Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

A unusual presentation of liver failure caused by Ibuprofen-sustained release capsules: A case report.

RATIONALE: Previous studies have shown that acetaminophen has the potential to induce hepatotoxicity in patients, rendering it a prominent drug implicated in the development of acute hepatic failure. However, there is currently no available literature reporting the impact of ibuprofen-sustained release capsules on liver failure. PATIENT CONCERNS: A 65-year-old man was presented with a 4-day history of tea-colored urine with oil avoidance, jaundiced skin, and anorexia, and impaired liver function. One ibuprofen-sustained release capsule was taken on the day before the onset of the disease due to "headache." DIAGNOSES: A diagnosis of this patient was made of liver failure due to taking ibuprofen-sustained release capsules. INTERVENTIONS: Initially, the patient discontinued the use of hepatotoxic drugs in order to prevent further exposure. Subsequently, the patient underwent a standard therapeutic regimen, which encompassed the administration of hepatoprotective agents, nutritional support drugs, correction of acid-base imbalances, and electrolyte abnormalities, as well as other relevant treatments. OUTCOMES: After 9 days of hepatoprotective and nutritional supplement therapy, the patient saw notable improvement in symptoms, reporting an absence of discomfort, subsided skin jaundice, clear urine, and liver function tests returning to a near normal range. The patient was granted permission to be discharged from the hospital while being prescribed drugs. After 2 weeks of follow-up, the patient reported an absence of discomfort and exhibited normal results in the liver function test. CONCLUSIONS: Liver failure caused by ibuprofen-sustained release capsules has not been reported. It is worth noting that conventional treatments such as suspending offending agents, and administration of hepatoprotective agents and nutritional support drugs have proven to be successful. LESSON: There is currently no known peer-reviewed literature indicating that the administration of ibuprofen-sustained release capsules leads to liver failure. When patients taking ibuprofen-sustained release capsules encounter symptoms such as anorexia, skin jaundice, lack of appetite, and nausea, it is recommended that they undertake a cardiac and liver function tests. In the event that ibuprofen-sustained release capsules induce liver injury, it is imperative to administer timely and immediate medical intervention.

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.

Variable Outcomes of Hepatitis E Infections in Patients with Hemato-Oncologic Diseases.

INTRODUCTION: The hepatitis E virus (HEV) represents an important cause of viral hepatitis and could cause chronic infections in immunocompromised patients. However, data about immunocompromised patients other than solid organ transplant recipients are limited. METHODS: We identified patients from a laboratory database and retrospectively compiled and analyzed clinical as well as laboratory data in detail. RESULTS: Overall, 22 severely immunosuppressed patients, excluding solid organ transplant recipients, were identified. Four patients did not experience viral clearance (one without and three despite ribavirin therapy). Three patients acquired the infection after allogeneic hematopoietic stem cell transplantation (alloHSCT) and recovered spontaneously, whereas another patient, infected prior to alloHSCT, developed a chronic infection. Four patients failed to clear HEV, resulting in fatal liver failure in 2 patients. The CD4+ cell counts increased in all but 1 patient attaining a sustained virological response (SVR), as compared to patients with clinical failure. Severe immunoglobulin deficiency did not appear to obviate the control of HEV. Six of ten (60%) patients with and nine of 12 (75%) patients without ribavirin therapy achieved an SVR. CONCLUSIONS: Upfront ribavirin therapy does not appear mandatory in patients without CD4+ lymphopenia, but a prolonged HEV replication carries the risk of liver failure. Our data suggest that chronic HEV infections could cause T-cell exhaustion, which might be overruled with ribavirin therapy.

Fatal hepatic failure following atorvastatin treatment: A case report.

RATIONALE: Atorvastatin is a commonly used statin for the treatment of hypercholesterolemia in people at high risk for coronary, cerebrovascular, and peripheral artery disease. However, fatal liver failure due to atorvastatin treatment has been rarely reported, especially during the very short incubation period. PATIENT CONCERNS: A 63-year-old male patient was admitted due to unexplained chest pain. After admission, his liver function had decreased < 24 hours after taking 20 mg tablets of atorvastatin due to lacunar infarction, which was improved after drug withdrawal. The treatment regimen was restarted 15 days later, but within 16 hours, the patient developed multiple organ failure, including liver failure and renal failure. DIAGNOSES: The pathological results after 7 days indicated focal inflammatory necrosis, virus and autoimmune correlation tests were negative, which did not rule out drug-induced liver injury. Interventions: receiving artificial liver therapy, continuous renal replacement therapy and other organ support treatment. OUTCOMES: The patient died 18 days after admission. LESSONS: Statin idiosyncratic liver injury is very rare, but the consequences can be serious.

Regional Citrate Anticoagulation or Heparin Anticoagulation for Renal Replacement Therapy in Patients With Liver Failure: A Systematic Review and Meta-Analysis.

In patients with liver failure complicated by acute kidney injury, renal replacement therapy (RRT) is often required to improve the internal environment. The use of anticoagulants for RRT in patients with liver failure remains controversial. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies. The methodological quality of the included studies was assessed using the Methodological Index for Nonrandomized Studies. A meta-analysis was performed using R software (version 3.5.1) and Review Manager (version 5.3.5). During RRT, 348 patients from 9 studies received regional citrate anticoagulation (RCA), and 127 patients from 5 studies received heparin anticoagulation (including heparin and LMWH). Among patients who received RCA, the incidence of citrate accumulation, metabolic acidosis, and metabolic alkalosis were 5.3% (95% confidence interval [CI]: 0%-25.3%), 26.4% (95% CI: 0-76.9), and 1.8% (95% CI: 0-6.8), respectively. The potassium, phosphorus, total bilirubin (TBIL), and creatinine levels were lower, whereas the serum pH, bicarbonate, base excess levels, and total calcium/ionized calcium ratio were higher after treatment than before treatment. Among patients who received heparin anticoagulation, the TBIL levels were lower, whereas the activated partial thromboplastin clotting time and D-dimer levels were higher after treatment than before treatment. The mortality rates in the RCA and heparin anticoagulation groups were 58.9% (95% CI: 39.2-77.3) and 47.4% (95% CI: 31.1-63.7), respectively. No statistical difference in mortality was observed between the 2 groups. For patients with liver failure, the administration of RCA or heparin for anticoagulation during RRT under strict monitoring may be safe and effective.

Hepatic failure in a patient with rheumatoid arthritis treated with methotrexate: A case report.

INTRODUCTION: Chronic liver damage from methotrexate (MTX) is not uncommon, and fatal outcome is rare. We experienced a case of hepatic failure leading to death. We considered the cause of death through this case and proposed a method to prevent the progression of this liver injury. PATIENT CONCERNS: We report the case of a patient with rheumatoid arthritis treated with MTX for 15 years. DIAGNOSIS, INTERVENTIONS, AND OUTCOMES: A liver biopsy revealed histological changes similar to those of advanced nonalcoholic steatohepatitis (NASH), most likely induced by MTX. MTX was discontinued after 4 years. Two years after the discontinuation, the patient died of irreversible hepatic failure. Her obesity, complicated by type 2 diabetes mellitus, might have aggravated MTX-induced NASH-like liver injury. CONCLUSION: Early diagnosis and immediate MTX discontinuation following NASH diagnosis and strict type 2 diabetes mellitus control might have prevented the irreversible progression of liver injury.

[The development of portal hypertension and liver failure on the background of long-term intake of vitamin A in a young woman. Case report].

The use of over-the-Counter (OTC) pharmaceuticals is a common phenomenon in today's society. We present a case of liver injury associated with long-term OTC use of vitamin A. The young patient took daily up to 15 capsules of a combined preparation for 2 years containing retinol palmitate 55 mg (100,000 IU) + Alpha-Tocopherol acetate 100 mg, the content of vitamin A in which significantly exceeded the recommended daily dose. Gradually, the patient noted the appearance of arthralgia, skin itching, hyperemia of the palms and feet, exfoliation of the skin on the soles, profuse hair loss, cracks in the corners of the mouth and in the area of the earlobes. Patient's condition worsened with the development of signs of liver cirrhosis in the form of portal hypertension (ascites, splenomegaly) and a decrease in the protein-synthetic function of the organ. Chronic viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis, Wilson's disease, alcoholic liver disease were exclude. Liver biopsy showed characteristic signs of hypervitaminosis A without fibrosis. A complete regression of symptoms was observe within 8 months after discontinuation of the drug. A toxicity can lead to serious liver injury and should be considere in the differential diagnosis of chronic liver disease. Vitamin A should only be prescribe for medical reasons, for a limited period of time, and under close medical supervision.

Hepatic failure with fatal outcome during pregnancy following administration of a single therapeutic dose of acetominophen: Case report and literature review.

Acetaminophen is generally regarded as a safe antipyretic and analgetic agent and is widely used in cases of pregnancy. However, acetaminophen is also one of the most frequently reported medications in cases of drug overdose. On the other hand, in the few instances described in the literature, where normal doses of acetaminophen administered during pregnancy may have had a fatal outcome, evidence existed pointing to a history of liver disease. It is therefore of interest that the patient in this report who died of liver failure after ingesting standard doses of acetaminophen also suffered from intrahepatic cholestasis during pregnancy although there was no history of liver disease. Other than these instances, there have been no previous reports in the literature of a normal, therapeutic dose of acetaminophen having a fatal outcome in pregnancy. This case emphasizes the need for caution when prescribing acetaminophen during pregnancy to patients with a history of liver disease, regardless of whether the liver function has returned to normal.

Voriconazole-induced severe skin allergy and neurological adverse event in a liver failure patient: A case report.

WHAT IS KNOWN AND OBJECTIVE: Triazole antifungal-associated severe skin allergy has received little attention. Here we report a case of an acute-on-chronic liver failure (ACLF) patient with diffused skin allergy pervading from the chest, abdomen, back, knees to perineum, with red colour and partially desquamation as well as a neurological adverse (insomnia) event after voriconazole treatment. CASE SUMMARY: A 40-year-old man with liver failure in our hospital had received voriconazole for invasive fungal infection therapy, and while waiting for liver transplantation exhibited a severe diffuse rash and a neurological adverse event. WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first report of a liver failure patient who suffered a severe allergy accompanied with a neurological adverse event after voriconazole administration.

Continuous Renal Replacement Therapy with Regional Citrate Anticoagulation in Children with Liver Dysfunction/Failure.

Regional citrate anticoagulation (RCA) is an option but citrate accumulation is risk and it is a giving up cause for this situation. This retrospective study was conducted in the pediatric intensive care unit (PICU) between May 2019 and April 2021. We investigated 47 patients with liver failure (LF) in our PICU, and RCA during continuous renal replacement therapy (CRRT) was applied to 10 (21.3%) of them. Half of them were male (n: 5/10), their mean age was 104.7 ± 66.20 months. Nine of them needed vasoactive support during follow-up. The most common indication for CRRT was hepatorenal syndrome (40%). There was no significant difference between liver transaminases and liver function tests before and after CRRT (p > 0.05). In terms of citrate toxicity of the patients, there was no significant difference between total calcium/ionized calcium, lactate level, pH and bicarbonate values before and after CRRT (p > 0.05). The mean total CRRT time was 110.2 ± 118.2 h, and the mean circuit lifespan was 43.8 ± 48.7 h; the mean number of circuits was 2.7 ± 2.4. Total Ca/ionized Ca >2.5 was a clinically relevant endpoint, but no patient interrupted dialysis for this cause. There was no complication about RCA. This study did not observe any adverse effects on acid-base status, transaminases, an increase in bilirubin during RCA-CRRT treatment in pediatric patients with LF. Total calcium/ionized calcium ratio, serum lactate level and prothrombin time level should be closely monitored daily in terms of citrate accumulation in this patient group.

A pharmacovigilance study of the association between tetracyclines and hepatotoxicity based on Food and Drug Administration adverse event reporting system data.

Background While tetracycline antibiotics are commonly prescribed in practice, the risk of drug-induced liver injury (DILI) remains controversial. Aim To evaluate the association of DILI with tetracycline antibiotics. Method All DILI cases of tetracycline antibiotics as primary suspected drugs were extracted from the US Food and Drug Administration adverse event reporting system (FAERS). The outcomes included severe DILI, hepatocellular injury, cholestatic injury, and liver failure. Disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and the information component (IC). Results A total of 1,435 liver injury cases associated with tetracycline antibiotics were identified. The DILI signal was detected in tigecycline, minocycline, and doxycycline. The RORs and the 95% confidence intervals (95% CI) of tigecycline, minocycline, and doxycycline were (ROR 5.85, 95% CI 4.96-6.91), (ROR 6.4, 95% CI 5.76-7.11), and (ROR 2.07, 95% CI 1.86-2.31), respectively. Compared to minocycline (ROR 5.5, 95% CI 4.94-6.12; IC 2.35, 95% CI 1.98-2.68) and doxycycline (ROR 1.91, 95% CI 1.71-2.12; IC 0.91, 95% CI 0.55-1.26), tigecycline showed a stronger association with hepatocellular injury (ROR 7.11, 95% CI 6.13-8.23; IC 2.68, 95% CI 2.16-3.13). Tigecycline also showed a stronger association with cholestatic injury (ROR 12.16, 95% CI 10.13-14.61; IC 3.51, 95% CI 2.79-4) than minocycline (ROR 3.23, 95% CI 2.59-4.04; IC 1.67, 95% CI 0.9-2.37) or doxycycline (ROR 2.86, 95% CI 2.47-3.31; IC 1.5, 95% CI 1-1.97). Tigecycline (ROR 6.56, 95% CI 4.57-9.41; IC 2.69, 95% CI 1.28-3.64) and minocycline (ROR 4.22, 95% CI 3.14-5.66; IC 2.06, 95% CI 1-2.93) showed a significant association with liver failure. Conclusion The data mining of FAERS suggested an association between DILI and tigecycline, minocycline, and doxycycline.

Liver failure caused by intravenous amiodarone and effective intervention measures: A case report.

WHAT IS KNOWN AND OBJECTIVE: We present a case of intravenous amiodarone-induced liver injury, pharmacy monitoring and its therapy. CASE SUMMARY: A 76-year-old male patient developed acute liver injury 24 h after starting intravenous amiodarone. His liver enzymes improved after discontinuing amiodarone and anti-inflammatory liver therapy, which used reduced glutathione, magnesium isoglycyrrhizinate and ademetionine1,4-butanedisulfonate for injection. WHAT IS NEW AND CONCLUSION: Amiodarone is a highly effective antiarrhythmic agent for the treatment and prevention of atrial and ventricular arrhythmias. Acute liver damage after intravenous amiodarone is rare but potentially harmful. Amiodarone loading should be adapted to the necessity of an immediate effect of the drug, and liver function should be monitored closely in critically ill patients. Timely stopped suspected drug and anti-inflammatory liver therapy may reduce the occurrence of drug-induced diseases.

Exosomes derived from human umbilical cord mesenchymal stem cells alleviate acetaminophen-induced acute liver failure through activating ERK and IGF-1R/PI3K/AKT signaling pathway.

This study aimed to investigate the therapeutic potential of human umbilical cord mesenchymal stem cells derived exosomes (hUCMSC-Exo) in acute liver failure (ALF) in mice as well as its underlying mechanism. We found that a single tail vein administration of hucMSC-Exo effectively enhanced the survival rate, inhibited apoptosis in hepatocytes, and improved liver function in APAP-induced mouse model of ALF. Furthermore, the deletion of glutathione (GSH) and superoxide dismutase (SOD), generation of malondialdehyde (MDA), and the over production of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP were also inhibited by hucMSC-Exo, indicating that hucMSC-Exo inhibited APAP-induced apoptosis of hepatocytes by reducing oxidative stress. Moreover, hucMSC-Exo significantly down-regulated the levels of inflammatory cytokines IL-6, IL-1ß, and TNF-α in APAP-treated livers. Western blot showed that hucMSC-Exo significantly promoted the activation of ERK1/2 and IGF-1R/PI3K/AKT signaling pathways in APAP-injured LO2 cells, resulting in the inhibition of apoptosis of LO2 cells. Importantly, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 could reverse the function of hucMSC-Exo on APAP-injured LO2 cells in some extent. Our results suggest that hucMSC-Exo offer antioxidant hepatoprotection against APAP in vitro and in vivo by inhibitiing oxidative stress-induced apoptosis via upregulation of ERK1/2 and PI3K/AKT signaling pathways.

Hepatitis C virus and hepatitis B virus in patients with schizophrenia.

ABSTRACT: This study evaluated the severe hepatic outcome (SHO) in patients with schizophrenia and viral hepatitis who received antipsychotics.Using the nationwide Taiwan National Health Insurance Research Database, patients first diagnosed with schizophrenia between 2002 and 2013 were identified. Patients diagnosed with schizophrenia who had viral hepatitis, including hepatitis B virus (HBV) or hepatitis C virus (HCV), were designated as the viral hepatitis group. A control group without viral hepatitis was matched for age, sex, and index year in a 2:1 ratio. Patients with severe hepatic outcomes before enrollment were excluded. The 2 cohorts were observed until December 31, 2013. The primary endpoint was occurrence of a SHO, including liver cancer, liver failure, liver decompensation, or transplantation.Among the 16,365 patients newly diagnosed with schizophrenia between January 2002 and December 2013, we identified 614 patients with viral hepatitis and 1228 matched patients without viral hepatitis. Of these 1842 patients, 41 (2.22%) developed SHOs, including 26 (4.23%) in the viral hepatitis group and 15 (1.22%) in the control group, during the mean follow-up period of 3.71 ±â€Š2.49 years. Cox proportional hazard analysis indicated that the SHO risk increased by 3.58 (95% confidence interval [CI]: 1.859-6.754; P < .001) in patients with schizophrenia and viral hepatitis. Moreover, patients with schizophrenia having HCV had a higher SHO risk than those without viral hepatitis (hazard ratio: 5.07, 95% CI: 1.612-15.956; P < .0001). Patients having both schizophrenia and viral hepatitis, especially HCV, had a higher risk of SHOs.

Rodenticide ingestion is an important cause of acute hepatotoxicity in Tamil Nadu, southern India.

BACKGROUND AND AIM: Though rodenticidal hepatotoxicity is reported from India, there is no systematic study to assess its magnitude. This study aimed to assess exposure to rodenticide as a risk factor for acute hepatotoxicity in Tamil Nadu, India. METHODS: We retrospectively analyzed acute hepatotoxicity caused by ingestion of hepatotoxin or potentially hepatotoxic drug overdose across 15 hospitals in 6 districts of Tamil Nadu from 1 January 2019 to 30 June 2019. Study exclusion criteria were idiosyncratic drug-induced liver injury and chronic liver diseases. RESULTS: Of the 702 patients, 685 gave history of consuming rodenticide; hepatotoxicity in the other patients resulted from paracetamol overdose (n=10) and due to other drugs (n=7); 97% patients had a suicidal intent. Of 671 patients with complete data, ratio of number of patients with hepatotoxicity due to rodenticide to paracetamol overdose was 450:6 (i.e. 75:1). The 451 rodenticidal hepatotoxicity patients (255 males, 75% were 15-34 years old) underwent conservative management (n=396), plasma exchange (n=54) and plasma exchange followed by liver transplant (n=1); 159 patients (35%) had poor outcome (131 died, 28 discharged in moribund state). Based on our observations, we estimate a case burden of 1584 rodenticidal hepatotoxicity patients (95% CI: 265-6119) with poor outcome in 554 patients in Tamil Nadu from January 2019 to June 2019. Population attributable risk for rodenticide as cause of hepatotoxicity was 22.7%. CONCLUSION: Rodenticide ingestion was an important cause of acute hepatotoxicity in Tamil Nadu. Most patients were young and one-third had poor outcome. Public health interventions are needed to address this.

Anaplastic lymphoma kinase tyrosine kinase inhibitor-induced hepatic failure in lung cancer patients: A study of signal mining and analysis of the FDA adverse event reporting system database.

WHAT IS KNOWN AND OBJECTIVE: Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors (ALK TKIs) are standard first-line therapy for non-small cell lung cancer patients with ALK rearrangement. Although some cases of hepatotoxicity related to these drugs have been reported, there is still a lack of investigation on severe hepatotoxicity, such as hepatic failure, with ALK TKIs. METHODS: We evaluated ALK TKI (crizotinib, alectinib, brigatinib, ceritinib and lorlatinib)-induced hepatic failure events (AIHFEs), by using the Reporting Odds Ratio (ROR) and Bayesian Confidence Propagation Neural Network method for mining the adverse event report signals in the FDA Adverse Event Reporting System (FAERS) database from Jan 2013 to Dec 2019. RESULTS AND DISCUSSION: The AIHFEs of "Hepatic failure," "hepatitis fulminant" and "hepatic necrosis" were defined as exposure event signals caused by ALK TKIs. The RORs of "Hepatic failure" were 4.95 (2.36-10.42) in alectinib, 3.77 (1.69-8.40) in ceritinib and 2.45 (1.60-3.76) in crizotinib, respectively. The ROR of "hepatitis fulminant" was 7.86 (3.52-17.54) in crizotinib. The Information Component value of "hepatic necrosis" was 1.97 (0.15) in alectinib. In reports of exposure-event signals, the clinical outcome of eventual death was common and could occur within 3 months. In the reports of "hepatic failure," there was no significant difference in the number of reports between men and women [OR=1.86 (0.94-3.67), p = 0.09]. WHAT IS NEW AND CONCLUSIONS: By mining the adverse event report signals in the FAERS database, we found the exposure event signals of AIHFEs in ALK TKIs were "hepatic failure," "hepatitis fulminant" and "hepatic necrosis". AIHFEs were more likely to appear in the reports of ceritinib, crizotinib and alectinib.