Case Report: Successful Reversal of Crizotinib-Induced Acute Liver Failure in Metastatic Lung Adenocarcinoma Using a Multi-Agent Therapeutic Approach

Case Report: Successful Reversal of Crizotinib-Induced Acute Liver Failure in Metastatic Lung Adenocarcinoma Using a Multi-Agent Therapeutic Approach | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Case Report: Successful Reversal of Crizotinib-Induced Acute Liver Failure in Metastatic Lung Adenocarcinoma Using a Multi-Agent Therapeutic Approach Seyedeh Mahdieh Khoshnazar, Saeedeh Khajoei Nejad, Sara Shafieipour This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6654785/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Metastatic lung adenocarcinoma patients treated with crizotinib may rarely develop severe adverse effects, including acute liver failure. Early recognition and management of drug-induced liver injury are crucial for patient outcomes. Case Presentation We report a 52-year-old female diagnosed with metastatic lung adenocarcinoma who developed acute liver failure during crizotinib therapy. After starting the second cycle, she presented with weakness, anorexia, and jaundice. Comprehensive clinical evaluation and laboratory tests confirmed drug-induced liver injury. The patient received supportive treatment, including intravenous N-acetylcysteine, dexamethasone, vitamin K, ursodeoxycholic acid, and rifampicin. Liver function tests and bilirubin levels were closely monitored. Conclusions The patient’s liver enzymes and bilirubin levels gradually normalized with appropriate supportive care. This case highlights the importance of vigilant hepatic monitoring during crizotinib treatment to promptly identify and manage potential hepatotoxicity. Crizotinib Acute liver failure Hepatotoxicity N-acetylcysteine Introduction Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC), accounting for approximately 85% of all lung cancers [ 1 , 2 ]. NSCLC often presents at an advanced stage, limiting the effectiveness of surgical interventions and necessitating systemic therapies [ 3 ]. Among individuals diagnosed with non-small cell lung cancer (NSCLC), approximately 2–8% exhibit rearrangements in the anaplastic lymphoma kinase (ALK) gene that led to the development of targeted therapies that have significantly improved outcomes for selected patient populations [ 2 ]. Crizotinib, a first-generation tyrosine kinase inhibitor (TKI), targets ALK, ROS1, and MET tyrosine kinases and has demonstrated superior efficacy compared to standard chemotherapy in ALK-positive NSCLC patients [ 4 ]. In August 2011, the U.S. Food and Drug Administration granted accelerated approval to crizotinib as a first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring ALK gene rearrangements [ 5 ]. While crizotinib has shown efficacy in treating ALK-positive NSCLC, its administration is associated with several adverse events. Among these, elevated liver transaminase levels are the most common, occurring in a significant proportion of patients. In rare instances, this hepatotoxicity can progress to acute liver failure, necessitating close monitoring of liver function during treatment [ 6 ]. Clinical studies have reported that severe hepatotoxicity occurs in approximately 0.1% of patients treated with crizotinib [ 7 ]. Alternative ALK inhibitors, such as alectinib, have been used successfully in patients who develop hepatotoxicity with crizotinib [ 8 ]. This case report presents a patient with metastatic lung adenocarcinoma who developed severe hepatic dysfunction shortly after initiating crizotinib therapy. The case underscores the importance of early recognition, prompt management of hepatotoxicity, and the need for vigilant monitoring of liver function in patients receiving crizotinib. Case Presentation Patient History A 52-year‐old female with no significant smoking history and no prior liver disease was diagnosed with metastatic lung adenocarcinoma in June 2024. Her past medical history was unremarkable except for a family history of malignancy. She had no known allergies and was not on any other hepatotoxic medications. After a multidisciplinary tumor board review, she was initiated on crizotinib therapy in August 2024 as she was found to harbor an ALK rearrangement. The patient’s performance status was good (ECOG 1) at the start of treatment, and baseline liver function tests were within normal limits. Laboratory Tests During the initial cycle of crizotinib therapy, spanning from mid-August to mid-September 2024, the patient's liver function tests remained within normal limits. However, ten days into the second cycle, initiated in late September 2024, the patient exhibited clinical signs suggestive of hepatic dysfunction, including weakness, anorexia, and jaundice. Subsequent laboratory evaluations revealed markedly elevated liver enzymes: aspartate aminotransferase (AST) at 1,193 U/L and alanine aminotransferase (ALT) at 1,238 U/L. Alkaline phosphatase (ALP) was elevated to 498 U/L. Total bilirubin levels peaked at 27.6 mg/dL, with direct bilirubin measured at 13 mg/dL. Coagulation studies indicated a prolonged prothrombin time (PT) and an increased international normalized ratio (INR), reflecting impaired hepatic synthetic function. These findings were consistent with acute liver failure, likely induced by crizotinib toxicity. Diagnosis Based on the temporal relationship between crizotinib initiation and the rapid deterioration in hepatic function, the patient was diagnosed with drug-induced acute liver failure. Differential diagnoses including viral hepatitis, autoimmune hepatitis, and biliary obstruction were ruled out by serological studies and imaging. The clinical presentation, laboratory abnormalities, and exclusion of alternative causes confirmed the diagnosis of crizotinib-induced hepatotoxicity. Treatment Upon hospital admission, the patient received immediate supportive care targeting the acute liver failure. Intravenous N-acetylcysteine (NAC) was administered to enhance hepatic detoxification pathways and restore mitochondrial function, leveraging its antioxidant properties and role in replenishing intracellular glutathione levels. To mitigate hepatic inflammation and oxidative stress, intravenous dexamethasone was introduced, capitalizing on its anti-inflammatory effects observed in cholestatic liver conditions. Given the evidence of coagulopathy, vitamin K supplementation was provided to support the synthesis of clotting factors, addressing potential deficiencies contributing to the impaired coagulation profile. Ursodeoxycholic acid was prescribed to improve bile flow and protect hepatocytes from bile acid-induced damage, aiding in the reduction of cholestasis. Additionally, rifampicin therapy was initiated with the aim of inducing hepatic microsomal enzymes, thereby enhancing drug metabolism and facilitating hepatic recovery. Ultrasound imaging confirmed normal liver dimensions with increased parenchymal echogenicity, indicative of hepatic steatosis, but showed no dilation of intrahepatic or extrahepatic biliary ducts.​ Outcome and Follow-Up During the hospital stay, the patient's liver function tests demonstrated a steady improvement. Aspartate aminotransferase (AST) levels decreased to 59 U/L, alanine aminotransferase (ALT) to 92 U/L, and alkaline phosphatase (ALP) to 251 U/L. Total bilirubin levels declined to 16.8 mg/dL, with direct bilirubin at 10.4 mg/dL. These improvements indicated a positive response to the supportive treatment regimen.​ Following discharge, the patient was closely monitored through serial liver function tests and imaging studies. Over a three-month period, there was a sustained improvement in hepatic parameters, and her overall clinical condition stabilized. Given the hepatotoxicity associated with crizotinib, a decision was made to transition the patient to an alternative targeted therapy regimen to mitigate the risk of further hepatic injury. She continues to undergo regular oncological and hepatic assessments to monitor her condition and ensure the efficacy and safety of the new treatment approach. Discussion The patient in this case report developed significant hepatotoxicity shortly after initiating crizotinib therapy for ALK-positive non-small cell lung cancer (NSCLC). Prompt recognition of liver dysfunction and immediate discontinuation of crizotinib, coupled with a comprehensive supportive treatment regimen including N-acetylcysteine (NAC), corticosteroids, vitamin K, ursodeoxycholic acid, and rifampicin led to a gradual normalization of liver function tests throughout hospitalization. This favorable outcome underscores the critical importance of early detection and intervention in managing crizotinib-induced liver injury. While crizotinib has demonstrated significant efficacy in treating ALK-positive NSCLC, its potential for hepatotoxicity necessitates vigilant monitoring of liver function, especially during the initial weeks of therapy. This case contributes to the growing body of evidence emphasizing the need for proactive management strategies to mitigate the risks associated with tyrosine kinase inhibitor-induced hepatotoxicity.​ Crizotinib is widely recognized for its efficacy in treating ALK-positive NSCLC; however, its hepatic side effects necessitate cautious usage [ 9 ]. Drug-induced liver injury (DILI) due to crizotinib can present within weeks of treatment initiation and ranges from asymptomatic enzyme elevations to fulminant liver failure [ 10 ]. The case presented here underscores the rapidity with which hepatic complications may develop and the critical importance of early intervention. Studies have demonstrated that early administration of agents such as N-acetylcysteine can mitigate the progression of liver injury by restoring hepatic glutathione levels and reducing oxidative stress [ 11 ]. Moreover, corticosteroids have been used to dampen the inflammatory cascade in severe DILI cases, although the evidence remains mixed regarding their efficacy [ 12 ]. There is growing literature supporting close monitoring of liver enzymes in patients receiving tyrosine kinase inhibitors, and our case adds to the body of evidence emphasizing the need for a proactive monitoring strategy [ 13 ]. Risk factors for developing crizotinib-induced hepatotoxicity include preexisting liver conditions, high body mass index, and potential drug-drug interactions [ 14 ]. Importantly, the decision to reintroduce crizotinib or switch to an alternative therapy must be individualized based on the severity of liver injury and the overall clinical scenario. Future research is needed to develop predictive biomarkers for hepatotoxicity and to refine dosing strategies that minimize the risk of liver injury while maintaining oncologic efficacy. Clinicians should also consider supportive therapies early in the course of DILI. A study highlighted that early intervention, particularly with NAC and corticosteroids was associated with improved outcomes and reduced mortality rates in patients with DILI from targeted agents [ 15 ]. Similarly, additional studies suggest that ursodeoxycholic acid may provide hepatoprotective effects in cholestatic liver injury scenarios [ 16 ]. In addition, as a novel ALK inhibitor, ceritinib could be also used as an alternative agent when crizotinib causes hepatitis [ 17 ]. Moreover, long-term follow-up and multidisciplinary collaboration between oncologists, hepatologists, and pharmacists are crucial in managing these complex cases. Our patient’s recovery and subsequent stabilization exemplify the benefits of integrated care and prompt therapeutic interventions in mitigating life-threatening hepatic complications. Conclusion This case highlights the significant risk of hepatotoxicity associated with crizotinib in the treatment of metastatic lung adenocarcinoma. Early recognition, immediate supportive care, and regular monitoring of liver enzymes are essential to mitigate liver damage and improve patient outcomes. Transitioning to alternative targeted therapies may be warranted in cases of severe liver injury. Additional research is needed to better understand the incidence, risk factors, and mechanisms underlying crizotinib-induced liver failure to inform future clinical guidelines. Declarations Funding Not Applicable. Conflicts of interest/Competing interests The other authors declare no conflict of interest for this article. Ethics approval This case report was a waiver study; however, it was approved by the Ethics Committee of Kerman University of Medical Sciences. Consent to participate Informed consent was obtained from the patient to be included in the study. Written Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images Availability of data and material Not applicable. Code availability Not applicable. Authors' contributions S.SH designed the study. S.KH collected the data. S.KH and SM.KH analyzed the results. SM.KH. wrote and reviewed the manuscript. All authors contributed to reviewing the manuscript. References Hendriks LE, Remon J, Faivre-Finn C, et al (2024) Non-small-cell lung cancer. Nature Rev Dis Primers 10(1):71. Kreitman K, Nair SP, & Kothadia JP, et al (2022) Successful Treatment of Crizotinib-Induced Fulminant Liver Failure: A Case Report and Review of Literature. Case Reports in Hepatol 2020(1):8247960. Simone II CB, & Jones JA, et al (2013) Palliative care for patients with locally advanced and metastatic non-small cell lung cancer. Ann palliative med 2(4):17888–17188. Gálffy G, Morócz É, Korompay R (2024). Targeted therapeutic options in early and metastatic NSCLC-overview. Pathol Oncol Res 30:1611715. Ou SHI (2011) Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Des Devel Ther 471–485. Zhang Y, Xu YY, Chen Y, et al, (2019) Crizotinib-induced acute fatal liver failure in an Asian ALK-positive lung adenocarcinoma patient with liver metastasis: a case report. World J Clin Cases 7(9):1080. Food and Drug Administration. Prescribing information Xalkori®(crizotinib). Food and Drug Administration, Silver Spring, MD, USA. 2013. Duarte FA, Rodrigues LB, Paes FR, et al (2021) Successful treatment with alectinib after crizotinib-induced hepatitis in ALK-rearranged advanced lung cancer patient: a case report. BMC Pul Med 21:1–4. Frampton JE (2013) Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced non-small cell lung cancer. Drugs 73(18):2031–2051. Jiang H, Jin Y, Yan H, et al (2021) Hepatotoxicity of FDA-approved small molecule kinase inhibitors. Expert Opinion on Drug Safety 20(3):335–348. De Andrade KQ, Moura FA, Dos Santos JM, et al (2015) Oxidative stress and inflammation in hepatic diseases: therapeutic possibilities of N-acetylcysteine. Int J mol sci 16(12):30269–30308. Björnsson ES, Vucic V, Stirnimann G, et al (2020) Role of corticosteroids in drug-induced liver injury. A systematic review. Front Pharmacol 13:820724. Xin S, Fang W, Li J, et al (2021) Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients. J cancer res and clin oncol 147:725–737. Jung D, Han JM, Yee J, et al (2018) Factors affecting crizotinib-induced hepatotoxicity in non-small cell lung cancer patients. Med Oncol 35:1–7. Stine JG, & Lewis JH (2016) Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. Expert rev gastroenterol Hepatol 10(4):517–536. Bessone F, Hillotte GL, Tamagnone N, et al (2025) Ursodeoxycholic Acid for the Management of Drug-induced Liver Injury: Role of Hepatoprotective and Anti-cholestatic Mechanisms. J Clin Translation Hepatol 13(2):162. Sassier M, Mennecier B, Gschwend A, et al (2016) Successful treatment with ceritinib after crizotinib induced hepatitis. Lung Cancer 95:15–16. Additional Declarations No competing interests reported. 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NSCLC often presents at an advanced stage, limiting the effectiveness of surgical interventions and necessitating systemic therapies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Among individuals diagnosed with non-small cell lung cancer (NSCLC), approximately 2\u0026ndash;8% exhibit rearrangements in the anaplastic lymphoma kinase (ALK) gene that led to the development of targeted therapies that have significantly improved outcomes for selected patient populations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Crizotinib, a first-generation tyrosine kinase inhibitor (TKI), targets ALK, ROS1, and MET tyrosine kinases and has demonstrated superior efficacy compared to standard chemotherapy in ALK-positive NSCLC patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In August 2011, the U.S. Food and Drug Administration granted accelerated approval to crizotinib as a first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring ALK gene rearrangements [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. While crizotinib has shown efficacy in treating ALK-positive NSCLC, its administration is associated with several adverse events. Among these, elevated liver transaminase levels are the most common, occurring in a significant proportion of patients. In rare instances, this hepatotoxicity can progress to acute liver failure, necessitating close monitoring of liver function during treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Clinical studies have reported that severe hepatotoxicity occurs in approximately 0.1% of patients treated with crizotinib [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Alternative ALK inhibitors, such as alectinib, have been used successfully in patients who develop hepatotoxicity with crizotinib [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This case report presents a patient with metastatic lung adenocarcinoma who developed severe hepatic dysfunction shortly after initiating crizotinib therapy. The case underscores the importance of early recognition, prompt management of hepatotoxicity, and the need for vigilant monitoring of liver function in patients receiving crizotinib.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient History\u003c/h2\u003e \u003cp\u003eA 52-year‐old female with no significant smoking history and no prior liver disease was diagnosed with metastatic lung adenocarcinoma in June 2024. Her past medical history was unremarkable except for a family history of malignancy. She had no known allergies and was not on any other hepatotoxic medications. After a multidisciplinary tumor board review, she was initiated on crizotinib therapy in August 2024 as she was found to harbor an ALK rearrangement. The patient\u0026rsquo;s performance status was good (ECOG 1) at the start of treatment, and baseline liver function tests were within normal limits.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLaboratory Tests\u003c/h3\u003e\n\u003cp\u003eDuring the initial cycle of crizotinib therapy, spanning from mid-August to mid-September 2024, the patient's liver function tests remained within normal limits. However, ten days into the second cycle, initiated in late September 2024, the patient exhibited clinical signs suggestive of hepatic dysfunction, including weakness, anorexia, and jaundice. Subsequent laboratory evaluations revealed markedly elevated liver enzymes: aspartate aminotransferase (AST) at 1,193 U/L and alanine aminotransferase (ALT) at 1,238 U/L. Alkaline phosphatase (ALP) was elevated to 498 U/L. Total bilirubin levels peaked at 27.6 mg/dL, with direct bilirubin measured at 13 mg/dL. Coagulation studies indicated a prolonged prothrombin time (PT) and an increased international normalized ratio (INR), reflecting impaired hepatic synthetic function. These findings were consistent with acute liver failure, likely induced by crizotinib toxicity.\u003c/p\u003e\n\u003ch3\u003eDiagnosis\u003c/h3\u003e\n\u003cp\u003eBased on the temporal relationship between crizotinib initiation and the rapid deterioration in hepatic function, the patient was diagnosed with drug-induced acute liver failure. Differential diagnoses including viral hepatitis, autoimmune hepatitis, and biliary obstruction were ruled out by serological studies and imaging. The clinical presentation, laboratory abnormalities, and exclusion of alternative causes confirmed the diagnosis of crizotinib-induced hepatotoxicity.\u003c/p\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eUpon hospital admission, the patient received immediate supportive care targeting the acute liver failure. Intravenous N-acetylcysteine (NAC) was administered to enhance hepatic detoxification pathways and restore mitochondrial function, leveraging its antioxidant properties and role in replenishing intracellular glutathione levels. To mitigate hepatic inflammation and oxidative stress, intravenous dexamethasone was introduced, capitalizing on its anti-inflammatory effects observed in cholestatic liver conditions. Given the evidence of coagulopathy, vitamin K supplementation was provided to support the synthesis of clotting factors, addressing potential deficiencies contributing to the impaired coagulation profile. Ursodeoxycholic acid was prescribed to improve bile flow and protect hepatocytes from bile acid-induced damage, aiding in the reduction of cholestasis. Additionally, rifampicin therapy was initiated with the aim of inducing hepatic microsomal enzymes, thereby enhancing drug metabolism and facilitating hepatic recovery. Ultrasound imaging confirmed normal liver dimensions with increased parenchymal echogenicity, indicative of hepatic steatosis, but showed no dilation of intrahepatic or extrahepatic biliary ducts.​\u003c/p\u003e\n\u003ch3\u003eOutcome and Follow-Up\u003c/h3\u003e\n\u003cp\u003eDuring the hospital stay, the patient's liver function tests demonstrated a steady improvement. Aspartate aminotransferase (AST) levels decreased to 59 U/L, alanine aminotransferase (ALT) to 92 U/L, and alkaline phosphatase (ALP) to 251 U/L. Total bilirubin levels declined to 16.8 mg/dL, with direct bilirubin at 10.4 mg/dL. These improvements indicated a positive response to the supportive treatment regimen.​\u003c/p\u003e \u003cp\u003eFollowing discharge, the patient was closely monitored through serial liver function tests and imaging studies. Over a three-month period, there was a sustained improvement in hepatic parameters, and her overall clinical condition stabilized. Given the hepatotoxicity associated with crizotinib, a decision was made to transition the patient to an alternative targeted therapy regimen to mitigate the risk of further hepatic injury. She continues to undergo regular oncological and hepatic assessments to monitor her condition and ensure the efficacy and safety of the new treatment approach.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe patient in this case report developed significant hepatotoxicity shortly after initiating crizotinib therapy for ALK-positive non-small cell lung cancer (NSCLC). Prompt recognition of liver dysfunction and immediate discontinuation of crizotinib, coupled with a comprehensive supportive treatment regimen including N-acetylcysteine (NAC), corticosteroids, vitamin K, ursodeoxycholic acid, and rifampicin led to a gradual normalization of liver function tests throughout hospitalization. This favorable outcome underscores the critical importance of early detection and intervention in managing crizotinib-induced liver injury. While crizotinib has demonstrated significant efficacy in treating ALK-positive NSCLC, its potential for hepatotoxicity necessitates vigilant monitoring of liver function, especially during the initial weeks of therapy. This case contributes to the growing body of evidence emphasizing the need for proactive management strategies to mitigate the risks associated with tyrosine kinase inhibitor-induced hepatotoxicity.​\u003c/p\u003e \u003cp\u003eCrizotinib is widely recognized for its efficacy in treating ALK-positive NSCLC; however, its hepatic side effects necessitate cautious usage [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Drug-induced liver injury (DILI) due to crizotinib can present within weeks of treatment initiation and ranges from asymptomatic enzyme elevations to fulminant liver failure [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The case presented here underscores the rapidity with which hepatic complications may develop and the critical importance of early intervention. Studies have demonstrated that early administration of agents such as N-acetylcysteine can mitigate the progression of liver injury by restoring hepatic glutathione levels and reducing oxidative stress [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Moreover, corticosteroids have been used to dampen the inflammatory cascade in severe DILI cases, although the evidence remains mixed regarding their efficacy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere is growing literature supporting close monitoring of liver enzymes in patients receiving tyrosine kinase inhibitors, and our case adds to the body of evidence emphasizing the need for a proactive monitoring strategy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRisk factors for developing crizotinib-induced hepatotoxicity include preexisting liver conditions, high body mass index, and potential drug-drug interactions [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Importantly, the decision to reintroduce crizotinib or switch to an alternative therapy must be individualized based on the severity of liver injury and the overall clinical scenario. Future research is needed to develop predictive biomarkers for hepatotoxicity and to refine dosing strategies that minimize the risk of liver injury while maintaining oncologic efficacy.\u003c/p\u003e \u003cp\u003eClinicians should also consider supportive therapies early in the course of DILI. A study highlighted that early intervention, particularly with NAC and corticosteroids was associated with improved outcomes and reduced mortality rates in patients with DILI from targeted agents [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Similarly, additional studies suggest that ursodeoxycholic acid may provide hepatoprotective effects in cholestatic liver injury scenarios [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In addition, as a novel ALK inhibitor, ceritinib could be also used as an alternative agent when crizotinib causes hepatitis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Moreover, long-term follow-up and multidisciplinary collaboration between oncologists, hepatologists, and pharmacists are crucial in managing these complex cases. Our patient\u0026rsquo;s recovery and subsequent stabilization exemplify the benefits of integrated care and prompt therapeutic interventions in mitigating life-threatening hepatic complications.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights the significant risk of hepatotoxicity associated with crizotinib in the treatment of metastatic lung adenocarcinoma. Early recognition, immediate supportive care, and regular monitoring of liver enzymes are essential to mitigate liver damage and improve patient outcomes. Transitioning to alternative targeted therapies may be warranted in cases of severe liver injury. Additional research is needed to better understand the incidence, risk factors, and mechanisms underlying crizotinib-induced liver failure to inform future clinical guidelines.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe other authors declare no conflict of interest for this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was a waiver study; however, it was approved by the Ethics Committee of Kerman University of Medical Sciences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient to be included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWritten Consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.SH designed the study. S.KH collected the data. S.KH and SM.KH analyzed the results. SM.KH. wrote and reviewed the manuscript. All authors contributed to reviewing the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHendriks LE, Remon J, Faivre-Finn C, et al (2024) Non-small-cell lung cancer. Nature Rev Dis Primers 10(1):71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKreitman K, Nair SP, \u0026amp; Kothadia JP, et al (2022) Successful Treatment of Crizotinib-Induced Fulminant Liver Failure: A Case Report and Review of Literature. Case Reports in Hepatol 2020(1):8247960.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimone II CB, \u0026amp; Jones JA, et al (2013) Palliative care for patients with locally advanced and metastatic non-small cell lung cancer. Ann palliative med 2(4):17888\u0026ndash;17188.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG\u0026aacute;lffy G, Mor\u0026oacute;cz \u0026Eacute;, Korompay R (2024). Targeted therapeutic options in early and metastatic NSCLC-overview. Pathol Oncol Res 30:1611715.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOu SHI (2011) Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Des Devel Ther 471\u0026ndash;485.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Xu YY, Chen Y, et al, (2019) Crizotinib-induced acute fatal liver failure in an Asian ALK-positive lung adenocarcinoma patient with liver metastasis: a case report. World J Clin Cases 7(9):1080.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFood and Drug Administration. Prescribing information Xalkori\u0026reg;(crizotinib). Food and Drug Administration, Silver Spring, MD, USA. 2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuarte FA, Rodrigues LB, Paes FR, et al (2021) Successful treatment with alectinib after crizotinib-induced hepatitis in ALK-rearranged advanced lung cancer patient: a case report. BMC Pul Med 21:1\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrampton JE (2013) Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced non-small cell lung cancer. Drugs 73(18):2031\u0026ndash;2051.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang H, Jin Y, Yan H, et al (2021) Hepatotoxicity of FDA-approved small molecule kinase inhibitors. Expert Opinion on Drug Safety 20(3):335\u0026ndash;348.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Andrade KQ, Moura FA, Dos Santos JM, et al (2015) Oxidative stress and inflammation in hepatic diseases: therapeutic possibilities of N-acetylcysteine. Int J mol sci 16(12):30269\u0026ndash;30308.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBj\u0026ouml;rnsson ES, Vucic V, Stirnimann G, et al (2020) Role of corticosteroids in drug-induced liver injury. A systematic review. Front Pharmacol 13:820724.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXin S, Fang W, Li J, et al (2021) Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients. J cancer res and clin oncol 147:725\u0026ndash;737.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJung D, Han JM, Yee J, et al (2018) Factors affecting crizotinib-induced hepatotoxicity in non-small cell lung cancer patients. Med Oncol 35:1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStine JG, \u0026amp; Lewis JH (2016) Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. Expert rev gastroenterol Hepatol 10(4):517\u0026ndash;536.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBessone F, Hillotte GL, Tamagnone N, et al (2025) Ursodeoxycholic Acid for the Management of Drug-induced Liver Injury: Role of Hepatoprotective and Anti-cholestatic Mechanisms. J Clin Translation Hepatol 13(2):162.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSassier M, Mennecier B, Gschwend A, et al (2016) Successful treatment with ceritinib after crizotinib induced hepatitis. Lung Cancer 95:15\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Crizotinib, Acute liver failure, Hepatotoxicity, N-acetylcysteine","lastPublishedDoi":"10.21203/rs.3.rs-6654785/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6654785/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction\u003c/h2\u003e \u003cp\u003eMetastatic lung adenocarcinoma patients treated with crizotinib may rarely develop severe adverse effects, including acute liver failure. Early recognition and management of drug-induced liver injury are crucial for patient outcomes.\u003c/p\u003e\u003ch2\u003eCase Presentation\u003c/h2\u003e \u003cp\u003eWe report a 52-year-old female diagnosed with metastatic lung adenocarcinoma who developed acute liver failure during crizotinib therapy. After starting the second cycle, she presented with weakness, anorexia, and jaundice. Comprehensive clinical evaluation and laboratory tests confirmed drug-induced liver injury. The patient received supportive treatment, including intravenous N-acetylcysteine, dexamethasone, vitamin K, ursodeoxycholic acid, and rifampicin. Liver function tests and bilirubin levels were closely monitored.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe patient\u0026rsquo;s liver enzymes and bilirubin levels gradually normalized with appropriate supportive care. This case highlights the importance of vigilant hepatic monitoring during crizotinib treatment to promptly identify and manage potential hepatotoxicity.\u003c/p\u003e","manuscriptTitle":"Case Report: Successful Reversal of Crizotinib-Induced Acute Liver Failure in Metastatic Lung Adenocarcinoma Using a Multi-Agent Therapeutic Approach","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-07 04:20:30","doi":"10.21203/rs.3.rs-6654785/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"36cdbc2c-d3ab-4c72-b00a-6ff9200def38","owner":[],"postedDate":"June 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-25T04:40:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-07 04:20:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6654785","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6654785","identity":"rs-6654785","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}