|
1
|
Lee WM, Barnard C, Rule JA, Orandi BJ, James LP, Stravitz RT, Durkalski V, Fontana RJ. Association of Acetaminophen (Paracetamol) Use With Severity and Outcomes in Patients With Viral Hepatitis-Associated Acute Liver Failure. Am J Gastroenterol 2025; 120:584-592. [PMID: 38994834 PMCID: PMC11724933 DOI: 10.14309/ajg.0000000000002941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 06/17/2024] [Indexed: 07/13/2024]
Abstract
INTRODUCTION Acute viral hepatitis (AVH) comprises 11% of acute liver failure (ALF) in North America while acetaminophen (APAP) toxicity represents 46%. The use of APAP to treat prodromal hepatitis symptoms is common. It is unknown if concurrent APAP use impacts liver injury in AVH-induced ALF. METHODS In this prospective, multicenter cohort study, 356 patients meeting criteria for AVH including hepatitis A, B, Epstein-Barr virus, and herpes simplex virus, all leading to ALF (hepatic encephalopathy after acute illness, international normalized ratio ≥1.5), or acute liver injury (acute liver injury, international normalized ratio >2.0, no hepatic encephalopathy) were reviewed for evidence of APAP use: APAP ingestion history or measurement of serum APAP level or APAP-CYS adducts, a specific biomarker released into blood with APAP injury. Patients were grouped by APAP exposure level, from high (measurable APAP levels or toxic APAP-CYS), medium (therapeutic APAP-CYS), low (history of APAP ingestion only and/or barely detectable APAP-CYS), or no exposure recorded. RESULTS Two hundred five of 356 patients (57.5%) with AVH-ALF had evidence of APAP use: 87 out of 356 (24%) demonstrated high or medium exposures. The aminotransferase and bilirubin levels of high/medium group resembled a mixed APAP-viral injury. Mortality was the highest (51.6%, 21.4%, 28.8%, and 30.5%), and transplant-free survival was the lowest (22.6%, 44.6%, 41.5%, and 40.4%) in the high exposure group compared with medium, low, and no exposure groups. However, the specific comparisons of mortality and transplant-free survival between the high exposure and no exposure groups were not statistically different even after adjusting for baseline patient characteristics differences. DISCUSSION APAP use in AVH-ALF is common and may negatively impact outcomes compared with little or no APAP exposure. Prospective studies of the safest and effective dose of APAP to use in patients with AVH are needed.
Collapse
Affiliation(s)
- William M. Lee
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX
| | - Carson Barnard
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX
| | - Jody A. Rule
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX
| | - Babak J. Orandi
- Departments of Surgery and Medicine, New York University, New York, NY
| | - Laura P. James
- Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, Little Rock, AR
| | - R. Todd Stravitz
- Section of Hepatology, Virginia Commonwealth University, Richmond, VA
| | - Valerie Durkalski
- Department of Public Health, Medical University of South Carolina, Charleston, SC
| | - Robert J. Fontana
- Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI
| | | |
Collapse
|
|
2
|
Li T, Li J, Jiang H, Skiles DB. Deep Learning Prediction of Drug-Induced Liver Toxicity by Manifold Embedding of Quantum Information of Drug Molecules. Pharm Res 2025; 42:109-122. [PMID: 39663331 DOI: 10.1007/s11095-024-03800-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 11/22/2024] [Indexed: 12/13/2024]
Abstract
PURPOSE Drug-induced liver injury, or DILI, affects numerous patients and also presents significant challenges in drug development. It has been attempted to predict DILI of a chemical by in silico approaches, including data-driven machine learning models. Herein, we report a recent DILI deep-learning effort that utilized our molecular representation concept by manifold embedding electronic attributes on a molecular surface. METHODS Local electronic attributes on a molecular surface were mapped to a lower-dimensional embedding of the surface manifold. Such an embedding was featurized in a matrix form and used in a deep-learning model as molecular input. The model was trained by a well-curated dataset and tested through cross-validations. RESULTS Our DILI prediction yielded superior results to the literature-reported efforts, suggesting that manifold embedding of electronic quantities on a molecular surface enables machine learning of molecular properties, including DILI. CONCLUSIONS The concept encodes the quantum information of a molecule that governs intermolecular interactions, potentially facilitating the deep-learning model development and training.
Collapse
Affiliation(s)
- Tonglei Li
- Department of Industrial & Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
| | - Jiaqing Li
- Department of Industrial & Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA
| | - Hongyi Jiang
- Department of Industrial & Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA
| | - David B Skiles
- Department of Industrial & Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA
| |
Collapse
|
|
3
|
Rule JA, Ajayi F, James LP, Tujios SR, Sussman NL, Rakela JL, Ganger D, Bass NL, Reuben A, Stravitz RT, Lee WM. Differentiating Ischemic Hepatitis from Acetaminophen Overdose in Acute Liver Failure: Role of Acetaminophen Adducts-Ischemic Hepatitis vs Acetaminophen Overdose. Dig Dis Sci 2024; 69:3952-3961. [PMID: 39222204 DOI: 10.1007/s10620-024-08602-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND AND AIMS Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis. METHODS Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication. RESULTS With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role. CONCLUSIONS Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases.
Collapse
Affiliation(s)
- Jody A Rule
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, USA
| | - Faith Ajayi
- Department of Internal Medicine UT Southwestern Medical Center, Dallas, TX, USA
| | - Laura P James
- Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Shannan R Tujios
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, USA
| | - Norman L Sussman
- Baylor College of Medicine, Houston, TX, USA
- Durect, Inc., Cupertino, CA, USA
| | - Jorge L Rakela
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Phoenix, AZ, USA
| | - Daniel Ganger
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Norman L Bass
- Department of Medicine, UCSF San Francisco, San Francisco, CA, USA
| | - Adrian Reuben
- Medical University of South Carolina, Charleston, SC, USA
| | - R Todd Stravitz
- Section of Hepatology, Virginia Commonwealth University, Richmond, VA, USA
| | - William M Lee
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, USA.
| |
Collapse
|
|
4
|
Zhu L, Yang X, Wu S, Dong R, Yan Y, Lin N, Zhang B, Tan B. Hepatotoxicity of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs). Drug Metab Rev 2024; 56:302-317. [PMID: 39120430 DOI: 10.1080/03602532.2024.2388203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024]
Abstract
Drug-induced liver injury (DILI) is one of the most frequently adverse reactions in clinical drug use, usually caused by drugs or herbal compounds. Compared with other populations, cancer patients are more prone to abnormal liver function due to primary or secondary liver malignant tumor, radiation-induced liver injury and other reasons, making potential adverse reactions from liver damage caused by anticancer drugs of particular concernduring clinical treatment process. In recent years, the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has changed the treatment status of a series of solid malignant tumors. Unfortunately, the increasing incidence of hepatotoxicitylimits the clinical application of EGFR-TKIs. The mechanisms of liver injury caused by EGFR-TKIs were complex. Despite more than a decade of research, other than direct damage to hepatocytes caused by inhibition of cellular DNA synthesis and resulting in hepatocyte necrosis, the rest of the specific mechanisms remain unclear, and few effective solutions are available. This review focuses on the clinical feature, incidence rates and the recent advances on the discovery of mechanism of hepatotoxicity in EGFR-TKIs, as well as rechallenge and therapeutic strategies underlying hepatotoxicity of EGFR-TKIs.
Collapse
Affiliation(s)
- Lulin Zhu
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Xinxin Yang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shanshan Wu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rong Dong
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Youyou Yan
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Nengming Lin
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Bo Zhang
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Biqin Tan
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| |
Collapse
|
|
5
|
Stravitz RT, Fontana RJ, Karvellas C, Durkalski V, McGuire B, Rule JA, Tujios S, Lee WM. Future directions in acute liver failure. Hepatology 2023; 78:1266-1289. [PMID: 37183883 PMCID: PMC10521792 DOI: 10.1097/hep.0000000000000458] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/20/2023] [Indexed: 05/16/2023]
Abstract
Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (ie, an international normalized ratio of prothrombin time of ≥1.5) and any degree of mental status alteration (HE). As a rare, orphan disease, it seemed an obvious target for a multicenter network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3364 adult patients were enrolled in the study registry (2614 ALF and 857 acute liver injury-international normalized ratio 2.0 but no encephalopathy-ALI) and >150,000 biosamples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, 4 prospective substudies were conducted and published, 2 interventional ( N -acetylcysteine and ornithine phenylacetate), 1 prognostic [ 13 C-methacetin breath test (MBT)], and 1 mechanistic (rotational thromboelastometry). To review ALFSG's accomplishments and consider next steps, a 2-day in-person conference was held at UT Southwestern Medical Center, Dallas, TX, entitled "Acute Liver Failure: Science and Practice," in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.
Collapse
Affiliation(s)
| | | | | | - Valerie Durkalski
- Medical University of South Carolina, Charleston, South Carolina, USA
| | | | - Jody A. Rule
- University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Shannan Tujios
- University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - William M. Lee
- University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| |
Collapse
|
|
6
|
Chiew AL, Isbister GK. Advances in the understanding of acetaminophen toxicity mechanisms: a clinical toxicology perspective. Expert Opin Drug Metab Toxicol 2023; 19:601-616. [PMID: 37714812 DOI: 10.1080/17425255.2023.2259787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/02/2023] [Accepted: 09/13/2023] [Indexed: 09/17/2023]
Abstract
INTRODUCTION Acetaminophen (paracetamol) is a commonly used analgesic and antipyretic agent, which is safe in therapeutic doses. Acetaminophen poisoning due to self-harm or repeated supratherapeutic ingestion is a common cause of acute liver injury. Acetylcysteine has been a mainstay of treatment for acetaminophen poisoning for decades and is efficacious if administered early. However, treatment failures occur if administered late, in 'massive' overdoses or in high-risk patients. AREAS COVERED This review provides an overview of the mechanisms of toxicity of acetaminophen poisoning (metabolic and oxidative phase) and how this relates to the assessment and treatment of the acetaminophen poisoned patient. The review focuses on how these advances offer further insight into the utility of novel biomarkers and the role of proposed adjunct treatments. EXPERT OPINION Advances in our understanding of acetaminophen toxicity have allowed the development of novel biomarkers and a better understanding of how adjunct treatments may prevent acetaminophen toxicity. Newly proposed adjunct treatments like fomepizole are being increasingly used without robust clinical trials. Novel biomarkers (not yet clinically available) may provide better assessment of these newly proposed adjunct treatments, particularly in clinical trials. These advances in our understanding of acetaminophen toxicity and liver injury hold promise for improved diagnosis and treatment.
Collapse
Affiliation(s)
- Angela L Chiew
- Department of Clinical Toxicology, Prince of Wales Hospital, Randwick, NSW, Australia
- Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, Australia
- New South Wales Poisons Information Centre, Sydney Children's Hospital, Sydney, New South Wales, Australia
| | - Geoffrey K Isbister
- New South Wales Poisons Information Centre, Sydney Children's Hospital, Sydney, New South Wales, Australia
- Clinical Toxicology Research Group, University of Newcastle, Callaghan, NSW, Australia
- Department of Clinical Toxicology, Calvary Mater Newcastle, Waratah, NSW, Australia
| |
Collapse
|
|
7
|
Liu Y, Li J, Xiao S, Liu Y, Bai M, Gong L, Zhao J, Chen D. Revolutionizing Precision Medicine: Exploring Wearable Sensors for Therapeutic Drug Monitoring and Personalized Therapy. BIOSENSORS 2023; 13:726. [PMID: 37504123 PMCID: PMC10377150 DOI: 10.3390/bios13070726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/02/2023] [Accepted: 07/08/2023] [Indexed: 07/29/2023]
Abstract
Precision medicine, particularly therapeutic drug monitoring (TDM), is essential for optimizing drug dosage and minimizing toxicity. However, current TDM methods have limitations, including the need for skilled operators, patient discomfort, and the inability to monitor dynamic drug level changes. In recent years, wearable sensors have emerged as a promising solution for drug monitoring. These sensors offer real-time and continuous measurement of drug concentrations in biofluids, enabling personalized medicine and reducing the risk of toxicity. This review provides an overview of drugs detectable by wearable sensors and explores biosensing technologies that can enable drug monitoring in the future. It presents a comparative analysis of multiple biosensing technologies and evaluates their strengths and limitations for integration into wearable detection systems. The promising capabilities of wearable sensors for real-time and continuous drug monitoring offer revolutionary advancements in diagnostic tools, supporting personalized medicine and optimal therapeutic effects. Wearable sensors are poised to become essential components of healthcare systems, catering to the diverse needs of patients and reducing healthcare costs.
Collapse
Affiliation(s)
- Yuqiao Liu
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Junmin Li
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Shenghao Xiao
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Yanhui Liu
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Mingxia Bai
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Lixiu Gong
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Jiaqian Zhao
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Dajing Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
- College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou 310007, China
| |
Collapse
|
|
8
|
Rao A, Rule JA, Cerro-Chiang G, Stravitz RT, McGuire BM, Lee G, Fontana RJ, Lee WM. Role of Hepatitis C Infection in Acute Liver Injury/Acute Liver Failure in North America. Dig Dis Sci 2023; 68:304-311. [PMID: 35546205 PMCID: PMC9094131 DOI: 10.1007/s10620-022-07524-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 04/18/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND While hepatitis A and B are well-known causes of acute liver failure (ALF), few well-documented cases of hepatitis C virus (HCV) infection (absent preexisting liver disease or other liver insults) have been described that result in ALF. We reviewed the Acute Liver Failure Study Group registry for evidence of HCV as a primary or contributing cause to ALF. METHODS From January 1998 to January 2017, 2,332 patients with ALF (INR ≥ 1.5, any degree of hepatic encephalopathy) and 667 with acute liver injury (ALI; INR ≥ 2.0, no hepatic encephalopathy) were enrolled. Anti-HCV testing was done routinely, with confirmatory RT-PCR testing for HCV RNA where necessary. RESULTS A total of 136 patients were anti-HCV-antibody positive, as follows: 56 HCV RNA negative, 65 HCV RNA positive, and 8 with no result nor sera available for testing. Only three subjects with ALI/ALF were determined to represent acute HCV infection. Case 1: 47-year-old female with morbid obesity (BMI 52.4) developed ALF and recovered, experiencing anti-HCV seroconversion. Case 2: 37-year-old female using cocaine presented with ALI and fully recovered. Case 3: 54-year-old female developed ALF requiring transplantation and was anti-HCV negative but viremic prior to transplant experiencing anti-HCV seroconversion thereafter. Among 1636 APAP overdose patients, the 52 with concomitant chronic HCV had higher 3-week mortality than the 1584 without HCV (31% vs 17%, p = 0.01). CONCLUSIONS ALI/ALF solely related to acute hepatitis C infection is very rare. Chronic HCV infection, found in at least 65 (2.2%) of ALI/ALF patients studied, contributed to more severe outcomes in APAP ALI/ALF; ClinicalTrials.gov number, NCT000518440. Trial Registration ClinicalTrials.gov number NCT000518440.
Collapse
Affiliation(s)
- Ashwin Rao
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, 75390-8887, USA
| | - Jody A Rule
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, 75390-8887, USA
| | - Giuliana Cerro-Chiang
- Division of Pulmonary Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Richard T Stravitz
- Lee-Hume Transplant Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Brendan M McGuire
- Division of Gastroenterology, University of Alabama, Birmingham, AL, USA
| | - Goo Lee
- Division of Anatomic Pathology, University of Alabama, Birmingham, AL, USA
| | - Robert J Fontana
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - William M Lee
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Blvd. Ste. 420, Dallas, TX, 75390-8887, USA.
| |
Collapse
|
|
9
|
Licata A, Minissale MG, Stankevičiūtė S, Sanabria-Cabrera J, Lucena MI, Andrade RJ, Almasio PL. N-Acetylcysteine for Preventing Acetaminophen-Induced Liver Injury: A Comprehensive Review. Front Pharmacol 2022; 13:828565. [PMID: 36034775 PMCID: PMC9399785 DOI: 10.3389/fphar.2022.828565] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 06/03/2022] [Indexed: 12/28/2022] Open
Abstract
Aims: N-Acetylcysteine (NAC) is used as an antidote in acetaminophen (APAP) overdose to prevent and mitigate drug-induced liver injury (DILI). Our objective was to systematically review evidence of the use of NAC as a therapeutic option for APAP overdose and APAP-related DILI in order to define the optimal treatment schedule and timing to start treatment. Methods: Bibliographic databases (PubMed, Web of Science, Embase, and MEDLINE) were searched for retrospective and prospective cohort studies, case series, and clinical trials. The prespecified primary outcomes were DILI-related mortality, hepatotoxicity, and adverse events (AEs). Results: In total, 34 studies of NAC usage in APAP-related DILI cases with 19,580 patients were identified, of which 2,376 patients developed hepatotoxicities. The mortality rate across different studies ranged from 0 to 52%. Large variability of NAC regimens was found, i.e., intravenous (I.V.) (100-150 mg/kg) and oral (70-140 mg/kg), and length of treatment varied-12, 24, or 48 h for I.V. regimen and 72 h for oral administration. The timing of initiation of NAC treatment showed different results in terms of occurrence of hepatotoxicity and mortality; if started within 8 h and no more than 24 h from APAP overdose, either intravenously or orally, NAC administration was efficacious in terms of mortality. The most frequent AEs reported were anaphylactic reactions, followed by cutaneous AEs for the IV route and intestinal AEs for the oral one. Conclusion: NAC improves hepatotoxicity and reduces mortality. Timing of treatment, ranging from 8 to 24 h from APAP overdose, regardless of the regimen or route of administration, is important to prevent or minimize liver damage, particularly in children and in elderly and obese patients.
Collapse
Affiliation(s)
- Anna Licata
- Medicina Interna ed Epatologia, Dipartimento di Promozione della Salute, Materno-infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro,” PROMISE, Università degli Studi di Palermo, Palermo, Italy
| | - Maria Giovanna Minissale
- Medicina Interna ed Epatologia, Dipartimento di Promozione della Salute, Materno-infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro,” PROMISE, Università degli Studi di Palermo, Palermo, Italy
| | - Simona Stankevičiūtė
- Medicina Interna ed Epatologia, Dipartimento di Promozione della Salute, Materno-infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro,” PROMISE, Università degli Studi di Palermo, Palermo, Italy
| | - Judith Sanabria-Cabrera
- UCICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Malaga, Spain
- Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Madrid, Spain
| | - Maria Isabel Lucena
- UCICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Malaga, Spain
- Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Madrid, Spain
- Servicio de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Raul J Andrade
- Servicio de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Piero Luigi Almasio
- Medicina Interna ed Epatologia, Dipartimento di Promozione della Salute, Materno-infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro,” PROMISE, Università degli Studi di Palermo, Palermo, Italy
| |
Collapse
|
|
10
|
Abstract
Abbreviated pathogenesis and clinical course of the acute liver failure syndrome. The pathogenesis and clinical course of the syndrome of acute liver failure (ALF) differs depending upon the etiology of the primary liver injury. In turn, the severity of the liver injury and resulting synthetic failure is often the primary determinant of whether a patient is referred for emergency liver transplantation. Injuries by viral etiologies trigger the innate immune system via pathogen-associated molecular patterns (PAMPs), while toxin-induced (and presumably ischemia-induced) injuries do so via damage-associated molecular patterns (DAMPs). The course of the clinical syndrome further depends upon the relative intensity and composition of cytokine release, resulting in an early proinflammatory phenotype (SIRS) and later compensatory anti-inflammatory response phenotype (CARS). The outcomes of overwhelming immune activation are the systemic (extrahepatic) features of ALF (cardiovascular collapse, cerebral edema, acute kidney injury, respiratory failure, sepsis) which ultimately determine the likelihood of death.Acute liver failure (ALF) continues to carry a high risk of mortality or the need for transplantation despite recent improvements in overall outcomes over the past two decades. Optimal management begins with identifying that liver failure is indeed present and its etiology, since outcomes and the need for transplantation vary widely across the different etiologies. Most causes of ALF can be divided into hyperacute (ischemia and acetaminophen) and subacute types (other etiologies), based on time of evolution of signs and symptoms of liver failure; the former evolve in 3 to 4 days and the latter typically in 2 to 4 weeks. Both involve intense release of cytokines and hepatocellular contents into the circulation with multiorgan effects/consequences.Management involves optimizing fluid balance and cardiovascular support, including the use of continuous renal replacement therapy, vasopressors, and pulmonary ventilation. Early evaluation for liver transplantation is advised particularly for acetaminophen toxicity, which evolves so rapidly that delay is likely to lead to death.Vasopressor support, high-grade hepatic encephalopathy, and unfavorable (subacute) etiologies heighten the need for urgent listing for liver transplantation. Prognostic scores such as Kings Criteria, Model for End-Stage Liver Disease, and the Acute Liver Failure Group prognostic index take these features into account and provide reasonable but imperfect predictive accuracy. Future treatments may include liver support devices and/or agents that improve hepatocyte regeneration.
Collapse
Affiliation(s)
- Shannan Tujios
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - R. Todd Stravitz
- Section of Hepatology, Department of Internal Medicine, Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - William M. Lee
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| |
Collapse
|
|
11
|
Yang R, Li K, Zou C, Wee A, Liu J, Liu L, Li M, Wu T, Wang Y, Ma Z, Wang Y, Liu J, Huang A, Sun Y, Chang B, Liang Q, Jia J, Zou Z, Zhao X. Alanine Aminotransferase and Bilirubin Dynamic Evolution Pattern as a Novel Model for the Prediction of Acute Liver Failure in Drug-Induced Liver Injury. Front Pharmacol 2022; 13:934467. [PMID: 35935831 PMCID: PMC9355525 DOI: 10.3389/fphar.2022.934467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
Aims: To develop, optimize, and validate a novel model using alanine aminotransferase (ALT) and total bilirubin (TB) dynamic evolution patterns in predicting acute liver failure (ALF) in drug-induced liver injury (DILI) patients.Methods: The demographics, clinical data, liver biopsy, and outcomes of DILI patients were collected from two hospitals. According to the dynamic evolution of ALT and TB after DILI onset, the enrolled patients were divided into ALT-mono-peak, TB-mono-peak, double-overlap-peak, and double-separate-peak (DSP) patterns and compared. Logistic regression was used to develop this predictive model in both discovery and validation cohorts.Results: The proportion of ALF was significantly higher in patients with the DSP pattern than in the ALT-mono-peak pattern and DOP pattern (10.0 vs. 0.0% vs. 1.8%,p < 0.05). The area under receiver operating characteristic curve (AUROC) of the DSP pattern model was 0.720 (95% CI: 0.682–0.756) in the discovery cohort and 0.828 (95% CI: 0.788–0.864) in the validation cohort in predicting ALF, being further improved by combining with international normalized ratio (INR) and alkaline phosphatase (ALP) (AUROC in the discovery cohort: 0.899; validation cohort: 0.958). Histopathologically, patients with the DSP pattern exhibited a predominantly cholestatic hepatitis pattern (75.0%, p < 0.05) with a higher degree of necrosis (29.2%, p = 0.084).Conclusion: DILI patients with the DSP pattern are more likely to progress to ALF. The predictive potency of the model for ALF can be improved by incorporating INR and ALP. This novel model allows for better identification of high-risk DILI patients, enabling timely measures to be instituted for better outcome.
Collapse
Affiliation(s)
- Ruiyuan Yang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Kexin Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Cailun Zou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Aileen Wee
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jimin Liu
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Liwei Liu
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Min Li
- Clinical Epidemiology and Evidence Base Medicine Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ting Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yu Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Zikun Ma
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yan Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jingyi Liu
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Ang Huang
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ying Sun
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Binxia Chang
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Qingsheng Liang
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Zhengsheng Zou
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
- *Correspondence: Xinyan Zhao,
| |
Collapse
|
|
12
|
Chen Y, Guan S, Guan Y, Tang S, Zhou Y, Wang X, Bi H, Huang M. Novel Clinical Biomarkers for Drug-Induced Liver Injury. Drug Metab Dispos 2022; 50:671-684. [PMID: 34903588 DOI: 10.1124/dmd.121.000732] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/07/2021] [Indexed: 11/22/2022] Open
Abstract
Drug-induced liver injury (DILI) remains a critical clinical issue and has been a treatment challenge today as it was in the past. However, the traditional biomarkers or indicators are insufficient to predict the risks and outcome of patients with DILI due to its poor specificity and sensitivity. Recently, the development of high-throughput technologies, especially omics and multiomics has sparked growing interests in identification of novel clinical DILI biomarkers, many of which also provide a mechanistic insight. Accordingly, in this minireview, we summarize recent advances in novel clinical biomarkers for DILI prediction, diagnosis, and prognosis and highlight the limitations or challenges involved in biomarker discovery or its clinical translation. Although huge work has been done, most reported biomarkers lack comprehensive information and more specific DILI biomarkers are still needed to complement the traditional biomarkers such as alanine aminotransferase (ALT) or aspartate transaminase (AST) in clinical decision-making. SIGNIFICANCE STATEMENT: This current review outlines an overview of novel clinical biomarkers for drug-induced liver injury (DILI) identified in clinical retrospective or prospective clinical analysis. Many of these biomarkers provide a mechanistic insight and are promising to complement the traditional DILI biomarkers. This work also highlights the limitations or challenges involved in biomarker discovery or its clinical translation.
Collapse
Affiliation(s)
- Youhao Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Shaoxing Guan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Yanping Guan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Siyuan Tang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Yanying Zhou
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Xueding Wang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Huichang Bi
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Min Huang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| |
Collapse
|
|
13
|
Bao Y, Phan M, Zhu J, Ma X, Manautou JE, Zhong XB. Alterations of Cytochrome P450-Mediated Drug Metabolism during Liver Repair and Regeneration after Acetaminophen-Induced Liver Injury in Mice. Drug Metab Dispos 2022; 50:694-703. [PMID: 34348940 PMCID: PMC9132219 DOI: 10.1124/dmd.121.000459] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/28/2021] [Indexed: 11/22/2022] Open
Abstract
Acetaminophen (APAP)-induced liver injury (AILI) is the leading cause of acute liver failure in the United States, but its impact on metabolism, therapeutic efficacy, and adverse drug reactions (ADRs) of co- and/or subsequent administered drugs are not fully investigated. The current work explored this field with a focus on the AILI-mediated alterations of cytochrome P450-mediated drug metabolism. Various levels of liver injury were induced in mice by treatment with APAP at 0, 200, 400, and 600 mg/kg. Severity of liver damage was determined at 24, 48, 72, and 96 hours by plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), microRNA miR122, and tissue staining. The expression and activities of CYP3A11, 1A2, 2B10, 2C29, and 2E1 were measured. Sedation efficacy and ADRs of midazolam, a CYP3A substrate, were monitored after APAP treatment. ALT, AST, and miR122 increased at 24 hours after APAP treatment with all APAP doses, whereas only groups treated with 200 and 400 mg/kg recovered back to normal levels at 72 and 96 hours. The expression and activity of the cytochromes P450 significantly decreased at 24 hours with all APAP doses but only recovered back to normal at 72 and 96 hours with 200 and 400, but not 600, mg/kg of APAP. The alterations of cytochrome P450 activities resulted in altered sedation efficacy and ADRs of midazolam, which were corrected by dose justification of midazolam. Overall, this work illustrated a low cytochrome P450 expression window after AILI, which can decrease drug metabolism and negatively impact drug efficacy and ADRs. SIGNIFICANCE STATEMENT: The data generated in the mouse model demonstrated that expression and activities of cytochrome P450 enzymes and correlated drug efficacy and ADRs are altered during the time course of liver repair and regeneration after liver is injured by treatment with APAP. Dose justifications based on predicted changes of cytochrome P450 activities can achieve desired therapeutic efficacy and avoid ADRs. The generated data provide fundamental knowledge for translational research to drug treatment for patients during liver recovery and regeneration who have experienced AILI.
Collapse
Affiliation(s)
- Yifan Bao
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.B., M.P., J.E.M., X.-b.Z.), and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.Z., X.M.)
| | - Mi Phan
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.B., M.P., J.E.M., X.-b.Z.), and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.Z., X.M.)
| | - Junjie Zhu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.B., M.P., J.E.M., X.-b.Z.), and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.Z., X.M.)
| | - Xiaochao Ma
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.B., M.P., J.E.M., X.-b.Z.), and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.Z., X.M.)
| | - José E Manautou
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.B., M.P., J.E.M., X.-b.Z.), and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.Z., X.M.)
| | - Xiao-Bo Zhong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.B., M.P., J.E.M., X.-b.Z.), and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.Z., X.M.)
| |
Collapse
|
|
14
|
Wong NZ, Reddy KR, Bittermann T. Acute Liver Failure Etiology Is an Independent Predictor of Waitlist Outcome but Not Posttransplantation Survival in a National Cohort. Liver Transpl 2022; 28:39-50. [PMID: 34081838 PMCID: PMC8639833 DOI: 10.1002/lt.26187] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/22/2021] [Accepted: 05/26/2021] [Indexed: 01/03/2023]
Abstract
The impact of acute liver failure (ALF) etiology on waitlist (WL) and posttransplantation outcomes, independent of severity of illness, is incompletely characterized. All adults (n = 1691) listed for primary liver transplantation (LT) between 2002 and 2019 with ALF due to acetaminophen toxicity (APAP), drug-induced liver injury (DILI), autoimmune hepatitis (AIH), and hepatitis B virus (HBV) were identified in the United Network for Organ Sharing database. ALF etiology was evaluated as an independent predictor of WL mortality and spontaneous survival (SS; versus outcome of LT), as well as post-LT overall survival, graft survival, and in-hospital mortality using multivariable models accounting for differences in clinical parameters at listing. Accounting for severity of illness at listing, WL mortality and SS for DILI, AIH, and HBV were each lower than those for APAP toxicity (adjusted relative risk ratio <1 in all analyses with P < 0.001 for both outcomes). ALF etiology was not associated with adjusted overall survival after LT (P = 0.09) or graft survival (P = 0.13). Inpatient mortality rate after LT was high at 9.0%. While ALF etiology was also not associated with adjusted inpatient mortality (P = 0.42), cause of death (COD) was different. For example, the rate of post-LT brain death was 5.3% for APAP toxicity, 3.0% for other DILI, 1.1% for AIH, and 3.0% for HBV (P = 0.02). ALF etiology is an independent predictor of WL outcome, even after adjusting for severity of illness, but is not associated with post-LT outcomes with the exception of COD. The majority of post-LT deaths for all ALF etiologies studied occurred during the index hospital stay, suggesting a continued need for enhanced prognostic tools to ensure efficient organ utilization and ALF- and etiology-specific post-LT care to prevent brain death.
Collapse
Affiliation(s)
- Natalie Z. Wong
- Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA
| | - K. Rajender Reddy
- Division of Gastroenterology / Transplant Hepatology, University of Pennsylvania, Philadelphia, PA
| | - Therese Bittermann
- Division of Gastroenterology / Transplant Hepatology, University of Pennsylvania, Philadelphia, PA,Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA
| |
Collapse
|
|
15
|
Xiao P, Li M, Zhou M, Zhao X, Wang C, Qiu J, Fang Q, Jiang H, Dong H, Zhou R. TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation. JCI Insight 2021; 6:149276. [PMID: 34877932 PMCID: PMC8675193 DOI: 10.1172/jci.insight.149276] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 10/27/2021] [Indexed: 01/02/2023] Open
Abstract
Tristetraprolin (TTP), an important immunosuppressive protein regulating mRNA decay through recognition of the AU-rich elements (AREs) within the 3′-UTRs of mRNAs, participates in the pathogenesis of liver diseases. However, whether TTP regulates mRNA stability through other mechanisms remains poorly understood. Here, we report that TTP was upregulated in acute liver failure (ALF), resulting in decreased mRNA stabilities of CCL2 and CCL5 through promotion of N6-methyladenosine (m6A) mRNA methylation. Overexpression of TTP could markedly ameliorate hepatic injury in vivo. TTP regulated the mRNA stabilization of CCL2 and CCL5. Interestingly, increased m6A methylation in CCL2 and CCL5 mRNAs promoted TTP-mediated RNA destabilization. Moreover, induction of TTP upregulated expression levels of WT1 associated protein, methyltransferase like 14, and YT521-B homology N6-methyladenosine RNA binding protein 2, which encode enzymes regulating m6A methylation, resulting in a global increase of m6A methylation and amelioration of liver injury due to enhanced degradation of CCL2 and CCL5. These findings suggest a potentially novel mechanism by which TTP modulates mRNA stabilities of CCL2 and CCL5 through m6A RNA methylation, which is involved in the pathogenesis of ALF.
Collapse
Affiliation(s)
- Pingping Xiao
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.,School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Mingxuan Li
- Hubei Province Key Laboratory of Allergy and Immunology and
| | - Mengsi Zhou
- Hubei Province Key Laboratory of Allergy and Immunology and
| | - Xuejun Zhao
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Cheng Wang
- Hubei Province Key Laboratory of Allergy and Immunology and
| | - Jinglin Qiu
- School of Pharmacy, Hubei University of Science and Technology, Xianning, China
| | - Qian Fang
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Hong Jiang
- Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Huifen Dong
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Rui Zhou
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| |
Collapse
|
|
16
|
Sattari M, Ostadi A, Hassani S, Mazloumi Z, Noshad H, Mirnia K, Salek Maghsoudi A. Plasma Concentration of Taurine Changes following Acetaminophen Overdose in Male Patients during Hospitalization. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:297-306. [PMID: 34567163 PMCID: PMC8457743 DOI: 10.22037/ijpr.2020.113698.14435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Changes in plasma concentration of taurine during hospitalization of acetaminophen poisoned patients have not been studied. Hepatotoxicity is a common consequence of acetaminophen overdose that may lead to acute liver failure. Numerous biomarkers for drug-induced liver injury have been explored. All biomarkers are usually obtainable 48 h following acetaminophen overdose. We have already introduced taurine as a non-specific early biomarker of acetaminophen overdose. This study aimed to follow up changes in plasma concentration of taurine during the first three days of acetaminophen overdose. Sixty-four male patients suffering from acetaminophen overdose were selected for the study. Four blood samples were taken from the patients every 12 h. Sixty blood samples were also taken from sixty healthy humans. The plasma concentration of taurine in both groups was analyzed an already developed HPLC method. Analysis of regression showed a significant correlation between means of plasma concentrations of taurine and acetaminophen, aspartate aminotransferase, Alanine aminotransferase, glutathione peroxidase, and prothrombin time during hospitalization. The high plasma concentration of taurine, 6 h or more after acetaminophen overdose, could be a useful early indicator of liver damage.
Collapse
Affiliation(s)
- Mohammadreza Sattari
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Ostadi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Internal Medicine, Sina Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shokoufeh Hassani
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeynab Mazloumi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hamid Noshad
- Department of Nephrology, Sina Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kayvan Mirnia
- Department of Neonatology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Armin Salek Maghsoudi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
17
|
Clinton JW, Kiparizoska S, Aggarwal S, Woo S, Davis W, Lewis JH. Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature. Drug Saf 2021; 44:1125-1149. [PMID: 34533782 PMCID: PMC8447115 DOI: 10.1007/s40264-021-01109-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2021] [Indexed: 12/13/2022]
Abstract
Drug-induced liver injury (DILI) remains an important, yet challenging diagnosis for physicians. Each year, additional drugs are implicated in DILI and this year was no different, with more than 1400 articles published on the subject. This review examines some of the most significant highlights and controversies in DILI-related research over the past year and their implications for clinical practice. Several new drugs were approved by the US Food and Drug Administration including a number of drugs implicated in causing DILI, particularly among the chemotherapeutic classes. The COVID-19 pandemic was also a major focus of attention in 2020 and we discuss some of the notable aspects of COVID-19-related liver injury and its implications for diagnosing DILI. Updates in diagnostic and causality assessments related to DILI such as the Roussel Uclaf Causality Assessment Method are included, mindful that there is still no single biomarker or diagnostic tool to unequivocally diagnose DILI. Glutamate dehydrogenase received renewed attention as being more specific than alanine aminotransferase. There were a few new reports of previously unrecognized hepatotoxins, including immune modulators and novel gene therapy drugs that we highlight. Updates and new developments of previously described hepatotoxins, such as immune checkpoint inhibitors and anti-tuberculosis drugs are reviewed. Finally, novel technologies such as organoid culture systems to better predict DILI preclinically may be coming of age and determinants of hepatocyte loss, such as calculating PALT are poised to improve our current means of estimating DILI severity and the risk of acute liver failure.
Collapse
Affiliation(s)
- Joseph William Clinton
- Department of Internal Medicine, Medstar Georgetown University Hospital, Washington, DC, USA.
| | - Sara Kiparizoska
- Department of Internal Medicine, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Soorya Aggarwal
- Division of Gastroenterology and Hepatology, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Stephanie Woo
- Department of Internal Medicine, Medstar Georgetown University Hospital, Washington, DC, USA
| | - William Davis
- Department of Internal Medicine, Medstar Georgetown University Hospital, Washington, DC, USA
| | - James H Lewis
- Division of Gastroenterology and Hepatology, Medstar Georgetown University Hospital, Washington, DC, USA
| |
Collapse
|
|
18
|
Datta A, Flynn NR, Barnette DA, Woeltje KF, Miller GP, Swamidass SJ. Machine learning liver-injuring drug interactions with non-steroidal anti-inflammatory drugs (NSAIDs) from a retrospective electronic health record (EHR) cohort. PLoS Comput Biol 2021; 17:e1009053. [PMID: 34228716 PMCID: PMC8284671 DOI: 10.1371/journal.pcbi.1009053] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 07/16/2021] [Accepted: 05/08/2021] [Indexed: 01/14/2023] Open
Abstract
Drug-drug interactions account for up to 30% of adverse drug reactions. Increasing prevalence of electronic health records (EHRs) offers a unique opportunity to build machine learning algorithms to identify drug-drug interactions that drive adverse events. In this study, we investigated hospitalizations' data to study drug interactions with non-steroidal anti-inflammatory drugs (NSAIDS) that result in drug-induced liver injury (DILI). We propose a logistic regression based machine learning algorithm that unearths several known interactions from an EHR dataset of about 400,000 hospitalization. Our proposed modeling framework is successful in detecting 87.5% of the positive controls, which are defined by drugs known to interact with diclofenac causing an increased risk of DILI, and correctly ranks aggregate risk of DILI for eight commonly prescribed NSAIDs. We found that our modeling framework is particularly successful in inferring associations of drug-drug interactions from relatively small EHR datasets. Furthermore, we have identified a novel and potentially hepatotoxic interaction that might occur during concomitant use of meloxicam and esomeprazole, which are commonly prescribed together to allay NSAID-induced gastrointestinal (GI) bleeding. Empirically, we validate our approach against prior methods for signal detection on EHR datasets, in which our proposed approach outperforms all the compared methods across most metrics, such as area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC).
Collapse
Affiliation(s)
- Arghya Datta
- Department of Computer Science and Engineering, Washington University in Saint Louis, Saint Louis, Missouri, United States of America
| | - Noah R. Flynn
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Dustyn A. Barnette
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Keith F. Woeltje
- Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America
- Center for Clinical Excellence at BJC HealthCare, Saint Louis, Missouri, United States of America
| | - Grover P. Miller
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - S. Joshua Swamidass
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, United States of America
- * E-mail:
| |
Collapse
|
|
19
|
Nekoukar Z, Moghimi M, Zakariaei Z, Fakhar M, Tabaripour R. Fulminant hepatorenal syndrome due to Acetaminophen toxicity: A case report. Clin Case Rep 2021; 9:e04037. [PMID: 34084485 PMCID: PMC8142301 DOI: 10.1002/ccr3.4037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 12/18/2022] Open
Abstract
HRS is a rare and poor prognosis complication of chronic acetaminophen toxicity, which presents by progressive decline in renal function secondary to liver failure.
Collapse
Affiliation(s)
- Zahra Nekoukar
- Department of Clinical PharmacyFaculty of PharmacyMazandaran University of Medical SciencesSariIran
| | - Minoo Moghimi
- Department of Clinical PharmacyFaculty of PharmacyMazandaran University of Medical SciencesSariIran
| | - Zakaria Zakariaei
- Toxoplasmosis Research CenterCommunicable Diseases InstituteIranian National Registry Center for Lophomoniasis and ToxoplasmosisMazandaran University of Medical SciencesSariIran
- Toxicology and Forensic Medicine DivisionOrthopedic Research CenterImam Khomeini HospitalMazandaran University of Medical SciencesSariIran
| | - Mahdi Fakhar
- Toxoplasmosis Research CenterCommunicable Diseases InstituteIranian National Registry Center for Lophomoniasis and ToxoplasmosisMazandaran University of Medical SciencesSariIran
| | - Rabeeh Tabaripour
- Toxoplasmosis Research CenterCommunicable Diseases InstituteIranian National Registry Center for Lophomoniasis and ToxoplasmosisMazandaran University of Medical SciencesSariIran
| |
Collapse
|
|
20
|
G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity. Redox Biol 2021; 43:101965. [PMID: 33933881 PMCID: PMC8105674 DOI: 10.1016/j.redox.2021.101965] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Abstract
Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein β5 (Gβ5), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gβ5 in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gβ5 in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gβ5 depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gβ5 knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gβ5 forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gβ5 in liver. Thus, Gβ5 sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage.
Collapse
|
|
21
|
González-Ponce HA, Martínez-Saldaña MC, Tepper PG, Quax WJ, Buist-Homan M, Faber KN, Moshage H. Betacyanins, major components in Opuntia red-purple fruits, protect against acetaminophen-induced acute liver failure. Food Res Int 2020; 137:109461. [PMID: 33233135 DOI: 10.1016/j.foodres.2020.109461] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 04/05/2020] [Accepted: 06/16/2020] [Indexed: 01/06/2023]
Abstract
Acetaminophen (APAP) misuse or overdose is the most important cause of drug-induced acute liver failure. Overdoses of acetaminophen induce oxidative stress and liver injury by the electrophilic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Plant-based medicine has been used for centuries against diseases or intoxications due to their biological activities. The aim of this study was to evaluate the therapeutic value of Opuntia robusta and Opuntia streptacantha fruit extracts against acetaminophen-induced liver damage and to identify the major biocomponents on them. Opuntia fruit extracts were obtained by peeling and squeezing each specie, followed by lyophilization. HPLC was used to characterize the extracts. The effect of the extracts against acetaminophen-induced acute liver injury was evaluated both in vivo and in vitro using biochemical, molecular and histological determinations. The results showed that betacyanins are the main components in the analyzed Opuntia fruit extracts, with betanin as the highest concentration. Therapeutic treatments with Opuntia extracts reduced biochemical, molecular and histological markers of liver (in vivo) and hepatocyte (in vitro) injury. Opuntia extracts reduced the APAP-increased expression of the stress-related gene Gadd45b. Furthermore, Opuntia extracts exerted diverse effects on the antioxidant related genes Sod2, Gclc and Hmox1, independent of their ROS-scavenging ability. Therefore, betacyanins as betanin from Opuntia robusta and Opuntia streptacantha fruits are promising nutraceutical compounds against oxidative liver damage.
Collapse
Affiliation(s)
- Herson Antonio González-Ponce
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands.
| | | | - Pieter G Tepper
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, the Netherlands
| | - Wim J Quax
- Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, the Netherlands
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, the Netherlands.
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, the Netherlands.
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, the Netherlands.
| |
Collapse
|
|
22
|
Lee WM. Acetaminophen Toxicity: A History of Serendipity and Unintended Consequences. Clin Liver Dis (Hoboken) 2020; 16:34-44. [PMID: 33042525 PMCID: PMC7538926 DOI: 10.1002/cld.984] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 05/14/2020] [Indexed: 02/04/2023] Open
Abstract
Watch an interview with the author.
Collapse
Affiliation(s)
- William M. Lee
- Division of Digestive and Liver DiseasesUT Southwestern Medical Center at DallasDallasTX
| |
Collapse
|
|
23
|
Li Y, Liu Z, Li L, Lian W, He Y, Khalil E, Mäkilä E, Zhang W, Torrieri G, Liu X, Su J, Xiu Y, Fontana F, Salonen J, Hirvonen J, Liu W, Zhang H, Santos HA, Deng X. Tandem-Mass-Tag Based Proteomic Analysis Facilitates Analyzing Critical Factors of Porous Silicon Nanoparticles in Determining Their Biological Responses under Diseased Condition. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2001129. [PMID: 32775170 PMCID: PMC7404168 DOI: 10.1002/advs.202001129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/25/2020] [Indexed: 05/11/2023]
Abstract
The analysis of nanoparticles' biocompatibility and immunogenicity is mostly performed under a healthy condition. However, more clinically relevant evaluation conducted under pathological condition is less known. Here, the immunogenicity and bio-nano interactions of porous silicon nanoparticles (PSi NPs) are evaluated in an acute liver inflammation mice model. Interestingly, a new mechanism in which PSi NPs can remit the hepatocellular damage and inflammation activation in a surface dependent manner through protein corona formation, which perturbs the inflammation by capturing the pro-inflammatory signaling proteins that are inordinately excreted or exposed under pathological condition, is found. This signal sequestration further attenuates the nuclear factor κB pathway activation and cytokines production from macrophages. Hence, the study proposes a potential mechanism for elucidating the altered immunogenicity of nanomaterials under pathological conditions, which might further offer insights to establish harmonized standards for assessing the biosafety of biomaterials in a disease-specific or personalized manner.
Collapse
Affiliation(s)
- Yunzhan Li
- State Key Laboratory of Cellular Stress BiologyInnovation Center for Cell SignalingNetworkSchool of Life SciencesXiamen UniversityFujian361101China
- State‐Province Joint Engineering Laboratory of Targeted Drugs from Natural ProductsSchool of Life SciencesXiamen UniversityFujian361101China
| | - Zehua Liu
- Drug Research programDivision of Pharmaceutical Chemistry and TechnologyDrug Research ProgramFaculty of PharmacyUniversity of HelsinkiHelsinkiFI‐00014Finland
| | - Li Li
- State Key Laboratory of Cellular Stress BiologyInnovation Center for Cell SignalingNetworkSchool of Life SciencesXiamen UniversityFujian361101China
- State‐Province Joint Engineering Laboratory of Targeted Drugs from Natural ProductsSchool of Life SciencesXiamen UniversityFujian361101China
| | - Wenhua Lian
- State Key Laboratory of Cellular Stress BiologyInnovation Center for Cell SignalingNetworkSchool of Life SciencesXiamen UniversityFujian361101China
- State‐Province Joint Engineering Laboratory of Targeted Drugs from Natural ProductsSchool of Life SciencesXiamen UniversityFujian361101China
| | - Yaohui He
- School of Pharmaceutical SciencesXiamen UniversityFujian361101China
| | - Elbadry Khalil
- Drug Research programDivision of Pharmaceutical Chemistry and TechnologyDrug Research ProgramFaculty of PharmacyUniversity of HelsinkiHelsinkiFI‐00014Finland
| | - Ermei Mäkilä
- Laboratory of Industrial PhysicsDepartment of PhysicsUniversity of TurkuTurkuFI‐20014Finland
| | - Wenzhong Zhang
- Department of ChemistryUniversity of HelsinkiHelsinkiFI‐00014Finland
| | - Giulia Torrieri
- Drug Research programDivision of Pharmaceutical Chemistry and TechnologyDrug Research ProgramFaculty of PharmacyUniversity of HelsinkiHelsinkiFI‐00014Finland
| | - Xueyan Liu
- State Key Laboratory of Cellular Stress BiologyInnovation Center for Cell SignalingNetworkSchool of Life SciencesXiamen UniversityFujian361101China
- State‐Province Joint Engineering Laboratory of Targeted Drugs from Natural ProductsSchool of Life SciencesXiamen UniversityFujian361101China
| | - Jingyi Su
- State Key Laboratory of Cellular Stress BiologyInnovation Center for Cell SignalingNetworkSchool of Life SciencesXiamen UniversityFujian361101China
- State‐Province Joint Engineering Laboratory of Targeted Drugs from Natural ProductsSchool of Life SciencesXiamen UniversityFujian361101China
| | - Yuanming Xiu
- State Key Laboratory of Cellular Stress BiologyInnovation Center for Cell SignalingNetworkSchool of Life SciencesXiamen UniversityFujian361101China
- State‐Province Joint Engineering Laboratory of Targeted Drugs from Natural ProductsSchool of Life SciencesXiamen UniversityFujian361101China
| | - Flavia Fontana
- Drug Research programDivision of Pharmaceutical Chemistry and TechnologyDrug Research ProgramFaculty of PharmacyUniversity of HelsinkiHelsinkiFI‐00014Finland
| | - Jarno Salonen
- Laboratory of Industrial PhysicsDepartment of PhysicsUniversity of TurkuTurkuFI‐20014Finland
| | - Jouni Hirvonen
- Drug Research programDivision of Pharmaceutical Chemistry and TechnologyDrug Research ProgramFaculty of PharmacyUniversity of HelsinkiHelsinkiFI‐00014Finland
| | - Wen Liu
- School of Pharmaceutical SciencesXiamen UniversityFujian361101China
| | - Hongbo Zhang
- Pharmaceutical Sciences Laboratory and Turku Bioscience CentreAbo Akademi UniversityTurkuFI‐20520Finland
| | - Hélder A. Santos
- Drug Research programDivision of Pharmaceutical Chemistry and TechnologyDrug Research ProgramFaculty of PharmacyUniversity of HelsinkiHelsinkiFI‐00014Finland
- Helsinki Institute of Life Science (HiLIFE)University of HelsinkiHelsinkiFI‐00014Finland
| | - Xianming Deng
- State Key Laboratory of Cellular Stress BiologyInnovation Center for Cell SignalingNetworkSchool of Life SciencesXiamen UniversityFujian361101China
- State‐Province Joint Engineering Laboratory of Targeted Drugs from Natural ProductsSchool of Life SciencesXiamen UniversityFujian361101China
| |
Collapse
|
|
24
|
Rodríguez-Morales AJ, Cardona-Ospina JA, Murillo-Muñoz MM. Gastroenterologists, Hepatologists, COVID-19 and the Use of Acetaminophen. Clin Gastroenterol Hepatol 2020; 18:2142-2143. [PMID: 32387226 PMCID: PMC7204721 DOI: 10.1016/j.cgh.2020.04.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/03/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Alfonso J Rodríguez-Morales
- Grupo de Investigación Biomedicina, Faculty of Medicine, Fundación Universitaria Autónoma de las Américas, Pereira, Colombia; Public Health and Infection Research Group, Faculty of Health Sciences, Universidad Tecnológica de Pereira, Pereira, Risaralda, Colombia
| | - Jaime A Cardona-Ospina
- Grupo de Investigación Biomedicina, Faculty of Medicine, Fundación Universitaria Autónoma de las Américas, Pereira, Colombia; Public Health and Infection Research Group, Faculty of Health Sciences, Universidad Tecnológica de Pereira, Pereira, Risaralda, Colombia; Emerging Infectious Diseases and Tropical Medicine Research Group, Instituto para la Investigacion en Ciencias Biomedicas, Sci-Help, Pereira Risaralda, Colombia
| | - Maria Mónica Murillo-Muñoz
- Grupo de Investigación Biomedicina, Faculty of Medicine, Fundación Universitaria Autónoma de las Américas, Pereira, Colombia
| |
Collapse
|
|
25
|
James LP, McGill MR, Roberts DW, Hinson JA, Lee WM. Advances in biomarker development in acetaminophen toxicity. Adv Clin Chem 2020; 98:35-50. [PMID: 32564787 DOI: 10.1016/bs.acc.2020.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Acetaminophen liver injury is the most common cause of acute liver injury in the United States and several other countries. Diagnosis of acetaminophen-induced acute liver injury in the clinic is challenging due to the lack of validated and specific biomarkers. The following chapter provides an overview of recent advances evaluating candidate biomarkers in development for acetaminophen acute liver injury. Relationships of biomarkers to mechanisms of acetaminophen toxicity and their potential role in confirming the diagnosis and/or predicting evolving toxicity are addressed.
Collapse
Affiliation(s)
- Laura P James
- Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
| | - Mitchell R McGill
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Dean W Roberts
- Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Jack A Hinson
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - William M Lee
- Digestive and Liver Diseases Division, UT Southwestern Medical Center at Dallas, Dallas, TX, United States
| |
Collapse
|
|
26
|
Chiew AL, James LP, Isbister GK, Pickering JW, McArdle K, Chan BSH, Buckley NA. Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5). J Hepatol 2020; 72:450-462. [PMID: 31760072 DOI: 10.1016/j.jhep.2019.10.030] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 10/25/2019] [Accepted: 10/30/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND & AIMS Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.
Collapse
Affiliation(s)
- Angela L Chiew
- Department of Pharmacology, School of Medical Sciences, University of Sydney, Sydney, Australia; Department of Clinical Toxicology, Prince of Wales Hospital, Sydney, Australia; NSW Poisons Information Centre, Children's Hospital at Westmead, Westmead, Australia.
| | - Laura P James
- Arkansas Children's Hospital and University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Geoffrey K Isbister
- NSW Poisons Information Centre, Children's Hospital at Westmead, Westmead, Australia; Clinical Toxicology Research Group, University of Newcastle, Newcastle, Australia
| | - John W Pickering
- Department of Medicine, University of Otago Christchurch, and Emergency Department Christchurch Hospital, Christchurch, New Zealand
| | - Kylie McArdle
- NSW Poisons Information Centre, Children's Hospital at Westmead, Westmead, Australia; Clinical Toxicology Research Group, University of Newcastle, Newcastle, Australia
| | - Betty S H Chan
- Department of Clinical Toxicology, Prince of Wales Hospital, Sydney, Australia; NSW Poisons Information Centre, Children's Hospital at Westmead, Westmead, Australia
| | - Nicholas A Buckley
- Department of Pharmacology, School of Medical Sciences, University of Sydney, Sydney, Australia; NSW Poisons Information Centre, Children's Hospital at Westmead, Westmead, Australia
| |
Collapse
|
|
27
|
Abstract
Drug-induced liver injury (DILI) is the most common cause of acute liver failure (ALF) in Western countries. Without liver transplantation, the mortality rate for ALF approaches greater than 80%. Acetaminophen-related ALF may be associated with a rapid progression but fortunately has a high chance for spontaneous survival compared with idiosyncratic DILI-related ALF. Several prognostic scoring systems for severe DILI have been developed to aid clinicians in selecting patients who require urgent liver transplantation. Patients who undergo liver transplantation for ALF are at risk for early graft loss and death and should be closely followed.
Collapse
Affiliation(s)
- Maneerat Chayanupatkul
- Department of Physiology, Chulalongkorn University, Pattayapat Building, 10th Floor, 1873 Rama IV Road, Pathumwan, Bangkok 10330, Thailand; Division of Gastroenterology, Department of Medicine, Chulalongkorn University, Pattayapat Building, 10th Floor, 1873 Rama IV Road, Pathumwan, Bangkok 10330, Thailand.
| | - Thomas D Schiano
- Division of Liver Diseases, Department of Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, Icahn Building, 3rd Floor, 1425 Madison Avenue, New York, NY 10029, USA
| |
Collapse
|
|
28
|
McCullough S, Dweep H, McGill MR, Bhattacharyya S, James L, Frankowski S, Woodall A, Kearns G, Gill P. Granzyme B and miR-378a Interaction in Acetaminophen Toxicity in Children. Microrna 2020; 9:121-132. [PMID: 31393259 PMCID: PMC10507677 DOI: 10.2174/2211536608666190808144456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/29/2019] [Accepted: 07/23/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND AIM Hepatic phase I drug-metabolizing enzymes CYP2E1, CYP1A2 and CYP3A4 catalyze the biotransformation of Acetaminophen (APAP) and are important in the mediation of toxicity. The potential role of other hepatic and non-hepatic Phase I enzymes in APAP toxicity has not been established. METHODS PCR array containing 84 genes involved in phase I drug metabolism was examined in subgroups of hospitalized children for APAP overdose, categorized as no toxicity (ALT ≤ 45 IU/L, n=5) and moderate toxicity (ALT ≥ 500 IU/L, n=5). RESULTS Significant downregulation was observed for ALDH6A1, CYP4F12 and GZMB in the no toxicity subgroup and ALDH1A1, CYP27A1 and GZMB in the moderate toxicity subgroup. qRTPCR confirmed significant downregulation for ALDH1A1, CYP4F12, and GZMB. In-silico analysis identified GZMB 3'UTR to be a target of miR-378a-5p. Overexpression of miR-378a-5p reduced the luciferase activity of GZMB 3'UTR reporter plasmid reportedly by 50%. NK-92 cells transfected with the miR-378a-5p mimic extended the effect of APAP on GZMB protein expression compared to mimic controls. In addition, miR-378a-5p was significantly upregulated in blood samples of children with APAP overdose undergoing NAC treatment. CONCLUSION Overall, our study suggests the presence of a novel signaling pathway, whereby miR- 378a-5p inhibits GZMB expression in children with APAP overdose.
Collapse
Affiliation(s)
- Sandra McCullough
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
| | - Harsh Dweep
- The Wistar Institute, 3601 Spruce St, Philadelphia, PA, 19104, USA
| | - Mitchell R. McGill
- Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Sudeepa Bhattacharyya
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
| | - Laura James
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
| | - Sara Frankowski
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
| | - Aaron Woodall
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
| | - Gregory Kearns
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
| | - Pritmohinder Gill
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
| |
Collapse
|
|
29
|
Abstract
Acute liver failure is a rare and severe consequence of abrupt hepatocyte injury, and can evolve over days or weeks to a lethal outcome. A variety of insults to liver cells result in a consistent pattern of rapid-onset elevation of aminotransferases, altered mentation, and disturbed coagulation. The absence of existing liver disease distinguishes acute liver failure from decompensated cirrhosis or acute-on-chronic liver failure. Causes of acute liver failure include paracetamol toxicity, hepatic ischaemia, viral and autoimmune hepatitis, and drug-induced liver injury from prescription drugs, and herbal and dietary supplements. Diagnosis requires careful review of medications taken, and serological testing for possible viral exposure. Because of its rarity, acute liver failure has not been studied in large, randomised trials, and most treatment recommendations represent expert opinion. Improvements in management have resulted in lower mortality, although liver transplantation, used in nearly 30% of patients with acute liver failure, still provides a life-saving alternative to medical management.
Collapse
Affiliation(s)
- R Todd Stravitz
- Hume-Lee Transplant Center of Virginia Commonwealth University, Richmond, VA, USA
| | - William M Lee
- Digestive and Liver Diseases Division, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
| |
Collapse
|
|
30
|
Leventhal TM, Gottfried M, Olson JC, Subramanian RM, Hameed B, Lee WM. Acetaminophen is Undetectable in Plasma From More Than Half of Patients Believed to Have Acute Liver Failure Due to Overdose. Clin Gastroenterol Hepatol 2019; 17:2110-2116. [PMID: 30731196 DOI: 10.1016/j.cgh.2019.01.040] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 01/08/2019] [Accepted: 01/12/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Evaluation of patients with acute liver injury (ALI) or acute liver failure (ALF) often includes measurement of plasma levels of acetaminophen, to determine exposure and/or toxicity. However, once liver injury has developed, acetaminophen might be undetectable in plasma. We investigated the association between level of acetaminophen measured and outcomes of patients designated as having ALF or ALI due to acetaminophen toxicity. METHODS We performed a retrospective analysis of data from 434 subjects in the Acute Liver Failure Study Group who met criteria for ALF (coagulopathy and hepatic encephalopathy within 26 weeks of the first symptoms, without pre-existing liver disease) or ALI (severe liver injury with coagulopathy but no encephalopathy) due to acetaminophen toxicity from January 1, 2010 through December 31, 2014. We collected data on patient demographics, biochemical features, reported acetaminophen use, N-acetylcysteine therapy, liver transplant, and outcomes. Descriptive statistics were used to assess patient demographics, clinical characteristics, and outcomes whereas differences in continuous variables between patients with vs without acetaminophen detection on admission were analyzed using the Wilcoxon rank-sum test. The primary aim was to determine the proportion of patients with detectable plasma levels of acetaminophen. RESULTS Acetaminophen was undetectable in serum samples from 227 patients (52%). There were no significant differences between groups of patients with detectable vs undetectable levels in demographic features, alcohol use, median levels of alanine aspartate, or use of N-acetylcysteine (given to 94.7% of patients with detectable acetaminophen vs 95.9% of those with undetectable acetaminophen; P=.63). We observed a significant difference in median dose taken between patients with detectable (29,500 mg; interquartile range, 15,000 mg-50,007 mg) vs no detectable parent compound (14,950 mg; interquartile range, 3960 mg-25,000) (P=.003). A lower proportion of patients with detectable plasma levels of acetaminophen (72.3%) survived without a liver transplant than of patients with undetectable levels (86.3%) in univariate analysis (P=.0006), although this was not significant in multivariable analysis (P=.12). Although most patients had unintentional overdoses, a higher proportion of patients with suicidal overdoses (43%) had detectable levels of acetaminophen than patients with accidental overdoses (29.3%; P=.01). CONCLUSION More than half of patients who present at the hospital with acetaminophen-induced ALI or ALF have undetectable levels of acetaminophen. Clinicians should not exclude acetaminophen toxicity because of undetectable levels or withhold N-acetylcysteine for patients with ALI or ALF when acetaminophen toxicity is suspected.
Collapse
Affiliation(s)
- Thomas M Leventhal
- Division of Gastroenterology and Hepatology, University of Kansas Medical Center, Kansas City, Kansas.
| | - Michelle Gottfried
- Public Health Sciences, Medical University of South Carolina, Charleston, South Caroline
| | - Jody C Olson
- Division of Gastroenterology and Hepatology, University of Kansas Medical Center, Kansas City, Kansas
| | - Ram M Subramanian
- Divisions of Hepatology and Critical Care, Emory University, Atlanta, Georgia
| | - Bilal Hameed
- Division of Gastroenterology, University of California San Francisco, San Francisco, California
| | - William M Lee
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | | |
Collapse
|
|
31
|
Sohail N, Hira K, Tariq A, Sultana V, Ehteshamul-Haque S. Marine macro-algae attenuates nephrotoxicity and hepatotoxicity induced by cisplatin and acetaminophen in rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:25301-25311. [PMID: 31256398 DOI: 10.1007/s11356-019-05704-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/06/2019] [Indexed: 06/09/2023]
Abstract
Cisplatin is considered one of the best anticancer medications often used for the treatment of various cancers even with its adverse effects. Acetaminophen (paracetamol) is a widely used analgesic-antipyretic drug that causes hepatotoxicity at higher than the effective doses. The present study assesses the nephroprotective and hepatoprotective effects of two seaweeds against cisplatin and acetaminophen toxicity in rats. Damage to the liver and kidney was induced by administering a single intraperitoneal dose of acetaminophen (600 mg/kg) or cisplatin (7 mg/kg) to groups of rats. The damage to the liver and kidney was assessed by the elevated liver (ALT, AST, ALP, LDH, electrolytes) and kidney (urea, creatinine) biomarkers. The ethanol extract of brown seaweed reversed the elevated levels of kidney and liver biomarkers along with triglycerides, cholesterol, and glucose. Among the two seaweeds, Sargassum ilicifolium showed better nephroprotective and hepatoprotective effects than the standard drug N-Acetyl-cysteine, Halymenia porphyroides showed only limited protection. Findings of this study provide evidence of nephroprotective and hepatoprotective effects of S. ilicifolium. Seaweed could be a beneficial dietary supplement to attenuate nephrotoxicity and hepatotoxicity.
Collapse
Affiliation(s)
- Nida Sohail
- Biotechnology and Drug Development Laboratory, Department of Biochemistry, University of Karachi, Karachi, 75270, Pakistan
| | - Khan Hira
- Institute of Biomedical Sciences, Dow University of Health Sciences, Karachi, Pakistan
| | - Amna Tariq
- M.A.H. Qadri Biological Research Centre, University of Karachi, Karachi, 75270, Pakistan
| | - Viqar Sultana
- Biotechnology and Drug Development Laboratory, Department of Biochemistry, University of Karachi, Karachi, 75270, Pakistan
| | | |
Collapse
|
|
32
|
Curry SC, Padilla-Jones A, Ruha AM, O'Connor AD, Kang AM, Wilkins DG, Jaeschke H, Wilhelms K, Gerkin RD. The Relationship Between Circulating Acetaminophen-Protein Adduct Concentrations and Alanine Aminotransferase Activities in Patients With and Without Acetaminophen Overdose and Toxicity. J Med Toxicol 2019; 15:143-155. [PMID: 30980348 DOI: 10.1007/s13181-019-00705-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/28/2019] [Accepted: 03/04/2019] [Indexed: 01/17/2023] Open
Abstract
INTRODUCTION Measurement of serum acetaminophen-protein adducts (APAP-CYS) has been suggested to support or refute a diagnosis of acetaminophen (APAP)-induced hepatotoxicity when ingestion histories are unreliable or unavailable and when circulating APAP concentrations are low or undetectable. Non-APAP overdose patients commonly have used APAP products in non-toxic quantities and, thus, will have measurable APAP-CYS concentrations, even when hepatic injury results from other causes, such as ischemic hepatitis. The relationship between alanine aminotransferase (ALT) activity and APAP-CYS concentration might assist in distinguishing between toxic and non-toxic APAP doses in patients suspected of drug overdose. METHODS We measured serial levels of serum APAP-CYS and ALT activities in 500 overdose patients in whom APAP toxicity was suspected on inpatient admission, but who were then classified at time of discharge and before results of APAP-CYS concentrations were available into three groups: 1) definite APAP group; 2) definitely not APAP group; and 3) indeterminate group. Subjects in the definite and definitely not APAP groups were selected in whom a plasma ALT activity was measured within ± 4 h of a serum APAP-CYS concentration. Regressions with correlation coefficients between APAP-CYS and ALT were calculated for repeat measures in the 335 subjects (908 blood samples) in the definite APAP group and 79 subjects (231 samples) in the definitely not APAP group, with an emphasis on APAP-CYS concentrations and calculation of 95% prediction intervals when ALT was ≥ 1000 IU/L. RESULTS A strong correlation was found between APAP-CYS and ALT in the definite APAP group over all ALT activities (r = 0.93, p < 0.001; N = 335), and when ALT was > 1000 IU/L (r = 0.82, p < 0.001, N = 144). In the 79 definitely not APAP subjects, no significant correlation was found when ALT exceeded 1000 IU/L (r = 0.04; p = 0.84, N = 32). All subjects in the definitely not APAP group displayed APAP-CYS concentrations < 3 μM. In definitely not APAP subjects, the great majority of APAP-CYS levels were below the 95% prediction interval for APAP-CYS concentrations in definite APAP group subjects when ALT was ≥ 1000 IU/L. However, some definitely not APAP group subjects who had ingested non-toxic doses of APAP displayed APAP-CYS concentrations as high as 2.8 μM in the face of ALT elevation from ischemic hepatitis. CONCLUSION The interpretation of serum APAP-CYS concentrations must always be made in light of detailed clinical information and the population being tested, especially because of some overlap in APAP-CYS levels in subjects with and without APAP toxicity.
Collapse
Affiliation(s)
- Steven C Curry
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA.
- Divisions of Medical Toxicology and Precision Medicine, and Clinical Data Analytics and Decision Support, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
- Center for Toxicology, Pharmacology, Education and Research, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
| | - Angela Padilla-Jones
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA
| | - Anne-Michelle Ruha
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA
- Divisions of Medical Toxicology and Precision Medicine, and Clinical Data Analytics and Decision Support, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
- Center for Toxicology, Pharmacology, Education and Research, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
| | - Ayrn D O'Connor
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA
- Divisions of Medical Toxicology and Precision Medicine, and Clinical Data Analytics and Decision Support, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
- Center for Toxicology, Pharmacology, Education and Research, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
| | - A Min Kang
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA
- Divisions of Medical Toxicology and Precision Medicine, and Clinical Data Analytics and Decision Support, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
- Center for Toxicology, Pharmacology, Education and Research, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
| | - Diana G Wilkins
- Center for Human Toxicology, University of Utah, Salt Lake City, UT, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Kelly Wilhelms
- Center for Toxicology, Pharmacology, Education and Research, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
| | - Richard D Gerkin
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA
| |
Collapse
|
|
33
|
Abstract
Drug-induced liver injury (DILI) is a major clinical and regulatory challenge. As a result, interest in DILI biomarkers is growing. So far, considerable progress has been made in identification of biomarkers for diagnosis (acetaminophen-cysteine protein adducts), prediction (genetic biomarkers), and prognosis (microRNA-122, high mobility group box 1 protein, keratin-18, glutamate dehydrogenase, mitochondrial DNA). Many of those biomarkers also provide mechanistic insight. The purpose of this chapter is to review major advances in DILI biomarker research over the last decade, and to highlight some of the challenges involved in implementation. Although much work has been done, more liver-specific biomarkers, more DILI-specific biomarkers, and better prognostic biomarkers for survival are all still needed. Furthermore, more work is needed to define reference intervals and medical decision limits.
Collapse
Affiliation(s)
- Mitchell R McGill
- Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
| |
Collapse
|
|
34
|
Khan H, Ullah H, Nabavi SM. Mechanistic insights of hepatoprotective effects of curcumin: Therapeutic updates and future prospects. Food Chem Toxicol 2019; 124:182-191. [PMID: 30529260 DOI: 10.1016/j.fct.2018.12.002] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 11/20/2018] [Accepted: 12/03/2018] [Indexed: 02/08/2023]
Abstract
The liver is the most essential organ of the body performing vital functions. Hepatic disorders affect the physiological and biochemical functions of the body. These disorders include hepatitis B, hepatitis C, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), liver cirrhosis, hepatic failure and hepatocellular carcinoma (HCC). Drugs related hepatotoxicity is one of the major challenges facing by clinicians as it is a leading cause of liver failure. During post-marketing surveillance studies, detection and reporting of drug-induced hepatotoxicity may lead to drug withdrawal or warnings. Several mechanisms are involved in hepatotoxicity such as cell membrane disruption, initiating an immune response, alteration of cellular pathways of drug metabolism, accumulation of reactive oxygen species (ROS), lipid peroxidation and cell death. Curcumin, the active ingredient of turmeric and exhibits therapeutic potential for the treatment of diabetes, cardiovascular disorders and various types of cancers. Curcumin is strong anti-oxidant and anti-inflammatory effects and thus it possesses hepatoprotective properties. Despite its low bioavailability, its hepatoprotective effects have been studied in various protocols of hepatotoxicity including acetaminophen, alcohol, lindane, carbon tetrachloride (CCL4), diethylnitrosamine and heavy metals induced hepatotoxicities. This report reviews the hepatoprotective effects of curcumin with a focus on its mechanistic insights in various hepatotoxic protocols.
Collapse
Affiliation(s)
- Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan.
| | - Hammad Ullah
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan
| | - Seyed M Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
35
|
Ganger DR, Rule J, Rakela J, Bass N, Reuben A, Stravitz RT, Sussman N, Larson AM, James L, Chiu C, Lee WM. Acute Liver Failure of Indeterminate Etiology: A Comprehensive Systematic Approach by An Expert Committee to Establish Causality. Am J Gastroenterol 2018; 113:1319. [PMID: 29946176 PMCID: PMC9252260 DOI: 10.1038/s41395-018-0160-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 05/15/2018] [Indexed: 02/08/2023]
Abstract
OBJECTIVES In the United States, the Acute Liver Failure Study Group (ALFSG) registry lists approximately 11% of cases as of indeterminate etiology (IND-ALF) as determined by the respective local site principal investigator (PI). Traditionally, IND-ALF has prompted concern that other viruses or toxins might be implicated. We hypothesized that many IND- ALF cases would have an identifiable etiology upon further investigation. Improving the identification process should reduce the number of truly indeterminate cases. METHODS Specific definitions for each etiology ("etiology-specific algorithms") were developed by a Causality Adjudication Committee that included six reviewers (each with 20 or more years of experience). Of 2718 patients with ALF, 303 initially deemed IND-ALF by site PIs underwent committee review guided by the algorithms. Acetaminophen (APAP) protein adducts were measured in sera when available, additional HEV testing was performed, and viral sequences sought by microarray analysis and metagenomic next-generation sequencing (mNGS). Study sites were asked to provide liver biopsy and/or explant reports and to update serological findings not reported previously. RESULTS Nearly half (142, 46.9%) of the 303 IND-ALF cases could be reassigned to a single, defined etiology and rated as highly likely or probable; 11 additional cases, upon review, did not meet ALF criteria. Amongst reassigned etiologies, 45 were previously unrecognized APAP, 34 autoimmune hepatitis (AIH), 24 drug-induced liver injury (DILI), 13 various viral causes, 12 ischemia, and 14 miscellaneous other etiologies. The remaining 150, deemed true IND-ALF, represented just 5.5%. CONCLUSIONS The indeterminate etiology in ALF includes patients with a diagnosis that is discernible after closer examination. Revision of etiologic diagnoses of indeterminate cases using added testing and expert opinion is useful in understanding all aspects of ALF.
Collapse
Affiliation(s)
- Daniel R. Ganger
- Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jody Rule
- Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jorge Rakela
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Nathan Bass
- Department of Medicine, UCSF San Francisco, San Francisco, CA, USA
| | - A Reuben
- Medical University of South Carolina, Charleston, SC, USA
| | - RT Stravitz
- Section of Hepatology Virginia Commonwealth University, Richmond, VA, USA
| | - Norman Sussman
- Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA
| | - Anne M. Larson
- Hepatology and Liver Transplantation, University of Washington, Seattle, WA, USA
| | - Laura James
- Section of Pediatric Pharmacology and Toxicology, Arkansas Children’s Hospital and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Charles Chiu
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA,UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA,Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA
| | - William M. Lee
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | |
Collapse
|
|
36
|
Yang E, Peng L, Lee WM. Multiple admissions for acetaminophen overdose: Acetaminophen frequent fliers, a new entity? Hepatology 2018; 68:1197-1199. [PMID: 29631324 DOI: 10.1002/hep.29917] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/05/2018] [Accepted: 03/28/2018] [Indexed: 02/05/2023]
Affiliation(s)
| | - Lan Peng
- Department of Pathology, UT Southwestern Medical Center at Dallas, Dallas, TX
| | | |
Collapse
|
|
37
|
Abstract
Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival.
Collapse
Affiliation(s)
- Arul M Thomas
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - James H Lewis
- Division of Gastroenterology, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Room M2408, Washington, DC 20007, USA.
| |
Collapse
|
|
38
|
Abstract
Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), although the worldwide frequency is variable. APAP hepatotoxicity develops either following intentional overdose or unintentional ingestion (therapeutic misadventure) in the background of several factors, such as concomitant use of alcohol and certain medications that facilitate the formation of reactive and toxic metabolites. Spontaneous survival is more common in APAP-induced ALF compared with non-APAP etiologies. N-acetylcysteine is recommended for all patients with APAP-induced ALF and it reduces mortality. Liver transplantation should be offered early to those who are unlikely to survive based on described prognostic criteria.
Collapse
|
|
39
|
Brennan PN, Donnelly MC, Simpson KJ. Systematic review: non A-E, seronegative or indeterminate hepatitis; what is this deadly disease? Aliment Pharmacol Ther 2018; 47:1079-1091. [PMID: 29468698 DOI: 10.1111/apt.14566] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 10/20/2017] [Accepted: 01/22/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND A significant proportion of cases of acute liver failure (ALF) do not have an identifiable cause; so called "non A-E," "non A, non B, non C," "seronegative" or "indeterminate" hepatitis. However, this entity is clinically not well described. AIM To collate the known incidence and outcomes in indeterminate hepatitis. This systematic review sought to identify potential aetiologies that ought to be considered, and identify likely future objectives in classification and treatment strategies for indeterminate hepatitis. METHODS Literature review to determine aetiological factors, prevalence and outcomes relating to indeterminate hepatitis. RESULTS There is significant heterogeneity within the reported cases of indeterminate hepatitis in the literature. Some of the potential infective aetiologies which are reviewed here include: parvovirus B19 (PVB19), herpes simplex virus (HSV), Toga-Like Virus and the Annelloviridae (including SEN-V). Interestingly, this condition predominately affects middle aged women, with subacute progression of the liver failure. In addition, the prognosis of indeterminate hepatitis is poor, with reduced spontaneous survival compared with other causes of acute liver failure and increased need for emergency liver transplantation. CONCLUSIONS Whilst various pathological processes have been implicated in the development of indeterminate hepatitis, the specific cause remains elusive. There is an urgent need for general consensus on a specific definition and exclusion of confounding aetiologies with coordinated multicentre investigation of this rare condition to identify aetiology and develop therapies to reduce the significant mortality and need for emergency liver transplantation associated with this condition.
Collapse
Affiliation(s)
- P N Brennan
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - M C Donnelly
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - K J Simpson
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
40
|
Heard K, Anderson VE, Lavonas EJ, Dart RC, Green JL. Serum paracetamol-protein adducts in ambulatory subjects: Relationship to recent reported paracetamol use. Biomarkers 2017; 23:288-292. [PMID: 29179598 DOI: 10.1080/1354750x.2017.1410857] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
CONTEXT Serum paracetamol-protein adducts (PPAs) are a novel potential biomarker of paracetamol exposure. The relationship between serum PPA concentrations and reported paracetamol use in ambulatory adults has not been previously described. MATERIALS AND METHODS This was a cross-sectional study of ambulatory adults. A detailed medication history was obtained from all subjects and subjects were stratified by reported paracetamol use in the 2 weeks prior to enrolment. Serum PPAs were measured in all subjects and correlated with reported dose, time of last ingestion and demographics. RESULTS We enrolled 230 in the paracetamol exposure arm and 74 in the no exposure arm. 98/230 (42.6%)of subjects who reported paracetamol exposure had PPA detected and 68/74 (91.9%) of subjects who denied paracetamol exposure had no PPA detected. PPA concentrations were positively correlated with total paracetamol dose and with more recent ingestion. DISCUSSION Detection of serum PPA generally reflects paracetamol exposure histories in ambulatory adults. Concentrations are well correlated with reported dose and time from last dose. CONCLUSIONS Serum PPA can be detected with reported therapeutic use of paracetamol but may not be detected in all patients who report taking paracetamol.
Collapse
Affiliation(s)
- Kennon Heard
- a Rocky Mountain Poison and Drug Center , Denver Health and Hospitals , Denver , CO , USA.,b Section of Medical Pharmacology and Toxicology, Department of Emergency Medicine , University of Colorado , Aurora , CO , USA
| | - Victoria E Anderson
- a Rocky Mountain Poison and Drug Center , Denver Health and Hospitals , Denver , CO , USA
| | - Eric J Lavonas
- a Rocky Mountain Poison and Drug Center , Denver Health and Hospitals , Denver , CO , USA.,b Section of Medical Pharmacology and Toxicology, Department of Emergency Medicine , University of Colorado , Aurora , CO , USA.,c Department of Emergency Medicine , Denver Health and Hospitals , Denver , CO , USA
| | - Richard C Dart
- a Rocky Mountain Poison and Drug Center , Denver Health and Hospitals , Denver , CO , USA.,b Section of Medical Pharmacology and Toxicology, Department of Emergency Medicine , University of Colorado , Aurora , CO , USA
| | - Jody L Green
- a Rocky Mountain Poison and Drug Center , Denver Health and Hospitals , Denver , CO , USA
| |
Collapse
|
|
41
|
Abstract
Acute liver failure (ALF) is a life-threatening condition of heterogeneous etiology. Outcomes are better with early recognition and prompt initiation of etiology-specific therapy, intensive care protocols, and liver transplantation (LT). Prognostic scoring systems include the King's College Criteria and Model for End-stage Liver Disease score. Cerebral edema and intracranial hypertension are reasons for high morbidity and mortality; hypertonic saline is suggested for patients with a high risk for developing intracranial hypertension, and when it does, mannitol is recommended as first-line therapy. Extracorporeal liver support system may serve as a bridge to LT and may increase LT-free survival in select cases.
Collapse
Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand; Division of Gastroenterology and Hepatology, Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
42
|
Gill P, Bhattacharyya S, McCullough S, Letzig L, Mishra PJ, Luo C, Dweep H, James L. MicroRNA regulation of CYP 1A2, CYP3A4 and CYP2E1 expression in acetaminophen toxicity. Sci Rep 2017; 7:12331. [PMID: 28951593 PMCID: PMC5614957 DOI: 10.1038/s41598-017-11811-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/30/2017] [Indexed: 01/29/2023] Open
Abstract
MicroRNAs (miRNAs) that regulate the cytochrome P-450 isoforms involved in acetaminophen (APAP) toxicity were examined in HepaRG cells treated with APAP (20 mM). In-vitro studies found that APAP protein adducts were increased at 1 h, followed by ALT increases at 12 and 24 h. CYP1A2, CYP3A4 and CYP2E1 mRNA levels were decreased, while miRNAs were increased for miR-122-5p, miR-378a-5p, miR-27b-3p at 6 h and miR-125b-5p at 12 h and miR-27b-3p at 24 h. Putative miRNA binding sites on the 3′UTRs of the CYPs were identified in-silico. Overexpression of miR-122-5p and miR-378a-5p in cells suppressed protein expression of CYP1A2, CYP3A4 and CYP2E1. Luciferase reporter assays confirmed the interaction between miR-122 and the 3′UTR of the CYP1A2 and CYP3A4. Thus, the in-vitro experiments showed that miR-122-5p and miR-378a-5p upregulation were associated with translational repression of CYPs. Serum samples of children with APAP overdose had significant elevation of miR-122-5p, miR-378a-5p, miR-125b-5p and miR-27b-3p, compared to healthy controls and receiver operator curves of the miRNAs had AUCs of 91 to 100%. Collectively, the data suggest that miRNA elevations in APAP toxicity represent a regulatory response to modify CYP1A2, CYP3A4 and CYP2E1 translation due to cellular stress and injury.
Collapse
Affiliation(s)
- Pritmohinder Gill
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA. .,Arkansas Children's Research Institute, Little Rock, AR, 72202, USA.
| | - Sudeepa Bhattacharyya
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA.,Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
| | - Sandra McCullough
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA.,Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
| | - Lynda Letzig
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA.,Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
| | - Prasun J Mishra
- Department of Biochemical and Cellular Pharmacology, Genentech, 1, DNA Way, South San Francisco, California, 94080, USA
| | - Chunqiao Luo
- Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
| | - Harsh Dweep
- The Wistar Institute, 3601 Spruce St, Philadelphia, Pennsylvania, 19104, USA
| | - Laura James
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA.,Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
| |
Collapse
|
|
43
|
Court MH, Zhu Z, Masse G, Duan SX, James LP, Harmatz JS, Greenblatt DJ. Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers. J Pharmacol Exp Ther 2017; 362:431-440. [PMID: 28663312 PMCID: PMC5562097 DOI: 10.1124/jpet.117.242107] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 06/26/2017] [Indexed: 02/05/2023] Open
Abstract
Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African-Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a 1-g oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between African-Americans and European-Americans. However, median oxidation clearance was 37% lower in African-Americans versus European-Americans (0.57 versus 0.90 ml/min per kilogram; P = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; P < 0.01) were observed for acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in women versus men. The UGT2B15*2 polymorphism was associated with variant-allele-number proportional reductions in acetaminophen total clearance (by 15-27%; P < 0.001) and glucuronidation partial clearance (by 23-48%; P < 0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein-adduct concentrations than *1/*2 (by 42%; P = 0.003) and *1/*1 (by 41%; P = 0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; P = 0.041) and *1C/*1C (by 44%; P = 0.048) African-Americans. Consequently, African-Americans oxidize acetaminophen more slowly than European-Americans, which may be partially explained by the CYP2E1*1D polymorphism. UGT2B15*2 influences acetaminophen pharmacokinetics in both African-Americans and European-Americans.
Collapse
Affiliation(s)
- Michael H Court
- Pharmacogenomics Laboratory (M.H.C., Z.Z.), Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington; Program in Pharmacology and Experimental Therapeutics (G.M., S.X.D., J.S.H., and D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute (L.P.J.), Little Rock, Arkansas
| | - Zhaohui Zhu
- Pharmacogenomics Laboratory (M.H.C., Z.Z.), Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington; Program in Pharmacology and Experimental Therapeutics (G.M., S.X.D., J.S.H., and D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute (L.P.J.), Little Rock, Arkansas
| | - Gina Masse
- Pharmacogenomics Laboratory (M.H.C., Z.Z.), Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington; Program in Pharmacology and Experimental Therapeutics (G.M., S.X.D., J.S.H., and D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute (L.P.J.), Little Rock, Arkansas
| | - Su X Duan
- Pharmacogenomics Laboratory (M.H.C., Z.Z.), Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington; Program in Pharmacology and Experimental Therapeutics (G.M., S.X.D., J.S.H., and D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute (L.P.J.), Little Rock, Arkansas
| | - Laura P James
- Pharmacogenomics Laboratory (M.H.C., Z.Z.), Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington; Program in Pharmacology and Experimental Therapeutics (G.M., S.X.D., J.S.H., and D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute (L.P.J.), Little Rock, Arkansas
| | - Jerold S Harmatz
- Pharmacogenomics Laboratory (M.H.C., Z.Z.), Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington; Program in Pharmacology and Experimental Therapeutics (G.M., S.X.D., J.S.H., and D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute (L.P.J.), Little Rock, Arkansas
| | - David J Greenblatt
- Pharmacogenomics Laboratory (M.H.C., Z.Z.), Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington; Program in Pharmacology and Experimental Therapeutics (G.M., S.X.D., J.S.H., and D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute (L.P.J.), Little Rock, Arkansas
| |
Collapse
|
|
44
|
The Natural History of Severe Acute Liver Injury. Am J Gastroenterol 2017; 112:1389-1396. [PMID: 28440304 PMCID: PMC5587371 DOI: 10.1038/ajg.2017.98] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 02/19/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.
Collapse
|
|
45
|
Li Y, Lu L, Luo N, Wang YQ, Gao HM. Inhibition of PI3K/AKt/mTOR signaling pathway protects against d-galactosamine/lipopolysaccharide-induced acute liver failure by chaperone-mediated autophagy in rats. Biomed Pharmacother 2017; 92:544-553. [PMID: 28577493 DOI: 10.1016/j.biopha.2017.05.037] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 05/05/2017] [Accepted: 05/08/2017] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE This study aims to investigate the effects of PI3K/AKt/mTOR signaling pathway on the proliferation and apoptosis in acute liver failure (ALF) by chaperone mediated autophagy (CMA). METHODS The hepatocytes extracted from both normal rats and rats with ALF were assigned to control, acute injury, P13K agonist, and P13K inhibitor groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used as part of this investigation to detect the expression of PI3K/AKt/mTOR signaling pathway related-proteins (PI3K, AKt, mTOR), apoptosis related-proteins (Fas, Bax, Bcl-2), chaperone-mediated autophagy (CMA) marker proteins (LAMP-2A, HSC 70), p-PI3K, p-AKt, p-4E-BPI, and p-S6K. An MTT assay was used for analysis of cell proliferation after transfection. Flow cytometry is performed to detect the cell apoptosis. RESULTS In comparison to the normal group, the model group showed enhanced positive rate of PI3K, AKt, mTOR, increased expression levels of PI3K, AKt, mTOR, Fas, Bax, p-PI3K, p-AKt, p-4E-BPI and p-S6K, reduced expression levels of Bcl-2, LAMP-2A and HSC 70. The results in vitro experiment: compared with the acute injury group, the PI3K agonist group showed elevated expression levels of PI3K, AKt, mTOR, Fas, Bax, p-PI3K, p-AKt, p-4E-BPI and p-S6K, decreased expression levels of Bcl-2, LAMP-2A and HSC 70, inhibited cell proliferation, more arrested cells in G1 stage, and promoted cell apoptosis. Opposing this, the P13K inhibitor group exhibited an opposite trend. CONCLUSION In conclusion, inhibition of the PI3K/AKt/mTOR signaling pathway plays a protective role in ALF by promoting CMA expression, which could arrest cell proliferation and promote cell apoptosis.
Collapse
Affiliation(s)
- Yin Li
- Intensive Care Unit, Emergency Medical Research Institute, Tianjin First Center Hospital, Tianjin 300192, PR China
| | - Ling Lu
- Intensive Care Unit, Emergency Medical Research Institute, Tianjin First Center Hospital, Tianjin 300192, PR China
| | - Ning Luo
- Intensive Care Unit, Emergency Medical Research Institute, Tianjin First Center Hospital, Tianjin 300192, PR China
| | - Yong-Qiang Wang
- Intensive Care Unit, Emergency Medical Research Institute, Tianjin First Center Hospital, Tianjin 300192, PR China
| | - Hong-Mei Gao
- Intensive Care Unit, Emergency Medical Research Institute, Tianjin First Center Hospital, Tianjin 300192, PR China.
| |
Collapse
|
|
46
|
Yang G, Zhang L, Ma L, Jiang R, Kuang G, Li K, Tie H, Wang B, Chen X, Xie T, Gong X, Wan J. Glycyrrhetinic acid prevents acetaminophen-induced acute liver injury via the inhibition of CYP2E1 expression and HMGB1-TLR4 signal activation in mice. Int Immunopharmacol 2017; 50:186-193. [PMID: 28668488 DOI: 10.1016/j.intimp.2017.06.027] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 06/05/2017] [Accepted: 06/23/2017] [Indexed: 12/21/2022]
Abstract
Acetaminophen (APAP) is a widely used antipyretic and analgesic drug, which is safe and effective at the therapeutic dose. Unfortunately, excessive dosage of APAP could cause severe liver injury due to lack of effective therapy. Successful therapeutic strategies are urgently requested in clinic. Glycyrrhetinic acid (GA), derived from a traditional medicine licorice, has been shown to exert anti-inflammatory and antioxidant actions. In this study, the effect and the underlying mechanism of GA on APAP-induced hepatotoxicity were explored. Our results showed that pretreatment with GA significantly reduced serum ALT and AST activities, alleviated hepatic pathological damages with hepatocellular apoptosis, down-regulated expression of CYP2E1 mRNA and protein, increased GSH levels, and reduced reactive oxygen species (ROS) productions in the liver of APAP-exposed mice. Furthermore, GA obviously inhibited APAP-induced HMGB1-TLR4 signal activation, as evaluated by reduced hepatic HMGB1 release, p-IRAK1, p-MAPK and p-IκB expression as well as the productions of TNF-α and IL-1β. In addition, GA attenuated hepatic neutrophils recruitment and macrophages infiltration caused by APAP. These findings reflected that GA could alleviate APAP-induced hepatotoxicity, the possible mechanism is associated with down-regulation of CYP2E1 expression and deactivation of HMGB1-TLR4 signal pathway.
Collapse
Affiliation(s)
- Genling Yang
- Laboratory Animal Center, Chongqing Medical University, Chongqing 40016, China
| | - Li Zhang
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 40016, China
| | - Li Ma
- Department of Pharmacology, Chongqing Medical University, Chongqing 40016, China
| | - Rong Jiang
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 40016, China
| | - Ge Kuang
- Department of Pharmacology, Chongqing Medical University, Chongqing 40016, China
| | - Ke Li
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 40016, China
| | - Hongtao Tie
- Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 40016, China
| | - Bin Wang
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xinyu Chen
- Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, China
| | - Tianjun Xie
- Department of Pharmacology, Chongqing Medical University, Chongqing 40016, China
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing 400016, China.
| | - Jingyuan Wan
- Department of Pharmacology, Chongqing Medical University, Chongqing 40016, China.
| |
Collapse
|
|
47
|
Yu YC, Mao YM, Chen CW, Chen JJ, Chen J, Cong WM, Ding Y, Duan ZP, Fu QC, Guo XY, Hu P, Hu XQ, Jia JD, Lai RT, Li DL, Liu YX, Lu LG, Ma SW, Ma X, Nan YM, Ren H, Shen T, Wang H, Wang JY, Wang TL, Wang XJ, Wei L, Xie Q, Xie W, Yang CQ, Yang DL, Yu YY, Zeng MD, Zhang L, Zhao XY, Zhuang H. CSH guidelines for the diagnosis and treatment of drug-induced liver injury. Hepatol Int 2017; 11:221-241. [PMID: 28405790 PMCID: PMC5419998 DOI: 10.1007/s12072-017-9793-2] [Citation(s) in RCA: 201] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 03/14/2017] [Indexed: 02/07/2023]
Abstract
Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.
Collapse
Affiliation(s)
- Yue-Cheng Yu
- Liver Disease Center of PLA, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing, 210002, China
| | - Yi-Min Mao
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200001, China.
| | - Cheng-Wei Chen
- Shanghai Liver Diseases Research Center, 85th Hospital, Nanjing Military Command, Shanghai, 200235, China.
| | - Jin-Jun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jun Chen
- Liver Diseases Center, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 201805, China
| | - Yang Ding
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Zhong-Ping Duan
- Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Qing-Chun Fu
- Shanghai Liver Diseases Research Center, 85th Hospital, Nanjing Military Command, Shanghai, 200235, China
| | - Xiao-Yan Guo
- Department of Gastroenterology, Second Affiliated Hospital, Xi'an Jiaotong University, Xian, 710004, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Xi-Qi Hu
- Department of Pathology, School of Medicine, Fudan University, Shanghai, 200433, China
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, 100069, China
| | - Rong-Tao Lai
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Dong-Liang Li
- Department of Hepatobiliary Disease, Fuzhou General Hospital of PLA, Fuzhou, 350025, China
| | - Ying-Xia Liu
- Department of Liver Disease, Shenzhen Third People's Hospital, Shenzhen, 518040, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200080, China
| | - Shi-Wu Ma
- Department of Infectious Diseases, Kunming General Hospital of PLA, Kunming, 650032, China
| | - Xiong Ma
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200001, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Affiliated Hospital, Hebei Medical University, Shijiazhuang, 050051, China
| | - Hong Ren
- Department of Infectious Diseases, Institute for Viral Hepatitis, Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Tao Shen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Beijing University, Beijing, 100083, China
| | - Hao Wang
- Institute of Hepatology, People's Hospital, Beijing University, Beijing, 100044, China
| | - Ji-Yao Wang
- Department of Gastroenterology, Zhongshan Hospital, School of Medicine, Fudan University, Shanghai, 200032, China
| | - Tai-Ling Wang
- Department of Pathology, China-Japan Friendship Hospital, Capital Medical University, Beijing, 100029, China
| | - Xiao-Jin Wang
- Shanghai Liver Diseases Research Center, 85th Hospital, Nanjing Military Command, Shanghai, 200235, China
| | - Lai Wei
- Institute of Hepatology, People's Hospital, Beijing University, Beijing, 100044, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100011, China
| | - Chang-Qing Yang
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065c, China
| | - Dong-Liang Yang
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yan-Yan Yu
- Department of Infectious Disease, Beijing University First Hospital, Beijing, 100034, China
| | - Min-de Zeng
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200001, China
| | - Li Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078c, China
| | - Xin-Yan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, 100069, China
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Beijing University, Beijing, 100083, China
| |
Collapse
|
|
48
|
Abstract
Pediatric acute liver failure is rare but life-threatening illness that occurs in children without preexisting liver disease. The rarity of the disease, along with its severity and heterogeneity, presents unique clinical challenges to the physicians providing care for pediatric patients with acute liver failure. In this review, practical clinical approaches to the care of critically ill children with acute liver failure are discussed with an organ system-specific approach. The underlying pathophysiological processes, major areas of uncertainty, and approaches to the critical care management of pediatric acute liver failure are also reviewed.
Collapse
|
|
49
|
Teschke R, Schulze J, Eickhoff A, Danan G. Drug Induced Liver Injury: Can Biomarkers Assist RUCAM in Causality Assessment? Int J Mol Sci 2017; 18:E803. [PMID: 28398242 PMCID: PMC5412387 DOI: 10.3390/ijms18040803] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 03/31/2017] [Accepted: 04/01/2017] [Indexed: 12/25/2022] Open
Abstract
Drug induced liver injury (DILI) is a potentially serious adverse reaction in a few susceptible individuals under therapy by various drugs. Health care professionals facing DILI are confronted with a wealth of drug-unrelated liver diseases with high incidence and prevalence rates, which can confound the DILI diagnosis. Searching for alternative causes is a key element of RUCAM (Roussel Uclaf Causality Assessment Method) to assess rigorously causality in suspected DILI cases. Diagnostic biomarkers as blood tests would be a great help to clinicians, regulators, and pharmaceutical industry would be more comfortable if, in addition to RUCAM, causality of DILI can be confirmed. High specificity and sensitivity are required for any diagnostic biomarker. Although some risk factors are available to evaluate liver safety of drugs in patients, no valid diagnostic or prognostic biomarker exists currently for idiosyncratic DILI when a liver injury occurred. Identifying a biomarker in idiosyncratic DILI requires detailed knowledge of cellular and biochemical disturbances leading to apoptosis or cell necrosis and causing leakage of specific products in blood. As idiosyncratic DILI is typically a human disease and hardly reproducible in animals, pathogenetic events and resulting possible biomarkers remain largely undisclosed. Potential new diagnostic biomarkers should be evaluated in patients with DILI and RUCAM-based established causality. In conclusion, causality assessment in cases of suspected idiosyncratic DILI is still best achieved using RUCAM since specific biomarkers as diagnostic blood tests that could enhance RUCAM results are not yet available.
Collapse
Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany.
- Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany.
| | - Johannes Schulze
- Institute of Occupational, Environmental and Social Medicine, Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany.
| | - Axel Eickhoff
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany.
- Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany.
| | - Gaby Danan
- Pharmacovigilance Consultancy, F-75020 Paris, France.
| |
Collapse
|
|
50
|
Serum Acetaminophen Protein Adduct Concentrations in Pediatric Emergency Department Patients. J Pediatr Gastroenterol Nutr 2017; 64:533-535. [PMID: 27846064 DOI: 10.1097/mpg.0000000000001459] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Acetaminophen toxicity is a common cause of pediatric liver failure. The diagnosis may be limited by the short window of detection of acetaminophen in serum. Recently acetaminophen protein adducts (APAP-CYS) have been used as a biomarker with a longer duration of detection. The objective of this study was to describe the serum concentrations of APAP-CYS in pediatric patients with and without reported therapeutic acetaminophen exposure. METHODS A cross-sectional study of children age 1 to <12 years presenting to a pediatric emergency department. Subjects were stratified by recent acetaminophen use and had serum APAP-CYS measured using LC/MS. RESULTS One hundred patients were enrolled. All of the patients whose caregivers denied acetaminophen exposure had nondetectable APAP-CYS. Fifty-two percent of subjects who were reported to have taken acetaminophen in the preceding 2 weeks had detectable serum APAP-CYS. The APAP-CYS concentrations were positively correlated with higher overall dose and more recent ingestion. CONCLUSIONS APAP-CYS is detectable in the majority of children taking acetaminophen and not detected in the majority of children who are not exposed to acetaminophen.
Collapse
|