Risks of Antithyroid Drug-Induced Severe Liver Injury

Abstract Background Zanubrutinib is a Bruton’s tyrosine kinase inhibitor that has been recently licensed in refractory mantle cell lymphoma and under assessment in phase 3 clinical trials for other B cell malignancies. To date, there are no reported cases of hepatotoxicity secondary to zanubrutinib. We report the first case of severe liver injury due to zanubrutinib. Case presentation A 56-year-old Caucasian male with a history of relapsed lymphoplasmacytic lymphoma was admitted to the hospital with new-onset jaundice, choluria, and pruritus for 10 days. He had been on zanubrutinib as part of a clinical trial for 30 months. His blood profile showed a severe hepatocellular injury with jaundice (alanine transaminase 2474 IU/L and total bilirubin 141 umol/L with mild coagulopathy). He had an extensive work-up including virology, autoimmune, and metabolic profiles in addition to abdominal ultrasound with no alternative explanation found for his liver injury. Zanubrutinib-induced liver injury was suspected, and causality assessment by the updated Roussel Uclaf Causality Assessment Method score showed a probable causal relationship with zanubrutinib. His liver histology was also consistent with drug-induced liver injury. His liver biochemistry improved following cessation of zanubrutinib and normalised after 8 weeks. Conclusion We report the first case of severe liver injury secondary to zanubrutinib after 30 months of treatment. This case raises clinical awareness regarding zanubrutinib-induced liver toxicity and the importance of drug withdrawal in the event of liver injury.

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A case of drug-induced toxic epidermal necrolysis complicated with severe liver injury.

Kanzo ◽

10.2957/kanzo.29.949 ◽

1988 ◽

Vol 29 (7) ◽

pp. 949-955 ◽

Cited By ~ 3

Author(s):

Kazuhiro MATSUEDA ◽

Yoshiko MATSUOKA ◽

Motowo MIZUNO ◽

Toshihiro HIGASHI ◽

Minoru UKIDA ◽

...

Keyword(s):

Liver Injury ◽

Toxic Epidermal Necrolysis ◽

Severe Liver ◽

Drug Induced

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Drug-Induced Liver Injury: A Unique Presentation of Single-Dose Administration of Propylthiouracil

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/2324709620951323 ◽

2020 ◽

Vol 8 ◽

pp. 232470962095132

Author(s):

Simcha Weissman ◽

Nishan G. Rajaratnam ◽

Nabeel Qureshi ◽

Faisal Inayat ◽

Sameh Elias

Keyword(s):

Single Dose ◽

Liver Injury ◽

Liver Enzymes ◽

Antithyroid Drug ◽

Thyroid Storm ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Elevated Liver Enzymes ◽

Pharmacologic Agents

Antithyroid drug-induced severe liver injury is an uncommon but serious complication. We hereby delineate the case of a 38-year-old female who presented to the emergency department for an impending thyroid storm. After initiation of a single dose of propylthiouracil, her liver enzymes went into the thousands. She was subsequently admitted to the intensive care unit. Propylthiouracil was discontinued and corticosteroids were initiated with the resolution of her elevated liver enzymes. On follow-up, her liver function was at its baseline and thyroid hormone levels were under control. We hope this report will encourage clinicians to cast a broad differential diagnosis in patients presenting with liver injury in the acute setting. Furthermore, it is imperative to raise awareness regarding the ever-increasing list of pharmacologic agents that can perpetuate drug-induced hepatotoxicity.

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The cross-talk of NLRP3 inflammasome activation and necroptotic hepatocyte death in acetaminophen-induced mice acute liver injury

Human & Experimental Toxicology ◽

10.1177/0960327120961158 ◽

2020 ◽

pp. 096032712096115

Author(s):

L Li ◽

S Shan ◽

K Kang ◽

C Zhang ◽

R Kou ◽

...

Keyword(s):

Liver Injury ◽

Cross Talk ◽

Nlrp3 Inflammasome ◽

Time Course ◽

Critical Role ◽

Inflammasome Activation ◽

Severe Liver ◽

Drug Induced ◽

The Cross ◽

Apap Hepatotoxicity

Overdose acetaminophen (APAP) can result in severe liver injury, which is responsible for nearly half of drug-induced liver injury in western countries. Previous studies have found that there existed massive hepatocellular necrosis and severe inflammatory response in APAP-induced liver injury. However, the mechanistic linkage between necroptosis and NLRP3 inflammasome pathway in APAP-induced hepatotoxicity remains poorly understood. In order to investigate the relationship between inflammation and hepatocytes death in APAP hepatotoxicity, a time-course model for APAP hepatotoxicity in C57/BL6 mice was established by intraperitoneal (i.p) injection of 300 mg/kg APAP in this study. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in necroptosis and NF-κB-NLRP3 inflammasome signaling pathway were determined by immunoblot and immunofluorescence analysis. The results demonstrated that APAP overdose resulted in a severe liver injury. Furthermore, the expression of critical molecules in NLRP3 inflammasome and necroptosis pathways peaked at 12–24 h, and then was decreased gradually, which is consistent with the pattern of pathological injury induced by APAP. Our further investigation found that the level of IL-1β in mouse liver was closely correlated with the level of phosphorylated MLKL following exposure to APAP. Furthermore, inhibition of necroptosis with necrostatin-1 significantly suppressed the activation of NLRP3 inflammasome signaling. Taken together, our results highlighted that the cross-talk between necroptosis and NLRP3 inflammasome played a critical role for promoting APAP-induced liver injury. Inhibition of the interaction of inflammation and necroptosis by pharmaceutical methods may represent a promising therapeutic strategy for APAP-induced liver injury.

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Meropenem-induced liver injury and beta-lactam cross-reactivity

BMJ Case Reports ◽

10.1136/bcr-2018-227124 ◽

2018 ◽

Vol 11 (1) ◽

pp. e227124 ◽

Cited By ~ 4

Author(s):

Timothy Tattersall ◽

Hugh Wright ◽

Andrew Redmond

Keyword(s):

Liver Injury ◽

Liver Enzymes ◽

Early Recognition ◽

Cross Reactivity ◽

Beta Lactam ◽

Severe Liver ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Rehabilitation Facility ◽

Elevated Liver Enzymes

A 63-year-old man admitted to hospital for the management of a frontal lobe abscess developed elevated liver enzymes within 48 hours of receiving meropenem. Liver enzymes reached a maximum at 5 days postadministration of meropenem, with alanine aminotransferase 1160 U/L, aspartate aminotransferase 787 U/L, alkaline phosphatase 297 U/L and gamma-glutamyltransferase 252 U/L. Meropenem was ceased and liver function normalised. Meropenem was administered for a second time later in the patient’s admission and again the patient developed rapidly increasing liver enzymes, with a mixed hepatocellular/cholestatic pattern. Other possible causes of liver injury were excluded following extensive investigations, and the patient’s liver enzymes continued to normalise following meropenem discontinuation. The patient was asymptomatic during the admission and was transferred to a rehabilitation facility. This case demonstrates that meropenem can cause severe liver injury and that early recognition of drug-induced liver injury is important.

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Acetaminophen: Dose-Dependent Drug Hepatotoxicity and Acute Liver Failure in Patients

Digestive Diseases ◽

10.1159/000374090 ◽

2015 ◽

Vol 33 (4) ◽

pp. 464-471 ◽

Cited By ~ 82

Author(s):

Hartmut Jaeschke

Keyword(s):

Cell Death ◽

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Severe Liver ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Apap Overdose ◽

Therapeutic Doses ◽

Dose Dependent

Background: Drug-induced liver injury is a rare but serious clinical problem. A number of drugs can cause severe liver injury and acute liver failure at therapeutic doses in a very limited number of patients (<1:10,000). This idiosyncratic drug-induced liver injury, which is currently not predictable in preclinical safety studies, appears to depend on individual susceptibility and the inability to adapt to the cellular stress caused by a particular drug. In striking contrast to idiosyncratic drug-induced liver injury, drugs with dose-dependent hepatotoxicity are mostly detected during preclinical studies and do not reach the market. One notable exception is acetaminophen (APAP, paracetamol), which is a safe drug at therapeutic doses but can cause severe liver injury and acute liver failure after intentional and unintentional overdoses. Key Messages: APAP overdose is responsible for more acute liver failure cases in the USA or UK than all other etiologies combined. Since APAP overdose in the mouse represents a model for the human pathophysiology, substantial progress has been made during the last decade in understanding the mechanisms of cell death, liver injury and recovery. More recently, emerging evidence based on mechanistic biomarker analysis in patients and studies of cell death in human hepatocytes suggests that most of the mechanisms discovered in mice also apply to patients. The rapid development of N-acetylcysteine as an antidote against APAP overdose was based on the early understanding of APAP toxicity in mice. However, despite the efficacy of N-acetylcysteine in patients who present early after APAP overdose, there is a need to develop intervention strategies for late-presenting patients. Conclusions: The challenges related to APAP toxicity are to better understand the mechanisms of cell death in order to limit liver injury and prevent acute liver failure, and also to develop biomarkers that better predict as early as possible who is at risk for developing acute liver failure with poor outcome.

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Leberschaden unter oraler Antikoagulation, Statin- und ACE-Hemmertherapie

Praxis ◽

10.1024/1661-8157/a000298 ◽

2010 ◽

Vol 99 (21) ◽

pp. 1259-1265 ◽

Cited By ~ 2

Author(s):

Bruggisser ◽

Terraciano ◽

Rätz Bravo ◽

Haschke

Keyword(s):

Liver Injury ◽

Wird Eine ◽

Drug Induced ◽

Drug Induced Liver Injury

Ein 71-jähriger Patient stellt sich mit Epistaxis und ikterischen Skleren auf der Notfallstation vor. Der Patient steht unter einer Therapie mit Phenprocoumon, Atorvastatin und Perindopril. Anamnestisch besteht ein langjähriger Alkoholabusus. Laborchemisch werden massiv erhöhte Leberwerte (ALAT, Bilirubin) gesehen. Der INR ist unter oraler Antikoagulation und bei akuter Leberinsuffizienz >12. Die weiterführenden Abklärungen schliessen eine Virushepatitis und eine Autoimmunhepatitis aus. Nachdem eine Leberbiopsie durchgeführt werden kann, wird eine medikamentös-toxische Hepatitis, ausgelöst durch die Komedikation von Atorvastatin, Phenprocoumon und Perindopril bei durch Alkohol bereits vorgeschädigter Leber diagnostiziert. Epidemiologie, Pathophysiologie und Klink der medikamentös induzierten Leberschäden (drug induced liver injury, DILI), speziell von Coumarinen, Statinen und ACE-Hemmern werden im Anschluss an den Fallbericht diskutiert.

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Drug-induced liver injury network (DILIN)

Hepatology ◽

10.1002/hep.20445 ◽

2004 ◽

Vol 40 (4) ◽

pp. 773-773 ◽

Cited By ~ 63

Author(s):

Jay H. Hoofnagle

Keyword(s):

Liver Injury ◽

Drug Induced ◽

Drug Induced Liver Injury

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