute liver failure in the United States, despite the availability of N-acetylcysteine, illustrates the clinical relevance of additional therapeutic approaches. While human mesenchymal stem cells (MSCs) have shown protection in mouse models of liver injury, the MSCs used are generally not cleared for human use and it is unclear whether these effects are due to xenotransplantation. Here we evaluated GMP manufactured clinical grade human Wharton's Jelly mesenchymal stem cells (WJMSCs), which are currently being investigated in human clinical trials, in a mouse model of APAP hepatotoxicity in comparison to human dermal fibroblasts (HDFs) to address these issues. C57BL6J mice were treated with a moderate APAP overdose (300mg/kg) and WJMSCs were administered 90min later. Liver injury was evaluated at 6 and 24h after APAP. WJMSCs treatment reduced APAP-induced liver injury at both time points unlike HDFs, which showed no protection. APAP-induced JNK activation as well as AIF and Smac release from mitochondria were prevented by WJMSCs treatment without influencing APAP bioactivation. Mechanistically, WJMSCs treatment upregulated expression of Gclc and Gclm to enhance recovery of liver GSH levels to attenuate mitochondrial dysfunction and accelerated recovery of pericentral hepatocytes to re-establish liver zonation and promote liver homeostasis. Notably, preventing GSH resynthesis with buthionine sulfoximine prevented the protective effects of WJMSCs. These data indicate that these GMP-manufactured WJMCs could be a clinically relevant therapeutic approach in the management of APAP hepatotoxicity in humans.

Early biomarkers predicting outcome in a porcine model of acetaminophen intoxication: A pilot study.

Acetaminophen intoxication has become the leading cause of acute liver failure (ALF) in Europe and the USA. To identify early biomarkers in order to predict the development of ALF in a porcine model of acetaminophen intoxication. Six German Landrace pigs received a single acetaminophen bolus of 1 g/kg body weight via a jejunal catheter. Cytokines and laboratory parameters were analyzed at 8-hour intervals for a total of 40 h. Three of the 6 animals survived the intoxication. The nonsurviving animals had an increase in serum lactate and interleukin (IL)-6, with a simultaneous decrease in prothrombin time (PT) and albumin concentration 8 h after intoxication. In all nonsurviving animals, elevated levels of tumor necrosis factor alpha (TNF-α) at baseline before intoxication and during the course of ALF were observed. The acetaminophen serum concentrations and toxicokinetics did not differ between the nonsurviving and surviving animals. Methemoglobinemia was proportional to the administered doses and acetaminophen blood levels, but methemoglobinemia did not affect survival. Tumor necrosis factor alpha, IL-6, lactate, prothrombin time, and albumin blood concentration were identified as early predictors of outcome after acetaminophen intoxication. An elevated TNF-α level before acetaminophen exposure was the earliest prognostic marker for a lethal outcome. Therefore, it could serve as a very early indicator of prognosis.

Creatinine accelerates APAP-induced liver damage by increasing oxidative stress through ROS/JNK signaling pathway.

Serum creatinine is an endogenous biomarker to estimate glomerular filtration rate (GFR) and is commonly used to assess renal function in clinical practice. Acetaminophen (APAP), the most available analgesic and antipyretic medication, is recommended as the drug of choice for pain control in patients with renal diseases. However, an overdose of APAP can lead to severe acute liver injury, which is also the most common cause of acute liver failure in western countries. The role of creatinine in APAP-induced liver injury is unclear and should be further explored. Herein, clinical data on patients with drug-induced liver injury revealed that the creatinine concentration between 82-442 μmol/L for female and 98–442 μmol/L for male is positively correlated with alanine aminotransferase (ALT), aspartate aminotransferase (AST). While there was no correlation between creatinine and ALT and AST when creatinine concentration is over 442 μmol/L. In addition, mice were administrated with creatinine intraperitoneally for 1 week before APAP injection to investigated the pathophysiological role of creatinine in APAP-induced acute liver injury. The results showed that creatinine administration aggravated hepatic necrosis and elevated serum lactate dehydrogenase (LDH) and ALT levels in mice upon APAP injection. The mechanism study demonstrated that creatinine could increase the production of reactive oxygen activation (ROS) and the activation of c-Jun N-terminal kinase (JNK). Furthermore, the liver injury was alleviated and the difference between APAP-treated mice and APAP combined with creatinine-treated mice was blunted after using specific ROS and JNK inhibitors. Significantly, creatinine stimulation aggravates APAP-induced cell death in HepaRG cells with the same mechanism. In summary, this study proposed that creatinine is closely related with liver function of drug-induced liver injury and exacerbates APAP-induced hepatocyte death by promoting ROS production and JNK activation, thus providing new insight into the usage of APAP in patients with kidney problems.

Galangin Nanoparticles Protect Acetaminophen-Induced Liver Injury: A Biochemical and Histopathological Approach.

One of the main causes of acute liver failure is overdose with acetaminophen. Excessive consumption of acetaminophen leads to the production of NAPQI (N-acetyl-p-benzoquinone imine) through the activity of the enzyme cytochrome c oxidase. For this purpose, the effect of galangin nanoparticles with antioxidant activities will be evaluated for the treatment of acetaminophen-induced hepatotoxicity. In this study, after the synthesis of galangin nanoparticles and particle size determination, mice were divided into six groups. Before treatment, a single dose (350 mg/kg) of acetaminophen was administered by gavage in all groups. The activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), as well as biochemical factors FRAP and MDA in serum were measured and a histopathological study was performed. The prepared nanoparticles produced in this research were characterized by the SEM, DLS, and ZETA potential, and the average particle size was obtained in the range of 150 nm. Serum levels of liver enzymes (AST and ALT) in the nanoparticle group decreased significantly compared with the control group (P < 0.05). In the group without treatment, the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes increased significantly compared with the treatment groups. Also, galangin nanoparticles, at a dose of 20 mg/kg, improve cell damage in hepatocytes and preserve the tissue structure of the liver. Galangin nanoparticles reduce the acetaminophen-induced hepatotoxicity by reducing the number of liver function indices. According to our findings, the liver-protective effects of the nanoparticle may be due to its antioxidant properties.

Management of Acute Liver Failure: Update 2022.

Abbreviated pathogenesis and clinical course of the acute liver failure syndrome. The pathogenesis and clinical course of the syndrome of acute liver failure (ALF) differs depending upon the etiology of the primary liver injury. In turn, the severity of the liver injury and resulting synthetic failure is often the primary determinant of whether a patient is referred for emergency liver transplantation. Injuries by viral etiologies trigger the innate immune system via pathogen-associated molecular patterns (PAMPs), while toxin-induced (and presumably ischemia-induced) injuries do so via damage-associated molecular patterns (DAMPs). The course of the clinical syndrome further depends upon the relative intensity and composition of cytokine release, resulting in an early proinflammatory phenotype (SIRS) and later compensatory anti-inflammatory response phenotype (CARS). The outcomes of overwhelming immune activation are the systemic (extrahepatic) features of ALF (cardiovascular collapse, cerebral edema, acute kidney injury, respiratory failure, sepsis) which ultimately determine the likelihood of death.Acute liver failure (ALF) continues to carry a high risk of mortality or the need for transplantation despite recent improvements in overall outcomes over the past two decades. Optimal management begins with identifying that liver failure is indeed present and its etiology, since outcomes and the need for transplantation vary widely across the different etiologies. Most causes of ALF can be divided into hyperacute (ischemia and acetaminophen) and subacute types (other etiologies), based on time of evolution of signs and symptoms of liver failure; the former evolve in 3 to 4 days and the latter typically in 2 to 4 weeks. Both involve intense release of cytokines and hepatocellular contents into the circulation with multiorgan effects/consequences.Management involves optimizing fluid balance and cardiovascular support, including the use of continuous renal replacement therapy, vasopressors, and pulmonary ventilation. Early evaluation for liver transplantation is advised particularly for acetaminophen toxicity, which evolves so rapidly that delay is likely to lead to death.Vasopressor support, high-grade hepatic encephalopathy, and unfavorable (subacute) etiologies heighten the need for urgent listing for liver transplantation. Prognostic scores such as Kings Criteria, Model for End-Stage Liver Disease, and the Acute Liver Failure Group prognostic index take these features into account and provide reasonable but imperfect predictive accuracy. Future treatments may include liver support devices and/or agents that improve hepatocyte regeneration.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

Inhibition of BTK improved APAP-induced liver injury via suppressing proinflammatory macrophages activation by restoring mitochondrion function

BackgroundAcetaminophen (APAP) overdose can cause severe liver injury and APAP-induced liver injury (AILI) is one of the leading causes of acute liver failure (ALF). Bruton’s tyrosine kinase (BTK) is a key tyrosine kinase in immune responses, which plays an important role in many inflammatory diseases. However, its effect on AILI is still not clear. Here, we aimed to assess the effect of BTK on AILI and explore its underlying mechanism. MethodsIn our study, western blot and immunohistochemistry were used to detect the expression of BTK in AILI. The C57BL/6 mice were used to check the protective effect of BTK inhibition on AILI and the activation of BTK was confirmed in mice macrophages treated with APAP. Immunofluorescence, immunohistochemistry, oxygen consumption rate (OCR) detection, polymerase chain reaction (PCR), flow cytometry and western blot were used to determine the role of BTK in mitochondrial dynamics and function of macrophages and the underlying mechanisms in AILI. ResultsOur results showed that BTK upregulated in AILI. BTK inhibition protected mice from AILI and BTK was activated in mice macrophages in response to APAP. Mechanically, BTK inhibition promoted mitochondrial fusion and restored mitochondrial function through phospholipase C gamma 2 (PLCγ2)-reactive oxygen species (ROS)-Optic Atrophy 1(OPA1) pathway in macrophages and finally suppressed the release of proinflammatory cytokines. ConclusionsIn conclusion, we found that BTK inhibition protected mice from AILI by restoring the mitochondrial function of macrophages through the improvement of the mitochondrial dynamic imbalance via PLCγ2-ROS-OPA1 signaling pathway, which indicated that BTK might be a potential therapeutic target of AILI.

Sarmentosin promotes USP17 and regulates Nrf2-mediated mitophagy and cellular oxidative stress to alleviate APAP-induced acute liver failure

BackgroundAn overdose of acetaminophen (APAP), the main cause of acute liver failure (ALF), induces oxidative stress that ultimately causes mitochondrial impairment and hepatotoxicity. The nuclear factor erythroid 2-related factor 2 (Nrf2) was widely recognized as an anti-oxidative stress mechanism. The present study was aimed at investigating whether sarmentosin, extract from traditional Chinese medicine, protects the liver against APAP-induced injury via activating Nrf2 and subsequently decreasing oxidative stress. MethodsMale ICR mice were treated with sarmentosin oral administration for 1 week and injected APAP (300 mg/kg. i.p.) for acute liver injury model. The liver and serum of mice for histological and biochemistry analysis. AML12 and LO2 cells were used in vitro assays. ResultsWe found that sarmentosin moderately increased accumulation of Nrf2 via upregulating USP17-mediated ubiquitin inhibition at the early stage of hepatocytes damage. The Nrf2 separating from bonding protein Keap1 translocated into nucleus and activated downstream gene of antioxidants. Mitophagy, a unique autophagy can remove Reactive Oxygen Species (ROS) damaged mitochondria, was elevated in this progress to maintain mitochondria function and ROS homeostasis. ConclusionIn summary, our research revealed that sarmentosin could alleviate APAP-induced liver acute injury through USP17-mediated Nrf2 overexpression and PINK1-dependent mitophagy.

Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice.

Background and AimsDrug-induced liver injury (DILI) is a common cause of acute liver failure and represents a significant global public health problem. When discussing the gut-liver axis, although a great deal of research has focused on the role of gut microbiota in regulating the progression of DILI, the gut commensal fungal component has not yet been functionally identified.MethodsMice were pretreated with fluconazole (FC) to deplete the gut commensal fungi and were then subject to acetaminophen (APAP) gavage. In addition, transcriptome sequencing was performed to identify differentially expressed genes (DEGs) between control and fluconazole-pretreated groups of the mice challenged with APAP.ResultsGut commensal fungi ablation through fluconazole pretreatment predisposed mice to APAP-induced hepatotoxicity, characterized by elevated serum liver enzyme levels and more severe centrilobular necrosis, which appears to be caused by robust inflammation and oxidative stress. The 16S rDNA sequencing results indicated that Akkermansia muciniphila abundance had significantly decreased in gut fungi-depleted mice, whereas increased abundance of Helicobacter rodentium was observed. The gene interaction network between DEGs identified by the transcriptome sequencing highlighted a significant enrichment of Cyp2a5 in the liver of APAP-treated mice that were preadministrated with fluconazole. Pharmacological inhibition of Cyp2a5 by 8-methoxypsoralen (8-MOP) could significantly attenuate hepatic inflammation and oxidative stress in mice, thereby conferring resistance to acute liver injury caused by APAP administration.ConclusionOur data highlighted the significance of gut commensal fungi in hepatic inflammation and oxidative stress of APAP mice, shedding light on promising therapeutic strategies targeting Cyp2a5 for DILI treatment.

Review of clinical characteristics, immune responses and regulatory mechanisms of hepatitis E-associated liver failure.

Hepatitis E virus (HEV) is the most common cause of acute liver failure (LF) and one of the most common factors causing acute injury in acute-on-chronic LF (ACLF). When HEV-related LF occurs, a series of changes take place in both the intrahepatic environment and extrahepatic microenvironment. The changed types and distribution of immune cells (infiltrating macrophages and increased lymphocytes) in liver tissue, as well the increased proinflammatory cytokines and chemokines in the blood, indicate that the occurrence and progression of HEV-related LF are closely related to immune imbalance. The clinical features and immune reaction in the body during HEV-related acute LF (ALF) and ACLF are complicated. This review highlights recent progress in elucidating the clinical manifestations of HEV-associated ALF and ACLF and discusses the corresponding systemic immune changes and possible regulatory mechanisms.

Acute Liver Failure.

Acute liver failure (ALF) is a rare but life-threatening disease process that can result in rapidly progressive encephalopathy, elevated intracranial pressure, and multiorgan failure. In the United States, the 2 most common causes of ALF in the intensive care unit (ICU) are acetaminophen overdose and hypoxic-ischemic hepatopathy. Less common causes of ALF include alcoholic hepatitis, nonacetaminophen drug-induced liver injury, acute viral hepatitis, Wilson's disease, autoimmune hepatitis, and acute fatty liver of pregnancy. Unfortunately, there are many cases in which the cause of liver failure is indeterminate. ALF is an ICU emergency that requires close monitoring, extensive workup to determine etiology, frequent support of hemodynamic, respiratory, and renal function, administration of targeted therapies depending on the cause, utilization of N-acetylcysteine if appropriate, and consideration for liver transplant in select cases. The primary objective of this article is to define, diagnose, and detail the management of ALF in an ICU setting.