Drug-Induced Hepatic Injury in Newborns and Children in Intensive Care Unit: A Retrospective Study of China

Abstract Purpose Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China. Methods Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). We also collated drug combinations that may affect CYP enzyme metabolism, which may be one of the mechanisms that lead to DILI. Results A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while children’s hepatic injury types were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the assessment by the RUCAM, in newborns, the drugs that were most considered to cause or associated with hepatic injury comprised medium and long chain fat emulsion (17%), sodium glycerophosphate (12%) and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%) and meropenem (8%) are the primary culprit of DILI in children. Drug combinations that may affect CYP enzyme metabolism frequently seen in neonates are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%) and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%) and diazepam + omeprazole (15.3%). Conclusions The drugs that have been found to have hepatotoxicity (meropenem, medium and long chain fat emulsion, ibuprofen.etc.) are also related to DILI in newborns and children. When giving these drugs to newborns and children, physicians need to be more cautious. Also, pay attention to the effect on CYP 450 enzymes when using multiple drugs at the same time.

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Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method

Frontiers in Pharmacology ◽

10.3389/fphar.2021.790108 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ling Ye ◽

Zeying Feng ◽

Longjian Huang ◽

Chengjun Guo ◽

Xiong Wu ◽

...

Keyword(s):

Liver Injury ◽

Hepatic Injury ◽

Causality Assessment ◽

Sodium Succinate ◽

Assessment Method ◽

Drug Combinations ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Methylprednisolone Sodium Succinate ◽

Enzyme Metabolism

Purpose: Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China.Methods: Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). At the same time, we also collated drug combinations that may affect CYP (Cytochrome P) enzyme metabolism, which may cause DILI.Results: A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while the hepatic injury types of children were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the RUCAM assessment, the drugs that were most considered to cause or be associated with hepatic injury in newborns were medium and long chain fat emulsions (17%), sodium glycerophosphate (12%), and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%), and meropenem (8%) were the primary culprits of DILI in children. Drug combinations frequently seen in neonates that may affect CYP enzyme metabolism are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%), and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%), and diazepam + omeprazole (15.3%).Conclusions: In this study, medium and long chain fat emulsions and sodium glycerophosphate have been strongly associated with DILI in newborns, while omeprazole and methylprednisolone sodium succinate play an important role in the DILI of children. Also, attention should be paid to the effect on CYP enzymes when using multiple drugs at the same time. In future DILI cases, it is advisable to use the latest RUCAM for prospective study design so that complete case data and high RUCAM scores can be collected.

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STANDARDIZATION OF MODEL OF INDUCTION OF HEPATOTOXICITY WITH ANTI-TUBERCULOSIS DRUGS IN WISTAR ALBINO RATS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i6.11971 ◽

2017 ◽

Vol 10 (6) ◽

pp. 150

Author(s):

Sarita M Kapgate ◽

Abhijit B Patil

Keyword(s):

Liver Injury ◽

Animal Studies ◽

Hepatic Injury ◽

Albino Rats ◽

Histopathological Changes ◽

First Line ◽

Drug Induced ◽

Significant Development ◽

Reported Study ◽

Wistar Albino Rats

Objective: The objective of the study to standardize the model of hepatotoxicity induced by ATT drugs in Wistar Albino rats. Isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), the first line drugs used in the treatment of tuberculosis (TB) associated with the potential adverse effect. Numerous animal studies were reported endeavoring induction and cure of anti-TB (ATT) drug-induced hepatotoxicity using herbal and chemical drugs. However, the previous reported study failed to replicate where Wistar albino rats were treated with INH, RMP, and PZA and had shown the significant development of liver injury. Hence in present paper, aimed to develop a standardize model of induction of hepatotoxicity with ATT drugs.Methods: Wistar rats were treated with ATT drugs in combination in various doses up to 4-8 weeks. Total nine experiments were conducted to achieve successful hepatotoxicity. The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were the biochemical parameters of assessment. Histopathological changes in the liver were also examined.Results: No evidence of any liver injury or an inflammatory infiltrate has been observed as had been reported in the previous studies. Rather decrease in serum ALT levels has been observed by researcher. In short, hepatic injury cannot be developed with the doses used in previous reported papers. The successful attempt to induce hepatotoxicity can be achieved with the doses of INH - 100, RMP - 300, PZA - 700 mg/kg. The findings were confirmed by the raised ALT, AST, and ALP levels compared with baseline. The histopathological changes also support the findings.Conclusion: The dose of INH - 100, RMP – 300 and PZM - 700 mg/kg. Succeeds to induce hepatotoxicity in Wistar albino rats and Swiss albino mice as well.

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Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib

Case Reports in Oncological Medicine ◽

10.1155/2019/3051945 ◽

2019 ◽

Vol 2019 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Nicholas Gravbrot ◽

Srinath Sundararajan

Keyword(s):

Liver Injury ◽

Liver Function ◽

Combination Therapy ◽

Hepatic Injury ◽

Mek Inhibitor ◽

New Combination ◽

Normal Range ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

First Case

Encorafenib/binimetinib is a new combination BRAF/MEK inhibitor used in the treatment of advanced or metastatic BRAFV600-mutant melanoma. Though generally tolerated well, mild to moderate aminotransferase elevations are common. However, significant liver injury has not been demonstrated in the literature. Here, we report the first case of severe hepatic injury associated with encorafenib/binimetinib in a 58-year-old gentleman requiring admission and extensive workup. He was successfully treated by withdrawing the combination therapy, and liver function returned to normal range.

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Ascites management by cell-free concentrated ascites reinfusion therapy during recovery from drug-induced acute liver injury: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-020-02507-5 ◽

2020 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

Koya Yasuda ◽

Mea Asou ◽

Tomohiko Asakawa ◽

Makoto Araki

Keyword(s):

Liver Injury ◽

Liver Regeneration ◽

Hepatic Injury ◽

Acute Liver Injury ◽

Artery Bypass ◽

Severe Disease ◽

International Normalized Ratio ◽

Cardiac Complications ◽

Massive Ascites ◽

Drug Induced

Abstract Background The symptoms of drug-induced hepatic injury are manifold; however, the presence of ascites indicates a severe disease condition. The rapid accumulation of ascites is distressing and requires palliative treatment. Because many cases are addressed by repeated large-volume paracentesis, often resulting in impairment due to protein and electrolyte loss, a different approach is required. Case presentation A 61-year-old Japanese man on maintenance dialysis was admitted to our hospital with acute liver injury. Our patient was diagnosed as having drug-induced liver injury due to warfarin or diltiazem, which started immediately after coronary artery bypass grafting 7 months previously. One month after admission, our patient’s hepatic encephalopathy remained grade 1 and his prothrombin time international normalized ratio was maintained at < 1.5. However, the liver was markedly atrophied with massive ascites. Although liver transplantation was desired, he was considered unfit for transplantation because of his renal and cardiac complications. Therefore, we devised a strategy to manage the massive ascites with cell-free concentrated ascites reinfusion therapy while awaiting liver regeneration. At first, cell-free concentrated ascites reinfusion therapy was required frequently because ascites accumulated rapidly. But the fluid retention interval was gradually extended as intended, and cell-free concentrated ascites reinfusion therapy was withdrawn after 8 months. During that time, the size of his liver increased from 1419 cm3 to 1587 cm3 on computed tomography. Conclusions Cell-free concentrated ascites reinfusion therapy is an apheresis therapy in which ascites are collected aseptically by paracentesis, concentrated, and then reinfused intravenously. This treatment has the advantage of preserving nutrition by reusing the fluid. Previously, cell-free concentrated ascites reinfusion therapy was used only for the management of ascites in patients with cirrhosis or carcinomatous peritonitis. This case suggests that palliation and maintenance of nutritional status with cell-free concentrated ascites reinfusion therapy may be useful as an adjunct to liver regeneration in drug-induced hepatic injury.

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Drug-Drug Combinations Can Enhance Toxicity as Shown by Monocyte-Derived Hepatocyte-like Cells From Patients With Idiosyncratic Drug-Induced Liver Injury

Toxicological Sciences ◽

10.1093/toxsci/kfz156 ◽

2019 ◽

Vol 171 (2) ◽

pp. 296-302 ◽

Cited By ~ 2

Author(s):

Andreas Benesic ◽

Kowcee Jalal ◽

Alexander L Gerbes

Keyword(s):

Liver Injury ◽

Liver Failure ◽

Drug Interactions ◽

Acute Liver Failure ◽

Causality Assessment ◽

Drug Combinations ◽

Positive Interactions ◽

In Vitro Test ◽

Drug Induced ◽

Drug Induced Liver Injury

Abstract Drug-induced liver injury (DILI) is a major cause for acute liver failure and regulatory actions on novel drugs. Individual patient characteristics are the main determinant of idiosyncratic DILI, making idiosyncratic DILI (iDILI) one of the most challenging diagnoses in hepatology. Individual drug-drug interactions might play a role in iDILI. However, the current approaches to iDILI diagnosis are focused on single drugs as causative agents. For the present analysis, 48 patients with acute liver injury who took 2 drugs and who were diagnosed as iDILI were investigated. A novel in vitro test was employed using monocyte-derived hepatocyte-like cells (MH cells) generated from these patients. iDILI diagnosis and causality were evaluated using clinical causality assessment supported by Roussel-Uclaf Causality Assessment Method. In 13 of these 48 patients (27%), combinations of drugs increased toxicity in the MH test when compared with the single drugs. Interestingly, whereas in 24 cases (50%) drug-drug combinations did not enhance toxicity, in 11 cases (23%) only the combinations caused toxicity. The incidence of severe cases fulfilling Hy’s law was higher in patients with positive interactions (57% vs 43%; p = .04), with acute liver failure occurring in 40% versus 8% (p = .01). The most common drug combinations causing increased toxicity were amoxicillin/clavulanate (8 of 9 cases) and diclofenac in combination with steroid hormones (4 of 9 cases). Drug-drug interactions may influence the incidence and/or the severity of idiosyncratic DILI. MH cell testing can identify relevant drug-drug interactions. The data generated by this approach may improve patient safety. Study identifier ClinicalTrials.gov NCT 02353455.

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Crocus sativus L. Extract Containing Polyphenols Modulates Oxidative Stress and Inflammatory Response against Anti-Tuberculosis Drugs-Induced Liver Injury

Plants ◽

10.3390/plants9020167 ◽

2020 ◽

Vol 9 (2) ◽

pp. 167 ◽

Cited By ~ 4

Author(s):

Adil Farooq Wali ◽

Jayachithra Ramakrishna Pillai ◽

Yusra Al Dhaheri ◽

Muneeb U. Rehman ◽

Ambreen Shoaib ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Inflammatory Response ◽

Hepatic Injury ◽

Standard Dose ◽

Crocus Sativus ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Response Status ◽

Crocus Sativus L

The purpose of this study is to analyze the polyphenolic rich extract of Crocus sativus L. petals (CSP) in modulating liver oxidative stress and inflammatory response status against rifampicin isoniazid (INH-RIF) drug-induced liver injury. The INH-RIF was administered for 14 days with varying doses in Wistar rats, while silymarin was administered as standard dose. We report the defensive impacts of CSP against INH-RIF induced liver oxidative stress and proinflammatory cytokine. The CSP treatment at both doses significantly controlled all modulating biochemical hepatic injury indicators and resulted in the attenuation of arbitral INH-RIF damage. The components present in CSP identified by LC–ESI-Q-TOF–MS were found to be flavonoids and fatty acids. It can be inferred that CSP possesses a hepatoprotective capacity against INH-RIF-mediated hepatic injury, which may prove to be a medically beneficial natural product for the management of drug-induced liver injury.

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Phenylpropionc acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity

10.1101/811984 ◽

2019 ◽

Author(s):

Sungjoon Cho ◽

Xiaotong Yang ◽

Kyoung-Jae Won ◽

Vanessa Leone ◽

Nathaniel Hubert ◽

...

Keyword(s):

Liver Injury ◽

Gut Microbiota ◽

Hepatic Injury ◽

Gut Bacteria ◽

Toxic Metabolite ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Protein Levels ◽

Cyp 2E1 ◽

Gut Microbe

ABSTRACTAcetaminophen (APAP) overdose causes hepatic injury and is major contributor to acute liver injury cases. To investigate potential roles of gut microbiota in APAP-induced liver injury, C57BL/6 mice from Jackson (JAX) or Taconic (TAC) were challenged with APAP. TAC mice were more susceptible to APAP toxicity, and this disappeared upon co-housing of JAX and TAC mice. When the cecum contents from JAX and TAC mice were transplanted to germ-free mice, the mice that received TAC gut microbiota exhibited more significant hepatotoxicity after APAP administration. Non-targeted metabolomic analysis using portal vein serum and liver tissue of the mice led to identification of 19 metabolites the levels of which are associated with JAX or TAC gut microbiota. A gut bacteria-derived metabolite phenylpropionic acid (PPA) levels in cecum contents and blood were higher in mice harboring JAX gut microbiota. PPA supplementation in drinking water alleviated APAP-induced hepatotoxicity in TAC mice. This was accompanied by reduced hepatic protein levels of cytochrome P450 (CYP) 2E1, the enzyme responsible for APAP bioactivation to a toxic metabolite. This illustrates a gut microbe-liver interaction mediated by a gut bacteria-derived metabolite in modulating drug-induced liver injury.

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Zhuang Gu Guan Jie Wan: Reasonable Application Can Alleviate the Liver Injury for Osteoarthritis Treatment

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6716529 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10

Author(s):

Bin Liu ◽

Danping Fan ◽

Wen Sun ◽

Kang Zheng ◽

Guoming Pang ◽

...

Keyword(s):

Liver Injury ◽

Hepatic Injury ◽

Cruciate Ligament ◽

Therapeutic Effects ◽

Drug Induced ◽

Interleukin 22 ◽

Chinese Patent Medicine ◽

Medial Meniscectomy ◽

Chinese Patent ◽

Patent Medicine

The potential toxicity of herbal drugs, particularly drug-induced liver injury (DILI), has received extensive attention as the use of Chinese herbal medicine has rapidly increased globally. As a classic Chinese patent medicine, Zhuang Gu Guan Jie Wan (ZGGJW) has been brought into focus recently because of its satisfactory therapeutic effects on osteoarthritis (OA) as well as its unanticipated side effects. This study aimed to decipher the puzzling phenomenon of liver injury developing in response to ZGGJW that varies by the subtype of OA. Normal, anterior cruciate ligament transaction (ACLT) and partial medial meniscectomy (MMx) induced OA and ovariectomy combined with ACLT and partial MMx induced rat models were used and treated orally with ZGGJW or distilled water for 30 days. The results from histopathology, biochemistry, and immunohistochemistry showed that ZGGJW induced liver injury, increased the level of malondialdehyde (MDA), and decreased the levels of total antioxidation capability (T-AOC), superoxide dismutase (SOD), interleukin-22 (IL-22), and signal transducer and activator of transcription factor 3 (STAT3) in the liver of normal rats, while liver injury was alleviated and showed different tendencies in the above markers for ACLT and partial MMx induction rats and ovariectomy combined with ACLT and partial MMx induction rats after ZGGJW treatment. In the OA disease states, hepatic injury induced by ZGGJW could be associated with an impairment in antioxidant capacity and the high levels of IL-22 and STAT3 after ZGGJW treatment may be responsible for the slight hepatic injury of ZGGJW based on the subtype of OA. This study provides a novel approach to better understanding of the risks and limitations when using potentially toxic Chinese patent medicine in clinical applications.

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A Severe Case of Drug-Induced Liver Injury after Gemcitabine Administration: A Highly Probable Causality Grading as Assessed by the Updated RUCAM Diagnostic Scoring System

Case Reports in Hepatology ◽

10.1155/2020/8812983 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Ilenia Mascherona ◽

Caterina Maggioli ◽

Maira Biggiogero ◽

Oreste Mora ◽

Lucia Marelli

Keyword(s):

Liver Injury ◽

Hepatic Injury ◽

Clinical Presentation ◽

Acute Liver Injury ◽

Severe Case ◽

Suspected Drug ◽

Serum Enzyme ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Clinically Significant

Gemcitabine is an antineoplastic drug used in several forms of advanced pancreatic, lung, breast, ovarian, and bladder cancer. Common side effects include bone marrow suppression, fatigue, diarrhea, nausea, gastrointestinal upset, rash, alopecia, and stomatitis. Transient serum enzyme elevations could be observed during therapy, but clinically significant acute liver injury has been rarely associated with its use. Few cases of acute liver injury have been reported in the literature. We reported the clinical case of a 73--year-old man who developed clinically significant acute hepatic injury after using gemcitabine. Possible causes, clinical presentation, and treatments are discussed. According to the updated RUCAM score, the case was rated 10 points and became a suspected drug-induced liver injury. Moreover, on the liver biopsy, there were histological findings of mild-to-moderate portal hepatitis, eosinophilia, bile duct injury, and mild perisinusoidal fibrosis, suggesting drug damage.

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Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3320325 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yonela Ntamo ◽

Khanyisani Ziqubu ◽

Nireshni Chellan ◽

Bongani B. Nkambule ◽

Tawanda M. Nyambuya ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Hepatic Injury ◽

Clinical Evidence ◽

Antioxidant Properties ◽

Pathological Feature ◽

Protective Effects ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Acetyl Cysteine

Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.

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