Drug-induced Acute Liver Failure Research Articles

Hepatic Sirt6 activation abrogates acute liver failure.

Acute liver failure (ALF) is a deadly illness due to insufficient detoxification in liver induced by drugs, toxins, and other etiologies, and the effective treatment for ALF is very limited. Among the drug-induced ALF, acetaminophen (APAP) overdose is the most common cause. However, the molecular mechanisms underlying APAP hepatoxicity remain incompletely understood. Sirtuin 6 (Sirt6) is a stress responsive protein deacetylase and plays an important role in regulation of DNA repair, genomic stability, oxidative stress, and inflammation. Here, we report that genetic and pharmacological activation of Sirt6 protects against ALF in mice. We first observed that Sirt6 expression was significantly reduced in the liver tissues of human patients with ALF and mice treated with an overdose of APAP. Then we developed an inducible Sirt6 transgenic mice for Cre-mediated overexpression of the human Sirt6 gene in systemic (Sirt6-Tg) and hepatic-specific (Sirt6-HepTg) manners. Both Sirt6-Tg mice and Sirt6-HepTg mice exhibited the significant protection against APAP hepatoxicity. In contrast, hepatic-specific Sirt6 knockout mice exaggerated APAP-induced liver damages. Mechanistically, Sirt6 attenuated APAP-induced hepatocyte necrosis and apoptosis through downregulation of oxidative stress, inflammation, the stress-activated kinase JNK activation, and apoptotic caspase activation. Moreover, Sirt6 negatively modulated the level and activity of poly (ADP-ribose) polymerase 1 (PARP1) in APAP-treated mouse liver tissues. Importantly, the specific Sirt6 activator MDL-800 exhibited better therapeutic potential for APAP hepatoxicity than the current drug acetylcysteine. Furthermore, in the model of bile duct ligation induced ALF, hepatic Sirt6-KO exacerbated, but Sirt6-HepTg mitigated liver damage. Collectively, our results demonstrate that Sirt6 protects against ALF and suggest that targeting Sirt6 activation could be a new therapeutic strategy to alleviate ALF.

Intravital observation of high-scattering and dense-labeling hepatic tissues using multi-photon fluorescence microscopy.

Achieving high-resolution and large-depth microscopic imaging in vivo under conditions characterized by high-scattering and dense-labeling, as commonly encountered in the liver, poses a formidable challenge. Here, through the optimization of multi-photon fluorescence excitation window, tailored to the unique optical properties of the liver, intravital microscopic imaging of hepatocytes and hepatic blood vessels with high spatial resolution was attained. It's worth noting that resolution degradation caused by tissue scattering of excitation light was mitigated by accounting for moderate tissue self-absorption. Leveraging high-quality multi-photon fluorescence microscopy, we discerned structural and functional alterations in hepatocytes during drug-induced acute liver failure. Furthermore, a reduction in indocyanine green metabolism rates associated with acute liver failure was observed using NIR-II fluorescence macroscopic imaging.

Liver failure after treatment with inotuzumab and polychemotherapy including PEG-asparaginase in a patient with relapsed Philadelphia chromosome–negative acute lymphoblastic leukemia

We present the case of a 58-year-old female patient who presented with an extramedullary B-ALL relapse after prior allogenic HSCT and blinatumomab therapy. The patient died from complications of a drug-induced acute liver failure after a salvage therapy combining inotuzumab ozogamicin (InO)-based induction followed by consolidation with high dose MTX and pegaspargase based on the GMALL protocol for older ALL patients. After a diagnosis of the extramedullary relapse in the form of a retro vesical chloroma, the patient received an individualized multi-agent chemotherapy based on induction chemotherapy for older patients in combination with InO. After four administrations of InO, in combination with vincristine, dexamethasone, cytarabine, and cyclophosphamide, CT-imaging showed a reduction in volume of the chloroma and response to therapy. Consolidation with high-dose methotrexate and pegaspargase was administered. The patient developed toxic liver damage manifested by hyperbilirubinemia and progressive hepatic encephalopathy. The diagnostic criteria for VOD were met, and therapy with defibrotide was initiated. Liver biopsy revealed no histological signs of VOD but instead steatohepatitis indicative of drug-induced toxicity. The patient ultimately died of hemorrhagic shock through postinterventional hemorrhage after liver biopsy. In conclusion, although InO shows promising results in the therapy of r/r ALL with and without additional chemotherapy, the combination with MTX and pegaspargase in an intensively pretreated patient with relapse after HCST may impart an increased risk for liver-related toxicity. Special caution is required when assessing fitness for further liver toxic regimens. A key takeaway is also the reminder that InO can cause liver damage not only in the form of VOD but also through direct hepatocellular toxicity.

Mixed micelles loaded with hesperidin protect against acetaminophen induced acute liver injury by inhibiting the mtDNA-cGAS-STING pathway

Excessive acetaminophen (APAP) is the main cause of drug-induced acute liver failure, and the pathogenesis has not been elucidated and there is a lack of effective drugs. Hesperidin (Hes), a rich flavanone in citrus peel with excellent biological activities, is a potential agent for treatment liver injury. Due to poor water solubility of Hes, this study prepared mixed micelles using polyvinyl pyrrolidone (PVP K17) and poloxamer 188, and encapsulated Hes (Hes-MMs). The results showed that Hes-MMs exhibited a uniform spherical shape with a particle size of 66.80±0.83nm, and Hes-MMs significantly improved the dispersibility, antioxidant activity, and cellular uptake of Hes. In vitro results showed that Hes-MMs protected the proliferation inhibition of HepG2 cells induced by APAP, inhibited the production of reactive oxygen species (ROS) and the damage of mitochondrial membrane potential (MMP) induced by APAP. Furthermore, Hes-MMs exerted liver protective effects by inhibiting APAP induced mtDNA release and activating the cGAS-STING pathway. In vivo results demonstrated that Hes-MMs showed protective and therapeutic effects on APAP induced liver injury, and their mechanisms were related to the mtDNA-cGAS-STING signaling pathway. In summary, our study demonstrated that the mtDNA-cGAS-STING pathway was involved in APAP induced acute liver injury, and Hes-MMs might be a potential therapeutic agent for treating APAP induced acute liver injury.

Single-Centre Experience With Low-Volume Plasma Exchange and Low-Dose Steroid to Treat Patients With Idiosyncratic Drug-Induced Acute Liver Failure

BackgroundIdiosyncratic drug induced liver injury (iDILI) causing acute liver failure (ALF) carries high short-term mortality and patients who meet King’s College hospital criteria for liver transplantation have 1-month survival of 34% without liver transplantation (PMID: 20949552). We present our experience with low volume plasma exchange (PLEX-LV, 50% of estimated plasma volume exchanged per session) and low dose steroid to treat iDILI ALF. MethodsWe retrospectively analyzed data of patients with iDILI (diagnosed as per RUCAM score), treated with PLEX-LV and low dose steroid (Prednisolone: 10 mg OD, with rapid taper) in our department from 2016 to 2022. Baseline and dynamic parameters (post-PLEX) were assessed as predictors of 1-month liver transplantation free survival. ResultsTwenty-two iDILI patients [probable: possible iDILI: 20:2, males: 9, age: 30 (14-84) years, median (range); MELD score: 30.5 (19-43)] underwent PLEX-LV for ALF during the study period.Causative agents were complementary and alternative medications (36%), antiepileptics (18%) antimicrobials (14%), antitubercular drugs (14%), antifungal drugs(9%)and others (9%). All patients had jaundice and encephalopathy; 9 patients also had ascites. None of the patients underwent liver transplantation. Study patients underwent 3 (1-7) PLEX sessions and 1.4 (0.6-1.6) litres of plasma was exchanged per session.One-month transplant free survival was 59% (13/22) in the study population and 63% (12/19) among patients who fulfilled Kings College Hospital Criteria for liver transplantation. Reduction of ≥25% in plasma Von Willebrand factor (VWF) levels after PLEX-LV predicted improved survival (HR: 0.09, 95%CI: 0.01-0.65; AUROC: 0.81; 95% CI: 0.6-1.0). ConclusionLow volume PLEX and low dose steroid appears a promising treatment option in patients with iDILI induced ALF not opting for liver transplantation. Dynamic changes in VWF level after PLEX predict 1 month survival in these patients.

Mn3O4 nanozymes prevent acetaminophen-induced acute liver injury by attenuating oxidative stress and countering inflammation

Acetaminophen (APAP) overdose is steadily becoming the chief reason for drug-induced acute liver failure, yet limited treatment is currently clinically available. Considering that the mechanism of APAP-induced hepatotoxicity is inseparable from oxidative stress and inflammation, a biocompatible Mn3O4 nanozyme mimicking superoxide dismutase (SOD) and catalase (CAT) activities and possessing reactive oxygen species (ROS)–scavenging capacity and antiapoptotic properties, is reported herein as a promising nanodrug to treat APAP-induced liver injury (AILI). Possessing bioactive enzyme–like functions, Mn3O4 nanoparticles (NPs) can not only reduce the oxidative stress on the liver by decreasing ROS accumulation but also downregulate the infiltration of inflammatory macrophages that secrete proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Notably, the bifunctional Mn3O4 NPs mediate nuclear factor–erythroid 2 p45-related factor 2 signaling pathway activation and nuclear factor kappa B signaling pathway inhibition to effectively prevent the already fragile APAP-overdosed murine hepatocytes from being attacked again, thus mitigating hepatocyte apoptosis and alleviating APAP-induced liver damage. Thus, the Mn3O4 nanozyme (Mn3O4 NPs) evaluated in this study has potential preventive and therapeutic effects on AILI.

Selenium Ameliorates Acetaminophen-Induced Oxidative Stress via MAPK and Nrf2 Pathways in Mice.

Overdose of acetaminophen (paracetamol), a widely used non-prescriptive analgesic and antipyretic medication, is one of the main causes of drug-induced acute liver failure around the world. Oxidative stress contributes to this hepatotoxicity. Antioxidants are known to protect the liver from oxidative stress. Selenium, a potent antioxidant, is a commonly used micronutrient. Here, we evaluated the protective effect of selenium on acetaminophen-induced hepatotoxicity. Treating Wistar albino mice with sodium selenite (1mg/kg) before or after inducing hepatotoxicity with acetaminophen (150mg/kg) significantly reduced the levels of liver injury biomarkers such as serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase. In addition, selenium-treated mice showed decreased levels of oxidative stress markers such as protein carbonyls and myeloperoxidase. Acetaminophen treatment stimulated all three mitogen-activated protein kinases (MAPKs) and Keap1 and decreased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 in liver and in isolated mouse peritoneal macrophages, which was reversed by selenium treatment. Our findings suggest that the reactive oxygen species-mediated Nrf2 and MAPK pathways are critical players in acetaminophen-induced hepatotoxicity. These key findings offer an alternative therapeutic target for addressing acetaminophen-induced hepatotoxicity.

Advances in the study of acetaminophen-induced liver injury.

Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury and acute liver failure. The diagnosis, screening, and management of APAP-induced liver injury (AILI) is challenging because of the complex mechanisms involved. Starting from the current studies on the mechanisms of AILI, this review focuses on novel findings in the field of diagnosis, screening, and management of AILI. It highlights the current issues that need to be addressed. This review is supposed to summarize the recent research progress and make recommendations for future research.

Rituximab administration one week before ABO-incompatible liver transplantation due to drug-induced acute liver failure with hepatic coma: a case report.

In cases of acute liver failure (ALF) with hepatic coma, early liver transplantation, including ABO-incompatible (ABOi) living donor liver transplantation (LDLT), should be considered. The ABO antibody barrier can be reduced using plasma exchange (PE) and the anti-CD20 antibody rituximab. Plasma exchange is also performed for drug-induced ALF and is effective for desensitization. Rituximab treatment usually requires 14days. There is presently no established desensitization protocol for ABOi-LDLT for ALF. Here, we report a case of drug-induced ALF with hepatic coma, which was treated with ABOi-LDLT using PE and rituximab 8days prior to surgery. A 33-year-old female, with a history of headaches for which she was taking analgesics daily, developed drug-induced ALF with hepatic coma. Her ABOi sister desired to become a liver donor. We initiated desensitization using rituximab (500mg) and mycophenolate mofetil (MMF, 2000mg/day), followed by five sessions of PE. Eight days after rituximab administration, ABOi-LDLT with splenectomy was performed. Postoperatively, the patient received local infusion via portal vein for 14days and immunosuppression with tacrolimus, methylprednisolone, and MMF. No episode of cellular or antibody-mediated rejection (AMR) was observed. The patient was discharged uneventfully 56days after ABOi-LDLT with no problems up to 15months after the transplant.

Clinical characteristics and prognosis of non-APAP drug-induced acute liver failure: a large multicenter cohort study

BackgroundThere is growing recognition of natural history, complications, and outcomes of patients who develop non-acetaminophen (APAP) drug-induced acute liver failure (ALF). To clarify high-risk factors and develop a nomogram model to predict transplant-free survival (TFS) in patients with non-APAP drug-induced ALF.MethodsPatients with non-APAP drug-induced ALF from 5 participating centers were retrospectively analyzed. The primary endpoint was 21-day TFS. Total sample size was 482 patients.ResultsRegarding causative agents, the most common implicated drugs were herbal and dietary supplements (HDS) (57.0%). The hepatocellular type (R ≥ 5) was the main liver injury pattern (69.0%). International normalized ratio, hepatic encephalopathy grades, the use of vasopressor, N-acetylcysteine, or artificial liver support system were associated with TFS and incorporated to construct a nomogram model (drug-induced acute liver failure-5, DIALF-5). The AUROC of DIALF-5 for 7-day, 21-day, 60-day, and 90-day TFS in the internal cohort were 0.886, 0.915, 0.920, and 0.912, respectively. Moreover, the AUROC of DIALF-5 for 21-day TFS had the highest AUROC, which was significantly higher than 0.725 of MELD and 0.519 of KCC (p < 0.05), numerically higher than 0.905 of ALFSG-PI but without statistical difference (p > 0.05). These results were successfully validated in the external cohort (147 patients).ConclusionsBased on easily identifiable clinical data, the novel DIALF-5 model was developed to predict transplant-free survival in non-APAP drug-induced ALF, which was superior to KCC, MELD and had a similar prediction performance to ALFSG-PI but is more convenient, which can directly calculate TFS at multiple time points.

MicroRNA-29a-3p Prevents Drug-Induced Acute Liver Failure through Inflammation-Related Pyroptosis Inhibition.

Little is known about the role of microRNA-29a-3p (miR-29a-3p) in inflammation-related pyroptosis, especially in drug-induced acute liver failure (DIALF). This study aimed to identify the relationship between miR-29a-3p and inflammation-related pyroptosis in DIALF and confirm its underlying mechanisms. Thioacetamide (TAA)- and acetaminophen (APAP)-induced ALF mouse models were established, and human samples were collected. The expression levels of miR-29a-3p and inflammation and pyroptosis markers were measured by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, or immunochemical staining in miR-29a-3p knock-in transgenic mouse (MIR29A(KI/KI)) DIALF models. In addition, RNA sequencing was conducted to explore the mechanisms. MiR-29a-3p levels were decreased in TAA- and APAP-induced DIALF models. MiR-29a-3p prevented DIALF caused by TAA and APAP. RNA sequencing and further experiments showed that the protective effect of miR-29a-3p on DIALF was mainly achieved through inhibition of inflammation-related pyroptosis, and the inhibition was dependent on activation of the PI3K/AKT pathway. In addition, miR-29a-3p levels were reduced, and pyroptosis was activated in both peripheral blood mononuclear cells and liver tissues of DIALF patients. The study supports the idea that miR-29a-3p inhibits pyroptosis by activating the PI3K/AKT pathway to prevent DIALF. MiR-29a-3p may be a promising therapeutic target for DIALF.

Circulating Cell-Free DNAs as a Biomarker and Therapeutic Target for Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury and acute liver failure, while the detection, prognosis prediction, and therapy for APAP-induced liver injury (AILI) remain improved. Here, it is determined that the temporal pattern of circulating cell-free DNA (cfDNA) is strongly associated with damage and inflammation parameters in AILI. CfDNA is comparable to alanine aminotransferase (ALT) in predicting mortality and outperformed ALT when combined with ALT in AILI. The depletion of cfDNA or neutrophils alleviates liver damage, while the addition of cfDNA or adoptive transfer of neutrophils exacerbates the damage. The combination of DNase I and N-acetylcysteine attenuates AILI significantly. This study establishes that cfDNA is a mechanistic biomarker to predict mortality in AILI mice. The combination of scavenging cfDNA and reducing oxidative damage provides a promising treatment for AILI.

Human endoderm stem cells reverse inflammation-related acute liver failure through cystatin SN-mediated inhibition of interferon signaling

Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.

GAS1 Promotes Ferroptosis of Liver Cells in Acetaminophen-Induced Acute Liver Failure.

Purpose: Acute liver failure (ALF) is a clinically fatal disease that leads to the rapid loss of normal liver function. Acetaminophen (APAP) is a leading cause of drug-induced ALF. Ferroptosis, defined as iron-dependent cell death associated with lipid peroxide accumulation, has been shown to be strongly associated with APAP-induced liver injury. Growth arrest-specific 1 (GAS1) is a growth arrest-specific gene, which is closely related to the inhibition of cell growth and promotion of apoptosis. However, the functional role and underlying mechanism of GAS1 in APAP-induced ferroptosis remain unknown. Methods: We established liver-specific overexpression of GAS1 (GAS1AAV8-OE) mice and the control (GAS1AAV8-vector) mice by tail vein injection of male mice with adeno-associated virus. APAP at 500 mg/kg was intraperitoneally injected into these two groups of mice to induce acute liver failure. The shRNA packaged by the lentivirus inhibits GAS1 gene expression in human hepatoma cell line HepaRG (HepaRG-shNC and HepaRG-shGAS1-2) and primary hepatocytes of mice with liver-specific overexpression of GAS1 were isolated and induced by APAP in vitro to further investigate the regulatory role of GAS1 in APAP-induced acute liver failure. Results: APAP-induced upregulation of ferroptosis, levels of lipid peroxides and reactive oxygen species, and depletion of glutathione were effectively alleviated by the ferroptosis inhibitor, ferrostatin-1, and downregulation of GAS1 expression. GAS1 overexpression promoted ferroptosis-induced lipid peroxide accumulation via p53, inhibiting its downstream target, solute carrier family 7 member 11. Conclusion: Collectively, our findings suggest that GAS1 overexpression plays a key role in aggravating APAP-induced acute liver injury by promoting ferroptosis-induced accumulation of lipid peroxides.

S2956 Delayed Onset Drug-Induced Acute Liver Failure Caused by Glatiramer Acetate (GA) in Multiple Sclerosis Requiring Liver Transplantation

Introduction: Glatiramer acetate (GA) has been used for multiple sclerosis (MS) since 1996. Regular liver function test monitoring is not required for the medication because there have not been any reported cases of liver toxicity.1Here, we report the first case of delayed onset GA-induced ALF requiring liver transplantation. Case Description/Methods: A 59-year-old woman with well-controlled MS presented to the emergency department with three weeks of jaundice and dark-colored urine. Initial labs showed AST 2527 IU/L (81x ULN), ALT 2512 IU/L (81x ULN), total bilirubin 22.7 mg/dL (19x ULN), ALP 210 IU/L (2x ULN), INR 2.65. Further workup showed normal ceruloplasmin, alpha-1-antitrypsin, and IgG. Hepatitis, HSV, VZV, T-spot, HIV, ANA, anti-mitochondrial antibody, anti-LKM antibody were negative. Anti-smooth muscle antibody was 1:40. Her liver enzymes were normal one year prior to presentation, and she had no family history of autoimmune or liver disease. Computed tomography abdomen/pelvis showed patent vasculature and no evidence of cirrhosis. MRI/MRCP showed no biliary obstruction. Her only medication was GA, which she had been taking since 2008. Physical exam was notable for mild asterixis, and she was started on IV N-acetyl cysteine for 3 days. Liver biopsy demonstrated submassive necrosis (70%) consistent with drug induced liver injury (Fig. 1A). GA was thought to be the most likely etiology of her liver injury and was held. Liver transplant was ultimately deferred because her liver enzymes and her mental status improved. She was discharge on day 6. Four days later she developed severe abdominal pain, lethargy and re-presented to the hospital. She was slow to respond, had scleral icterus and asterixis with AST 909 IU/L, ALT 839 IU/L, total bilirubin 27.2 mg/dL, INR 2.94. The patient underwent expedited liver transplant evaluation and was listed on the same day. She successfully underwent deceased donor liver transplant three days later. Liver explant showed mixed zone 1 and 3 liver necrosis (50%) with associated inflammation, mild lobular inflammation and cholestasis (Fig. 1B-D). Discussion: Our case illustrates the first case of GA-induced ALF requiring liver transplantation. Previous reports showed that patients with GA drug-induced-liver injury recovered completely in 1-5 months after drug withdrawal and time of presentation ranges from 1 to 8 months, as opposed to 14 years in our case. Patients on GA should have long term regular liver monitoring.Figure 1.: Histological analysis of pre-transplant and explant liver. A. Hematoxylin and eosin (H&E) stain of the pre-transplant biopsy showed extensive necrosis including zone 3 (x100). B. Gross picture of explant (weight 500.3 gram). The surface showed wrinkles, which were characteristics of acute liver failure with massive hepatocyte necrosis. C. H&E stain of explant showed no viable hepatocytes in the worst area. (x200). D. Masson trichrome stain showed no fibrosis, which confirms the acute process (x200).

S2984 Drug-Induced Liver Failure Masquerading as Late Onset Wilson Disease: A Case Report

Introduction: The use of herbal and dietary supplements has increased occurrences of drug-induced liver failure. Acute liver failure (ALF) can rapidly progress to multiorgan failure with about 50% of patients requiring a liver transplant. About 10% of all ALF cases have been due to drug injury while only about 2% have been due to Wilson disease (WD). This article provides a detailed case review of ALF due to the use of alkaline water that was originally thought to be due to WD. Case Description/Methods: A 35-year-old male with no known past medical history is brought into the emergency department (ED) with altered mental status for the past 2 to 3 weeks. The patient was found to be in acute renal failure and ALF. Computed tomography (CT) of the head was unremarkable and a CT of the abdomen showed hepatomegaly and hepatic steatosis without evidence of cirrhosis. Abdominal ultrasound was negative for portal vein thrombus, and laboratory findings were significant for reduced ceruloplasmin. Due to the absence of other causes for his ALF, the patient's presentation was thought to be due to WD. An ophthalmologist conducted a slit-lamp exam, which was negative for Kayser-Fleischer rings. A liver biopsy showed focal liver cholestasis, bile ductular reaction, and mixed portal inflammation suggestive of drug-induced liver injury. Examination of the liver core biopsies displayed acute and chronic periportal inflammatory infiltrate with eosinophils. The patient’s acute encephalopathy completely resolved after six days, and the patient subsequently reported drinking an alkaline water daily 10-days before the onset of symptoms. After ten days, the patient was transferred to a transplant center, however, with improving liver function and resolution of symptoms, the patient was discharged home without the need for further treatment. (Figure) (Table). Discussion: Due to increased consumption of herbal and dietary supplements in the United States, the rates of drug-induced liver failure have increased. Many cases of drug-induced liver failure due to these sources are underreported and when they are discovered have been linked to increased rates of liver transplant. This case not only highlights drug-induced acute liver failure and its complicated presentation, but also brings into consideration alkaline water as a potential source for ALF. Cases such as this demonstrate that a thorough history and further understanding of herbal and dietary supplements cannot be overlooked when attempting to elucidate a source in instances of ALF.Figure 1.: Computed tomography of the head and abdomen. (a) Axial view of head. No abnormalities in the basal ganglia. (b) Coronal view of abdomen. Table 1. - Laboratory test results of the patient a day before admission, on the day of admission, five days after admission, ten days after admission, and two days after transfer to an outside facility Variable (normal range) Two days before admission Day of admission Five days after admission Ten days after admission Two days after transfer White Blood Cell k/mm3 (3.10-10.20) 11.13 26.27 14.75 12.20 13.17 Hemoglobin g/dL (13.1-16.8) 14.9 16.3 11.0 9.2 8.9 Platelet k/mm3 (119-332) 314 354 182 163 274 Lactic Acid mmol/L (0.50-1.90) > 11.70 1.08 1.39 BUN mg/dL (5-26) 9 18 102 30 38 Creatinine mg/dL (0.55-1.30) 0.81 2.11 11.11 1.97 2.0 Bilirubin, Total mg/dL (0.0-1.2) 0.5 2.1 5.0 1.7 1.3 Bilirubin, Direct mg/dL (< = 0.5) 1.6 2.9 1.1 AST U/L (8-34) 40 11,867 193 90 65 ALT U/L (10-49) < 7 1,001 171 394 289 Alk-Phos U/L (46-116) 89 152 135 165 126 INR (0.80-1.2) 5.37 1.19 0.95 1.0 Prothrombin time (9.3-12.4 seconds) 53 12.6 10.2 11.8 Ceruloplasmin mg/dL (16.0-31.0) 8.7 13.5 24.6 Copper ug/dL (72-166) 52 82 76 Urine Copper Level ug/L 2787 Urine Copper mcg/24hrs (9-71) 40 Alk-Phos (IU/L) to total bilirubin (mg/dL) ratio 72.38 AST, aspartate transaminase; ALT, alanine transaminase; Alk-Phos, alkaline phosphatase; INR, International Normalization Ratio; aPTT, activated partial thromboplastin

Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review.

Introduction: Apart from cessation of the implicated agent leading to drug-induced liver injury (DILI), there is no standard therapy for DILI. Corticosteroids have been used in DILI, although their efficacy is unclear. Published data showed either beneficial effects or no improvement associated with steroid therapy. The aim of the current study was to perform a systematic review of the role of corticosteroids in the treatment of DILI. Methods: A search was performed in PubMed, searching for the terms: “corticosteroids” and “drug-induced liver injury”. Observation studies were included, but case reports excluded. Results: A total of 24 papers were retrieved. Most of these were observational studies on the effects of corticosteroids in moderate/severe DILI (n = 8), reports on the corticosteroid treatment in patients with drug-induced autoimmune hepatitis (DI-AIH) (n = 5), and effects of corticosteroids in drug-induced fulminant acute liver failure (ALF, n = 2). Furthermore, treatment of corticosteroids in patients with liver injury due to check point inhibitors (CPIs) was addressed in nine studies. In moderate/severe DILI, six out of eight studies suggested steroid treatment to be beneficial, whereas two studies showed negative results. All five observational studies on the effects of corticosteroids in DI-AIH showed good therapeutic response with rapid and long lasting effects after discontinuation of corticosteroids and without evidence of relapse. Steroid therapy was not associated with improved overall survival in patients with drug-induced fulminant ALF. CPIs-induced liver injury was found to improve spontaneously in 33–50% without corticosteroids, and the rate of patients who were treated responded to steroids in 33–100% (mean 72%). Conclusions: The majority of studies analyzing the effects of corticosteroids in moderate/severe DILI have demonstrated beneficial effects. However, this was not the case in drug-induced fulminant ALF. Patients with DI-AIH had an excellent response to corticosteroids. The majority of those with CPIs-induced liver injury responded to corticosteroids; however, patients without treatment usually recovered spontaneously. The observational design and comparison with historical controls in these studies makes it very difficult to draw conclusions on the efficacy of corticosteroids in DILI. Therefore, there is a strong need for a randomized controlled trial to properly assess the role of corticosteroids in DILI.

The Potential Protective Effect of Curcumin and α-Lipoic Acid on N-(4-Hydroxyphenyl) Acetamide-induced Hepatotoxicity Through Downregulation of α-SMA and Collagen III Expression.

Background and objectivesN-(4-hydroxyphenyl) acetamide (NHPA) is the most commonly used analgesic and antipyretic agent worldwide; however, it remains the leading cause of drug-induced acute liver failure. This study explored the potential impact of curcumin (Curc) and/or α-lipoic acid (Lip acid) on liver damage induced by NHPA overdose.Materials and MethodsMale Wistar rats were intoxicated with a single oral dose of NHPA (1000 mg/kg) and treated with Curc (200 mg/kg p. o.) and/or Lip acid (100 mg/kg i. p.). These treatments were given in 2 doses at 2 hours and 10 hours post-NHPA-administration. Animals were sacrificed 24 hours post-NHPA-administration.ResultsTreatment with Curc and/or Lip acid showed effective reduction of NHPA-induced liver injury, demonstrated by reducing serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, as well as hepatic nitric oxide and malondialdehyde. Curc and/or Lip acid treatments counteracted these changes. They also ameliorated NHPA-induced centrilobular hepatocellular necrosis, evidenced by histopathological examination. Moreover, Curc and Lip acid reduced the expression of alpha-smooth muscle actin and collagen III, upregulated by NHPA intoxication in response to oxidative stress and inflammation.Discussion and ConclusionCurc and Lip acid can be considered as promising natural therapies against liver injury, induced by NHPA, through their antioxidant and antifibrotic actions.

Eight-Fold Increase in Dietary Supplement-Related Liver Failure Leading to Transplant Waitlisting Over the Last Quarter Century in the United States.

We investigated the trends in listing and outcomes of drug-induced acute liver failure (DIALF) over the last quarter century in the United States using the United Network for Organ Sharing (UNOS) database. We examined waitlisted patients in the UNOS database between 1995 and 2020 with a diagnosis of DIALF and assessed trends in etiologies, demographic and clinical characteristics, and outcomes over 3 periods: 1995-2003, 2004-2012, and 2013-2020. Patients with DIALF and cirrhosis were classified as drug-induced acute-on-chronic liver failure. Implicated agents including acetaminophen (APAP) and herbal or dietary supplements (HDSs) were ascertained. There were 2146 individuals with DIALF during the study period. The observed demographic trends between the earliest and latest period included fewer pediatric patients (18.8% to 13.5%) but with an increasing number of males in non-APAP DIALF (31.8% to 41.4%) and increased racial diversity in APAP DIALF. Antimicrobials remained the most common non-APAP agents across all periods, but antiepileptics, propylthiouracil, and mushroom poisoning decreased, while HDSs markedly increased from 2.9% to 24.1% of all non-APAP DIALF patients. The overall 5-year post-liver transplantation (LT) patient survival improved significantly over the 3 periods (69.9% to 77.4% to 83.3%) and was evident for both APAP and non-APAP DIALF. Over the last quarter century, there has been an 8-fold increase in HDS-related liver failure necessitating waitlisting for liver transplantation in the United States. There are other important temporal trends during the study period, including improved survival following LT among both APAP and non-APAP DIALF patients.

Protopanaxatriol-type saponin protects against acetaminophen-induced liver injury through ROS-mediated JNK pathway

Worldwide, drug-induced acute liver failure is associated with a high rate of morbidity and mortality. Acetaminophen (APAP), a widely used analgesic, is one of the most common causes of acute liver injury. The purpose of this study was to determine the protective effect of protopanaxatriol-type saponin (PTS) against APAP-induced liver injury and to elucidate the mechanisms underlying this effect. Mice were pretreated with PTS via gavage for 7 days prior to receiving APAP. The results indicated that PTS was highly effective in preventing hepatotoxicity caused by APAP. Meanwhile, pretreatment with PTS resulted in a decrease in inflammation and oxidative stress. Furthermore, PTS reversed the histological change and reduced hepatic injury. Additionally, PTS inhibited the expression of proteins associated with APAP induced hepatic apoptosis in the liver. Taken together, our findings indicated that PTS protected against liver injury caused by APAP by alleviating oxidative stress, inflammation, and apoptosis via the ROS-mediated JNK pathway. Our findings suggest that PTS may have the potential as a novel therapeutic agent for APAP-induced liver injury.